Handbook of Clinical Anesthesia

Chapter 22

Drug Interactions

Modern drug regimens often involve use of multiple drugs in combination, which introduces the risk of drug interactions (Rosow C, Levine WC: Drug interactions. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 549–566).

  1. Problems Created by Drug–Drug Interactions
  2. The probability of a drug–drug interaction increases with the number of drugs administered.
  3. Drug interactions are uncommon even though many patients take multiple drugs (antihypertensives, antidepressants, gastrointestinal drugs) before surgery and then receive five to 10 drugs during anesthesia. (Many reactions are not significant. Drugs have a large safety margin, and many interactions are not recognized.)
  4. Why Combine Drugs?The goal of combining drugs is to decrease toxicity while maintaining efficacy (hypertension, chemotherapy, prophylaxis against grand mal seizures).
  5. Pharmaceutical Interactions
  6. A chemical or physical interaction may occur between drugs before they are administered to form a precipitate (e.g., thiopental or ketamine injected with succinylcholine; epinephrine injected with sodium bicarbonate as during cardiopulmonary resuscitation).
  7. A chemical or physical interaction may occur between drugs before they are administered to form a toxic compound (e.g., desflurane or isoflurane in contact with dry soda lime forms carbon monoxide; nitric oxide in contact with oxygen forms nitrogen dioxide).

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III. Pharmacokinetic Interactions

  1. A pharmacokinetic interaction occurs when one drug alters the absorption, metabolism, or elimination of another drug.
  2. Absorptionmay be altered because of direct chemical or physical interaction between drugs in the body (e.g., orally administered tetracycline is inactivated by chelation with antacids; opioids slow gastric emptying) or changes in regional blood flow (e.g., local administration of epinephrine slows absorption of local anesthetics; congestive heart failure or shock may alter the onset and intensity of drug effect by decreasing tissue perfusion).
  3. Distribution-related drug interactions occur when distribution of a second drug is altered by hemodynamics (drug-induced changes in cardiac output), drug ionization (“ion trapping”), or binding to plasma and tissue proteins (α1-acid glycoprotein concentrations increase postoperatively; after myocardial infarction or trauma, albumin concentrations may be decreased by hepatic cirrhosis).
  4. A drug that is highly bound to plasma protein effectively exists in a depot (similar to a drug given by intramuscular administration).
  5. Altered protein binding or displacement from protein binding sites has been dogma for many years, but the true clinical relevance of this type of interaction is not clear.
  6. Metabolism
  7. Drugs administered to inhibit acetylcholinesterase (as for reversal on nondepolarizing neuromuscular blocking drugs) also inhibit pseudocholinesterase and prolong the duration of action of succinylcholine.
  8. Monoamine Oxidase Interactions
  9. Inhibition of monoamine oxidase (MAO), which is present in tissues throughout the body, by MAO inhibitors may produce interactions with drugs that affect sympathetic neurotransmission (e.g., ephedrine produces an exaggerated response as more presynaptic transmitter is available for release; “wine and cheese” interaction caused by the tyramine content of foods) or interactions that involve central nervous system depressants (e.g., hyperpyrexia and

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hypertension that may progress to seizures and coma in patients receiving meperidine).

  1. Current clinical opinion favors continuing MAO inhibitor therapy up to the time of surgery.
  2. Patients taking MAO inhibitors have the potential for perioperative hemodynamic instability, yet beta-blockers, direct vasodilators, and direct-acting vasopressors appear to be safe and effective treatments in most circumstances.
  3. Hepatic Biotransformation
  4. Many anesthetic drugs undergo oxidative metabolism by one of the isoforms of cytochrome P450 found in liver microsomes.
  5. P450 isoforms have low substrate specificity such that drugs of diverse structures (general anesthetics, opioids, barbiturates, benzodiazepines) can be biotransformed by a single group of enzymes.
  6. Inhibitors or inducers or these enzymes may also affect the clearance of broad groups of drugs (Table 22-1).

Table 22-1 Classification of Pharmacodynamic Drug Interactions

Additive Interactions (most likely to occur when drugs with identical mechanisms of action are combined)
Administration of two aminosteroid nondepolarizing muscle relaxants
Administration of nitrous oxide with a volatile anesthetic
Antagonistic Drug Interactions
Deliberate
   Administration of neostigmine, naloxone, flumazenil
Unintended
   Succinylcholine and a nondepolarizing muscle relaxant
   Epidural opioid administered after establishing a block with chloroprocaine
Synergistic Drug Interactions (most likely to occur when drugs of different classes or mechanisms are administered to produce the same effect)
Potentiation of opioids by NSAIDs
Potentiation of nondepolarizing muscle relaxants by volatile anesthetics
Potentiation between hypnotics that have related mechanisms of action (act on γ-aminobutyric acid, a chloride ionophore)

NSAID = nonsteroidal antiinflammatory drug.

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  2. Removal of a drug from the blood by hepatic biotransformation (hepatic clearance) is dependent on hepatic blood flow and intrinsic clearance (the maximal ability of the liver to metabolize that drug or extraction ratio).
  3. For drugs with a high extraction ratio (lidocaine, morphine, propranolol), hepatic blood flow is the rate-limiting factor in overall hepatic clearance. Decreases in hepatic blood flow (anesthesia, congestive heart failure) result in increased plasma concentrations.
  4. For drugs with a low extraction ratio (diazepam, alfentanil), hepatic enzyme activity is the rate-limiting factor.
  5. The most common reason for increased intrinsic clearance is enzyme induction of cytochrome P450 enzymes (microsomal or CYP enzymes). The most important subfamily appears to be CYP3A, which is found in greatest abundance in human liver and is responsible for the metabolism of a large number of drugs.
  6. Drugs may also inhibit the hepatic biotransformation of other drugs by competing for the same P450 enzymes (e.g., protease inhibitors may inhibit the metabolism of midazolam and fentanyl by inhibiting CYP3A4).
  7. Drug eliminationmay result in pharmacokinetic drug interactions via alterations in renal or pulmonary clearance.
  8. Pharmacodynamic Interactions
  9. A pharmacodynamic interaction occurs when one drug alters the sensitivity of a target receptor or tissue to the effects of a second drug. Pharmacokinetic interaction

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is a change in the amount of active drug reaching receptor sites.

Table 22-2 Drugs That Induce or Inhibit Hepatic Drug Metabolism

Inhibitors

Inducers

Phenobarbital

Cimetidine

Phenytoin

Ketoconazole

Rifampicin

Erythromycin

Carbamazepine

Disulfiram

Ethanol

Ritonavir

  1. The dose–response curve or concentration–response curve for one drug is shifted by another drug (Table 22-2).
  2. Pharmacodynamic Interactions Affecting Hemodynamics
  3. Prior recommendations that cardiovascular stimulant or depressant drugs should be discontinued before

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surgery because they interfere with protective responses to the trauma of anesthesia and surgery are no longer advocated.

Table 22-3 Effects of Antihypertensive Drugs During Anesthesia

Class

Drugs

Effects

α-Blockers

Phenoxybenzamine
Phentolamine
Prazosin

Hypotension or vasodilation
Reflex tachycardia

Beta-blockers

Propranolol
Metoprolol
Atenolol

Hypotension
Decreased myocardial contractility
Bradycardia, heart block

Mixed α/beta blocker

Labetalol

Hypotension or vasodilation, bradycardia, heart block

Calcium channel blockers

Verapamil
Diltiazem
Nifedipine
Nicardipine

Hypotension or vasodilation
Decreased myocardial contractility
Bradycardia
Heart block

Direct vasodilation

Nitroglycerin
Isosorbide
Hydralazine

Hypotension or vasodilators
Reflex tachycardia

Angiotensin-converting enzyme inhibitors

Captopril
Enalapril
Lisinopril

Hypotension or vasodilation
Hyperkalemia

Angiotensin II

Losartan
Valsartan
Thiazides
Furosemidey
Bumetanide

Hypotension or blockers
Hyperkalemia
Hypovolemia
Hypokalemia
Possible vasodilation

Table 22-4 Drug Interactions Between Combinations of Central Nervous System Depressants

Opioid–Hypnotic
Fentanyl decreases dose requirements for thiopental (more rapid awakening after short surgical procedures).
Opioids potentiate propofol.
Infusions of remifentanil or alfentanil decrease the needed infusion rate of propofol.
Opioid–Benzodiazepine
Alfentanil (weak hypnotic but highly selective depressant of central nervous system [sedation]) decreases the hypnotic (sleep) dose of midazolam.
Benzodiazepine–Hypnotic
Midazolam potentates the hypnotic effects of propofol.
Volatile Anesthetic–Opioid
Opioids produce dose-dependent decreases in MAC.
α2-Agonist Interactions
Clonidine and dexmedetomidine potentiate opioid analgesia and decrease MAC (may reflect depression of the locus ceruleus, which is the main adrenergic nucleus in the brain as well as being important for sleep, memory, and analgesia).

MAC = minimum alveolar concentration.

  1. Patients with hypertension who remain well controlled are less likely to have wide swings in systemic blood pressure during surgery.
  2. Abrupt discontinuation of vasoactive medications may actually increase cardiovascular instability (rebound hypertension, cardiac dysrhythmias).
  3. The majority of cardiovascular drug interactions are extensions of the known pharmacology of the drugs (Table 22-3).
  4. There is currently no consensus on the preoperative management of patients taking angiotensin-converting enzyme inhibitors.
  5. Continuation through the perioperative period may be associated with an increased incidence of hypotension during induction of general anesthesia.

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Table 22-5 Evidence for Herbal Toxicity

Herb

Common Use

Claimed Toxicity

Supporting Evidence

Ephedra

Weight loss
Antitussive
Bacteriostatic

Cardiac dysrhythmias
Enhanced sympathomimetic effects
Stroke
Hypertension

Oral ephedra is known to cause adverse CNS and cardiac events

Echinacea

Common cold prevention
Urinary tract infections
Bronchitis

Hepatotoxicity
Decrease corticosteroid effect

No evidence
Laboratory evidence of macrophage activation

Garlic

Lipid lowering
Hypertension
Antiplatelet
Antioxidant

Potentiates warfarin

No evidence of interaction with warfarin
Decreased platelet aggregation in vitro

Ginger

Nausea
Antispasmodic

Inhibits thromboxane synthetase

In vitro evidence of thromboxane synthetase inhibition

Ginkgo

Circulatory stimulant

Inhibits platelet activating factor

Reports of increased bleeding

Goldenseal

Diuretic
Antiinflammatory
Laxative
Hemostatic

Oxytocic
Paralysis in overdose
Edema
Hypertension

No evidence

Kava

Anxiolytic

Hepatotoxicity
Potentiates barbiturates and benzodiazepines

Reports of hepatotoxicity
Clinical studies demonstrating sedation and anxiolysis

Licorice

Gastric or duodenal ulcer
Gastritis
Bronchitis

Hypokalemia
Hypertension
Edema

Hypokalemia with abuse

St John's Wort

Depression

Decreased digoxin level
Enzyme induction
Prolonged anesthesia

Supportive clinical data
Supportive clinical data
Reports of prolonged emergence

Valerian

Sedative
Anxiolytic

Potentiates barbiturates

Small clinical trial shows decreased sleep latency

Vitamin E

Anti-aging
Prevents stroke
Prevents pulmonary emboli
Prevents atherosclerosis
Promotes wound healing

Hypertension
Bleeding

No evidence
Decreased platelet aggregation in vitro

CNS = central nervous system.

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  2. Withholding these drugs for 24 hours may decrease hypotension but may also make blood pressure extremely labile during surgery.
  3. Chronic blockade of the angiotensin system reduces the vasoconstrictor response to norepinephrine. (This may explain why drug-induced hypotension is resistant to sympathetic drugs.)
  4. Patients with acute cocaine intoxicationmay present with hypertension, tachycardia, and myocardial ischemia (resembles pheochromocytoma). Administration of a beta-blocker alone may allow unopposed α-adrenergic stimulation and large increases in systemic vascular resistance.
  5. Pharmacodynamic Interactions Affecting Analgesia or Hypnosis

(Table 22-4)

VII. Herbal Preparations and Drug Interactions

(Table 22-5)

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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