PharmCards: Review Cards for Medical Students [5th Edition] 1496384288, 9781496384287, 9781496384300

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Copyright © 2019 Lippincott Williams & Wilkins First Edition, 1995 Second Edition, 2002 Third Edition, 2007 Fourth Edition, 2010 All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner. The publisher is not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material contained herein. This publication contains infor mation relating to general principles of medical care that should not be construed as specific instructions for individual patients. Manufacturers’ product information and package inserts should be reviewed for current information, including contraindications, dosages, and precautions. Printed in China Acquisitions Editor: Matt Hauber Development Editor: Amy Millholen Editorial Coordinator: Tim Rinehart Marketing Manager: Phyllis Hitner Design Coordinator: Holly McLaughlin Production Project Manager: Bridgett Dougherty Manufacturing Coordinator: Margie Orzech-Zeranko Compositor: Absolute Service, Inc. Printer: RRD Shenzhen 06 07 08 09 10 1 2 3 4 5 6 7 8 9 10

Contributing Authors Feras Akbik, MD, PhD Resident, Neurology Brigham and Women’s Hospital

Ryan Denu MD, PhD student University of Wisconsin-Madison

Contents Preface Sample PharmCard with Annotated Sections Key to Abbreviations Fundamentals Cards PHARMACOKINETICS I PHARMACOKINETICS II PHARMACODYNAMICS PROTEIN BINDING CYTOCHROME P450 ENZYME SYSTEM P-GLYCOPROTEIN Classification Schema 1. ADRENERGIC AGENTS 2. CHOLINERGIC AGENTS 3. CARDIOVASCULAR & RENAL AGENTS 4. HEMATOLOGIC AGENTS 5. ENDOCRINE AGENTS 6. ANTIMICROBIAL AGENTS 7. CNS AGENTS 8. ANTI-INFLAMMATORY AGENTS 9. ANTINEOPLASTIC AGENTS 10. MISCELLANEOUS AGENTS Class Cards

A B C D

NORADRENERGIC JUNCTION ADRENERGIC AGENTS CHOLINERGIC AGENTS PHARMACOLOGIC TREATMENT OF HYPERTENSION E PHARMACOLOGIC TREATMENT OF HEART FAILURE F DIURETICS G ANTIARRHYTHMICS NORMAL CARDIAC ELECTROPHYSIOLOGY H ANTIPLATELET AGENTS ANTICOAGULANTS, PROCOAGULANTS, FIBRINOLYTICS I PHARMACOLOGIC TREATMENT OF ASTHMA J STEROID BIOSYNTHESIS K PHARMACOLOGIC TREATMENT OF DIABETES L PHARMACOLOGIC TREATMENT OF DYSLIPIDEMIA M ANTIBACTERIALS N PENICILLIN ANTIBACTERIALS O ANTIMYCOBACTERIAL AGENTS P ANTIFUNGAL AGENTS Q ANTIVIRALS R HIV THERAPY ANTIRETROVIRAL AGENTS S HCV THERAPY T ANTIEPILEPTIC AGENTS U DOPAMINE AGONISM & ANTAGONISM IN CNS SEROTONIN AGONISM & ANTAGONISM

V ANTINEOPLASTICS W MONOCLONAL ANTIBODIES (mAbs) X EICOSANOIDS Drug Cards 1-1 EPINEPHRINE 1-2 DOPAMINE 1-3 DOBUTAMINE (Dobutrex) 1-4 AMPHETAMINE 1-5 EPHEDRINE 1-6 COCAINE 1-7 METHYLDOPA (Aldomet) 1-8 PHENYLEPHRINE (Neo-Synephrine) 1-9 CLONIDINE (Catapres) 1-10 DEXMEDETOMIDINE (Precedex) 1-11 PHENTOLAMINE (Regitine) 1-12 PRAZOSIN (Minipress) 1-13 ISOPROTERENOL (Isuprel) 1-14 ALBUTEROL (Proventil, Ventolin) 1-15 MIRABEGRON (Myrbetriq) 1-16 METOPROLOL (Lopressor) 1-17 CARVEDILOL (Coreg) 1-18 TIMOLOL (Timoptic) 1-19 FENOLDOPAM (Corlopam) 2-1 2-2 2-3 2-4 2-5

NICOTINE SUCCINYLCHOLINE (Anectine) PANCURONIUM (Pavulon) BETHANECHOL (Urecholine) PILOCARPINE (Isopto Carpine, Salagen)

2-6 2-7 2-8 2-9 2-10 2-11 2-12

ATROPINE BENZTROPINE (Cogentin) IPRATROPIUM (Atrovent) OXYBUTYNIN (Ditropan, Oxytrol) NEOSTIGMINE (Prostigmin) DONEPEZIL (Aricept) SARIN

3-1 3-2 3-3 3-4 3-5 3-6 3-7 3-8 3-9 3-10 3-11 3-12 3-13 3-14 3-15 3-16 3-17 3-18 3-19 3-20 3-21 3-22

NITROGLYCERIN NITROPRUSSIDE (Nipride) NESIRITIDE (Natrecor) HYDRALAZINE (Apresoline) CAPTOPRIL (Capoten) LOSARTAN (Cozaar) SACUBITRIL/VALSARTAN ALISKIREN (Tekturna) NIFEDIPINE (Procardia, Adalat) VERAPAMIL (Calan, Isoptin, Verelan) RANOLAZINE (Ranexa) DIGOXIN (Lanoxin) MILRINONE (Primacor) SILDENAFIL (Viagra) EPOPROSTENOL (Flolan) BOSENTAN (Tracleer) FUROSEMIDE (Lasix) HYDROCHLOROTHIAZIDE (HCTZ) SPIRONOLACTONE (Aldactone) ACETAZOLAMIDE (Diamox) MANNITOL PROCAINAMIDE (Procan)

3-23 3-24 3-25 3-26 3-27 3-28

LIDOCAINE (Xylocaine) FLECAINIDE (Tambocor) AMIODARONE (Cordarone) IBUTILIDE (Corvert) IVABRADINE (Corlanor) ADENOSINE (Adenocard)

4-1 4-2 4-3 4-4 4-5 4-6 4-7 4-8 4-9 4-10 4-11 4-12 4-13 4-14 4-15

ACETYLSALICYLIC ACID (Aspirin) CLOPIDOGREL (Plavix) VORAPAXAR (Zontivity) EPTIFIBATIDE (Integrilin) DIPYRIDAMOLE (Persantine) HEPARIN ENOXAPARIN (Lovenox) BIVALIRUDIN (Angiomax) WARFARIN (Coumadin) RIVAROXABAN (Xarelto) ALTEPLASE (TPA, Activase) TRANEXAMIC ACID (Cyklokapron) ERYTHROPOIETIN (Epogen) FILGRASTIM (Neupogen, G-CSF) ELTROMBOPAG (Promacta)

5-1 5-2 5-3 5-4 5-5 5-6 5-7

PREDNISONE BECLOMETHASONE (Vanceril, Beclovent) ESTRADIOL CLOMIPHENE (Clomid, Milophene, Serophene) TAMOXIFEN (Nolvadex) ANASTROZOLE (Arimidex) PROGESTERONE

5-8 5-9 5-10 5-11 5-12 5-13 5-14 5-15 5-16 5-17 5-18 5-19 5-20 5-21 5-22 5-23 5-24 5-25 5-26 5-27 5-28 5-29 5-30 5-31 5-32 5-33 5-34

TESTOSTERONE FLUTAMIDE (Eulexin) FINASTERIDE (Proscar, Propecia) LEUPROLIDE (Lupron) OCTREOTIDE (Sandostatin) OXYTOCIN (Pitocin) VASOPRESSIN (Pitressin) LEVOTHYROXINE (Synthroid) METHIMAZOLE (Tapazole) INSULIN METFORMIN (Glucophage) ROSIGLITAZONE (Avandia) GLYBURIDE (Micronase) NATEGLINIDE (Starlix) LIRAGLUTIDE (Victoza) SITAGLIPTIN (Januvia) EMPAGLIFLOZIN (Jardiance) ACARBOSE (Precose) ATORVASTATIN (Lipitor) EVOLOCUMAB (Repatha) EZETIMIBE (Zetia) FENOFIBRATE (TriCor) NIACIN CHOLESTYRAMINE (Questran) ALENDRONATE (Fosamax) TERIPARATIDE (Forteo) CINACALCET (Sensipar)

6-1 6-2

PENICILLIN NAFCILLIN (Nafcil, Unipen)

6-3 6-4 6-5 6-6 6-7 6-8 6-9 6-10 6-11 6-12 6-13 6-14 6-15 6-16 6-17 6-18 6-19 6-20 6-21 6-22 6-23 6-24 6-25 6-26 6-27 6-28 6-29 6-30 6-31

AMPICILLIN CLAVULANIC ACID CEFAZOLIN CEFTAROLINE (Teflaro) IMIPENEM (Primaxin) VANCOMYCIN (Vancocin) POLYMYXIN B GENTAMICIN (Garamycin) DOXYCYCLINE (Vibramycin) ERYTHROMYCIN CLINDAMYCIN (Cleocin) CHLORAMPHENICOL (Chloromycetin) SULFAMETHOXAZOLE (Gantanol) TRIMETHOPRIM (TMP) CIPROFLOXACIN (Cipro) METRONIDAZOLE (Flagyl) ISONIAZID (INH) PYRAZINAMIDE (PZA) ETHAMBUTOL (Myambutol) RIFAMPIN (Rimactane) DAPSONE AMPHOTERICIN B (Fungizone) VORICONAZOLE (Vfend) MICONAZOLE (Monistat) TERBINAFINE (Lamisil) CASPOFUNGIN (Cancidas) FLUCYTOSINE (Ancobon) GRISEOFULVIN (Fulvicin, Grifulvin) CHLOROQUINE (Aralen)

6-32 6-33 6-34 6-35 6-36 6-37 6-38 6-39 6-40 6-41 6-42 6-43 6-44 6-45 6-46 6-47 6-48 6-49 6-50 6-51

ARTEMETHER PRIMAQUINE PENTAMIDINE (Pentam 300, NebuPent) ABACAVIR (Ziagen) TENOFOVIR (Viread) EFAVIRENZ (Sustiva) RALTEGRAVIR (Isentress) DARUNAVIR (Prezista) RITONAVIR (Norvir) ENFUVIRTIDE (Fuzeon) MARAVIROC (Selzentry) ACYCLOVIR (Zovirax) FOSCARNET (Foscavir) ENTECAVIR (Baraclude) INTERFERON ALPHA LEDIPASVIR SOFOSBUVIR (Sovaldi) SIMEPREVIR (Olysio) OSELTAMIVIR (Tamiflu) AMANTADINE (Symmetrel)

7-1 7-2 7-3 7-4 7-5 7-6 7-7 7-8 7-9

PHENYTOIN (Dilantin) CARBAMAZEPINE (Tegretol) TOPIRAMATE (Topamax) PERAMPANEL (Fycompa) VALPROIC ACID (Depakote) ETHOSUXIMIDE (Zarontin) GABAPENTIN (Neurontin) TIAGABINE (Gabitril) PHENOBARBITAL (Luminal)

7-10 7-11 7-12 7-13 7-14 7-15 7-16 7-17 7-18 7-19 7-20 7-21 7-22 7-23 7-24 7-25 7-26 7-27 7-28 7-29 7-30 7-31 7-32 7-33 7-34 7-35 7-36 7-37 7-38

PROPOFOL (Diprivan) DIAZEPAM (Valium) ZOLPIDEM (Ambien) BACLOFEN (Lioresal) HALOTHANE PROCAINE (Novocain) MEMANTINE (Namenda) RILUZOLE (Rilutek) SUMATRIPTAN (Imitrex) ERGOTAMINE (Ergomar) BUSPIRONE (Buspar) LORCASERIN (Belviq) ONDANSETRON (Zofran) ALOSETRON (Lotronex) FLUOXETINE (Prozac) VENLAFAXINE (Effexor) NEFAZODONE (Serzone) AMITRIPTYLINE (Elavil) PHENELZINE (Nardil) LEVODOPA/CARBIDOPA (Sinemet) PRAMIPEXOLE (Mirapex) PROCHLORPERAZINE (Compazine) CHLORPROMAZINE (Thorazine) HALOPERIDOL (Haldol) OLANZAPINE (Zyprexa) ARIPIPRAZOLE (Abilify) LITHIUM APREPITANT (Emend) MORPHINE

7-39 7-40 7-41 7-42 7-43

CODEINE PENTAZOCINE (Talwin) DIPHENOXYLATE (Lomotil) METHADONE (Dolophine) NALOXONE (Narcan)

8-1 IBUPROFEN (Motrin, Advil, Nuprin, etc.) 8-2 CELECOXIB (Celebrex) 8-3 ACETAMINOPHEN (Tylenol) 8-4 ZAFIRLUKAST (Accolate) 8-5 CYCLOSPORINE (Sandimmune) 8-6 SIROLIMUS (Rapamycin) 8-7 ANTITHYMOCYTE GLOBULIN (Thymoglobulin) 8-8 ETANERCEPT (Enbrel) 8-9 ANAKINRA (Kineret) 8-10 SECUKINUMAB (Cosentyx) 8-11 NATALIZUMAB (Tysabri) 8-12 MYCOPHENOLATE MOFETIL (CellCept) 8-13 METHOTREXATE 8-14 INTERFERON BETA (Avonex, Betaseron) 8-15 HYDROXYCHLOROQUINE (Plaquenil) 8-16 SULFASALAZINE (Azulfidine) 8-17 CROMOLYN (Intal, Nasalcrom) 8-18 DIPHENHYDRAMINE (Benadryl) 8-19 FEXOFENADINE (Allegra) 8-20 ALLOPURINOL (Lopurin, Zyloprim) 8-21 COLCHICINE 8-22 PROBENECID (Benemid) 9-1

ALKYLATING AGENTS

9-2 9-3 9-4 9-5 9-6 9-7 9-8 9-9 9-10 9-11 9-12 9-13 9-14 9-15 9-16 9-17 9-18 9-19 9-20 9-21 9-22 9-23 9-24 9-25 9-26 9-27 9-28 9-29

CISPLATIN BLEOMYCIN (Blenoxane) DOXORUBICIN (Adriamycin) ETOPOSIDE (Toposar) DACTINOMYCIN (Cosmegen) OLAPARIB (Lynparza) CYTARABINE (Cytosar-U) FLUDARABINE (Fludara) 5-FLUOROURACIL (5-FU) HYDROXYUREA (Hydrea) MERCAPTOPURINE (Purinethol) VINCRISTINE (Oncovin) PACLITAXEL (Taxol) ALL-TRANS RETINOIC ACID (ATRA, Vesanoid) AZACITIDINE (Vidaza) IMATINIB (Gleevec) CRIZOTINIB (Xalkori) IBRUTINIB (Imbruvica) TRASTUZUMAB (Herceptin) BEVACIZUMAB (Avastin) VEMURAFENIB (Zelboraf) RUXOLITINIB (Jakafi) PALBOCICLIB (Ibrance) RITUXIMAB (Rituxan) BORTEZOMIB (Velcade) NIVOLUMAB (Opdivo) LENALIDOMIDE (Revlimid) VENETOCLAX (Venclexta)

10-1

CIMETIDINE (Tagamet)

10-2 10-3 10-4 10-5 10-6 10-7 10-8 10-9 10-10 10-11 10-12 10-13 10-14

OMEPRAZOLE (Prilosec) MISOPROSTOL (Cytotec) LATANOPROST (Xalatan) THEOPHYLLINE (Theo-Dur, Slo-bid) URSODIOL (Actigall) VITAMINS I VITAMINS II ETHANOL (EtOH) DISULFIRAM (Antabuse) METHANOL LEAD CARBON MONOXIDE CYANIDE

Bibliography Index

Preface When we were studying for the USMLE Step I (the “Boards”), we found that there was no single adequate source for the relevant pharmacology. Many review books were too sparse and telegraphic and left many questions unanswered. On the other hand, major pharmacology texts were too verbose and detailed to use to study for the Boards. We therefore decided to assemble our own summaries of the important drugs. Our goal was to create a reference work that emphasized the “high-yield” facts but was also complete enough to provide a conceptual framework for learning rather than simple memorization. We opted for an index card format to allow for both an “active” style of flashcard studying and flexible organization. The widespread use of PharmCards since the first edition was published is gratifying and confirmed the need for such a study aid. In this fifth edition, we have redrawn the figures and added full color to enhance their readability. We have expanded the class cards to provide greater detail on drugs for diabetes, lipids, and hepatitis C. We have maintained the grouping of drug cards by category (e.g., adrenergic, cholinergic, and so on) and then by class (e.g., α-agonists, α-antagonists, βagonists, and so on) as we have received positive feedback that this structure facilitates comparing and contrasting similar agents. Some drugs defy easy classification; in these cases, we have positioned them where we thought they would be most helpful for study. Also note that some diseases are treated with drugs that span drug categories (e.g., asthma and glaucoma). In these cases, we have listed on each card the name and class of the other relevant drugs to treat that disease. Since the publication of the fourth edition, there have been major advances in the field of pharmacology. A deeper understanding of the molecular mechanisms of disease has led to exquisitely tailored pharmacotherapy. Combined angiotensin receptor-neprilysin inhibitors (ARNIs) for heart

failure, sodium glucose cotransporter 2 (SGLT2) inhibitors for diabetes, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for hypercholesterolemia, and checkpoint inhibitors for cancer therapy are a few examples of new or expanded drug classes that have been incorporated into this fifth edition of PharmCards. A few words of advice: 1. Don’t be overwhelmed by the large amount of information contained in the cards. Frequently, understanding the mechanism of a drug and how that relates to the drug’s clinical use and side effects is sufficient. 2. Concentrate on understanding the major drug classes before diving into the sea of drug names. The class cards are designed to facilitate this approach. 3. Read through PharmCards several times before trying to memorize anything. This will give you perspective on what to memorize, and you may be surprised by how much you can recall without resorting to rote memorization. 4. PharmCards are geared toward studying for the Boards, but they also include information that we found particularly useful on the wards. We hope that their usefulness will extend beyond that one fateful day of test taking and that these cards may serve as a quick source of information that bridges basic and clinical pharmacology on the wards. We also thank the editorial and production staffs at Wolters Kluwer Health, including Tim Rinehart for his help in bringing this project to completion. A project of this magnitude requires a tremendous investment of time and energy, and we thank our wives and families for being so supportive throughout the process. Best of luck on the Boards! E.C.J. M.S.S.

GENERIC NAME (Trade Name —should not be memorized!)

class

Mechanism The most important section when studying for USMLE Step I! The explanation often starts at the molecular level and then moves on to organ level effects. Some of the molecular detail is unlikely to be tested on the Boards but is included to provide you with a stronger conceptual foundation. Resistance

Also an important section. Usually seen with antimicrobials, antineoplastics, and so on.

Clinical

For the Boards, it is important to understand how the mechanism of action explains the clinical utility. One need not, however, know the exact spectrum of activity at the species level for antimicrobials, the specific arrhythmias for which antiarrhythmics are used, the tumors for which antineoplastics are used, and so on. For third-year students, clinical indications take on increased importance; these cards can serve as a useful bridge from basic to clinical pharmacology.

Side Effects The most common as well as the severe and unique side effects are worth memorizing. Antidote

This section is found on toxin cards and certain drugs when there is a specific treatment for intoxication (beyond supportive care).

Contraindic. Life-threatening absolute contraindications are important and are usually italicized. In general, this section serves to emphasize which side effects are severe enough to prompt usage of a different agent. Metabolism Noted here are atypical routes of administration, particularly short or long half-lives, and routes of metabolism that are subject to clinically relevant alterations. Interactions Reserved for notable drug–drug interactions. Notes

Drugs similar to the prototype discussed above are listed here along with their distinguishing features. It is important to know of their

existence and their significant differences from the prototype.

CATEGORY PROTOTYPICAL AGENT Related agent Related agent Related agent

In the top right-hand corner, chemical structures are occasionally provided if they help illustrate a point. These structures should not be memorized.

Figures and tables are included here to help clarify pathways and compare related agents.

Key to Abbreviations 5-HT

5-hydroxytryptamine (serotonin)

AC

adenylate cyclase

ACE

angiotensin converting enzyme

ACEI

angiotensin converting enzyme inhibitor

ACS

acute coronary syndrome

ACh

acetylcholine

AChR

acetylcholine receptor

ADH

antidiuretic hormone

ADP

adenosine diphosphate

AF

atrial fibrillation

AFL

atrial flutter

AIDS

acquired immune deficiency syndrome

ALL

acute lymphocytic leukemia

AML

acute myelogenous leukemia

AMP

adenosine monophosphate

ANA

antinuclear antibody

aPTT

activated partial thromboplastin time

ARB

angiotensin receptor blocker

ARNI

angiotensin blocker-neprilysin inhibitor

ATI

angiotensin I

ATII

angiotensin II

ATIII

antithrombin III

ATP

adenosine triphosphate

AV

atrioventricular

BBB

blood–brain barrier

BNP

B-type natriuretic peptide

BP

blood pressure

CAD

coronary artery disease

cAMP

cyclic adenosine monophosphate

CCB

calcium channel blocker

CDC

Centers for Disease Control and Prevention

CHF

congestive heart failure

CMV

cytomegalovirus

CNS

central nervous system

CO

cardiac output

COMT

catechol O-methyl transferase

COPD

chronic obstructive pulmonary disease

COX

cyclooxygenase

CSF

cerebrospinal fluid

CV

cardiovascular

CVA

cerebrovascular accident

CYP450

cytochrome P450

DA

dopamine

DAG

diacyl glycerol

DBP

diastolic blood pressure

DCT

distal convoluted tubule

DHF

dihydrofolate

DHFR

dihydrofolate reductase

DVT

deep vein thrombosis

EBV

Epstein-Barr virus

FAD

flavin adenine dinucleotide

FMN

flavin mononucleotide

FSH

follicle-stimulating hormone

Gi

inhibitory G protein

Gs

stimulatory G protein

G6PD

glucose 6-phosphate dehydrogenase

GABA

gamma-amino butyric acid

GC

guanylate cyclase

GFR

glomerular filtration rate

GI

gastrointestinal

GMP

guanosine monophosphate

GnRH

gonadotropin-releasing hormone

GU

genitourinary

HBV

hepatitis B virus

HCV

hepatitis C virus

HDL

high-density lipoprotein

HIV

human immunodeficiency virus

HR

heart rate

HSV

herpes simplex virus

IDL

intermediate-density lipoprotein

Ig

immunoglobulin

IM

intramuscular

IMP

inosine monophosphate

IP3

inositol 1,4,5-triphosphate

IV

intravenous

LDL

low-density lipoprotein

LFT

liver function test

LH

luteinizing hormone

LMWH

low-molecular-weight heparin

LO

lipoxygenase

MAC

Mycobacterium avium–intracellulare complex

MAO

monoamine oxidase

MI

myocardial infarction

NAD

nicotinamide adenine dinucleotide

NADP

nicotinamide adenine dinucleotide phosphate

NE

norepinephrine

NM

neuromuscular

NSAID

nonsteroidal anti-inflammatory drug

OTC

over-the-counter

PABA

para-aminobenzoic acid

PCSK9

proprotein proprotein convertase subtilisin/kexin type 9

PCT

proximal convoluted tubule

PDE

phosphodiesterase

PGX

prostaglandins (X = A, B, C, etc.)

PIP2

phosphatidyl inositol 4,5-bisphosphate

PLA2

phospholipase A2

PO

per os (by mouth)

PPD

purified protein derivative

PRPP

5-phosphoribosyl-1-pyrophosphate

PSVT

paroxysmal supraventricular tachycardia

PT

prothrombin time

PTH

parathyroid hormone

RBC

red blood cell

RR

respiratory rate

RSV

respiratory syncytial virus

SBP

systolic blood pressure

SC

subcutaneous

SERM

selective estrogen receptor modulator

SGLT2

sodium glucose cotransporter 2

SIADH

syndrome of inappropriate antidiuretic hormone

SLE

systemic lupus erythematosus

SVR

systemic vascular resistance

TB

tuberculosis

TCA

tricyclic antidepressant

TF

tissue factor

TG

triglyceride

THF

tetrahydrofolate

TIA

transient ischemic attack

TNF

tumor necrosis factor

TNFR

tumor necrosis factor receptor

TXA2

thromboxane

UFH

unfractionated heparin

UTI

urinary tract infection

VF

ventricular fibrillation

VLDL

very low-density lipoprotein

VT

ventricular tachycardia

vWF

von Willebrand factor

VZV

varicella-zoster virus

PHARMACOKINETICS I

fundamentals

Overview

Pharmacokinetics refers to the movement of drugs through the body (input, distribution, and output). In other words, what the body does to the drug. Pharmacokinetic information about a drug can be found in the metabolism section of a PharmCard. These processes govern the concentration of the drug in the patient’s serum (and other tissues), and understanding will help maximize efficacy while minimizing toxicity.

Input

Input is the one aspect of pharmacokinetics over which the clinician exerts control. Drug dose, frequency, and route of administration may be varied to optimize therapy. Availability refers to the fraction of an administered dose that reaches the systemic circulation. By definition, intravenous drugs have 100% availability. Availability by other routes varies considerably from drug to drug and must be determined empirically. Oral availability represents a special case in that it is a function not only of absorption from the gut but also of first-pass metabolism in the liver, where the drug may be “premetabolized” (via portal circulation) before reaching the systemic circulation.

Distribution

Most drugs not only remain solely in the circulating plasma but also “distribute” into tissues, extracellular fluid, lipids, and so on. Volume of distribution (Vd) relates plasma concentration of the drug (C) to the total amount in the body. This is an “apparent volume” with no anatomic meaning that must be determined empirically. Drugs that extensively distribute into tissues (particularly lipid) can have a Vd substantially greater than the actual volume of the body and may have tissue concentrations vastly higher than serum concentrations. Steady-state serum concentration is unaffected by Vd (it is a function only of input and output), but the time required to achieve this concentration can be long if Vd is large.

Output

Drug output is the other major determinant of serum drug concentration. Renal excretion is the primary route of elimination for most watersoluble compounds. Its efficiency is influenced not only by GFR, but by acidification or alkalinization of the urine, which will enhance excretion of weak bases or acids, respectively. Hepatic clearance plays a prominent role in the elimination of lipophilic compounds. Metabolism proceeds in the liver by a two-step process: phase I reactions add oxygen moieties via the P450 enzyme system (q.v.). Subsequent phase II reactions conjugate large, hydrophilic groups to these oxygen moieties. The resulting metabolites are more hydrophilic than the parent compounds and can be excreted in the bile, urine, or both. Frequently, these metabolites are pharmacologically inactive, although many important exceptions occur. In fact, some “parent compounds” are inactive pharmacologically and require the generation of active metabolites in the liver to produce an effect; this may not occur in the setting of liver failure. Other drugs are eliminated by a plethora of mechanisms. Examples include P-glycoprotein (q.v.)–mediated excretion, degradation of catecholamines by COMT and MAO, heparin metabolism by the reticuloendothelial system, and exhalation of anesthetic gases. Regardless of the means of drug elimination, it is useful to estimate the rate of output. The great majority of drugs follow so-called first-order kinetics, in which the rate of elimination is directly proportional to the serum drug concentration. Clearance (CL) is a frequently used constant for describing this proportionality. It is defined as the ratio of the rate of elimination (or output) to the drug’s concentration (C); conceptually, it corresponds to the volume of plasma that the body could clear completely of drug per unit time. The body’s capacity to handle some drugs is so constrained that these drugs are eliminated at a fixed rate, regardless of drug concentration. This is referred to as zero-order kinetics.

PHARMACOKINETICS II Half-life

fundamentals

Half-life (t½) is the time required to change the amount of drug in the body by one-half during elimination or a constant infusion. For drugs that follow first-order kinetics, t½ is independent of drug concentration. After starting a new drug, 4 half-lives (50% → 75% → 87.5% → 93.75%) are required to achieve >90% of the steady state concentration.

Maintenance To maintain a therapeutic concentration, one must administer a drug Dose at the same rate that it is eliminated from the body (i.e., input = output). Thus, at steady state, the administration of 1,200 mg of a given drug daily will result in the elimination of 1,200 mg of the same drug regardless of whether it is given in one dose, 600 mg every 12 hours, 300 mg every 6 hours, or as a continuous infusion at 50 mg/hour. For drugs that follow first-order kinetics, output is proportional to concentration. Therefore, administration of any of the preceding maintenance dose (MD) schedules will yield the same average drug concentration, although peaks and troughs will be greatest for the once-daily dosing schedule. This concentration can be calculated by solving for CT using the equation at left (CT = 50 mg/hour ÷ CL). Loading Dose

Attainment of therapeutic drug concentration can be substantially delayed while a drug accumulates in the body. As noted above, a drug must be administered for 4 half-lives in order to attain >90% of its CT. For drugs with long half-lives or in urgent situations, it may be desirable to give a large initial or loading dose (LD) to rapidly bring drug levels into the therapeutic range.

PHARMACODYNAMICS Overview

fundamentals

Pharmacodynamics refers to the effect and mode of the action of the drug on the body, that is, what the drug does to the body. Pharmacodynamic information can be found in the mechanism, clinical, and side effects sections of a PharmCard.

Agonists & Agonists bind to and activate receptors. In contrast, antagonists bind Antagonists to receptors but do not activate them. Therefore, antagonists typically bring about clinical effects by preventing agonists (either endogenous or administered drugs) from activating their receptors. Whereas competitive antagonists can be overcome by increasing the concentration of the agonist, irreversible antagonists produce a degree of blockade that is independent of the concentration of the agonist. At full receptor occupancy, partial agonists elicit a lesser response than do full agonists. Weak partial agonists may be clinical antagonists if they lessen the effect of endogenous agonists. Dose– Response

Predicting the effect of a drug in relation to serum concentration is a central concept. At low doses, efficacy, or drug effect, increases in proportion to concentration. At higher doses, efficacy is partially

limited by the body’s ability to respond. For example, a kidney can only produce so much urine, regardless of the amount of diuretic to which it is exposed. Emax is the maximum attainable efficacy of the drug. By definition, a full agonist has a higher Emax than a partial agonist. The effect at a given concentration (C) depends on both Emax and the drug concentration required to produce 50% of the Emax (EC50). Potency is reflected in the EC50. Thus, high-potency drugs achieve their effects at lower concentrations than do low-potency drugs. Note that whereas the clinical utility of a drug mainly depends on its efficacy, the dose required to achieve a given effect depends on both potency and efficacy. Therapeutic Clearly, some drugs are more toxic than others. In clinical practice, it Index is useful to know how likely a drug is to produce dose-related toxicity. Clinical drug trials and animal studies are conducted to determine the median dose of a drug required to produce a desired clinical effect in 50% of patients (the ED50) as well as the median dose required to produce toxicity (TD50 or LD50 if the toxic effect is lethal). The therapeutic index (TI) is the ratio of these two doses. Drugs with a low TI require more precise dose selection and serum monitoring than those with a high TI.

PROTEIN BINDING

fundamentals

Overview

Competition for and displacement from serum protein binding sites is a frequently touted reason for drug–drug interactions. Although this mechanism seems intuitively obvious, there are no clinically relevant examples of this phenomenon; most interactions ascribed to protein-binding competition have proven to be caused by alteration in drug clearance. In clinical practice, protein binding is only relevant for the interpretation of serum drug levels.

Carrier Proteins

Albumin is the major serum-binding protein, especially for acidic drugs. α1-Acid glycoprotein is the predominant binding protein for basic drugs; as an acute phase reactant, its concentration can be greatly elevated in inflammatory states. β-Lipoproteins are also important binding proteins for some basic drugs.

Free Drug When drugs are bound to serum proteins, they are Concentration pharmacologically inactive. Only the unbound, or free, drug is available to interact with receptors and exert its effect. The observation that some drugs could be displaced from their binding sites on serum proteins, thus increasing the concentration of free drug, led to the theory that this increase in free drug concentration could explain many drug–drug interactions. In the body, however, this increase in concentration is only transient because any increase in free drug concentration also increases output (output = clearance × concentration).

Serum Drug Levels

An appreciation of fraction of drug bound to serum proteins is critical in the interpretation of serum drug levels. Because measurement of free drug levels is technically difficult, measurement of the total concentration of drug in the serum (i.e., free + protein bound) is generally used. In the example above, after a transient increase, the concentration of free drug eventually returned to the same level, but paradoxically, the total drug concentration decreases when such a displacement interaction occurs. Interpretation of this decrease in total concentration as a decrease in the free drug concentration could lead to unnecessary increases in drug dosing and potential toxicity.

CYTOCHROME P450 ENZYME SYSTEM

fundamentals

Mechanism

Human cytochrome P450 (also called CYP450) refers to a superfamily of heme-containing enzymes that catalyze the monooxygenation of xenobiotics (e.g., drugs, toxins) and endogenous compounds (e.g., steroids, prostaglandins). P450 enzymes are primarily located in the smooth endoplasmic reticulum of the liver and are thought to have evolved to enable animals to detoxify chemicals in plants. Metabolism of lipophilic drugs is traditionally divided into two phases. First, the P450 enzyme system incorporates a reactive oxygen moiety into the drug (phase I). In phase II, other enzyme systems conjugate soluble groups (e.g., acetyl, glucuronate) to this reactive species. The resulting hydrophilic metabolites can be active or inactive pharmacologically; occasionally, they are more potent or toxic than the parent compounds (e.g., acetaminophen). Moreover, some compounds are inactive (prodrugs) until they undergo P450 metabolism.

Side Effects

Many xenobiotics induce the expression of specific P450 isoenzymes. This permits the liver to respond to changing environmental conditions and is responsible clinically for many drug–drug interactions. Some xenobiotics also inhibit specific P450 isoenzymes (see table).

Nomenclature P450 enzymes are classified based on amino acid similarity. Families are numbered and subfamilies receive letter designations. For example, CYP2D6 is the sixth member of the D subfamily of family 2. The major families involved in drug metabolism are CYP1, CYP2, and CYP3. Notes

P450 enzymes are named for their characteristic absorbance at 450 nm when exposed to carbon monoxide.

CYTOCHROME P450 INTERACTIONS Isoenzyme

Inhibitor

Inducer

Substrate

CYP1A2

Cimetidine Ciprofloxacin

Cigarette smoke

Theophylline

CYP2C8

Cimetidine

Phenobarbital Rifampin

Diazepam

CYP2C9

Amiodarone Cimetidine Isoniazid

Rifampin

Phenytoin Warfarin

CYP2C19

Fluconazole Omeprazole

Phenytoin Rifampin

CYP2D6

Cimetidine Fluoxetine Quinidine

CYP2E1

Disulfiram

Ethanol Isoniazid

Ethanol Halothane, isoflurane

CYP3A4

Cimetidine Erythromycin Fluconazole Ritonavir, Verapamil

Phenobarbital Rifampin

Carbamazepine Cyclosporine Midazolam Terfenadine

Prodrug Substratea

Losartan

Clopidogrel β-Blockers Codeine TCAs

Codeine Tamoxifen

TCAs, tricyclic antidepressants. aNote that generally, the pharmacologic effect of a drug will ↑ with P450 inhibition (because of ↓ metabolic degradation). However, if the drug requires P450-mediated biotransformation to become an active compound, then the pharmacologic effect will ↓ with P450 inhibition (because of ↓ active metabolite formation).

P-GLYCOPROTEIN

fundamentals

Mechanism P-glycoprotein (P-gp) is a multisubstrate transporter that uses ATP

hydrolysis to pump xenobiotics (drugs, toxins, etc.) out of cells against steep concentration gradients. Its primary function is to prevent absorption of toxic compounds by the gut and to facilitate their excretion into bile and the renal proximal tubules. P-gp expression in brain and testis capillary endothelium limits the ability of toxins to enter these sensitive tissues. Cells that normally express P-gp (e.g., colonic epithelium) display intrinsic resistance to many anticancer drugs. Overexpression of Pgp in tumor cells confers a multidrug resistance (MDR) phenotype. For this reason, P-gp is sometimes referred to as MDR1. Metabolism P-gp is responsible for many drug–drug interactions. Inducers and inhibitors of P-gp have been identified (see table on reverse). Drugs that are subject to P-gp efflux can have poor oral availability and, in the presence of P-gp inducers or inhibitors, markedly varied oral availability. CYP3A4 and P-gp have many common substrates, inducers, and inhibitors (compare table on reverse to P450 table). Thus, some drug–drug interactions are amplified by the combined effects of altered absorption (via P-gp) and metabolism (via CYP3A4). Notes

The “P” in P-glycoprotein derives from the fact that it regulates the apparent permeability of cells to many drugs.

P-GLYCOPROTEIN INTERACTIONS Inhibitora

Inducer

Verapamil Rifampin Cyclosporin A St. John’s wort Quinidine Ritonavir Erythromycin, clarithromycin Ketoconazole, itraconazole Midazolam Tamoxifen

Substrate Digoxin Doxorubicin, daunorubicin Vincristine, vinblastine Etoposide, teniposide Paclitaxel Cyclosporin A, tacrolimus Saquinavir, amprenavir, ritonavir Methotrexate Hydrocortisone, dexamethasone Terfenadine

aP-glycoprotein inhibition may increase serum levels of a substrate by decreasing its excretion and by increasing its absorption. Furthermore, in tissues expressing high levels of P-gp (e.g., MDR tumors), Pgp inhibition can increase intracellular concentrations of drugs by preventing their export.

Classification Schema 1. ADRENERGIC AGENTS Direct Sympathomimetic Epinephrine Dopamine Dobutamine Indirect Sympathomimetic Amphetamine Ephedrine Cocaine Sympathoplegic Methyldopa α-Adrenoceptor Agonists and Antagonists Phenylephrine Clonidine Dexmedetomidine Phentolamine Prazosin β-Adrenoceptor Agonists and Antagonists Isoproterenol Albuterol Mirabegron Metoprolol Carvedilol Timolol D1-Agonist Fenoldopam

2. CHOLINERGIC AGENTS Nicotinic Agonist Nicotine Succinylcholine Antinicotinic Pancuronium Muscarinic Agonist Bethanechol Pilocarpine Antimuscarinic Tertiary Amine Atropine Benztropine Quaternary Amine Ipratropium Oxybutynin Cholinesterase Inhibitor Therapeutic Neostigmine Donepezil Toxin Sarin

3. CARDIOVASCULAR & RENAL AGENTS Direct Vasodilators Nitroglycerin Nitroprusside Nesiritide Hydralazine ACEI, ARBs, ARNI, & Renin Inhibitors Captopril Losartan Sacubitril/Valsartan Aliskiren Calcium Channel Blockers Nifedipine Verapamil Other Antianginals Ranolazine Inotropes & Pulmonary Arterial Vasodilators Digoxin Milrinone Sildenafil Epoprostenol Bosentan Diuretics Furosemide Hydrochlorothiazide Spironolactone Acetazolamide Mannitol Antiarrhythmics Procainamide

Lidocaine Flecainide Amiodarone Ibutilide Ivabradine Adenosine

4. HEMATOLOGIC AGENTS Antiplatelet Acetylsalicylic acid Clopidogrel Vorapaxar Eptifibatide Dipyridamole Anticoagulant Heparin Enoxaparin Bivalirudin Warfarin Rivaroxaban Fibrinolytic Alteplase Procoagulant Tranexamic acid Hematopoietic Erythropoietin Filgrastim Eltrombopag

5. ENDOCRINE AGENTS Glucocorticoids Prednisone Beclomethasone Estrogens, SERMs, & Progestins Estradiol Clomiphene Tamoxifen Anastrozole Progesterone Androgens & Antiandrogens Testosterone Flutamide Finasteride Hormones Leuprolide Octreotide Oxytocin Vasopressin Thyroid Hormone & Antithyroids Levothyroxine Methimazole Glucose-Lowering Drugs Insulin Metformin Rosiglitazone Glyburide Nateglinide Liraglutide Sitagliptin

Empagliflozin Acarbose Hypolipidemics Atorvastatin Evolocumab Ezetimibe Fenofibrate Niacin Cholestyramine Bisphosphonates & Other Bone Mineral Homeostatic Drugs Alendronate Teriparatide Cinacalcet

6. ANTIMICROBIAL AGENTS Antibacterials β-Lactams and Other Cell Wall Agents Penicillin Nafcillin Ampicillin Clavulanic acid Cefazolin Ceftaroline Imipenem Vancomycin Polymyxin B Protein Synthesis Inhibitors Gentamicin Doxycycline Erythromycin Clindamycin Chloramphenicol Antimetabolites Sulfamethoxazole Trimethoprim Others Ciprofloxacin Metronidazole Antimycobacterials Cell Wall Agents Isoniazid Pyrazinamide Ethambutol Other Agents

Rifampin Dapsone Antifungals Cell Wall Agents Amphotericin B Voriconazole Miconazole Terbinafine Caspofungin Other Agents Flucytosine Griseofulvin Antimalarials Chloroquine Artemether Primaquine Antiparasitic Pentamidine Antiretrovirals RT Inhibitors Abacavir Tenofovir Efavirenz Integrase Inhibitor Raltegravir Protease Inhibitor Darunavir CYP450 inhibitor Ritonavir Entry Inhibitors Enfuvirtide Maraviroc Antivirals

Antiherpesviral Acyclovir Foscarnet Hepatitis Antivirals Entecavir Interferon alpha Ledipasvir Sofosbuvir Simeprevir Influenza Antivirals Oseltamivir Amantadine

7. CNS AGENTS Antiepileptics Phenytoin Carbamazepine Topiramate Perampanel Valproic acid Ethosuximide Gabapentin Tiagabine Phenobarbital Sedative-hypnotics Propofol Diazepam Zolpidem Antispasmodic Baclofen General Anesthetic Halothane Local Anesthetic Procaine Glutamate Antagonists Memantine Riluzole Serotonin Agonists & Antagonists Sumatriptan Ergotamine Buspirone Lorcaserin Ondansetron

Alosetron Antidepressants Fluoxetine Venlafaxine Nefazodone Amitriptyline Phenelzine Dopamine Agonists & Antagonists Levodopa/Carbidopa Pramipexole Prochlorperazine Antipsychotics Chlorpromazine Haloperidol Olanzapine Aripiprazole Lithium NK1 (Substance P) Inhibitor Aprepitant Opioids & Opioid Antagonists Morphine Codeine Pentazocine Diphenoxylate Methadone Naloxone

8. ANTI-INFLAMMATORY AGENTS COX Inhibitors Ibuprofen Celecoxib Acetaminophen Leukotriene Antagonist Zafirlukast Immunosuppressants Cyclosporine Sirolimus Antithymocyte globulin Etanercept Anakinra Secukinumab Natalizumab Mycophenolate mofetil Methotrexate Immunomodulators Interferon beta Hydroxychloroquine Sulfasalazine Cromolyn Antihistamines Diphenhydramine Fexofenadine Antigout Allopurinol Colchicine Probenecid

9. ANTINEOPLASTIC AGENTS DNA Damaging Agents Alkylating agents Cisplatin Bleomycin Doxorubicin Etoposide Transcription Inhibitor Dactinomycin PARP Inhibitor Olaparib Antimetabolite Cytarabine Fludarabine 5-Fluorouracil Hydroxyurea Mercaptopurine Antimicrotubule Vincristine Paclitaxel Gene Expression Modifiers All-trans retinoic acid Azacitidine Kinase Inhibitors Tyrosine kinase inhibitors Imatinib Crizotinib Ibrutinib Trastuzumab Bevacizumab

Other kinase inhibitors Vemurafenib Ruxolitinib Palbociclib Antitumor Monoclonals Rituximab Proteosome Inhibitor Bortezomib Immune Checkpoint Inhibitor Nivolumab Immunomodulator Lenalidomide BCL-2 Inhibitor Venetoclax

10. MISCELLANEOUS AGENTS H2 Blocker Cimetidine Proton Pump Inhibitor Omeprazole Prostaglandins Misoprostol Latanoprost PDE Inhibitor Theophylline GI Agent Ursodiol Miscellaneous Vitamins I, II Toxin Methanol Lead Carbon monoxide Cyanide Ethanol Disulfiram

NORADRENERGIC JUNCTION

A

B

ADRENERGIC AGENTS Class

Direct sympathomimetics

Agent

α1

α2

β1

β2

Epinephrine

+

+

+

+

Norepinephrine

+

+

+

Dopamine

+

+

Dobutamine

+

+

Fenoldopam Agonist α-Adrenoceptor Blocker

Agonist β-Adrenoceptor Blocker

Phenylephrine

+ +

Clonidine

+

Phentolamine

−

Prazosin

−

Isoproterenol

D1

−

+

Albuterol

+ +

Propranolol

−

Metoprolol

−

−

+, stimulation; −, inhibition. For simplicity, only main receptor effects are shown; see specific drug cards for lesser effects and for the relative potencies of a drug at each of the adrenergic receptors. Receptor subtype specificity (e.g., metoprolol for β1 receptors) is not absolute, especially at higher doses. Indirect sympathomimetics have an apparent receptor profile that is generally the same as norepinephrine. The primary effect of stimulation of the adrenoceptor subtypes is as follows: α1 → vasoconstriction α2 → ↓ sympathetic outflow and vasodilatation β1 → ↑ HR and ↑ contractility β2 → smooth muscle relaxation → vasodilatation and bronchodilation D1 → renal and splanchnic vasodilatation

C

CHOLINERGIC AGENTS

CHOLINERGIC AGENTS MUSCARINIC AGENTS Although potency at any given receptor subtype varies, muscarinic agent selectivity relies on the poor systemic absorption of quaternary amine agonists or antagonists, which thus act locally, usually at M3 receptors. Receptor

Location

Agonists

Antagonists

M1

CNS

Stimulation

↓ Motion sickness, ↓ extrapyramidal effects

M2

CV

↓ → HR

↑ HR

Eye

Miosis, ciliary contraction (glaucoma treatment)

Pupillary dilatation (mydriasis), cycloplegia

GI/GU

↑ Motility, ↑ secretions, bladder detrusor contraction, and sphincter relaxation

↓ Motility, ↓ secretions, ↓ bladder tone

M3

M4 & M5

Lung

Bronchoconstriction and ↑ Bronchodilation and ↓ secretions secretions

CNS

?

? NICOTINIC AGENTS

Receptor Location

Agonists

Antagonists

NN

Neuronal: on postganglionic autonomic neurons, adrenal medulla, CNS

CNS and ganglionic stimulation

Ganglionic blockade → hypotension (and many side effects)

NM

Muscle: neuromuscular junction

Fasciculations, paralysis (depolarizing blockade)

Paralysis (nondepolarizing blockade)

D

PHARMACOLOGIC TREATMENT OF HYPERTENSION

TYPES OF VASODILATORS Arteriolar dilators

Mixed vasodilators

Venodilators

↓ Afterload

↓ Afterload, ↓ preload

↓ Preload

Hydralazine Minoxidil CCBs Fenoldopam

ACEIs, ARBs, renin inhibitors Nitroprusside Nesiritide α1-Blockers α2-Central agonists

Nitrates

PHARMACOLOGIC TREATMENT OF HEART FAILURE

E

F

DIURETICS

EFFECT OF DIURETICS ON SERUM ELECTROLYTES Class

Prototype

K+

HCO3−

Ca2+

Mg2+

Urate

Loop

Furosemide

↓↓

↑

↓

↓

↑

Thiazide

HCTZ

↓

↑

↑

↓

↑

Spironolactone

↑

↓

↓

—

—

Amiloride

↑

↓

↑

—

—

Acetazolamide

↓

↓↓

—

—

—

Potassium sparing CA inhibitor

Note: A process that increases serum HCO3− is by definition a metabolic alkalosis. A process that decreases serum HCO3− is by definition a metabolic acidosis.

G

ANTIARRHYTHMICS Class (prototype)

Electrophysiologic effects Purkinje cells

Clinical uses

Pacemaker cells

Class IA Moderate Na+ (procainamide) block Prolong repolarization

↓Slope phase 4 ↑threshold for firing

AF/AFL

Class IB (lidocaine)

Mild Na+ block Shorten repolarization

↓Slope phase 4 ↑threshold for firing

Post-MI ventricular arrhythmias

Class IC (flecainide)

Marked Na+ block No change in repolarization

↓Slope phase 4 ↑threshold for firing

AF and WPW in patients with structurally normal hearts

↓Slope phase 4 Prolong repolarization at AV node

Rate control AF/AFL PSVT VT

No effect

Ibutilide: AF/AFL Amiodarone: AF, VT

Class II β-blockers (metoprolol) Class III (ibutilide) (amiodarone) Class IV CCB (verapamil)

No effect

Marked prolong of repolarization

No effect

Slow AP rise Prolong repolarization at AV node

Rate control of AF/AFL PSVT

AF, atrial fibrillation; AFL, atrial flutter; AP, action potential; AV, atrioventricular; MI, myocardial infarction; PSVT, paroxysmal supraventricular tachycardia; VT, ventricular tachycardia; WPW, WolffParkinson-White syndrome. Adapted from Lilly LS, ed. Pathophysiology of Heart Disease. 4th ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2006.

NORMAL CARDIAC ELECTROPHYSIOLOGY

ANTIPLATELET AGENTS

ANTICOAGULANTS, PROCOAGULANTS, FIBRINOLYTICS

H

PHARMACOLOGIC TREATMENT OF ASTHMA

I

STEROID BIOSYNTHESIS

J

PHARMACOLOGIC TREATMENT OF DIABETES K

Category

Class

Insulin

Biguanide

Example

Mechanism

↓ HbA1c

Lispro NPH Glargine

Activates tyrosine kinase receptor, promotes storage of glucose

Dose dependent

Metformin

Activation of AMPkinase, ↑ glucose uptake, ↓ gluconeogenesis

~1.5%

Insulin sensitizer

Thiazolidinediones Rosiglitazone PPAR-α activator, ↑ glucose uptake Sulfonylureas

Glyburide

Activates K channel on β cells causing insulin release

~1% ~1.5%

Meglitinides

Secretagogue GLP-1RA

DPP-4 inhibitor

Nateglinide

Modulates K channel on β cells causing insulin release

~1%

Liraglutide

Activates GLP-1 receptor on β cells, inhibits glucagon release, delays gastric emptying

~1%

Sitagliptin

Prevents degradation of GLP-1 and GIP

~0.7%

SGLT2i

Empagliflozin Promotes glycosuria

~0.6%

Amylinomimetic

Pramlintide

Inhibits glucagon release, delays gastric emptying

~0.6%

α-Glucosidase inhibitor

Acarbose

Delays intestinal absorption of carbohydrates

~0.6%

L

PHARMACOLOGIC TREATMENT OF DYSLIPIDEMIA

LDLC

TG

HDLC

Class

Example

Mechanism

Statins

Atorvastatin

HMG-CoA reductase inhibitor → upregulation LDL receptor

20– 10– 5–10% 60% ↓ 25% ↓ ↑

PCSK9i

Evolocumab

Inhibits PCSK9, preventing degradation of LDL receptor

50– 15– 5–10% 60% ↓ 20% ↓ ↑

Cholesterol absorption inhibitor

Ezetimibe

Blocks NPC1L1 protein 20– 10% ↓ in jejunum → ↓ 25% ↓ delivery of cholesterol to liver → upregulation LDL receptor

—

Fibrates

Fenofibrate

PPAR-α agonist → ↑ lipoprotein lipase activity

5–15% 35– 5–15% ↓ 50% ↓ ↑

Niacin

n/a

↓ Hepatic synthesis of triglycerides

10– 20% ↓ 15% ↑ 15% ↓

Resins

Cholestyramine Bind bile acids in 20% ↓ 35– intestine, interrupting 50% ↓ enterohepatic bile acid circulation → upregulation LDL receptor

5% ↑

M

ANTIBACTERIALS

SITES OF ACTION OF MAJOR ANTIBACTERIALS Ribosomal subunit Folate pathway

DNA

RNA

30S

50S

Sulfamethoxazole Ciprofloxacin Rifampin Gentamicin Erythromycin Trimethoprim Doxycycline Clindamycin Chloramphenicol Linezolid Quinupristin/dalfopristin

N

PENICILLIN ANTIBACTERIALS Generation

Mechanism details Spectrum

Example

Natural penicillin

Penicillinase susceptible

Streptococcus, Meningococcus, ± Pneumococcus Anaerobes except Bacteroides fragilis

Penicillin

Penicillinase resistant

Bulky R group confers penicillinase resistance.

Methicillin-sensitive Staphylococcus aureus (MSSA) Streptococcus

Nafcillin

Aminopenicillin Hydrophilic amino Natural penicillin spectrum group confers and Proteus ± greater gramHaemophilus influenzae, negative activity. Escherichia coli, Penicillinase Salmonella, Shigella susceptible

Ampicillin

Ureidopenicillin Ureido group confers greater gram-negative and anaerobe activity. Penicillinase susceptible

Aminopenicillin spectrum and Klebsiella, Pseudomonas and Enterobacteriaceae (E. coli, Enterobacter, Serratia)

Piperacillin

β-Lactamase inhibitor

Adds S. aureus (MSSA) and Clavulanic B. fragilis acid

Prevents degradation of susceptible penicillins

OTHER β-LACTAM ANTIBACTERIALS Class

Spectrum

Example

Cephalosporins First

Gram-positive cocci (GPC) including methicillinsensitive Staphylococcus aureus (MSSA) and Streptococci Also some gram-negative rods (GNRs) such as Escherichia coli, Proteus, Klebsiella

Cefazolin

Second

Adds Haemophilus influenzae, Moraxella catarrhalis

Cefuroxime

Third

Adds most remaining GNRs (except Pseudomonas)

Ceftriaxone

ThirdAP

Almost all GNRs (including Pseudomonas), less good GPC coverage

Ceftazidime

Fourth

Similar to third-AP but retains excellent GPC coverage

Cefepime

Fifth

Active against methicillinresistant Staphylococcus aureus (MRSA), GNR coverage similar to third

Ceftaroline

Monobactam

Most GNRs, no gram positives, Aztreonam no anaerobic coverage

Carbapenem

Extremely broad spectrum, covers almost everything except highly resistant pathogens such as MRSA, vancomycin-resistant enterococcus (VRE)

AP, antipseudomonal.

Imipenem

O

ANTIMYCOBACTERIAL AGENTS

SPECTRUM OF ANTIMYCOBACTERIAL ACTIVITY Drug

TB

Mycobacterium leprae

MAC

Isoniazid

⊕

Ethionamide

+

Ethambutol

⊕

⊕

Streptomycin

⊕

+

Amikacin

+

+

+

Clarithromycin

+

Dapsone

⊕

Aminosalicylic acid

+

Rifampin

⊕

Rifabutin

+

⊕

⊕

+ ⊕

Levofloxacin

+

+

+

Moxifloxacin

+

+

+

⊕

Clofazimine Pyrazinamide

⊕

⊕, therapy of choice; +, acceptable alternative.

+

P

ANTIFUNGAL AGENTS

SPECTRUM OF ACTIVITY OF ANTIFUNGAL AGENTS Systemic infections Mold

Drug

Mechanism

Amphotericin Binds Nystatin ergosterol and disrupts membrane Flucytosine

Voriconazole

Fluconazole Miconazole

Blocks ergosterol precursor synthesis

Dimorphics

Dermatophytes

Blasto Histo Asperg Zygom Crypto Candida Coccidio Sporotrichosis Tinea Onychomycosis

⊕a

+

⊕a

+b

Antimetabolite

Posaconazole

Itraconazole

Yeasts

Superficial infections

+ ⊕ +

⊕a

⊕a

⊕a

+ + + ⊕

+ ⊕ +c

+ ⊕ +

+b

+

⊕

+ + +

⊕ ⊕

Ketoconazole

Terbinafine

+ +

Blocks early step in ergosterol synthesis

Inhibits cell wall (βMicafungin glucan) Anidulafungin synthesis Caspofungin

+b +b +b

⊕ ⊕ ⊕

⊕, therapy of choice; +, acceptable alternative. aAmphotericin, the established agent for severe infections, is being supplanted by the newer broadspectrum azoles. bUsed as an adjuvant agent for severe infections. cNot used for histoplasmosis.

⊕

Q

ANTIVIRALS

SPECTRUM OF ACTIVITY OF ANTIVIRAL AGENTS DNA viruses

RNA viruses Influenza

Drug

HSV

EBV

VZV

Acyclovir

⊕

+a

⊕

Ganciclovir

+

+

⊕

Foscarnet

+

+

+

Cidofovir

+

+

+

Trifluridine

+

Lamivudine

CMV

HBV

⊕

A

B

RSV

Tenofovir

⊕

Entecavir

⊕

Telbivudine

⊕ ⊕

Ribavirin Interferon α

+

Amantadine

+

Zanamivir

⊕

⊕

⊕, therapy of choice; +, acceptable alternative. aOral hairy leukoplakia only, antiviral therapy is not indicated for infectious mononucleosis.

HIV THERAPY Overview

R

Drug therapy has transformed HIV infection from a fatal disease to a chronic illness. Improved survival of treated patients and continued spread of the epidemic require that all clinicians be familiar with management of this disease.

Viral It is now appreciated that asymptomatic HIV infection, the period Dynamics between recovery from acute infection and the onset of AIDS, is anything but quiescent. Production of 1010 to 1011 virions daily and the constant mutation of the viral genome resulting from the low fidelity of reverse transcriptase (RT) frustrate the ability of the immune system to contain the infection. The concentration of HIV virions in the blood reflects the balance of immune response to viral production and predicts the rate of CD4+ T-cell depletion and risk of progression to AIDS. Therapy

Inhibition of the production of infectious virions by drug therapy shifts this balance in favor of the immune system and allows it to contain the infection by lysing most infected cells. Unless patients remain on therapy indefinitely, however, recrudescence of viral replication from genomes integrated into “reservoir” cells will occur. The mainstay of therapy is multidrug regimens. This approach is required because the high rate of mutation of the HIV genome (caused by RT infidelity) ensures that resistance to any one drug is present in at least some of the viral genomes. Institution of any one drug will select for these resistant genotypes and ultimately make the drug useless in that patient. Using multiple agents simultaneously and close monitoring of the concentration of HIV virions during therapy (i.e., ensuring they decrease to undetectable levels) minimize the emergence of resistance.

ANTIRETROVIRAL AGENTS

HCV THERAPY

S

T

ANTIEPILEPTIC AGENTS

(Adapted from Rho, JM, Sankar, R. The pharmacologic basis of antiepileptic drug action. Epilepsia 1999;40:1471–1483.)

ANTIEPILEPTICS Generalized Major mode of action

Na+ channel blockade

Glutamate inhibition

GABA potentiation

Agent

Focal

Absence Tonic- Partial Myoclonic Status clonic epilepticus

Phenytoin

⊕

⊕

Carbamazepine

⊕

⊕

Lamotrigine

⊕

+

⊕

Zonisamideb

+

+

+

Topiramateb

⊕

⊕

Felbamatea,b

+

+

Tiagabine

+

Vigabatrin

+

Diazepam

+

+

+

+

+

+

⊕

Phenobarbital ⊕

Ethosuximide T-type Ca++ channel block Trimethadione

+

Valproic acidb

⊕

Miscellaneous (unknown)

+ +

⊕

⊕

Gabapentin

+

⊕

Pregabalin

+

+

Levetiracetam

+

+

⊕, first-line therapy; +, acceptable alternative. aSevere toxicity limits use of this drug to seizures refractory to all other agents. bAgent acts via multiple mechanisms.

+

⊕

DOPAMINE AGONISM & ANTAGONISM IN CNS

SEROTONIN AGONISM & ANTAGONISM

U

ANTINEOPLASTICS

(Adapted from Hardman and Limbird [eds]. Goodman and Gilman's The Pharmacologic Basis of Therapeutics [11th ed]. New York: McGraw-Hill, 2006.)

ANTINEOPLASTICS

V

W

MONOCLONAL ANTIBODIES (mAbs) Mechanism

Clinical use

Example

Kill cells

Abs are not directly 1. Chemotherapy 1. Rituximab toxic to cells but rely Alemtuzumab on several different Gemtuzumab mechanisms. 2. Immunosuppression 2. Basiliximab • Ab-dependent, cellDaclizumab mediated cytotoxicity (ADCC): Immune cells bearing Fc receptors (primarily neutrophils, macrophages, and natural killer cells) bind the Fc portion of the Ab and kill the target cell via release of cytotoxic granules and phagocytosis. • Triggering complement cascade • Fused to a toxin (e.g., anti-CD20 mAb fused to radioactive 131I)

Block signaling

By binding to either the 1. Platelet inhibition 1. Abciximab receptor or the ligand, 2. Immunosuppression 2. Infliximab mAb creates steric or modulation Omalizumab hindrance that 3. Antiangiogenesis 3. Bevacizumab prevents ligandreceptor coupling.

Neutralize particles

By binding to particles (defined broadly to include drugs,

1. Drug antidote 2. Antiviral

1. Digibind 2. Palivizumab

viruses, and so on), mAb can neutralize the normal effect of these particles.

Most monoclonal antibodies (mAbs) generated in mice have several limitations: 1. Mouse mAb Fc interacts inconsistently with human Fc receptors. 2. Mouse mAbs have a short serum half-life. 3. Mouse Fc can induce human anti-mouse antibodies (HAMA), resulting in: a) potential for anaphylaxis with retreatment b) potential for decreased efficacy secondary to HAMA interference with mAb

For this reason, efforts to humanize mAbs have been undertaken.

Chimeric mAbs are made by fusing the antigen binding (Fab) portion of the mouse mAb to the Fc region of human IgG1. Humanized mAbs are made by inserting only the peptides within the mouse Fab that are directly involved in antigen binding into a human IgG1. There are three of these complementarity determining regions (CDR1, CDR2, and CDR3) in each heavy and light chain. Human mAbs are composed solely of human IgG amino acids. Standard suffixes are used for therapeutic mAbs, thus you can tell how “humanized” an antibody is by its name.

X

EICOSANOIDS

Downstream Intracellular Endogenous Receptor signaling calcium ligand

Pharmacologic agonists Clinical effects

EP1

Gq →↑ IP 3

↑

PGE2

Lubiprostone Dinoprostone

Smooth muscle contraction (primarily gastric)

EP2

Gs →↑ cAMP

↓

PGE2

Alprostadil Dinoprostone

Smooth muscle relaxation (primarily uterine & bronchial)

EP3*

Gi →↓ cAMP

↓

PGE2

Misoprostol Dinoprostone

↓ Gastric acid secretion ↑ Gastric mucus secretion Smooth muscle

contraction Fever EP4

Gi →↑ cAMP

↓

PGE2

Alprostadil Dinoprostone

Smooth muscle relaxation (primarily arterial & intestinal) ↑ GFR, natriuresis & diuresis

FP

Gq →↑ IP3

↓

PGF2α

Carboprost Latanoprost

Smooth muscle contraction (primarily intestinal, uterine, & bronchial) ↑ outflow of aqueous humor

IP

Gs →↑ cAMP

↓

PGI2 Epoprostenol (prostacyclin)

Smooth muscle relaxation (primarily arterial, bronchial, & uterine) Platelet inhibition ↑ GFR, natriuresis & dieresis

TP

Gq →↑ IP3

↑

TXA2 (thromboxane)

Smooth muscle contraction (primarily arterial, bronchial, & uterine) Platelet activation ↓ GFR

CysLT1

Gq →↑ IP3

↓

LTD4

Zafirlukast

Bronchoconstriction Eosinophil

chemoattractant *Splice variants exist, each with somewhat different downstream signaling.

EPINEPHRINE

direct sympathomimetic

1-1

Mechanism Stimulates α1-, α2-, β1-, and β2-adrenoceptors (β predominant at low doses; α at high doses). α1: (PIP2 cascade) → vascular smooth muscle contraction (↑ SVR), pupillary dilator muscle contraction (mydriasis), pilomotor contraction; hepatic glycogenolysis. α2: (Gi, ↓ cAMP) → feedback inhibition of adrenergic neurotransmitter release. β1: (Gs, ↑ cAMP) → ↑ HR and inotropy. β2: (Gs, ↑ cAMP) → smooth muscle relaxation: bronchial and vascular (including coronary arteries). Net effect equivalent to sympathetic stimulation: ↑ BP, HR & CO, coronary dilation, ↓ secretions, ↓ blood flow to splanchnic beds, bronchodilation. ↑ HR & inotropy → ↑ stroke volume & SBP; vasodilation → ↓ DBP. At higher doses, stimulation of α receptors → ↑ SBP & DBP. Clinical

Cardiac arrest, cardiogenic shock, severe hypotension. Severe bronchospasm (e.g., due to asthma), anaphylaxis. Nasal decongestant. Ophthalmic vasoconstrictor and mydriatic. Used in conjunction with local anesthetic to prolong anesthetic effect (by ↓ washout).

Side Effects Can precipitate myocardial ischemia or infarction (due to ↑ cardiac work) and arrhythmias. Contraindic. Narrow-angle glaucoma. Use with caution in patients with coronary disease. Do not use in peripheral IV infusion or inject into fingers, toes, ears, nose (when used with local anesthetic), as vasoconstriction may cause necrosis of these tissues. Metabolism IV or SC. Action terminated by reuptake into presynaptic nerve terminal. Inactivated by COMT & MAO. Notes

NOREPINEPHRINE (Levophed) is similar but no effect on β2-

adrenoceptors. Net effect is peripheral vasoconstriction and ↑ BP, ± ↑ inotropy. DROXIDOPA (Northera) is a prodrug that can cross the blood–brain barrier and is converted to norepinephrine by dopa-decarboxylase. Used to treat neurogenic orthostatic hypotension.

ADREN EPINEPHRINE Norepinephrine Droxidopa

DOPAMINE

direct sympathomimetic

1-2

Mechanism Endogenous catecholamine (precursor to norepinephrine) that stimulates D1, β1, and α1 adrenoceptors (D > β1 > α). D1: renal and splanchnic vasodilation. β1: (Gs, ↑ cAMP) → ↑ HR and inotropy. α1: (PIP2 cascade) → vascular smooth muscle contraction (↑ SVR). The net effect depends on the dose, but there is much overlap and individual variation: Low dose: D1 effects predominate → ↑ renal perfusion. Medium dose: β1 effects predominate → ↑ CO. High dose: α1 effects predominate → ↑ SVR. Clinical

Decompensated congestive heart failure (treated with medium doses), especially when associated with hypotension and reduced urine output. Vasopressor (when used at high doses). May enhance natriuresis in patients with poor renal perfusion, but when added to diuretics in patients with congestive heart failure, was no better than diuretics alone and did not prevent or treat renal failure.

Side Effects Arrhythmias. Metabolism IV. Action terminated by reuptake into presynaptic nerve terminal. Also inactivated by COMT and MAO enzymes. Although dopamine is a neurotransmitter, peripheral infusions have no CNS effect as dopamine does not cross the BBB. Notes

ADREN DOPAMINE

DOBUTAMINE (Dobutrex)

direct sympathomimetic

1-3

Mechanism Synthetic analog of dopamine that stimulates β1-adrenoceptors and to a lesser extent β2- and α1-adrenoceptors. β1: (Gs, ↑ cAMP) → ↑ inotropy and HR (although for unclear reasons, inotropic effects more pronounced). β2: (Gs, ↑ cAMP) → vascular smooth muscle relaxation. α1: (PIP2 cascade) → vascular smooth muscle contraction. Net effect is ↑ cardiac contractility and ↑ CO. Tends to mildly ↓ SVR due to counterbalancing of β2 and α1 effects; overall effect on BP is variable and depends on balance between ↑ CO and ↓ SVR. Despite ↑ HR, dobutamine can actually ↓ myocardial oxygen demand by ↑ inotropy and ↓ SVR. Clinical

Acute management of decompensated congestive heart failure. Fast onset of action. After 24 to 72 hours of continuous therapy, downregulation of receptors and other desensitization mechanisms will ↓ efficacy of drug.

Side Effects Arrhythmias. Possible hypotension. Contraindic. Hypotension. Hypertrophic cardiomyopathy (worsens outflow tract obstruction). Metabolism IV. Inactivated by COMT and MAO enzymes. Notes

ADREN DOBUTAMINE

AMPHETAMINE

indirect sympathomimetic

1-4

Mechanism After presynaptic uptake, causes release of endogenous norepinephrine and, at higher doses, dopamine and serotonin. Clinical

Attention deficit hyperactivity disorder (ADHD): disorder characterized by motor hyperactivity, ↓ attention span, impulsiveness. Paradoxically, amphetamines ↓ symptoms. CNS stimulatory effects used for prevention and reversal of fatigue, treatment of depression and narcolepsy, and transient boosting of physical performance. Suppression of appetite has been used to treat obesity.

Side Effects Dependence, with high potential for addiction and abuse. Restlessness, anxiety, tremor, hyperreflexia. ↑ BP, tachyarrhythmias. Antidote

NH4Cl to acidify the urine (↑ excretion). Antipsychotics to control CNS effects.

Contraindic. Concurrent MAO inhibitor treatment.

Notes

of abuse.

METHYLPHENIDATE (Ritalin), DEXMETHYLPHENIDATE (Focalin), DEXTROAMPHETAMINE (Dexedrine), and LISDEXAMFETAMINE (Vyvanse) are used for ADHD. Dextroamphetamine, PHENTERMINE (Pro-Fast), BENZPHETAMINE (Didrex), and DIETHYLPROPION (Tenuate) are used for weight loss. ATOMOXETINE (Strattera) inhibits NE reuptake and is used to treat ADHD. MODAFINIL (Provigil) and ARMODAFINIL (Nuvigil), although structurally unrelated to amphetamine, potentiate NE and DA neurotransmission, possibly by inhibiting reuptake; used to treat narcolepsy and somnolence. Methamphetamine (“speed,” “crystal meth”) and methylenedioxymethamphetamine (MDMA or “ecstasy”) are drugs

ADREN AMPHETAMINE Methylphenidate Dexmethylphenidate Dextroamphetamine Lisdexamfetamine Phentermine Benzphetamine Diethylpropion Atomoxetine Modafinil Armodafinil Fenfluramine and dexfenfluramine were halogenated amphetamines that stimulated serotonin release and were given in combination with other amphetamines such as phentermine (“Phen-Fen”) for weight loss. However, their use was found to be associated with the development of pulmonary hypertension and valvular heart disease. Interestingly, the latter adverse effect is also seen in patients with carcinoid, a tumor

EPHEDRINE

indirect sympathomimetic

1-5

Mechanism Stimulates release of NE from sympathetic neurons (see epinephrine for a detailed discussion of receptors); also has some activity as a direct adrenergic agonist. Net effect is ↑ HR and ↑ CO, variably ↑ SVR; collectively → ↑ BP. ↓ Secretions and bronchodilation. Potent stimulator of CNS. Clinical

Nasal decongestant: secondary to ↓ volume of nasal mucosa via vascular effects. Treatment of orthostatic hypotension.

Side Effects Hypertension, cardiac arrhythmias. CNS effects: insomnia, anxiety, tremors. Contraindic. Hypertension, hyperthyroidism, cardiovascular disease, concomitant MAO use. Metabolism Does not contain a catechol moiety. Therefore, is not metabolized by COMT in the liver and thus is effective after PO administration. Notes

PSEUDOEPHEDRINE (Sudafed and others) is a stereoisomer of ephedrine that is much less potent and is used in OTC cold medications for its ability to ↓ secretions. Dietary supplements containing plant-derived ephedrine alkaloids (called ephedra or ma huang) were promoted to increase energy and aid weight loss. The FDA banned their sale due to safety concerns.

ADREN EPHEDRINE Pseudoephedrine

COCAINE

indirect sympathomimetic

1-6

Mechanism Indirect sympathomimetic potentiates norepinephrine > epinephrine by blocking reuptake of catecholamines at adrenergic nerve terminals (normally, uptake terminates effects of catecholamines). CNS: general stimulation → euphoria, dysphoria, followed by depression. Depression of medullary centers → death. Cardiovascular (CV): small doses → bradycardia via central vagal stimulation; moderate doses → tachycardia, vasoconstriction, arrhythmia, MI. Local anesthetic: blocks Na+ ion channels → ↓ nerve fiber conduction. Thermoregulation: pyrogenic. Clinical

Local anesthetic.

Side Effects CV: myocardial ischemia, coronary vasospasm, fatal arrhythmias. High potential for abuse. Metabolism Active by all routes of administration. Degraded by plasma esterases. Notes

Crack is a form of free-base cocaine (i.e., the conjugate base of cocaine salt) that can be smoked.

ADREN COCAINE

METHYLDOPA (Aldomet)

sympathoplegic

1-7

Mechanism Methyldopa is an analog of L-dopa. It acts centrally where, after conversion in the brain to methylnorepinephrine (methyl-NE), it binds to and activates presynaptic α2-adrenoceptors (with greater affinity than NE does), causing downregulation of NE release in the vasomotor center. The ↓ sympathetic outflow from the vasomotor center leads to ↓ SVR and ↓ BP. Clinical

Antihypertensive, especially in pregnancy, in which it has an excellent safety record.

Side Effects Hemolytic anemia: alters RBC surface antigens so that they become immunogenic. Hepatotoxicity. Edema, impotence, sedation. Lactation: inhibition of dopamine in the hypothalamus → ↑ prolactin. Notes

Guanadrel is taken up into sympathetic nerve endings and concentrated in neurotransmitter vesicles, thereby replacing and depleting norepinephrine. It was abandoned as an antihypertensive because it caused postural hypotension. Reserpine interferes with the ability of neurotransmitter storage vesicles in sympathetic nerve terminals to store catecholamines, which instead leak out into the cytoplasm and are metabolized by MAO. It was abandoned as an antihypertensive because it caused severe depression.

ADREN METHYLDOPA

PHENYLEPHRINE (Neo-Synephrine)

α1-agonist

1-8

Mechanism Binds to α1-adrenoceptors, activating PIP2 cascade → activation of protein kinase C and ↑ intracellular Ca2+. Causes contraction of vascular smooth muscle → ↑ systemic vascular resistance → ↑ BP (both systolic and diastolic). Causes contraction of pupillary dilator muscle → mydriasis (pupillary dilation) without cycloplegia (paralysis of ciliary muscle), as is caused by antimuscarinic drugs. Clinical

Vasopressor (administered IV). Nasal decongestant (administered topically): secondary to ↓ volume of nasal mucosa via vascular effects. Mydriatic (pupil dilator) without cycloplegia.

Side Effects Repeated use as a nasal decongestant may lead to rebound mucosal swelling (potentially due to receptor desensitization or mucosal damage from prolonged vasoconstriction). Extravasation can lead to tissue necrosis. Metabolism The drug is not a catecholamine, so it is not inactivated by COMT. Therefore, it has a relatively long duration of action. Notes

MIDODRINE (ProAmatine), a prodrug, is converted to an α1-agonist and is used to treat postural hypotension, typically in patients with an impaired autonomic nervous system. XYLOMETAZOLINE (Neo-Synephrine), OXYMETAZOLINE (Afrin), TETRAHYDROZOLINE (Visine), and NAPHAZOLINE (Clear Eyes) are α-agonists used as topical nasal and conjunctival decongestants.

ADREN PHENYLEPHRINE Midodrine Xylometazoline Oxymetazoline Tetrahydrozoline Naphazoline

CLONIDINE (Catapres)

α2-agonist

1-9

Mechanism Activates presynaptic α2-adrenoceptors on sympathetic neurons → downregulation of NE release. Some α2-adrenoceptors are postsynaptic on vascular smooth muscle, where their stimulation → vasoconstriction. Also binds to imidazoline receptors in CNS, which may contribute to antihypertensive effect. When given IV → vasoconstriction and hypertension (activation of postsynaptic α2-receptors on vascular smooth muscle), followed by a longer period of hypotension (↓ sympathetic outflow due to presynaptic α2-receptor activation). Orally → accumulates in CNS → activation of presynaptic α2receptors in cardiovascular control center → suppression of sympathetic outflow. Clinical

Antihypertensive. Treatment of opioid withdrawal. Antidiarrheal in patients with autonomic neuropathy (↑ NaCl absorption and ↓ HCO3− secretion in GI tract).

Side Effects Immediate cessation can result in rebound hypertension. Therefore, drug should be tapered gradually. Dry mouth, sedation, sexual dysfunction. Metabolism PO, dermal patch.

Notes

BRIMONIDINE (Alphagan) and APRACLONIDINE (Iopidine) are topical agents used to ↓ intraocular pressure (via ↓ aqueous humor formation and ↑ outflow) and thus treat glaucoma. Pharmacologic therapy for glaucoma includes facilitating aqueous humor outflow with PGF2α analogs (see latanoprost), α2-agonists, and muscarinic agonists (see pilocarpine) and ↓ aqueous humor formation with βblockers (see timolol), α2-agonists, and carbonic anhydrase inhibitors (see acetazolamide).

ADREN CLONIDINE Brimonidine Apraclonidine

DEXMEDETOMIDINE (Precedex)

α2-agonist

110

Mechanism Activation of α2-adrenoceptors: in the locus ceruleus → hypnosis; in the spinal cord → analgesia. Activation of presynaptic α2-adrenoceptors on sympathetic neurons → downregulation of NE release → moderate ↓ heart rate, SVR, and SBP. (Bolus injection can cause transient hypertension due to activation of postsynaptic α2-receptors on vascular smooth muscle.) Clinical

Sedation and analgesia (felt to provide a more “physiologic” sleep, with less delirium and minimal respiratory depression). Used to help transition from sedation to awakening in intubated patients.

Side Effects Vascular effects as noted above. Metabolism IV. Notes

TIZANIDINE (Zanaflex) is an α2-agonist that increases presynaptic inhibition and thereby reduces muscle spasm with minimal cardiovascular effects.

ADREN DEXMEDETOMIDINE Tizanidine

PHENTOLAMINE (Regitine)

nonselective αblocker

111

Mechanism Nonselective competitive antagonist of α-adrenoceptors. α-blockade → dilation of vascular smooth muscle → ↓ SVR → ↓ BP. Clinical

Antihypertensive, particularly in patients with pheochromocytoma. Treatment of sympathomimetic amine overdose, including extravasation into soft tissue.

Side Effects Orthostatic hypotension. Reflex tachycardia and arrhythmias (caused by α2-blockade, which causes ↑ NE release and thereby ↑ β1-adrenoceptor stimulation). Contraindic. Coronary artery disease. Metabolism IM or IV. Short duration of action. Notes

PHENOXYBENZAMINE (Dibenzyline) is similar but binds irreversibly to α-adrenoceptors (slight selectivity for α1). Also inhibits neuronal and extraneuronal NE reuptake. Ideal for treatment of pheochromocytomas because its irreversible binding prevents even massive amounts of catecholamines from overcoming the blockade (a single dose is effective for days, until new receptors are generated).

ADREN PHENTOLAMINE Phenoxybenzamine

PRAZOSIN (Minipress)

α1-blocker

112

Mechanism Reversible α1-adrenoceptor antagonist. Blockade on vascular smooth muscle → arteriolar and venous vasodilation → ↓ BP and ↓ venous return. Low affinity for α2-adrenoceptors may explain relative lack of reflex tachycardia compared with nonselective α-blockers (α2-blockade would prevent negative feedback and thereby allow ↑ NE release, leading to β1 stimulation of the heart). Inhibition of smooth muscle contraction in prostate → relief of urinary symptoms caused by benign prostatic hyperplasia (BPH). Clinical

Hypertension. BPH. Treatment of Raynaud phenomenon (vasospasm that can lead to digital ischemia).

Side Effects Orthostatic hypotension, syncope. Dry mouth, nightmares, sexual dysfunction, lethargy. Metabolism PO. Short half-life necessitates twice-daily dosing.

Notes

TERAZOSIN (Hytrin) and DOXAZOSIN (Cardura) have longer half-lives and can be dosed once daily. TAMSULOSIN (Flomax) and SILODOSIN (Rapaflo) have greater selectivity for α1A (blood vessels and prostate) over α1B (blood vessels and heart) receptors; may explain why little effect on BP but particularly useful in BPH. ALFUZOSIN (Uroxatral) is another α1blocker (no subtype selectivity) that is used primarily to treat BPH. Yohimbine is a naturally occurring α2-adrenoceptor antagonist derived from the bark of the Yohimbe tree. Touted as dietary supplement to treat erectile dysfunction (but scant evidence).

ADREN PRAZOSIN Terazosin Doxazosin Tamsulosin Silodosin Alfuzosin

ISOPROTERENOL (Isuprel)

nonselective βagonist

113

Mechanism Selectively stimulates β-adrenoceptors. β1: (GS, ↑ cAMP) → ↑ HR and inotropy. β2: (GS, ↑ cAMP) → vascular smooth muscle relaxation. Net effect is ↑ HR, ↑ contractility, and hence ↑ CO. ↑ Contractility → ↑ pulse pressure while vasodilation → ↓ diastolic BP; thus, systolic BP usually remains unchanged while mean arterial pressure falls slightly. Clinical

Used in hemodynamically stable torsades de pointes to increase the sinus rate and shorten QT interval. Has been used in emergencies to stimulate heart rate in patients with bradycardia or heart block while awaiting insertion of an artificial pacemaker, but dopamine or epinephrine preferred.

Side Effects Can precipitate tachyarrhythmias and myocardial ischemia or infarction (due to ↑ cardiac work). Contraindic. Patients at risk for tachyarrhythmias and patients with ischemic heart disease. Metabolism IV. Metabolized primarily in liver and other tissues by COMT. Notes

ADREN ISOPROTERENOL

ALBUTEROL (Proventil, Ventolin)

β2-agonist

114

Mechanism Activates the β2-adrenoceptor, causing stimulation of adenylate cyclase, ↑ cAMP, myosin light-chain kinase phosphorylation and inactivation, and consequent relaxation of smooth muscle and bronchodilation. β-agonists may also ↓ airway inflammation by ↓ release of leukotrienes and histamine. Clinical

Acute treatment of bronchospasm such as in asthma, bronchitis, and COPD. Long-acting β2-agonists (see below) can be used for long-term control of asthma.

Side Effects Skeletal muscle tremor, restlessness, apprehension. Sinus tachycardia and other arrhythmias. Contraindic. Caution in patients with cardiovascular disease and hyperthyroidism. Avoid concomitant use of MAO inhibitors & TCAs. Metabolism PO, nebulized, inhaled. Not a substrate for COMT, hence long acting.

Notes

daily.

LEVALBUTEROL (Xopenex), METAPROTERENOL (Alupent), and PIRBUTEROL (Maxair) are similar. TERBUTALINE (Brethine) can be used IV to treat status asthmaticus. Also used to suppress premature labor. SALMETEROL (Serevent), FORMOTEROL (Foradil), and ARFORMOTEROL (Brovana) are long-acting β-adrenoceptor agonists (LABAs) that can be given just twice daily due to high lipid solubility and hence easier entry and buildup in smooth muscle cells. They are added to inhaled corticosteroids (see beclomethasone) as long-term control medications for asthma and/or COPD but may ↑ risk of asthma-related deaths when used as monotherapy. INDACATEROL (Arcapta), OLODATEROL (Striverdi), and VILANTEROL (Ellipta) are ultra-LABAs that can be given once

ADREN ALBUTEROL Levalbuterol Metaproterenol Pirbuterol Terbutaline Salmeterol Formoterol Arformoterol Indacaterol Olodaterol Vilanterol

MIRABEGRON (Myrbetriq)

β3-agonist

115

Mechanism Activates β3-adrenoceptors, which are found in brown adipose tissue, the gallbladder, and the urinary bladder. Activation of the receptors in the latter location results in smooth muscle relaxation. Clinical

Treat symptoms of overactive bladder (urinary urgency & frequency).

Side Effects Small ↑ BP & HR. Contraindic. Uncontrolled hypertension. Metabolism PO. Hepatic metabolism and urinary excretion. Notes

The role of manipulating β3-adrenoceptors to affect lipolysis and thermoregulation is under study.

ADREN MIRABEGRON

METOPROLOL (Lopressor)

β1-blocker

116

Mechanism 2nd gen β-blocker that selectively inhibits β1-adrenoceptors (although at high doses, some β2-blockade). Cardiac conductive tissue: acts as a class II antiarrhythmic: ↓ phase 4 slope in pacemaker cells → ↓ HR → ↓ myocardial O2 demand. ↑ Refractory period at AV node (thereby blocking reentrant arrhythmias); inhibits ectopic foci. Cardiac myocytes: causes ↓ cAMP → ↓ intracellular Ca2+ → ↓ inotropy → ↓ cardiac output and ↓ myocardial O2 demand. Clinical

Ischemic heart disease: ↓ angina (↓ myocardial O2 demand), ↑ survival after MI. Hypertension. Aortic dissection: ↓ rate of development of systolic BP → ↓ risk of dissection extension. Tachyarrhythmias: rate control of AF and AFL; terminate PSVT; prevent ventricular tachycardia.

Side Effects Bradycardia, hypotension, CHF, fatigue, depression, impotence, ↓ libido. Although relatively β1-selective, may precipitate bronchospasm by blocking β2-mediated bronchodilation. Contraindic. Bradycardia, heart block, hypotension, decompensated CHF, severe asthma or COPD. Prinzmetal and cocaine-induced angina: inhibition of β2-mediated vasodilation → coronary vasospasm. Notes

ATENOLOL (Tenormin) and BISOPROLOL (Zebeta) are longer acting. ESMOLOL (Brevibloc) has a very short half-life (~10 minutes) and is given as IV infusion. ACEBUTOLOL (Sectral) is a β1-blocker with intrinsic sympathomimetic activity (ISA) and thus less likely to cause bradycardia but less suited for angina. PROPRANOLOL (Inderal), NADOLOL (Corgard), and PINDOLOL (Visken) are first-generation, nonselective β1- and β2blockers, with the latter two having ISA. Used for similar indications as 2nd gen with the addition of portal hypertension to

prevent variceal bleeding [↓ cardiac output (β1-blockade) and splanchnic vasoconstriction (β2-blockade) → ↓ portal pressures], thyrotoxicosis (control symptoms), and migraine prevention. Similar side effect profile except more likely to cause bronchospasm.

ADREN METOPROLOL Atenolol Bisoprolol Esmolol Acebutolol Propranolol Nadolol Pindolol

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

CLASSIFICATION OF β-BLOCKERS

Generation Properties

Pure antagonists

Partial agonists (i.e., possess intrinsic sympathomimetic activity [ISA])

1st

Nonselective Propranolol, Nadolol (Timolol, Levobunolol, Metipranolol)

Pindolol (Carteolol)

2nd

β1-selective

Acebutolol

Metoprolol, Atenolol, Bisoprolol, Esmolol

(Betaxolol, Levobetaxolol) 3rd

Vasodilatory Carvedilol, Nebivolol

Labetalol

Parentheses denote β-blockers primarily administered topically for glaucoma.

CARVEDILOL (Coreg)

vasodilatory βblocker

117

Mechanism 3rd gen nonselective β-blocker that has vasodilatory effects caused by α1 and Ca2+ entry blockade. Heart failure triggers a compensatory sympathetic nervous system response with ↑ adrenergic stimulation. Although initially compensatory, cardiac adrenergic stimulation is ultimately deleterious for four reasons: 1. ↑ HR & CO → ↑ myocardial oxygen demand and ischemia 2. ↑ SVR → ↑ afterload → ↑ myocardial oxygen demand and ischemia 3. Norepinephrine promotes myocyte necrosis and cardiac fibrosis. 4. Continued norepinephrine exposure → β-receptor downregulation Net result on LV is ↑ mechanical stress, ↑ fibrosis, ↓ responsiveness to intermittent adrenergic stimuli. By blocking prolonged cardiac adrenergic stimulation, β-blockers can reverse these maladaptive processes. Clinical

Compensated heart failure (improves symptoms, ejection fraction, and survival).

Side Effects Hypotension, bradycardia, bronchospasm. Can initially exacerbate heart failure symptoms (especially if patient not compensated or if dose escalated too aggressively). Contraindic. Decompensated heart failure. Notes

2nd gen β-blockers metoprolol and bisoprolol have also been used to treat heart failure. However, carvedilol appears particularly beneficial perhaps due to its additional vasodilatory effects. NEBIVOLOL (Bystolic) is a selective β1-blocker that has nitricoxide–mediated vasodilating properties. LABETALOL (Normodyne, Trandate) is another nonselective βblocker that also causes α1-blockade (although five- to tenfold more potent β- than α-blocker) and partial β2-agonism. Used to treat

hypertension.

ADREN CARVEDILOL Nebivolol Labetalol

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

CLASSIFICATION OF β-BLOCKERS

Generation Properties

Pure antagonists

Partial agonists (i.e., possess intrinsic sympathomimetic activity [ISA])

1st

Nonselective Propranolol, Nadolol (Timolol, Levobunolol, Metipranolol)

Pindolol (Carteolol)

2nd

β1-selective

Acebutolol

3rd

Vasodilatory Carvedilol, Nebivolol

Metoprolol, Atenolol, Bisoprolol, Esmolol (Betaxolol, Levobetaxolol)

Labetalol

Parentheses denote β-blockers primarily administered topically for glaucoma.

TIMOLOL (Timoptic)

nonselective βblocker

118

Mechanism Nonselective β1- and β2-adrenoceptor competitive antagonist. Same cardiovascular effects as propranolol. Can also be given as eye drops, in which case its main effect is to ↓ aqueous humor formation. The lack of local anesthetic activity (compared with most other βblockers) allows this drug to be used on the eye without fear of allowing lesions to occur on an anesthetized cornea. Clinical

Glaucoma (see pilocarpine for more information on medical therapy for this disease).

Metabolism Topical for ophthalmologic therapy. PO for cardiovascular therapy.

Notes

CARTEOLOL (Ocupress), LEVOBUNOLOL (Betagan), and METIPRANOLOL (OptiPranolol) are similar agents. BETAXOLOL (Betoptic) is β1-selective. Less efficacious because β2receptors predominate in the ciliary body epithelium but may be better tolerated than nonselective agents in patients with asthma or COPD. Glaucoma is a disease marked by ↑ intraocular pressure because of poor absorption of aqueous humor (made by ciliary body in posterior chamber and drains out via anterior chamber). Narrow-angle glaucoma is caused by the iris partially blocking the entrance into the trabecular network at the canal of Schlemm; acute angle closure glaucoma is precipitated by dilation of the iris (thereby exacerbating the blockage) and is a medical emergency. Wide-angle glaucoma is caused by poor trabecular tone without any physical impediment to outflow. Pharmacologic therapy for glaucoma includes facilitating aqueous humor outflow with PGF2α analogs (see latanoprost), α2-agonists (see brimonidine), and muscarinic agonists (see pilocarpine) and ↓ aqueous humor formation with β-blockers, α2-agonists, and carbonic anhydrase inhibitors (see acetazolamide).

ADREN TIMOLOL Carteolol Levobunolol Metipranolol Betaxolol

CLASSIFICATION OF β-BLOCKERS

Generation Properties

Pure antagonists

Partial agonists (i.e., possess intrinsic sympathomimetic activity [ISA])

1st

Nonselective Propranolol, Nadolol (Timolol, Levobunolol, Metipranolol)

Pindolol (Carteolol)

2nd

β1-selective

Acebutolol

3rd

Vasodilatory Carvedilol, Nebivolol

Metoprolol, Atenolol, Bisoprolol, Esmolol (Betaxolol)

Labetalol

Parentheses denote β-blockers primarily administered topically for glaucoma.

FENOLDOPAM (Corlopam)

D1-agonist

119

Mechanism D1 receptor agonist leading to renal and splanchnic vasodilation. Some stimulation of α2-adrenoceptors, leading to feedback inhibition of adrenergic neurotransmitter release. Net effect is renal, mesenteric, peripheral, and coronary vasodilation. Despite ↓ BP, renal blood flow is maintained and natriuresis promoted. Clinical

Treatment of hypertensive crises.

Side Effects Hypotension, arrhythmias. Hypokalemia. ↑ Intraocular pressure. Metabolism IV. Hepatic metabolism. Notes

Whereas fenoldopam, a pure D1-agonist, causes ↓ BP, dopamine itself, because it also is an α- and β-adrenoceptor agonist, causes ↑ BP.

ADREN FENOLDOPAM

NICOTINE

nicotinic agonist

2-1

Mechanism Prototypical agonist for nicotinic acetylcholine (ACh) receptors, which are ligand-gated Na+ and K+ channels → rapid depolarization of target cell (unlike the G protein-coupled muscarinic receptors). Nm subtype receptors (at neuromuscular endplate) are responsible for skeletal muscle contraction. Pharmacologic activation can lead to fasciculations, spasms, and, at high doses, depolarizing blockade. Nn subtype nicotinic receptors stimulate both sympathetic and parasympathetic postganglionic neurons, resulting in: Adrenal medulla: epinephrine release. Cardiac: ↑ HR (due to epinephrine and sympathetic > parasympathetic stimulation). Vascular (mostly sympathetic innervation): peripheral vasoconstriction. GI (mostly parasympathetic innervation): ↑ gut motility and secretion. Carotid bodies: ↑ RR (caused by chemoreceptor activation). Medullary emetic chemoreceptors: nausea and vomiting. Clinical

Used clinically to aid smoking cessation by easing nicotine craving. Low doses found in cigarettes cause ↑ HR, ↑ BP, ↑ RR, ↓ appetite. High doses can result in medullary depression, bradycardia, and neuromuscular blockade.

Side Effects Dependence: Activation of nicotinic receptors on neurons in the brain’s dopaminergic reward pathway (ventral tegument area) is responsible for nicotine’s strong addiction potential. Metabolism Rapidly absorbed through the skin, lungs, and gut. For smoking cessation, used orally as a gum or topically as a patch. Notes

VARENICLINE (Chantix) is a partial nicotinic agonist that is highly effective in supporting smoking cessation but may be associated with psychiatric symptoms, including suicidal ideation.

CHOLIN NICOTINE Varenicline

SUCCINYLCHOLINE (Anectine)

nicotinic agonist

2-2

Mechanism Binds nicotinic acetylcholine receptors (Nm subtype), causing their channels to open and the neuromuscular membrane to depolarize. Drug is not inactivated by acetylcholinesterase, so prolonged depolarization ensues. This forces all acetylcholine receptors to remain in the inactive state and prevents generation of further action potentials in response to acetylcholine. This depolarizing blockade cannot be reversed by a cholinesterase inhibitor or overcome by tetanic stimulation. Clinical

Paralysis for brief surgical procedures.

Side Effects Malignant hyperthermia (see halothane). Hypotension, arrhythmias, respiratory collapse. ↑ Intraocular pressure. Metabolism Hydrolyzed by plasma and liver pseudocholinesterases (within 5 to 10 minutes). Notes

See pancuronium for an example of a nondepolarizing neuromuscular blocker.

CHOLIN SUCCINYLCHOLINE

PANCURONIUM (Pavulon)

antinicotinic

2-3

Mechanism Competitive antagonist of Nm subtype of nicotinic acetylcholine receptors located in the neuromuscular junction. Nondepolarizing blockade results in skeletal muscle paralysis that can be overcome by tetanic stimulation or by administration of a cholinesterase inhibitor such as neostigmine (contrast with depolarizing blockade produced by succinylcholine). Clinical

Induction of paralysis for surgery or to facilitate mechanical ventilation of critically ill patients.

Side Effects Histamine release at higher doses → flushing, edema, erythema, hypotension, and tachycardia. ↑ HR and ↑ CO caused by vagolytic effects from weak antimuscarinic activity. Metabolism IV. Rapid onset of action and short half-life.

Notes

The purified active ingredient of curare (a generic term for South American arrow poisons) is tubocurarine, a nondepolarizing neuromuscular blocker that has been replaced by newer agents with fewer side effects. VECURONIUM (Norcuron) and ROCURONIUM (Zemuron) are similar. ATRACURIUM (Tracrium), CISATRACURIUM (Nimbex), and MIVACURIUM (Mivacron) are preferred in patients with multiorgan system failure because their metabolism is independent of hepatic and renal function. Cisatracurium also causes less histamine release. HEXAMETHONIUM is the prototypical antagonist of Nn subtype nicotinic receptors found at parasympathetic and sympathetic ganglia. It is no longer used to treat hypertensive crises because of the protean side effects that result from loss of all autonomic tone.

CHOLIN PANCURONIUM Vecuronium Rocuronium Atracurium Cisatracurium Mivacurium Hexamethonium

BETHANECHOL (Urecholine)

muscarinic agonist

2-4

Mechanism A quaternary choline ester that acts as a muscarinic receptor agonist (predominantly subtype M3 found in smooth muscle and various glands). Effect depends on the tissue: GU: ↑ detrusor tone and ↓ outlet resistance of internal sphincter. GI: ↑ motility and secretion. Weak agonist at M2 receptors: minimal cardiac effects. Exerts little effect at M1, M4, and M5 receptors because it crosses BBB poorly. See atropine for details of these receptor subtypes. Clinical

Gastric atony after vagotomy (↑ motility), reduce reflux (↑ LES tone). Urinary retention (in the absence of obstruction).

Side Effects Pulmonary: bronchoconstriction, ↑ secretions. GI: nausea, vomiting, cramps, and diarrhea. Ophthalmic: miosis. Contraindic. Asthmatics (because of bronchoconstriction). Notes

METHACHOLINE is a quaternary choline ester that is a nonselective muscarinic agonist. It is used as an inhalational agent to aid the diagnosis of asthma (“methacholine challenge” → excessive bronchoconstriction via M3 receptors in bronchial smooth muscle in asthmatic patients).

CHOLIN BETHANECHOL Methacholine

PILOCARPINE (Isopto Carpine, Salagen)

muscarinic agonist

2-5

Mechanism An alkaloid nonselective muscarinic acetylcholine receptor agonist. Ophthalmic (M3 receptor) effects predominate because of topical application and minimal systemic absorption: contraction of sphincter muscles of the iris → miosis and frees the entrance to canal of Schlemm (therapy for narrow-angle glaucoma); enhances tone of trabecular network (therapy for wide-angle glaucoma); contraction of the ciliary muscle → accommodation and loss of far vision. See atropine for details of these receptor subtypes. Clinical

Glaucoma: both narrow and wide angle (drug of choice). Dry mouth caused by Sjögren syndrome or radiation therapy of head and neck cancer.

Side Effects With topical use, stinging and local irritation. When taken orally, can produce sweating and can worsen asthma and COPD. Notes

CARBACHOL, another quaternary choline ester, is a nonselective cholinergic agonist (can activate nicotinic and muscarinic receptors) used topically for glaucoma. Pharmacologic therapy for glaucoma includes facilitating aqueous humor outflow with PGF2α analogs (see latanoprost), α2-agonists (see brimonidine on clonidine card), and muscarinic agonists, and ↓ aqueous humor formation with β-blockers (see timolol), α2agonists, and carbonic anhydrase inhibitors (see acetazolamide).

CHOLIN PILOCARPINE Carbachol Glaucoma is a disease marked by ↑ intraocular pressure because of poor absorption of aqueous humor (which is made by the ciliary body in the posterior chamber and drains out via the anterior chamber). Narrow-angle glaucoma is caused by the iris partially blocking the entrance into the trabecular network at the canal of Schlemm; acute angle closure glaucoma is precipitated by dilation of the iris (thereby exacerbating the blockage) and is a medical emergency. Wide-angle glaucoma is caused by poor trabecular tone without any physical impediment to outflow.

ATROPINE

antimuscarinic

2-6

Mechanism A tertiary amine alkaloid that is a nonselective antagonist of muscarinic receptors: M1 (IP3/DAG): found in CNS and enteric nervous system. Blockade can produce confusion/delirium and ↓ acid secretion from gastric parietal cells. M2 (↑ K+, ↓ cAMP): found on SA and AV nodes. Blockade produces ↑ HR. M3 (IP3/DAG): found in smooth muscle and various glands. Blockade produces ↓ saliva, ↓ bronchial secretion, ↓ sweat, mydriasis, accommodation of eye inhibited (cycloplegia), inhibition of micturition, ↓ GI tone and motility, ↓ GI secretions. M4 (↑ K+, ↓ cAMP) and M5 (IP3/DAG): found in CNS. May contribute to CNS effects. Clinical

Treatment of bradycardia, including that caused by cholinesterase inhibitor overdose. Ophthalmic: causes cycloplegia and mydriasis. GI: used as an antimotility agent to treat noninfectious causes of diarrhea.

Side Effects “Red as a beet, blind as a bat, dry as a bone, hot as a hare, and mad as a hatter.” In other words: dilatation of superficial vessels → “atropine flush,” blurred vision, ↓ secretions, hyperthermia (atropine fever caused by ↓ sweat), delirium, and hallucinations. Contraindic. Narrow-angle glaucoma (relaxation of constrictor muscles of iris → obstruction of canal of Schlemm). Notes

Atropine was first isolated from the plant Atropa belladonna, so named because extracts from the plant were allegedly used by Italian women to dilate their pupils. SCOPOLAMINE is another tertiary amine alkaloid used for motion sickness prophylaxis. HOMATROPINE (Isopto Atropine), CYCLOPENTOLATE

(Cyclogyl), and TROPICAMIDE (Mydriacyl) are used in ophthalmology to produce mydriasis. Unlike α-agonists, they produce cycloplegia at high doses.

CHOLIN ATROPINE Scopolamine Homatropine Cyclopentolate Tropicamide

BENZTROPINE (Cogentin)

antimuscarinic

2-7

Mechanism A tertiary amine alkaloid that acts as an antagonist of muscarinic receptors found in the CNS and at parasympathetic effector sites. Like atropine, it can ↓ GI/GU secretions, ↓ GI motility, and ↑ HR. Utility derives from action on GABAergic neurons in corpus striatum. Under normal conditions, these neurons are stimulated by cholinergic neurons and inhibited by dopaminergic neurons from the substantia nigra. In Parkinson disease, progressive loss of dopaminergic neurons allows cholinergic-mediated stimulation to go unchecked. Benztropine compensates for this by blocking cholinergic neurons in the corpus striatum. This relationship is referred to as the dopaminergic–cholinergic balance. Clinical

Parkinson’s disease: second- or third-line therapy. Parkinsonism secondary to antipsychotics (see haloperidol).

Side Effects Hyperthermia (caused by ↓ sweat), glaucoma, urinary retention, dry mouth, constipation, blurred vision, sedation, amnesia, delirium, hallucinations. Contraindic. Narrow-angle glaucoma (relaxation of constrictor muscles of iris → obstruction of the canal of Schlemm). Notes

Because tertiary amine alkaloids are more lipophilic than their quaternary amine counterparts (see ipratropium), these agents are able to cross the BBB and exert CNS effects. BIPERIDEN (Akineton) and TRIHEXYPHENIDYL (Artane) are similar.

CHOLIN BENZTROPINE Biperiden Trihexyphenidyl

IPRATROPIUM (Atrovent)

antimuscarinic

2-8

Mechanism A nonselective muscarinic antagonist that acts on receptors found at parasympathetic effector sites. Because the drug is a quaternary amine, it is poorly absorbed systemically. When used as an inhaled agent, it affects predominantly M3 acetylcholine receptors found in smooth muscle and glands of the bronchi (see atropine for more about muscarinic acetylcholine receptor subtypes). The main clinical effects are ↓ bronchoconstriction and ↓ bronchial secretions. Clinical

COPD (first-line therapy) and asthma (second-line therapy for flares).

Side Effects Minimal due to poor systemic absorption: dry mouth, sedation. Metabolism Inhaled. Quaternary amine group impairs systemic absorption. Notes

TIOTROPIUM (Spiriva) is an antimuscarinic with some selectivity for M1 and M3 muscarinic receptors. It is also a quaternary ammonium, so upon inhalation, it predominantly blocks M3 receptors on airway smooth muscles, leading to bronchodilation. ACLIDINIUM (Tudorza Pressair) and UMECLIDINIUM (Incruse Ellipta) are long-acting, M3-selective antimuscarinics used for COPD. GLYCOPYRROLATE (Robinul) is a nonselective antimuscarinic agent used preoperatively to reduce salivary, tracheobronchial, and pharyngeal secretions by blocking the action of ACh at parasympathetic sites on smooth muscle and secretory glands.

CHOLIN IPRATROPIUM Tiotropium Aclidinium Umeclidinium Glycopyrrolate

OXYBUTYNIN (Ditropan, Oxytrol)

antimuscarinic

2-9

Mechanism Competitive muscarinic acetylcholine receptor antagonist. A quaternary amine, its central effects are minimal. Its main effect is on the muscarinic receptors of the GI/GU systems (M3 subtype), where it relaxes smooth muscle walls, ↑ sphincter tone, and ↓ secretions. Blockade of M1 receptors in the enteric nervous system: ↓ gastric acid production, but better tolerated agents are now used for this indication (see omeprazole and cimetidine). Clinical

Urinary incontinence.

Side Effects Parasympathetic blockade: pupillary dilatation, tachycardia, ↓ GI motility and secretions. Contraindic. Pyloric obstruction, retentive bladder. Narrow-angle glaucoma (relaxation of constrictor muscles of iris → obstruction of the canal of Schlemm). Notes

DARIFENACIN (Enablex), FESOTERODINE (Toviaz), FLAVOXATE (Urispas), PROPANTHELINE (Pro-Banthine), SOLIFENACIN (Vesicare), TOLTERODINE (Detrol), and TROSPIUM (Sanctura) are other muscarinic antagonists used to treat urinary incontinence. DICYCLOMINE (Bentyl) and HYOSCYAMINE (Cystospaz, Levsin) can be used as antispasmodics in the treatment of irritable bowel syndrome.

CHOLIN OXYBUTYNIN Darifenacin Fesoterodine Flavoxate Propantheline Solifenacin Tolterodine Trospium Dicyclomine Hyoscyamine

NEOSTIGMINE (Prostigmin)

cholinesterase inhibitor

210

Mechanism Carbamate inhibitor of acetylcholine esterase (AChE) that is highly resistant to hydration (the means by which substrate are released and AChE is regenerated) → accumulation of acetylcholine at neuromuscular (NM) junctions and synapses. Skeletal muscle: reverses nondepolarizing NM blockade (see pancuronium). High doses cause a depolarizing NM blockade (see succinylcholine). Bowel and bladder smooth muscle: causes ↑ tone, ↑ motility, relaxation of sphincters. Parasympathetic effects on the heart: ↓ HR, ↓ cardiac contractility, ↓ conduction velocity through AV node. Clinical

Reverse nondepolarizing NM blockade (e.g., coming out of surgical anesthesia). Myasthenia gravis. Increase GI motility in postoperative patients and those with a neurogenic ileus. Treatment of urinary retention secondary to bladder atony.

Metabolism Quaternary carbamates have poor absorption and do not penetrate into the CSF. Notes

PYRIDOSTIGMINE (Mestinon) is a similar agent used to treat myasthenia gravis. EDROPHONIUM (Tensilon) is a noncarbamate AChE inhibitor with a short half-life that is used to diagnose myasthenia gravis. “Tensilon test”: ↑ ACh in NM junction is able to overcome ACh receptor antibodies, leading to sudden, short-lasting improvement followed by ↓ muscle strength. Edrophonium can also differentiate cholinergic crisis (from overmedication) from worsening myasthenia. Edrophonium will worsen a crisis but improve undermedication.

CHOLIN NEOSTIGMINE Pyridostigmine Edrophonium

DONEPEZIL (Aricept)

cholinesterase inhibitor

211

Mechanism Noncovalent acetylcholine esterase inhibitor → augmented cholinergic neurotransmission. Disproportionate loss of cholinergic neurons projecting from subcortical areas has been found in Alzheimer disease. Clinical

Alzheimer dementia. The drug produces a modest increase in cognitive function but does not appear to halt progression of the underlying disease.

Side Effects Diarrhea, nausea and vomiting, and other cholinergic side effects. Avoid using other cholinergic agents simultaneously. Metabolism Crosses BBB readily, making it useful for treatment of Alzheimer disease (in contrast to neostigmine). Notes

GALANTAMINE (Reminyl), RIVASTIGMINE (Exelon), and TACRINE (Cognex) are similar agents, although tacrine is rarely used because of hepatotoxicity. PHYSOSTIGMINE (Antilirium) is a carbamate cholinesterase inhibitor that is a tertiary amine and thus readily crosses the BBB. It is used as an antidote for anticholinergic delirium (e.g., from atropine overdose). Occasionally used for glaucoma (increased ACh → iris contraction and enhanced trabecular network tone; see pilocarpine); however, there is an ↑ incidence of cataracts with prolonged use.

CHOLIN DONEPEZIL Galantamine Rivastigmine Tacrine Physostigmine

SARIN

cholinesterase inhibitor

212

Mechanism Organophosphate “nerve gas,” a potent suicide inhibitor of acetylcholinesterase (AChE). The resulting alkylphosphorylated enzyme is extremely resistant to hydration (the means by which AChE is regenerated into its active form), leading to accumulation of ACh at NM junctions and neuronal synapses. Clinical

Acute poisoning manifests as follows: CNS: coma, respiratory depression, seizures. Muscarinic: bradycardia, nausea, vomiting, diarrhea, blurring of vision, sweating, salivation. Nicotinic: muscle twitching, fasciculations, weakness, flaccid paralysis.

Antidote

Cholinesterase regenerator (see below) but must be given before “aging” occurs (further chemical changes to cholinesterase that make inhibition irreversible). ACh receptor–blockers (e.g., atropine): to ↓ muscarinic hyperactivity that would otherwise cause potentially fatal bradycardia.

Metabolism Absorbed rapidly through the skin, GI tract, and lungs. Notes

DFP (diisopropyl fluorophosphate), SOMAN, TABUN, and VX are similar nerve agents. PARATHION and MALATHION are used as insecticides because they are metabolized into active AChE inhibitors, more efficiently by insects than mammals. Poisoning resembles nerve gas exposure. PRALIDOXIME (Protopam) is a cholinesterase regenerator. Regeneration of phosphorylated AChE is due to pralidoxime’s higher affinity for phosphorus. Thus, it is effective only in organophosphate toxicity (i.e., no effect if enzyme is carbamylated as occurs with neostigmine and physostigmine).

CHOLIN SARIN DFP Soman Tabun VX Parathion Malathion Pralidoxime

NITROGLYCERIN

direct vasodilator

3-1

Mechanism Nitroglycerin is metabolized by mitochondrial aldehyde dehydrogenase into free nitrite ions (NO2−), which are then reduced to nitric oxide (NO). NO stimulates guanylate cyclase → ↑ cGMP → activation of cGMP-dependent protein kinases. These, in turn, cause ↓ intracellular Ca2+ and activation of myosin light-chain (MLC) phosphatase → MLC dephosphorylation → vascular smooth muscle relaxation. Results in dilation of veins and ↑ venous capacitance → ↓ preload and thereby ↓ myocardial wall tension and O2 demand. Nitroglycerin may also ↑ oxygen supply by ↓ coronary vasospasm. NO can cause vasodilation of both arteries and veins, but aldehyde dehydrogenase is enriched in the mitochondria of venous smooth muscle cells, and therefore, nitroglycerin predominantly affects venous vascular tone. Clinical

Treatment of angina. Often taken with a β-blocker to minimize reflex tachycardia. Congestive heart failure. Control of hypertension, especially in patients with known coronary artery disease.

Side Effects Hypotension, tachycardia, throbbing headaches resulting from meningeal arterial dilatation. Tolerance frequently develops. Metabolism Can be given sublingual (avoiding extensive first-pass metabolism by hepatic nitrate reductase), transdermal, PO, or IV. Nitrate-free periods prevent tolerance but may precipitate angina. Notes

Sublingual tablets lose their potency when exposed to light. ISOSORBIDE DINITRATE (Isordil) and ISOSORBIDE MONONITRATE (Monoket, Imdur) are long-acting oral forms.

CV NITROGLYCERIN Isosorbide Dinitrate Isosorbide Mononitrate

NITROPRUSSIDE (Nipride)

direct vasodilator

3-2

Mechanism Contact with RBCs leads to decomposition of the drug and release of nitric oxide (NO). NO, via activation of guanylate cyclase causes vasodilation. See nitroglycerin. Causes vasodilation of both arterioles and veins, thereby ↓ both preload and afterload. Clinical

Hypertensive crisis. Acute aortic dissection. Given concomitantly with a β-blocker to prevent reflex tachycardia and ↑ contractility, both of which would lead to an increased rate of pressure development, which could lead to further progression of the dissection. Decompensated congestive heart failure with high SVR.

Side Effects Hypotension, reflex tachycardia. In patients with CAD, can precipitate angina because of coronary steal (see dipyridamole). In patients with COPD, can cause hypoxemia because of global pulmonary arteriolar vasodilation and therefore loss of compensatory ventilation–perfusion (V/Q) matching. Metabolism of nitroprusside leads to the release of cyanide, which is partially detoxified by the mitochondrial enzyme rhodanese to thiocyanate. Both can exert toxic effects: Cyanide toxicity: inhibition of cellular respiration → lactic acidosis, arrhythmias, hypotension, cytotoxic hypoxia (see cyanide). Thiocyanate toxicity: weakness, disorientation, psychosis, muscle spasms. Contraindic. Hepatic or renal disease (increases risk of thiocyanate intoxication). Metabolism IV. Onset and offset of action in minutes. Notes

CV NITROPRUSSIDE

NESIRITIDE (Natrecor)

direct vasodilator

3-3

Mechanism Recombinant B-type natriuretic peptide (BNP), a vasoactive peptide hormone synthesized primarily by ventricular myocytes and released in response to ventricular wall stretch. BNP binds to guanylate cyclase–coupled natriuretic peptide receptors → ↑ intracellular cGMP and hence vasodilation (see nitroglycerin). The net effect is both arteriolar and venous vasodilation, leading to ↓ preload and afterload. Clinical

Short-term treatment of decompensated congestive heart failure, but benefit on top of standard therapy unclear.

Side Effects Hypotension. Metabolism IV. Cleared via proteolytic cleavage by neutral endopeptidase (NEP) and other enzymes. Notes

The natriuretic peptides are a family of vasoactive hormones that also include atrial or A-type natriuretic peptide (ANP) and C-type natriuretic peptide (CNP), which is synthesized in the CNS and vascular endothelium. The presence of ↑ plasma levels of endogenous BNP and ANP have been used to aid in the diagnosis of CHF.

CV NESIRITIDE

HYDRALAZINE (Apresoline)

direct vasodilator

3-4

Mechanism Remains unclear. ↑ permeability to K+ (→ membrane hyperpolarization) and inhibition of sarcoplasmic release of Ca2+ are leading possibilities. Net effect is arteriolar vasodilation. Also acts as an antioxidant that inhibits synthesis of superoxide (O2−). In conjunction with nitrates (which lead to the formation of NO), can help restore the “nitroso–redox” balance that can be disrupted in patients with CHF. Clinical

Hypertension. Generally not first line but useful in hypertensive urgency (because of the rapid onset of action when given IV), pregnancy (excellent safety record), and refractory hypertension. CHF: given with nitrates to ↓ afterload and help restore nitroso–redox balance. Often used in patients with renal failure who cannot tolerate ACEI. ↓ mortality when added to standard therapy (ACEI/ARB and β-blockers) in black patients with advanced CHF (who appear to have lower levels of NO and less activation of the renin–angiotensin system than white patients).

Side Effects Headache, nausea, sweating, and flushing. Self-limited lupus-like syndrome in 10%. Reflex ↑ HR, contractility, renin activity, and fluid retention in response to vasodilation, so often given with β-blocker, diuretic, or both. Metabolism PO or IV. Hepatic acetylation. Toxicity more likely in patients who are slow acetylators. Notes

MINOXIDIL (Loniten, Rogaine) causes vasodilation by opening ATP-sensitive K+ channels → membrane hyperpolarization and relaxation of arteriolar smooth muscle. Best known for its side effect, hypertrichosis, and its topical use to treat early male pattern baldness. DIAZOXIDE (Hyperstat, Proglycem) also opens K+ channels on vascular smooth muscle and pancreatic β cells, the latter effect leading to inhibition of insulin secretion and its use for refractory

hypoglycemia (in contrast to sulfonylureas, which inhibit the K+ channel).

CV HYDRALAZINE Minoxidil Diazoxide

CAPTOPRIL (Capoten)

ACE inhibitor

3-5

Mechanism Reversibly inhibits angiotensin converting enzyme (ACE), which catalyzes angiotensin I (ATI) → angiotensin II (ATII), thereby blocking the renin–angiotensin–aldosterone (RAA) axis. Renin is secreted by the juxtaglomerular apparatus in the kidney with ↓ renal arteriole pressure, ↓ Na+ delivery, or sympathetic stimulation. Renin cleaves angiotensinogen, releasing ATI. ATI is converted to ATII by ACE, a protease expressed on endothelial cells in pulmonary and other vascular beds. ATII is a potent vasoconstrictor and stimulates renal Na+ reabsorption, adrenal aldosterone secretion, and posterior pituitary ADH secretion. ATII also directly causes cardiac hypertrophy and fibrosis. ACE inhibitors (ACEIs) also prevent ACE from inactivating bradykinin, an endogenous vasodilator. Effect of ACEIs is arteriolar and venous vasodilation. Aldosterone secretion minimally affected due to non-RAA pathways. Clinical

Hypertension. Heart failure with reduced ejection fraction (HFrEF): ↓ afterload, ↓ adverse LV remodeling, ↓ symptoms, ↑ survival. ↓ Proteinuria and progression of renal disease in diabetic and nondiabetic nephropathy. Ischemic heart disease: ↓ mortality, MI, stroke, CHF, incidence of diabetes.

Side Effects Hypotension, especially in Na+-depleted patient. “Captopril cough” (~5%): upper airway irritation, possibly related to ↓ bradykinin clearance. Angioedema, which may also be due to ↓ bradykinin clearance. Acute renal failure and hyperkalemia: ATII constricts glomerular efferent arterioles > afferents, thereby allowing GFR to be maintained in low-volume states. Blockade of ATII production may lead to decompensation and renal insufficiency. Contraindic. Renal insufficiency. Bilateral renal artery stenosis. Pregnancy (ACEI

are fetopathic). Notes

See the reverse side for once-daily ACEI (captopril needs to be taken three times a day).

CV CAPTOPRIL Enalapril (Vasotec) Lisinopril (Prinivil, Zestril) Cilazapril (Dynorm) Benazepril (Lotensin) Fosinopril (Monopril) Moexipril (Univasc) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik)

LOSARTAN (Cozaar)

angiotensin receptor blocker

3-6

Mechanism Competitive angiotensin II subtype 1 (AT1) receptor blocker (ARB). These receptors are located on vascular smooth muscle, and stimulation results in vasoconstriction (via Gq protein-coupled activation of phospholipase C → ↑ IP3 and DAG → mobilization of sequestered Ca2+). Like ACEI, ARBs cause arteriolar and venous vasodilation. ARBs mechanism of action leads to two important differences compared to ACEI: 1. ARBs can block both ACE- and non–ACE-mediated (e.g., heart chymase mediated) ATII synthesis. 2. ARBs do not impair bradykinin clearance. Clinical

Hypertension. Heart failure (HF) with reduced ejection fraction. Comparable to ACEI (↓ HF symptoms, ↑ survival). ↓ Proteinuria and progression of renal disease in diabetic and nondiabetic nephropathy.

Side Effects Hypotension, especially in Na+-depleted patient. Acute renal failure and hyperkalemia (see captopril). Unlike ACEIs, rarely associated with cough or angioedema. Contraindic. Renal insufficiency. Bilateral renal artery stenosis. Pregnancy. Notes

Other similar ARBs include AZILSARTAN (Edarbi), CANDESARTAN (Atacand), EPROSARTAN (Teveten), IRBESARTAN (Avapro), OLMESARTAN (Benicar), TELMISARTAN (Micardis), and VALSARTAN (Diovan). AT2 receptors mediate vasodilation; drugs targeting these receptors remain under study. Synthetic ATII (Giapreza) is approved as a vasoconstrictor in distributive shock, but thrombosis is a side effect and thus should be given with an antithrombotic as prophylaxis.

CV LOSARTAN Azilsartan Candesartan Eprosartan Irbesartan Olmesartan Telmisartan Valsartan Angiotensin II

SACUBITRIL/VALSARTAN

ARNI

3-7

Mechanism Atrial (ANP) and B-type natriuretic peptides (BNP) induce vasodilation, natriuresis, and diuresis but are degraded by neutral endopeptidase (NEP, aka neprilysin). NEP also degrades other vasoactive peptides including the vasodilator bradykinin (which also ↑ prostaglandin levels) and the vasoconstrictor angiotensin II (ATII). Pure NEP inhibitors had only modest beneficial effects in HTN & CHF because of the counteracting effect of ↑ ANP & BNP and ↑ ATII. Combining an ACEI with an NEP inhibitor led to a better antihypertensive effect than either alone, but inhibition of two enzymes that degraded bradykinin led to an elevated risk of angioedema. Combining an ARB with an NEP inhibitor (“angiotensin receptorneprilysin inhibitor” or ARNI) solved these issues. The results are arteriolar & venous vasodilation and natriuresis. Clinical

Heart failure with reduced ejection fraction. ↓ CV mortality and HF hospitalizations compared with ACEI, thus leading to ARNI being preferred over ACEI or ARB in patient with symptomatic HF despite being on an ACEI or ARB.

Side Effects Compared with ACEI, hypotension more common, but no ↑ risk of renal failure. Although rare, trend toward slightly more angioedema. Contraindic. History of angioedema. Pregnancy. Notes

The trade name for the combination is Entresto. Currently being studied in HF with preserved EF and in acute MI.

CV SACUBITRIL/VALSARTAN

ALISKIREN (Tekturna)

renin inhibitor

3-8

Mechanism Binds to and inhibits renin, thereby blocking the conversion of angiotensinogen to angiotensin and thus reduces levels of angiotensin II and aldosterone. There is a compensatory increase in circulating renin levels (as is also seen with ACEI and ARBs), but plasma renin activity is low (in contrast to what is seen with ACEI and ARBs). Clinical

Hypertension.

Side Effects Hypotension, especially in Na+-depleted patient. Hyperkalemia. Renin inhibition does not ↑ bradykinin levels; therefore, cough or angioedema is less likely to occur than with ACEI. Rash; gastrointestinal distress. Contraindic. Renal insufficiency. Pregnancy. Strong P-glycoprotein (P-gp) inhibitors such as cyclosporine, as they lead to ↑ drug levels. Metabolism CYP3A4 and P-gp. Notes

CV ALISKIREN

NIFEDIPINE (Procardia, Adalat)

calcium channel blocker

3-9

Mechanism A dihydropyridine calcium channel blocker (CCB) that binds to L-type Ca2+ channels (long-lasting, voltage-dependent, high-conductance channels), inhibiting inward movement of Ca2+. L-type Ca2+ channels are encoded by a single gene that undergoes alternative splicing to the Cav1.2a variant (encodes channels found on cardiac myocytes and conductive tissue) and the Cav1.2b variant (encodes channels found on vascular smooth muscle). Dihydropyridine CCBs show relative selectivity for channels encoded by the Cav1.2b variant and thus act predominantly on vascular smooth muscle → peripheral arteriolar vasodilation. May trigger compensatory reflex tachycardia. At high doses, can act on cardiac myocytes and cause ↓ inotropy. Clinical

Hypertension. Primary pulmonary hypertension. Relief of vasospasm in Prinzmetal angina and Raynaud phenomenon. Ischemic heart disease (long-acting preparations only): antianginal effect as a result of coronary vasodilation (↑ myocardial oxygen supply) and ↓ BP (↓ myocardial oxygen demand).

Side Effects Hypotension, CHF, flushing, headaches, dizziness, peripheral edema. Avoid short-acting CCB in CAD because of risk of reflex tachycardia → angina.

Notes

AMLODIPINE (Norvasc), FELODIPINE (Plendil), ISRADIPINE (DynaCirc), and NISOLDIPINE (Sular) are second-generation dihydropyridine CCBs that show even greater vascular smooth muscle selectivity. NICARDIPINE (Cardene) and CLEVIDIPINE (Cleviprex) can be given IV to treat hypertensive emergencies. NIMODIPINE (Nimotop) is a second-generation lipophilic dihydropyridine CCB that is used after subarachnoid hemorrhages to ↓ risk of vasospasm in the cerebral vasculature.

CV NIFEDIPINE Amlodipine Felodipine Isradipine Nisoldipine Nicardipine Clevidipine Nimodipine

CALCIUM CHANNEL BLOCKERS Class

Prototype

Peripheral Coronary ↓ ↓ SA node ↓ AV vasodilation vasodilation Inotropy automaticity conduction

1st-gen Nifedipine DHP

+++

+++

+

+

0

2ndAmlodipine gen DHP

+++

+++

0

+

0

++

++

++

+++

++

+

++

+++

+++

+++

Diltiazem NonDHP Verapamil DHP, dihydropyridine.

VERAPAMIL (Calan, Isoptin, Verelan)

calcium channel blocker

310

Mechanism A nondihydropyridine calcium channel blocker (CCB) that binds to Ltype Ca2+ channels (“long-lasting,” voltage-dependent, highconductance channels), inhibiting inward movement of Ca2+ and decreasing the rate of recovery of these channels. Unlike dihydropyridine CCB, verapamil binds to both the a & b channel variants (see nifedipine) and thus induces ↓ HR and ↓ inotropy, coronary vasodilation, and mild peripheral arteriolar vasodilation. Class IV antiarrhythmic: slows conduction at the SA and AV nodes (the two locations where impulses depend on Ca2+ for their action potentials); ↓ phase 4 slope, ↓ the rate of the rise of phase 0 slope (the action potential), and ↑ refractoriness. Clinical

Hypertension. Supraventricular tachycardias: terminate PSVT; rate control of AF, AFL. Ischemic heart disease: ↓ HR (↓ myocardial O2 demand) ± coronary vasodilation (↑ myocardial O2 supply) → ↓ angina. Relief of vasospasm in Prinzmetal angina. Hypertrophic cardiomyopathy (↓ outflow tract obstruction).

Side Effects Heart block, bradycardia, CHF (avoid in patients with known CHF), edema. Constipation (↓ activity of GI smooth muscle). P-gp inhibitor. ↑ Serum levels of digoxin (P-gp–mediated renal tubular excretion). Notes

DILTIAZEM (Cardizem) is a CCB that is similar to verapamil but causes less coronary vasodilation and less negative inotropy.

CV VERAPAMIL Diltiazem

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

CALCIUM CHANNEL BLOCKERS Class

Peripheral Coronary ↓ ↓ SA node ↓ AV Prototype vasodilation vasodilation Inotropy automaticity conduction

1st-gen Nifedipine DHP

+++

+++

+

+

0

2ndAmlodipine gen DHP

+++

+++

0

+

0

Diltiazem

++

++

++

+++

++

Verapamil

+

++

+++

+++

+++

NonDHP

DHP, dihydropyridine.

RANOLAZINE (Ranexa)

anti-anginal

311

Mechanism Reduces diastolic tension and therefore myocardial ischemia by inhibiting late sodium current (INa). This current is caused by the influx of Na+ during the plateau phase of the action potential through voltage-gated channels that fail to inactivate immediately after initial depolarization and remain open for several hundred milliseconds. Normally, late INa constitutes inactivated > resting channels), called “use dependence.” Clinical

Emergent treatment of wide-complex tachycardias of unknown etiology. Maintenance of sinus rhythm in patients with AF, AFL, PSVT, but now used less frequently.

Side Effects ↑ QT interval and potentially proarrhythmic (causing torsades de pointes). Lupus-like syndrome (arthritis, pleurisy, pericarditis, ⊕ ANA) without vasculitis. Hypotension (seen with IV use; caused by ganglionic blockade). Metabolism PO, IV. Metabolized by N-acetylation. Slow acetylators are more likely to develop lupus-like syndrome. Major metabolite, N-acetyl procainamide, lacks Na+ blockade, but ↑ QT. Notes

QUINIDINE (Quinaglute, Quinidex), a diastereomer of quinine, is the active substance in the bark of the cinchona plant, a treatment in the 18th century for palpitations, and was the first class IA antiarrhythmic. It has moderate anticholinergic effects, which can cause ↑ AV conduction in the setting of AF or AFL, and αadrenergic blocking effects, which can cause hypotension. Side effects include tinnitus, hemolytic anemia, and thrombocytopenia. Rarely used nowadays. DISOPYRAMIDE (Norpace) is another similar class IA antiarrhythmic and has marked anticholinergic and negative inotropic properties, the latter property making it a useful

antiarrhythmic in patients with hypertrophic cardiomyopathy.

CV PROCAINAMIDE Quinidine Disopyramide

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

LIDOCAINE (Xylocaine)

antiarrhythmic

323

Mechanism Class IB antiarrhythmic: mild Na+ channel blockade. Purkinje cells: mild iNa channel blockade, depressing phase 0 depolarization, ↓ conduction velocity; shortens repolarization. Decreases the slope of the normal phase 4 depolarization of pacemaker cells and raises the threshold, thereby decreasing pacemaker activity. Lidocaine blocks activated and inactivated, but not resting, channels. In normal myocardium, Na+ channels return to their resting state during diastole and rapidly become drug free. When the resting membrane potential is increased (e.g., ischemia) or when the frequency of excitation is increased (e.g., arrhythmias), Na+ channels tend to stay in their inactivated state and therefore remain blocked, giving lidocaine a preferential effect on arrhythmogenic tissue. Clinical

Treatment of acute ventricular arrhythmias caused by myocardial ischemia, cardiac surgery, or digoxin. Local anesthetic.

Side Effects CNS: paresthesias, tremor, nausea, slurred speech, agitation, seizures. ↓ Cardiac contractility (usually mild). Contraindic. Wolff-Parkinson-White syndrome (can facilitate conduction down the bypass tract), severe heart block. Metabolism IV, IM. Notes

MEXILETINE (Mexitil) is a similar agent that can be given PO.

CV LIDOCAINE Mexiletine

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

FLECAINIDE (Tambocor)

antiarrhythmic

324

Mechanism Class IC antiarrhythmic: marked Na+ channel blockade. Purkinje cells: marked iNa channel blockade, depressing phase 0 depolarization, ↓ conduction velocity. Essentially no effect on repolarization or refractory period, except at AV node and accessory conduction pathways. Pacemaker cells: ↓ slope of phase 4, ↑ threshold for depolarization. Clinical

Reserved for supraventricular arrhythmias (e.g., AF, WolffParkinson-White syndrome) in patients with structurally normal hearts.

Side Effects Proarrhythmic effects: ↑ mortality in patients with underlying structural heart disease. Contraindic. Preexisting second- or third-degree AV block or bifascicular block. Structural heart disease (e.g., known CAD, prior MI, cardiomyopathy). Pacemakers: may ↓ ability of pacemaker to capture. Notes

PROPAFENONE (Rythmol) is a class IC antiarrhythmic that also has some weak β-blocker (class II) activity. Used for supraventricular arrhythmias. Side effects include development of a metallic taste and constipation.

CV FLECAINIDE Propafenone

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

AMIODARONE (Cordarone)

antiarrhythmic

325

Mechanism Primarily a class III antiarrhythmic: K+ channel blocker prolonging repolarization. Also exerts actions that fall into each of the other three classes: Na+ channel blocker (class I), β-blocker (class II), and Ca2+ channel blocker (class IV). Also a vasodilator (secondary to α-blockade and calcium channel blockade) and a negative inotropic agent (secondary to β-blockade and calcium channel blockade). Clinical

Ventricular arrhythmias: drug of choice to treat VT/VF. Although can be used to prevent ventricular arrhythmias, implantable cardiac defibrillators (ICDs) have emerged as treatment of choice. Atrial fibrillation: most efficacious drug in maintaining sinus rhythm in patients with paroxysmal AF. Side effects limit enthusiasm for long-term use.

Side Effects ↑ QT interval, but unlike other agents that ↑ QT interval, torsades de pointes is uncommon. Thyroid dysfunction (hyperthyroidism and hypothyroidism, 5%): related to the iodine moiety. ↑ Serum transaminases are common, but clinically significant hepatic injury is rare. Pulmonary fibrosis (10% to 15%). Microcrystalline deposits in cornea and skin, giving patient a slate gray appearance (~5%). Cutaneous photosensitivity (25%). Metabolism IV and PO.

Notes

heart failure.

DRONEDARONE (Multaq) is a non–iodine-containing oral derivative of amiodarone used for chronic treatment of patients with atrial fibrillation. It has a better side effect profile than amiodarone but is contraindicated in patients with decompensated or severe

CV AMIODARONE Dronedarone

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

IBUTILIDE (Corvert)

antiarrhythmic

326

Mechanism Class III antiarrhythmic: K+ channel blockade. Purkinje cells: potent iKr channel blockade, prolonging repolarization. Clinical

Pharmacologic cardioversion of atrial fibrillation or flutter.

Side Effects ↑QT interval. Torsades de pointes: polymorphic VT (“twisting of the points,” i.e., the QRS axis) in patients with a prolonged QT interval. Metabolism IV. Interactions Concomitant use of other medications that prolong the QT interval (e.g., tricyclic antidepressants and phenothiazines) should be avoided. Notes

DOFETILIDE (Tikosyn) is a similar class III antiarrhythmic that can be given PO to aid pharmacologic cardioversion of atrial fibrillation or flutter. Although a PO medication, because of the risk of torsades de pointes, therapy should be initiated in the hospital. As with ibutilide, concomitant use of other medications that prolong the QT interval should be avoided. SOTALOL (Betapace) is a class III antiarrhythmic that also has some nonselective β-blocker (class II) activity. It is used to maintain sinus rhythm in patients with a history of atrial fibrillation and as a second-line agent for ventricular arrhythmias.

CV IBUTILIDE Dofetilide Sotalol

(Adapted from Lilly LS, ed. Pathophysiology of Heart Disease, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006.)

IVABRADINE (Corlanor)

antiarrhythmic

327

Mechanism Blocks If, the so-called “funny channel.” These channels are highly expressed in the SA node (and also in the AV node and Purkinje fibers). The ion channel lets in both sodium & potassium upon hyperpolarization. At the end of an SA node action potential, the membrane repolarization triggers activation of If, which then supplies an inward current that ultimately leads to SA node depolarization and thus sets the cardiac rate. Thus, blockade of this channel reduces HR without affecting inotropy or vascular tone. Clinical

Patients with heart failure with reduced ejection fraction who remain symptomatic despite β-blockers (or are intolerant of β-blockers) and have an HR ≥70 bpm.

Side Effects Bradycardia, atrial fibrillation. Luminous phenomenon—visual disturbances seen in a minority of people taking this agent may be due to inhibition of a closely related channel found in the retina. Contraindic. HR > V1 receptors. It is used to treat diabetes insipidus, mild hemophilia A (deficiency of coagulation factor VIII), and some types of von Willebrand disease. CONIVAPTAN (Vaprisol) is a V1 and V2 receptor antagonist used to treat euvolemic hyponatremia. TOLVAPTAN (Samsca) is a V2 selective antagonist used for the treatment of hyponatremia in congestive heart failure and in euvolemia.

ENDO VASOPRESSIN Desmopressin Conivaptan Tolvaptan

LEVOTHYROXINE (Synthroid)

thyroid hormone

515

Mechanism The main thyroid hormones are 3,5,3′,5′-tetraiodothyronine (thyroxine, T4) and 3,5,3′-triiodothyronine (T3). They are formed by the coupling of iodinated tyrosine residues. Levothyroxine is synthetic T4. Most circulating hormone is T4 (90%), which has a long half-life (1 week). In contrast, T3 has a shorter half-life (1 day) but is 4 times as potent. Most T4 gets deiodinated peripherally (primarily in the liver) to T3, and thus serves as a circulating reservoir for thyroid hormone activity. Thyroid hormone binds to thyroid receptors (TRα and TRβ), and the receptor–hormone complex binds to promoters of certain genes, thereby regulating transcription. Thyroid receptors are ubiquitous, and thyroid hormone–receptor complexes typically upregulate metabolism and energy expenditure by acting on key intermediary metabolic enzymes. Clinical

Replacement therapy for hypothyroidism (signs and symptoms of which include fatigue, weight gain, cold intolerance, bradycardia, and myxedema). Suppression of a nonautonomous thyroid nodule (exogenous thyroid hormone → ↓ TSH → ↓ growth of the nodule).

Side Effects Excessive doses can cause hyperthyroidism (signs and symptoms of which include restlessness, tachycardia, atrial fibrillation, weight loss, and heat intolerance). Notes

LIOTHYRONINE (Cytomel) is synthetic T3. The shorter half-life makes it a less attractive method of replacement therapy. It is, however, occasionally used in severely ill hypothyroid patients.

ENDO LEVOTHYROXINE Liothyronine

METHIMAZOLE (Tapazole)

antithyroid

516

Mechanism Inhibits thyroid peroxidase, preventing incorporation of iodide ion into tyrosyl residues of thyroglobulin. This effect results in decreased production of triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine). Clinical

Hyperthyroidism. The antithyroid effect takes several weeks to manifest because drug blocks thyroid hormone synthesis but not release. The thyroid gland’s large stores of synthesized thyroid hormone (bound to thyroglobulin and stored as colloid) must be exhausted.

Side Effects Agranulocytosis, aplastic anemia, allergic reactions, skin rash. Contraindic. Pregnancy—associated with specific birth defects. Propylthiouracil (see below) may be preferred in this setting because it is more strongly protein bound and therefore less likely to cross the placenta. Notes

PROPYLTHIOURACIL (PTU) is similar but used only in limited circumstances because it causes hepatic toxicity or failure in about 0.1% of patients. In addition to use in pregnancy, PTU is sometimes used to treat severe thyroid storm because of its ability to block peripheral conversion of T4 → T3 (T3 is 4 times as potent as T4).

ENDO METHIMAZOLE Propylthiouracil

INSULIN

glucose-lowering

517

Mechanism Binds extracellular receptor that has tyrosine kinase activity. Effects vary with the target tissue. Broadly speaking, it is an anabolic hormone that signals a state of satiety. Liver: ↑ storage of glucose as glycogen in liver via induction of glucose kinase, phosphofructokinase, and glycogen synthase phosphatase; inhibits glycogenolysis; and inhibits gluconeogenesis via repression of pyruvate carboxylase, fructose bisphosphatase, and glucose 6-phosphatase. Muscle: glucose (and potassium) uptake; stimulates glycogen and protein synthesis. Adipose: facilitates triglyceride storage by activating plasma lipoprotein lipase, increasing glucose transport into cells, and decreasing intracellular lipolysis. Clinical

Glucose control in diabetics: required in type I and used in type II if inadequate control with oral agents. Treatment of stress-induced hyperglycemia (e.g., with surgery or infection). Administered with glucose to treat life-threatening hyperkalemia.

Side Effects Hypoglycemia. Weight gain. Metabolism Typically given SC. Given IV for diabetic ketoacidosis. Inhaled form recently approved.

Notes

PRAMLINTIDE (Symlin) is an analog of amylin, a peptide hormone cosecreted with insulin from pancreatic β cells. Pramlintide, like endogenous amylin, is thought to delay gastric emptying and inhibit secretion of glucagon. Given before a meal, it ↓ postprandial glucose in diabetics. Side effects include nausea, vomiting, anorexia, and headaches. GLUCAGON is a hormone that promotes catabolism of glycogen and gluconeogenesis. Used to treat hypoglycemia and for β-blocker overdose (↑ intracardiac cAMP even if β-receptors blocked).

ENDO INSULIN Pramlintide Glucagon

Type

Examples

Onset

Peak Duration Use

Rapid-acting

Aspart, glulisine, lispro

Immed. 1–2 h

slowly firing, myelinated > unmyelinated, and smaller > larger nerve fibers. Therefore, pain fibers blocked first. Clinical

Local anesthetic for minor surgical procedures. Spinal and epidural anesthesia. Often given with an α1-adrenoceptor agonist (e.g., epinephrine) to increase the drug’s duration of action (vasoconstriction limits removal and metabolism of the drug).

Side Effects CNS: restlessness, paresthesias, tinnitus, tremors, convulsions. Cardiac: bradycardia, heart block, hypotension. Metabolism Ester-based local anesthetics are rapidly metabolized by plasma cholinesterase. Amide-based anesthetics are hydrolyzed in the liver and tend to have longer half-lives. Notes

ARTICAINE (Septocaine) and CHLOROPROCAINE (Nesacaine) are short-duration anesthetics. MEPIVACAINE (Carbocaine), PRILOCAINE (Citanest), and lidocaine are medium-duration anesthetics. BUPIVACAINE (Marcaine) and ROPIVACAINE (Naropin) are long-duration anesthetics. BENZOCAINE (Orajel), DIBUCAINE (Nupercainal), TETRACAINE (Pontocaine), and cocaine are topical anesthetics.

CNS PROCAINE Articaine Chloroprocaine Mepivacaine Prilocaine Bupivacaine Ropivacaine Benzocaine Dibucaine Tetracaine

LOCAL ANESTHETICS Amide

Ester

Short acting

ARTICAINE (Septocaine) PROCAINE (Novocaine) CHLOROPROCAINE (Nesacaine)

Medium acting

MEPIVACAINE (Carbocaine) PRILOCAINE (Citanest) LIDOCAINE

Long acting

BUPIVACAINE (Marcaine)

Topical

ROPIVACAINE (Naropin) DIBUCAINE (Nupercainal)

BENZOCAINE (Orajel) TETRACAINE (Pontocaine)

MEMANTINE (Namenda)

glutamate antagonist

716

Mechanism Blocks N-methyl-d-aspartate (NMDA) subtype of glutamate receptors → ↓ decline in function in Alzheimer disease, which may be partly caused by overstimulation of the NMDA glutamate receptor and resultant excitotoxicity. Clinical

Treatment of moderate to severe Alzheimer dementia. Unlike cholinesterase inhibitors (see donepezil), memantine may be neuroprotective but not clear whether this can result in clinically meaningful changes in disease progression. Possible treatment for vascular dementia.

Side Effects Dizziness, confusion, hallucinations, agitation. Metabolism PO. Renally cleared. Notes

Memantine has been used in combination with cholinesterase inhibitors (see donepezil) for more effective treatment of Alzheimer dementia. Glutamate receptors are the major mediators of excitatory neurotransmission in the CNS. Ionotropic glutamate receptors are ion channels that mediate fast excitatory neurotransmission upon release of glutamate into a synapse. Metabotropic glutamate receptors relay excitatory glutamate signals via second messengers. The ionotropic glutamate receptors are further subdivided by their response to the selective agonists: NMDA, α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA), and kainic acid (KA). The NMDA subtypes conduct Ca++ >> Na+ and the AMPA and KA subtypes conduct Na+ >> Ca++.

CNS MEMANTINE

RILUZOLE (Rilutek)

glutamate antagonist

717

Mechanism Reduces glutamate-induced excitotoxicity through three proposed mechanisms: 1. Inhibition of glutamate release. 2. Noncompetitive block of NMDA subtype of glutamate receptor. 3. Direct inhibitory action on voltage-dependent sodium channels. Clinical

Amyotrophic lateral sclerosis (ALS)—demonstrated to have a beneficial effect on survival.

Side Effects Elevated LFTs (requires monitoring). Nausea, weakness, dizziness. Notes

EDARAVONE (Radicava) is the only other FDA-approved medication to extend survival in ALS patients. The mechanism of action is unknown, but it was designed as a free radical scavenger. It is also used to augment stroke recovery in Japan but is not approved for that indication in the United States.

CNS RILUZOLE Edaravone

SUMATRIPTAN (Imitrex)

serotonin agonist

718

Mechanism Selective serotonin agonist for 5-HT1B and 5-HT1D receptor subtypes → vasoconstriction of intracranial arteries (including arteriovenous anastomoses) and presynaptic suppression of release of vasoactive and nociceptive neuropeptides. These actions counter two components of the pathogenesis of migraines: 1. Trigeminal nerve activation → release of vasoactive neuropeptides at vascular terminals of trigeminal nerve → inflammation, perivascular edema, stretching and activation of nociceptive afferents. 2. Alterations in cerebral blood flow, including vasodilation of arteriovenous anastomoses → diversion of blood away from capillaries → cerebral ischemia. Clinical

Acute treatment of migraine with or without aura.

Side Effects Coronary artery vasospasm → angina, myocardial infarction, arrhythmias. Hypertensive episodes. Paresthesias, flushing, diaphoresis. 5-HT1 selectivity gives this drug a better side effect profile than the older ergot alkaloids (see ergotamine). Contraindic. Coronary, cerebrovascular, or peripheral vascular disease. Uncontrolled hypertension. Metabolism IM, PO, sublingual, intranasal. Metabolized by MAO-A. Interactions Should not be used within 14 days of treatment with MAO-A inhibitors. Notes

ALMOTRIPTAN (Axert), ELETRIPTAN (Relpax), FROVATRIPTAN (Frova), NARATRIPTAN (Amerge), RIZATRIPTAN (Maxalt), and ZOLMITRIPTAN (Zomig) are similar “triptans.” Other medications used to treat migraines include NSAID (see ibuprofen) for acute pain relief, metoclopramide for treatment of

severe nausea or vomiting (as ondansetron and other serotonin antagonists are contraindicated), and β-blockers, CCBs, TCAs, SSRIs, and antiepileptics for prophylaxis.

CNS SUMATRIPTAN Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Zolmitriptan

ERGOTAMINE (Ergomar)

serotonin agonist

719

Mechanism An ergot alkaloid, the drug is a partial agonist at 5-HT receptors, thereby causing intracranial vasoconstriction and suppression of meningeal nociceptive pathways (see sumatriptan). Drug is nonspecific; it interacts with multiple 5-HT receptors and α1adrenoceptors. Clinical

Historically used for acute treatment of migraine but largely replaced by triptans (see sumatriptan) which are more specific and cause fewer side effects.

Side Effects Nausea and vomiting caused by activation of CNS emesis centers (see ondansetron) make their use in migraines (symptoms of which include nausea and vomiting) problematic and have relegated ergot alkaloids to second-line therapy. Coronary artery vasospasm. Paresthesias, myalgias. Uterine smooth muscle contraction. Contraindic. Vascular disease, uncontrolled hypertension, and pregnancy.

Notes

derivative.

DIHYDROERGOTAMINE (Migranal) can be given intranasally, IM, and IV. METHYLERGONOVINE (Methergine) is an ergot alkaloid that causes marked uterine smooth muscle contraction and is used to control postpartum hemorrhage. Bromocriptine (see pramipexole), another ergot alkaloid, acts primarily as a dopamine agonist and is used for hyperprolactinemia and Parkinson disease. Lysergic acid diethylamide (LSD) is a hallucinogenic ergot

CNS ERGOTAMINE Dihydroergotamine Methylergonovine

BUSPIRONE (Buspar)

serotonin agonist

720

Mechanism Selective partial agonist of 5-HT1A serotonin receptors. Clinical

Anxiolytic without sedation. Cannot be used to treat benzodiazepine withdrawal.

Side Effects Tachycardia, palpitations, GI distress. Less abuse potential than benzodiazepines; no rebound anxiety or withdrawal symptoms with discontinuation. Contraindic. Hepatic or renal impairment. Metabolism PO. Hepatic oxidation to active metabolite. Interactions Use of MAO inhibitors may lead to hypertensive crisis. Concomitant consumption of grapefruit juice can lead to markedly increased levels of buspirone because of inhibition of CYP3A4. Notes

CNS BUSPIRONE

LORCASERIN (Belviq)

serotonin agonist

721

Mechanism An agonist of 5-HT2C serotonin receptors in the arcuate nucleus of the hypothalamus, activating the production of proopiomelanocortin (POMC). POMC is cleaved to many products, including α melanocyte-stimulating hormone (MSH), a potent signal of satiety. Of note, leptin also stimulates POMC neurons and inhibits neuropeptide Y (NPY) neurons, which promote hunger. Conversely, ghrelin, a hunger hormone secreted into the blood by cells of the GI, stimulates NPY neurons. Clinical

Weight loss (5% to 10%).

Side Effects Headache, dizziness, nausea, constipation; hypoglycemia in patients with diabetes. Unlike other weight loss drugs, has been shown to not increase the risk of major adverse cardiovascular events, valvulopathy or pulmonary hypertension. Metabolism PO. Hepatic metabolism. Interactions Avoid concomitant use of serotonergic drugs (e.g., SSRIs, triptans, bupropion, MAO inhibitors) as can trigger serotonin syndrome. Notes

Previous serotonin agonists were withdrawn because they caused valvulopathy and pulmonary hypertension. Several pharmacologic agents are indicated for weight loss: amphetamine-based (phentermine alone and with topiramate), serotonin agonists (lorcaserin), and GI lipase inhibitor (orlistat).

CNS LORCASERIN

ONDANSETRON (Zofran)

serotonin antagonist

722

Mechanism Selective serotonin antagonist that blocks 5-HT3 receptors in the medulla and GI tract. Emesis is controlled by the central pattern generator (CPG, previously called “vomiting center”) in the lateral reticular formation of the medulla. Sources of input include the nucleus tractus solitarius (NTS), the area postrema (AP), the vestibular apparatus, and visceral afferents. The neuropharmacology is incompletely understood but is divided into a peripheral pathway that is responsible for acute emesis and is signaled via dopamine and serotonin (5-HT3) receptors to the NTS and AP. A second pathway, the central pathway, is associated with delayed emesis (often due to chemotherapy) and is signaled via substance P agonism at NK1 receptors. Clinical

Potent antiemetic, particularly for chemotherapy-induced and postoperative nausea.

Side Effects Headache and constipation are most common. Extrapyramidal symptoms are extremely rare. Notes

DOLASETRON (Anzemet), GRANISETRON (Kytril), and PALONOSETRON (Aloxi) are other 5-HT3 antagonist antiemetics. The three major classes of antiemetics are the serotonin antagonists, NK1 antagonists (see aprepitant), and the dopamine antagonists (see prochlorperazine). Some antihistamines (e.g., diphenhydramine, promethazine, hydroxyzine) also are good antiemetics (probably because of a combination of H1 and cholinergic blockade).

CNS ONDANSETRON Dolasetron Granisetron Palonosetron

ALOSETRON (Lotronex)

serotonin antagonist

723

Mechanism Antagonist of 5-HT3 receptors in the GI tract, leading to ↓ motility, ↓ electrolyte secretion, ↑ fluid reabsorption, ↓ afferent pain neurotransmission. Clinical

Diarrhea-predominant irritable bowel syndrome (IBS) in women (see metabolism). Benefit likely related to countering of ↑ 5-HT– containing enterochromaffin cells and visceral hypersensitivity in these patients. Diarrhea from carcinoid syndrome.

Side Effects Constipation, toxic megacolon. Ischemic colitis, thought to be caused by suppression of intestinal relaxation → prolonged spasm and ischemia. This rare but severe adverse effect led to temporary withdrawal of this drug. Specialized physician certification, patient education, and a patient–physician contract are now required for use. Contraindic. Constipation (including constipation-predominant IBS), inflammatory bowel disease (ulcerative colitis and Crohn disease), and diverticulitis. Metabolism Lower plasma concentrations and less clinical efficacy are seen at equivalent doses in men. Notes

CNS ALOSETRON

For simplicity, molecular signaling downstream 5-HT receptors and all receptor subtypes are not shown.

FLUOXETINE (Prozac)

antidepressant

724

Mechanism Prototypical selective serotonin reuptake inhibitor (SSRI), which preferentially inhibit serotonin reuptake at the synaptic cleft and thereby potentiates serotonin neurotransmission. SSRIs have minimal antihistamine, antimuscarinic, and α1adrenoceptor blockade effects. Clinical effects are not seen for several weeks, suggesting that desensitization and downregulation of presynaptic inhibitory autoreceptors may explain the long-term effects. Clinical

Major depressive disorder (first line), bulimia, obsessive-compulsive disorder, anxiety, panic disorder, premenstrual dysphoric disorder.

Side Effects Receptor selectivity results in fewer side effects from SSRIs than from TCAs. ↑ Stimulation of 5-HT3 receptors is thought to lead to GI distress, sexual dysfunction, and ↓ libido. Suicidal ideation in adolescents and young adults. Interactions Serotonin syndrome (hyperthermia, muscle rigidity, changes in mental status, and hemodynamic instability) can occur when given with MAO inhibitors. Metabolism SSRIs inhibit CYP2D6, thereby altering metabolism of other drugs. Notes

PAROXETINE (Paxil), SERTRALINE (Zoloft), FLUVOXAMINE (Luvox), CITALOPRAM (Celexa), and ESCITALOPRAM (Lexapro) are other SSRIs. Antidepressants can be divided into five categories: SSRIs, serotoninnorepinephrine reuptake inhibitors (see venlafaxine), atypicals (see nefazodone), tricyclics (see amitriptyline), and MAO inhibitors (see phenelzine).

CNS FLUOXETINE Paroxetine Sertraline Fluvoxamine Citalopram Escitalopram MECHANISM OF ACTION

Antidepressant class

5-HT NE reuptake reuptake inhibition inhibition Other

Side effect profile

SSRIs

+++

0/+

Minimal

SNRIs

++

+/++

Minimal

0 to ++

0/+

Variable 5Some anti-H1 HT1 (sedation) and agonism mild anti-α1 and 5-HT2 (hypotension) antagonism

—

—

Variable effects on 5-HT, NE, DA

Serotonin modulators

Atypicals Others

Tricyclics

+ to +++

+ to +++

Variable

Anti-H1 (sedation) Anti-M1 (blurred vision) Anti-α1 (hypotension)

MAO inhibitors

—

—

MAO inhibition

Mild anti-α1 (hypotension)

VENLAFAXINE (Effexor)

antidepressant

725

Mechanism Prototypical serotonin-norepinephrine reuptake inhibitor (SNRI), which inhibits serotonin and norepinephrine reuptake at the synaptic cleft and thereby potentiate their neurotransmission. Inhibits serotonin uptake more so than norepinephrine. SNRIs have minimal antihistamine, antimuscarinic, and α1adrenoceptor blockade effects. Clinical

Major depressive disorder, anxiety, panic disorder.

Side Effects Stimulation of 5-HT3 receptors is thought to lead to GI distress, sexual dysfunction, and ↓ libido. Suicidal ideation in adolescents and young adults. Interactions Serotonin syndrome (hyperthermia, muscle rigidity, changes in mental status, and hemodynamic instability) can occur when given with MAO inhibitors. Notes

Other SNRIs include: DESVENLAFAXINE (Pristiq) and DULOXETINE (Cymbalta), which, like venlafaxine, inhibit 5-HT reuptake more so than NE; MILNACIPRAN (Savella), which inhibits reuptake of 5-HT and NE roughly equally, and LEVOMILNACIPRAN (Fetzima), which inhibits NE reuptake more than 5-HT. However, relative effects on 5-HT and NE for these drugs vary based on dose. Antidepressants can be divided into five categories: selective serotonin reuptake inhibitors (see fluoxetine), SNRIs, atypicals (see nefazodone), tricyclics (see amitriptyline), and MAO inhibitors (see phenelzine).

CNS VENLAFAXINE Desvenlafaxine Duloxetine Milnacipran Levomilnacipran MECHANISM OF ACTION

Antidepressant class

5-HT NE reuptake reuptake inhibition inhibition Other

Side effect profile

SSRIs

+++

0/+

Minimal

SNRIs

++

+/++

Minimal

0 to ++

0/+

Variable 5Some anti-H1 HT1 (sedation) and agonism mild anti-α1 and 5-HT2 (hypotension) antagonism

—

—

Variable effects on 5-HT, NE, DA

Serotonin modulators

Atypicals Others

Tricyclics

MAO inhibitors

+ to +++

+ to +++

—

—

Variable

Anti-H1 (sedation) Anti-M1 (blurred vision) Anti-α1 (hypotension) MAO

Mild anti-α1

inhibition

(hypotension)

NEFAZODONE (Serzone)

antidepressant

726

Mechanism An atypical antidepressant that has minimal amine reuptake effects. Nefazodone modulates serotoninergic neurotransmission, specifically being a 5-HT2 antagonist, which leads to ↑ 5-HT1 activity, and a mild 5-HT and NE reuptake inhibitor. Clinical

Major depressive disorder.

Side Effects Sedation (because of H1 blockade). GI distress. Rare reports of hepatic failure.

Notes

TRAZODONE (Desyrel) is similar to nefazodone but more sedating and can cause priapism. VILAZODONE (Viibryd) and VORTIOXETINE (Brintellix) are serotonin modulators that inhibit 5-HT reuptake (like SSRIs), with vilazodone also being a 5-HT1A partial agonist and vortioxetine also being a 5-HT1A agonist, a 5-HT1B partial agonist, and a 5-HT3 antagonist. MIRTAZAPINE (Remeron) is an atypical antidepressant that has minimal amine reuptake effects but antagonizes postsynaptic 5-HT2 and 5-HT3 receptors. Also blocks presynaptic α2-adrenoreceptors on noradrenergic and serotonergic neurons → ↑ NE and 5-HT release. Net effect is ↑ 5-HT1 activity. BUPROPION (Wellbutrin or Zyban) is another atypical antidepressant that blocks dopamine uptake (and to a very minor extent, NE and 5-HT uptake) and is also used to facilitate smoking cessation. A rare but serious side effect is seizure. Antidepressants can be divided into five categories: SSRIs (see fluoxetine), serotonin-norepinephrine reuptake inhibitors (see venlafaxine), atypicals, tricyclics (see amitriptyline), and MAO inhibitors (see phenelzine).

CNS NEFAZODONE Trazodone Vilazodone Vortioxetine Mirtazapine Bupropion Mechanism of Action

Antidepressant class

5-HT NE reuptake reuptake inhibition inhibition Other

Side effect profile

SSRIs

+++

0/+

Minimal

SNRIs

++

+/++

Minimal

0 to ++

0/+

Variable 5Some anti-H1 HT1 (sedation) and agonism mild anti-α1 and 5-HT2 (hypotension) antagonism

—

—

Variable effects on 5-HT, NE, DA

Serotonin modulators

Atypicals Others

Tricyclics

+ to +++

+ to +++

Variable

Anti-H1 (sedation) Anti-M1 (blurred vision) Anti-α1 (hypotension)

MAO inhibitors

—

—

MAO inhibition

Mild anti-α1 (hypotension)

AMITRIPTYLINE (Elavil)

antidepressant

727

Mechanism Prototypical tricyclic antidepressant (TCA) that inhibits reuptake of norepinephrine (NE) and serotonin (5-HT), thereby potentiating their neurotransmission. Clinical effects are not seen for several weeks, suggesting that desensitization and downregulation of presynaptic inhibitory autoreceptors may explain the long-term effects. Clinical

Major depressive disorder. Neuropathic and chronic pain, migraine prophylaxis. ADHD in children.

Side Effects Antihistamine: sedation, weight gain; secondary amines cause less sedation than tertiary amines. Anticholinergic: blurred vision, dry mouth, urinary retention, constipation, agitation, tachycardia, sweating. α1-Adrenoceptor blockade: postural hypotension, tachycardia. Arrhythmias caused by class IA antiarrhythmic properties (Na+ channel blockade). Overdose leads to coma, metabolic acidosis, hyperpyrexia, and cardiac arrhythmias. Notes

TCAs may be subdivided into tertiary amines and secondary amines (often demethylated metabolites of tertiary amines). Other tertiary amines: IMIPRAMINE (Tofranil), CLOMIPRAMINE (Anafranil), and DOXEPIN (Sinequan). Secondary amines inhibit NE over 5-HT uptake; also milder side effects because of less histamine, cholinergic, and α1 blockade. Secondary amines: DESIPRAMINE (Norpramin), NORTRIPTYLINE (Aventyl), PROTRIPTYLINE (Vivactil), AMOXAPINE (Asendin), & MAPROTILINE (Ludiomil). TRIMIPRAMINE (Surmontil) is classified chemically as a TCA but does not block amine reuptake. Instead it antagonizes 5-HT2A and α1 adrenergic receptors. Antidepressants can be divided into five categories: selective serotonin reuptake inhibitors (see fluoxetine), serotonin-norepinephrine

reuptake inhibitors (see venlafaxine), atypicals (see nefazodone), tricyclics, and MAO inhibitors (see phenelzine).

CNS AMITRIPTYLINE Imipramine Clomipramine Doxepin Desipramine Nortriptyline Protriptyline Amoxapine Maprotiline Trimipramine MECHANISM OF ACTION

Antidepressant class

5-HT NE reuptake reuptake inhibition inhibition Other

Side effect profile

SSRIs

+++

0/+

Minimal

SNRIs

++

+/++

Minimal

0 to ++

0/+

Variable 5Some anti-H1 HT1 (sedation) and agonism mild anti-α1 and 5-HT2 (hypotension) antagonism

—

—

Variable effects on 5-HT, NE, DA

Serotonin modulators

Atypicals Others

Variable

Anti-H1 (sedation)

Tricyclics

MAO inhibitors

+ to +++

+ to +++

—

—

Anti-M1 (blurred vision) Anti-α1 (hypotension) MAO inhibition

Mild anti-α1 (hypotension)

PHENELZINE (Nardil)

antidepressant

728

Mechanism Prototypical monoamine oxidase (MAO) inhibitor. MAO is a mitochondrial enzyme that metabolizes catecholamines; can be subdivided into MAO-A (selective for 5-HT, epinephrine, NE, and tyramine) and MAO-B (selective for DA). Inhibition of these enzymes by MAO inhibitors results in buildup of amine levels in the brain. Clinical

Major depressive disorder (third-line agents).

Side Effects Orthostatic hypotension, impotence. Hepatotoxicity. Hypertensive reactions, especially in conjunction with sympathomimetics or foods containing tyramine (e.g., aged cheeses, smoked meats, red wine), which is usually metabolized by MAO. In the absence of MAO activity, tyramine accumulates and acts as an indirect sympathomimetic (i.e., it causes release of NE from sympathetic nerve terminals) and can trigger a hypertensive crisis. Interactions Can trigger serotonin syndrome (hyperthermia, muscle rigidity, changes in mental status, and hemodynamic instability) in patients taking SSRIs, amphetamines, or meperidine. Notes

TRANYLCYPROMINE (Parnate) is a reversible MAO inhibitor, and ISOCARBOXAZID (Marplan) is an irreversible MAO inhibitor. MAO inhibitors selective for MAO-B (e.g., selegiline) are used in the treatment of Parkinson disease. Antidepressants can be divided into five categories: SSRIs (see fluoxetine), serotonin-norepinephrine reuptake inhibitors (see venlafaxine), atypicals (see nefazodone), tricyclics (see amitriptyline), and MAO inhibitors.

CNS PHENELZINE Tranylcypromine Isocarboxazid MECHANISM OF ACTION

Antidepressant class

5-HT NE reuptake reuptake inhibition inhibition Other

Side effect profile

SSRIs

+++

0/+

Minimal

SNRIs

++

+/++

Minimal

0 to ++

0/+

Variable 5Some anti-H1 HT1 (sedation) and agonism mild anti-α1 and 5-HT2 (hypotension) antagonism

—

—

Variable effects on 5-HT, NE, DA

Serotonin modulators

Atypicals Others

Tricyclics

MAO inhibitors

+ to +++

+ to +++

—

—

Variable

Anti-H1 (sedation) Anti-M1 (blurred vision) Anti-α1 (hypotension) MAO inhibition

Mild anti-α1 (hypotension)

LEVODOPA/CARBIDOPA (Sinemet)

dopamine agonist

729

Mechanism Levodopa is a DA precursor that crosses the BBB and is converted by dopa decarboxylase into DA. Carbidopa, a peripheral dopa decarboxylase inhibitor (it does not cross the BBB), is given in combination with levodopa to maximize delivery of the prodrug to the CNS. Normally, dopaminergic neurons arising in the substantia nigra inhibit GABAergic neurons in the corpus striatum. In Parkinson disease, dopaminergic neurons are lost, releasing the inhibition of GABAergic neurons. Restoration of dopaminergic neurotransmission can alleviate the symptoms. Clinical

Parkinson disease.

Side Effects Dyskinesias (particularly choreoathetosis). Over time, patients have a diminishing response to levodopa. Higher doses can improve response but often lead to dyskinesias, with patients rapidly cycling between being “on” (regaining movement but dyskinetic) and “off” (bradykinetic). GI: anorexia, nausea, vomiting. CV: tachycardia, postural hypotension, arrhythmias. Behavioral: anxiety, agitation, confusion, delusions, hallucinations, depression. Notes

ENTACAPONE (Comtan) and TOLCAPONE (Tasmar) are inhibitors of catechol O-methyl transferase (COMT), an important enzyme for degradation of biogenic amines such as dopamine. Given in conjunction with levodopa to inhibit its degradation and prolong its effects. SELEGILINE (Deprenyl) and RASAGILINE (Azilect) inhibit MAO-B, a mitochondrial enzyme that selectively metabolizes dopamine, and thus are also used to treat Parkinson disease. Other treatments for Parkinson disease include D2-agonists (see pramipexole); anticholinergics (see benztropine), which counterbalance the loss of dopaminergic input to the corpus

striatum; and amantadine, which has modest dopaminergic and anticholinergic properties.

CNS LEVODOPA/CARBIDOPA Entacapone Tolcapone Selegiline Rasagiline

PRAMIPEXOLE (Mirapex)

dopamine agonist

730

Mechanism Selective D2 and D3 receptor agonist. Normally, dopaminergic neurons arising in the substantia nigra inhibit GABAergic neurons in the corpus striatum. In Parkinson disease, dopaminergic neurons are lost, releasing the inhibition of GABAergic neurons. Restoration of dopaminergic neurotransmission alleviates symptoms. Clinical

Parkinson disease (first-line therapy).

Side Effects Nausea (as might be expected because dopamine (DA) antagonists are antiemetics), constipation, postural hypotension, somnolence. Compulsive behavior manifests with long-term use (e.g., gambling).

Notes

ROPINIROLE (Requip) and ROTIGOTINE (Neupro) are similar compounds. Former also used for restless legs syndrome (lower extremity dysesthesias); latter given as transdermal patch (allowing continuous DA agonism). BROMOCRIPTINE (Parlodel) and CABERGOLINE (Dostinex) are ergot alkaloids (see ergotamine) that are D2 agonists. Used for hyperprolactinemia (DA is a physiologic inhibitor of prolactin secretion from the anterior pituitary) and rarely for Parkinson disease. Side effects include coronary vasospasm, postural hypotension, hallucinations, delirium, and pulmonary and retroperitoneal fibrosis. APOMORPHINE (Apokyn) is a DA agonist used to treat Parkinson disease. High affinity for D4 and moderate affinity for D2, D3, and D5 receptors and α-adrenoceptors and highly emetogenic. Unfortunately, coadministration of 5-HT blockers (see ondansetron) is contraindicated because of risk of hypotension. Other treatments for Parkinson disease include DA precursors and degradation inhibitors (see levodopa/carbidopa), anticholinergics (see benztropine), and amantadine, which has modest dopaminergic and anticholinergic properties.

CNS PRAMIPEXOLE Ropinirole Rotigotine Bromocriptine Cabergoline Apomorphine

PROCHLORPERAZINE (Compazine)

dopamine antagonist

731

Mechanism A D2 dopamine receptor antagonist that also has some anticholinergic and antihistamine effects. Emesis is controlled by the central pattern generator (CPG, previously called “vomiting center”) in the lateral reticular formation of the medulla. Sources of input include the nucleus tractus solitarius (NTS), the area postrema (AP), the vestibular apparatus, and visceral afferents. The neuropharmacology is incompletely understood but is divided into a peripheral pathway that is responsible for acute emesis and is signaled via dopamine and serotonin (5-HT3) receptors to the NTS and AP. A second pathway, the central pathway, is associated with delayed emesis (often due to chemotherapy) and is signaled via substance P agonism at NK1 receptors. Clinical

Antiemetic; motion sickness.

Side Effects Sedation. Extrapyramidal symptoms (parkinsonism, restlessness, acute dystonic reactions, and oculogyric crisis [eyes forced upwards due to dystonia]). Galactorrhea (caused by blockade of dopamine’s normal inhibition of prolactin secretion). Notes

DROPERIDOL (Inapsine) is a similar D2-antagonist antiemetic. METOCLOPRAMIDE (Reglan) and TRIMETHOBENZAMIDE (Tigan) are antiemetics that are D2 antagonists and weak 5-HT3 antagonists. Accelerate gastric emptying and used to treat gastroparesis. DRONABINOL (Marinol) is a marijuana derivative with antiemetic effects, perhaps via the NTS/AP. The three major classes of antiemetics are the serotonin antagonists (see ondansetron), NK1 antagonists (see aprepitant), and the dopamine antagonists. Some antihistamines (e.g., diphenhydramine, promethazine, hydroxyzine) also are good antiemetics (probably because of a combination of H1 and

cholinergic blockade).

CNS PROCHLORPERAZINE Droperidol Metoclopramide Trimethobenzamide Dronabinol

CHLORPROMAZINE (Thorazine)

antipsychotic

732

Mechanism The dopamine (DA) hypothesis of schizophrenia states that psychosis results from excess brain DA activity. Therefore, it was thought that blocking DA receptors, specifically D2 receptors in mesolimbic and mesocortical paths, should be efficacious. Chlorpromazine is a prototypical D2 receptor antagonist low-potency antipsychotic; its low affinity for D2 receptors minimizes extrapyramidal side effects, but the high doses required can inhibit other receptors. Clinical

Schizophrenia, particularly the “positive” symptoms of delusions, hallucinations, and hyperactivity. Also used for mania, schizoaffective disorder, Tourette syndrome, and suppression of hiccups. Antiemetic (see prochlorperazine); antipruritic for intractable itching (via H1 blockade).

Side Effects Cholinergic blockade → dry mouth, constipation, urinary retention, visual problems. α-Adrenergic blockade → postural hypotension, impotence, sedation. Histamine blockade → sedation. DA blockade (nigrostriatal) → extrapyramidal dysfunction: parkinsonism, akathisia, dystonia. Tardive dyskinesia (see haloperidol). Neuroleptic malignant syndrome: hyperpyrexia, catatonia, rigidity. DA blockade (tuberoinfundibular) → ↑ prolactin → amenorrhea– galactorrhea, infertility. Risk of arrhythmias and sudden cardiac death attributable to QT prolongation. Notes

LOXAPINE (Loxitane), MOLINDONE (Moban), and THIORIDAZINE (Mellaril) are other low-potency antipsychotics. Antipsychotics can be divided into three functional categories: low potency, high potency (see haloperidol), and atypicals (see olanzapine and aripiprazole).

CNS CHLORPROMAZINE Loxapine Molindone Thioridazine

ANTIPSYCHOTICS Antipsychotic

Class

Prototype

Low Chlorpromazine potency

Side effect profile

AntiD2

Extrapyramidal Antianti-D2 M1 (parkinsonism, (e.g., Anti– tardive blurred Anti-H1 5-HT2 dyskinesia) vision) (sedation)

+

0

+

+++

++

High Haloperidol potency

+++

0

+++

+

+

Atypicals Olanzapine

+

+++

+

0/+

++

+

0

++

SDAMs Aripiprazole

Partial Partial agonist agonist 5-HT1

HALOPERIDOL (Haldol)

antipsychotic

733

Mechanism High-potency dopamine (DA) blocker. See chlorpromazine for details of DA antagonists for treatment of schizophrenia. Highpotency agents have high affinity for the D2 dopamine receptor, which allows the use of low doses with minimal cross-reactivity at other receptors but which also leads to prominent antidopaminergic side effects. Clinical

Schizophrenia, particularly the “positive” symptoms of delusions, hallucinations, and hyperactivity. Mania, schizoaffective disorder, Tourette syndrome. Preferred over low-potency agents for treating delirium in the elderly (“sundowning”) because of low anticholinergic side effect profile.

Side Effects Relatively free of cholinergic, α-adrenergic, and histamine-blocking side effects. Side effects due to potent DA blockade (and, in the case of extrapyramidal side effects, lack of counterbalancing cholinergic blockade): DA blockade (nigrostriatal) → extrapyramidal dysfunction. parkinsonism, akathisia, dystonia. Tardive dyskinesia: a greatly feared, irreversible complication of long-term use characterized by oral–facial dyskinesias and widespread choreoathetosis or dystonia. Thought to result from compensatory ↑ in DA activity in extrapyramidal neural pathways. Neuroleptic malignant syndrome: hyperpyrexia, catatonia, rigidity. DA blockade (tuberoinfundibular) → ↑ prolactin → amenorrhea– galactorrhea, infertility. Risk of arrhythmias attributable to QT prolongation. Notes

FLUPHENAZINE (Prolixin), PERPHENAZINE (Trilafon), PIMOZIDE (Orap), THIOTHIXENE (Navane), and TRIFLUOPERAZINE (Stelazine) are other high-potency antipsychotics.

Antipsychotics can be divided into three functional categories: low potency (see chlorpromazine), high potency, and atypicals (see olanzapine and aripiprazole).

CNS HALOPERIDOL Fluphenazine Perphenazine Pimozide Thiothixene Trifluoperazine

ANTIPSYCHOTICS Antipsychotic

Class

Prototype

Low Chlorpromazine potency

Side effect profile

AntiD2

Extrapyramidal Antianti-D2 M1 (parkinsonism, (e.g., Anti– tardive blurred Anti-H1 5-HT2 dyskinesia) vision) (sedation)

+

0

+

+++

++

High Haloperidol potency

+++

0

+++

+

+

Atypicals Olanzapine

+

+++

+

0/+

++

+

0

++

SDAMs Aripiprazole

Partial Partial agonist agonist 5-HT1

OLANZAPINE (Zyprexa)

antipsychotic

734

Mechanism An atypical antipsychotic, these drugs have clinical efficacy out of proportion to their ability to block D2 receptors. Olanzapine may act via serotonin (5-HT2A) blockade, which may not only help with some of the “negative” symptoms of schizophrenia (see below) but also blunt some of the extrapyramidal side effects of D2 antagonism by disinhibiting nonmesolimbic dopaminergic transmission. Clinical

Schizophrenia, including both “positive” symptoms of delusions, hallucinations, and hyperactivity and “negative” symptoms of withdrawal and blunted emotions. Atypicals often chosen as firstline agents because of their slightly greater efficacy and better side effect profile (especially vs. high-potency drugs).

Side Effects Extrapyramidal dysfunction, somnolence, and hypotension can occur but generally mild. Weight gain and diabetes mellitus. Notes

RISPERIDONE (Risperdal), its primary active metabolite PALIPERIDONE (Invega), and the chemically related ILOPERIDONE (Fanapt) are other atypicals that inhibit 5-HT2A more than D2 but are still potent D2 inhibitors and thus carry ↑ risk of extrapyramidal side effects. QUETIAPINE (Seroquel) is an atypical that also inhibits H1, α1, and M1 receptors; thus associated with sedation and hypotension. CLOZAPINE (Clozaril) is an atypical antipsychotic used infrequently because it can cause agranulocytosis. Antipsychotics can be divided into three functional categories: low potency (see chlorpromazine), high potency (see haloperidol), and atypicals.

CNS OLANZAPINE Risperidone Paliperidone Iloperidone Quetiapine Clozapine

ANTIPSYCHOTICS Antipsychotic

Class

Prototype

Low Chlorpromazine potency

Side effect profile

AntiD2

Extrapyramidal Antianti-D2 M1 (parkinsonism, (e.g., Anti– tardive blurred Anti-H1 5-HT2 dyskinesia) vision) (sedation)

+

0

+

+++

++

High Haloperidol potency

+++

0

+++

+

+

Atypicals Olanzapine

+

+++

+

0/+

++

+

0

++

SDAMs Aripiprazole

Partial Partial agonist agonist 5-HT1

ARIPIPRAZOLE (Abilify)

antipsychotic

735

Mechanism As an atypical antipsychotic, acts via modulation of serotonin and dopaminergic neurotransmission. Unlike other atypicals, it is a partial agonist (not antagonist) at D2 receptors and a partial agonist at 5-HT1 receptors and thus sometimes referred to as “serotonin– dopamine activity modulators” (SDAMs). Clinical

Schizophrenia, including both the “positive” symptoms of delusions, hallucinations, and hyperactivity and the “negative” symptoms of withdrawal and blunted emotions. Atypicals are often chosen as first-line agents because of their slightly greater efficacy and better side effect profile (especially vs. high-potency drugs).

Side Effects Extrapyramidal dysfunction, somnolence, and hypotension can occur but generally mild. Notes

BREXPIPRAZOLE (Rexulti) and CARIPRAZINE (Vraylar) are similar atypicals. ASENAPINE (Saphris), LURASIDONE (Latuda), and ZIPRASIDONE (Geodon) are D2 antagonists (not partial agonist); the latter is also a 5-HT and NE reuptake inhibitor and therefore useful as an antidepressant. Antipsychotics can be divided into three functional categories: low potency (see chlorpromazine), high potency (see haloperidol), and atypicals.

CNS ARIPIPRAZOLE Brexpiprazole Cariprazine Asenapine Lurasidone Ziprasidone

ANTIPSYCHOTICS Antipsychotic

Class

Prototype

Low Chlorpromazine potency

Side effect profile

AntiD2

Extrapyramidal Antianti-D2 M1 (parkinsonism, (e.g., Anti– tardive blurred Anti-H1 5-HT2 dyskinesia) vision) (sedation)

+

0

+

+++

++

High Haloperidol potency

+++

0

+++

+

+

Atypicals Olanzapine

+

+++

+

0/+

++

+

0

++

SDAMs Aripiprazole

Partial Partial agonist agonist 5-HT1

LITHIUM

antipsychotic

736

Mechanism Unknown. Major possibilities under investigation include the following: Inhibits recycling of neuronal membrane phosphoinositides, which may ↓ generation of second messengers in α-adrenergic and muscarinic neurotransmission, thereby blunting hyperactivity in these pathways. Observation that exerts no psychotropic effect in normal individuals consistent with this mechanism. May act via ion transport because it can substitute for Na+. May directly affect neurotransmitter activity: ↑ 5-HT effects and ↓ DA and NE turnover. Clinical

Treatment of bipolar affective disorder. Adjunctive therapy in severe recurrent depression or schizophrenia. Used in treatment of SIADH (taking advantage of a key side effect, nephrogenic diabetes insipidus).

Side Effects Tremor, hyperactivity, hyperreflexia. At toxic levels, confusion may develop. Mild ↓ thyroid function, but thyroid enlargement and clinical hypothyroidism are rare. Partially reversible nephrogenic diabetes insipidus (downregulates kidney’s response to ADH). Leukocytosis. Contraindic. Pregnancy. Use with caution in volume depletion and renal disease. Interactions Thiazides and NSAIDs interfere with renal clearance → ↑ serum lithium level. Antipsychotics ↑ extrapyramidal side effects. Notes

Levels must be monitored, particularly in the setting of diuretic use and changes in renal function. Dialysis may be required in case of overdose.

CNS LITHIUM

APREPITANT (Emend)

NK1 inhibitor

737

Mechanism NK1 receptor antagonist that blocks substance P, the primary mediator of the central pathway for emesis. Emesis is controlled by the central pattern generator (CPG, previously called “vomiting center”) in the lateral reticular formation of the medulla. Sources of input include the nucleus tractus solitarius (NTS), the area postrema (AP), the vestibular apparatus, and visceral afferents. The neuropharmacology is incompletely understood but is divided into a peripheral pathway that is responsible for acute emesis and is signaled via dopamine and serotonin (5-HT3) receptors to the NTS and AP. A second pathway, the central pathway, is associated with delayed emesis (often due to chemotherapy) and is signaled via substance P agonism at NK1 receptors. Clinical

Potent antiemetic for chemotherapy-induced delayed emesis. Usually combined with other agents.

Side Effects Hiccups and fatigue. Drug is also a moderate CYP3A4 inhibitor → drug interactions. Notes

FOSAPREPITANT (Emend) is a prodrug that is rapidly converted to aprepitant. It is more water soluble than the active compound and can therefore be administered IV. NETUPITANT is a similar agent available as a combination tablet: Akynzeo = netupitant + palonosetron (see ondansetron). The three major classes of antiemetics are the serotonin antagonists (see ondansetron), NK1 antagonists, and the dopamine antagonists (see prochlorperazine). Some antihistamines (e.g., diphenhydramine, promethazine, hydroxyzine) also are good antiemetics (probably because of a combination of H1 and cholinergic blockade).

CNS APREPITANT Fosaprepitant Netupitant

MORPHINE

opioid

738

Mechanism Agonist for mu (μ) opioid receptors. On presynaptic neurons, inhibits release of substance P and other nociceptive neurotransmitters (via ↓ Ca2+ entry) and on postsynaptic nociceptive neurons, ↑ K+ conductance → hyperpolarization and inhibition. Weak kappa (κ) and delta (δ) opioid receptor agonist. Clinical

Analgesia for severe pain (note that tolerance can develop). Cough (opiates suppress cough reflex) and diarrhea (via ↓ GI motility), but less potent opioids tend to be used. Acute pulmonary edema: venodilatation → ↓ preload; ↓ perception of dyspnea.

Side Effects Respiratory depression; biliary colic; nausea and vomiting (via brainstem NTS/AP); pruritus. Constipation and miosis (even with tolerance). Dependence. Withdrawal → lacrimation, rhinorrhea, diaphoresis, piloerection, nausea, and tachypnea. Overdose → triad of coma, pinpoint pupils, and respiratory depression (treat with naloxone). Notes

HYDROMORPHONE (Dilaudid), OXYMORPHONE (Numorphan), and LEVORPHANOL (Levo-Dromoran), are similar, strong opioid agonists. MEPERIDINE (Demerol) is used for rigors and moderate to severe pain. Buildup of its metabolite normeperidine can lead to seizures. FENTANYL (Sublimaze), SUFENTANIL (Sufenta), ALFENTANIL (Alfenta), and REMIFENTANIL (Ultiva) are short-acting IV agents used for general anesthesia. Transdermal fentanyl patches used in cancer pain. Heroin is an illicit opiate derived from morphine that rapidly penetrates the CNS.

CNS MORPHINE Hydromorphone Oxymorphone Levorphanol Meperidine Fentanyl Sufentanil Alfentanil Remifentanil

OPIOID RECEPTORS Endogenous agonist

Exogenous agonists

Receptor

Effects

Mu (μ)

Analgesia Euphoria, dependence ↓ GI motility Miosis Respiratory depression

Endomorphins β-endorphin

Morphine Codeine Diphenoxylate Methadone

Kappa (κ)

Analgesia Psychotomimesis Diuresis Miosis

Dynorphins

Pentazocine

Delta (δ)

Analgesia ↓ GI motility

Enkephalins β-endorphin

Morphine is a naturally occurring alkaloid, originally isolated from the opium poppy. Subsequently,

morphine and other opiates were found to act through receptors for endogenous peptide neurotransmitters. The term “opioids” refers broadly to all ligands (endogenous and exogenous) for the three classes of opioid receptors.

CODEINE

opioid

739

Mechanism Codeine is a prodrug that must be demethylated into morphine, in a CYP2D6-dependent process, to produce clinically significant analgesia. Requirement for conversion into an active form makes codeine a weak agonist and susceptible to drug–drug interactions. CNS: analgesia (↑ tolerance to pain) and suppression of cough reflex (potentially through nonopioid receptors in the medulla that bind codeine). GI/GU: ↓ motility. Clinical

Mild to moderate analgesia. As with other opioids, often combined with nonopioid analgesics (e.g., acetaminophen) to reduce dose of opioid required to achieve adequate pain relief. Antitussive (attractive agent because antitussive effects occur at doses that have minimal analgesic or respiratory depressive effects).

Side Effects Constipation, nausea and vomiting. Dependence uncommon. Respiratory depression only at very high doses. Metabolism Patients with hypofunctional CYP2D6 isoforms “poor metabolizers” or those receiving CYP2D6 inhibitors may not experience adequate analgesia due to inadequate conversion of codeine into morphine.

Notes

OXYCODONE (Roxicodone) and HYDROCODONE (Hycodan) are potent oral opioid agonists, also often given in combination with aspirin, acetaminophen, or ibuprofen (e.g., Percodan, Percocet, Vicodin). These medications, particularly long-acting oxycodone (OxyContin), have high potential for abuse. TRAMADOL (Ultram) is a weak μ antagonist that also blocks 5-HT and NE reuptake. TAPENTADOL (Nucynta) is similar: a weak μ antagonist, blocks NE reuptake but not 5-HT. DEXTROMETHORPHAN, an OTC antitussive, is a d-isomer of a methylated opioid and has no analgesic or addictive properties.

CNS CODEINE Oxycodone Hydrocodone Tramadol Tapentadol Dextromethorphan

OPIOID RECEPTORS Endogenous agonist

Exogenous agonists

Receptor

Effects

Mu (μ)

Analgesia Euphoria, dependence ↓ GI motility Miosis Respiratory depression

Endomorphins β-endorphin

Morphine Codeine Diphenoxylate Methadone

Kappa (κ)

Analgesia Psychotomimesis Diuresis Miosis

Dynorphins

Pentazocine

Delta (δ)

Analgesia ↓ GI motility

Enkephalins β-endorphin

Morphine is a naturally occurring alkaloid, originally isolated from the opium poppy. Subsequently, morphine and other opiates were found to act through receptors for endogenous peptide neurotransmitters. The term “opioids” refers broadly to all ligands (endogenous and exogenous) for the three classes of opioid receptors.

PENTAZOCINE (Talwin)

opioid

740

Mechanism The prototypical mixed opioid agonist–antagonist, an agonist at kappa (κ) receptors but only a partial agonist/weak antagonist at mu (μ) receptors. Activation of κ receptors results in primarily spinal-level analgesia. Partial agonist activity at μ receptors can result in supraspinal analgesia but in the presence of stronger, pure μ agonists can result in reduction in analgesia and precipitate withdrawal. Clinical

Analgesia for moderate pain.

Side Effects Dependence: Mixed opioid agonist–antagonists were designed to have little abuse potential but some of the more potent members of this class do generate dependence. Respiratory depression: unlike pure μ agonists, there appears to be a ceiling at relatively low doses (i.e., ↑ dose does not proportionately ↑ degree of respiratory depression). Contraindic. Concomitant administration of pure μ agonists. Respiratory depression. Notes

BUTORPHANOL (Stadol) and BUPRENORPHINE (Buprenex) are similar stronger agents and are used for moderate to severe pain; buprenorphine is also used to treat opioid dependence. NALBUPHINE (Nubain) is a potent κ agonist and a complete μ antagonist that is also used for moderate to severe pain.

CNS PENTAZOCINE Butorphanol Buprenorphine Nalbuphine

OPIOID RECEPTORS Endogenous agonist

Exogenous agonists

Receptor

Effects

Mu (μ)

Analgesia Euphoria, dependence ↓ GI motility Miosis Respiratory depression

Endomorphins β-endorphin

Morphine Codeine Diphenoxylate Methadone

Kappa (κ)

Analgesia Psychotomimesis Diuresis Miosis

Dynorphins

Pentazocine

Delta (δ)

Analgesia ↓ GI motility

Enkephalins β-endorphin

Morphine is a naturally occurring alkaloid, originally isolated from the opium poppy. Subsequently, morphine and other opiates were found to act through receptors for endogenous peptide neurotransmitters. The term “opioids” refers broadly to all ligands (endogenous and exogenous) for the three classes of opioid receptors.

DIPHENOXYLATE (Lomotil)

opioid

741

Mechanism Acts on mu (μ) receptors in the bowel to abolish local peristalsis. Relieves diarrhea through ↓ GI motility. Its selective antidiarrheal action appears to result from poor systemic absorption. Clinical

Antidiarrheal.

Side Effects Ileus. ↑ Risk of chronic Salmonella carriage if used for diarrhea caused by Salmonella. Little to no morphine-like subjective effects (euphoria) at therapeutic doses. Metabolism PO. Poorly absorbed → excreted in feces. Notes

LOPERAMIDE (Imodium) is similar. Opiate antidiarrheals are contraindicated in most cases of infectious diarrhea, particularly those caused by Clostridium difficile infection, because of an increased risk of ileus, toxic megacolon, and sepsis.

CNS DIPHENOXYLATE Loperamide

OPIOID RECEPTORS Endogenous agonist

Exogenous agonists

Receptor

Effects

Mu (μ)

Analgesia Euphoria, dependence ↓ GI motility Miosis Respiratory depression

Endomorphins β-endorphin

Morphine Codeine Diphenoxylate Methadone

Kappa (κ)

Analgesia Psychotomimesis Diuresis Miosis

Dynorphins

Pentazocine

Delta (δ)

Analgesia ↓ GI motility

Enkephalins β-endorphin

Morphine is a naturally occurring alkaloid, originally isolated from the opium poppy. Subsequently, morphine and other opiates were found to act through receptors for endogenous peptide neurotransmitters. The term “opioids” refers broadly to all ligands (endogenous and exogenous) for the three classes of opioid receptors.

METHADONE (Dolophine)

opioid

742

Mechanism Primarily a mu (μ) agonist with pharmacologic properties similar to morphine. Often used for withdrawal symptoms based on the following properties: 1. Effective analgesic activity. 2. Efficacy by oral route. 3. Extended duration of action in suppressing withdrawal symptoms (i.e., a long half-life). 4. Tendency to show persistent effects with repeated administration. Clinical

Treatment of opioid withdrawal symptoms, particularly in cases of heroin dependence. Analgesia. Occasionally used as an antiperistaltic.

Side Effects Similar to those described for morphine. QT prolongation. Metabolism Absorbed by all routes. Peak concentration occurs in the brain within 1 to 2 hours after IM administration. Interactions Rifampin and phenytoin accelerate metabolism of methadone and can precipitate withdrawal symptoms. Notes

Increasingly used for outpatient pain management in cancer patients.

CNS METHADONE

NALOXONE (Narcan)

opioid antagonist

743

Mechanism Pure antagonist at opioid mu (μ) receptors, reversing the effects of opioid agonists (e.g., on respiratory drive, consciousness, pupil size, bowel activity) within minutes. In absence of exogenous opioids, naloxone has no clinical effect. Clinical

Acute opioid overdose (i.e., respiratory depression, hypotension, coma). The PO form is used for reversal of severe opioid-induced constipation.

Side Effects Can precipitate abrupt withdrawal and return of severe pain in cases of physical dependence. Transient tachypnea (overshoot phenomenon). Metabolism IV. Short duration of action; repeat dosing every 2 to 3 minutes may be necessary to maintain reversal of respiratory suppression.

Notes

develops.

NALTREXONE (Trexan) can be administered PO, and one oral dose lasts for 48 hours. It is used for outpatient management of both alcohol and heroin dependence. METHYLNALTREXONE (Relistor) is a μ antagonist administered SC to relieve opioid-induced constipation. NALOXEGOL (Movantik) is a similar agent administered PO. These agents do not ↓ analgesia or precipitate withdrawal, likely because they do not cross the BBB. ALVIMOPAN (Entereg) is another μ antagonist used to treat postoperative ileus. It too does not ↓ analgesia or precipitate withdrawal, likely because of its poor PO absorption. The need to administer PO necessitates initiation of therapy before ileus

CNS NALOXONE Naltrexone Methylnaltrexone Naloxegol Alvimopan

IBUPROFEN (Motrin, Advil, Nuprin, etc.)

NSAID

8-1

Mechanism Prototypical member of the nonsteroidal anti-inflammatory drug (NSAID) family, it is a nonselective reversible inhibitor of cyclooxygenase (COX)-1 and COX-2. In the setting of inflammation, cytokines stimulate phospholipase A2 to release arachidonic acid (AA) from phospholipids. AA is transformed by COX-1/2 into prostaglandins, prostacyclin, and thromboxane. Prostaglandins result in vasodilation, edema, leukocyte infiltration and activation, resetting of the body’s thermostat, and hyperalgesia. Because they are reversible COX inhibitors, NSAIDs have less of an antiplatelet effect than does aspirin. Clinical

Anti-inflammatory and analgesic used in rheumatic diseases (e.g., osteoarthritis, rheumatoid arthritis, gout) and musculoskeletal syndromes (e.g., strains, sprains). Antipyretic.

Side Effects Gastric erosions and bleeding caused by ↓ PGE2 and prostacyclin synthesis → vasoconstriction and ischemia, ↓ mucus, ↑ gastric acid and, to a lesser extent, topical irritation. Renal insufficiency (↓ prostaglandin-mediated renal arteriolar vasodilation), which can lead to Na+ retention, hypertension, and an exacerbation of CHF. Can also cause interstitial nephritis and papillary necrosis. May ↑ risk of cardiovascular and cerebrovascular events because of ↓ prostacyclin or by interfering with irreversible antiplatelet effect of concomitant aspirin by temporarily blocking access to COX-1. Hypersensitivity reactions (urticaria, erythema multiforme). Notes

INDOMETHACIN (Indocin) is used to induce closure of a patent ductus arteriosus (PDA), which requires the presence of PGE2 and prostacyclin to remain patent. Other NSAIDs are listed on the reverse.

INFLAM IBUPROFEN see chart

Duration of action

Examples

Short acting t1/2 ≤6 h; typically dosed qid or tid

DICLOFENAC (Voltaren), ETODOLAC (Lodine), FENOPROFEN (Fenortho, Nalfon), FLURBIPROFEN (Ansaid), IBUPROFEN (Motrin et al.), INDOMETHACIN (Indocin), KETOPROFEN (Orudis), KETOROLAC (Toradol), MECLOFENAMATE (Meclomen), MEFENAMIC ACID (Ponstel), TOLMETIN (Tolectin)

Intermediate acting DIFLUNISAL (Dolobid), NAPROXEN (Naprosyn, t1/2 8–16 h; typically dosed Anaprox, Aleve), SULINDAC (Clinoril) bid Long acting t1/2 ≥20 h; typically dosed qd

MELOXICAM (Mobic), NABUMETONE (Relafen), OXAPROZIN (Daypro), PIROXICAM (Feldene)

CELECOXIB (Celebrex)

coxib

8-2

Mechanism Prototypical coxib, a selective reversible inhibitor of cyclooxygenase (COX)-2. COX-1 is expressed constitutively in most tissues, including platelets (where TXA synthase → thromboxane → platelet activation) and the gastric mucosa (where PGE synthase → PGE2 → gastric cytoprotection). COX-2 is expressed constitutively in the brain and kidney and is induced at sites of inflammation where it mediates production of proinflammatory prostaglandins (see ibuprofen). COX-2 may be upregulated in endothelial cells at sites of atherosclerosis (where PGI synthase → prostacyclin → platelet inhibition). Clinical

Anti-inflammatory and analgesic used in rheumatic diseases (e.g., osteoarthritis, rheumatoid arthritis). No more effective than traditional NSAIDs.

Side Effects Less gastropathy than with nonselective COX inhibitors because coxibs do not inhibit COX-1–mediated gastric cytoprotection. Advantage lost in patients taking aspirin. Hypertension because of loss of COX-2–generated prostaglandins that cause renal arteriolar vasodilation. Increased incidence of thrombotic cardiovascular events (MI, stroke) associated with long-term use (especially at higher doses), presumably because coxibs do not inhibit platelet-mediated thromboxane synthesis but do impair production of prostacyclin by endothelial cells. This adverse effect led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market. Notes

Coxibs ↓ risk of colorectal adenomas, presumably by ↓ PGE2mediated inhibition of the tumor suppressor adenomatous polyposis coli (APC); similar data for NSAIDs and ASA. However, given side effects, routine use for prevention of colorectal cancer is currently not recommended.

INFLAM CELECOXIB COX-1

Expression Constitutive

Platelets TXA2 → vasoconstriction and thrombosis

✓

Endothelium prostacyclin → vasodilation and platelet inhibition

✓

Gastric mucosa PGE2 and prostacyclin → gastric protection

✓

Kidney PGE2 and prostacyclin → vasodilation

✓

Leukocytes PGE2 → inflammation Net clinical effects of inhibition

Induced by inflammatory cytokines, vascular shear stress, etc.

Conversion of AA to PGG2 and PGH2

Function Subsequent prostanoids derived from PGG2/H2 and their effects

COX-2

NSAID (nonselective)

✓

✓

✓ Platelet inhibition and vasodilation ↓ Inflammation Gastric ulceration ↓ GFR and HTN

Coxib (COX-2 selective)

↓ Inflammation Platelet activation Vasoconstriction ↓ GFR and HTN

ACETAMINOPHEN (Tylenol)

analgesic

8-3

Mechanism Reversibly inhibits cyclooxygenase, seemingly better in the CNS than in peripheral tissues. This may be because of inactivation of the drug peripherally by peroxidases released during inflammatory response. As a result, acts as an antipyretic and analgesic but has no significant anti-inflammatory or antiplatelet effects. Clinical

Analgesic for mild to moderate pain. Antipyretic. Preferred over aspirin, especially in children, because there is no association between Reye syndrome (see acetylsalicylic acid) and acetaminophen use for viral infections.

Side Effects Low toxicity at therapeutic doses. Hepatotoxicity: Major route of metabolism is O-glucuronidation, but small amount is N-hydroxylated by CYP2E1. The latter produces very reactive species that are scavenged by glutathione. After glutathione reserves are exhausted (e.g., by an acetaminophen overdose), these metabolites react with sulfhydryl groups of proteins → hepatic necrosis and potentially hepatic failure. Regular ethanol consumption increases risk of acetaminophen hepatic toxicity (CYP2E1 induced by alcohol and malnutrition). Preferred over NSAIDs in patients at risk for bleeding. Notes

ACETYLCYSTEINE (Mucomyst) can be used in cases of acetaminophen overdose as a reducing equivalent to help compensate for depletion of glutathione. It has been studied as prophylaxis against contrast-induced acute renal failure, but the most recent large studies show no benefit.

INFLAM ACETAMINOPHEN Acetylcysteine

ZAFIRLUKAST (Accolate)

leukotriene antagonist

8-4

Mechanism Leukotriene D4 (LTD4) receptor blocker. Leukotrienes are produced by the action of 5-lipoxygenase on arachidonic acid (AA) and are synthesized by several cells involved in airway inflammation, including eosinophils, mast cells, and basophils. LTB4 is a neutrophil chemoattractant. LTC4 and LTD4 are potent bronchoconstrictors now recognized to be the principal components of the “slow-reacting substance of anaphylaxis” seen in asthma. Clinical

Asthma: ↑ airway caliber, ↓ bronchial reactivity, ↓ airway inflammation. Used for chronic maintenance therapy, not for acute attacks. Particularly useful in aspirin-induced asthma, which is thought to be due to the shift in AA metabolism from prostaglandins to leukotrienes induced by aspirin.

Side Effects Churg-Strauss syndrome (systemic vasculitis with peripheral eosinophilia, pulmonary infiltrates, and myocarditis) reported as a rare complication. The syndrome is thought to be unmasked by the tapering of steroids made possible by the addition of the leukotriene receptor antagonists. Inhibits CYP2C9 and CYP3A4. Notes

MONTELUKAST (Singulair) is another leukotriene receptor blocker used for chronic maintenance therapy for asthma. ZILEUTON (Zyflo) inhibits 5-lipoxygenase that catalyzes the committed step in leukotriene synthesis and has similar clinical efficacy. It can cause hepatotoxicity. It is metabolized by the CYP450 system and can ↑ serum concentrations of theophylline (another drug used in asthma) and warfarin.

INFLAM ZAFIRLUKAST Montelukast Zileuton

CYCLOSPORINE (Sandimmune)

immunosuppressant

8-5

Mechanism Inhibits calcineurin, a protein phosphatase required for transcription of IL-2, the key autocrine T-cell activator. This inhibition suppresses cell-mediated immunity. Normally, calcineurin mediates dephosphorylation of NFAT (nuclear factor of activated T cells) → NFAT nuclear translocation and IL-2 promoter binding → ↑ IL-2 expression (creating a positive feedback loop which activates T cells). Cyclosporine binds to a cell protein called cyclophilin, and this cyclophilin/cyclosporine complex blocks calcineurin activity. Clinical

Immunosuppression for organ transplant recipients. Treatment of graft-versus-host disease in bone marrow transplant recipients.

Side Effects Nephrotoxicity. Hypertension, hirsutism, gum hyperplasia. Interactions CYP3A4 inhibitors such as erythromycin or voriconazole can dramatically elevate cyclosporine levels, resulting in increased immunosuppression and risk of nephrotoxicity. Notes

Cyclosporine was isolated from fungi as a potential antibiotic. The fortuitous discovery that it was a potent immunosuppressant revolutionized the field of solid organ transplantation. TACROLIMUS (FK506) is a chemically unrelated immunosuppressant that binds a different cellular protein (FKBP). The tacrolimus–FKBP complex inhibits calcineurin and produces immunosuppression in a manner exactly analogous to cyclosporine. Tacrolimus may be less nephrotoxic. PIMECROLIMUS (Elidel) is a topical calcineurin inhibitor that is used for atopic dermatitis (eczema).

INFLAM CYCLOSPORINE Tacrolimus Pimecrolimus

SIROLIMUS (Rapamycin)

immunosuppressant

8-6

Mechanism Sirolimus, like the chemically related tacrolimus, binds to FKBP; the complex, however, does not inhibit calcineurin but instead blocks IL-2 responsiveness of T cells by inhibiting mTOR (mammalian target of rapamycin) kinase. mTOR is a key component of the proliferative response that T cells undergo when stimulated with IL2. In other cell types, mTOR dysregulation is associated with neoplasia: mTOR inhibitors can be used in the treatment of some types of malignancy (see below). Clinical

Immunosuppression for organ transplant recipients. Prevention of cardiac stent restenosis: Sirolimus-eluting coronary artery stents inhibit neointimal hyperplasia and ↓ restenosis rates. Tuberous sclerosis: One of the principal functions of the genes mutated in this disorder (TSC1 & TSC2) is to regulate mTOR. Preliminary studies suggest that some tuberous sclerosis tumors respond to sirolimus.

Side Effects Anemia, leukopenia, thrombocytopenia; ↑ cholesterol & triglycerides; diarrhea, nausea, constipation. Notes

TEMSIROLIMUS (Torisel) is a similar agent that is used for the treatment of advanced renal cell carcinoma. EVEROLIMUS (Afinitor, Zortress) is a similar agent that is used for the treatment of breast, renal cell, and neuroendocrine tumors as well as for immunosuppression in organ transplant recipients. Also used to coat coronary stents to prevent restenosis. ZOTAROLIMUS is another mTOR inhibitor used on coronary stents.

INFLAM SIROLIMUS Temsirolimus Everolimus Zotarolimus

ANTITHYMOCYTE GLOBULIN (Thymoglobulin)

immunosuppressant

8-7

Mechanism Purified gamma globulin fractions of antiserum from rabbits immunized against human thymocytes. These polyclonal antibodies against an array of T-lymphocytes surface molecules deplete circulating T lymphocytes by inducing complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity (ADCC, see monoclonal antibody class card). Clinical

Prevention and treatment of acute rejection of transplanted organs: ↓ incidence of acute rejection. Aplastic anemia and other conditions in which immunosuppression may be indicated.

Side Effects Fever, chills, thrombocytopenia, leukopenia, hemolysis, respiratory distress, serum sickness, and anaphylaxis. Adverse effects ameliorated with steroids, acetaminophen, and diphenhydramine. Notes

ATGAM is purified gamma globulin obtained by immunization of horses with human thymocytes. BASILIXIMAB (Simulect) and DACLIZUMAB (Zenapax) are monoclonal antibodies against the IL-2 receptor on T cells and are used for prophylaxis and treatment of acute rejection. Compared with polyclonal antibodies, they have fewer adverse effects, less efficacy acutely but similar long-term efficacy. ABATACEPT (Orencia) is a fusion protein of human IgG to the costimulatory inhibitor CTLA4. CTLA4 binds to CD80 & CD86 molecules on antigen presenting cells, blocking their ability to costimulate (primary stimulus being MHC/TCR), thus blocking Tcell activation. Used for refractory rheumatoid arthritis.

INFLAM ANTITHYMOCYTE GLOBULIN Atgam Basiliximab Daclizumab Abatacept

ETANERCEPT (Enbrel)

immunosuppressant

8-8

Mechanism Dimeric fusion protein consisting of the extracellular ligand-binding portion of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. Each molecule of etanercept can bind to and inactivate two TNF molecules, thus inhibiting the inflammatory cascade downstream of this key cytokine. Clinical

Autoimmune diseases: rheumatoid arthritis (RA), juvenile rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Side Effects As with all TNF inhibitors, associated with increased risk tuberculosis as well as atypical mycobacterial infections. Likely predisposes to other opportunistic infections as well, including listeria, cryptococcosis, histoplasmosis, and candidal infections. Exacerbation of multiple sclerosis and other demyelinating diseases has been reported. Notes

INFLIXIMAB (Remicade), ADALIMUMAB (Humira), CERTOLIZUMAB (Cimzia), and GOLIMUMAB (Simponi) are monoclonal antibodies that bind to and inhibit the action of both soluble and transmembrane forms of TNFα. They are used to treat severe Crohn disease, and the first two agents are also approved for RA.

INFLAM ETANERCEPT Infliximab Adalimumab Certolizumab Golimumab

ANAKINRA (Kineret)

immunosuppressant

8-9

Mechanism Recombinant IL-1Ra, an endogenous competitive antagonist of the interleukin 1 (IL-1) receptor. IL-1Ra competitively inhibits binding of IL-1α and IL-1β, endogenous agonists of this receptor. This limits their proinflammatory effects: vasodilatation, diapedesis, induction of acute phase proteins, and fever. Clinical

Rheumatoid arthritis (RA)—clinical trials for RA led to its approval but seldom used for this indication because its effects are modest compared to anti-TNF agents (see etanercept). Cryopyrin-associated periodic syndromes (CAPS)—a group of rare autoimmune diseases characterized by excessive IL-1β production due to mutations in components of the inflammasome, a cellular structure that converts IL-1β to its active form.

Side Effects Significant ↑ risk of infection when used in combination with an antiTNFα agent. Notes

The success of anti-TNF therapy led to the development of other agents targeting inflammatory cytokines. In general, these agents treat a narrower spectrum of conditions and/or are less effective than anti-TNF therapy. RILONACEPT (Arcalyst) is a dimeric fusion protein of the ligandbinding domain of IL-1 receptor type 1 (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc portion of human IgG1. Binds and inhibits IL-1α and IL-1β analogous to etanercept inhibition of TNF. Used to treat CAPS. CANAKINUMAB (Ilaris) is an antibody against IL-1β used for CAPS and as second-line agent for gout. Also shown to reduce CV events in patients with CV disease and a high elevated C-reactive protein level. SILTUXIMAB (Sylvant) is an antibody against IL-6 approved for treatment of KSHV negative multicentric Castleman disease, and TOCILIZUMAB (Actemra) is an antibody against the IL-6 receptor—used to treat RA, giant cell arteritis, and cytokine release syndromes associated with cancer immunotherapy.

INFLAM ANAKINRA Rilonacept Canakinumab Siltuximab Tocilizumab

SECUKINUMAB (Cosentyx)

immunosuppressant

810

Mechanism Antibody that binds to interleukin-17A (IL-17A) and blocks its interaction with the IL-17A receptor, limiting keratinocyte proliferation and other proinflammatory effects of this cytokine. Clinical

Used to treat psoriasis, psoriatic arthritis, and ankylosing spondylitis.

Side Effects Dose dependent increased risk of infections, including tuberculosis (although less severe than with TNF inhibitors). Notes

The keratinocyte hyperproliferation characteristic of psoriasis is now appreciated to be driven by autoimmune phenomena in genetically susceptible individuals: in the skin, production of inflammatory cytokines (IL-1, IL-6, TGFβ, and IL-23) by inflammatory dendritic cells → differentiation of CD4+ helper T cells into Th17 cells → production of IL-17A, a cytokine that acts as a potent stimulus of keratinocyte proliferation. IXEKIZUMAB (Taltz) is another anti–IL-17A antibody, and BRODALUMAB (Siliq) is an antibody against the IL-17A receptor; both are used for psoriasis. USTEKINUMAB (Stelara) is an antibody against IL-12B, a subunit of the IL-12 and IL-23 proinflammatory cytokines, and is used for psoriasis, psoriatic arthritis, and Crohn disease. GUSELKUMAB (Tremfya) is an antibody against IL-23A (p19), a subunit of IL-23, and is used for psoriasis.

INFLAM SECUKINUMAB Ixekizumab Brodalumab Ustekinumab Guselkumab

The discovery of a new subset of effector T cells, Th17, distinct from Th1 and Th2, has revolutionized treatment of some autoimmune diseases, such as psoriasis. Drugs have been developed that target cytokines that promote Th17 cell development or are secreted by Th17 cells.

NATALIZUMAB (Tysabri)

immunosuppressant

811

Mechanism Antibody against alpha4 (α4) integrin, which associates with different beta subunits to form integrin receptors found on inflammatory lymphocytes and monocytes that facilitate their adhesion to vascular endothelium → migration into inflamed tissue. Alpha4beta1 (α4β1) integrin binds to VCAM-1, a ligand found primarily in the CNS, alpha4beta7 (α4β7) binds to addressin, a ligand found primarily on mucosal vascular endothelial cells. Clinical

Autoimmune diseases: multiple sclerosis (MS)—reduces infiltration of inflammatory cells into the brain. Crohn disease—reduces infiltration of inflammatory cells into the gut.

Side Effects Progressive multifocal leukoencephalopathy (PML)—an opportunistic infection due to unchecked replication of JC polyoma virus in the brain that results from impaired immune surveillance in the CNS. Notes

VEDOLIZUMAB (Entyvio) is an antibody against α4β7 integrin heterodimer, a cell surface receptor that binds to addressin, a ligand found primarily on mucosal vascular endothelium that blocks interaction its receptor on T cells. Inhibition reduces T-cell infiltration across endothelium into inflamed GI tissues. Used to treat Crohn disease. Not effective for MS and carries much lower, if any, risk for PML.

INFLAM NATALIZUMAB Vedolizumab

MYCOPHENOLATE MOFETIL (CellCept)

immunosuppressant

812

Mechanism The active metabolite of this drug, mycophenolic acid, is a potent inhibitor of IMP dehydrogenase, the rate-limiting step in the de novo synthesis of GMP. This inhibition is particularly toxic to activated B and T lymphocytes, which rely primarily on the de novo pathway for purine biosynthesis. Additionally, mycophenolic acid binds with higher affinity to the type II IMP dehydrogenase isoform that is expressed in lymphocytes. This results in impaired lymphocyte proliferation → immunosuppression. Clinical

Immunosuppression for solid organ transplantation. Treatment of rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and inflammatory bowel disease.

Side Effects Myelosuppression, GI symptoms (nausea, cramping, diarrhea). Notes

AZATHIOPRINE (Imuran) is an older agent that inhibits de novo purine synthesis (both GMP and AMP). Azathioprine is a prodrug that is first converted into 6-mercaptopurine (6-MP), which acts as an IMP dehydrogenase inhibitor. 6-MP also inhibits PRPP, the enzyme that catalyzes the rate-limiting step in de novo purine synthesis. LEFLUNOMIDE (Arava) is an inhibitor of pyrimidine synthesis taken orally in the treatment of rheumatoid arthritis.

INFLAM MYCOPHENOLATE MOFETIL Azathioprine Leflunomide

METHOTREXATE

immunosuppressant

813

Mechanism Folic acid is a vitamin required for the transfer of activated one-carbon units in multiple synthetic pathways. Methotrexate, a folic acid analog, inhibits dihydrofolate reductase (DHFR) and prevents folate recycling. This leads to decreased synthesis of purine nucleotides, thymidylate, and the amino acids serine and methionine. Impaired nucleic acid synthesis disproportionately affects rapidly dividing cells. Resistance

Impaired uptake of drug or ↓ half-life (caused by ↓ formation of polyglutamate methotrexate derivatives, which have a much longer intracellular half-life than the parent drug). Altered forms of DHFR that have a decreased affinity for the drug.

Clinical

Immunosuppression for rheumatic diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic lupus erythematosus, and Wegener vasculitis. Antineoplastic: used in combination chemotherapy for many malignancies. Ectopic pregnancy.

Side Effects Myelosuppression, GI hemorrhagic enteritis, arachnoiditis, and neurotoxicity are usually dose-limiting. Pneumonitis, hepatic toxicity, and alopecia are also common. Notes

Leucovorin rescue: Toxic effects on normal cells may be reduced by administration of folinic acid (a.k.a. leucovorin or citrovorum factor), which is preferentially taken up by normal cells versus tumor cells. PEMETREXED (Alimta), a weak DHFR antagonist, mainly inhibits folate-dependent enzymes in the de novo thymidine and purine biosynthesis pathways. Used for non–small cell lung cancers and mesothelioma. PRALATREXATE (Folotyn) is an antifolate that may be preferentially taken up by cancer cells. Used to treat T-cell lymphomas.

GLUCARPIDASE (Voraxaze), an enzyme that degrades methotrexate, used to rapidly reduce toxic drug levels.

INFLAM METHOTREXATE Pemetrexed Pralatrexate Glucarpidase

INTERFERON BETA (Avonex, Betaseron)

immunomodulator

814

Mechanism Beta interferon is a type I interferon that induces a potent antiviral state in target cells (see interferon alpha card). Early studies of interferon therapy for multiple sclerosis (MS) were undertaken with the belief that a viral infection caused or triggered the disease. MS now generally believed to be an autoimmune disease and the effect of interferon to be immunomodulatory. The details of this immunomodulation are unknown. Clinical

MS: interferon beta can ↓ relapse frequency in the relapsing/remitting form of this disease.

Side Effects Flu-like symptoms: fever, myalgias, malaise. Neutropenia, thrombocytopenia. Associated with exacerbation of depression and suicidality.

Notes

Interferon beta-1A (Avonex, Rebif) is recombinant beta interferon. Interferon beta-1B (Betaseron) is recombinant beta interferon with a single cysteine to serine substitution. The name “interferon” derives from the fact that these proteins were initially discovered because of their ability to interfere with viral replication Alpha interferons are a family of 20 related type I interferons. Beta interferon is a type I interferon secreted by many cell types. Gamma interferon is a type II interferon secreted by activated CD4 T cells. It has only weak antiviral properties, and its major physiologic action is to potentiate macrophage inflammatory reactions (e.g., increases their ability to kill mycobacteria).

INFLAM INTERFERON BETA

HYDROXYCHLOROQUINE immunomodulator (Plaquenil)

815

Mechanism Antirheumatic: attributed in part to inhibitory effects on processing of peptide antigens and their assembly into MHC by macrophages; similar effects on posttranslational processing of proteins may account for the observed effects on release of cytokines, including TNFα, IL-1β, and gamma interferon. Antimalarial: identical mechanism as chloroquine, although seldom used for this indication. Clinical

Rheumatoid arthritis and juvenile inflammatory arthritis. Systemic lupus erythematosus: used to treat articular, cutaneous, pleuritic, and constitutional symptoms. Discoid lupus: used to treat cutaneous manifestations. Sjögren syndrome: used to treat salivary gland swelling and extraglandular features.

Side Effects Retinopathy, manifest by decreased visual acuity, scotomata, or pigmented changes in the retina. Corneal deposits may be seen. Maculopapular rash. Hyperpigmentation in photo-exposed areas due to ↑ binding to melanin-containing cells. Rare symptomatic myopathy or cardiomyopathy. Notes

INFLAM HYDROXYCHLOROQUINE

SULFASALAZINE (Azulfidine)

immunomodulator

816

Mechanism Formed by linkage of sulfapyridine (a sulfonamide antibiotic) to 5aminosalicylic acid (5-ASA) via an azo bond. Linkage minimizes absorption of the drug in the upper GI tract. In the colon, however, bacteria break the azo bond and free the salicylate derivative, which acts locally as an anti-inflammatory molecule. Clinical

Inflammatory bowel disease (IBD): treatment of acute flares and maintenance of remission. Rheumatoid arthritis and polyarticular juvenile rheumatoid arthritis.

Side Effects Sulfa allergy → rash, fever, Stevens-Johnson syndrome, hepatitis, nephritis, bone marrow suppression.

Notes

BALSALAZIDE (Colazal) is 5-ASA linked to an inert carrier via an azo bond, and OLSALAZINE (Dipentum) is composed of two 5ASA molecules linked by an azo bond. Bacteria in the colon break the azo bond and free the salicylate derivative. Useful in patients with sulfa allergies. MESALAMINE (Asacol, Apriso, Pentasa, Lialda, Rowasa) is unconjugated 5-ASA and is available in a variety of formulations. The particular preparation one selects is based on the anatomic extent of the patient’s IBD. Asacol and Apriso are delayed-release mesalamine tablets protected by a pH-sensitive coating. When the pH is > 6 to 7, the coating dissolves, thereby releasing mesalamine in the ileum and beyond. Pentasa and Lialda have special coatings (ethylcellulose and a multihydrophilic & lipophilic matrix, respectively), allowing the release of mesalamine throughout the GI tract. Rowasa is used as a rectal suspension enema to deliver mesalamine to the rectum and distal colon.

INFLAM SULFASALAZINE Balsalazide Olsalazine Mesalamine

CROMOLYN (Intal, Nasalcrom)

immunomodulator

817

Mechanism Alters chloride channels → cell stabilization. 1. Airway nerves: ↓ cough. 2. Mast cells and eosinophils: ↓ response to antigen challenge, inhibit degranulation, and ↓ release of mediators (leukotrienes, histamine). Clinical

Prophylaxis for asthma: inhibits immediate and late asthmatic responses to antigen challenge or exercise. No effect once acute bronchospasm has occurred. Prophylaxis of allergic rhinitis and allergic conjunctivitis; not useful in the acute setting.

Side Effects Infrequent and mild, caused by deposition: throat irritation, cough. Rare dermatitis and myositis. Metabolism Inhaled; ophthalmic solution for allergic conjunctivitis. Notes

NEDOCROMIL (Tilade) differs structurally but is thought to have the same mechanism of action. LODOXAMIDE (Alomide) and PEMIROLAST (Alamast) are mast cell stabilizers used for prevention of allergic conjunctivitis. OMALIZUMAB (Xolair) is a humanized monoclonal antibody against human IgE that is found on the surface of mast cells and basophils. The drug blocks IgE-mediated mast cell and basophil activation and is indicated for moderate to severe asthma not controlled by inhaled corticosteroids. 0.2% risk of anaphylaxis.

INFLAM CROMOLYN Nedocromil Lodoxamide Pemirolast Omalizumab

DIPHENHYDRAMINE (Benadryl)

antihistamine

818

Mechanism 1st gen. competitive inhibitor of histamine H1 receptors. Smooth muscle: antagonizes constriction of bronchial & vascular smooth muscle. Capillaries: blocks ↑ permeability that normally → edema & wheal formation. CNS: causes sedation. Effects on smooth muscle & capillaries antagonize allergic reactions. 1st gen. antihistamines also have other effects not attributable to H1blockade, including muscarinic, α-adrenoceptor, and serotonin blockade. Clinical

Allergic reactions: treatment of IgE (immediate, type I) hypersensitivity, urticaria, allergic rhinitis (“hay fever”). Ineffective for angioedema, asthma, atopic dermatitis. Motion sickness, vertigo, and nausea (especially antihistamines that have strong antimuscarinic effects). Insomnia: used as a mild sedative in young persons. Reverse extrapyramidal side effects of phenothiazines (via anticholinergic activity [see benztropine]).

Side Effects Sedation. Blurred vision, dry mucous membranes, urinary retention (antimuscarinic effects). Postural hypotension (α1-blockade). Use caution in the elderly because of increased sensitivity to these side effects.

Notes

CYPROHEPTADINE (Periactin) is an antihistamine and antiserotonergic agent for perennial and seasonal allergic rhinitis and other allergic symptoms, including urticaria. ALCAFTADINE (Lastacaft), AZELASTINE (Astepro, Optivar), BEPOTASTINE (Bepreve), EMEDASTINE (Emadine), EPINASTINE (Elestat), KETOTIFEN (Zaditor), and OLOPATADINE (Patanase, Patanol) are antihistamines and mast cell stabilizers (see cromolyn) used to treat allergic conjunctivitis and/or allergic rhinitis. See reverse for other 1st gen. antihistamines.

INFLAM DIPHENHYDRAMINE Cyproheptadine (Periactin) Alcaftadine (Lastacaft) Azelastine (Astepro, Optivar) Bepotastine (Bepreve) Emedastine (Emadine) Epinastine (Elestat) Ketotifen (Zaditor) Olopatadine (Patanase, Patanol) Brompheniramine (Dimetapp Allergy) Chlorpheniramine (ChlorTrimeton)

Clemastine (Tavist) Dexchlorpheniramine (Polaramine) Dimenhydrinate (Dramamine) Hydroxyzine (Atarax, Vistaril) Meclizine (Antivert) Promethazine (Phenergan)

FEXOFENADINE (Allegra)

antihistamine

819

Mechanism 2nd gen. (“nonsedating”) competitive inhibitor of histamine H1 receptors: Smooth muscle: antagonizes constriction of bronchial and vascular smooth muscle. Capillaries: blocks ↑ permeability that normally leads to edema and wheal formation. The effects on smooth muscle and capillaries serve to antagonize allergic reactions. These agents are not as lipid soluble and therefore do not cross the BBB as readily; thus, they cause less sedation with fewer non–H1blocking effects than 1st gen. antihistamines. Clinical

Allergic reactions: symptomatic treatment of IgE (immediate, type I) hypersensitivity, urticaria, allergic rhinitis (“hay fever”). Ineffective for angioedema, asthma, and atopic dermatitis.

Side Effects Sedation may still be seen with some 2nd gen. antihistamines at high doses. Notes

Because these agents are less lipid soluble than 1st gen. antihistamines (see diphenhydramine), they do not cross the BBB as readily, cause less sedation, and have fewer non–H1-blocking effects. LORATADINE (Claritin), DESLORATADINE (Clarinex, an active metabolite of loratadine), CETIRIZINE (Zyrtec), and LEVOCETIRIZINE (Xyzal, the active enantiomer of cetirizine) are other second-generation agents. Cetirizine and levocetirizine cause somnolence in a small minority of patients.

INFLAM FEXOFENADINE Loratadine Desloratadine Cetirizine Levocetirizine

ALLOPURINOL (Lopurin, Zyloprim)

antigout

820

Mechanism Inhibits xanthine oxidase (XO), which catalyzes the following reaction in the purine catabolic pathway: hypoxanthine → xanthine → uric acid (normal pathway). Allopurinol is a purine and itself is metabolized by XO to alloxanthine, which is also an XO inhibitor. Inhibition of XO leads to ↓ uric acid formation and ↓ blood and urine urate levels, preventing uric acid crystals from precipitating in joints and in the renal tubules. Clinical

Gout and grossly elevated uric acid serum levels. Recurrent uric acid renal stones. Tumor lysis syndrome (tumor death → massive release of DNA → uric acidemia).

Side Effects Allergic skin reactions. Can precipitate acute gouty arthritis if used as sole agent because uric acid is rapidly mobilized from the tissue; typically given with colchicine to avoid this complication. Interactions Inhibits metabolism and inactivation of mercaptopurine, azathioprine, theophylline, and warfarin. Probenecid and other uricosurics hasten renal excretion of allopurinol. Notes

FEBUXOSTAT (Uloric) is a nonpurine XO inhibitor that appears to be more effective than allopurinol in ↓ uric acid levels. ↑ Incidence of cardiovascular death. Similar interactions with mercaptopurine, azathioprine, and theophylline. RASBURICASE (Elitek) is recombinant urate oxidase (an enzyme that humans lack) which oxidizes uric acid to allantoin which, unlike uric acid, is soluble and easily excreted by the kidneys. PEGLOTICASE (Krystexxa) is a pegylated form of urate oxidase and is longer acting. Both of these agents are used to treat or prevent severe hyperuricemia associated with tumor lysis syndrome.

INFLAM ALLOPURINOL Febuxostat Rasburicase Pegloticase

COLCHICINE

antigout

821

Mechanism Binds tubulin (microtubular protein). This interferes with mitotic spindles and produces depolymerization and disappearance of fibrillar microtubules of granulocytes and other motile cells. This latter effect inhibits migration of granulocytes to sites of inflammation → ↓ inflammatory response and ↓ phagocytosis. Also known to ↓ LTB4 production and inhibit histamine release from mast cells. Clinical

Acute gout (second-line agent to NSAIDs). Prophylaxis against gout attacks. Pericarditis: reduces recurrence. Treatment of familial Mediterranean fever, leukocytoclastic vasculitis, and pseudogout.

Side Effects Inhibition of mitotic spindle formation impacts rapidly proliferating cells: GI: nausea, vomiting, diarrhea, abdominal pain, hemorrhagic gastroenteritis. Bone marrow: temporary leukopenia followed by leukocytosis. Aplastic anemia and agranulocytosis with long-term use. Hair follicles: alopecia. Long-term use can lead to myopathy, particularly in patients with renal insufficiency. Contraindic. Use caution in patients with GI, hepatic, or renal disease. Notes

INFLAM COLCHICINE

PROBENECID (Benemid)

antigout

822

Mechanism Competes with uric acid for weak acid carrier transporter (an anion exchanger in the proximal convoluted tubule) and thereby inhibits uric acid reabsorption → accelerated excretion of urate. Clinical

Gout: used chronically to avoid attacks; does not alter acute course. Most effective in patients with preserved renal function. Prolongs action of penicillins by inhibiting tubular secretion.

Side Effects Formation of uric acid renal stones (↑ urine volume and urine ↑ pH minimize risk). Inhibits renal excretion of penicillins, indomethacin, and sulfonylureas (potentially inducing hypoglycemia). GI irritation. Contraindic. Acute gouty attacks: Therapy should not be started until after the attack has subsided. Uric acid nephrolithiasis as increasing urinary uric acid exacerbates this condition. Notes

SULFINPYRAZONE (Anturane) is similar. In addition, the drug has antiplatelet effects: It inhibits platelet granule release, adherence to subendothelial cells, and prostaglandin synthesis.

INFLAM PROBENECID Sulfinpyrazone

ALKYLATING AGENTS

DNA damaging

9-1

Mechanism Cell cycle–nonspecific (CCNS) antineoplastic agents that act via formation of reactive intermediates that alkylate nucleophilic groups on DNA bases, especially guanine. Leads to cross-linking of bases, abnormal base pairing, and DNA strand breakage. Resistance

Upregulation of the DNA repair protein methylguanine-DNAmethyltransferase (MGMT). Also by ↑ production of glutathione (inactivates alkylating agents) or ↓ drug permeability.

Clinical

Used to treat a wide range of tumors: hematologic, breast, ovary, lung, testis, brain, and others. Because alkylating agents are CCNS, they are cytotoxic to dividing and nondividing cells; this permits them to be used against slower growing malignancies (i.e., those with lower growth fractions) that are generally quite resistant to cell cycle–specific drugs.

Side Effects Most toxic to rapidly dividing cells. Tissues with high rates of turnover (e.g., hair follicles, bone marrow, GI epithelium) account for most of the side effects. Myelosuppression is the usual dose-limiting toxicity. Nausea, vomiting, alopecia, amenorrhea, and male sterility are also common. Secondary malignancies (especially AML and non-Hodgkin lymphoma) can arise years after drug exposure and are caused by DNA damage to nontumor cells. Notes

ONC ALKYLATING AGENTS

ALKYLATING AGENTS Class

Prototype(s)

Nitrogen mustard MECHLORETHAMINE

Phosphoramide mustards

Major uses Hodgkin lymphoma

Toxicities (limiting in bold, unusual in italic) Myelosuppression nausea, vomiting, phlebitis, skin vesicant, amenorrhea, male sterility

CYCLOPHOSPHAMIDE Breast cancer, non- Myelosuppression IFOSFAMIDE Hodgkin hemorrhagic lymphoma, cystitis, N/V, leukemias amenorrhea, male sterility, alopecia CHLORAMBUCIL

Chronic lymphocytic leukemia

Myelosuppression amenorrhea, male sterility

Aromatic mustards

MELPHALAN

Multiple myeloma

Myelosuppression pulmonary infiltrates, and fibrosis, amenorrhea, male sterility

Ethyleneimine

THIOTEPA

Breast and ovarian

Myelosuppression

cancer Chronic myelogenous leukemia

amenorrhea, male sterility

Alkyl sulfonate

BUSULFAN

Nitrosoureas

CARMUSTINE (BCNU) Melanoma, GI LOMUSTINE (CCNU) cancers BENDAMUSTINE Brain cancers ESTRAMUSTINE Chronic STREPTOZOCIN lymphocytic leukemia Prostate cancer Islet cell cancers, carcinoid

Myelosuppression, nausea, vomiting

Triazine

ALTRETAMINE DACARBAZINE PROCARBAZINE TEMOZOLOMIDE

Ovarian cancer Melanoma and lymphoma Brain cancer Brain cancer (GBM)

Myelosuppression nausea, vomiting

Antibiotic

MITOMYCIN

GI Myelosuppression, adenocarcinomas GI mucositis

Myelosuppression pulmonary fibrosis hyperpigmentation, menorrhea, male sterility

CISPLATIN

DNA damaging

9-2

Mechanism Cell cycle–nonspecific (CCNS) antineoplastic agent containing a reactive platinum atom that cross-links DNA by a nonalkylation reaction but is otherwise mechanistically similar to the alkylating agents in its action. Leads to cross-linking of bases, abnormal base pairing, and DNA strand breakage. Resistance

Arises by ↑ DNA repair, ↓ drug permeability.

Clinical

Germ cell tumors including ovarian and testicular, bladder cancer, and many other advanced or metastatic cancers. Because platinum coordination compounds are CCNS, they are cytotoxic to dividing and nondividing cells; this permits them to be used against slower growing malignancies (i.e., those with lower growth fractions) that are generally quite resistant to cell cycle– specific drugs.

Side Effects Renal tubular damage, ototoxicity, peripheral neuropathy. Myelosuppression is common. Nausea, vomiting, alopecia, amenorrhea, and male sterility are also common. Notes

CARBOPLATIN and OXALIPLATIN are similar platinum coordination compounds, used for testicular/ovarian cancers and metastatic colon cancer, respectively.

ONC CISPLATIN Carboplatin Oxaliplatin

BLEOMYCIN (Blenoxane)

DNA damaging

9-3

Mechanism A cell cycle–specific antibiotic that acts during the G2 phase of the cell cycle. It complexes with metal ions (predominantly Fe), intercalates into DNA, and functions as a ferrous oxidase to generate oxygen free radicals that cause both single and double strand DNA breaks. Antitumor effects derive largely from double strand breaks as their repair is more difficult and error prone. Clinical

Lymphomas (Hodgkin and non-Hodgkin) and germ cell testicular cancers.

Side Effects Pulmonary fibrosis is usually dose-limiting; significant ↓ lung function in 10% of patients. Skin changes are common: ulcers, alopecia, stomatitis, hyperpigmentation. Minimal myelosuppression. Metabolism Degraded by bleomycin hydrolase, a cytosolic aminopeptidase found in many tissues (low levels of this enzyme in the lung and skin may account for toxicity). Notes

High concentrations of oxygen can exacerbate bleomycin pulmonary toxicity, even years after drug administration. Thus, treatment of hypoxemia in a patient with prior bleomycin therapy can be extremely challenging.

ONC BLEOMYCIN

DOXORUBICIN (Adriamycin)

DNA damaging

9-4

Mechanism Cell cycle–nonspecific (CCNS) anthracycline that intercalates with DNA, interfering with topoisomerase II → DNA strand breaks → sister chromatid exchange and DNA scission. Drug is also converted into reactive intermediates that generate oxygen free radicals by multiple pathways, one of which is iron dependent → tumor killing + cardiotoxicity (see notes). Resistance

Mediated by accelerated efflux, ↑ glutathione, ↓ topoisomerase II.

Clinical

Leukemias, lymphomas, and breast cancer.

Side Effects Cardiomyopathy is caused by free radicals and related to cumulative dose received. Myelosuppression and GI mucositis are the other dose-limiting toxicities. Radiation recall reaction: erythema and desquamation at site of prior radiotherapy. Toxic extravasation: necrosis of involved tissue. Notes

DAUNORUBICIN (Cerubidine) and IDARUBICIN (Idamycin) are anthracyclines used to treat acute leukemias. EPIRUBICIN (Ellence) is an anthracycline used to treat breast cancer. It is less cardiotoxic and less potent than doxorubicin. VALRUBICIN (Valstar) is an anthracycline administered intravesicularly to treat bladder cancer. Side effects include hematuria, dysuria, incontinence, and urinary frequency. MITOXANTRONE (Novantrone), an anthracene, is structurally related to the anthracyclines but is less prone to forming quinone free radicals and thus less cardiotoxic. DEXRAZOXANE (Zinecard), an iron chelator, may reduce anthracycline cardiotoxicity.

ONC DOXORUBICIN Daunorubicin Idarubicin Epirubicin Valrubicin Mitoxantrone Dexrazoxane

ETOPOSIDE (Toposar)

DNA damaging

9-5

Mechanism Acts during the late S to G2 phase of the cell cycle to form a ternary complex with DNA and topoisomerase II → inhibits ability of topoisomerase II to reseal double-stranded DNA breaks → accumulation of broken DNA strands and cell death. Resistance

Mediated by increased efflux of drug or ↓ topoisomerase II expression.

Clinical

Testicular and small cell lung cancers. Lymphoma, AML, Kaposi sarcoma, osteosarcoma, and neuroblastoma.

Side Effects Leukopenia, vomiting, and nausea are the usual dose-limiting toxicities. An unusually high rate of secondary leukemias with a characteristic translocation (involving 11q23) has been seen in children after treatment with etoposide. This translocation is thought to be a side effect of the double-stranded DNA breaks induced by the drug. Notes

TENIPOSIDE (Vumon) is a similar agent. TOPOTECAN (Hycamtin) causes DNA damage by inhibiting topoisomerase I, an enzyme that cuts and relegates single-stranded DNA breaks. It is used in the treatment of ovarian cancers. Myelosuppression is its major side effect. IRINOTECAN (Camptosar) is another topoisomerase I inhibitor used in the treatment of colon and pancreatic cancers. Diarrhea is a prominent side effect.

ONC ETOPOSIDE Teniposide Topotecan Irinotecan

DACTINOMYCIN (Cosmegen)

transcription inhibitor

9-6

Mechanism A cell cycle–nonspecific antibiotic that tightly binds double-stranded DNA → blockade of mRNA transcription. Also causes singlestrand breaks in DNA and can impair DNA replication. Clinical

Rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor in children → potentially curative when combined with surgery and radiation. Choriocarcinoma and related gestational trophoblastic neoplasms.

Side Effects Myelosuppression and GI mucositis are the usual dose-limiting toxicities. Nausea and vomiting are also common. Toxic extravasation: necrosis of involved tissue. Notes

ONC DACTINOMYCIN

OLAPARIB (Lynparza)

PARP inhibitor

9-7

Mechanism Small molecule inhibitor of poly ADP ribose polymerase (PARP), an enzyme that plays an essential role in repair of single-stranded DNA breaks. These unrepaired single-strand breaks become doublestranded DNA breaks during mitosis (occurs frequently in dividing tumor cells). This is especially toxic to those with mutant BRCA1 or BRCA2 alleles as BRCA1/2 are required for repair of double strandbreaks by homologous recombination. Thus, BRCA1/2 mutant cancers must repair double-strand breaks by error-prone nonhomologous end joining → excessively high rate of mutations and cell death. Resistance

Drug efflux pumps.

Clinical

Ovarian cancer with BRCA1 or BRCA2 mutations.

Side Effects Myelosuppression, secondary malignancy (MDS/AML), pneumonitis, nausea, vomiting. Notes

The BRCA1 and BRCA2 genes were initially identified as genes mutated in families with high rates of breast and ovarian cancer. Their role in DNA repair was discovered subsequently. RUCAPARIB (Rubraca) is a PARP inhibitor used for BRCA1/2 mutant ovarian cancer. NIRAPARIB (Zejula) is a PARP inhibitor used for ovarian, fallopian tube, and primary peritoneal cancers.

ONC OLAPARIB Rucaparib Niraparib

CYTARABINE (CytosarU)

antimetabolite

9-8

Mechanism Analog of deoxycytidine that acts during S phase of cell cycle. Activated by deoxycytidine kinase: cytarabine → AraCMP → AraCDP → AraCTP. AraCTP is incorporated into DNA and inhibits further DNA replication or repair. Potent inducer of tumor cell differentiation → growth arrest. Resistance

Arises via ↓ activation by deoxycytidine kinase or ↑ inactivation by cytidine deaminase. ↓ Drug uptake and ↑ intracellular dCTP concentrations may also be important.

Clinical

Acute leukemias.

Side Effects Myelosuppression and GI mucositis are usual dose-limiting toxicities. Nausea, vomiting, and alopecia are also common. Metabolism Converted by cytidine deaminase to inactive arauridine (AraU), mainly in the liver. Notes

GEMCITABINE (Gemzar) is phosphorylated by cell enzymes and acts as a chain terminator when incorporated into DNA. It is used in the treatment of lung and pancreatic cancers. NELARABINE (Arranon), a guanosine analog used for T-cell ALL, is converted by cell enzymes into ara-GTP, which is incorporated into DNA, blocking further synthesis.

ONC CYTARABINE Gemcitabine Nelarabine

FLUDARABINE (Fludara)

antimetabolite

9-9

Mechanism A cell cycle–specific antimetabolite analog of adenosine that is resistant to degradation by adenosine deaminase (ADA). Phosphorylated to fludarabine triphosphate, which inhibits DNA polymerase and other enzymes, leading to chain termination during DNA synthesis and repair. Lymphocytes are particularly susceptible to elevated fludarabine triphosphate levels, just as they are to deoxyadenosine triphosphate (dATP) accumulation in congenital ADA deficiency (see notes). Clinical

Chronic lymphocytic leukemia (CLL).

Side Effects Myelosuppression. Severe depletion of CD4+ T cells can lead to opportunistic infections. Notes

ADA converts adenosine → inosine and prevents excessive intracellular dATP concentrations. Severe combined immunodeficiency (SCID) is caused by congenital ADA deficiency → high intracellular levels of dATP and the near absence of B and T lymphocytes. CLADRIBINE (Leustatin) is another ADA-resistant adenosine analog that accumulates as 2-chloroATP. Used to treat Waldenström macroglobulinemia and hairy cell leukemia (lymphocyte malignancies). PENTOSTATIN (Nipent) is an analog of dATP and potent inhibitor of ADA. Accumulation of dATP is toxic to lymphocytes. Used to treat hairy cell leukemia but is more immunosuppressive than cladribine. CLOFARABINE (Clolar) is an adenosine analog used to treat refractory ALL and AML.

ONC FLUDARABINE Cladribine Pentostatin Clofarabine

5-FLUOROURACIL (5FU)

antimetabolite

910

Mechanism A cell cycle–specific antimetabolite that acts during the S phase of the cell cycle. Cellular enzymes convert 5-FU into 5-FdUMP, which inhibits thymidylate synthase, preventing DNA synthesis 5-FU is also converted into FUMP by pyrimidine monophosphate kinase. FUMP can be incorporated into RNA and interfere with RNA processing and function. Resistance

Amplification or mutation of thymidylate synthase. ↓ Pyrimidine monophosphate kinase (↓ incorporation into RNA).

Clinical

Solid tumors (colorectal, pancreatic, breast, gastric, bladder, head and neck). Topically for solar keratoses or basal cell carcinoma.

Side Effects Myelosuppression and GI mucositis are the usual dose-limiting toxicities. Nausea, vomiting, alopecia, and cerebellar ataxia are also common. Notes

CAPECITABINE (Xeloda) is a 5-FU prodrug that may be slightly less toxic because of more efficient conversion to 5-FU by tumor cells. Used to treat breast cancer. FLOXURIDINE (FUDR) is a prodrug converted into 5-FU by the liver and therefore is especially useful for treating hepatic metastasis of colorectal cancer.

ONC 5FLUOROURACIL Capecitabine Floxuridine

HYDROXYUREA (Hydrea)

antimetabolite

911

Mechanism A cell cycle–specific chemotherapeutic agent that acts during S phase as an inhibitor of ribonucleotide reductase → depletion of deoxynucleoside triphosphates and impaired DNA synthesis. Clinical

Myeloproliferative diseases, especially chronic myeloid leukemia: used as cytoreductive therapy for patients in stable phase (i.e., used to prevent extreme leukocytosis and its attendant complications such as stroke). Sickle cell disease: upregulates expression of the (normal) fetal hemoglobin gene by an unclear mechanism → decreased propensity to sickle.

Side Effects Myelosuppression. Nausea, vomiting, diarrhea at higher doses. Metabolism PO. Renal excretion. Notes

ANAGRELIDE (Agrylin) is used as cytoreductive therapy for essential thrombocythemia. The exact mechanism is unclear, but the drug appears to disrupt megakaryocyte maturation. At therapeutic doses, anagrelide reduces platelet counts without significant changes in white cell counts, red cell counts, or coagulation parameters.

ONC HYDROXYUREA Anagrelide

MERCAPTOPURINE (Purinethol)

antimetabolite

912

Mechanism A cell cycle–specific antimetabolite, 6-mercaptopurine (6-MP) is an analog of adenine. 6-MP is converted to 6-thioIMP by the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase. 6-thioIMP accumulates in cells and inhibits purine production by blocking: IMP →→ GMP (by inhibiting IMP dehydrogenase) and PRPP → ribosylamine 5-phosphate (the rate-limiting step for de novo purine synthesis catalyzed by PRPP aminotransferase). Clinical

Acute lymphocytic leukemia (ALL): maintenance of remission. Inflammatory bowel disease.

Side Effects Myelosuppression is the usual dose-limiting toxicity. GI side effects (nausea, vomiting, rarely pancreatitis). Metabolism Metabolized by xanthine oxidase. Mercaptopurine’s efficacy and toxicity are increased when coadministered with allopurinol. Notes

THIOGUANINE (6-TG) is also a purine analog that works similarly to 6-MP. Used to treat acute leukemia in adults.

ONC MERCAPTOPURINE Thioguanine

VINCRISTINE (Oncovin)

antimicrotubule

913

Mechanism A cell cycle–specific vinca alkaloid that binds to tubulin dimers and prevents microtubule polymerization. This prevents separation of sister chromatids, causing mitotic arrest and blocking cell division (cytokinesis failure → apoptosis). Resistance

Amplification of tubulin-producing genes. Efflux of drug from cells (can be reversed by calcium channel blockers).

Clinical

Leukemias, lymphomas, Wilms tumor, neuroblastoma, brain tumors, breast and bladder cancers.

Side Effects Peripheral neuropathy is the usual dose-limiting toxicity.

Notes

Its minimal myelosuppression makes this agent important for acute lymphocytic leukemia (ALL): Patients frequently present with “functional pancytopenia” and cannot tolerate further myelosuppression. VINBLASTINE (Velban) is another vinca alkaloid used to treat testicular tumors and Hodgkin lymphoma. It causes more myelosuppression and less peripheral neuropathy than vincristine. VINORELBINE (Navelbine) is a synthetic vinca alkaloid that is used to treat non–small cell lung cancer and breast cancer. Myelosuppression is the usual dose-limiting toxicity. ERIBULIN (Halaven) is a novel agent that disrupts microtubule dynamics by a distinct mechanism and is approved for treatment of breast cancer and liposarcomas.

ONC VINCRISTINE Vinblastine Vinorelbine Eribulin

PACLITAXEL (Taxol)

antimicrotubule

914

Mechanism A cell cycle–specific taxane that binds to tubulin and prevents microtubule depolymerization (contrast with vincristine). During metaphase, stabilization of microtubules results in aberrant multiple polar spindles and blocks cell division (cytokinesis failure → apoptosis). Clinical

Used to treat a wide variety of solid tumors, including ovarian, breast, and lung. Prevention of restenosis after coronary artery stenting: Paclitaxel coating of these stents limits cell migration to their lumens.

Side Effects Peripheral neuropathy. Hypersensitivity reaction, including dyspnea, hypotension, and urticaria in up to 5%. Also causes myelosuppression, alopecia, and mild nausea and vomiting. Notes

Originally isolated from the bark of the Pacific yew tree, one of the slowest growing trees in the world. Now produced from renewable resources. DOCETAXEL (Taxotere) and CABAZITAXEL (Jevtana) are semisynthetic taxanes used in a variety of solid tumors (especially advanced prostate cancer); mechanism and side effect profile are similar to those of paclitaxel. IXABEPILONE (Ixempra) is a nontaxane that also disrupts mitosis via binding and stabilizing microtubules. It can be used to treat taxane-resistant breast cancer.

ONC PACLITAXEL Docetaxel Cabazitaxel Ixabepilone

ALL-TRANS RETINOIC ACID (ATRA, Vesanoid)

gene expression modifier

915

Mechanism A derivative of vitamin A (or retinoid) used to treat acute promyelocytic leukemia (APML). Most APML cells have a translocation of chromosomes 15 and 17, creating a chimeric gene composed of the retinoic acid receptor (RAR) alpha and the PML gene. The resultant fusion protein, in the absence of ATRA ligand, acts as a dominant negative, blocking normal RAR-mediated myeloid differentiation. Upon binding of ATRA, the PML-RAR fusion protein becomes dissociated from transcription repressors (e.g., NCoR), and normal terminal differentiation of the cell is restored. Clinical

APML induction therapy.

Side Effects Retinoic acid syndrome: dyspnea, fever, and weight gain. Thought to be attributable to capillary leak; can be treated with steroids. Vitamin A toxicity: headache, fever, dry skin, hepatitis, and conjunctivitis. Neurologic: depression, confusion, and agitation. Contraindic. Pregnancy: ATRA is a potent teratogen. Notes

ARSENIC TRIOXIDE is usually coadministered with ATRA; this compound binds to and degrades PML and the PML-RAR fusion, inducing differentiation of leukemic promyelocytes. Topical ATRA (Retin-A) is used to treat acne. ISOTRETINOIN (Accutane) is another retinoid used to treat acne that is also teratogenic.

ONC ALL-TRANS RETINOIC ACID Arsenic Trioxide Isotretinoin

AZACITIDINE (Vidaza)

gene expression modifier

916

Mechanism A cytosine analog that competitively inhibits DNA methyltransferase → hypomethylation of cytosine residues on chromosomal DNA and “unsilencing” of genes. Enhanced expression of tumor suppressor genes is believed to account for this drug’s efficacy. At high doses, also acts as a cell cycle–specific antimetabolite in a manner analogous to cytarabine. Clinical

Myelodysplastic syndromes, acute myelogenous leukemia.

Side Effects Myelosuppression.

Notes

Neoplastic changes can be genetic and irreversible (e.g., deletion or mutation of gene) or epigenetic and potentially reversible (e.g., modifications of DNA or chromatin structure that affect gene expression). Epigenetic therapies such as azacytidine offer the potential to undo some of the steps that led to the development of malignancy. DECITABINE (Dacogen) is a related, more potent DNA methyltransferase inhibitor that is also used to treat myelodysplastic syndromes. VORINOSTAT (Zolinza), BELINOSTAT (Beleodaq), PANOBINOSTAT (Farydak), and ROMIDEPSIN (Istodax) are histone deacetylase (HDAC) inhibitors used to treat T-cell lymphomas and multiple myeloma. HDACs normally function to silence genes; thus their inhibition promotes histone acetylation and results in “unsilencing” of genes.

ONC AZACITIDINE Decitabine Vorinostat Belinostat Panobinostat Romidepsin

IMATINIB (Gleevec)

tyrosine kinase inhibitor

917

Mechanism Small-molecule inhibitor of the ABL tyrosine kinase as well as the c-kit and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Binds to and blocks ATP acceptor site of these kinases, thus preventing substrate phosphorylation. In chronic myelogenous leukemia (CML), the ABL tyrosine kinase is dysregulated by fusion to the BCR protein. The resultant BCR-ABL fusion protein is a constitutively active kinase that activates multiple signaling pathways that promote cell division and resistance to apoptosis, resulting in leukemia. Resistance

Amplification of the BCR-ABL fusion gene or point mutations in the ATP-binding pocket.

Clinical

CML: chronic phase and blast crisis. C-kit positive GI stromal tumors (GIST). PDGF receptor–dependent neoplasia: hypereosinophilic syndrome and others.

Side Effects Generally well tolerated; nausea, rash, and musculoskeletal pain have been described.

Notes

The BCR-ABL oncoprotein is central to the pathogenesis of CML and almost always results from a t(9:22) translocation (the Philadelphia chromosome). DASATINIB (Sprycel), NILOTINIB (Tasigna), and BOSUTINIB (Bosulif) are second-generation tyrosine kinase inhibitors with higher affinity for the ABL kinase; used to treat imatinib-resistant CML. PONATINIB (Iclusig) is a third-generation inhibitor used to treat CML resistant to second-generation agents.

ONC IMATINIB Dasatinib Nilotinib Bosutinib Ponatinib

CRIZOTINIB (Xalkori)

tyrosine kinase inhibitor

918

Mechanism Tyrosine kinase inhibitor with activity against anaplastic lymphoma kinase (ALK). A subset of non–small cell lung cancers (NSCLCs) has inversion in chromosome 2 that creates a fusion of the EML4 gene and the ALK. EML4-ALK fusion results in constitutive ALK activity (analogous to BCR-ABL fusion, see imatinib). Less frequently, genes other than EML4 are fused to ALK. ALK fusion positive NSCLC is a distinct disease, often seen in nonsmokers for which therapies targeting the EGFR (commonly mutated other NSCLC subtypes) are generally not effective. Resistance

ALK mutations that block crizotinib binding. EML4-ALK gene amplification. Upregulation/activation of alternative receptor tyrosine kinases (e.g., EGFR).

Clinical

NSCLC with ALK fusions (almost always adenocarcinomas).

Side Effects Hepatotoxicity, bradycardia, QT interval prolongation, pneumonitis, hyperglycemia. Notes

The ALK gene was named for its association with a subset of peripheral T-cell lymphomas; it was later implicated in NSCLC, a much more common disease. CERITINIB (Zykadia) and ALECTINIB (Alecensa) are secondgeneration ALK inhibitors used for NSCLC resistant to crizotinib.

ONC CRIZOTINIB Ceritinib Alectinib

IBRUTINIB (Imbruvica)

tyrosine kinase inhibitor

919

Mechanism Aberrant signaling through the B-cell receptor (BCR) is observed in many B-cell lymphomas. This agent irreversibly inhibits Bruton tyrosine kinase (BTK), a critical mediator of the BCR signaling cascade. In lymphomas that have become addicted to tonic BCR signaling, this causes impaired growth and apoptosis. There is some evidence that BTK inhibition also causes B-cell migration out of the supportive solid lymphoid tissue microenvironments, making them more sensitive to other chemotherapy agents. Resistance

BTK mutation → prevent ibrutinib binding. Gain-of-function mutation in phospholipase C → bypass need for BTK in BCR activation.

Clinical

Chronic lymphocytic leukemia (CLL), mantle cell lymphoma, Waldenström macroglobulinemia.

Side Effects Edema, myelosuppression, diarrhea. Notes

B lymphocytes not only secrete antibodies but also display them on their surface in conjunction with signaling molecules collectively called the BCR. Binding of antigen to BCR activates signaling cascades that promote the proliferation to that B cell, amplifying the response against that antigen. IDELALISIB (Zydelig) is a PI3K delta inhibitor used for second-line treatment of CLL. Side effects include liver toxicity, severe diarrhea, colitis, and pneumonitis.

ONC IBRUTINIB Idelalisib

TRASTUZUMAB (Herceptin)

antireceptor tyrosine kinase

920

Mechanism Monoclonal antibody targeting human epidermal growth factor (EGF) receptor 2 (HER2). Binds to HER2 receptors on tumor cells, preventing activation of the HER2 tyrosine kinase domain, blocking tumor growth, survival, and VEGF production (see bevacizumab). Tumor cells are likely targeted for antibody-dependent cellular cytotoxicity (ADCC) as well. Clinical

HER2 overexpressing breast cancer.

Resistance

Activating mutations in molecules downstream of these receptors (e.g., KRAS mutations).

Side Effects Cardiotoxicity possibly synergistic with anthracyclines (see doxorubicin).

Notes

The HER family of tyrosine kinase receptors are activated by different ligands: EGF activates HER1 (a.k.a EGFR), heregulins binds HER3 and HER4, and the HER2 ligand is unknown. These receptors can heterodimerize. HER2/HER3 heterodimers are especially potent signaling molecules. PERTUZUMAB (Perjeta), an anti-HER2 antibody for breast cancer, inhibits HER2/HER3 dimerization. LAPATINIB (Tykerb) is a small molecule HER2 kinase inhibitor; used to treat HER2+ breast cancer. CETUXIMAB (Erbitux) and PANITUMUMAB (Vectibix) are monoclonal antibodies against HER1/EGFR used to treat colon cancer and non–small cell lung cancer. ERLOTINIB (Tarceva) and GEFITINIB (Iressa) are HER1/EGFR tyrosine kinase inhibitors used to treat non–small cell lung cancer and pancreatic cancer. AFATINIB (Gilotrif) is a covalent/irreversible inhibitor of HER1/EGFR, HER2, and HER4 kinases.

ONC TRASTUZUMAB Pertuzumab Lapatinib Cetuximab Panitumumab Erlotinib Gefitinib Afatinib

BEVACIZUMAB (Avastin)

antiangiogenesis

921

Mechanism Humanized monoclonal antibody that binds vascular endothelial growth factor A (VEGF-A) and prevents VEGF-mediated angiogenesis. In order to continue to grow beyond their original blood supply, tumors subvert the VEGF angiogenesis pathway. Normally, VEGF allows blood vessel formation when tissue growth is required (e.g., during wound healing). Angiogenesis is also central to the pathogenesis of the neovascular or “wet” subtype of macular degeneration, the leading cause of adult blindness in industrialized countries. Clinical

Advanced or metastatic breast, colon, renal cell, brain (GBM), and non–small cell lung cancer.

Side Effects Bleeding and poor wound healing (particularly at tumor sites), GI perforation, HTN, and proteinuria.

Notes

VEGF-A is the most important in this family of growth factors (which includes VEGF-A through E and placental growth factors 1 and 2) for angiogenesis. RANIBIZUMAB (Lucentis) is a monoclonal antibody against VEGFA; used for macular degeneration. PEGAPTANIB (Macugen) is a VEGF-A binding agent used to treat macular degeneration. SORAFENIB (Nexavar) and SUNITINIB (Sutent) are tyrosine inhibitors used to treat unresectable liver and renal cell cancers. Their spectrum of activity includes VEGF receptors. ZIV-AFLIBERCEPT (Zaltrap) is a VEGF trap, a recombinant fusion protein comprised of portions of the VEGF-1 and VEGF-2 binding receptors. It is used for metastatic colon cancer. RAMUCIRUMAB (Cyramza) is an anti-VEGFR2 antibody used for advanced cancers.

ONC BEVACIZUMAB Ranibizumab Pegaptanib Sorafenib Sunitinib Ziv-Aflibercept Ramucirumab

Adapted from Becker J. Signal transduction inhibitors—a work in progress. Nat Biotechnol. 2004;22:15–18.

VEMURAFENIB (Zelboraf)

serine/threonine kinase inhibitor

922

Mechanism Growth factor receptors are commonly mutated in cancer as is the mitogen activated protein (MAP) kinase cascade (RAS → RAF → MEK → ERK) through which they signal. This agent was designed to inhibit B-RAF V600E, the most common B-RAF activating mutation seen in malignant melanoma. It also inhibits B-RAF V600K (a less common mutation) but has no effect on normal BRAF. Resistance

B-RAF amplification. Overexpression of cell surface tyrosine kinase receptors or activating mutations of N-RAS (either of these produce signals via the nonmutant B-RAF allele’s gene product which vemurafenib does not inhibit).

Clinical

Malignant melanoma with B-RAF V600K or V600E mutation— contraindicated in melanoma lacking these mutations as drug is weak activator of wild type B-RAF and can promote tumor progression.

Side Effects Arthralgia, skin rash, photosensitivity. Notes

Vemurafenib derives its name from V600E MUtation RAF inhibitor. DABRAFENIB (Tafinlar) is another V600E/K B-RAF inhibitor. TRAMETINIB (Mekinist) and COBIMETINIB (Cotellic) are MEK inhibitors used with B-RAF inhibitors for melanoma, as resistance develops quickly to single-agent therapy.

ONC VEMURAFENIB Dabrafenib Trametinib Cobimetinib

RUXOLITINIB (Jakafi)

Janus kinase inhibitor

923

Mechanism Inhibitor of Janus kinases (JAK) 1 and 2. Activating mutations in JAK2 cause polycythemia vera, by allowing growth of erythroid progenitors in the absence erythropoietin. JAK2 mutations have also been linked to several myeloproliferative diseases such as myelofibrosis. Resistance

JAK mutations that prevent ruxolitinib binding.

Clinical

Myelofibrosis, polycythemia vera.

Side Effects Myelosuppression, infections, liver toxicity, hyperlipidemia, nonmelanoma skin cancer. Notes

JAK-STAT linked receptors include those for cytokines, interferons, and some hematopoietic growth factors. Ligand binding initially activates JAK1 to JAK3 and subsequently the STAT family of transcription factors which enter the nucleus and drives transcription. TOFACITINIB (Xeljanz) is a JAK1/3 inhibitor used to block excessive cytokine signaling in autoimmune/inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

ONC RUXOLITINIB Tofacitinib

PALBOCICLIB (Ibrance)

CDK4/6 inhibitor

924

Mechanism Inhibits cyclin-dependent kinases (CDKs) 4 and 6, arresting cells in the G1 phase. Resistance

Amplification of cyclins E or A, which activate CDK2 and allow the cell to continue through the cell cycle independent of CDK4/6. Loss of retinoblastoma (Rb) protein. Activated CDK4/6 normally phosphorylates Rb, derepressing E2F transcription factors and promoting transcription of genes required for cell cycle progression. Without Rb, cells can progress to S phase independent of CDK4/6.

Clinical

Breast cancer (because cyclin D is often amplified or overexpressed in breast cancer).

Side Effects Myelosuppression, infections, thromboembolic events. Notes

CDKs control progression through the cell cycle. Different CDKs control specific phases of the cell cycle (see figure on back). Cyclin D binds and activates CDK4 and CDK6, which regulate progression from G1 into S phase. Cyclins E and A bind CDK2, which regulates progression through S phase. Cyclin B binds and activates CDK1, which regulates progression through mitosis (M phase). RIBOCICLIB (Kisqali) is another CDK4/6 inhibitor used to treat breast cancer.

ONC PALBOCICLIB Ribociclib

RITUXIMAB (Rituxan)

antitumor monoclonal

925

Mechanism A chimeric monoclonal antibody targeted to the CD20 antigen found on the surface of B-cell precursors and mature B cells. Binding of rituximab to CD20 blocks B-cell differentiation and division and promotes tumor cell lysis by complement and antibody-dependent, cell-medicated cytotoxicity. Clinical

B-cell lymphomas. Autoimmune hemolytic anemia: eliminates autoreactive B cells. Moderate to severe rheumatoid arthritis refractory to TNF inhibitors (see etanercept).

Side Effects Infusion-related fevers, chills, hives, flushing, and sometimes dyspnea are common. Impairment of humoral immunity is limited because plasma cells (which are responsible for the bulk of circulating antibody) do not express CD20. Memory B cells, however, do express CD20.

Notes

OBINUTUZUMAB (Gazyva) and OFATUMUMAB (Arzerra) are anti-CD20 antibodies for CLL. BLINATUMOMAB (Blincyto) is an anti-CD19 antibody used to treat ALL. IBRITUMOMAB (Zevalin) and TOSITUMOMAB (Bexxar) are anti-CD20 antibodies covalently bound to yttrium-90 or iodine-131, respectively, which enhance their killing of B-cell lymphomas. ALEMTUZUMAB (Campath), a CD52 antibody, is used for T-cell lymphoma, CLL, and induction therapy for transplant recipients. BRENTUXIMAB VEDOTIN (Adcetris) is an anti-CD30 antibody covalently bound to a microtubule disruptor (see vincristine) that gets activated after entering the cancer cell.

ONC RITUXIMAB Obinutuzumab Ofatumumab Blinatumomab Ibritumomab Tositumomab Alemtuzumab Brentuximab Vedotin

BORTEZOMIB (Velcade)

proteasome inhibitor

926

Mechanism Bortezomib is an inhibitor of the 26S subunit of the proteasome, a protein complex that degrades proteins targeted for destruction by polyubiquitylation. This disruption of regulated protein turnover interferes with multiple signaling pathways, including NF-κ-B, a transcription factor that protects tumor cells from apoptosis. Disruption of these pathways and possibly the inability to degrade misfolded proteins results in cell death. Clinical

Multiple myeloma: used in refractory or relapsed disease. Non-Hodgkin lymphoma.

Side Effects Fatigue, malaise, weakness, and myelosuppression. Peripheral neuropathy develops in 30% of patients but usually improves with cessation of the drug. Notes

CARFILZOMIB (Kyprolis) and IXAZOMIB (Ninlaro) are also proteasome inhibitors used for relapsed or refractory multiple myeloma.

ONC BORTEZOMIB Carfilzomib Ixazomib

NIVOLUMAB (Opdivo)

immune checkpoint inhibitor

927

Mechanism Antibody to PD-1 that blocks signaling of this T-cell “immune checkpoint” receptor that normally functions to limit T-cell activation and prevent autoimmunity. Many tumors upregulate the PD-1 ligand, PD-L1 (or rarely PD-L2), thereby impairing antitumor immune responses. Clinical

Advanced/metastatic melanoma. Non–small cell lung, renal cell, head, and neck cancers; Hodgkin lymphoma.

Side Effects Autoimmunity, including fatal myocarditis; edema, fatigue.

Notes

PEMBROLIZUMAB (Keytruda) is another anti–PD-1 antibody used for melanoma. ATEZOLIZUMAB (Tecentriq) and AVELUMAB (Bavencio) are anti–PD-L1 antibodies (i.e., against the ligand) approved for non– small cell lung cancer and Merkel cell carcinoma, respectively. IPILIMUMAB (Yervoy) and TREMELIMUMAB (Yervoy) are antibodies against CTLA-4, another checkpoint receptor on T cells whose ligands are found on antigen presenting cells. Thus, CTLA-4 is thought to be more important in regulating antitumor immune response initiation. In general, targeting CTLA-4 produces a less dramatic antitumor than targeting PD-1, but the combination is synergistic. ALDESLEUKIN (Proleukin) is recombinant interleukin-2 (IL-2), a cytokine that activates CD4+ and CD8+ T cells and enhances antitumor activity of NK cells. Used for melanoma and renal cell carcinoma. Flu-like symptoms are common. Vascular leak syndrome is the dose-limiting toxicity.

ONC NIVOLUMAB Pembrolizumab Atezolizumab Avelumab Ipilimumab Tremelimumab Aldesleukin

LENALIDOMIDE (Revlimid)

immunomodulator

928

Mechanism This drug, like all thalidomide analogs (see notes), binds to cereblon (an enzyme that catalyzes the addition of ubiquitin chains onto other proteins, targeting them for degradation), altering its specificity to include the Ikaros transcription factors IKZF1 and IKZF3. Loss of Ikaros activity downregulates many genes, including IRF4 (which promotes myeloma survival) and FGF8 (essential for fetal limb development). Clinical

Multiple myeloma. Myelodysplastic syndrome (see also azacitidine).

Side Effects Thrombocytopenia, neutropenia, diarrhea, rash, pruritus, and fatigue. Contraindic. Pregnancy—see thalidomide in notes section.

Notes

POMALIDOMIDE (Pomalyst) is a similar agent used for relapsed or refractory multiple myeloma. THALIDOMIDE (Thalomid) is an infamous drug, originally marketed as a sedative. If taken during the first trimester of pregnancy, it caused an otherwise rare birth defect (phocomelia, characterized by shortening or complete absence of limbs). Withdrawn from the market after about 10,000 “thalidomide babies” were born in the late 1950s. Later reintroduced as an immunomodulator for autoimmune diseases. Most recently, found to have potent activity against multiple myeloma—all prior to the elucidation of its mechanism of action. This agent has largely replaced by newer analogs.

ONC LENALIDOMIDE Pomalidomide Thalidomide

VENETOCLAX (Venclexta)

BCL-2 inhibitor

929

Mechanism Inhibits B-cell lymphoma 2 (BCL-2), a negative regulator of the intrinsic apoptosis pathway that works by sequestering proapoptotic proteins such as Bim and Bax. Many lymphoid malignancies overexpress BCL-2, which impairs apoptosis and increases resistance to chemotherapy (see notes). Thus, BCL-2 inhibition may directly kill lymphoma cells and increase their sensitivity to other chemotherapy agents. Resistance

Overexpression of the other major antiapoptotic proteins in the BCL-2 family: BCL-XL and MCL-1.

Clinical

Chronic lymphocytic leukemia.

Side Effects Myelosuppression, tumor lysis syndrome, fertility problems for males, nausea, diarrhea. Notes

BCL-2 is so named because the gene encoding it was originally identified as being involved in a chromosomal translocation in a Bcell lymphoma cell line. The intrinsic apoptosis pathway is activated as a result of “danger” signals within a cell, such as unregulated growth. Many tumors evade this defense by upregulating BCL-2 family members. Many chemotherapy agents kill cancer cells indirectly via toxic effects that trigger “danger” signals and activate the intrinsic apoptosis pathway. The extrinsic apoptosis pathway is activated by extracellular ligands (e.g., T cells trigger apoptosis in a target cell using this pathway).

ONC VENETOCLAX

CIMETIDINE (Tagamet)

H2 blocker

10-1

Mechanism Competitively inhibits histamine at H2 receptors. Primary effect is on parietal cells of stomach, where histamine acts as one of the three physiologic stimulants to gastric acid secretion. H2 blockers also blunt the effects of the other two stimuli, gastrin and vagal stimulation, suggesting that their full effects are at least partially mediated through histamine as well. Clinical

Gastroesophageal reflux disease (GERD). Peptic ulcer disease: relieves symptoms and promotes healing.

Side Effects Mental status changes (e.g., confusion, disorientation) in elderly patients. Antiandrogen effects: enhances prolactin secretion, inhibits CYP450 hydroxylation of estradiol → ↑ plasma estradiol → gynecomastia in men and galactorrhea in women. Competes with renal secretion of creatinine → ↑ serum creatinine without true renal insufficiency. Contraindic. Use caution in elderly patients and in patients with renal or hepatic impairment. Interactions May ↑ blood levels of many drugs via CYP450 inhibition (see CYP450 card for examples). Notes

RANITIDINE (Zantac), FAMOTIDINE (Pepcid), and NIZATIDINE (Axid) are similar but do not inhibit CYP450 and do not cause mental status changes in the elderly.

MISC CIMETIDINE Ranitidine Famotidine Nizatidine

OMEPRAZOLE (Prilosec)

proton pump inhibitor

10-2

Mechanism Inhibits the gastric parietal cell proton pump, an H+/K+ ATPase. Proton pump inhibitors (PPIs) are prodrugs that become activated in acidic environment of gastric parietal cells. Activated form binds covalently with sulfhydryl groups on cysteines on H+/K+ ATPase, inactivating the pump. Despite short half-life of the drug, inactivation of pump molecules is irreversible, so acid secretion can resume only after new pump molecules are synthesized. A single dose per day can essentially eliminate all gastric acid secretion. Clinical

Peptic ulcer disease: relieves symptoms and promotes healing. Part of combination therapy (antibiotics + PPI) to eradicate Helicobacter pylori infection. Severe or refractory erosive esophagitis from gastroesophageal reflux disease (GERD). Zollinger-Ellison syndrome.

Side Effects Headache, diarrhea, nausea, flatulence. Chronic suppression of HCl secretion eliminates a key defense against pathogens spread by fecal–oral route: ↑ risk of infection by enteric pathogens, especially Clostridium difficile. Interactions ↓ Antiplatelet effect of clopidogrel (by inhibiting CYP2C19 conversion from prodrug to active compound or possibly through altering gastric pH). No convincing data for any clinical ramifications. Notes

DEXLANSOPRAZOLE (Dexilant), ESOMEPRAZOLE (Nexium), LANSOPRAZOLE (Prevacid), PANTOPRAZOLE (Protonix), and RABEPRAZOLE (AcipHex) are other PPIs.

MISC OMEPRAZOLE Dexlansoprazole Esomeprazole Lansoprazole Pantoprazole Rabeprazole

MISOPROSTOL (Cytotec)

prostaglandin

10-3

Mechanism A PGE1 derivative, it acts as an agonist at EP3 prostaglandin receptors on parietal cells in the stomach, inhibiting gastric acid secretion and promoting secretion of mucus and other cytoprotective factors. Clinical

↓ NSAID-induced gastritis. Also used to induce cervical ripening and as an abortifacient.

Side Effects Diarrhea (dose related). Can exacerbate inflammatory bowel disease.

Notes

LUBIPROSTONE (Amitiza) is a PGE1 derivative that stimulates chloride channel opening in the intestine, thereby accelerating intestinal transit time. Used to treat chronic constipation, including secondary to irritable bowel syndrome. Side effects include nausea and headache. DINOPROSTONE (PGE2, Prepidil, Cervidil) and CARBOPROST (Hemabate, PGF2α derivative) induce cervical ripening and uterine contractions. Used early in pregnancy as an abortifacient, at term to induce labor, and after delivery to control uterine bleeding. ALPROSTADIL (PGE1, Caverject) injected into corpora cavernosa to cause smooth muscle relaxation. Used for erectile dysfunction but has been supplanted by oral phosphodiesterase inhibitors (see sildenafil). SUCRALFATE, or sulfated aluminum sucrose, selectively binds to necrotic peptic ulcer tissue and acts as a barrier to acid, pepsin, and bile. May also stimulate synthesis of protective prostaglandins. Used as stress ulcer prophylaxis. Requires presence of acid for maximal effect (therefore should not coadminister with an H2 blocker or a PPI). Interferes with PO absorption of many drugs.

MISC MISOPROSTOL Lubiprostone Dinoprostone Carboprost Alprostadil Sucralfate

LATANOPROST (Xalatan)

prostaglandin

10-4

Mechanism A PGF2α derivative, it binds to FP receptors (so named because their primary ligand is F2α prostaglandin), a Gq-coupled receptors that ↑ phospholipase C → smooth muscle contraction. When applied topically to the eye, facilitates outflow of aqueous humor through uveoscleral and trabecular meshwork pathways, thereby ↓ intraocular pressure. Clinical

Glaucoma (treatment of choice).

Side Effects Permanent increase in pigment of the iris and eyelid and may increase eyelash growth. Bacterial keratitis may occur. Notes

BIMATOPROST (Lumigan), TAFLUPROST (Zioptan), and TRAVOPROST (Travatan) are similar agents. Pharmacologic therapy for glaucoma includes ↑ aqueous humor outflow with PGF2α analogs, α2-agonists (see brimonidine), and muscarinic agonists (see pilocarpine) as well as ↓ aqueous humor formation with βblockers (see timolol), α2-agonists, and carbonic anhydrase inhibitors (see acetazolamide).

MISC LATANOPROST Bimatoprost Tafluprost Travoprost Glaucoma is a disease marked by ↑ intraocular pressure because of poor absorption of aqueous humor (which is made by the ciliary body in the posterior chamber and drains out via the anterior chamber). Narrow-angle glaucoma is caused by the iris partially blocking the entrance into the trabecular network at the canal of Schlemm; acute-angle closure glaucoma is precipitated by dilation of the iris (thereby exacerbating the blockage) and is a medical emergency. Wide-angle glaucoma is caused by poor trabecular tone without any physical impediment to outflow.

THEOPHYLLINE (Theo-Dur, Slo-bid)

PDE inhibitor

10-5

Mechanism Prototypical methylxanthine, a nonspecific phosphodiesterase (PDE) inhibitor. The resultant ↑ cAMP levels cause airway smooth muscle relaxation and tachycardia (analogous to effects of β-agonists such as albuterol). Also blocks adenosine receptors (the A1 subtype of P1 purinergic receptors). This results in disinhibition of adenylate cyclase leading to ↑ cAMP → bronchodilation and tachycardia. Inhibits synthesis and release of inflammatory mediators from mast cells and basophils (likely caused by PDE4 inhibition). CNS stimulant; ↑ gastric secretions. Clinical

COPD and asthma (third-line agent).

Side Effects Narrow therapeutic window and efficacy and toxicity are closely related to its peak serum concentration. Mild reactions include tremor, agitation, insomnia, headaches (may potentiate migraines because it induces cerebral vasoconstriction), and emesis. Serious reactions include arrhythmias and seizures.

Notes

Naturally occurring methylxanthines include theophylline (found in tea), theobromine (found in cocoa and chocolate), and CAFFEINE (found in coffee and tea). Caffeine is an effective stimulant and, when taken in combination with acetaminophen and aspirin, can be used to treat migraines. AMINOPHYLLINE is the ethylenediamine derivative of theophylline and is also used for asthma. ROFLUMILAST (Daliresp) is a specific PDE4 inhibitor that reduces airway inflammation but limited effects on lung function. Used in stable COPD to reduce risk of exacerbations. APREMILAST (Otezla) is another PDE4 inhibitor used to treat psoriasis and psoriatic arthritis.

MISC THEOPHYLLINE Caffeine Aminophylline Roflumilast Apremilast

URSODIOL (Actigall)

GI agent

10-6

Mechanism Prevents formation of cholesterol gallstones through three mechanisms: 1. ↓ Hepatic secretion of cholesterol into the bile. 2. ↓ Cholesterol synthesis by inhibiting HMG-CoA reductase. 3. ↓ Reabsorption of cholesterol by the intestine. Clinical

Dissolution of radiolucent cholesterol gallstones; ineffective against calcified cholesterol gallstones and pigment stones. Primary biliary cirrhosis.

Side Effects Nausea, vomiting, diarrhea, abdominal pain. Contraindic. Pregnancy. Notes

Ursodiol was first identified in the bile of bears (genus Ursidae) and likely protects them against cholelithiasis during hibernation.

MISC URSODIOL

VITAMINS I

miscellaneous

10-7

THIAMINE (Vitamin B1) Mechanism Essential cofactor for decarboxylation of α-keto acids and keto sugars by mitochondria. Clinical

Deficiency → impaired carbohydrate metabolism. Mild (dry beriberi): peripheral neuropathy. Severe (wet beriberi): high output CHF, Wernicke encephalopathy.

RIBOFLAVIN (Vitamin B2) Mechanism Forms the core of FAD and FMN, electron acceptors used by many metabolic enzymes. Clinical

Deficiency → angular stomatitis; dermatitis of the face; and a smooth, purple tongue.

NICOTINAMIDE (Vitamin B3) Mechanism Forms the core of NAD and NADP, electron acceptors used by many metabolic enzymes. Clinical

Deficiency → dermatitis, diarrhea, and dementia (the three D’s).

PANTOTHENIC ACID (Vitamin B5) Mechanism With cysteine and ATP, forms CoA, an acyl group carrier used by many enzymes. Clinical

Deficiency is rare.

PYRIDOXAL PHOSPHATE (Vitamin B6) Mechanism Cofactor required for enzymatic interconversion of amino acids and αketo acids. Clinical

Deficiency → peripheral neuropathy, anemia, glossitis, and irritability (see isoniazid).

MISC VITAMINS I Thiamine (Vitamin B1) Riboflavin (Vitamin B2) Nicotinamide (Vitamin B3) Pantothenic Acid (Vitamin B5) Pyridoxal Phosphate (Vitamin B6) The water-soluble vitamins consist of the B complex (name given to a group of vitamins found in the same sources: yeast extracts and liver) and vitamin C (found in citrus fruits). Some factors found in the B complex turned out not to be true vitamins (hence the missing numbers), and some true vitamins in the complex are not numbered. Folate, another B vitamin, is discussed on the methotrexate card.

VITAMINS II

miscellaneous

10-8

BIOTIN (another “B vitamin”) Mechanism Cofactor required for carboxylation reactions. Clinical

Deficiency (rare) → perioral dermatitis, alopecia, conjunctivitis, and ataxia.

CYANOCOBALAMIN (Vitamin B12, intrinsic factor) Mechanism Cofactor required for folate recycling, methionine synthase, and methylmalonyl mutase. Clinical

Deficiency → megaloblastic anemia (caused by folate depletion) and subacute combined degeneration of spinal cord (posterior column disease, not a result of folate depletion).

ASCORBIC ACID (Vitamin C) Mechanism Antioxidant and cofactor in oxygenation reactions. Clinical

Deficiency → scurvy (petechiae, poor wound healing, follicular hyperkeratosis, gum changes).

RETINOIC ACID (Vitamin A) Mechanism Combines with the protein opsin to form rhodopsin, the light-sensing pigment in the retina. Clinical

Deficiency → blindness, follicular keratosis, xerophthalmia (dry corneas). Excess → dry pruritic skin, bone pain, anorexia, hepatosplenomegaly, papilledema.

TOCOPHEROL (Vitamin E) Mechanism Only established role can act as an antioxidant for polyunsaturated fats. Clinical

Deficiency (extremely rare) → ataxia with inborn errors in vitamin E metabolism.

MISC VITAMINS II Biotin Cyanocobalamin (Vitamin B12, Intrinsic Factor) Ascorbic Acid (Vitamin C) Retinoic Acid (Vitamin A) Tocopherol (Vitamin E) Vitamins A, D, E, and K are the lipid-soluble vitamins. Severe fat malabsorption or steatorrhea can result in concomitant deficiency of all of these vitamins. Unlike the water-soluble vitamins, which can be readily excreted when ingested in excess, these vitamins can accumulate in fatty tissue and the liver and produce toxicity. See teriparatide for a discussion of vitamin D. See warfarin for a discussion of vitamin K.

ETHANOL (EtOH)

toxin

10-9

Mechanism Ethanol probably exerts its CNS-depressing effects through GABAA receptors, although the precise mechanism is not understood. Clinical

In clinical settings, most commonly encountered as a toxin. Exerts acute (intoxicating) effect and can cause chronic end-organ damage. Formerly used in the management of methanol (and ethylene glycol) poisoning.

Side Effects CNS: acute: sedation, inhibition of ADH secretion, loss of inhibition, impaired judgment, ataxia, respiratory depression; chronic: along with thiamine deficiency, can lead to Wernicke-Korsakoff syndrome (characterized by ataxia, confusion, and paralysis of extraocular muscles). CV: acute: vasodilation, sometimes with marked hypothermia; chronic: associated with dilated cardiomyopathy. GI: increases gastric acid secretion. May cause absorption defects, exacerbate nutritional deficiencies. Acute or chronic pancreatitis and cirrhosis of liver. Endocrine: gynecomastia, testicular atrophy, and salt retention (↓ hepatic clearance of steroids). Fetal alcohol syndrome: Ethanol use in pregnancy is associated with teratogenic effects, including mental retardation, growth deficiencies, and characteristic malformations of the face and head (midfacial hypoplasia). Metabolism See disulfiram card for a discussion of ethanol metabolism.

MISC ETHANOL

DISULFIRAM (Antabuse)

ethanol metabolism inhibitor

1010

Mechanism Irreversibly inactivates aldehyde dehydrogenase → ↑ acetaldehyde upon ingestion of ethanol. In the absence of disulfiram, this enzyme rapidly converts acetaldehyde to nontoxic acetic acid. Effects of acetaldehyde: vasodilatation (flushing), throbbing in head and neck, respiratory difficulty, sweating, thirst, nausea, vomiting, ↓ BP → shock, chest pain. Potential for adverse alcohol reactions persists until new enzymes are synthesized (≤14 days). Clinical

Treatment of chronic alcoholism but compliance poor and hence effectiveness low.

Side Effects Urticaria, allergic dermatitis, acne, fatigue, tremor, headache, dizziness. Teratogenic. Notes

Two major enzyme systems participate in metabolizing ethanol to acetaldehyde. 1. Alcohol dehydrogenase, a NAD-dependent enzyme found mainly in the liver, accounts for most of this conversion. In chronic alcohol use, demand for NAD can lead to niacin deficiency. 2. CYP2E1 normally accounts for only a small fraction of alcohol metabolism, but its role increases with blood alcohol level, chronic alcohol use, or CYP2E1 inducing agents such as barbiturates. ACAMPROSATE (Campral) is a weak GABAA-receptor agonist and weak inhibitor of the NMDA subtype of glutamate receptors. May also affect serotonin and adrenergic receptors. Appears to modulate neuronal hyperexcitability during withdrawal from alcohol. Among alcoholics who achieve abstinence, ↓ rate of relapse. Side effects include nausea, vomiting, and diarrhea.

MISC DISULFIRAM Acamprosate

METHANOL

toxin

1011

Mechanism Metabolized by alcohol dehydrogenase to formaldehyde and then by aldehyde dehydrogenase to formic acid. Accumulation of formic acid accounts for most of the toxic effects of methanol. Formic acid also blocks the mitochondrial cytochrome oxidase system, leading to a superimposed lactic acidosis. The retina and optic nerve are particularly sensitive to formic acid, and substantially sublethal doses can result in permanent blindness. Clinical

Characteristic visual impairment (“like being in a snow storm”) and ultimately blindness. Metabolic acidosis and death. As toxic effects caused by metabolites, symptoms can be delayed for as long as 12 to 36 hours after ingestion.

Antidote

FOMEPIZOLE (Antizol) is an inhibitor of alcohol dehydrogenase that can prevent conversion of methanol (and ethylene glycol) into toxic metabolites. Ethanol can be used as a competitive substrate (alcohol dehydrogenase has a higher affinity for ethanol), but fomepizole is preferred. Folate administration to facilitate formic acid degradation (formic acid is slowly metabolized in the liver to CO2 in a folate-dependent process). Oral charcoal (↓ further absorption of methanol) and sometimes hemodialysis.

Notes

Methanol is a common industrial solvent and a component of shellac and varnish. Methanol is sometimes added to ethanol to make it undrinkable (called denaturing). The metabolic acidosis caused by methanol will have ↑ anion gap and ↑ plasma osmolality gap (ethylene glycol creates a similar metabolic profile).

MISC METHANOL Fomepizole

LEAD

toxin

1012

Mechanism Toxicity of lead (Pb2+) arises from its ability to replace other divalent cations, particularly Ca2+ and Zn2+ in specific metalloproteins, impairing their normal function. For example, replacement of Zn2+ in δ-aminolevulinate dehydratase results in impaired heme biosynthesis and anemia. Clinical

Acute toxicity: abdominal pain, nausea, vomiting, metallic taste, muscle weakness, paresthesias. Chronic toxicity: microcytic anemia, anorexia, abdominal pain (lead colic), neuropathy, encephalopathy, infertility, interstitial nephropathy. Cognitive dysfunction: Epidemiologic studies have linked low-level lead exposure to cognitive impairment in preschool children. This prompted a decrease in the acceptable Pb levels from 60 to 10 mcg/dL.

Antidote

Acute intoxication can be treated by chelation therapy: CaNa2EDTA, dimercaprol, D-penicillamine, or succimer.

Metabolism Adults absorb about 10% of ingested lead; children, 40%. Lead binds extensively to hemoglobin in erythrocytes, and its half-life in the blood is about 50 days. Lead can replace Ca2+ in the bones, forming characteristic “lead lines” that can be seen on radiographs. This deposition in bone can help buffer the soft tissues from lead toxicity. Excretion is predominately in the urine. Notes

Lead was formerly used as a pigment for house paints. Dried paint chips from old houses remain a major source of chronic lead intoxication in children.

MISC LEAD

CARBON MONOXIDE

toxin

1013

Mechanism Binds irreversibly to hemoglobin with 200 times greater affinity than does oxygen. The resultant carboxyhemoglobin cannot transport O2. CO can also bind to cytochromes and interfere with their function. Clinical

Mild cases can present complaining only of headache. Carboxyhemoglobin levels are routinely measured in patients with acute headache. In severe cases, patients look “cherry red” from carboxyhemoglobin even though there is extreme tissue hypoxia.

Treatment

Treat with 100% O2 (hyperbaric) and blood transfusions if needed.

Notes

CO is a colorless, odorless gas. Improperly ventilated furnaces are a common cause of poisoning. Household CO detectors are an increasingly available preventive measure. Heme biodegradation produces a small amount of endogenous CO. Cigarette smokers have significantly higher levels of carboxyhemoglobin in their blood than do nonsmokers.

MISC CARBON MONOXIDE

CYANIDE

toxin

1014

Mechanism Cyanide (CN−) has a high affinity for Fe3+, and when inhaled or ingested, it reacts rapidly with trivalent iron of cytochrome oxidase in mitochondria → inhibited cellular respiration, lactic acidosis, cytotoxic hypoxia. Clinical

Patients present with tachycardia, headache, drowsiness, hypotension, lactic acidosis, coma, and convulsions. Rapidly fatal (1 to 15 minutes). Because utilization of oxygen is blocked, venous blood is bright red.

Antidote

Amyl nitrite is used to prevent or reverse binding of CN− to Fe3+ of cytochrome oxidase by providing a large pool of Fe3+ to compete for CN−. It oxidizes hemoglobin (Fe2+) → methemoglobin (Fe3+), which can bind CN−, to form cyanmethemoglobin. Thiosulfate (S2O32−) administration accelerates detoxification of CN−. Hyperbaric O2 potentiates protective effects of amyl nitrite and thiosulfate but has little effect when used alone. Gastric lavage: to remove any residual toxin in the case of ingestion.

Metabolism Mitochondrial enzyme rhodanase converts CN− to thiocyanate (S2O32− + CN− → SCN− + SO32−), which is relatively nontoxic and is excreted in urine. Notes

Bitter almond odor is characteristic of HCN gas. Sources include metabolism of certain drugs (e.g., nitroprusside). Also used to fumigate ships and buildings and in metallurgy, electroplating, insecticides, and rodenticides.

MISC CYANIDE

Bibliography Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier/Saunders; 2014. Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2005. Gilbert DN, Saag MS, eds. The Sanford Guide to Antimicrobial Therapy 2017. 47th ed. Sperryville, VA: Antimicrobial Therapy Inc; 2017. Golan DE, Tashjian AH Jr, Armstrong EJ, et al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. Hamilton RJ, ed. Tarascon Pocket Pharmacopoeia: 2017 Classic Shirt-Pocket Edition. 18th ed. Burlington, VT: Jones & Bartlett Learning; 2017. Kasper DL, Fauci AS, Hauser SL, et al. Harrison’s Manual of Medicine. 19th ed. New York, NY: McGraw-Hill; 2016. Katzung BG, Trevor AJ, eds. Basic & Clinical Pharmacology. 13th ed. New York, NY: McGraw-Hill; 2014. Lilly LS, ed. Pathophysiology of Heart Disease. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier/Saunders; 2015. The Medical Letter on Drugs and Therapeutics. New Rochelle, NY; The Medical Letter.

UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com.

Index The main drugs described in these cards are in boldface; related agents are in regular type. Abacavir, 6-35 Abatacept, 8-7 Abciximab, 4-4 Abiraterone, 5-9 Acamprosate, 10-10 Acarbose, 5-25 Acebutolol, 1-16 Acetaminophen, 8-3 Acetazolamide, 3-20 Acetylcysteine, 8-3 Acetylsalicylic acid, 4-1 Aclidinium, 2-8 Acyclovir, 6-43 Adalimumab, 8-8 Adefovir dipivoxil, 6-36 Adenosine, 3-28 Afatinib, 9-20 Albiglutide, 5-22 Albuterol, 1-14 Alcaftadine, 8-18 Aldesleukin, 9-27 Alectinib, 9-18 Alemtuzumab, 9-25 Alendronate, 5-32 Alfentanil, 7-38

Alfuzosin, 1-12 Alirocumab, 5-27 Aliskiren, 3-8 Alkylating agents, 9-1 Allopurinol, 8-20 All-trans retinoic acid, 9-15 Almotriptan, 7-18 Alogliptin, 5-23 Alosetron, 7-23 Alprazolam, 7-11 Alprostadil, 10-3 Alteplase, 4-11 Altretamine, 9-1 Alvimopan, 7-43 Amantadine, 6-51 Ambrisentan, 3-16 Amikacin, 6-10 Amiloride, 3-19 Aminocaproic acid, 4-12 Aminophylline, 10-5 Amiodarone, 3-25 Amitriptyline, 7-27 Amlodipine, 3-9 Amoxapine, 7-27 Amoxicillin, 6-3 Amphetamine, 1-4 Amphotericin B, 6-24 Ampicillin, 6-3 Anagrelide, 9-11 Anakinra, 8-9 Anastrozole, 5-6 Andexanet, 4-10 Angiotensin II, 3-6

Anidulafungin, 6-28 Antithymocyte globulin, 8-7 Apixaban, 4-10 Apomorphine, 7-30 Apraclonidine, 1-9 Apremilast, 10-5 Aprepitant, 7-37 Arformoterol, 1-14 Argatroban, 4-8 Aripiprazole, 7-35 Armodafinil, 1-4 Arsenic trioxide, 9-15 Artemether, 6-32 Artesunate, 6-32 Articaine, 7-15 Ascorbic acid, 10-8 Asenapine, 7-35 Atazanavir, 6-39 Atenolol, 1-16 Atezolizumab, 9-27 Atgam, 8-7 Atomoxetine, 1-4 Atorvastatin, 5-26 Atovaquone, 6-34 Atracurium, 2-3 Atropine, 2-6 Avelumab, 9-27 Avibactam, 6-4 Azacitidine, 9-16 Azathioprine, 8-12 Azelastine, 8-18 Azilsartan, 3-6 Azithromycin, 6-12

Aztreonam, 6-7 Bacitracin, 6-8 Baclofen, 7-13 Balsalazide, 8-16 Basiliximab, 8-7 Beclomethasone, 5-2 Belinostat, 9-16 Benazepril, 3-5 Bendamustine, 9-1 Benzocaine, 7-15 Benzphetamine, 1-4 Benztropine, 2-7 Bepotastine, 8-18 Besifloxacin, 6-17 Betaxolol, 1-18 Bethanechol, 2-4 Bevacizumab, 9-21 Bezafibrate, 5-29 Bicalutamide, 5-9 Bimatoprost, 10-4 Biotin, 10-8 Biperiden, 2-7 Bisoprolol, 1-16 Bivalirudin, 4-8 Bleomycin, 9-3 Blinatumomab, 9-25 Bortezomib, 9-26 Bosentan, 3-16 Bosutinib, 9-17 Botulinum toxin A, 7-13 Brentuximab Vedotin, 9-25 Brexpiprazole, 7-35 Brimonidine, 1-9

Brinzolamide, 3-20 Brodalumab, 8-10 Bromocriptine, 7-30 Brompheniramine, 8-18 Budesonide, 5-2 Bumetanide, 3-17 Bupivacaine, 7-15 Buprenorphine, 7-40 Bupropion, 7-26 Buspirone, 7-20 Busulfan, 9-1 Butenafine, 6-27 Butoconazole, 6-26 Butorphanol, 7-40 Cabergoline, 7-30 Cabazitaxel, 9-14 Caffeine, 10-5 Calcitonin, 5-32 Canagliflozin, 5-24 Canakinumab, 8-9 Candesartan, 3-6 Cangrelor, 4-2 Capecitabine, 9-10 Captopril, 3-5 Carbachol, 2-5 Carbamazepine, 7-2 Carbon monoxide, 10-13 Carboplatin, 9-2 Carboprost, 10-3 Carfilzomib, 9-26 Cariprazine, 7-35 Carmustine, 9-1 Carteolol, 1-18

Carvedilol, 1-17 Caspofungin, 6-28 Cefaclor, 6-5 Cefadroxil, 6-5 Cefazolin, 6-5 Cefdinir, 6-5 Cefepime, 6-5 Cefixime, 6-5 Cefoxitin, 6-5 Cefotaxime, 6-5 Cefpodoxime, 6-5 Cefprozil, 6-5 Ceftaroline, 6-6 Ceftazidime, 6-5 Ceftibuten, 6-5 Ceftolozane, 6-6 Ceftriaxone, 6-5 Cefuroxime, 6-5 Cefuroxime axetil, 6-5 Celecoxib, 8-2 Cephalexin, 6-5 Ceritinib, 9-18 Certolizumab, 8-8 Cetirizine, 8-19 Cetrorelix, 5-11 Cetuximab, 9-20 Chlorambucil, 9-1 Chloramphenicol, 6-14 Chlordiazepoxide, 7-11 Chloroprocaine, 7-15 Chloroquine, 6-31 Chlorothiazide, 3-18 Chlorpheniramine, 8-18

Chlorpromazine, 7-32 Chlorpropamide, 5-20 Chlorthalidone, 3-18 Cholestyramine, 5-31 Ciclesonide, 5-2 Cidofovir, 6-36 Cilazapril, 3-5 Cilostazol, 3-13 Cimetidine, 10-1 Cinacalcet, 5-34 Ciprofloxacin, 6-17 Cisatracurium, 2-3 Cisplatin, 9-2 Citalopram, 7-24 Cladribine, 9-9 Clarithromycin, 6-12 Clavulanic acid, 6-4 Clemastine, 8-18 Clevidipine, 3-9 Clindamycin, 6-13 Clobazam, 7-11 Clofarabine, 9-9 Clomiphene, 5-4 Clomipramine, 7-27 Clonazepam, 7-11 Clonidine, 1-9 Clopidogrel, 4-2 Clorazepate, 7-11 Clotrimazole, 6-26 Cloxacillin, 6-2 Clozapine, 7-34 Cobicistat, 6-40 Cobimetinib, 9-22

Cocaine, 1-6 Codeine, 7-39 Colchicine, 8-21 Colesevelam, 5-31 Colestipol, 5-31 Colistin, 6-9 Conivaptan, 5-14 Cosyntropin, 5-1 Crizotinib, 9-18 Cromolyn, 8-17 Cyanide, 10-14 Cyanocobalamin, 10-8 Cyclopentolate, 2-6 Cyclophosphamide, 9-1 Cyclosporine, 8-5 Cyproheptadine, 8-18 Cyproterone, 5-9 Cytarabine, 9-8 Dabigatran, 4-8 Dabrafenib, 9-22 Dacarbazine, 9-1 Daclatasvir, 6-47 Daclizumab, 8-7 Dactinomycin, 9-6 Dalbavancin, 6-8 Dalteparin, 4-7 Danazol, 5-7 Dantrolene, 7-14 Dapagliflozin, 5-24 Dapsone, 6-23 Daptomycin, 6-9 Darbepoetin, 4-13 Darifenacin, 2-9

Darunavir, 6-39 Dasabuvir, 6-48 Dasatinib, 9-17 Daunorubicin, 9-4 Decitabine, 9-16 Deferoxamine, 4-13 Deferasirox, 4-13 Degarelix, 5-11 Demeclocycline, 6-11 Denosumab, 5-32 Desflurane, 7-14 Desipramine, 7-27 Desirudin, 4-8 Desloratadine, 8-19 Desmopressin, 5-14 Desvenlafaxine, 7-25 Dexchlorpheniramine, 8-18 Dexlansoprazole, 10-2 Dexmedetomidine, 1-10 Dexmethylphenidate, 1-4 Dexrazoxane, 9-4 Dextroamphetamine, 1-4 Dextromethorphan, 7-39 DFP (diisopropyl fluorophosphate), 2-12 Diazepam, 7-11 Diazoxide, 3-4 Dibucaine, 7-15 Diclofenac, 8-1 Dichlorphenamide, 3-20 Dicloxacillin, 6-2 Dicyclomine, 2-9 Didanosine, 6-35 Diethylpropion, 1-4

Diflunisal, 8-1 Digoxin, 3-12 Dihydroergotamine, 7-19 Diltiazem, 3-10 Dimenhydrinate, 8-18 Dinoprostone, 10-3 Diphenhydramine, 8-18 Diphenoxylate, 7-41 Dipyridamole, 4-5 Disopyramide, 3-22 Disulfiram, 10-10 Dobutamine, 1-3 Docetaxel, 9-14 Dofetilide, 3-26 Dolasetron, 7-22 Dolutegravir, 6-38 Donepezil, 2-11 Dopamine, 1-2 Doripenem, 6-7 Dorzolamide, 3-20 Doxazosin, 1-12 Doxepin, 7-27 Doxorubicin, 9-4 Doxycycline, 6-11 Dronabinol, 7-31 Dronedarone, 3-25 Droperidol, 7-31 Droxidopa, 1-1 Dulaglutide, 5-22 Duloxetine, 7-25 Dutasteride, 5-10 Econazole, 6-26 Eculizumab, 4-13

Edaravone, 7-17 Edoxaban, 4-10 Edrophonium, 2-10 Efavirenz, 6-37 Efinaconazole, 6-25 Elbasvir, 6-47 Eletriptan, 7-18 Eltrombopag, 4-15 Elvitegravir, 6-38 Emedastine, 8-18 Empagliflozin, 5-24 Emtricitabine, 6-35 Enalapril, 3-5 Enflurane, 7-14 Enfuvirtide, 6-41 Enoxaparin, 4-7 Entacapone, 7-29 Entecavir, 6-45 Enzalutamide, 5-9 Ephedrine, 1-5 Epinastine, 8-18 Epinephrine, 1-1 Epirubicin, 9-4 Eplerenone, 3-19 Epoprostenol, 3-15 Eprosartan, 3-6 Eptifibatide, 4-4 Ergotamine, 7-19 Eribulin, 9-13 Erlotinib, 9-20 Ertapenem, 6-7 Erythromycin, 6-12 Erythropoietin, 4-13

Escitalopram, 7-24 Eslicarbazepine, 7-2 Esmolol, 1-16 Esomeprazole, 10-2 Estazolam, 7-11 Estradiol, 5-3 Estramustine, 9-1 Eszopiclone, 7-12 Etanercept, 8-8 Ethacrynic acid, 3-17 Ethambutol, 6-21 Ethanol, 10-9 Ethionamide, 6-19 Ethosuximide, 7-6 Etidronate, 5-32 Etodolac, 8-1 Etomidate, 7-10 Etoposide, 9-5 Etravirine, 6-37 Everolimus, 8-6 Evolocumab, 5-27 Exemestane, 5-6 Exenatide, 5-22 Ezetimibe, 5-28 Famciclovir, 6-43 Famotidine, 10-1 Febuxostat, 8-20 Felbamate, 7-3 Felodipine, 3-9 Fenofibrate, 5-29 Fenoldopam, 1-19 Fenoprofen, 8-1 Fentanyl, 7-38

Fesoterodine, 2-9 Fexofenadine, 8-19 Fidaxomicin, 6-22 Filgrastim, 4-14 Finasteride, 5-10 Flavoxate, 2-9 Flecainide, 3-24 Floxuridine, 9-10 Fluconazole, 6-25 Flucytosine, 6-29 Fludarabine, 9-9 Fludrocortisone, 5-1 Flumazenil, 7-11 Flunisolide, 5-2 5-Fluorouracil, 9-10 Fluoxetine, 7-24 Fluoxymesterone, 5-8 Fluphenazine, 7-33 Flurazepam, 7-11 Flurbiprofen, 8-1 Flutamide, 5-9 Fluticasone, 5-2 Fluvastatin, 5-26 Fluvoxamine, 7-24 Fomepizole, 10-11 Fondaparinux, 4-7 Formoterol, 1-14 Fosamprenavir, 6-39 Fosaprepitant, 7-37 Foscarnet, 6-44 Fosinopril, 3-5 Fosphenytoin, 7-1 Frovatriptan, 7-18

Fulvestrant, 5-4 Furosemide, 3-17 Gabapentin, 7-7 Galantamine, 2-11 Ganciclovir, 6-43 Gefitinib, 9-20 Gemcitabine, 9-8 Gemfibrozil, 5-29 Gemifloxacin, 6-17 Gentamicin, 6-10 Glimepiride, 5-20 Glipizide, 5-20 Glucagon, 5-17 Glucarpidase, 8-13 Glyburide, 5-20 Glycopyrrolate, 2-8 Golimumab, 8-8 Goserelin, 5-11 Granisetron, 7-22 Grazoprevir, 6-49 Griseofulvin, 6-30 Guselkumab, 8-10 Haloperidol, 7-33 Halothane, 7-14 Heparin, 4-6 Hexamethonium, 2-3 Histrelin, 5-11 Homatropine, 2-6 Hydralazine, 3-4 Hydrochlorothiazide, 3-18 Hydrocodone, 7-39 Hydromorphone, 7-38 Hydroxychloroquine, 8-15

Hydroxyprogesterone, 5-7 Hydroxyurea, 9-11 Hydroxyzine, 8-18 Hyoscyamine, 2-9 Ibandronate, 5-32 Ibritumomab, 9-25 Ibrutinib, 9-19 Ibuprofen, 8-1 Ibutilide, 3-26 Idarubicin, 9-4 Idarucizumab, 4-8 Idelalisib, 9-19 Ifosfamide, 9-1 Iloperidone, 7-34 Iloprost, 3-15 Imatinib, 9-17 Imipenem, 6-7 Imipramine, 7-27 Indacaterol, 1-14 Indapamide, 3-18 Indinavir, 6-39 Indomethacin, 8-1 Infliximab, 8-8 Insulin, 5-17 Interferon alpha, 6-46 Interferon beta, 8-14 Ipilimumab, 9-27 Ipratropium, 2-8 Irbesartan, 3-6 Irinotecan, 9-5 Isavuconazole, 6-25 Isocarboxazid, 7-28 Isoflurane, 7-14

Isoniazid, 6-19 Isoproterenol, 1-13 Isosorbide dinitrate, 3-1 Isosorbide mononitrate, 3-1 Isotretinoin, 9-15 Isradipine, 3-9 Itraconazole, 6-25 Ivabradine, 3-27 Ixabepilone, 9-14 Ixazomib, 9-26 Ixekizumab, 8-10 Ketamine, 7-10 Ketoconazole, 6-26 Ketoprofen, 8-1 Ketorolac, 8-1 Ketotifen, 8-18 Labetalol, 1-17 Lamivudine, 6-35 Lamotrigine, 7-1 Lanreotide, 5-12 Lansoprazole, 10-2 Lanthanum carbonate, 5-34 Lapatinib, 9-20 Latanoprost, 10-4 Lead, 10-12 Ledipasvir, 6-47 Leflunomide, 8-12 Lenalidomide, 9-28 Letrozole, 5-6 Leuprolide, 5-11 Levalbuterol, 1-14 Levetiracetam, 7-7 Levobunolol, 1-18

Levocetirizine, 8-19 Levodopa/carbidopa, 7-29 Levofloxacin, 6-17 Levomilnacipran, 7-25 Levonorgestrel, 5-7 Levorphanol, 7-38 Levothyroxine, 5-15 Lidocaine, 3-23 Linagliptin, 5-23 Linezolid, 6-13 Liothyronine, 5-15 Liraglutide, 5-22 Lisdexamfetamine, 1-4 Lisinopril, 3-5 Lithium, 7-36 Lodoxamide, 8-17 Lomitapide, 5-27 Lomustine, 9-1 Loperamide, 7-41 Lopinavir/ritonavir, 6-39 Loratadine, 8-19 Lorazepam, 7-11 Lorcaserin, 7-21 Losartan, 3-6 Lovastatin, 5-26 Loxapine, 7-32 Lubiprostone, 10-3 Luliconazole, 6-26 Lumefantrine, 6-32 Lurasidone, 7-35 Macitentan, 3-16 Malathion, 2-12 Mannitol, 3-21

Maprotiline, 7-27 Maraviroc, 6-42 Mechlorethamine, 9-1 Meclizine, 8-18 Meclofenamate, 8-1 Medroxyprogesterone, 5-7 Mefenamic acid, 8-1 Mefloquine, 6-31 Megestrol, 5-7 Meloxicam, 8-1 Melphalan, 9-1 Memantine, 7-16 Meperidine, 7-38 Mepivacaine, 7-15 Mercaptopurine, 9-12 Meropenem, 6-7 Mesalamine, 8-16 Metaproterenol, 1-14 Metformin, 5-18 Methacholine, 2-4 Methadone, 7-42 Methanol, 10-11 Methazolamide, 3-20 Methicillin, 6-2 Methimazole, 5-16 Methohexital, 7-10 Methotrexate, 8-13 Methyclothiazide, 3-18 Methyldopa, 1-7 Methylergonovine, 7-19 Methylnaltrexone, 7-43 Methylphenidate, 1-4 Methyltestosterone, 5-8

Metipranolol, 1-18 Metoclopramide, 7-31 Metolazone, 3-18 Metoprolol, 1-16 Metronidazole, 6-18 Mexiletine, 3-23 Micafungin, 6-28 Miconazole, 6-26 Midazolam, 7-11 Midodrine, 1-8 Mifepristone, 5-7 Miglitol, 5-25 Milnacipran, 7-25 Milrinone, 3-13 Minocycline, 6-11 Minoxidil, 3-4 Mipomersen, 5-27 Mirabegron, 1-15 Mirtazapine, 7-26 Misoprostol, 10-3 Mitomycin, 9-1 Mitoxantrone, 9-4 Mivacurium, 2-3 Modafinil, 1-4 Moexipril, 3-5 Molindone, 7-32 Mometasone, 5-2 Montelukast, 8-4 Morphine, 7-38 Moxifloxacin, 6-17 Mycophenolate mofetil, 8-12 Nabumetone, 8-1 Nadolol, 1-16

Nafarelin, 5-11 Nafcillin, 6-2 Naftifine, 6-27 Nalbuphine, 7-40 Naloxegol, 7-43 Naloxone, 7-43 Naltrexone, 7-43 Nandrolone, 5-8 Naphazoline, 1-8 Naproxen, 8-1 Naratriptan, 7-18 Natalizumab, 8-11 Nateglinide, 5-21 Nebivolol, 1-17 Nedocromil, 8-17 Nefazodone, 7-26 Nelarabine, 9-8 Nelfinavir, 6-39 Neomycin, 6-10 Neostigmine, 2-10 Nesiritide, 3-3 Netupitant, 7-37 Nevirapine, 6-37 Niacin, 5-30 Nicardipine, 3-9 Nicotinamide, 10-7 Nicotine, 2-1 Nifedipine, 3-9 Nilotinib, 9-17 Nilutamide, 5-9 Nimodipine, 3-9 Niraparib, 9-7 Nisoldipine, 3-9

Nitroglycerin, 3-1 Nitroprusside, 3-2 Nitrous oxide, 7-14 Nivolumab, 9-27 Nizatidine, 10-1 Norepinephrine, 1-1 Norethindrone, 5-7 Norgestrel, 5-7 Nortriptyline, 7-27 Nystatin, 6-24 Obinutuzumab, 9-25 Octreotide, 5-12 Ofatumumab, 9-25 Ofloxacin, 6-17 Olanzapine, 7-34 Olaparib, 9-7 Olmesartan, 3-6 Olodaterol, 1-14 Olopatadine, 8-18 Olsalazine, 8-16 Omalizumab, 8-17 Ombitasvir, 6-47 Omeprazole, 10-2 Ondansetron, 7-22 Oprelvekin, 4-15 Oritavancin, 6-8 Orlistat, 5-28 Oseltamivir, 6-50 Oxacillin, 6-2 Oxaliplatin, 9-2 Oxandrolone, 5-8 Oxaprozin, 8-1 Oxazepam, 7-11

Oxcarbazepine, 7-2 Oxiconazole, 6-26 Oxybate, 7-13 Oxybutynin, 2-9 Oxycodone, 7-39 Oxymetazoline, 1-8 Oxymorphone, 7-38 Oxytocin, 5-13 Paclitaxel, 9-14 Palbociclib, 9-24 Paliperidone, 7-34 Palonosetron, 7-22 Pamidronate, 5-32 Pancuronium, 2-3 Panitumumab, 9-20 Panobinostat, 9-16 Pantoprazole, 10-2 Pantothenic acid, 10-7 Parathion, 2-12 Paricalcitol, 5-34 Paritaprevir, 6-49 Paroxetine, 7-24 Pegaptanib, 9-21 Pegfilgrastim, 4-14 Pegloticase, 8-20 Pegvisomant, 5-12 Pembrolizumab, 9-27 Pemetrexed, 8-13 Pemirolast, 8-17 Penciclovir, 6-43 Penicillin, 6-1 Pentamidine, 6-34 Pentazocine, 7-40

Pentobarbital, 7-10 Pentostatin, 9-9 Peramivir, 6-50 Perindopril, 3-5 Perampanel, 7-4 Perphenazine, 7-33 Pertuzumab, 9-20 Phenelzine, 7-28 Phenobarbital, 7-9 Phenoxybenzamine, 1-11 Phentermine, 1-4 Phentolamine, 1-11 Phenylephrine, 1-8 Phenytoin, 7-1 Physostigmine, 2-11 Pilocarpine, 2-5 Pimecrolimus, 8-5 Pimozide, 7-33 Pindolol, 1-16 Pioglitazone, 5-19 Piperacillin, 6-3 Pirbuterol, 1-14 Piroxicam, 8-1 Pitavastatin, 5-26 Plerixafor, 4-14 Polymyxin B, 6-9 Pomalidomide, 9-28 Ponatinib, 9-17 Posaconazole, 6-25 Pralatrexate, 8-13 Pralidoxime, 2-12 Pramipexole, 7-30 Pramlintide, 5-17

Prasugrel, 4-2 Pravastatin, 5-26 Prazosin, 1-12 Prednisone, 5-1 Pregabalin, 7-7 Prilocaine, 7-15 Primaquine, 6-33 Primidone, 7-9 Probenecid, 8-22 Procainamide, 3-22 Procaine, 7-15 Procarbazine, 9-1 Prochlorperazine, 7-31 Progesterone, 5-7 Proguanil, 6-16 Promethazine, 8-18 Propafenone, 3-24 Propantheline, 2-9 Propofol, 7-10 Propranolol, 1-16 Propylthiouracil, 5-16 Protamine, 4-6 Protriptyline, 7-27 Pseudoephedrine, 1-5 Pyrazinamide, 6-20 Pyridostigmine, 2-10 Pyridoxal phosphate, 10-7 Pyrimethamine, 6-16 Quetiapine, 7-34 Quinapril, 3-5 Quinidine, 3-22 Quinine, 6-31 Quinupristin/dalfopristin, 6-13

Rabeprazole, 10-2 Raloxifene, 5-5 Raltegravir, 6-38 Ramelteon, 7-12 Ramipril, 3-5 Ramucirumab, 9-21 Ranibizumab, 9-21 Ranitidine, 10-1 Ranolazine, 3-11 Rasagiline, 7-29 Rasburicase, 8-20 Remifentanil, 7-38 Repaglinide, 5-21 Reteplase, 4-11 Retinoic acid, 10-8 Ribavirin, 6-48 Ribociclib, 9-24 Riboflavin, 10-7 Rifabutin, 6-22 Rifampin, 6-22 Rifapentine, 6-22 Rifaximin, 6-22 Rilonacept, 8-9 Rilpivirine, 6-37 Riluzole, 7-17 Rimantadine, 6-51 Riociguat, 3-14 Risedronate, 5-32 Risperidone, 7-34 Ritonavir, 6-40 Rituximab, 9-25 Rivaroxaban, 4-10 Rivastigmine, 2-11

Rizatriptan, 7-18 Rocuronium, 2-3 Roflumilast, 10-5 Romidepsin, 9-16 Romiplostim, 4-15 Ropinirole, 7-30 Ropivacaine, 7-15 Rosiglitazone, 5-19 Rosuvastatin, 5-26 Rotigotine, 7-30 Rucaparib, 9-7 Ruxolitinib, 9-23 Sacubitril, 3-7 Salmeterol, 1-14 Saquinavir, 6-39 Sargramostim, 4-14 Sarin, 2-12 Saxagliptin, 5-23 Scopolamine, 2-6 Secobarbital, 7-10 Secukinumab, 8-10 Selegiline, 7-29 Semaglutide, 5-22 Sertaconazole, 6-26 Sertraline, 7-24 Sevelamer, 5-34 Sevoflurane, 7-14 Sildenafil, 3-14 Silodosin, 1-12 Siltuximab, 8-9 Simeprevir, 6-49 Simvastatin, 5-26 Sirolimus, 8-6

Sitagliptin, 5-23 Sofosbuvir, 6-48 Solifenacin, 2-9 Soman, 2-12 Sorafenib, 9-21 Sotalol, 3-26 Spironolactone, 3-19 Stavudine, 6-35 Streptokinase, 4-11 Streptomycin, 6-10 Streptozocin, 9-1 Succinylcholine, 2-2 Sucralfate, 10-3 Sufentanil, 7-38 Sulbactam, 6-4 Sulfacetamide, 6-15 Sulfadiazine, 6-15 Sulfamethoxazole, 6-15 Sulfasalazine, 8-16 Sulfinpyrazone, 8-22 Sulfisoxazole, 6-15 Sulindac, 8-1 Sumatriptan, 7-18 Sunitinib, 9-21 Suvorexant, 7-12 Tabun, 2-12 Tacrine, 2-11 Tacrolimus, 8-5 Tadalafil, 3-14 Tafluprost, 10-4 Tamoxifen, 5-5 Tamsulosin, 1-12 Tapentadol, 7-39

Tasimelteon, 7-12 Tazobactam, 6-4 Tedizolid, 6-13 Telavancin, 6-8 Telbivudine, 6-45 Telmisartan, 3-6 Temazepam, 7-11 Temozolomide, 9-1 Temsirolimus, 8-6 Tenecteplase, 4-11 Teniposide, 9-5 Tenofovir, 6-36 Terazosin, 1-12 Terbinafine, 6-27 Terbutaline, 1-14 Terconazole, 6-25 Teriparatide, 5-33 Testosterone, 5-8 Tetracaine, 7-15 Tetracycline, 6-11 Tetrahydrozoline, 1-8 Thalidomide, 9-28 Theophylline, 10-5 Thiamine, 10-7 Thioguanine, 9-12 Thioridazine, 7-32 Thiotepa, 9-1 Thiothixene, 7-33 Tiagabine, 7-8 Ticagrelor, 4-2 Ticlopidine, 4-2 Tigecycline, 6-11 Tiludronate, 5-32

Timolol, 1-18 Tinidazole, 6-18 Tioconazole, 6-26 Tiotropium, 2-8 Tipranavir, 6-39 Tirofiban, 4-4 Tizanidine, 1-10 TMP-SMX, 6-16 Tobramycin, 6-10 Tocilizumab, 8-9 Tocopherol, 10-8 Tofacitinib, 9-23 Tolazamide, 5-20 Tolbutamide, 5-20 Tolcapone, 7-29 Tolmetin, 8-1 Tolnaftate, 6-27 Tolterodine, 2-9 Tolvaptan, 5-14 Topiramate, 7-3 Topotecan, 9-5 Toremifene, 5-5 Torsemide, 3-17 Tositumomab, 9-25 Tramadol, 7-39 Trametinib, 9-22 Trandolapril, 3-5 Tranexamic acid, 4-12 Tranylcypromine, 7-28 Trastuzumab, 9-20 Travoprost, 10-4 Trazodone, 7-26 Tremelimumab, 9-27

Treprostinil, 3-15 Triamcinolone, 5-2 Triamterene, 3-19 Triazolam, 7-11 Trifluoperazine, 7-33 Trifluridine, 6-44 Trihexyphenidyl, 2-7 Trimethadione, 7-6 Trimethobenzamide, 7-31 Trimethoprim, 6-16 Trimipramine, 7-27 Triptorelin, 5-11 Tropicamide, 2-6 Trospium, 2-9 Umeclidinium, 2-8 Urokinase, 4-11 Ursodiol, 10-6 Ustekinumab, 8-10 Valacyclovir, 6-43 Valganciclovir, 6-43 Valproic acid, 7-5 Valrubicin, 9-4 Valsartan, 3-6, 3-7 Vancomycin, 6-8 Vardenafil, 3-14 Varenicline, 2-1 Vasopressin, 5-14 Vecuronium, 2-3 Vedolizumab, 8-11 Velpatasvir, 6-47 Vemurafenib, 9-22 Venetoclax, 9-29 Venlafaxine, 7-25

Verapamil, 3-10 Vigabatrin, 7-8 Vilanterol, 1-14 Vilazodone, 7-26 Vildagliptin, 5-23 Vinblastine, 9-13 Vincristine, 9-13 Vinorelbine, 9-13 Vitamins, 10-7–10-8 Vorapaxar, 4-3 Voriconazole, 6-25 Vorinostat, 9-16 Vortioxetine, 7-26 VX, 2-12 Warfarin, 4-9 Xylometazoline, 1-8 Zafirlukast, 8-4 Zaleplon, 7-12 Zanamivir, 6-50 Zidovudine, 6-35 Zileuton, 8-4 Ziprasidone, 7-35 Ziv-Aflibercept, 9-21 Zoledronic acid, 5-32 Zolmitriptan, 7-18 Zolpidem, 7-12 Zonisamide, 7-1 Zotarolimus, 8-6