Pharmcards review cards for medical students [4 ed.] 9780781787413, 0781787416

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PharmCards Review Cards for Medical Students Fourth Edition Eric C. Johannsen, M.D. Infectious Disease Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School

Marc S. Sabatine, M.D., M.P.H. Cardiovascular Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School

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Copyright © 2010 Lippincott Williams & Wilkins, a Wolters Kluwer business 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 information 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 the People’s Republic of China ISBN 13: 978-0-7817-8741-3 ISBN 10: 0-7817-8741-6 Acquisitions Editor: Susan Rhyner Managing Editor: Stacey Sebring Marketing Manager: Christen Melcher Production Editor: Bridgett Dougherty Compositor: Absolute Service/MDC Printer: C&C Offset 06 07 08 09 10 1 2 3 4 5 6 7 8 9 10

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Contents Preface......................................................................................................

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Sample PharmCard with Annotated Sections ......................................

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Key to Abbreviations................................................................................

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Fundamentals Cards..............................................................................

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Classification Schema ...........................................................................

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Class Cards...............................................................................................

A

Drug Cards................................................................................................

1

Bibliography .........................................................................................

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Index ......................................................................................................

247

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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 fourth edition, we have redrawn the figures and added a second color to enhance their readability. We have expanded the class cards to now cover the complex dopaminergic and serotoninergic transmission pathways and added a card describing P-glycoprotein’s role in drug metabolism to the fundamentals section. We have maintained the grouping of drug cards by category (e.g., adrenergic, cholinergic, and so on) and then by class (e.g., ␣ agonists, ␣ antagonists, ␤ agonists, 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 third 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. Renin inhibitors, oral Xa factor inhibitor, thrombopoietin receptor agonists, dipeptidyl peptidase-4 inhibitors for diabetes, and entry and integrase inhibitors for HIV are a few examples of new drug classes that have been incorporated into this fourth edition of PharmCards.

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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 Lippincott Williams & Wilkins, including Charley Mitchell and Stacey Sebring for their 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 for being so supportive throughout the process. Best of luck on the Boards! E.C.J. M.S.S. Boston, 2009

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

class

iv

Mechanism

The most important section 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

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 for antimicrobials, the specific arrhythmias for which antiarrhythmics are used, and so on. For third-year students, clinical indications take on increased importance.

Side Effects

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

Antidote

On toxin cards and drugs when there is a specific treatment for intoxication.

Contraindic.

Life-threatening absolute contraindications are important and are usually italicized.

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 are listed here along with their distinguishing features. It is important to know of them and their significant differences from the prototype.

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CATEGORY PROTOTYPICAL 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.

Related agent

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

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Key to Abbreviations 5-HT AC ACh AChR ACE ACEI ACS ADH ADP AF AFL AIDS ALL AML AMP ANA ARB ATI

5-hydroxytryptamine (serotonin) adenylate cyclase acetylcholine acetylcholine receptor angiotensin converting enzyme angiotensin converting enzyme inhibitor acute coronary syndrome antidiuretic hormone adenosine diphosphate atrial fibrillation atrial flutter acquired immune deficiency syndrome acute lymphocytic leukemia acute myelogenous leukemia adenosine monophosphate antinuclear antibodies angiotensin receptor blocker angiotensin I

ATII ATIII ATN ATP AV BBB BP CAD cAMP cGMP CCB CHF CMV CNS CO COMT COPD COX

angiotensin II antithrombin III acute tubular necrosis adenosine triphosphate atrioventricular blood–brain barrier blood pressure coronary artery disease cyclic adenosine monophosphate cyclic guanosine monophosphate calcium channel blocker congestive heart failure cytomegalovirus central nervous system cardiac output catechol O-methyl transferase chronic obstructive pulmonary disease cyclooxygenase

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CSF CV CVA CYP450 DA DAG DBP DCT DHF DHFR DIC DNA DVT EBV FAD FMN FSH Gi

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cerebrospinal fluid cardiovascular cerebrovascular accident cytochrome P450 dopamine diacyl glycerol diastolic blood pressure distal convoluted tubule dihydrofolate dihydrofolate reductase disseminated intravascular coagulation deoxyribonucleic acid deep vein thrombosis Epstein-Barr virus flavin adenine dinucleotide flavin mononucleotide follicle-stimulating hormone inhibitory G protein

Gs G6PD GABA GC GFR GI GMP GnRH GU HBV HCV HDL HIV HR HSV IDL Ig IM

stimulatory G protein glucose 6-phosphate dehydrogenase gamma-amino butyric acid guanylate cyclase glomerular filtration rate gastrointestinal guanosine monophosphate gonadotropin-releasing hormone genitourinary hepatitis B virus hepatitis C virus high-density lipoprotein human immunodeficiency virus heart rate herpes simplex virus intermediate-density lipoprotein immunoglobulin intramuscular

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Key to Abbreviations IMP IP3 IV JGA LDL LFT LH LMWH LO LTX mAb MAC MAO MEOS MI MLCK NAD

inosine monophosphate inositol 1,4,5-triphosphate intravenous juxtaglomerular apparatus low-density lipoprotein liver function test luteinizing hormone low-molecular-weight heparin lipoxygenase leukotrienes (X ⫽ A, B, C, and so on) monoclonal antibody Mycobacterium avium–intracellulare complex monoamine oxidase microsomal ethanol oxidizing system myocardial infarction myosin light-chain kinase nicotinamide adenine dinucleotide

NADP NE NM NSAID OTC PABA PAC PCT PDE PFT PGX PIP2 PLA2 PO PPD PR PRPP

nicotinamide adenine dinucleotide phosphate norepinephrine neuromuscular nonsteroidal anti-inflammatory drug over-the-counter para-aminobenzoic acid premature atrial contraction proximal convoluted tubule phosphodiesterase pulmonary function test prostaglandins (X ⫽ A, B, C, etc.) phosphatidyl inositol 4,5-bisphosphate phospholipase A2 per os (by mouth) purified protein derivative per rectum 5-phosphoribosyl-1-pyrophosphate

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PSVT PT PTH PTT RBC RNA RR RSV SBP SC SERM SIADH SL SLE SVR TB TCA

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paroxysmal supraventricular tachycardia prothrombin time parathyroid hormone partial thromboplastin time red blood cell ribonucleic acid respiratory rate respiratory syncytial virus systolic blood pressure subcutaneous selective estrogen receptor modulator syndrome of inappropriate antidiuretic hormone sublingual systemic lupus erythematosus systemic vascular resistance tuberculosis tricyclic antidepressant

TF TFPI TFT TG THF TIA TNF TPR TXA2 UFH UTI VLDL VT vWF VZV

tissue factor tissue factor pathway inhibitor thyroid function test triglyceride tetrahydrofolate transient ischemic attack tumor necrosis factor total peripheral resistance thromboxane unfractionated heparin urinary tract infection very low-density lipoprotein ventricular tachycardia von Willebrand’s factor varicella-zoster virus

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PHARMACOKINETICS I

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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 first-pass metabolism in the liver, where the drug may be “pre-metabolized” (via portal circulation) before reaching the systemic circulation.

Distribution

Most drugs do not 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 Amt in body the total amount in the body. This is an “apparent volume” with no anatomic meaning that must be Vd = C 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.

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Output

CL =

Output C

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Drug output is the other major determinant of serum drug concentration. Renal excretion is the primary route of elimination for most water-soluble 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.

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PHARMACOKINETICS II Half-life t 12 =

ln(2) × Vd CL

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Half-life (t1/2) 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, t1/2 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 at the same rate that it is eliminated from the body (i.e., input ⫽ output). Thus, at steady state, the administration of 1200 mg of a given Dose drug daily will result in the elimination of 1200 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. MD = CL × CT 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 LD = Vd × CT

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 therapeutic concentration (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.

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conc.

conc. serum Drugs that remain intravascular will have the smallest volume of distribution (Vd is shaded).

serum ECF lipid Drugs that distribute into the extracellular fluid (ECF), lipid, or other compartments will have a large Vd and require a larger loading dose.

PLASMA CONC

Dashed black line depicts X mg dose every Y hours. Gray line depicts 4X mg dose every 4Y hours. Solid black line depicts continuous IV infusion at a rate of X/Y mg/hr

TIME For each maintenance dose schedule, the rate of input is X/Y mg/hr and the average serum concentration is the same, but the peaks and troughs increase with increased dosing interval.

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PHARMACODYNAMICS

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Overview

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 & Antagonists

Agonists bind to and activate receptors. In contrast, antagonists bind 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 Effect = C ⎞ effects at lower concentrations than do low-potency drugs. Note that whereas the clinical utility of a ⎛ Emax ⎜ ⎝ EC50 + C ⎠⎟ drug mainly depends on its efficacy, the dose required to achieve a given effect depends on both potency and efficacy.

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Therapeutic Index TI =

TD50 ED50

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Clearly, some drugs are more toxic than others. In clinical practice, it 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.

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PROTEIN BINDING

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Overview

Competition for and displacement from serum protein binding sites is a frequently touted reason for drugdrug 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. ␣1-Acid glycoprotein is the predominant binding protein for basic drugs; as an acute phase reactant, its concentration can be greatly elevated in inflammatory states. ␤-Lipoproteins are also important binding proteins for some basic drugs.

Free Drug When drugs are bound to serum proteins they are pharmacologically inactive. Only the unbound, or free, Concentration 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).

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10 ng/ml (free)

100 ng/ml displacement

(total)

time

5 ng/ml (free)

by drug

95 ng/ml (bound) initial state

Serum Drug Levels

50 ng/ml 90 ng/ml (bound) transient elevation of free drug

45 ng/ml (bound)

(total)

new steadystate

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.

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CYTOCHROME P450 ENZYME SYSTEM

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Mechanism

Human cytochrome P450 (also called CYP450) refers to a superfamily of heme-containing enzymes that catalyze the mono-oxygenation 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.

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CYTOCHROME P450 INTERACTIONS Isoenzyme CYP1A2 CYP2C8 CYP2C9

CYP2C19 CYP2D6

CYP2E1 CYP3A4

Inhibitor Cimetidine Ciprofloxacin Cimetidine Amiodarone Cimetidine Isoniazid Fluconazole Omeprazole Cimetidine Fluoxetine Quinidine Disulfiram Cimetidine Erythromycin Fluconazole Ritonavir, Verapamil

Inducer Cigarette Smoke

Substrate Theophylline

Phenobarbital Rifampin Rifampin

Diazepam Phenytoin Warfarin

Phenytoin Rifampin

Ethanol Isoniazid Phenobarbital Rifampin

Prodrug Substrate†

Losartan

Clopidogrel ␤-Blockers Codeine TCAs Ethanol Halothane, isoflurane Carbamazepine Cyclosporine Midazolam Terfenadine

Codeine Tamoxifen

Note 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).

†

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P-GLYCOPROTEIN

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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 P-gp in tumor cells confers a multi-drug resistance (MDR) phenotype. For this reason, P-gp is sometimes referred to as MDR1.

Metabolism

P-glycoprotein 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.

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P-GLYCOPROTEIN INTERACTIONS †

INHIBITOR Verapamil Cyclosporin A Quinidine Ritonavir Erythromycin, Clarithromycin Ketoconazole, Itraconazole Midazolam Tamoxifen

†

INDUCER Rifampin St. John’s wort

SUBSTRATE Digoxin Doxorubicin, Daunorubicin Vincristine, Vinblastine Etoposide, Teniposide Paclitaxel Cyclosporin A, Tacrolimus Saquinavir, Amprenavir, Ritonavir Methotrexate Hydrocortisone, Dexamethasone Terfenadine

P-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), P-gp inhibition can increase intracellular concentrations of drugs by preventing their export.

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Classification Schema 1. ADRENERGIC AGENTS Direct Sympathomimetic Epinephrine Norepinephrine Dopamine Dobutamine Indirect Sympathomimetic Amphetamine Ephedrine Cocaine Sympathoplegic Methyldopa

␣-Adrenoceptor Agonists and Antagonists Phenylephrine Clonidine Phentolamine Prazosin

␤-Adrenoceptor Agonists and Antagonists Isoproterenol Albuterol Metoprolol Carvedilol Timolol D1-Agonist Fenoldopam

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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

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Classification Schema 3. CARDIOVASCULAR & RENAL AGENTS Direct Vasodilators Nitroglycerin Nitroprusside Nesiritide Hydralazine ACE Inhibitors, ARBs, & Renin Inhibitors Captopril Losartan 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 Adenosine

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4. HEMATOLOGIC AGENTS Antiplatelet Acetylsalicylic acid Clopidogrel Eptifibatide Dipyridamole

Anticoagulant Heparin Enoxaparin Lepirudin Warfarin Rivaroxaban Drotrecogin

Fibrinolytic Alteplase Procoagulant Aminocaproic acid Hematopoietic Erythropoietin Filgrastim Eltrombopag

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Classification Schema Glucocorticoids Prednisone Beclomethasone Estrogens, SERMs, & Progestins Estrogens Clomiphene Tamoxifen Anastrozole Progestins Androgens & Anti-androgens Testosterone Flutamide Finasteride

5. ENDOCRINE AGENTS Hormones Leuprolide Octreotide Oxytocin Vasopressin Thyroid Hormone & Antithyroids Levothyroxine Methimazole Hypoglycemics Insulin Glyburide Nateglinide Exenatide Metformin Rosiglitazone Acarbose

Hypolipidemics Atorvastatin Gemfibrozil Niacin Cholestyramine Ezetimibe Bisphosphonates & Other Bone Mineral Homeostatic Drugs Alendronate Teriparatide Cinacalcet

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6. ANTIMICROBIAL AGENTS Antibacterials ␤-lactams and other cell wall agents Penicillin Nafcillin Ampicillin Ticarcillin Clavulanic acid Cephalosporins 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 Primaquine Antiparasitic Pentamidine Antiretrovirals Protease inhibitor Saquinavir Entry inhibitors Enfuvirtide Maraviroc Integrase inhibitor Raltegravir

RT inhibitors Efavirenz Zidovudine Tenofovir Antivirals Antiherpesvirus agents Acyclovir Foscarnet Trifluridine Hepatitis antivirals Entecavir Ribavirin Interferon alpha Influenza antivirals Zanamivir Amantadine

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Classification Schema 7. CNS AGENTS Antiepileptics Phenytoin Carbamazepine Topiramate Valproic acid Ethosuximide Gabapentin Tiagabine GABAergic Phenobarbital Thiopental Diazepam Zolpidem Baclofen General Anesthetic Halothane Local Anesthetic Procaine

Glutamate Antagonists Memantine Riluzole Serotonin Agonists & Antagonists Sumatriptan Ergotamine Buspirone Ondansetron Alosetron Antidepressants Amitriptyline Fluoxetine Nefazodone Phenelzine

Dopamine Agonists & Antagonists Levodopa/carbidopa Pramipexole Prochlorperazine Antipsychotics Chlorpromazine Haloperidol Olanzapine Lithium Opioids & Opioid Antagonists Morphine Codeine Pentazocine Diphenoxylate Methadone Naloxone

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8. ANTI-INFLAMMATORY AGENTS COX Inhibitors Ibuprofen Celecoxib Acetaminophen Leukotriene Antagonist Zafirlukast

Immunosuppressants Cyclosporine Sirolimus Antithymocyte globulin Mycophenolate mofetil Methotrexate Etanercept Immunomodulators Interferon-beta Hydroxychloroquine Thalidomide Sulfasalazine Cromolyn

Antihistamines Diphenhydramine Fexofenadine Antigout Allopurinol Colchicine Probenecid

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Classification Schema 9. ANTINEOPLASTIC AGENTS DNA Damaging Agents Alkylating agents Bleomycin Doxorubicin Etoposide Transcription Inhibitor Dactinomycin Antimetabolite Cytarabine Fludarabine 5-Fluorouracil Hydroxyurea Mercaptopurine

Tubulin Poisons Vincristine Paclitaxel Gene Expression Modifiers All-trans retinoic acid Azacytidine Tyrosine Kinase Signaling Inhibitors Imatinib Trastuzumab Anti-angiogenesis Bevacizumab

Anti-tumor Monoclonals Rituximab Gemtuzumab Other Bortezomib Aldesleukin Asparaginase

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10. MISCELLANEOUS AGENTS H2-Blocker Cimetidine Proton Pump Inhibitor Omeprazole Prostaglandins Misoprostol Latanoprost

PDE Inhibitor Theophylline GI Agent Ursodiol Miscellaneous Disulfiram Vitamins I, II

Toxin Carbon monoxide Cyanide Ethanol Lead Methanol Strychnine

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NORADRENERGIC JUNCTION NORADRENERGIC JUNCTION MAO-A inhibitors phenelzine NE

MAO-A

NE

DA

–

A

DOPA

NE

NE

indirect sympathomimetics amphetamine ephedrine

+

–

methyl NE

methyl NE

Ca2+

– NE

Gi α2 adrenoceptor

– reuptake inhibitors cocaine amitriptyline

Tyr

sympathoplegics methyldopa + reserpine

metabolites

reu pta ke

DA

A

Ca2+ NE

+ α2-agonists clonidine

adrenoceptors

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ADRENERGIC AGENTS Class

Direct sympathomimetics

Agonist ␣-Adrenoceptor Blocker Agonist ␤-Adrenoceptor Blocker

Agent Epinephrine Norepinephrine Dopamine Dobutamine Fenoldopam Phenylephrine Clonidine Phentolamine Prazosin Isoproterenol Albuterol Propranolol Metoprolol

␣1 ⫹ ⫹ ⫹

B ␣2 ⫹ ⫹

␤1 ⫹ ⫹ ⫹ ⫹

␤2 ⫹

D1

⫹ ⫹

⫹ ⫺ ⫺

⫹ ⫺ ⫹ ⫺ ⫺

⫹ ⫹ ⫺

⫹, 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 ␤1 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: ␣1 → vasoconstriction ␤2 → smooth muscle relaxation → vasodilatation and bronchodilation ␣2 → ↓ sympathetic outflow and vasodilatation D1 → renal and splanchnic vasodilatation ␤1 → ↑ HR and ↑ contractility

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CHOLINERGIC AGENTS

C

prolongs effect (inhibits degradation)

Cholinesterase inhibitor Neostigmine Donepezil Sarin

Nicotinic Agonist

Muscarinic Agonist Bethanechol Pilocarpine

Acetylcholine Carbachol

Nicotine

Succinylcholine (depolarizing blockade)

K+ –

M1-M5

or

–

–

–

Gprotein

+

Na = stimulation

–

= blockade

Nn

Atropine (3º) Benztropine (3º) Ipratropium (4º) Oxybutynin (4º) Anti-muscarinic

Nm (non-depolarizing blockade)

Hexamethonium

Pancuronium

neuronal

muscle

Anti-nicotinic

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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 M1 M2 M3

Location CNS CV Eye GI/GU

M4 & M5

Receptor NN NM

Lung CNS

Agonists Stimulation ↓ HR Miosis, ciliary contraction (glaucoma treatment) ↑ motility, ↑ secretions, bladder detrusor contraction, and sphincter relaxation Bronchoconstriction and ↑ secretions ?

Location Neuronal: on postganglionic autonomic neurons, adrenal medulla, CNS Muscle: neuromuscular junction

Nicotinic agents Agonists

Antagonists ↓ motion sickness, ↓ extrapyramidal effects ↑ HR Pupillary dilatation (mydriasis), cycloplegia ↓ motility, ↓ secretions, ↓ bladder tone Bronchodilation and ↓ secretions ?

Antagonists

CNS and ganglionic stimulation Ganglionic blockade → hypotension (and many side effects) Fasciculations, paralysis Paralysis (nondepolarizing blockade) (depolarizing blockade)

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PHARMACOLOGIC TREATMENT OF HYPERTENSION heart

CCB verapamil

– venodilators nitroglycerin

β-blockers metoprolol, propranolol

–

–

brain

– α-blockers prazosin phentolamine

sympathoplegics methyldopa α2-agonists clonidine

–

mixed vasodilators nitroprusside, nesiritide

veins

–

D

arterioles

kidneys

– ARB: losartan vasoconstriction

arteriolar dilators hydralazine, minoxidil CCB nifedipine D1-agonists fenoldopam

–

ACEI: captopril renin inhib aliskiren

+

ATII

–

Na ACE

ATI

–

renin

angiotensinogen

diuretics HCTZ

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TYPES OF VASODILATORS Arteriolar dilators ↓ afterload Hydralazine Minoxidil CCBs Fenoldopam

Mixed vasodilators ↓ afterload, ↓ preload ACEIs, ARBs, renin inhib Nitroprusside Nesiritide ␣1-Blockers ␣2-Central agonists

Venodilators ↓ preload Nitrates

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PHARMACOLOGIC TREATMENT OF HEART FAILURE

E if

β-blockers

-agonist

2 inotropes activity β1-agonists (e.g., dobutamine)

indicated in compensated CHF contraindicated in acute CHF

+ –

PDE inhibitors (e.g., milrinone) digoxin

afterload heart

venodilators

mixed vasodilators

arteriolar dilators

nitroglycerin morphine

ACE, ARB nitroprusside nesiritide

hydralazine

preload

afterload

–

–

– arterioles

veins

diuretics ACEI and ARB have additional beneficial effects, beyond vasolidation, by decreasing levels of ATII and aldosterone, hormones that can promote cardiac fibrosis.

furosemide, HCTZ spironolactone nesiritide

+ natriuresis preload

kidneys Na

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Page F

DIURETICS

glomerulus

F

DCT

PTH Ca2+

PCT

– glucose amino acids

–

PTH

collecting duct ClNa+

thiazides HCTZ

– PO43-

HCO3-

–

ThAL

–

acetazolamide

Loop of Henle

K+ Na+

aldosterone

H+ Na+ 2 ClK+

loop diuretics furosemide

K+-sparing spironolactone ADH

H2O

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EFFECT OF DIURETICS ON SERUM ELECTROLYTES Class Loop Thiazide Potassium sparing CA inhibitor

Prototype Furosemide HCTZ Spironolactone Amiloride Acetazolamide

K⫹ ↓↓ ↓ ↑ ↑ ↓

HCO3⫺ ↑ ↑ ↓ ↓ ↓↓

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.

Ca2⫹ ↓ ↑ ↓ ↑ —

Mg2⫹ ↓ ↓ — — —

Urate ↑ ↑ — — —

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ANTIARRHYTHMICS Class (prototype) Class IA (procainamide) Class IB (lidocaine) Class IC (flecainide) Class II ß-blockers (metoprolol) Class III (ibutilide) (amiodarone) Class VI CCB (verapamil)

Electrophysiologic effects Purkinje cells Pacemaker cells Moderate Na+ block slope phase 4 Prolong threshold for repolarization firing slope phase 4 Mild Na+ block threshold for Shorten firing repolarization slope phase 4 Marked Na+ block threshold for No change in firing repolarization slope phase 4 No effect Prolong repolarization at AV node Marked prolong of repolarization

No effect

No effect Slow AP rise Prolong repolarization at AV node

G Clinical uses AF/AFL

Post-MI ventricular arrhythmias AF and WPW in patients with structurally normal hearts Rate control AF/AFL PSVT VT Ibutilide: AF/AFL Amiodarone: AF, VT

Rate control of AF/AFL PSVT

AF, atrial fibrillation; AFL, atrial flutter; MI, myocardial infarction; PSVT, paroxysmal supraventricular tachycardia; VT, ventricular tachycardia; WPW, Wolff-Parkinson-White syndrome. Adapted from Lilly LS, ed. Pathophysiology of Heart Disease. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.

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NORMAL CARDIAC ELECTROPHYSIOLOGY

Phase 1 Cl– influx

Phase 2 Ca2+ influx balances K+ efflux

Phase 0 Na+ influx

Phase 3 K+ efflux

Ca2+ influx

K+ efflux threshold for firing

Phase 4 Resting membrane potential

Purkinje cell

Phase 4

Pacemaker current = If (Spontaneous depolarization) Na+ influx

Pacemaker cell

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Page H

ANTIPLATELET AGENTS

H

plaque rupture tissue factor

epi, PAF

vWF collagen

thrombin

endothelial cells

coagulation cascade

+

platelet activation TXA2

ADP

–

TxS C OX1

TXA2

COX-1 inhibitors aspirin nonselective NSAIDs

AA

IIIa IIb –

platelet 5-HT

+

+

GP llb/lIla inhibitors eptifibatide, abciximab, tirofiban

fibrinogen

IIIa IIb platelet inhibition

+

PDE

cAMP

–

AC P2Y12

ADP receptor blockers clopidogrel, prasugrel, ticlopidine

– dipyridamole

-

ATP platelet

–

adenosine

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XII

Extrinsic Pathway VIIa +TF

XIIa XI

TFPI

XIa

– IX

IXa – VIIIa Ca2+, PL

tenase complex

LMWH (anti-Xa > anti-IIa) enoxaparin heparin (anti-IIa ≈ anti-Xa) + ATIII + ATIII

+ ATIII

thrombomodulin

prothrombinase complex

– (prothrombin) II

fibrin

– plasminogen TPA, RPA, TNK

+

UK SK+plasmin

IIa (thrombin) fibrinogen

= vitamin K dependent

∴ inhibited by warfarin

– –

plasmin fibrin

–

fibrin split products

α 2-antiplasmin aprotinin

fibrinolytics

Protein S

Xa – Va Ca2+, PL

X

Protein C

direct thrombin inhibitors (only anti-IIa) lepirudin, bivalirudin, argatroban, dabigatran aminocaproic acid

(only anti-Xa)

Intrinsic Pathway

oral Xa inhibitors rivaroxaban fondaparinux

ANTICOAGULANTS, PROCOAGULANTS, FIBRINOLYTICS

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PHARMACOLOGIC TREATMENT OF ASTHMA bronchi & alveoli

I

antimuscarinic ipratropium co

ns

brain

– tric

tio

ACh vagus

n

sympathetic

leukotrienes

–

–

IgE LO

–

arachidonic acid PLA2

–

phospholipids

mast cell

+ AC

–

–

adenosine

cAMP

leukotriene antag. zafirlukast, zileuton glucocorticoids prednisone beclomethasone

β2-agonists albuterol

ATP

dil at ion

um lg

E

iz al

ti-

–

an

om

cromolyn

n io at n m io m ict fla t r in o n s c

ab

bronchial lumen

– AMP

PDE

theophylline smooth muscle

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PHARMACOLOGIC TREATMENT OF DIABETES

J

incretins exenatide

+

pramlintide liver

GLP-1

glucagon

+ glycogenolysis gluconeogenesis

–

sulfonylureas glyburide

+

stre

am

inactive hormones

of glucose

DPP-4 inhib. sitagliptin glinides nateglinide

insulin

gluco

+

se

stomach

in presence

+

bloo d

–

GIP

pancreas

+

thiazolidinedione rosiglitazone biguanide metformin

–

DPP-4

–

intestines

– pramlintide

–

adipose

α-glucosidase inhib acarbose in response to oral glc

+ thiazolidinedione rosiglitazone

GLP-1 & GIP

muscle

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PHARMACOLOGIC TREATMENT OF DYSLIPIDEMIA

intestines

statins (atorvastatin)

liver

acetyl CoA

bil aci e ds

–

HMG-CoA reductase

+

– resins

ezetimibe

–

cholesterol small HDL

ApoA

+

TGs

LDL receptor

– FFAs

LDL

(cholestyramine)

chol.

Extrahepatic tissues chol. LCAT

fibrates (gemfibrozil)

hepatic lipase

cholesterol chylomicrons

chylomicron remnants

VLDL

FFAs

– plasma lipoprotein lipase

+

CETP

IDL

+

triglycerides

lipoprotein lipase

niacin

muscle adipose

HDL

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Page K

ANTIBACTERIALS

K PABA

CELL WALL

ciprofloxacin

DNA gyrase

–

crosslinked peptidoglycans

β-lactams penicillins cephalosporins aztreonam imipenem

–

cross-linking

–

rifampin

RNAP + nucleotides

dihydropteroate synthetase

linear peptidoglycans

30S

vancomycin

–

P

single peptidoglycans

linezolid (50S) (blocks initiation complex formation)

THF

mRNA

polymerization

50S

–

–

–

DHF

DHFR

erythromycin (50S) quinupristin (50S)

A

–

sulfamethoxazole

translocase

trimethoprim pyrimethamine

gentamicin (30S) (blocks formation of a functional 70S and induces misreading)

P P

A

doxycycline (30S) polymyxin

(blocks entry of aa-tRNA)

–

– EF-Tu aa-tRNA

A

EF-Tu aa-tRNA

clindamycin (50S) dalfopristin (50S) chloramphenicol (50S)

peptidyl transferase P

A

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SITES OF ACTION OF MAJOR ANTIBACTERIALS Folate pathway Sulfamethoxazole Trimethoprim

DNA Ciprofloxacin

RNA Rifampin

Ribosomal subunit 30S 50S Gentamicin Erythromycin Doxycycline Clindamycin Chloramphenicol Linezolid Quinupristin/ dalfopristin

Cell wall Penicillins Cephalosporins Aztreonam Imipenem Vancomycin Polymyxin B

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Page L

PENICILLIN ANTIBACTERIALS Generation

Mechanism details

Spectrum

L Example

Natural penicillin

Penicillinase susceptible

Streptococcus, Meningococcus, ⫾ Pneumococcus Anaerobes except B. fragilis

Penicillin

Penicillinase resistant

Bulky R group confers penicillinase resistance

Methicillin-sensitive Staphylococcus aureus (MSSA) Streptococcus

Nafcillin

Aminopenicillin

Hydrophilic amino group confers greater gram-negative activity Penicillinase susceptible

Natural penicillin spectrum and Proteus ⫾ H. influenzae, E. coli, Salmonella, Shigella

Ampicillin

Carboxypenicillin

Carboxy group confers greater gramnegative and anaerobe activity Penicillinase susceptible

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

Ticarcillin

Ureidopenicillin

Ureido group confers even greater gram-negative activity Penicillinase susceptible

Carboxypenicillin spectrum and Klebsiella

Piperacillin

␤-Lactamase inhibitor

Prevents degradation of susceptible penicillins

Adds Staph. aureus (MSSA) and B. fragilis

Clavulanic acid

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OTHER BETA-LACTAM ANTIBACTERIALS

Cephalosporins

Class First

Second Third Third-AP Forth Monobactam Carbapenem

AP, anti-pseudomonal

Spectrum Gram-positive cocci (GPC) including methicillin-sensitive Straphylococcus aureus (MSSA) and Streptococci Also some gram-negative rods (GNRs) such as E. coli, Proteus, Klebsiella Adds H. influenzae, M. catarrhalis Adds most remaining GNRs (except Pseudomonas) Almost all GNRs (including Pseudomonas), less good GPC coverage Similar to Third-AP, but retains excellent GPC coverage Most GNRs, no gram positives, no anaerobic coverage Extremely broad spectrum, covers almost everything except highly-resistant pathogens such as methicillin-resistant Staph aureus (MRSA), vancomycin-resistant enterococcus (VRE)

Example Cefazolin

Cefuroxime Ceftriaxone Ceftazidime Cefepime Aztreonam Imipenem

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ANTIMYCOBACTERIAL AGENTS

M PABA

fluoroquinolones moxifloxacin levofloxacin ofloxacin ciprofloxacin

dapsone aminosalicylic acid

–

dihydropteroate synthetase

–

DNA gyrase

DHF

rifampin rifabutin rifapentine

–

RNAP nucleotides

DHFR

mRNA

THF galactose

arabinose

polymerization

galactan

–

arbinan

30S

ethambutol

50S

pyrazinamide

– peptidoglycan arabinogalactan mycolic acid

(inhibits translocation)

50S

short chain fatty acids

–

clarithromycin (50S)

–

Acetyl-CoA

30S

isoniazid ethionamide

–

streptomycin (30S) amikacin (30S) (induce misreading)

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SPECTRUM OF ANTIMYCOBACTERIAL ACTIVITY Drug Isoniazid Ethionamide Ethambutol Streptomycin Amikacin Clarithromycin Dapsone Aminosalicylic acid Rifampin Rifabutin Fluoroquinolones Clofazamine Pyrazinamide

TB ⊕ ⫹ ⊕ ⊕ ⫹

M. leprae ⫹

⫹ ⊕ ⫹ ⊕ ⫹ ⫹ ⊕

MAC ⫽ mycobacterium avium complex. ⊕ ⫽ therapy of choice; ⫹ ⫽ acceptable alternative.

MAC

⊕ ⫹ ⊕

⊕ ⫹ ⫹ ⊕

⫹ ⊕ ⫹ ⫹

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Page N

ANTIFUNGAL AGENTS

N

5-FU

–

flucytosine

(inhibits thymidine synthesis)

mRNA

griseofulvin

squalene squalene epoxidase

–

lanosterol

14 demethylase

–

terbinafine tolnaftate

1,3

– mitotic spindles

azoles voriconazole miconazole

– ergosterol

amphotericin B nystatin (bind ergosterol and disrupt membrane)

glucose

caspofungin micafungin

glucan synthase

– 1,3 β glucan

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SPECTRUM OF ACTIVITY OF ANTIFUNGAL AGENTS Mold

Drug Amphotericin Nystatin Flucytosine Voriconazole Itraconazole Fluconazole Miconazole Ketoconazole Terbinafine

Caspofungin Micafungin Anidulafungin

Mechanism Binds ergosterol and disrupts membrane Antimetabolite Blocks ergosterol synthesis

Blocks ergosterol precursor synthesis Inhibits cell wall (beta glucan) synthesis

Asperg ⊕a

Systemic Infections Yeasts Dimorphics Blasto Histo SporotriCrypto Candida Coccidio chosis ⊕a ⊕a ⫹ ⊕a

⫹b ⊕ ⫹

⊕

⫹b ⫹ ⫹ ⊕

⫹ ⊕ ⫹c

⫹ ⊕ ⫹

Superficial infections Dermatophytes

Tinea

Candida ⊕

⫹ ⫹ ⫹ ⫹

⫹b

Onychomycosis

⊕ ⊕ ⫹ ⊕

⊕ ⊕ ⊕

⊕ ⫽ therapy of choice; ⫹ ⫽ acceptable alternative. aAmphotericin is generally preferred over azoles for severe infections, but side effects limit its use in uncomplicated cases. bUsed as an adjuvant agent for severe infections. cNot used for histoplasmosis.

⫹ ⊕ ⊕ ⫹

N

N

N

N

O

OH

N

N

O

OH deoxythymidine

HOCH2 O

O

HN

deoxycytidine

OH

HOCH2 O

O

NH2

CH3

HO

N

O

O

HN

O

HN

OH Trifluridine

N

O

N

O

CF3

O

HN

N

N

O

N

OH Idoxuridine

N

I

Lamivudine

S

HOCH2 O

O

N N

NH2

N

N

(3TC)

N

O

HN N

O

O

CH2

HOCH2

Entecavir

OH

HOCH2

N

O

OH Telbivudine

O

HN N H N 2

N

Ribavirin

O

NH2

HO

N

N

N

O OCH2P(C3H9O4)2

Tenofovir Disoproxil Fumurafe

O OCH2P(C6H11O3)2 H3C

Gancyclovir

OH

HOCH O

HOCH2 O

OH

N

N

Adefovir Dipivoxil

N

OCH2P(OH)2

Cidofovir

N

NH2

HOCH2 O

O

N

N

NH2

N H 2N

N

Acyclovir

HOCH2 O

H2N

HN

Vidarabine

OH

N

N

Nucleoside analog

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N

deoxyguanosine

N

N

N HOCH2 O

N

NH2

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HOCH2 O

H2N

HN

deoxvadenosine

OH

HOCH2 O

N

NH2

DNA base

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ANTIVIRALS O

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SPECTRUM OF ACTIVITY OF ANTIVIRAL AGENTS DNA Viruses Drug Acyclovir Ganciclovir Foscarnet Cidofovir Trifluridine Lamivudine Tenofovir Entecavir Telbivudine Ribavirin Interferon ␣ Amantadine Zanamivir

HSV

EBV

VZV

CMV

⊕ ⫹ ⫹ ⫹ ⫹

⫹*

⊕ ⫹ ⫹ ⫹

⊕ ⫹ ⫹

HBV

RNA Viruses Influenza RSV A B

HCV

⊕ ⊕ ⊕ ⊕ ⊕ ⊕ ⫹ ⊕

⊕ ⫽ therapy of choice; ⫹ ⫽ acceptable alternative. *Oral hairy leukoplakia only, antiviral therapy is not indicated for infectious mononucleosis.

⊕

⊕ ⊕

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Page P

HIV THERAPY

P

Overview

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 dynamics

It is now appreciated that asymptomatic HIV infection, the period 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.

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ANTIRETROVIRAL AGENTS Enfuvirtide

Maraviroc binding

–

–

fusion

CD4

CCR5

integrase uncoating

– provirus

reverse transcriptase

–

Raltegravir

cell DNA

cell DNA

transcription

Zidovudine Efavirenz Tenofovir assembly

Saquinavir

– maturation

release

translation

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ANTIEPILEPTIC AGENTS Inhibitory neuronal projection

GABA

Excitatory neuronal projection volatge-gated Na+channel

Vigabatrin

glutamate glutamate decarboxylase

Q

–

Na+

Phenytoin Carbamazepine Valproic Acid Lamotrigine Felbamate Topiramate Zonisamide

Tiagabine

– succinate GABA-T semi-aldehyde (inactive)

depolarization

–

GABA reuptake transporter

Benzodiazepines Barbiturates + Topiramate

GABA

post-synaptic neuron

+

glutamate

vesicle release

Topiramate

Felbamate

–

Cl–

glutamate

post-synaptic neuron

AMPA/ receptor Kainate

GABAAreceptor

+

Na+(& Ca++)

+

– NMDA receptor

Ca++(& Na+)

Adapted from Rho JM, Sankar R. The Pharmacologic basis of antiepileptic drug action. Epilepsia 40(11):1471–1483, 1999.

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ANTIEPILEPTICS Generalized Major mode of action Na⫹ channel blockade

Glutamate inhibition GABA potentiation

T-type Ca⫹⫹ channel block Misc. (unknown)

Agent Phenytoin Carbamazepine Lamotrigine Zonisamide† Topiramate† Felbamate*† Tiagabine Vigabatrin Diazepam Phenobarbital Ethosuximide Trimethadione Valproic acid† Gabapentin Pregabalin Levetiracetam

Absence

⊕ ⫹

⫹ ⊕ ⫹ ⊕

Focal

Tonic-clonic ⊕ ⊕ ⫹ ⫹ ⊕ ⫹

⫹ ⊕

Partial ⊕ ⊕ ⊕ ⫹ ⊕ ⫹ ⫹ ⫹

Myoclonic

⫹

⫹ ⫹ ⫹

⊕

⊕

⫹ ⫹ ⫹

⊕ ⫹ ⫹

⊕ ⫽ first-line therapy *Severe toxicity limits use of this drug to seizures refractory to all other agents. †Agent acts via multiple mechanisms.

Status epilept. ⫹

⊕

⫹ ⫹

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DOPAMINE AGONISM & ANTAGONISM IN CNS

R

antiparkinsonians L-dopa, pramipexole entacapone, selegiline corpus striatum

+ DA

–

normal movement

mesolimbic & mesocortical pathways

agitation, hallucinations, psychosis

parkinsonism

+ DA

lateral reticular formation

– sedation

antipsychotics chlorpromazine, haloperidol, olanzapine

For simplicity, neither molecular signaling downstream of the DA receptor nor receptor subtypes are shown.

DA

nausea & vomiting

+ – relief of nausea & vomiting

antiemetics (anti-DA) prochlorperazine droperidol, metoclopramide

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SEROTONIN AGONISM & ANTAGONISM TCAs & SSRIs amitriptyline fluoxetine

ergot alkaloids ergotamine migraine prophylaxis

5-HT receptor

elevated mood

cortex

–

5-HT2 receptor

Both 5=HT reuptake inhibitors and 5=HT2 receptor antagonist relieve depression.

+ 5-HT3

atypical antidepressants nefazodone

lateral reticular form.

triptans sumatriptan (5-HT1agonist)

nausea & vomiting

– relief of nausea & 5-HT 1 vomiting

antiemetics (anti-5-HT) ondansetron

+ –

n nstrictio vasoco

migraine relief

Used for constipationpredom IBS

cerebral vasodi lation

headache 5-HT 4

+ 5-HT3

alosetron

–

Used for diarrhea-predom IBS For simplicity, neither molecular signaling downstream of 5-HT receptors nor all receptor subtypes are shown.

tegaserod

stool output (constipation)

intestines

+

stool ouput (diarrhea)

Bleomycin

Inhibit proteosome Alter protein turnover

Bortezomib

Deaminates asparagine Inhibits protein synthesis

L-asparginase

mRNA

Intercalate DNA, induce breaks inhibit RNA synthesis

Dactinomycin

Intercalate DNA: breakage (via topoisomerase II) + generate free radicals

Doxorubicin

Proteins

–

–

–

–

Kinase inhibition

Imatinib

Alter microtuble function

Vincristine Paclitaxel

Alter gene expression

Tamoxifen All-trans retinoic acid Azacytadine

Crosslink DNA

Alkylating agents Cisplatin

DNA

Induce strand breakage via DNA topoisomerase inhibition

Etoposide Topotecan

Inhibit DNA synthesis

Cytarabine Fludarabine

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Damage DNA Prevent repair

Deoxyribonucleotides

–

Inhibit ribonucleotide reductase

Hydroxyurea

Pyrimidine precursors

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–

Inhibit thymidine synthesis

Ribonucleotides

Inhibit purine synthesis & interconversion

Mercaptopurine

5 - Fluorouracil

Inhibit purine ring synthesis Inhibit thymidine synthesis

Methotrexate

–

Purine precursors

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ANTINEOPLASTICS S

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

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ANTINEOPLASTICS Vincristine Paclitaxel

– M phase

Bleomycin

–

G2phase

specialized protein synthesis preparation for mitosis

–

–

G1phase cell growth RNA synthesis protein synthesis

Tamoxifen

CCNS drugs Alkylating agents Cisplatin Dactinomycin Doxorubicin

S phase

Etoposide

– Topotecan

Steroid hormones

mitosis

DNA synthesis Antimetabolites

–

Cytarabine 5-Fluorouracil Fludarabine Mercaptopurine Methotrexate

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MONOCLONAL ANTIBODIES (Abs) Mechanism Kill cells

Clinical use

Abs are not directly toxic to cells but rely on several different mechanisms. • Ab-dependent, cell-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 CD-20 mAb fused to radioactive I-131)

1. Chemotherapy

Block signaling

By binding to either the receptor or the ligand, mAb creates steric hindrance that prevents ligand-receptor coupling.

Neutralize particles

By binding to particles (defined broadly to include drugs, viruses, and so on), mAb can neutralize the normal effect of these particles.

1. Platelet inhibition 2. Immunosuppression or modulation 3. Antiangiogenesis 1. Drug antidote 2. Antiviral

2. Immunosuppression

T Example 1. Rituximab Alemtuzumab Gemtuzumab 2. Basiliximab Daclizumab

1. Abciximab 2. Infliximab Omalizumab 3. Bevacizumab 1. Digibind 2. Palivizumab

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EICOSANOIDS

U

phospholipid phospholipase A2

–

COX

arachidonic acid lipoxygenase

O

glucocorticoids COOH

aspirin NSAIDs

O

–

COOH

Prostaglandin (PG) G2

–

zileuton

P450

free radicals

HPETEs

Epoxides

Isoprostanes

Leukotriene (LT) A4

cell signaling

vasoconstriction

HOO

PGH2

specific synthases

PGE1 PGE2 PGF2 PGI2 TXA2

effects on vascular & GI/GU smooth muscle

PG nomenclature Last letter: substitutions in pentene ring Subscript: # of double bonds in side chain

LTB4

LTC4

LTE4

LTD4

– bronchoconstriction

zafirlukast

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Receptor EP1

Downstream signaling Gq → ↑ IP3

Intracellular calcium ↑

Endogenous ligand PGE2

Pharmacologic agonists Lubiprostone Dinoprostone Alprostadil Dinoprostone Misoprostol Dinoprostone

EP2

Gs → ↑ cAMP

↓

PGE2

EP3*

Gi → ↓ cAMP

↑

PGE2

EP4

Gs → ↑ cAMP

↓

PGE2

Alprostadil Dinoprostone

FP

Gq → ↑ IP3

↑

PGF2␣

Carboprost Latanoprost

IP

Gs → ↑ cAMP

↓

PGI2 (prostacyclin)

Epoprostenol

TP

Gq → ↑ IP3

↑

TXA2 (thromboxane)

CysLT1

Gq → ↑ IP3

↑

LTD4

Zafirlukast

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

Clinical effects Smooth muscle contraction (primarily gastric) Smooth muscle relaxation (primarily uterine & bronchial) ↓ Gastric acid secretion ↑ Gastric mucus secretion Smooth muscle contraction Fever Smooth muscle relaxation (primarily arterial & intestinal) ↑ GFR, natriuresis & diuresis Smooth muscle contraction (primarily intestinal, uterine, & bronchial) ↑ outflow of aqueous humor Smooth muscle relaxation (primarily arterial, bronchial, & uterine) Platelet inhibition ↑ GFR, natriuresis & dieresis Smooth muscle contraction (primarily arterial, bronchial, & uterine) Platelet activation ↓ GFR Bronchoconstriction Eosinophil chemoattractant

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direct sympathomimetic

1

Stimulates ␣1-, ␣2-, ␤1-, and ␤2-adrenoceptors (␤ predominant at low doses; ␣ at high doses). ␣1: (PIP2 cascade) → vascular smooth muscle contraction (↑ SVR), pupillary dilator muscle contraction (mydriasis), pilomotor contraction; hepatic glycogenolysis. ␣2: (Gi, ↓ cAMP) → feedback inhibition of adrenergic neurotransmitter release. ␤1: (Gs, ↑ cAMP) → ↑ HR and inotropy. ␤2: (Gs, ↑ cAMP) → smooth muscle relaxation: bronchial, vascular (including coronary arteries), and uterine; hepatic glycogenolysis. Net effect equivalent to sympathetic stimulation: ↑ BP, HR & CO, coronary dilation, ↓ secretions, ↓ blood flow to splanchnic beds, bronchodilation, mydriasis, ↑ glucose in blood. ↑ HR & inotropy → ↑ stroke volume & SBP, vasodilation → ↓ DBP. At higher doses, stimulation of ␣ 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, pregnancy. Use with caution in patients with coronary disease. Do not use in peripheral IV infusion or inject into fingers, toes, ears, nose (especially when used with local anesthetic), as vasoconstriction may cause necrosis of these tissues. Metabolism Can be administered IV or SC. Action terminated by reuptake into presynaptic nerve terminal. Also inactivated by COMT and MAO enzymes. Notes Epinephrine ⫽ adrenaline. Mechanism

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ADREN EPINEPHRINE

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NOREPINEPHRINE (Levophed)

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direct sympathomimetic

2

Mechanism

Selectively stimulates ␣1-, ␣2-, and ␤1-adrenoceptors (␣1 ⫽ ␣2 ⬎ ␤1); unlike epinephrine, no effect on ␤2-adrenoceptors. ␣1: (PIP2 cascade) → vascular smooth muscle contraction (↑ SVR), pupillary dilator muscle contraction (mydriasis), pilomotor contraction, and hepatic glycogenolysis. ␣2: (Gi, ↓ cAMP) → feedback inhibition of adrenergic neurotransmitter release. ␤1: (Gs, ↑ cAMP) → ↑ HR and inotropy. Net effect is peripheral vasoconstriction and ↑ BP, ⫾ ↑ inotropy, and if BP ↑ sufficiently, a reflex ↓ HR.

Clinical

Severe hypotension, septic shock.

Side Effects

Can precipitate myocardial ischemia or infarction (due to ↑ cardiac work), and arrhythmias. Extravasation can lead to tissue necrosis.

Contraindic.

Pregnancy. Use with caution in patients with coronary disease.

Metabolism

Inactivated by MAO and COMT.

Notes

Norepinephrine ⫽ noradrenaline.

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ADREN NOREPINEPHRINE

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DOPAMINE

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direct sympathomimetic

3

Mechanism

Endogenous catecholamine (precursor to norepinephrine) that stimulates D1, ␤1, and ␣1 adrenoceptors (D ⬎ ␤1 ⬎ ␣). D1: renal and splanchnic vasodilation. ␤1: (Gs, ↑ cAMP) → ↑ HR and inotropy. ␣1: (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 and diuresis. Medium dose: ␤1 effects predominate → ↑ CO. High dose: ␣1 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). Enhances natriuresis in patients with poor renal perfusion (although does not prevent or treat renal failure per se; it merely ↑ renal blood flow and hence facilitates natriuresis).

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

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ADREN DOPAMINE

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DOBUTAMINE (Dobutrex)

direct sympathomimetic

4

Mechanism

Synthetic analog of dopamine that stimulates ␤1-adrenoceptors and to a lesser extent ␤2- and ␣1-adrenoceptors. ␤1: (Gs, ↑ cAMP) → ↑ inotropy and HR (although for unclear reasons, inotropic effects more pronounced). ␤2: (Gs, ↑ cAMP) → vascular smooth muscle relaxation. ␣1: (PIP2 cascade) → vascular smooth muscle contraction. Net effect is ↑ cardiac contractility and ↑ CO. Tends to mildly ↓ SVR due to counterbalancing of ␤2 and ␣1 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. After ⬃1 week of continuous therapy, downregulation of receptors 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

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ADREN DOBUTAMINE

↑ inotropy

+

dobutamine

heart

vasodilation

– arterioles

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AMPHETAMINE Mechanism Clinical

Side Effects Antidote Contraindic. Notes

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indirect sympathomimetic

5

After presynaptic uptake, causes release of endogenous norepinephrine and, at higher doses, dopamine and serotonin. 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. Dependence, with high potential for addiction and abuse. Restlessness, anxiety, tremor, hyperreflexia. ↑ BP, tachyarrhythmias. NH4Cl to acidify the urine (↑ excretion). Antipsychotics to control CNS effects. Concurrent MAO inhibitor treatment. METHYLPHENIDATE (Ritalin), DEXMETHYLPHENIDATE (Focalin), DEXTROAMPHETAMINE (Dexedrine), and LISDEXAMFETAMINE (Vynase) are used for ADHD. Dextroamphetamine and PHENTERMINE (Pro-Fast) have been used for weight loss. SIBUTRAMINE (Meridia) inhibits uptake of NE, 5-HT, and to a lesser extent, DA in CNS and has been 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, daytime somnolence from obstructive sleep apnea, and shift work sleep disorder. Methamphetamine (“speed,” “crystal meth”) and methylenedioxymethamphetamine (MDMA or “ecstasy”) are drugs of abuse.

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ADREN AMPHETAMINE Methylphenidate Dexmethylphenidate Dextroamphetamine Lisdexamfetamine Phentermine Sibutramine 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 that releases serotonin.

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EPHEDRINE

indirect sympathomimetic

6

Mechanism

Stimulates release of NE from sympathetic neurons (see norepinephrine 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.

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ADREN EPHEDRINE Pseudoephedrine

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indirect sympathomimetic

COCAINE

7

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. 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

Cardiovascular: 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.

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ADREN COCAINE

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METHYLDOPA (Aldomet)

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sympathoplegic

8

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 ␣2-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

RESERPINE (Serpasil) binds tightly to neurotransmitter storage vesicles in sympathetic nerve terminals, preventing storage of catecholamines, which instead leak out into the cytoplasm and are metabolized by MAO. The neurons, depleted of neurotransmitters, release little or no catecholamines when depolarized. It was once used as an antihypertensive, but has largely been abandoned because it causes severe depression.

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ADREN METHYLDOPA Reserpine

brain

– heart

sympathoplegics methyldopa

arterioles

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PHENYLEPHRINE (Neo-Synephrine)

Page 9

␣1-agonist

9

Mechanism

Binds to ␣1-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 ␣1-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 ␣-agonists used as topical nasal and conjunctival decongestants.

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ADREN PHENYLEPHRINE Midodrine Xylometazoline Oxymetazoline Tetrahydrozoline Naphazoline

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CLONIDINE (Catapres) Mechanism

Clinical

Side Effects Metabolism Notes

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␣2-agonist

10

Activates presynaptic ␣2-adrenoceptors on sympathetic neurons → downregulation of NE release. Some ␣2-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 post-synaptic ␣2-receptors on vascular smooth muscle), followed by a longer period of hypotension (↓ sympathetic outflow due to presynaptic ␣2-receptor activation). Orally → accumulates in CNS → activation of presynaptic ␣2-receptors in cardiovascular control center → suppression of sympathetic outflow. Antihypertensive. Treatment of opioid withdrawal. Antidiarrheal in patients with autonomic neuropathy (↑ NaCl absorption and ↓ HCO3⫺ secretion in GI tract). Immediate cessation can result in rebound hypertension. Therefore drug should be tapered gradually. Dry mouth, sedation, sexual dysfunction. PO, dermal patch. DEXMEDETOMIDINE (Precedex) is a similar compound used for perioperative sedation, analgesia, and ↓ secretions. 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 PGF2␣ analogs (see latanoprost), ␣2-agonists, and muscarinic agonists (see pilocarpine) and ↓ aqueous humor formation with ␤-blockers (see timolol), ␣2-agonists, and carbonic anhydrase inhibitors (see acetazolamide).

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ADREN CLONIDINE Dexmedetomidine Brimonidine Apraclonidine

brain

– heart

α2 -agonists clonidine

arterioles

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PHENTOLAMINE (Regitine)

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nonselective ␣-blocker

11

Mechanism

Nonselective competitive antagonist of ␣-adrenoceptors. ␣-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 ␣2-blockade, which causes ↑ NE release and thereby ↑ ␤1-adrenoceptor stimulation).

Contraindic.

Coronary artery disease.

Metabolism

IM or IV. Short duration of action.

Notes

PHENOXYBENZAMINE (Dibenzyline) is similar but binds irreversibly to ␣-adrenoceptors (slight selectivity for ␣1). 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).

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ADREN PHENTOLAMINE Phenoxybenzamine

brain

–

veins

α-blockers prazosin phentolamine

–

arterioles

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PRAZOSIN (Minipress)

␣1-blocker

12

Mechanism

Reversible ␣1-adrenoceptor antagonist. Blockade on vascular smooth muscle → arteriolar and venous vasodilation → ↓ BP and ↓ venous return. Low affinity for ␣2-adrenoceptors may explain relative lack of reflex tachycardia compared with nonselective ␣-blockers (␣2-blockade would prevent negative feedback and thereby allow ↑ NE release, leading to ␤1 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’s 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) has greater selectivity for ␣1A (blood vessels and prostate) over ␣1B (blood vessels and heart) receptors; may explain why little effect on BP but particularly useful in BPH. ALFUZOSIN (Uroxatral) is another ␣1-blocker (no subtype selectivity) that is used primarily to treat BPH. YOHIMBINE (Yocon) is an ␣2-adrenoceptor antagonist that causes ↑ NE release and has been used to treat erectile dysfunction, but it has largely been replaced by PDE inhibitors (see sildenafil).

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ADREN PRAZOSIN Terazosin Doxazosin Tamsulosin Alfuzosin

brain

Yohimbine

–

veins

α-blockers prazosin phentolamine

–

arterioles

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ISOPROTERENOL (Isuprel)

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nonselective ␤-agonist

13

Mechanism

Selectively stimulates ␤-adrenoceptors. ␤1: (GS, ↑ cAMP) → ↑ HR and inotropy. ␤2: (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

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ADREN ISOPROTERENOL

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ALBUTEROL (Proventil, Ventolin)

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␤-agonist

14

Activates the ␤2-adrenoceptor, causing stimulation of adenylate cyclase, ↑ cAMP, myosin light-chain kinase phosphorylation and inactivation, and consequent relaxation of smooth muscle and bronchodilation. ␤-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 ␤2-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 LEVALBUTEROL (Xopenex), METAPROTERENOL (Alupent), and PIRBUTEROL (Maxair) are similar. TERBUTALINE (Brethine) can be used IV for the treatment of status asthmaticus. Also used to suppress premature labor. SALMETEROL (Serevent), FORMOTEROL (Foradil), and ARFORMOTEROL (Brovana) have longer durations of action (due to high lipid solubility and hence easier entry and buildup in smooth muscle cells) and are used as long-term control medications for asthma and/or COPD. Although longacting ␤-agonists (LABAs) ↓ frequency of asthma episodes, those episodes that do occur may be more severe and even fatal, underscoring that inhaled corticosteroids (see beclomethasone) are preferred long-term control medications. RITODRINE (Yutopar) is used in pregnancy to relax uterine smooth muscle and suppress premature labor (second-line agent). Mechanism

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ADREN ALBUTEROL Levalbuterol Metaproterenol

AC

β2-agonists

Pirbuterol Terbutaline Salmeterol Formoterol Arformoterol

P

+ ATP

AC*

cAMP

PDE III

AMP

myosin light chain kinase protein kinase A

+

Ritodrine

myosin light chain kinase

P

myosin light chain

myosin light chain myosin light chain phosphotase

actin

smooth muscle relaxation

smooth muscle contraction

bronchodilation

bronchoconstriction

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METOPROLOL (Lopressor) Mechanism

Clinical

Side Effects Contraindic. Notes

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␤1-blocker

15

2nd gen. ␤-blocker that selectively inhibits ␤1-adrenoceptors (although at high doses, some ␤2-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. 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. Bradycardia, hypotension, CHF, fatigue, depression, impotence, ↓ libido. Although relatively ␤1-selective, may precipitate bronchospasm by blocking ␤2- mediated bronchodilation. Bradycardia, heart block, hypotension, decompensated CHF, severe asthma or COPD. Prinzmetal’s and cocaine-induced angina: inhibition of ␤2-mediated vasodilation → coronary vasospasm. ATENOLOL (Tenormin) and BISOPROLOL (Zebeta) are longer acting. ESMOLOL (Brevibloc) has a very short half-life (⬃10 min) and is given as IV infusion. ACEBUTOLOL (Sectral) is a ␤1-blocker with intrinsic sympathomimetic activity (ISA) and thus less likely to cause bradycardia but less suited for patients with angina. PROPRANOLOL (Inderal), NADOLOL (Corgard), PINDOLOL (Visken), and PENBUTOLOL (Levatol) are 1st gen., non-selective ␤1- and ␤2-blockers, 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 (␤1-blockade) and splanchnic vasoconstriction (␤2-blockade) → ↓ portal pressures], thyrotoxicosis (control symptoms), and migraine prevention. Similar side effect profile except more likely to cause bronchospasm.

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ADREN CLASS II

METOPROLOL

ECG s = Ø/↑ PR, Ø QRS, ↓ QT

Atenolol Bisoprolol Esmolol Acebutolol

Decrease slope of phase 4

Propranolol Nadolol

Prolong repolarization

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

Pindolol Penbutolol

CLASSIFICATION OF ␤-BLOCKERS Generation

Properties

Pure antagonists

1st

Nonselective

2nd

␤1-selective

3rd

Vasodilatory

Propranolol, Nadolol (Timolol, Levobunolol, Metipranolol) Metoprolol, Atenolol, Bisoprolol, Esmolol (Betaxolol, Levobetaxolol) Carvedilol, Nebivolol

Parentheses denote ␤-blockers primarily administered topically for glaucoma.

Partial agonists [ie, possess intrinsic sympathomimetic activity (ISA)] Pindolol, Penbutolol (Carteolol) Acebutolol Labetalol

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CARVEDILOL (Coreg)

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vasodilatory ␤-blocker

16

Mechanism

3rd gen. nonselective ␤-blocker that has vasodilatory effects caused by ␣1 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) ↑ heart rate and cardiac output → ↑ 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 → ␤-receptor downregulation Net result on LV is ↑ mechanical stress, ↑ fibrosis, ↓ responsiveness to intermittent adrenergic stimuli. By blocking prolonged cardiac adrenergic stimulation, ␤-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. ␤-blockers metoprolol and bisoprolol have also been used to treat heart failure. 3rd gen. agents, perhaps due to vasodilation, appear particularly beneficial in treating heart failure. NEBIVOLOL (Bystolic) is a selective ␤1-blocker that has nitric-oxide–mediated vasodilating properties. LABETALOL (Normodyne, Trandate) is another nonselective ␤-blocker that also causes ␣1-blockade (although 5 to 10-fold more potent ␤- than ␣-blocker) and partial ␤2-agonism. Used to treat hypertension.

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ADREN CLASS II

CARVEDILOL

ECG Δs = Ø/↑ PR, Ø QRS, ↓ QT

Nebivolol Labetalol

Decrease slope of phase 4

Prolong repolarization

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

CLASSIFICATION OF ␤-BLOCKERS Generation 1st

Properties Nonselective

2nd

␤1-selective

3rd

Vasodilatory

Pure antagonists Propranolol, Nadolol (Timolol, Levobunolol, Metipranolol) Metoprolol, Atenolol, Bisoprolol, Esmolol (Betaxolol, Levobetaxolol) Carvedilol, Nebivolol

Parentheses denote ␤-blockers primarily administered topically for glaucoma.

Partial agonists [ie, possess intrinsic sympathomimetic activity (ISA)] Pindolol, Penbutolol (Carteolol) Acebutolol Labetalol

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TIMOLOL (Timoptic)

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nonselective ␤-blocker

17

Mechanism

Nonselective ␤1- and ␤2-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 ␤-blockers) 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) and LEVOBETAXOLOL (Betaxon) are ␤1-selective. They are less efficacious because ␤2-receptors 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 PGF2␣ analogs (see latanoprost), ␣2-agonists (see brimonidine), and muscarinic agonists (see pilocarpine) and ↓ aqueous humor formation with ␤-blockers, ␣2-agonists, and carbonic anhydrase inhibitors (see acetazolamide).

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ADREN TIMOLOL Carteolol Levobunolol Metipranolol Betaxolol Levobetaxolol

CLASSIFICATION OF ␤-BLOCKERS Generation 1st

Properties Nonselective

2nd

␤1-selective

3rd

Vasodilatory

Pure antagonists Propranolol, Nadolol (Timolol, Levobunolol, Metipranolol) Metoprolol, Atenolol, Bisoprolol, Esmolol (Betaxolol, Levobetaxolol) Carvedilol, Nebivolol

Parentheses denote ␤-blockers primarily administered topically for glaucoma.

Partial agonists [ie, possess intrinsic sympathomimetic activity (ISA)] Pindolol, Penbutolol (Carteolol) Acebutolol Labetalol

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FENOLDOPAM (CORLOPAM)

D1-agonist

18

Mechanism

D1 receptor agonist leading to renal and splanchnic vasodilation. Some stimulation of ␣2-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 ␣- and ␤-adrenoceptor agonist, causes ↑ BP.

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ADREN FENOLDOPAM

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NICOTINE Mechanism

Clinical

Side Effects Metabolism Notes

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nicotinic agonist

19

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. 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. 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. Rapidly absorbed through the skin, lungs, and gut. For smoking cessation, used orally as a gum or topically as a patch. 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.

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CHOLIN NICOTINE Varenicline

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SUCCINYLCHOLINE (Anectine)

nicotinic agonist

20

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 5–10 minutes).

Notes

See pancuronium for an example of a nondepolarizing neuromuscular blocker.

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CHOLIN SUCCINYLCHOLINE

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PANCURONIUM (Pavulon)

antinicotinic

21

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

DOXACURIUM (Nuromax), VECURONIUM (Norcuron), ROCURONIUM (Zemuron), and PIPECURONIUM (Arduan) 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. The purified active ingredient of curare (a generic term for South American arrow poisons) is tubocurarine, a nondepolarizing neuromuscular blocker. 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.

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CHOLIN PANCURONIUM Doxacurium Vecuronium Rocuronium Pipecuronium Atracurium Cisatracurium Mivacurium Hexamethonium

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BETHANECHOL (Urecholine)

muscarinic agonist

22

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).

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CHOLIN BETHANECHOL Methacholine

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PILOCARPINE (Isopto Carpine, Salagen)

muscarinic agonist

23

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’s 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 PGF2␣ analogs (see latanoprost), ␣2-agonists (see brimonidine on clonidine card), and muscarinic agonists, and ↓ aqueous humor formation with ␤-blockers (see timolol), ␣2-agonists, and carbonic anhydrase inhibitors (see acetazolamide).

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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.

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ATROPINE Mechanism

Clinical

Side Effects

Contraindic. Notes

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antimuscarinic

24

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. Treatment of bradycardia. Cholinesterase inhibitor overdose: treat bradycardia caused by vagal hyperactivity. Ophthalmic: causes cycloplegia and mydriasis. GI: Used as an antimotility agent to treat noninfectious causes of diarrhea. “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. Narrow-angle glaucoma (relaxation of constrictor muscles of iris → obstruction of canal of Schlemm). 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 ␣-agonists, they produce cycloplegia at high doses.

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CHOLIN ATROPINE Scopolamine Homatropine Cyclopentolate Tropicamide

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BENZTROPINE (Cogentin)

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antimuscarinic

25

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’s disease, progressive loss of dopaminergic neurons allows cholinergicmediated 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.

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CHOLIN BENZTROPINE Biperiden Trihexyphenidyl

Normal substantia nigra

DA

Parkinson’s substantia nigra

AC h

substantia nigra

ACh

DA

Benztropine Therapy

ACh

DA

–

-

+

corpus striatum

-

+

corpus striatum

GABA

GABA

Normal movement

Hypokinesia

-

+

corpus striatum

GABA

Improved movement

benztropine

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IPRATROPIUM (Atrovent)

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antimuscarinic

26

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. 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.

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CHOLIN IPRATROPIUM Tiotropium Glycopyrrolate bronchi & alveoli

antimuscarinic ipratropium co

ns

bronchial lumen

brain

– tric

tio

n

ACh vagus

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OXYBUTYNIN (Ditropan, Oxytrol)

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antimuscarinic

27

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), 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.

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CHOLIN OXYBUTYNIN Darifenacin Flavoxate Propantheline Solifenacin Tolterodine Trospium Dicyclomine Hyoscyamine

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NEOSTIGMINE (Prostigmin)

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cholinesterase inhibitor

28

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 junctions and synapses. Skeletal muscle: reverses nondepolarizing neuromuscular blockade (see pancuronium). High doses cause a depolarizing neuromuscular blockade (see succinylcholine). Bowel and bladder smooth muscle: causes ↑ tone, ↑ motility, relaxation of sphincters. Parasympathetic stimulation of the heart: ↓ HR, ↓ cardiac contractility, ↓ conduction velocity through AV node.

Clinical

Reverse nondepolarizing neuromuscular 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.

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CHOLIN NEOSTIGMINE Pyridostigmine Edrophonium

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DONEPEZIL (Aricept)

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cholinesterase inhibitor

29

Mechanism

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

Clinical

Alzheimer’s 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’s 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.

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CHOLIN DONEPEZIL Galantamine Rivastigmine Tacrine Physostigmine

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SARIN

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cholinesterase inhibitor

30

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). Acetylcholine 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, and TABUN 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).

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CHOLIN SARIN DFP Soman Tabun Parathion Malathion Pralidoxime

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NITROGLYCERIN

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direct vasodilator

31

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 ␤-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.

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CV H2C–O–NO2 HC–O–NO2 H2C–O–NO2

NITROGLYCERIN Isosorbide Dinitrate Isosorbide Mononitrate

Nitroglycerin

myosin light chain kinase

P

myosin light chain

myosin light chain myosin light chain phosphatase

cGMP-dependent protein kinases

↓ Ca2+

smooth muscle contraction

cGMP

smooth muscle relaxation

PDE V

GMP vasodilation

actin

+

nitrates nitroglycerin

vasoconstriction GC*

NO

GC

GTP

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NITROPRUSSIDE (Nipride)

direct vasodilator

32

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 ␤-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

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CV NITROPRUSSIDE

+

NO

-

-

CN

CN

-

CN

CN

CN

-

Nitroprusside

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NESIRITIDE (Natrecor)

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direct vasodilator

33

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. In addition, nesiritide may also enhance natriuresis and improve the response to diuretics.

Clinical

Short-term treatment of decompensated congestive heart failure.

Side Effects

Hypotension. Data from recent meta-analyses suggest there may be an increased risk of renal dysfunction and death. Larger trials are ongoing to address the risk-benefit ratio for this medication.

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.

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CV NESIRITIDE

nesiritide ↓ preload

↓ afterload

–

+

veins

– arterioles

↑ natriuresis ↓ preload

kidneys

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HYDRALAZINE (Apresoline) Mechanism

Clinical

Side Effects

Metabolism Notes

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direct vasodilator

34

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. 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. Congestive heart failure: given with nitrates to ↓ afterload, ↓ preload, 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 ␤-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). 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 ␤-blocker, diuretic, or both. PO or IV. Hepatic acetylation. Toxicity more likely in patients who are slow acetylators. 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 ␤ 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).

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CV HYDRALAZINE Minoxidil Diazoxide

hydralazine ↓ afterload

– arterioles

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CAPTOPRIL (Capoten) Mechanism

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ACE inhibitor

35

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 in response to ↓ renal arteriole pressure, ↓ Na⫹ delivery, or sympathetic neuronal 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 also prevent ACE from inactivating bradykinin, an endogenous vasodilator. Effect of ACE inhibitors (ACEI) is arteriolar and venous vasodilation. Aldosterone secretion minimally affected due to non-RAA pathways. Clinical Hypertension. Congestive heart failure: ↓ 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 tid).

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CV CAPTOPRIL Enalapril (Vasotec)

Perindopril (Aceon)

Lisinopril (Prinivil, Zestril)

Quinapril (Accupril)

Benazepril (Lotensin)

Ramipril (Altace)

Fosinopril (Monopril)

Trandolapril (Mavik)

Moexipril (Univasc)

vasoconstriction aldosterone synthesis catecholamine release

ACEI captopril

ATII

–

bradykinin

– ACE lungs

ATI renin

angiotensinogen kidneys

inactive metabolites

vasodilation angioedema cough

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LOSARTAN (COZAAR)

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angiotensin receptor blocker

36

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. Congestive heart failure. Clinical efficacy comparable to that seen with ACEI (↓ symptoms, ↑ survival). Combined therapy with ACEI ⫹ ARB results in further ↓ CHF hospitalizations and possibly mortality. ↓ 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 ACE inhibitors, rarely associated with cough or angioedema.

Contraindic.

Renal insufficiency. Bilateral renal artery stenosis. Pregnancy.

Notes

Other similar ARBs include: CANDESARTAN (Atacand), EPROSARTAN (Teveten), IRBESARTAN (Avapro), OLMESARTAN (Benicar), TELMISARTAN (Micardis), and VALSARTAN (Diovan). AT2 receptors mediate vasodilation; drugs targeting these receptors remain under study.

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CV LOSARTAN Candesartan

Olmesartan

Eprosartan

Telmisartan

Irbesartan

Valsartan

ARB losartan vasoconstriction aldosterone synthesis catecholamine release

–

ATII

ACE lungs

ATI renin

angiotensinogen kidneys

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ALISKIREN (Tekturna)

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renin inhibitor

37

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. It is unknown if renin inhibitors will improve outcomes in patients with heart failure, diabetes, and renal disease, as ACEI and ARBs have been proven to do.

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-glycoprotein.

Notes

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CV ALISKIREN vasoconstriction aldosterone synthesis catecholamine release

ATII

ACE lungs

ATI renin

kidneys

–

renin inhibitor aliskiren

angiotensinogen

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NIFEDIPINE (Procardia, Adalat)

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calcium channel blocker

38

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’s angina and Raynaud’s 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 NISLODIPINE (Sular) are second-generation dihydropyridine CCBs, which show even greater vascular smooth muscle selectivity. NICARDIPINE (Cardene) and CLEVIPINE (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.

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CV NIFEDIPINE Amlodipine

Nicardipine

Felodipine

Clevipine

Isradipine

Nimodipine

Nislodipine

CALCIUM CHANNEL BLOCKERS Class 1st-gen DHP 2nd-gen DHP Non-DHP

Prototype Nifedipine Amlodipine Diltiazem Verapamil

DHP ⫽ dihydropyridine.

Peripheral vasodilation ⴙⴙⴙ ⴙⴙⴙ ⫹⫹ ⫹

Coronary vasodilation ⴙⴙⴙ ⴙⴙⴙ ⫹⫹ ⫹⫹

↓ Inotropy ⴙ 0 ⫹⫹ ⫹⫹⫹

↓ SA node automaticity ⴙ ⴙ ⫹⫹⫹ ⫹⫹⫹

↓ AV conduction 0 0 ⫹⫹ ⫹⫹⫹

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VERAPAMIL (Calan, Isoptin, Verelan)

calcium channel blocker

39

Mechanism

A nondihydropyridine calcium channel blocker (CCB) that binds to L-type Ca2⫹ channels (“long-lasting,” voltage-dependent, high-conductance 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’s 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.

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CV VERAPAMIL

CLASS IV ECG Δs = Ø/↑ PR, Ø QRS, ↓ QT

Diltiazem

Decrease slope of phase 4

Prolong repolarization

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

CALCIUM CHANNEL BLOCKERS Class 1st-gen DHP 2nd-gen DHP Non-DHP

Prototype Nifedipine Amlodipine Diltiazem Verapamil

DHP ⫽ dihydropyridine.

Peripheral vasodilation ⫹⫹⫹ ⫹⫹⫹ ⴙⴙ ⴙ

Coronary vasodilation ⫹⫹⫹ ⫹⫹⫹ ⴙⴙ ⴙⴙ

↓ Inotropy ⫹ 0 ⴙⴙ ⴙⴙⴙ

↓ SA node automaticity ⫹ ⫹ ⴙⴙⴙ ⴙⴙⴙ

↓ AV conduction 0 0 ⴙⴙ ⴙⴙⴙ

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RANOLAZINE (Ranexa)

anti-anginal

40

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 ⬍1% of peak Na⫹ influx. However, this contribution is increased in the setting of myocardial ischemia. Higher levels of intracellular Na⫹ lead to increased activity of the Na⫹/Ca2⫹ exchanger (see digoxin) and consequently higher intracellular Ca2⫹ levels. Ca2⫹ overload leads to abnormal myocardial contraction and impaired relaxation,.

Clinical

Treatment of angina.

Side Effects

Constipation, nausea, dizziness, headache. Mild QT interval prolongation, but no documented increased risk of torsades de pointes.

Contraindic.

Strong CYP3A inhibitors or inducers. Hepatic disease.

Metabolism

Metabolized by CYP 3A4 and 2D6.

Notes

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CV RANOLAZINE

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DIGOXIN (Lanoxin)

cardiac glycoside

41

Mechanism

Inhibits cellular Na⫹/K⫹ ATPase pump, causing ↑ intracellular Na⫹, which impairs Na⫹/Ca2⫹ exchanger and results in ↑ intracellular Ca2⫹. ↑ stores of Ca2⫹ in sarcoplasmic reticulum allow subsequent action potentials to liberate more Ca2⫹ to activate contractile apparatus → positive inotropy. ↓ sympathetic tone and ↑ vagal tone, resulting in slowing of impulse conduction through the AV node → ↑ AV block.

Clinical

Congestive heart failure (CHF): ↓ hospitalization for CHF. Historically attributed to ↑ myocardial contractility, but modulation of autonomic tone may be just as important. Atrial fibrillation and atrial flutter: slows ventricular rate by ↓ conduction through the AV node.

Side Effects

Narrow therapeutic window. Toxicity manifests with AV block and atrial tachycardias. “Dig delirium” ⫽ nausea, blurred vision, and visual hallucinations (usually yellow-green).

Antidote

Digibind (digoxin immune Fab), K⫹ supplementation, antiarrhythmics, cardiac pacer.

Contraindic.

Hypokalemia: K⫹ and digoxin compete for binding to the Na⫹/K⫹ ATPase pump; thus, hypokalemia potentiates the drug’s effects. Second- or third-degree AV block. Wolff-Parkinson-White (WPW) patients who develop AF: ↑ impulse transmission through accessory pathway → VF.

Metabolism

Very long half-life. Renal excretion.

Interactions

↑ Serum levels of digoxin with amiodarone (↓ hepatic uptake) and verapamil (↓ renal tubular excretion).

Notes

In the 18th century, William Withering, a physician and botanist, described the utility of an extract from the foxglove plant (digitalis) to treat dropsy (an old term for edema).

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CV DIGOXIN Digitalis directly inhibits the Na+/K+ ATPase pump

ATP

2 K+ Inhibition of the Na /K ATPase pump results in ↑ [Na+]in +

+

3 Na+

ADP + P

↑ [Na+]in results in indirect inhibition of the Na+/Ca2+ exchanger

3 Na+ Inhibition of the Na /Ca2+ exchanger results in ↑ [Ca2+]in

2 Ca2+

+

Additional Note: ECG may show ↑ PR, ↓ QT, scooping of the ST segments, and T-wave inversion. These ECG changes are called “dig effect” and are not a sign of digoxin intoxication.

↑ [Ca2+]in results in greater contractile force

SR

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MILRINONE (Primacor)

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PDE inhibitor

42

Mechanism

Inhibits phosphodiesterase (PDE) III, which is found in cardiac and smooth muscle. As PDE III inactivates cAMP, PDE III inhibitors → ↑ cAMP via ↓ degradation. In the myocardium, this leads to ↑ Ca2⫹ influx → ↑ cardiac contractility. In vascular smooth muscle, leads to myosin light-chain kinase phosphorylation and inactivation → myosin light-chain dephosphorylation → smooth muscle relaxation → arteriolar and venous vasodilation. Milrinone’s cAMP-mediated effects on vascular smooth muscle are analogous to albuterol’s cAMP-mediated effect on bronchial smooth muscle.

Clinical

Treatment of decompensated heart failure: ↑ inotropy and ↓ afterload → ↑ CO and ↓ pulmonary capillary wedge pressure. Restricted to patients with refractory CHF who have failed to respond to vasodilators and diuretics.

Side Effects

Potentially life-threatening ventricular arrhythmias. Hypotension, hepatotoxicity, thrombocytopenia.

Metabolism

IV.

Notes

INAMRINONE (Inocor) is a less potent PDE III inhibitor with a greater rate of side effects. Chronic use of oral PDE III inhibitors in patients with heart failure led to ↑ mortality. CILOSTAZOL (Pletal) is an oral PDE III inhibitor that mainly causes peripheral vasodilation and is used to treat claudication.

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CV MILRINONE

PDE III inhibitors milrinone

Inamrinone Cilostazol

ATP

AC

Effect of PDE III inhibition within the heart

phospholamban protein kinase A

release of inhibition of SR

↑Ca2+ influx

↑ inotropy

PDE III

–

AMP

Effect of PDE III inhibition within vascular smooth muscle myosin light chain kinase

+

phospholamban

cAMP

+ P

protein kinase A

myosin light chain kinase

dephosphorylation of myosin light chain

smooth muscle relaxation

vasodilation

P

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SILDENAFIL (Viagra, Revatio)

PDE inhibitor

43

Mechanism

Phosphodiesterase (PDE) V inhibitor. As PDE V inactivates cGMP, PDE V inhibitors → ↑ cGMP via ↓ degradation. ↑ cGMP → dephosphorylation of myosin light-chain → vascular smooth muscle relaxation. In the penis, this facilitates inflow of blood into the corpora cavernosa. In the pulmonary circulation, this ↓ vascular resistance.

Clinical

Erectile dysfunction. Pulmonary arterial hypertension.

Side Effects

Headache, flushing, priapism. Potentiates vasodilation of nitroglycerin, which works through activation of guanylate cyclase, resulting in ↑ cGMP. Thus, concomitant blockade of cGMP degradation by sildenafil leads to greatly ↑ cGMP → marked vasodilation and hypotension. Alteration in color vision (blue tinge to vision) caused by inhibition of PDE6, which is involved in photoreceptor signal transduction. Reports of sudden visual loss caused by nonarteritic ischemic optic neuropathy, but causality not proven.

Notes

TADALAFIL (Cialis) and VARDENAFIL (Levitra) are similar compounds with longer half-lives.

EPOPROSTENOL (FLOLAN)

prostaglandin

43

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CV SILDENAFIL Tadalafil myosin light chain kinase

Vardenafil

P

myosin light chain

myosin light chain myosin light chain phosphatase

actin

cGMP-dependent protein kinases

↓ Ca2+

smooth muscle contraction

cGMP

smooth muscle relaxation

–

PDE V

GMP vasodilation

PDE V inhibitor sildenafil

vasoconstriction *

GC

GTP

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EPOPROSTENOL (Flolan)

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prostaglandin

44

Mechanism

A preparation of prostacyclin (PGI2), it binds to and activates the IP receptor (so named because its primary ligand is I2 prostaglandin), a Gs-coupled receptor that activates adenylate cyclase → ↑ cAMP → myosin light-chain kinase phosphorylation → myosin light-chain dephosphorylation → vascular smooth muscle vasodilation (see milrinone for details of cAMP-mediated vasodilation). PGI2 may also work through inhibition of platelets and effects on vascular growth and remodeling. This notion is supported by the observation of ↓ pulmonary vascular resistance even in patients without a short-term hemodynamic response.

Clinical

Pulmonary arterial hypertension (both primary and secondary to connective tissue disorders such as scleroderma): relieves symptoms and improves survival.

Side Effects

Jaw pain, headache, flushing, nausea, diarrhea. Infection because of the need for an indwelling IV delivery system (see below).

Metabolism

Very short half-life (3 minutes) and light and temperature sensitive (requiring continuous cooling). For ambulatory patients, administered as a continuous IV infusion via an indwelling catheter.

Notes

TREPROSTINIL (Remodulin), which is given SC or IV, and ILOPROST (Ventavis), which is inhaled, are other prostacyclin analogues. Orally stable analogues remain under study.

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CV EPOPROSTENOL Treprostinil Iloprost

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BOSENTAN (Tracleer)

endothelin antagonist

45

Mechanism

Endothelin (ET) is a peptide synthesized by endothelial cells and the most potent natural vasoconstrictor known. ET has three isoforms, with ET-1 the most relevant for vascular tone. The two ET receptors (ETA and ETB) are both coupled to G proteins and appear to affect phospholipase C. ETA receptors are located on vascular smooth muscle, and their activation leads to vasoconstriction. ETB receptors are located on endothelial cells; activation leads to synthesis and release of both NO (by stimulating eNOS) and prostacyclin (by stimulating COX), thereby causing vasodilation. ET-1 also induces vascular smooth muscle proliferation, fibrosis, and inflammation. Bosentan is a competitive antagonist of both ETA and ETB receptors, but the net effect is vasodilation.

Clinical

Pulmonary arterial hypertension (PAH).

Side Effects

Headache, facial flushing, leg edema. Hepatitis (especially at higher doses). Teratogenic.

Metabolism

Metabolized by and induces CYP2C9 and CYP3A4.

Interactions

Induction of CYP2C9 and CYP3A4 can cause ↓ levels of warfarin, a drug that patients with pulmonary arterial hypertension frequently take.

Notes

AMBRISENTAN (Letairis) is a selective ETA receptor antagonist also used for PAH.

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CV BOSENTAN Ambrisentan

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FUROSEMIDE (Lasix)

Page 46

diuretic

46

Mechanism

Inhibits NaCl reabsorption (via Naⴙ/Kⴙ/2Clⴚ cotransporter) in thick ascending limb of the loop of Henle. ↑ urinary excretion of K⫹ because reabsorption is less efficient in the face of ↑ Na⫹ delivery to the collecting duct. Also induces volume depletion → ↑ aldosterone activity and ↑ urinary K⫹ losses. ↑ urinary excretion of Mg2⫹ and Ca2⫹ because reabsorption is dependent on the luminal electropositivity generated by the Na⫹/K⫹/2Cl⫺ cotransporter. ↑ renal blood flow without altering the glomerular filtration rate (mechanism unclear).

Clinical

Edematous states (e.g., pulmonary edema caused by CHF and ascites caused by cirrhosis). ↑ urine output in acute renal failure (but does not alter course of renal failure). Hypercalcemia, hyperkalemia.

Side Effects

Hypokalemia, metabolic alkalosis, hypomagnesemia. Ototoxicity (reversible): more common in patients with renal insufficiency or in those receiving other ototoxic drugs. Hyperuricemia: ↑ urate reabsorption caused by ↑ proximal Na⫹ reabsorption (i.e., volume depletion).

Contraindic.

Sulfa allergy.

Metabolism

PO, IV. Half-life is 2–3 hours.

Notes

BUMETANIDE (Bumex) is another loop diuretic. TORSEMIDE (Demadex) is a loop diuretic that has roughly equal potency IV and PO. ETHACRYNIC ACID (Edecrin) is the only loop diuretic without a sulfa group and therefore can be used in patients who are allergic to sulfa drugs.

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CV FUROSEMIDE Bumetanide

Ethacrynic Acid

Torsemide

DCT

glomerulus

collecting duct

PCT ClNa+ K+ 3-

HCO

Na+

ThAL

–

loop of Henle

H+ Na+ 2 ClK+

loop diuretics furosemide

ADH

H2O

aldosterone

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HYDROCHLOROTHIAZIDE (HCTZ)

diuretic

47

Mechanism

Inhibits Naⴙ/Clⴚ transporter in the early segment of the distal convoluted tubule (DCT). ↑ urinary K⫹ excretion because reabsorption is less efficient in the face of ↑ Na⫹ delivery to collecting duct. Also induces volume depletion → ↑ aldosterone activity and ↑ urinary K⫹ losses. Enhanced Ca2⫹ reabsorption (in contrast to loop diuretics) because Ca2⫹ and Na⫹ compete for ATPdependent reabsorption in DCT.

Clinical

Hypertension: initial therapy of choice in uncomplicated hypertension. Initially ↓ BP by ↓ blood volume and cardiac output; later Na⫹ depletion → ↓ SVR (mechanism unclear). Edema (e.g., because of CHF), but usually as adjunctive therapy if loop diuretics insufficient. Diabetes insipidus: mitigates by inducing mild volume depletion; compensatory ↑ Na⫹ (⫹ H2O) reabsorption in the proximal convoluted tubule (PCT) ↓ delivery to the DCT. Less free water is available for excretion, and polyuria is diminished. Recurrent renal calcium stone formation.

Side Effects

Hypokalemia, metabolic alkalosis, hypercalcemia, hypomagnesemia. Hyponatremia: secondary to impaired diluting capacity. Hyperuricemia: ↑ urate reabsorption because of ↑ proximal Na⫹ reabsorption (i.e., volume depletion). Hyperglycemia, ↑ cholesterol, ↑ triglycerides.

Contraindic.

Sulfa allergy. May increase toxicity of lithium.

Notes

CHLOROTHIAZIDE (Diuril), CHLORTHALIDONE (Hygroton, Thalitone), INDAPAMIDE (Lozol), and METOLAZONE (Zaroxolyn) are similar thiazide diuretics.

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CV HYDROCHLOROTHIAZIDE Chlorothiazide

Indapamide

Chlorthalidone

Metolazone

DCT

glomerulus

collecting duct

–

PCT

thiazides HCTZ HCO3-

ClNa+ K+ Na+

ThAL

H+ Na+ 2 ClK+

loop of Henle

ADH

H2O

aldosterone

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SPIRONOLACTONE (Aldactone)

Page 48

diuretic

48

Mechanism

A K⫹-sparing diuretic, this drug is a synthetic steroid that is a competitive antagonist of aldosterone at the aldosterone receptor in the distal convoluted tubule. Aldosterone enhances apical Na⫹ and K⫹ channel activity and basolateral Na⫹/K⫹ ATPase activity, leading to ↑ Na⫹ absorption and ↑ K⫹ excretion. The Na⫹ retention leads to hypertension and consequently accelerated atherosclerosis and ↑ risk of MI, stroke, and CHF. Aldosterone also has a direct effect on the heart, causing myocardial fibrosis. Inhibition of aldosterone → ↓ Na⫹ absorption and ↓ K⫹ excretion, ↓ BP, and possibly less cardiac fibrosis.

Clinical

Edema secondary to CHF, cirrhosis, and the nephrotic syndrome. CHF (even without frank edema) to attenuate adverse cardiac remodeling and reduce mortality. Hypertension. Often added to other diuretic regimens to help minimize K⫹ loss. Primary hyperaldosteronism.

Side Effects

Hyperkalemia (especially in patients with renal impairment). Hyponatremia. Hypochloremic acidosis (blocks aldosterone’s effect on the Na⫹/H⫹ anti-porter). Gynecomastia (caused by binding to progesterone and androgen receptors).

Notes

TRIAMTERENE (Dyrenium) is similar but has a shorter half-life. EPLERENONE (Inspra) has a lower affinity for other steroid hormone receptors and therefore is less likely to cause gynecomastia. AMILORIDE (Midamor) is similar in effect to spironolactone, but it directly inhibits Na⫹ reabsorption in the collecting tubule, therefore working independent of the presence of aldosterone. Unlike spironolactone, it causes ↑ Ca2⫹ reabsorption and thus is used to treat Ca2⫹-based nephrolithiasis.

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CV SPIRONOLACTONE Triamterene

Amiloride

Eplerenone

DCT

glomerulus

collecting duct

PCT ClNa+ K+ HCO3-

–

ThAL Na+ 2 ClK+ loop of Henle

Na+

aldosterone

H+

K+-sparing spironolactone ADH

H 2O

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ACETAZOLAMIDE (Diamox)

Page 49

diuretic

49

Mechanism

Inhibits carbonic anhydrase (CA), which catalyzes HCO3⫺ → CO2 ⫹ OH⫺ in the proximal convoluted tubule of the kidney. Normally, CO2 then diffuses into proximal tubule cells and recombines with OH⫺ to form HCO3⫺, which is transported across the basolateral membrane into the bloodstream. Thus, inhibition of CA results in ↓ reabsorption of bicarbonate → bicarbonate. CA is also located in the ciliary body of the eye and in the choroid plexus. Inhibition of CA in these locations results in ↓ production of aqueous humor and ↓ CSF production, respectively.

Clinical

Chronic management of glaucoma (via ↓ aqueous humor production). Treatment of alkalosis. Alkalinization of urine to facilitate excretion of weak acids (e.g., cystine in cystinuria, uric acid in tumor lysis syndrome, phenobarbital overdoses). High-altitude sickness: mechanism probably related to ↓ CSF, but incompletely understood.

Side Effects

Metabolic acidosis. Renal stones: calcium phosphate is less soluble in alkalinized urine. Patients with hepatic impairment can develop encephalopathy (presumably via ↓ ability to excrete NH3 and other nitrogenous waste products in alkaline urine).

Notes

METHAZOLAMIDE (Neptazane) is another oral CA inhibitor and BRINZOLAMIDE (Azopt) and DORZOLAMIDE (Trusopt) are topical CA inhibitors used to treat glaucoma. Pharmacologic therapy for glaucoma includes ↑ aqueous humor outflow with PGF2␣ analogs (see latanoprost), ␣2-agonists (see brimonidine), and muscarinic agonists (see pilocarpine) as well as ↓ aqueous humor formation with ␤-blockers (see timolol), ␣2-agonists, and CA inhibitors.

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CV ACETAZOLAMIDE Methazolamide Brinzolamide Dorzolamide DCT

glomerulus

collecting duct

PCT ClNa+

–

K+

HCO3-

Na+

ThAL

H+ Na+ 2 ClK+

acetazolamide loop of Henle

ADH

H2O

aldosterone

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MANNITOL

diuretic

50

Mechanism

An osmotic diuretic not subject to tubular reabsorption. Its osmotic pull impairs reabsorption of water in the lumen → osmotic diuresis. It may also inhibit sodium and chloride reabsorption in the proximal tubule and the ascending loop of Henle.

Clinical

Maintain high urine flow. ↓ intracranial or intraocular pressure through volume depletion.

Side Effects

Extracellular volume expansion: the drug rapidly distributes into the extracellular compartment and pulls water out of cells. This can lead to pulmonary edema. Hypernatremia.

Contraindic.

Anuria, severe renal failure. Severe dehydration. CHF, severe pulmonary congestion.

Metabolism

This drug is poorly absorbed and therefore must be given parenterally.

Notes

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CV MANNITOL

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PROCAINAMIDE (Procan SR, Pronestyl) Mechanism

Clinical Side Effects

Metabolism Notes

antiarrhythmic

51

Class IA antiarrhythmic: moderate Naⴙ channel blockade. Purkinje cells: moderate iNa channel blockade, depressing phase 0 depolarization, ↓ conduction velocity; blocks K⫹ channels, prolonging repolarization. Pacemaker cells: ↓ slope of phase 4, ↑ threshold for depolarization. IA antiarrhythmics selectively block channels that are being used more frequently (i.e., ↑ affinity for activated ⬎ inactivated ⬎ resting channels), called “use dependence”. Emergent treatment of wide-complex tachycardias of unknown etiology. Maintenance of sinus rhythm in patients with AF, AFL, PSVT, but now used less frequently. ↑ 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). 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. 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 ␣-adrenergic 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.

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CV PROCAINAMIDE Quinidine Disopyramide

CLASS IA ECG Δs = Ø PR, ↑ QRS, ↑ QT

Moderate Na+ channel block

Prolong repolarization

Raise threshold

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

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LIDOCAINE (Xylocaine)

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antiarrhythmic

52

Mechanism

Class IB antiarrhythmic: mild Naⴙ 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.

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CV LIDOCAINE Mexiletine

CLASS IB ECG Δs = Ø PR, Ø QRS, Ø/↓ QT

Mild Na+ channel block

Shorten repolarization

Raise threshold

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

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FLECAINIDE (Tambocor)

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antiarrhythmic

53

Mechanism

Class IC antiarrhythmic: marked Naⴙ 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, Wolff-Parkinson-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 an IC antiarrhythmic that also has some weak ␤-blocker (class II) activity. Used for supraventricular arrhythmias. Side effects include development of a metallic taste and constipation. MORICIZINE (Ethmozine) is an IC antiarrhythmic that also has some class IB properties. As with other IC agents, fatal proarrhythmic side effects may occur.

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CV FLECAINIDE Propafenone Moricizine

CLASS IC ECG Δs = ↑ PR, ↑↑ QRS, ↑ QT

Marked Na+ channel block

No change in repolarization

Raise threshold

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

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AMIODARONE (Cordarone)

Page 54

antiarrhythmic

54

Mechanism

Primarily a class III antiarrhythmic: Kⴙ channel blocker prolonging repolarization. Also exerts actions that fall into each of the other three classes: Na⫹ channel blocker (class I), ␤-blocker (class II), and Ca2⫹ channel blocker (class IV). Also a vasodilator (secondary to ␣-blockade and calcium channel blockade) and a negative inotropic agent (secondary to ␤-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 (10–15%). Microcrystalline deposits in cornea and skin, giving patient a slate gray appearance (⬃5%). Cutaneous photosensitivity (25%).

Metabolism

IV and PO.

Notes

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 heart failure.

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CV AMIODARONE

I O

Dronedarone

C

O CH2 CH2 N

C2H5 C2H5

O

I CH2 CH2 CH2 CH3

Amiodarone

CLASS III ECG Δs = ↑ PR, ↑ QRS, ↑↑ QT

Marked prolongation of repolarization

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

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IBUTILIDE (Corvert)

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Page 55

antiarrhythmic

55

Mechanism

Class III antiarrhythmic: Kⴙ 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 ␤-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.

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CV IBUTILIDE Dofetilide Sotalol

CLASS III ECG Δs = ↑ PR, ↑ QRS, ↑↑ QT

Marked prolongation of repolarization

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

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ADENOSINE (Adenocard)

Page 56

antiarrhythmic

56

Mechanism

Nucleoside and physiologic autacoid that stimulates P1 purinergic receptors. Cardiac effects are mediated by the A1 subtype of the P1 purinergic receptor, stimulation of which results in G protein–mediated ↓ cAMP and ↑ outward K⫹ current → membrane hyperpolarization and suppression of Ca2⫹dependent action potentials. The important pharmacologic effects are: ↓ rate of discharge of pacemaker cells and ↓ rate of conduction through AV node. Other physiologic effects include dilation of coronary and cerebral blood vessels and bronchoconstriction.

Clinical

Used diagnostically and therapeutically for supraventricular tachyarrhythmias to slow or block AV conduction and thereby potentially terminate reentrant arrhythmias that depend on the AV node as part of the reentrant circuit. No effect on ventricular arrhythmias. Also used to perform pharmacologic cardiac stress tests: adenosine-induced coronary vasodilation results in ↑ flow to myocardium perfused by healthy coronary arteries and thereby “steals” flow away from ischemic myocardium supplied by already maximally dilated diseased segments.

Side Effects

Transient high-grade AV block. Flushing (20%). Shortness of breath, chest pain, and bronchoconstriction (⬃10%).

Contraindic.

AV block (second or third degree), sick sinus syndrome, ventricular tachycardia.

Metabolism

IV. Half-life is ⬃10 seconds.

Interactions

Increased dose required in patients receiving methylxanthines, which competitively inhibit action at P1 receptors.

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CV ADENOSINE

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ACETYLSALICYLIC ACID (Aspirin)

Page 57

antiplatelet

57

Mechanism

Irreversibly inhibits cyclooxygenase (COX)-1 and COX-2, blocking arachidonic acid → PGG2 and thereby production of subsequent prostaglandins. Anti-inflammatory and antipyretic: interferes with PGE2 synthesis (see ibuprofen for details). Antiplatelet: ↓ platelet production of TXA2 (platelet activator and vasoconstrictor); ↓ endothelial cell production of PGI2 (platelet aggregation inhibitor and vasodilator). Endothelial cells can resynthesize COX but platelets cannot, therefore, net effect is antiplatelet.

Clinical

Analgesia, anti-inflammatory, antipyretic (e.g., headaches, arthritis, dysmenorrhea, myalgias, fever). Prophylaxis and treatment of arterial thrombosis (acute coronary syndromes and stroke).

Side Effects

Gastritis and GI bleeding because of ↓ synthesis of protective prostaglandins. ↓ GFR (caused by ↓ renal arteriole vasodilatory prostaglandins); analgesic nephropathy. Can precipitate asthma (inhibition of COX may favor production of leukotrienes). Chronic mild intoxication (“salicylism”) causes tinnitus, ↓ hearing, vertigo. Acute intoxication leads to metabolic acidosis (accumulation of acid), respiratory alkalosis (↑ respiratory rate caused by direct effect on medulla), hyperpyrexia, coma, and cardiopulmonary collapse.

Contraindic.

Use with caution in patients with known peptic ulcer disease. Avoid in children because of the potential for Reye’s syndrome (see back).

Metabolism

Low doses for cardioprotection; higher doses for inflammation. COX inhibition irreversible, but ⬃10% of platelets replaced each day; therefore, antiplatelet effect lasts for ⬃7 days.

Notes

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HEME ACETYLSALICYLIC ACID

platelet activation TXA2 ADP 5-HT

TXA2

TxS

– COX AA -1

COX-1 inhibitors aspirin nonselective NSAIDs

platelet

platelet activation vasoconstriction Reye’s syndrome consists of rapidly progressive liver failure and encephalopathy. It is seen exclusively in children ⬍15 years old, usually after an upper respiratory infection. It is associated with aspirin use but can also occur in its absence.

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CLOPIDOGREL (Plavix)

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Page 58

ADP receptor blocker

58

Mechanism

A thienopyridine that irreversibly inhibits the platelet P2Y12 ADP receptor, blocking ADP-mediated platelet activation.

Clinical

Routinely given after coronary artery stenting to ↓ risk of stent thrombosis. Acute coronary syndromes. Usually given in combination with aspirin because of their complementary mechanisms of action.

Side Effects

Bleeding. Dyspepsia and rashes (⬃5% for each); neutropenia (⬍0.1%).

Metabolism

A loading dose is given to approach steady-state antiplatelet effect after several hours. Like acetylsalicylic acid, the antiplatelet effect is irreversible, but ⬃10% of platelets are replaced daily; therefore, antiplatelet effect lasts for ⬃7 days. Clopidogrel is a prodrug that is metabolized to an active compound by the CYP450 system. Patients treated with clopidogrel who have a reduced-function CYP2C19 allele have been found to have lower levels of circulating active drug, lesser platelet inhibition, and higher rates of ischemic events.

Notes

TICLOPIDINE (Ticlid), an older thienopyridine, has a worse side effect profile (dyspepsia and rash, ⬃20%), including neutropenia (⬃1%) and thrombotic thrombocytopenic purpura (⬍0.1%). PRASUGREL (Effient) is a 3rd generation thienopyridine that achieves a higher degree of antiplatelet effect and with less variability. Compared with clopidogrel, it reduces ischemic events (including stent thrombosis) and increases bleeding. TICAGRELOR is a reversible P2Y12 ADP receptor blocker that, compared with clopidogrel, achieves a higher degree of platelet inhibition and a reduction in ischemic events, including cardiovascular death.

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HEME CLOPIDOGREL Ticlopidine Prasugrel

platelet platelet activation ADP 5-HT

IIIa

IIb TXA2

fibrinogen

IIb

IIIa

+ platelet activation

– P2Y12

ADP receptor blockers clopidogrel, prasugrel, ticlopidine

platelet

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EPTIFIBATIDE (Integrilin)

Page 59

GP IIb/IIIa inhibitor

59

Mechanism

The final step of platelet aggregation occurs when fibrinogen molecules bind to activated glycoprotein (GP) IIb/IIIa receptors on the surface of platelets and thereby crosslink platelets. Eptifibatide is a synthetic peptide based on pygmy rattlesnake venom that contains an analog of the key binding sequence in fibrinogen and thereby inhibits platelet aggregation by blocking fibrinogen binding.

Clinical

Acute coronary syndromes. Especially used in the setting of percutaneous coronary interventions: ↓ platelet microemboli → ↓ MI, ↓ need for urgent revascularization, and modest ↓ death.

Side Effects

Bleeding, thrombocytopenia.

Contraindic.

Active or recent internal bleeding, major surgery or trauma, ↓ platelets or bleeding disorder. History of CVA or known intracranial neoplasm, arteriovenous malformation, or aneurysm.

Metabolism

IV. Half-life ⬃2 hours. Renally cleared (and thus requires dose-adjustment if renal insufficiency).

Notes

TIROFIBAN (Aggrastat) is a non-peptide small molecule that mimics the structure of fibrinogen’s GP IIb/IIIa binding sequence and is used for indications similar to eptifibatide. ABCIXIMAB (ReoPro) is an Fab fragment of a chimeric monoclonal antibody against the GP IIb/IIIa receptor. It is used during PCI to decrease ischemic complications. Unlike the above small-molecule inhibitors, abciximab has a long half-life (⬃8–12 hours) and is not renally cleared. Congenital deficiency of the GP IIb/IIIa receptor results in Glanzmann’s thrombasthenia, a bleeding disorder.

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HEME EPTIFIBATIDE Tirofiban Abciximab

tirofiban, abciximab platelet platelet activation config → fbgn binding

IIIa IIb – fibrinogen

GP IIb/IIIa inhibitors eptifibatide, tirofiban, abciximab

IIIa IIb

platelet

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DIPYRIDAMOLE (Persantine)

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antiplatelet

60

Mechanism

Inhibits platelet activation by ↑ cAMP within platelets via two mechanisms: 1. ↑ cAMP production: blocks uptake of adenosine → stimulation of adenyl cyclase. 2. ↓ cAMP degradation: inhibits phosphodiesterase. ↑ cAMP also decreases vascular tone (myosin light-chain kinase is phosphorylated and inactivated as cAMP levels increase, analogous to albuterol’s cAMP-mediated effect on bronchial smooth muscle). Decreased vascular tone (vasodilation) in normal vessels can “steal” blood away from stenotic vessels in the same circulation because the latter vessels are already maximally dilated.

Clinical

Prophylaxis of thromboembolic events in patients with a history of TIA or CVA. Sometimes given in combination with aspirin (combination pill trade name is Aggrenox), as they have different and complementary antiplatelet mechanisms of action. Used to perform pharmacologic cardiac stress tests: dipyridamole vasodilates normal coronary arterioles, thereby stealing flow away from ischemic myocardium, which is supplied by arterioles already maximally dilated due to the proximal arterial stenosis (adenosine is also used for this purpose).

Side Effects

Headache, diarrhea.

Contraindic.

Use caution in patients with hypotension (may cause peripheral vasodilatation).

Metabolism

PO.

Notes

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HEME DIPYRIDAMOLE

platelet platelet inhibition PDE

cAMP AC

–

AMP

dipyridamole

–

ATP

–

adenosine

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HEPARIN Mechanism

Clinical

Side Effects

Contraindic. Metabolism Notes

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anticoagulant

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A fast-acting anticoagulant, heparin is a naturally occurring glycosaminoglycan with a high binding affinity for antithrombin III (ATIII). ATIII is a serine protease inhibitor that binds to and inactivates thrombin and other serine proteases, such as factors X, IX, and XI. When bound to heparin, ATIII undergoes a conformational change that makes its serine protease binding site more accessible. Heparin also acts as a catalytic template, binding to and bringing together thrombin and ATIII and thereby ↑ thrombin–ATIII reaction 1000-fold. As soon as ATIII has bound to thrombin, heparin is released and can bind to new ATIII. Prophylaxis and initial treatment of venous thrombosis (deep vein thrombosis and pulmonary embolism) and atrial fibrillation until long-acting oral anticoagulants can take effect. Treatment of arterial thrombosis (acute coronary syndromes and stroke). Bleeding. Thrombocytopenia: heparin-induced thrombocytopenia (HIT) type I is caused by heparin-mediated platelet aggregation; occurs in ⬃10% of cases and is mild and self-limiting. HIT type II, caused by antibodies formed against heparin-platelet factor 4 complexes, occurs in ⬃1% of patients and can be associated with life-threatening paradoxical thrombosis, and thus mandates immediate discontinuation of heparin and initiation of alternative anticoagulation. Active bleeding, bleeding disorders, conditions potentially worsened by anticoagulation (e.g., aortic dissection), history of HIT type II. Safe during pregnancy because it does not cross the placenta. IV, SC. Eliminated by the reticuloendothelial system. Half-life is 60–90 minutes. Effect followed clinically by measuring activated partial thromboplastin time (aPTT). PROTAMINE is a basic protein that binds to and neutralizes heparin, rapidly reversing anticoagulation.

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HEME HEPARIN Protamine Intrinsic Pathway

Extrinsic Pathway

heparin

VIIa + TF XII

XIIa + ATIII

XI

XIa IX

IXa VIIIa Ca2+, PL

tenase complex X

(prothrombin) II

Xa – Va Ca2+, PL

prothrombinase complex IIa (thrombin)

fibrinogen

(anti-IIa ≈ anti-Xa)

– fibrin

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ENOXAPARIN (Lovenox) Mechanism

Clinical

Side Effects Metabolism Notes

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anticoagulant

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Low-molecular-weight heparin (LMWH) consists of fragments of standard unfractionated heparin (UFH). Like UFH, LMWH contains the key pentasaccharide sequence that binds to and activates ATIII. ATIII then binds to and inactivates factor Xa and thrombin. Unlike UFH, only a small percentage of LMWH contains enough polysaccharide residues to bind thrombin and ATIII simultaneously and serve as a catalytic template. Therefore, LMWH exerts its anticoagulant effect more proximally in the coagulation cascade by predominantly inactivating factor Xa rather than by inactivating thrombin. Prophylaxis and initial treatment of venous thrombosis (deep vein thrombosis and pulmonary embolism) and atrial fibrillation until long-acting oral anticoagulants can take effect. Treatment of arterial thrombosis (acute coronary syndromes [ACS]). Bleeding. Protamine can be used to try to neutralize LMWH, but the success rate varies. LMWH is less likely than UFH to trigger heparin-induced thrombocytopenia (HIT) type II (see heparin). SC, IV. LMWH has more predictable and stable bioavailability than UFH. Thus, it is typically given as a weight-adjusted SC injection with a half-life of 8–12 hours. Unlike UFH, LMWH has little effect on the activated partial thromboplastin time (aPTT). Anti-Xa levels can be followed, but given predictable response to a weight-adjusted dose, routine monitoring is not indicated. DALTEPARIN (Fragmin) and TINZAPARIN (Innohep) are other LMWHs. DANAPAROID (Orgaran) is a partially depolymerized mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate that, like LMWH, inhibits factor Xa more than thrombin. FONDAPARINUX (Arixtra), a synthetic pentasaccharide that exclusively inhibits Xa, is currently used for prophylaxis and treatment of DVT and PE and has shown efficacy with low rates of bleeding in patients with ACS.

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HEME ENOXAPARIN Dalteparin Tinzaparin Danaparoid Fondaparinux

fondaparinux (only anti-Xa) tenase complex

coagulation cascade X

(prothrombin) II

+ ATIII

Xa – Va Ca2+, PL

(anti-Xa > anti-IIa)

prothrombinase complex

fibrinogen

IIa (thrombin)

thrombin

LMWH are not long enough to bind to thrombin as well as ATIII. Therefore, although they activate ATIII, LMWH do not serve as a catalytic template to bring thrombin and ATIII together. This difference results in preferential Xa inhibition.

LMWH

+ ATIII

ATIII

–

≈

UFH

Xa ATIII

UFH

thrombin ATIII

LMWH

fibrin