Pharmacology in Clinical Neurosciences: A Quick Guide [1st ed.] 9789811535901, 9789811535918

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Hemanshu Prabhakar Charu Mahajan Indu Kapoor   Editors

Pharmacology in Clinical Neurosciences A Quick Guide

Pharmacology in Clinical Neurosciences

Hemanshu Prabhakar • Charu Mahajan • Indu Kapoor Editors

Pharmacology in Clinical Neurosciences A Quick Guide

Editors Hemanshu Prabhakar Department of Neuroanesthesiology & Critical Care All India Institute of Medical Sciences New Delhi, Delhi, India

Charu Mahajan Department of Neuroanaesthesiology & Critical Care All India Institute of Medical Sciences New Delhi, Delhi, India

Indu Kapoor Department of Neuroanaesthesiology & Critical Care All India Institute of Medical Sciences New Delhi, Delhi, India

ISBN 978-981-15-3590-1 ISBN 978-981-15-3591-8 https://doi.org/10.1007/978-981-15-3591-8

(eBook)

# Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Contents

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Analgosedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kelsey Woods-Morgan, Brian Gilbert, Nicole Davis, Michael Reichert, and Katleen W. Chester

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2

Inhalational Anaesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas Hargreaves, Christina Yap, and Catriona Kelly

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3

Intravenous Anesthetic Agents . . . . . . . . . . . . . . . . . . . . . . . Ankur Luthra, Rajeev Chauhan, and Summit D. Bloria

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4

Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hossam El Beheiry

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5

Neuromuscular Blocking Drugs (NMBDS) . . . . . . . . . . . . . Ankur Khandelwal and Hemanshu Prabhakar

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6

Reversal Agents and Antagonists . . . . . . . . . . . . . . . . . . . . . Archana Hinduja and Sarah M. Adriance

135

7

Anticholinergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ravi K. Grandhi and Alaa AbdElsayed

165

8

Anti-epileptic Drugs (AEDs) . . . . . . . . . . . . . . . . . . . . . . . . Ankur Khandelwal, Charu Mahajan, and Hemanshu Prabhakar

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Osmotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vanitha Rajagopalan and Nidhi Gupta

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Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

499

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Antifungal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Suman Sokhal, Navdeep Sokhal, and Vasudha Singhal

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13

Anticoagulants and Antiplatelets . . . . . . . . . . . . . . . . . . . . . Varsha Allampalli, Jibin Mathew, Reza Gorji, and Fenghua Li

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14

Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brittany D. Bissell and Brian Gilbert

745

15

Antihypertensives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kiran Jangra and Navneh Samagh

769

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Contents

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Vasopressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Casey C. May, Beth E. Varnes, and Keaton S. Smetana

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Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jamie Micheletto, Brian Phan, and Eljim Tesoro

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Miscellaneous Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rajeeb K. Mishra and Indu Kapoor

1047

About the Editors

Hemanshu Prabhakar, MBBS, MD, PhD is currently working as a Professor in the Department of Neuroanaesthesiology and Critical Care at the All India Institute of Medical Sciences, New Delhi. Dr. Prabhakar, having a research experience spanning over 20 years, is a member of various National and International societies. His extensive research in the field of neuroanaesthesia and critical care has been published in various national and international journals across the globe. Dr. Prabhakar is an eminent author and has various book titles to his name. He was featured in the Limca Book of Records 2019 for publishing several books on a niche subject. Charu Mahajan, MBBS, MD, DM is currently working as an Associate Professor in the Department of Neuroanaesthesiology and Critical Care at All India Institute of Medical Sciences, New Delhi. She has research experience of over a decade backing her profile and has been awarded with the prestigious NBM Gold medal in the subject of surgery in the year 2003. She has more than 50 publications to her name in the form of books and journal alike. She is also the reviewer of various prestigious national journals like the Neurology India and Indian Journal of Anaesthesia and is the member of various scientific bodies such as the SNACC, ISNACC and ISA. Indu Kapoor, MBBS, MD from the prestigious institute Lady Hardinge Medical College and MD from UCMS Delhi is currently serving as an Associate Professor in the Department of Neuroanaesthesiology and Critical Care at All India Institute of Medical Sciences, New Delhi. She has more than 30 research papers published in national and international journals across the globe and numerous chapter contributions in reputed titles. She has also been awarded with the reputed Dr. TN. JHA Memorial Award by the Indian Society of Anaesthesiologists and Smt. Chandra and Sh. Narayan Wadhwani Memorial Award.

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Analgosedation Kelsey Woods-Morgan, Brian Gilbert, Nicole Davis, Michael Reichert, and Katleen W. Chester

1.1

Propofol

Drug name: Propofol Chemical name: 2,6-Diisopropylphenol Ingredients: Active component propofol, soybean oil at 100 mg/mL, glycerol at 22.5 mg/mL, egg lecithin at 12 mg/mL, and disodium edetate 0.005% or metabisulfite to prevent bacterial and fungal growth. Sodium hydroxide is titrated to a pH of 7–8.5.

K. Woods-Morgan Department of Pharmacy Practice, Shenandoah University, Bernard J Dunn School of Pharmacy, Winchester, VA, USA B. Gilbert Department of Pharmacy, Wesley Medical Center, Wichita, KS, USA N. Davis Department of Pharmacy, Mount Sinai, New York, NY, USA M. Reichert Department of Pharmacy, Emory Healthcare, Atlanta, GA, USA K. W. Chester (*) Department of Pharmacy and Clinical Nutrition, Grady Memorial Hospital, Atlanta, GA, USA e-mail: [email protected]

1.1.1

Chemical Properties

Structure:

Molecular formula: C12H18O Molecular weight: 178.27 Color: White, oil-in-water emulsion Odor: n/a Taste: n/a Solubility: The active ingredient is insoluble in water. The final product is 1% emulsion. Boiling point: 242
C Melting point: 18
C Vapor pressure: n/a

1.1.2

Mechanism of Action

Propofol acts primarily by modulating gammaaminobutyric acid (GABA). Propofol induces the presynaptic release of GABA while also agonizing postsynaptic GABAA. Additionally, propofol is an N-methyl-D-aspartate (NMDA) receptor antagonist and interacts with dopamine

# Springer Nature Singapore Pte Ltd. 2020 H. Prabhakar et al. (eds.), Pharmacology in Clinical Neurosciences, https://doi.org/10.1007/978-981-15-3591-8_1

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by potentially promoting dopamine release and acting as an agonist at D2 receptors.

1.1.3

Pharmacokinetics

Absorption: With the initiation of propofol, there is an initial rapid equilibration between plasma and brain which is responsible for the rapid onset of anesthesia. Absorption follows a threecompartment linear model which includes the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues. Distribution: Volume of distribution is 60 L/ kg in healthy adults at steady state. Due to high protein-binding properties, critical illness, pregnancy, hypoalbuminemia, and other conditions resulting in low protein states can impact the volume of distribution and free concentrations. Distribution and metabolic clearance result in an initial rapid decline in plasma levels. The decline decreases over time as the tissues become saturated and equilibrate with the plasma. The rate and the duration of the infusion determine the point at which equilibration occurs. Longer durations of infusions, such as those lasting 10 or more days, can result in significant accumulation in tissues. This results in a slowed reduction of circulating plasma propofol

concentrations corresponding with delayed awakening times. Daily reduction of propofol infusion rates to achieve the minimum therapeutic concentration can improve awakening times. The impact of infusion duration on the decline of plasma levels after discontinuation of the infusion is displayed in Fig. 1.1. Excretion: Propofol is primarily eliminated through hepatic conjugation to inactive metabolites that are then excreted by the kidney. Half-life is dependent on the time of the infusion. At 3 h, half-life is 10 min but increases to 30 min after 8 h of infusion. By 10 days of infusion, the half-life prolongs in the range of 1–3 days.

1.1.4

Pharmacodynamics

Central nervous system: Decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Propofol does not impact cerebrovascular reactivity to carbon dioxide. Propofol has sedative, amnestic, and anticonvulsant activity (in higher doses). Cardiovascular system: Decreases in blood pressure of >30% may occur and are more common with bolus doses versus continuous infusions. The hemodynamic effects are dose dependent. If hypotension occurs, it often has no

Fig. 1.1 Impact of duration on decline of plasma propofol levels after discontinuation of infusion

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impact on heart rate or cardiac output but bradycardia has been reported. If the patient is receiving ventilatory assistance, the risk of depressed cardiac output increases. Respiratory system: Apnea occurs in both pediatric and adult patients, lasting 30–60 s in 24% of adult patients who receive 2–2.5 mg/kg. Pediatric patients from birth through 16 years old who received bolus doses experienced apnea lasting less than 30 s in 12% of patients and apnea lasting 30–60 s in 10% of patients. Maintenance of anesthesia with propofol decreases spontaneous minute ventilation. A variable rate infusion is preferred to minimize undesired cardiorespiratory effects during monitored anesthesia care. Although propofol may be used for procedural sedation in the absence of mechanical ventilation, judicious use of low doses combined with proper intravenous fluid hydration and hemodynamic and respiratory monitoring is imperative. Renal and hepatic system: Dysfunction or impairment of these organ systems does not impact the pharmacodynamic profile of propofol, although lower initial doses should be considered with hepatic impairment and titrated to desired effects. In the setting of propofol-related infusion syndrome (PRIS), propofol may cause rhabdomyolysis which could cause AKI. Propofol may increase serum triglyceride concentrations with continuous infusions as a result of its formulation. Gastrointestinal system: n/a Genitourinary system: n/a Musculoskeletal system: n/a Immune system: Can increase plasma histamine levels. Propofol can cause serious and even fatal anaphylactic and anaphylactoid reactions, particularly in the setting of soy or egg allergy. Hematological system: n/a

1.1.5

Indications (Clinical Uses)

– Initiation and maintenance of monitored anesthesia care sedation – Combined sedation and regional anesthesia – Induction of general anesthesia – Maintenance of general anesthesia

3

– ICU sedation of intubated, mechanically ventilated patients – Procedural sedation in combination with analgesia

1.1.6

Contraindications

– Patients with allergies to eggs, egg products, soybeans, or soy products – Patients with a known hypersensitivity to propofol or any of its ingredients

1.1.7

Drug Interactions

– Opioids and benzodiazepines result in similar cardiorespiratory effects as propofol. In combination, these medications can result in more pronounced sedative, respiratory, and cardiac effects. – Inhaled agents such as isoflurane, enflurane, and halothane may increase the anesthetic, sedative, and cardiorespiratory effects of propofol.

1.1.8

Side Effects

Central nervous system: Hypertonia/dystonia, paresthesia, agitation, dizziness, chills, somnolence, delirium Cardiovascular system: Bradycardia, arrhythmia, hypotension, decreased cardiac output, premature atrial contractions, syncope Respiratory system: Apnea, respiratory acidosis when weaning, wheezing, decreased lung function, cough, laryngospasm, hypoxia Metabolic: Hyperlipemia, hypomagnesemia Gastrointestinal system: Hypersalivation, nausea Genitourinary system: Cloudy urine, green urine Musculoskeletal system: Injection-site burning or pain, rash, pruritus, phlebitis, myalgia Immune system: Anaphylaxis/anaphylactoid reactions, sepsis Hematological system: Leukocytosis

4

1.1.9

K. Woods-Morgan et al.

Precaution

– Lower induction doses and slower maintenance rate should be used in the elderly and debilitated. – Patients should be continuously monitored during administration for signs of hypotension, bradycardia, and apnea. – Caution should be employed when used in patients with lipid metabolism disorders such as pancreatitis, diabetic hyperlipemia, and primary hyperlipoproteinemia. – There is risk of seizure during the recovery phase after administration in patients with epilepsy or with prolonged infusion duration. – Use of larger veins for administration may reduce the pain of infusion. – Some institutions require propofol to be administered using an in-line filter. If a filter is used, the filter pore size should be 5 microns or greater. – Sterile technique must be used when preparing a vial for administration. After a vial has been opened, the tubing and remaining propofol in the vial should be discarded to reduce the risk of infection.

1.1.10

Toxicity

Propofol infusion syndrome (PRIS) – Syndrome was first described in pediatric patients but can also occur in adult patients. – The clinical features of PRIS include acute, refractory bradycardia in the presence of metabolic acidosis, rhabdomyolysis, hyperlipemia, and/or an enlarged or fatty liver. The risk of PRIS increases with length of infusion and dose. Infusion rates greater than 80 mcg/kg/min in adults and infusions greater than 48 h have been associated with increased risk. – A retrospective cohort analysis looking at head-injured adult patients found that the odds ratio for PRIS was 1.93 for every mg/kg/hr increase in mean propofol doses up

to 5 mg/kg/h [Cremer OL; 2001; 11197401]. Of note, the manufacturer-specified maximum infusion rate is 4 mg/kg/h (~67 mcg/kg/min) although many institutions will implement maximum rates of 50–80 mcg/kg/min with rates exceeding this range in extreme circumstances for short periods of time. – The mechanism of PRIS is currently proposed to be due to a mitochondrial defect leading to impaired mitochondrial respiratory chain function resulting in metabolic acidosis. – Early recognition of PRIS is important in successful treatment. Routine laboratory monitoring to evaluate for metabolic acidosis and renal function is warranted. Routine monitoring of creatinine kinase may also be considered. Management should include discontinuation of the infusion, cardiorespiratory support, and hemodialysis as indicated.

1.1.11

Advantages

Propofol may have neuroprotective effect against brain ischemia in addition to its effects on depressing seizure activity and decreasing intracranial pressure. Propofol can be utilized in patients with brain injury to significantly reduce intracranial pressure and cerebral perfusion pressure (7)(7)(7) (7). Propofol has anticonvulsant activity which may be useful for status epilepticus. The recovery times are shorter with propofol compared to benzodiazepines allowing for accurate neurologic examination sooner after drug discontinuation.

Suggested Reading Cremer OL, Moons KG, Bouman EA, Kruijswijk JE, de Smet AM, Kalkman CJ (2001) Longterm propofol infusion and cardiac failure in adult head-injured patients. Lancet 357 (9250):117–118 Diprivan (propofol). [package insert] (2017). Fresenius Kabi, LLC, Lake Zurich, IL

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Herregods L, Verbeke J, Rolly G, Colardyn F (1988) Effect of propofol on elevated intracranial pressure. Preliminary results. Anaesthesia 43 Suppl:107–109 Sud P, Lee DC (2019) Sedative-Hypnotics. In: Lewis S. Nelsen, et al (eds) Goldfrank’s toxicologic emergencies, 11e. McGraw-Hill, New York, NY Kam PC, Cardone D (2007) Propofol infusion syndrome. Anaesthesia 62(7):690–701 Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H (2008) The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther 14(2):95–106 Krajčová A, Waldauf P, Anděl M, Duška F (2015) Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care 19:398 National Center for Biotechnology Information. PubChem Database. Propofol, CID¼4943, https://pubchem.ncbi.nlm.nih.gov/compound/ 4943. Accessed 14 Apr 2019

1.2

5

Molecular formula: C13H17ClN2 IUPAC name: 5-[(1~[S])-1(2,3-dimethylphenyl)ethyl]-1~(H)-imidazole; hydrochloride Molecular weight: 236.743 g/mol Color: White powder Solubility: 174 mg/L (at 20
C) Boiling point: 381.9
C Melting point: 146–149
C

1.2.2

Mechanism of Action

DEX acts preferentially on alpha-2 adrenoreceptor within the brainstem. These receptors are G-protein coupled and the by-product is inhibition of norepinephrine release producing sympatholytic, sedative, and some proposed analgesic properties without affecting respiratory drive. In addition, activation of the alpha-2 adrenoreceptors causes dose-dependent hypotension and bradycardia. High doses or rapid administrations of DEX may activate alpha-1 adrenoreceptors peripherally causing a brief hypertensive response.

Dexmedetomidine

Drug name: Dexmedetomidine (DEX) Chemical name: 4-((S)-alpha,2,3trimethylbenzyl)imidazole monohydrochloride

1.2.1 Structure:

Chemical Properties

1.2.3

Pharmacokinetics

Absorption: Primary utilization of DEX is as an IV infusion since oral bioavailability is ~16% secondary to extensive first-pass metabolism. Intranasal bioavailability is ~41% after atomization. The onset of action for the IV form is approximately 5–10 min while the intranasal route onset of action is 45–60 min. Distribution: 1.31–2.46 L/kg; 94% protein bound; obesity and hypoalbuminemia have been shown to increase relative volume of distribution. The elimination half-life of DEX is approximately 2 h. Metabolism: DEX undergoes extensive biotransformation with minimal parent compound found in either urine or feces. Metabolism of DEX involves direct glucuronidation and oxidative metabolism to inactive metabolites. DEX follows linear kinetics at the recommended doses.

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Excretion: The majority of total dose recovered in urine following a DEX infusion is in the form of the inactive metabolites. Less than 1% of the parent drug is recovered in the urine. Patients with renal failure may accumulate metabolites if exposed to prolonged infusions.

1.2.5

Procedural sedation, sedation induction, sedation maintenance, pre-anesthesia

1.2.6 1.2.4

Pharmacodynamics

Central nervous system: Activation of pre- and postsynaptic alpha-2 adrenoreceptors in the locus coeruleus produces sedation and hypnotic effects by inhibition of release of norepinephrine from presynaptic vesicles. Sedation is a concentration-dependent effect with plasma concentrations of 0.2–0.3 ng/mL producing sedation no deeper than arousal to voice. The sedation produced by DEX is unique to other continuous-infusion sedatives in that it is perceived as a light sedative corresponding to a Richmond Agitation-Sedation Scale of 0 to (3) depending on the dose. The proposed analgesic effects of DEX may stem from activation of alpha-adrenoreceptors in the central nervous system which suppresses pain by the hyperpolarization of interneurons and reduction in the release of substance P and glutamate. Although DEX has mild, opioid-sparing properties, it should not be used as monotherapy for its analgesic effects. Cardiovascular system: At low concentrations DEX causes bradycardia and hypotension with activation of peripheral alpha-2 adrenoreceptors; however, at high concentrations or rapid administration alpha-1 adrenoreceptors are activated and hypertension may result. Pronounced hypertension then causes a baroreceptor response which leads to transient decreases in heart rate. Cardiac output decreases slowly as heart rate drops; however, no effect on stroke volume is seen until supratherapeutic doses. Respiratory system: Minimal respiratory depression is seen at therapeutic concentrations of DEX. Hypercapnic arousal phenomena have been shown to remain intact with DEX utilization.

Indications (Clinical Use)

Contraindications

Contraindications include allergies to any component of the formulation, bradycardia, and AV node block. Prolonged infusions should be limited and caution should be taken when administering to geriatrics, patients who are hypotensive or hypertensive, and patients with renal or hepatic impairment.

1.2.7

Drug Interactions

DEX is a substrate of CYP2D6 and dose adjustments may be needed with concomitant therapies which are also substrates in the same CYP450 enzyme pathway. Antihypertensive agents: Concomitant utilization with DEX may increase the risk for profound hypotension and arrhythmias. Barbiturates: Concomitant utilization with DEX may increase the risk for respiratory depression, hypotension, and sedation. Beta-blockers: Concomitant utilization with DEX may increase the risk for profound bradycardia and hypotension. Cardiac glycosides: Concomitant utilization with DEX may increase the risk of bradycardia and hypotension. Diuretics: Concomitant utilization with DEX may increase the risk of hypotension. Muscle relaxers: Concomitant utilization with DEX may increase the risk for respiratory depression, hypotension, and sedation.

1.2.8

Side Effects

Central nervous system: Agitation, anxiety, confusion, delirium, hallucinations, headache, tolerance, and withdrawal

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Cardiovascular system: Bradycardia, hypertension, hypotension, tachycardia, atrial fibrillation, myocardial infarction, peripheral edema, cardiac arrest, and QT prolongation Endocrinology and metabolic: Chills, fever, hyperglycemia, hypoglycemia, hypokalemia, hypocalcemia, hypomagnesemia, and diaphoresis Respiratory system: Acute respiratory distress syndrome, bronchospasm, pleural effusion, wheezing, pulmonary edema, and bronchospasm Hepatobiliary: Increased serum transaminases and hyperbilirubinemia Gastrointestinal system: Nausea, constipation, vomiting, abdominal pain, and diarrhea Genitourinary: Oliguria Hematologic system: Anemia, bleeding, and urticaria Hypersensitivity: Anaphylaxis, angioedema, and hypersensitivity reaction

1.2.9

Precautions

Tapering is not typically required; however, it may be considered in patients requiring prolonged infusions and large doses. Drug-drug interactions must be considered when utilizing DEX. Patients may require higher doses when subject to stress (trauma, surgery, severe infection) to achieve adequate effect.

1.2.10

Toxicity

A biphasic response with respect to blood pressure is seen with DEX toxicity where initially patients will be hypertensive followed by profound hypotension. Severe bradycardia is also common with DEX toxicity. Hypoglycemia, seizures, and increased somnolence are also possible with DEX toxicity. A withdrawal syndrome may occur after acute DEX toxicity.

1.2.11

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monitored while on DEX therapy with titration to desired effect.

1.2.12

Availability

DEX is supplied as an injectable solution; the intravenous formulation may be utilized for intranasal administration via atomizer.

1.2.13

Dosages

1.2.13.1 Adults • Patients who received higher doses and/or longer regimens should have a taper performed to mitigate withdrawal symptoms. • Dose adjustments must be considered in those with renal and hepatic dysfunction. • Critically ill patients may require higher dosing requirements. • Sedation scales are utilized to titrate to desired effect including Richmond Agitation Sedation Scale and Sedation-Agitation Scale. • Ceiling effects may occur with higher doses. • Bolus doses prior to initiating an infusion are not usually required given the short onset of action. Bolus doses should be used judiciously given the risk of hemodynamic adverse effects with large doses administered over short periods of time. Procedural Sedation: • IV dose: 1 mcg/kg over 10 min; infusion: 0.2–1.5 mcg/kg/h – Geriatrics may require smaller dose – Fiber-optic intubation: 0.7 mcg/kg/h Continuous Sedation • 1 mcg/kg over 10 min; infusion 0.2–1.5 mcg/ kg/h • Dose reduction in non-intubated patients may be necessary

Monitoring Alcohol Withdrawal:

Heart rate, heart rhythm, blood pressure, and sedation requirements should be continuously

• Intravenous: 0.4–1.2 mcg/kg/h

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– Does not prevent seizures but mitigates withdrawal symptoms

1.2.13.2 Pediatrics Procedural Sedation: • Intravenous dose: 0.7–1 mcg/kg/h • Intranasal dose: – Children: 1–4 mcg/kg divided between each nostril as a single dose 30–60 min prior to procedure – Infants: 2–3 mcg/kg divided between each nostril as a single dose 30–60 min prior to procedure Pre-anesthesia: • Intranasal dose: 1–2 mcg/kg divided between each nostril as a single dose 30–60 min prior to anesthesia • Has been shown to minimize anesthetic needs Continuous Sedation: • Intravenous Dose: – Children: 0.5–1 mcg/kg given over 10 min for induction; infusion: 0.2–2.5 mcg/kg/ h titrated to appropriate sedation/agitation scale – Term neonates: 0.05–0.2 mcg/kg over 10 min; infusion: 0.05–0.2 mcg/kg/h – Premature neonates: 0.05–0.5 mcg/kg over 10 min; infusion: 0.05–0.3 mcg/kg/h

1.2.14

Advantages

DEX is a short-acting sedative, with multiple routes of administration, rapid onset, and a favorable pharmacokinetic/pharmacodynamic profile. Unlike other continuous infusions, DEX does not impair the respiratory drive. Providers may use this medication to lightly sedate agitated patients during the peri-extubational period.

Given the short duration of action after discontinuation of the infusion, DEX allows providers to obtain an accurate neurological exam sooner than with benzodiazepine infusions. DEX reduces the shivering threshold and may be used within institutional protocols for shivering during therapeutic temperature modulation. Suggested Reading Bailey AM, Baum RA, Horn K, Lewis T, Morizio K, Schultz A, et al (2017) Review of intranasally administered medications for use in the emergency department. J Emerg Med 53 (1):38–48 Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al (2013) Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 41(1):263–306 Choi HA, Ko SB, Presciutti M, Fernandez L, Carpenter AM, Lesch C, et al (2011) Prevention of shivering during therapeutic temperature modulation: the Columbia anti-shivering protocol. Neurocrit Care 14(3):389–394 Katzung BG (2012) Basic & clinical pharmacology. 12th edn. Lange Medical Books/McGraw Hill, New York, NY Lexicomp Online (2019) Lexi-Drugs Online. Wolters Kluwer Clinical Drug Information, Inc., Hudson, OH National Center for Biotechnology Information. PubChem Database. Dexmedetomidine, CID¼5311068, https://pubchem.ncbi.nlm. nih.gov/compound/5311068. Accessed 14 Apr 2019 Ng KT, Shubash CJ, Chong JS (2019) The effect of dexmedetomidine on delirium and agitation in patients in intensive care: systematic review and meta-analysis with trial sequential analysis. Anaesthesia 74(3):380–392 Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P (2017) Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet 56(8):893–913

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1.3

Midazolam

Drug name: Midazolam Chemical name: Midazolam

1.3.1

9

channel causing channel opening, thereby enhancing the inhibitory effects of GABA. 3. Midazolam has a two times greater affinity for the GABAA receptor when compared to diazepam.

Chemical properties 1.3.3

Structure:

Pharmacokinetics

Absorption: 1. 2. 3. 4. 5.

Oral: Poor, 36% bioavailability IV: Complete, 100% IM: Nearly complete, >90% IN: Mostly, 75% Buccal: 75.4% Distribution:

Molecular formula: C18H13ClFN3 IUPAC name: 8-Chloro-6-(2-fluorophenyl)1-methyl-4~(H)-imidazo[1,5-a][1,4] benzodiazepine Molecular weight: 325.771 g/mol Color: colorless Odor: Faint Taste: Bitter Solubility: 0.024 mg/mL Boiling point: 496
C at 760 mmHg Melting point: 159
C Vapor pressure: 5.12  106 mmHg at 25
C

1.3.2

Mechanism of Action

1. Midazolam acts as a depressant on the central nervous system causing sedation. 2. It binds to an allosteric site (i.e., benzodiazepine (BZD) receptor) of the gammaaminobutyric acid A (GABAA) chloride

1. The volume of distribution is 1–3 L/kg and does not greatly change in obese, elderly, or pregnancy. 2. In patients subcutaneous. Addition of epinephrine decreases the rate and extent of systemic absorption.

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Table 4.3 Maximum doses and preparations of commonly used local anesthetics for local infiltration, and peripheral nerve blocks Dose without epinephrine (mg/kg)

Dose with epinephrine (mg/kg)

Available preparations

7 1 10–15

10 1.5 15–20

1%, 2% 1% 2%, 3%

4–5

5–7

Bupivacaine/levobupivacaine (Marcaine, Sensorcaine)

2

3

Mepivacaine (Carbocaine) Ropivacaine (Naropin) Etidocaine (Duranest)

4–5 2–3

7 3 4–5

0.5%, 1%, 2%, 4% 1:100,000 Epi with 1%, 2% 1:200,000 Epi with 0.5%, 1%, 1.5%, 2% 0.125%, 0.25%, 0.5%, 0.75% 1:200,000 Epi with 0.25%, 0.5%, 0.75% 1% 0.2%, 0.5%, 0.75% 1:200,000 Epi with 1%, 1.5% 1:100,000 Epi with 4% 1:200,000 Epi with 4%

Local anesthetic Esters Procaine (Novocaine) Tetracaine (Pentocaine) 2-Chloroprocaine (Nesacaine) Amides Lidocaine (Xylocaine)

Articaine (Septocaine)

7

Table 4.4 Maximum doses of local anesthetics used for spinal and epidural anesthesia Local anesthetic Esters 2-Chloroprocaine Tetracaine Amides Lidocaine Bupivacaine Ropivacaine Levobupivacaine

Spinal doses (mg/kg)

Epidural doses (mg/kg)

Epidural infusion (mg/kg/h)

Not applicable 0.2

10–30 Not applicable

10 Not applicable

1–2.5 0.3–0.5 Not applicable Not applicable

5–7 2–3 2.5–4 2.5–4

2–3 0.4 0.4–0.5 0.4

2. The extent of the intrinsic vasodilator activity of local anesthetics is linear to their systemic absorption. The only vasoconstrictor local anesthetic is cocaine (topically used). The increased lipophilicity of a LA can offset the effects of intrinsic vasodilation, e.g., etidocaine. 3. LAs except cocaine are poorly absorbed from the gastrointestinal tract and undergo significant first-pass liver effect.

4.6.2

Distribution

1. The peak plasma concentration depends on the extent and rate of absorption, rate of biotransformation, and effect of redistribution from the intravascular compartment to the high, intermediate, and poor vessel groups. 2. Redistribution of LAs into the body depends mainly on cardiac output, tissue blood flow, hepatic function, and protein binding. The effect of protein binding is similar to the effect

4

Local Anesthetics

of lipid solubility of local anesthetics and is inversely related to the blood levels of the drug, i.e. the more LA protein binding the less is the distribution of the LA into the body. 3. Lidocaine, prilocaine, and bupivacaine has a first-pass pulmonary effect; that is, they are extracted by lung tissues. Hence, such effect can limit their concentrations in the systemic circulation. 4. Placental transfer amide local anesthetics may be clinically significant. Protein binding is inversely proportional to placental transfer. Fetal acidosis can result in an “ion trapping” effect and leads to accumulation of LAs in the fetus. Ester local anesthetics are not available for transfer because of their rapid hydrolysis by placental and tissue esterase.

4.6.3

Metabolism

1. Ester LAs are hydrolyzed in the plasma by pseudo (plasma) cholinesterase. The rate of enzymatic hydrolysis varies: 2-chloroprocaine is the fastest, and tetracaine is the slowest. 2. Amide LAs are primarily metabolized in the liver by microsomal mixed function oxidase enzymes. Amide LAs have different degrees of degradation. Prilocaine is the most rapidly metabolized; lidocaine and mepivacaine are intermediate; bupivacaine, ropivacaine, and etidocaine are the slowest drugs metabolized. 3. Patients with lower hepatic perfusion (hypotension, congestive heart failure) or liver dysfunction (advanced cirrhosis) are unable to degrade amide LAs at a normal speed. 4. Higher clearance of the ester LAs results in increase in their margin of safety compared to the amide LAs.

99

2. Water-soluble metabolites of LAs are easily excreted by the kidneys.

4.7 4.7.1

Excretion

1. Less than 5% of LAs administered are excreted by the kidneys because they are poorly water-soluble compounds.

Central Nervous System (CNS)

LAs cross the blood-brain barrier and cause CNS depression. At therapeutic levels, there are no significant CNS effects. Historically, lidocaine, mepivacaine, and procaine were used to control generalized epileptic seizures in lower doses.

4.7.2

Cardiovascular System

LAs decrease electrical excitability of the myocardium, conduction rate, and force of contraction. Procainamide is a class 1a and lidocaine class 1b anti-arrhythmic drug that are used in controlling ventricular arrhythmias. LAs have a vasodilator effect except cocaine that vasoconstricts blood vessels.

4.7.3

Respiratory System

At lower blood levels, LAs cause direct relaxation of bronchial smooth muscles. At toxic blood levels, they may lead to respiratory depression and arrest resulting from generalized CNS depression.

4.8

Indications (Clinical Uses)

Table 4.5 shows the clinical uses of common LAs.

4.9 4.6.4

Pharmacodynamics

Contraindications

1. Allergy to LAs. 2. Presence of acute inflammation or suppurative infection at the site of insertion of the needle. 3. Presence of congenital methemoglobinemia. 4. Presence of atypical plasma cholinesterase.

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H. El Beheiry

Table 4.5 Clinical uses of local anesthetics Clinical Local anesthetic uses Concentration Low potency—short duration Cocaine Topical 4–10% Benzocaine Topical Up to 20% Procaine Infiltration 0.25–1% Spinal 10% 2-Chloroprocaine Infiltration 1% PNB 2% Epidural 2–3% Intermediate potency and duration Lignocaine, Topical 4% lidocaine Infiltration 1–2% IVRA 0.5% PNB 1–2% Epidural 1.5–2% Prilocaine Topical 25 mg/ml cream 0.5–1% Infiltration 0.25–0.5% IVRA 1.5–2% PNB 2–3% Epidural Mepivacaine Infiltration 0.5–1% PNB 1–1.5% Epidural 1.5–2% Spinal 2–4% High potency—longer duration Infiltration 0.25% Bupivacaine and PNB 0.25–0.5% levobupivacaine Epidural 0.1–0.5% Spinal 0.5–0.75% Ropivacaine Infiltration 0.2–0.5% PNB 0.5–1% Epidural 0.5–1% Etidocaine Infiltration 0.5% PNB 0.5–1% Epidural 1–1.5% Tetracaine Topical 2% Spinal 0.5%

Notes Limited use, addictive Limited use Slow onset, metabolized by plasma cholinesterases, limited systemic toxicity Fast onset, limited systemic toxicity, preservative-free preparations are safer for use

Versatile agent, can be used intravenously for suppression of ventricular arrhythmias, and management of acute and chronic neuropathic pain

Most rapidly metabolized amide local anesthetic, higher doses lead to systemic methemoglobinemia

Can substitute lidocaine for spinal anesthesia, in higher maternal doses accumulates in the fetal circulation

Differential sensory without motor block can be achieved with 0.1% solutions

Has greater degree of motor-sensory selectivity, less neurotoxic and cardiotoxic More potent for motor compared to sensory blockade

Commonly used in ophthalmic topical solutions

PNB indicates peripheral nerve block, IVRA indicates intravenous regional anesthesia

5. Contraindications for LA solutions containing epinephrine include unstable angina, refractory arrhythmias, uncontrolled or untreated heart failure, untreated or uncontrolled severe hypertension, recent myocardial infarction or coronary bypass surgery (20% above ideal body weight (IBW), in which case the dosing weight can be estimated by the following equation: IBW + 0.4 (TBW–IBW). 3. Infective endocarditis treatment, Enterococcus (native or prosthetic valve) (off-label): 3 mg/kg/day IV/IM divided every 8 h for 4–6 weeks in combination with a beta-lactam and for 6 weeks when administered with vancomycin Organism sensitivity testing should determine the choice of concomitant antibiotic and treatment duration 4. S. aureus (prosthetic valve; methicillin susceptible or resistant) (off-label): 3 mg/kg/day IV/IM divided every 8–12 h for 3–5 days for native valve infections or for 2 weeks for prosthetic valve infections in combination with other antibiotics Organism sensitivity testing should determine the choice of concomitant antibiotic 5. Viridans group streptococcus and S. bovis (native or prosthetic valve) (off-label): 3 mg/kg/day IV/IM daily (preferred) or divided every 8 h for 2 weeks for native or prosthetic valve infections or for 6 weeks for

6. 7.

8.

9.

Antibiotics

prosthetic valve infections with relatively or fully resistant strains in combination with other antibiotics Organism sensitivity testing and source of infection should determine the choice of concomitant antibiotic Cystic fibrosis (off-label): 7.5–10.5 mg/kg/day IV/IM divided every 8 h Pelvic inflammatory disease (off-label): Loading dose: 2 mg/kg IV or IM Maintenance dose: 1.5 mg/kg IV/IM every 8 h plus clindamycin IV or 3–5 mg/kg IV daily May initiate transition from parenteral to oral therapy of either oral doxycycline or oral clindamycin within 24–48 h of clinical improvement for total treatment duration of 14 days Plague (Yersinia pestis) treatment; off-label use: 5 mg/kg IV/IM daily for 10 days or 2 mg/kg IV/IM loading dose; then 1.7 mg/kg/ dose IV/IM every 8 h for 10–14 days or until 2 days after patient is afebrile; doxycycline, ciprofloxacin, or chloramphenicol could be used as third-line alternatives Mycobacterium infection, gentamicin liposome injection: For disseminated Mycobacterium avium-intracellulare infection. Gentamicin may be administered IV/IM: Infuse over 30–120 min when administering IV Dosing regimens are numerous and are adjusted based on creatinine clearance and changes in volume of distribution, and on the body space where distribution of the agent will occur. Monitor peak (4–12 mg/L) and trough (1–2 mg/L).

Dose is based on actual body weight unless >20% above ideal body weight; then dosage requirement may best be estimated using a dosing weight of IBW + 0.4 (TBW–IBW). Pediatrics 1. Susceptible infections: Infants: 2.5 mg/kg/dose IV/IM every 8 h Children and adolescents: 2–2.5 mg/kg/dose IV/IM every 8 h

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Anti-30S Ribosomal Subunit: Aminoglycosides

28 days: 3 mg/kg/day IV/IM 30–36 weeks’ gestation: 0–14 days: 3 mg/kg/day IV/IM >14 days: 5 mg/kg/day IV/IM divided every 12 h >36 weeks’ gestation: 0–7 days: 5 mg/kg/day IV/IM divided every 12 h >7 days: 7.5 mg/kg/day IV/IM divided every 8h

10.20.1.9 Drug Interactions 1. Acyclovir, aminoglycosides, amphotericin B, capreomycin, cephalosporins, cisplatin, methoxyflurane, polymyxin B, vancomycin: May increase the risk of nephrotoxicity, ototoxicity, or neurotoxicity. Use together cautiously. 2. Bumetanide, ethacrynic acid, furosemide, mannitol, urea: Increase the risk of ototoxicity. Use cautiously. 3. Dimenhydrinate, other antiemetic and antivertigo drugs: May mask gentamicininduced ototoxicity. Use cautiously. 4. General anesthetics, neuromuscular blockers such as succinylcholine and tubocurarine: Increase neuromuscular blockade. Monitor patient closely. 5. Indomethacin (I.V.): Increases peak and trough gentamicin levels. Monitor serum gentamicin levels closely. 6. Penicillin: Causes synergistic bactericidal effect against P. aeruginosa; Escherichia coli; Klebsiella, Citrobacter, Enterobacter, and Serratia species; and Proteus mirabilis; however, drugs are physically and chemically incompatible and are inactivated when mixed or given together. Do not mix drugs.

10.20.1.10 Advantages 1. Rapid bactericidal activity with control of gram-negative infections, such as Pseudomonas aeruginosa

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2. Low rates of resistance among gram-negative pathogens 3. Long period of effect, which allows once-daily therapy and reduces the risk of toxicity 4. Low rates of hypersensitivity reactions 5. Low cost

10.20.1.11 Precautions 1. Use with caution among neonates, infants, elderly patients, and patients with renal disorders, neuromuscular disorders, or hearing dysfunction. 2. Patients treated with aminoglycosides should receive clinical observation due to the high risk of toxicity associated. 3. Risk of ototoxicity, which presents with tinnitus or vertigo—may indicate vestibular injury. Advanced age and dehydration increase the risk for ototoxicity. 4. Risk of nephrotoxicity. 5. Diuretics may enhance aminoglycoside toxicity. 6. Use caution in patients with hypocalcemia, hypomagnesemia, or hypokalemia.

10.20.1.12 Toxicity 1. Mild and reversible nephrotoxicity in 5–25% of patients. Gentamicin accumulates in proximal renal tubular cells and causes cell damage. 2. May cause irreversible ototoxicity, which seems to be correlated to cumulative lifetime exposure. 3. Further toxicity may lead to retrograde degeneration of the eighth cranial (vestibulocochlear) nerve. Symptoms include vertigo, nausea, vomiting, dizziness, and loss of balance.

10.20.1.13 Monitoring 1. Check for kidney and renal functions for all patients before starting gentamicin. 2. Premature infants and neonates need extensive monitoring because of their renal immaturity.

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The dose should be adjusted if renal function is reduced. 3. Patients need to be counseled to report any adverse effects, since they are mainly dose related. Dose should be adjusted accordingly in order to prevent ototoxicity and nephrotoxicity. 4. Fluid balance monitoring and dehydration should be corrected before starting treatment. Blood serum levels should be measured frequently, especially in patients with renal impairment and the elderly.

Suggested Reading Bidzseranova A, Toth G, Telegdy G (1991) The effects of receptor blockers on atrial natriuretic peptide-induced action on passive avoidance behavior in rats. Pharmacol Biochem Behav 40(2):237–239 Dally MB, Kurrle S, Breslin AB (1978) Ventilatory effects of aerosol gentamicin. Thorax 33 (1):54–56 Fuchs A, Zimmermann L, Bickle Graz M, Cherpillod J, Tolsa J-F, Buclin T, Giannoni E (2016) Gentamicin exposure and Sensorineural hearing loss in preterm infants. PLoS One 11(7):e0158806. https://doi.org/10.1371/jour nal.pone.0158806 Gentamycin (1979) JPMA. J Pak Med Assoc 29 (4):68–69 Hodiamont CJ, Juffermans NP, Bouman CSC, de Jong MD, Mathôt RAA, van Hest RM (2017) Determinants of gentamicin concentrations in critically ill patients: a population pharmaco-

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kinetic analysis. Int J Antimicrob Agents 49 (2):204–211. https://doi.org/10.1016/j. ijantimicag.2016.10.022 Kopecky WJ, Parrino PA (1979) Digital readout of feedback control temperature for use in local current field hyperthermia. Med Phys 6 (3):219–220. https://doi.org/10.1118/1. 594566 Selimoglu E (2007) Aminoglycoside-induced ototoxicity. Curr Pharm Des 13(1):119–126 Vandewalle A, Farman N, Morin JP, Fillastre JP, Hatt PY, Bonvalet JP (1981) Gentamicin incorporation along the nephron: autoradiographic study on isolated tubules. Kidney Int 19(4):529–539 Wynn RL (1985) Gentamycin for prophylaxis of bacterial endocarditis: a review for the dentist. Oral Surg Oral Med Oral Pathol 60 (2):159–165 Windholz M, Brown HD (1978) “The Merck index”: the merits of using computers in publishing. J Chem Inf Comput Sci 18 (3):129–133

10.20.2 Neomycin Chemical names: A component of neomycin that is produced by Streptomyces fradiae. Hydrolysis yields neamine and neobiosamine B.

10.20.2.1 Chemical Properties Structure:

10.20

Anti-30S Ribosomal Subunit: Aminoglycosides

Source: PubChem URL: https://pubchem.ncbi.nlm.nih.gov Molecular formula: C23H46N6O13 IUPAC name: (2R,3S,4R,5R,6R)-5-amino-2(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-amino6-(aminomethyl)-4,5-dihydroxyoxan-2-yl]oxy-3hydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-3hydroxycyclohexyl]oxyoxane-3,4-diol Molecular weight: 614.65 g/mol Solubility: Soluble in water, methanol, and acidified alcohols. Practically insoluble in common organic solvents. Physical description: Liquid Melting point: 6 mg/mL (as sulfate form) Vapor pressure: 1.60  1028 mmHg at 25
C (est)

10.20.2.2 Mechanism of Action 1. Binds to the 26S rRNA of bacteria, interfering with protein synthesis, and disrupting the integrity of bacterial cell membrane. 2. N-acetylation, adenylylation, or O-phosphorylation deactivates aminoglycosides. 3. The drug changes the outer membrane permeability of bacterial cell wall, decreasing the membrane transport, active efflux, and drug trapping. 4. The mutation and methylation of the aminoglycoside-binding site alter the 30S ribosomal subunit.

10.20.2.3 Pharmacokinetics Absorption 1. Poorly absorbed from the GI tract (approximately 3%). 2. Significant amounts may be absorbed through ulcerated or denuded mucosa or if inflammation is present.

Distribution 1. After oral administration, low concentrations of neomycin were found in intestinal wall and muscles.

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2. The amount of the drug absorbed and transferred to tissues is cumulative with the repeated doses, until a steady state is achieved. 3. Progressive accumulation also occurs in the inner ear and the release of tissue bound occurs slowly over a period of weeks after drug discontinuation. 4. Peak plasma concentrations of 2.5–6.1 μg/mL 1–4 h after the dose in most patients.

Metabolism 1. After parenteral administration, neomycin undergoes negligible biotransformation.

Excretion 1. The small fraction that is absorbed is distributed in the tissues and is excreted by the kidney. 2. The unabsorbed fraction is eliminated unchanged in the feces.

10.20.2.4 Pharmacodynamics 1. Refer to Pharmacodynamics section under Gentamicin.

10.20.2.5 Indications (Clinical Uses) 1. For the treatment of bacterial blepharitis, bacterial conjunctivitis, corneal injuries, corneal ulcers, and meibomianitis. 2. Also used for prophylaxis of ocular infections following foreign body removal. Contraindications: Contraindicated in cases of hypersensitivity, ulcerative bowel disease, and intestinal obstruction.

10.20.2.6 Side Effects Aminoglycosides all have serious toxicities which often limit their applicability and the dose and duration of therapy. The most common serious adverse effects of aminoglycosides are ototoxicity, neuropathy, and nephrotoxicity.

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1. Ear, eyes, nose, throat: Ototoxicity with oral use. 2. Gastrointestinal: Nausea, vomiting, diarrhea, malabsorption syndrome, and Clostridium difficile-related colitis with oral use. 3. Genitourinary: Nephrotoxicity with oral use. 4. Musculoskeletal: Neuromuscular blockade with topical use. 5. Skin: Rash, contact dermatitis, and urticaria with topical use.

10.20.2.7 Availability 1. Available in oral and topical formulations 2. Tablet (500 mg) and oral solution (25 mg/mL) 3. Cream (0.5%)/ointment (0.5%)

10.20.2.8 Dosages Adults 1. Pre-op intestinal antisepsis: 1 g by mouth at 19, 18, and 9 h pre-op OR 1 g by mouth every hour for 4 doses, THEN 1 g every 4 h to complete 24 h of dosing OR 88 mg/kg/day divided by mouth every 4 h for 2–3 days pre-op Maximum: Up to 12 g 24–48 h prior to surgery 2. Hepatic encephalopathy: Acute: 4–12 g/day by mouth divided every 6 h for 5–6 days OR 3–6 g/day for 1–2 weeks Chronic: Up to 4 g/day by mouth 3. Diarrhea caused by enteropathogenic E. coli: 3 g/day by mouth divided every 6 h 4. External ear canal infection: 2–5 drops into ear canal three or four times daily for 7–10 days 5. Topical bacterial infections, burns, wounds, skin grafts, following surgical procedure, lesions, pruritus, trophic ulcerations, and edema: Rub in small amount gently two or three times daily, or as directed

10

Antibiotics

Pediatrics 1. Neonates Diarrhea in preterm and term babies: 50 mg/ kg/day PO divided every 6 h 2. Children External ear infection: 2–5 drops into early canal three or four times daily for 7–10 days Hepatic encephalopathy: 50–100 mg/kg/day by mouth divided every 8 h for 5–6 days, no more than 12 g/24 h Bowel prep: 90 mg/kg/day by mouth divided every 4 h for 2–3 days Diarrhea caused by enteropathogenic E. coli: 50 mg/kg/day by mouth divided every 6 h for 2–3 days Topical bacterial infections, burns, wounds, skin grafts, following surgical procedure, lesions, pruritus, trophic ulcerations, and edema: Rub in small amount gently two or three times daily, or as directed

10.20.2.9 Drug Interactions 1. Medications that affect kidneys or hearing may increase the risk for kidney damage and hearing loss when taken concomitant with neomycin. 2. Neomycin may interfere with hormonal birth control, particularly those with estrogen, resulting in pregnancy. 10.20.2.10 Advantages 1. The drug can be taken with or without food, and the tablet may be cut or crushed. 2. The drug is considered safe and effective as a topical agent, and helps prevent infections in minor skin trauma.

10.20.2.11 Precautions 1. The drug may contain ingredients that can cause allergic reactions, and patients should

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Anti-30S Ribosomal Subunit: Aminoglycosides

be investigated for allergies to the drug or other antibiotics. 2. Investigate hearing problems, intestinal problems, kidney function, myasthenia gravis, and Parkinson’s disease before using the medication. 3. Neomycin can cause live bacterial vaccines to not work well. Do not have immunizations while using this medication. 4. This medication should not be used during pregnancy, and breastfeeding women should use with caution.

10.20.2.12 Toxicity 1. Overdose is unlikely to occur with oral neomycin. 2. Prolonged treatment could result in systemic drug levels capable of causing neurotoxicity, ototoxicity, and/or nephrotoxicity. 3. Nephrotoxicity occurs due to drug accumulation in renal proximal tubular cells. 4. Tubular cells regenerate and the nephrotoxicity is usually mild reversible. 5. Ototoxicity occurs due to drug accumulation in the endolymph and perilymph of the inner ear, causing low- and high-frequency hearing loss. 6. Further toxicity can cause degeneration of auditory nerve, and vestibular toxicity presents with vertigo, nausea, vomiting, dizziness, and loss of balance.

10.20.2.13 Monitoring 1. Measure BUN/Cr at baseline, and then periodically during treatment. 2. Measure serum drug levels with chronic treatment and monitor for hepatic encephalopathy. 3. Urinalysis. 4. Audiometry monitoring in high-risk patients, planned prolonged treatment, if excessive drug levels are found, or if patient presents with signs and symptoms of hearing impairment.

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Suggested Reading American Society of Health-System Pharmacists | National Eye Institute. (n.d.). https://nei.nih. gov/content/american-society-health-systempharmacists. Accessed 30 Dec 2018 Bonomo RA, Van Zile PS, Li Q, Shermock KM, McCormick WG, Kohut B (2007) Topical triple-antibiotic ointment as a novel therapeutic choice in wound management and infection prevention: a practical perspective. Expert Rev Anti-Infect Ther 5(5):773–782. https://doi.org/ 10.1586/14787210.5.5.773 DailyMed - NEOMYCIN SULFATE- neomycin sulfate tablet. (n.d.). https://dailymed.nlm.nih. gov/dailymed/drugInfo.cfm?setid¼a35a558c7d96-43fb-917b-475189772edd. Accessed 31 Dec 2018 Selimoglu E (2007) Aminoglycoside-induced ototoxicity. Curr Pharm Des 13(1):119–126 Shakil S, Khan R, Zarrilli R, Khan AU (2008) Aminoglycosides versus bacteria--a description of the action, resistance mechanism, and nosocomial battleground. J Biomed Sci 15 (1):5–14. https://doi.org/10.1007/s11373-0079194-y Vandewalle A, Farman N, Morin JP, Fillastre JP, Hatt PY, Bonvalet JP (1981) Gentamicin incorporation along the nephron: autoradiographic study on isolated tubules. Kidney Int 19(4):529–539 Windholz M, Brown HD (1978) “The Merck index”: the merits of using computers in publishing. J Chem Inf Comput Sci 18 (3):129–133

10.20.3 Amikacin Chemical names: Organic compound known as 4,6-disubstituted 2-deoxystreptamine. These are 2-deoxystreptamine aminoglycosides that are glycosidically linked to a pyranose of a furanose unit at the C4 and C6 positions.

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Antibiotics

10.20.3.1 Chemical Properties Structure:

Source: PubChem URL: https://pubchem.ncbi.nlm.nih.gov Molecular formula: C22H43N5O13 IUPAC name: (2S)-4-amino-N[(1R,2S,3S,4R,5S)-5-amino-2-[(2S,3R,4S,5S,6R)4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan2-yl]oxy-4-[(2R,3R,4S,5S,6R)-6-(aminomethyl)-3, 4,5-trihydroxyoxan-2-yl]oxy-3-hydroxycyclohexyl]2-hydroxybutanamide Molecular weight: 585.608 g/mol Color: White crystalline powder from methanol-isopropanol Solubility: Soluble in water Physical description: Solid Melting point: 203–204
C Valor pressure: 5.79  1028 mmHg at 25
C

10.20.3.2 Mechanism of Action 1. Binds to bacterial 30S ribosomal subunits and interferes with mRNA binding and tRNA acceptor sites, interfering with bacterial growth. 2. This leads to disruption of normal protein synthesis and production of nonfunctional or toxic peptides.

10.20.3.3 Pharmacokinetics Absorption 1. Rapidly absorbed after intramuscular administration. Rapid absorption occurs from the peritoneum and pleura. 2. Poor oral and topical absorption. 3. Poorly absorbed from bladder irrigations and intrathecal administration. 4. Peak plasma time for intramuscular (IM) dose is 45–120 min.

Distribution 1. Following IM administration of a single dose of amikacin of 7.5 mg/kg in adults with normal renal function, peak plasma amikacin concentrations of 17–25 μg/mL are attained within 45 min to 2 h. 2. Following IV infusion of the same dose given over 1 h peak plasma concentrations of the drug average 38 μg/mL immediately following the infusion, 5.5 μg/mL at 4 h, and 1.3 μg/mL at 8 h. 3. Amikacin has been found in bone, heart, gallbladder, and lung tissue. Amikacin is also

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Anti-30S Ribosomal Subunit: Aminoglycosides

431

distributed into bile, sputum, bronchial secretions, and interstitial, pleural, and synovial fluids.

2. Use cautiously in patients with impaired renal function or neuromuscular disorders, in neonates and infants, and in elderly patients.

Metabolism 1. Not metabolized and excreted unchanged in the urine by glomerular filtration

10.20.3.7 Side Effects Aminoglycosides all have serious toxicities which often limit their applicability and the dose and duration of therapy. The most common serious adverse effects of aminoglycosides are ototoxicity, neuropathy, and nephrotoxicity.

Excretion 1. 94–98% of the drug is renally excreted in adults with normal renal function. 2. Excreted primarily by glomerular filtration; small amounts may be excreted in bile and breast milk. 3. Half-life: 2–3 h in patients with normal renal function. 4. In patients with severe renal damage, half-life may extend to 30–86 h.

10.20.3.4 Pharmacodynamics Renal System: Reabsorption of a small amount of the drug by the proximal tubule results in accumulation in the renal cortex, which may be responsible for nephrotoxicity. Refer to Pharmacodynamics section under Gentamicin for additional information. 10.20.3.5 Indications (Clinical Uses) 1. Short-term treatment of serious susceptible infections, including septicemia, respiratory tract, bones and joints, CNS (e.g., meningitis), skin, and intra-abdominal (e.g., peritonitis) infections. 2. Burns and postoperative infections, complicated and recurrent UTIs, or uncomplicated UTIs not susceptible to other antibiotics are also treated with amikacin.

10.20.3.6 Contraindications 1. Contraindicated in patients hypersensitive to drug or other aminoglycosides.

1. Central nervous system: Neuromuscular blockade 2. Ear, eyes, nose, throat: Ototoxicity 3. Genitourinary: Nephrotoxicity, azotemia 4. Musculoskeletal: Arthralgia, acute muscular paralysis 5. Effects on lab test results: May increase BUN, creatinine, nonprotein nitrogen, and nitrogenous compound (urea) levels 6. Rare: Rash, drug fever, headache, tremor, GI upset, paresthesia, eosinophilia, anemia, hypotension, hypomagnesemia

10.20.3.8 Availability 1. Amikacin is administered intravenously (IV), intramuscularly (IM), and via nebulized inhalation. 2. Injectable solution: 50 mg/mL and 250 mg/ mL.

10.20.3.9 Dosages Adults 1. General dosing: 15 mg/kg/day IV/IM divided every 8–12 h 2. Urinary tract infection: 250 mg IV/IM every 12 h Extended interval dosing (every 24 h): First dose: 15 mg/kg IV based on lean body weight Subsequent doses: consult pharmacist 3. Hospital-acquired pneumonia: 20 mg/kg/day IV; may administer with antipseudomonal beta-lactam or carbapenem

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Pediatrics 1. General dosing: 15–22.5 mg/kg/day IV/IM divided every 8 h 2. Neonates: 7 days old: 29 weeks gestational age: 18 mg/kg IV/IM every 48 h 30–33 weeks gestational age: 18 mg/kg IV/IM every 36 h 34 weeks gestational age: 15 mg/kg IV/IM every 24 h >7 days old: 30–33 weeks gestational age: 15 mg/kg IV/IM every 24 h 34 weeks gestational age: 15 mg/kg IV/IM every 12–18 h 8–28 days old and 28 days old and 24 h after lesion onset). Suppressive therapy (immunocompetent patients): 1 g daily. Suppressive therapy (immunocompetent patients with 9 recurrences annually): 500 mg daily; transmission reduction for source partner, 500 mg daily. Suppressive therapy (HIV-infected patients): 500 mg every 12 h.

Pediatric 1. Chickenpox: 2 years: 20 mg/kg every 8 h for 5 days; not to exceed 1 g every 8 h 2. Herpes labialis (cold sores):