Drug Interactions During Anesthesia

CLINICAL ANESTHESIA

0195-5616/99 $8.00 + .00

DRUG INTERACTIONS DURING ANESTHESIA General Principles Katrina A. Mealey, DVM, PhD, and Nora S. Matthews, DVM

Drug interactions result when the pharmacological effect of one drug is altered by the concurrent administration of another. Drug interactiQns may result in a diminution of drug activity (antagonistic), or an increase in drug activity or possible drug toxicity (either additive or synergistic). A drug interaction may be beneficial if it leads to improvement in therapy or adverse if it is harmful to the patient. The combination of opioids and hypnotics is illustrative of a beneficial synergistic interaction that is used in anesthesia on a daily basis. Unfortunately, many drug interactions are potentially harmful to patients. The frequency of clinically significant beneficial or adverse drug interactions in veterinary medicine is unknown, and determining whether or not a particular combination of drugs may cause an interaction in a given patient is difficult. Knowledge of common mechanisms of drug interactions allows the veterinarian to be aware of potential drug interactions so that the patient can be monitored or the therapeutical regimen altered accordingly. The most important drug interactions are those that involve drugs associated with severe toxicity and a low therapeutical index as is the case with most drugs used for anesthesia. Additionally, the potential for drug interactions increases exponentially with the number of drugs that a patient receives. 36 Because anesthesia generally involves administration of several different drugs, the anesthetized patient may be at greater ' From the Department of Veterinary Clinical Sciences, Washington State University, Pullman, Washington (KAM); and the Department of Small Animal Medicine and Surgery, Texas A&M University, College Station, Texas (NSM)

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 29 • NUMBER 3 • MAY 1999

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risk than other patients for experiencing adverse drug interactions. This article describes the potential adverse drug interactions that may occur with drugs used in anesthesia.

MECHANISMS OF DRUG INTERACTIONS

Drug interactions may be a result of pharmaceutical, pharmacokinetic, or pharmacodynamic effects. Pharmaceutical drug interactions result from direct chemical or physical reactions of drugs with each other or with materials in their containers. They are also referred to as chemically or physically incompatible drugs. Pharmacokinetic drug interactions occur when a drug alters the absorption, distribution, metabolism, or excretion of another drug. Pharmacodynamic drug interactions occur between drugs with similar or opposite pharmacological effects and frequently involve interactions at the same or a related receptor.

Pharmaceutical Interactions

Pharmaceutical drug interactions are generally the result of either pH incompatibilities of two drugs mixed in the same solution or physical inactivation of one drug by another. For example, an obvious incompatibility occurs in the form of a precipitate when the opioid meperidine (pH 3.5) is mixed with thiopental (pH 10.8). Alternatively, a physical inactivation is exemplified by the neutralization of aminoglycosides by penicillins if both are mixed in the same syringe or fluid bag. Although a visible change is not produced, a pharmacological alteration does occur. Drug interactions involving physical inactivation may also occur in vivo. For example, protamine (base) combines with heparin (acid) to form a stable salt, resulting in complete inactivation of heparin. Finally, drugs may interact with components of the container, intravenous tubing, or syringe. Diazepam interacts with plasticizers and may absorb onto the surface of intravenous tubing or syringes. Consequently, the patient receives a lower than expected drug dose, resulting in reduced clinical effects.

Pharmacokinetic Interactions

Pharmacokinetic drug interactions are a more frequent source of adverse reactions in the anesthetized patient. Pharmacokinetic drug interactions occur when one drug alters the absorption, distribution, metabolism, or elimination of another drug, resulting in either increased or decreased pharmacological effects. The net result is a change in free drug concentration in plasma.

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Absorption

Drug absorption refers to movement of drug from the site of administration to the systemic circulation. Most orally administered drugs are absorbed from the proximal small intestine, and their rate of absorption is influenced by gastric and intestinal motility. Opioid and anticholinergic drugs delay gastric emptying and, subsequently, absorption of most orally administered drugs. Delayed drug absorption may also occur with drugs administered by the subcutaneous or intramuscular route of administration. For example, administration of epinephrine in conjunction with a local anesthetic agent delays systemic drug absorption and consequently prolongs the duration of local anesthetic action. In this case, the drug interaction is beneficial. Inhalation anesthetic agents may also interact with each other to alter the rate of uptake at the alveolar level. This has been called the "second gas effect," and it occurs when a second gas (e.g., nitrous oxide) is added to an inspired mixture. The result is an accelerated rate of increase in alveolar concentration of the initial anesthetic gas (e.g., halothane). Distribution

Once a drug reaches the systemic circulation, it is distributed to various sites throughout the body. The pattern of drug distribution is dependent on several factors, including tissue blood flow, lipid solubility of the drug, and degree of protein binding. Both intravenous and inhalation anesthetic agents cause hemodynamic changes that affect tissue perfusion. Frequently, blood is shunted away from splanchnic vessels, compromising oxygen delivery to the renal parenchyma. This may increase the nephrotoxic potential of many drugs, including aminoglycosides and nonsteroidal anti-inflammatory agents (NSAIDs). Additionally, reduced hepatic and renal blood flow may delay the clearance of many drugs. With the exception of neuromuscular blocking agents and local anesthetics, the central nervous system (CNS) is the site of action for drugs used in anesthesia. In order to reach the CNS, these drugs must be highly lipid soluble. Because lipid-soluble drugs easily cross cell membranes, they distribute to many tissues in the body in addition to the CNS. Their presence in other tissues increases the risk of drug interactions at these locations. Within the blood, many drugs bind to plasma proteins such as albumin and alpha1-acid glycoprotein. Drug binding to proteins significantly affects distribution, because only free drug can cross cell membranes. Drugs that are highly (>80%) protein bound are more likely to be involved in adverse drug interactions, as displacement of even a small amount of drug from the protein (e.g., due to displacement by another drug) significantly increases the amount of unbound (free) drug. For example, displacement of only 1% of a drug that is 99% protein bound (e.g., NSAIDs) actually doubles the amount of free drug in the

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circulation. 6 Prolongation of barbiturate anesthesia occurs in rats after injection of radiographic contrast agents and results from displacement of protein-bound barbiturate by the contrast agent.29 Another example is prolongation of succinylcholine paralysis in the presence of certain local anesthetics. 51 Table 1 lists drugs used in anesthesia that are highly bound to plasma proteins. These drugs should be used cautiously if administered concurrently with other drugs that are characterized by a high degree of protein binding. Metabolism and Elimination

Renal excretion is the most important route of elimination for polar drugs and metabolites. The lipophilic nature of drugs used in anesthesia generally inhibits their ability to be directly eliminated from the body by renal excretion. Therefore, hepatic metabolism is an important means for eliminating anesthetic drugs. Because the cytochrome P450 enzyme family is the major catalyst of biotransformation reactions for many drugs, it is the site of a significant number of drug interactions. There are many instances when administration of one drug alters the metabolism of another either by inducing (increasing) or inhibiting (decreasing) hepatic P450 enzyme activity. Enzyme induction generally requires repeated exposure to the inducing agent (e.g., phenobarbital), whereas enzyme inhibition can occur following a single dose. Table 2 lists drugs that inhibit or induce cytochrome P450 enzymes. Another drug interaction mechanism involving biotransformation occurs when drugs that are metabolized by the same enzyme compete with each other for binding sites on the enzyme, thereby decreasing the rate of metabolism of the lower affinity drug. The result is increased plasma levels of parent drug and prolonged or exaggerated pharmacological effects. Propofol ~mpairs the intrinsic clearance of propranolol by this mechanism. 3 Enzyme inhibition is more frequently associated with clinically relevant adverse drug interactions than is enzyme induction. Because many of the drugs used in anesthesia are metabolized by hepatic cytochrome

Table 1. ANESTHETIC DRUGS THAT ARE HIGHLY PROTEIN BOUND Drug

Protein Bound (%)

Alfentanil Bupivicaine Acepromazine Diazepam Fentanyl Lorazepam Midazolam Sufentanyl Temazepam Propofol Thiopental

92 95 99 98 84 91 95 93

97

98 85

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633

Table 2. DRUGS THAT INDUCE OR INHIBIT CYTOCHROME P450 ENZYMES Inducers

Inhibitors

Barbiturates Primidone Rifampicin

Antimicrobials Fluoroquinolones Erythromycin Isoniazid Antifungals Ketoconazole ltraconazole Fluconazole (minor) Calcium channel blockers Diltiazem Verapamil Cimetidine Omeprazole Propofol

P450 enzymes,' inhibition of these enzymes may have important clinical consequences. Several case reports in the human literature describe increased and prolonged pharmacological effects, including respiratory depression and deep unconsciousness, when patients who were being treated with erythromycin (a cytochrome P450 inhibitor) received either midazolam22 or alfentanil. 4 Both of these drugs are metabolized by cytochrome P450 enzymes. Other drugs that have been shown to inhibit the metabolism of midazolam include cimetidine, the azole antifungal drugs, and calcium channel blockers. 37, 43 The proton pump inhibitor omeprazole decreases the clearance of diazepam in humans/ but no adverse effects have been reported. The fact that barbiturates are potent inducers of hepatic P450 enzymes is well known by veterinarians. Because enzyme induction generally requires multiple exposures to the inducing agent, administration of barbiturates during a single anesthetic procedure is unlikely to produce significant drug interactions. If a patient is receiving chronic phenobarbital or primidone therapy for epilepsy, however, enzyme induction probably has occurred, and increased hepatic clearance of some drugs, including benzodiazepines and opioids, should be expected. Another adverse consequence of enzyme induction involves the metabolism of fluorinated volatile anesthetics. Biotransformation of these drugs may result in the formation of hepatotoxic or nephrotoxic metabolites. Patients receiving drugs that induce cytochrome P450 enzymes are at increased risk for developing halothane-induced hepatic toxicity. 18, 35 Human patients receiving isoniazid (a P450 inducer) metabolize enflurane and isoflurane in such a way as to liberate potentially nephrotoxic free fluoride ions. 32 Although the kidney is considered to be the most important organ for elimination of drugs and metabolites, no clinically important anesthetic drug interactions involving renal excretion have been reported. The lung is an important excretory organ for inhalant anesthetics. If ventila-

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tion is depressed by opioids, excretion of inhalation anesthetic agents is delayed and anesthesia is prolonged. Pharmacodynamic Interactions

Pharmacodynamic interactions shift the dose-response curve of one or more drugs. These interactions frequently occur when two drugs acting at the same or a related receptor are given concomitantly. For example, yohimbine, an alpha2-adrenoreceptor antagonist and naloxone, an opiate-receptor antagonist, diminish the effects of alpharreceptor agonists (e.g., xylazine) and opioids, respectively. These drug interactions are often exploited in veterinary practice either to expedite the patient's recovery or to reduce adverse effects related to excessive drug doses. Pharmacodynamic antagonism that is unintended is not usually encountered in anesthesia. By comparison, pharmacodynamic interactions resulting in additive or synergistic interactions are frequently encountered in anesthesia. Generally, these interactions are both predictable and useful, with the goal of combining drugs being to decrease toxicity while increasing efficacy. Examples of how this is accomplished include the potentiation of opioid analgesia by NSAIDs, or combining a barbiturate and a benzodiazepine to produce synergistic sedative/ hypnotic effects. Although these additive and synergistic types of interactions are qualitatively predictable, the magnitude of the effects is variable. For this reason, it is critical that anesthesia practitioners carefully titrate drugs used in combination and be prepared to address respiratory, CNS, or cardiovascular problems. Toxicity from drug interactions is more likely to result in morbidity or mortality when it occurs in a setting where it is not rapidly recognized and treated. Such problems arose in human patients shortly after the introduction of midazolam when opioid-midazolam combinations were first used by nonanesthesia personnel for endoscopic and radiological procedures. The extreme sedation and unexpected ventilatory depression resulted in several deaths. 2 Because of the large amount of interpatient variability in response to anesthetic drugs even when they are used alone, the addition of a second or third drug makes it more difficult to predict therapeutical and toxic effects. Diligent patient monitoring allows for early recognition of signs of toxicity and appropriate treatment. Additional Interactions by Drug Class Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) is an enzyme that metabolically inactivates many neurotransmitters throughout the body, including epinephrine, norepinephrine, dopamine, and serotonin. MAO consists of two

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subtypes, MAO-A and MAO-B. These subtypes differ in their substrate specificity, tissue distribution, and susceptibility to various MAO inhibitors. Because of the widespread distribution of MAO and its influence over a variety of neurotransmitters, there is considerable potential for adverse interactions with other drugs that affect neurotransmitter metabolism. During treatment with MAO inhibitors, excessive amounts of neurotransmitters accumulate in the brain and in sympathetic nerve terminals. Administration of indirectly acting sympathomimetic drugs such as ephedrine causes an exaggerated release of norepinephrine and a potentially fatal hypertensive response.U Fatal drug interactions have also occurred between opioids and MAO inhibitors. These combinations have resulted in hyperpyrexia, coma, severe hypertension, seizures, and delirium. 9' 34 The opioids most commonly associated with these interactions are meperidine and pentazocine, and these drugs should be avoided in patients receiving MAO inhibitors. Until recently, MAO inhibitors were not used in veterinary medicine; however, with the recent introduction of selegiline (L-deprenyl), which is approved for the treatment of canine pituitary-dependent hyperadrenocorticism, this is likely to change. Although drug interactions are less likely to occur with selective MAO inhibitors such as selegiline (MAO-B), several human patients have experienced significant toxic effects. 40, 54 Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and doxepine act as competitive inhibitors to block the reuptake of serotonin and other neurotransmitters into nerve terminals. Patients receiving these drugs are highly sensitive to the effects of epinephrine and norepinephrine and are predisposed to cardiac arrhythmias, cardiovascular instability during anesthesia, and increased sensitivity to pressor agents. 13 Pancuronium and ketamine also inhibit neuronal reuptake of these drugs, and their concurrent use with TCAs significantly increases the likelihood of adverse clinical effects. Cardiac arrhythmias in both dogs and cats have resulted from such drug combinations_B, 16 Despite the fact that little information exists on the appropriate doses of TCAs for use in dogs and cats, their use is recommended for a multitude of behavioral problems. 38 Tricyclic Antidepressants and Anesthesia

Specific recommendations regarding the use of individual anesthetic agents cannot be made at this time, as little research has been conducted in the veterinary field. Side effects that have been seen with TCAs during anesthesia include tachycardia, cardiac arrhythmias, hypertension, hypotension, prolonged narcosis or coma, and hyporeflexia. 8 The side effects seen may be dependent on whether TCA administration is recent or of chronic duration. Initially, preventing reuptake leads to high levels of norepinephrine; however, with time, the receptors "downregu-

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late" and are less responsive to catecholamines.45 TCA administration should not be withdrawn before anesthesia, and if possible, anesthesia and surgery should be post~ed until the animal has been stabilized on medication for 14 to 21 days or longer. Drugs to avoid (or use with caution) are (1) cardioactive drugs (e.g., norepinephrine, epinephrine, ephedrine), (2) thiopental (especially if halothane is used), 45 (3) alpha2 agonists (as alpha2 hyperresponsiveness has been seen), (4) lidocaine with epinephrine,5 and (5) opioids, as their sedative and respiratory depressant effects may be increased. 49 Patients should be carefully monitored for arrhythmias, hypertension, or hypotension. With chronic TCA administration, hypotension may be difficult to treat even with vasopressors. 46 Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRis), the newest generation of antidepressant drugs, are the most frequently prescribed drugs in the United States. 25 This class of drugs, which includes fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and fluvoxamine, acts by inhibiting the presynaptic serotonin reuptake transporter, resulting in increased levels of serotonin at the synaptic cleft. In veterinary medicine, these agents are recommended for treatment of behavioral problems, despite the fact that there have been no safety and efficacy studies performed in veterinary patients. Several case reports (human) and evidence from human clinical trials indicate that SSRis are associated with adverse drug interactions. SSRis inhibit cytochrome P450 isoenzymes responsible for metabolizing benzodiazepines, resulting in reduced clearance of diazepam and potentially other benzodiazepines. 25 Meperidine and pentazocine may also interact with SSRis but through a different mechanism. Like SSRis, meperidine and pentazocine block presynaptic reuptake of serotonin; thus, their concurrent administration can produce what is called the "serotonin syndrome." The serotonin syndrome results from increased synaptic concentrations of serotonin in the brain stem and spinal cord. Clinical signs of serotonin syndrome include agitation, coma, myoclonus, hyperreflexia, fever, tachycardia, and cardiovascular instability. It may result in disseminated intravascular coagulation, myoglobinuria, renal failure, cardiac arrhythmia, and death unless recognized early and treated appropriatelyY· 24 Antibiotics

Several classes of antibiotics, including aminoglycosides, tetracyclines, polymixins, and lincosamides, possess neuromuscular blocking activity, with the aminoglycosides being the most potent. Aminoglycosides inhibit neuromuscular transmission by preventing the presynaptic release of acetylcholine, although the typical neuromuscular blockers (e.g., atracurium) function by antagonizing the postsynaptic receptor. When the two classes of drugs are administered concurrently at clinically

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relevant doses, potentiation of neuromuscular blockade can occur. This effect has been documented in human7 and veterinary patients. 30 Recovery from neuromuscular blockade is prolonged; thus, ventilatory support should be made available. Aminoglycoside-induced block may be overcome by administration of calcium salts. Antineoplastic Agents

Several unrelated drug interactions have been described involving cyclophosphamide. In one study, a 100% mortality rate resulted when cyclophosphamide-treated rodents were anesthetized with halothane. 10 The mechanism for the interaction is unknown, and similar problems have not been reported in human patients. Cyclophosphamide also inhibits plasma cholinesterase activity. This can result in prolonged neuromuscular blockade after administration of neuromuscular blocking drugs such as mivacurium. 33

CONCLUSIONS It is not possible to commit to memory all drug interactions of potential clinical importance. Understanding the mechanisms and pharmacokinetic principles of drug interactions is helpful in predicting which drugs are more likely to be associated with clinically significant adverse drug interactions. Studies identifying the types of patients that are predisposed to adverse effects of particular drug interactions and studies of the clinical characteristics of drug interactions (time course and dose dependency) are needed in veterinary medicine. Similarly, epidemiological studies are needed to determine the incidence of adverse drug interactions in anesthetized patients (perhaps a reporting system should be initiated). Although few adverse drug interactions have been reported in veterinary patients, it is probable that they indeed occur but are erroneously attributed to atypical or idiosyncratic drug reactions on the part of the patient to a particular anesthetic agent. An increased level of awareness regarding the potential for adverse drug interactions may aid in increased recognition of their occurrence, with appropriately directed therapy resulting in improved patient outcome. This review has not attempted to provide a comprehensive list of all potential drug interactions involving anesthetic drugs but rather to serve as an aid in understanding the mechanisms involved in drug interactions. It should be re-emphasized that many drug interactions are desirable and can be used to optimize therapeutical efficacy. Clinically important examples of both beneficial and adverse interactions have been described relating to each drug interaction mechanism discussed. Additionally, this review identified several important drug classes that have the potential to produce life-threatening complications when used in combination with various anesthetic drugs. Finally, a table (Table. 3)

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Table 3. INTERACTIONS INVOLVING DRUGS USED IN ANESTHESIA Anesthetic Drug

Inhalants

Interacting Drug Class

Benzodiazepines Opioids Alpha, agonists Ketamine Propofol Barbiturates Local anesthetics Verapamil MAO inhibitors

Result

t

MAC

t

MAC

Methoxyflurane

Barbiturates

Renal toxicity

Halothane

Tricyclical antidepressants Aminophylline, theophilline Epinephrine Phenylephrine Phenothiazines Barbiturates Benzodiazepines Phenobarbital and primidone MAO inhibitors, SSRis

Risk of cardiac arrhythmias

Opioids

Meperidine and pentazocine Alfentanil Benzodiazepines Midazolam

Erythromycin Cimetidine Phenothiazines Barbiturates Opioids Clarithromycin, erythromycin, azole Antifungals, B blockers, SSRis

t

CNS depression, t respiratory suppression

Mechanism

Pharmacodynamic

Unknown CNS catecholamine concentration Metabolism to nephrotoxicants Unknown

References

11, 20, 31, 41

20 14, 19, 50

Pharmacodynamic

11, 20, 31, 47, 48

t Opioid concentrations Serotonin syndrome

Pharmacokinetic Pharmacodynamic

11, 25

t Alfentanil concentrations t CNS depression

Pharmacokinetic Pharmacodynamic

11,20 11,20

t

Pharmacokinetic

11, 20, 53

Midazolam concentrations

Diazepam

Intravenous preparations containing ethanol Alpha2 agonists

Dissociatives Ketamine Barbiturates

Thiopental

Phenothiazines

Omeprazole, i3 blockers, cimetidine, fluoroquinolones, azole antifungals, SSRis Metronidazole Phenothiazines Butyrophenones Calcium channel blockers Opioids Phenothiazines Barbiturates Benzodiazepines Thyroid hormone Theophylline, aminophylline Naloxone Opioids Benzodiazepines Phenothiazines Alpha2 agonists Adrenergic drugs Propofol, inhalant anesthetics Halothane

Benzodiazepines Opioids Barbiturates Alpha2 agonist i3 blockers Alpha2 agonists Tricyclical antidepressants

0\ (JJ

\D

Pharmacokinetic

20, 21, 28

20

Additive hypotensive effects

Metronidazole inhibits aldehyde dehydrogenase Pharmacodynamic

Arrhythmias Potentiates analgesia i CNS depression

Unknown Pharmacodynamic Pharmacodynamic

20 42 20,42

Hypertension and tachycardia Seizures May reduce analgesic effects i CNS depression

Unknown Unknown Pharmacodynamic Pharmacodynamic

27 23 44 11,20

t Risk of arrhythmias Synergistic anesthetic effects j Thiopental concentration

Unknown Pharmacodynamic Pharmacokinetic (halothane decreases thiopental volume of distribution) Pharmacodynamic

11

j Diazepam concentrations

Vomiting

j CNS depression

j Phenothiazine concentrations, additive hypotension Additive hypotension j Concentration of tricyclical antidepressants

20

11

11

11,20

Pharmacokinetic Pharmacodynamic Pharmacodynamic Pharmacokinetic

17

Table continued on following page

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Table 3. INTERACTIONS INVOLVING DRUGS USED IN ANESTHESIA Continued Anesthetic Drug

Propofol

Local anesthetics Neuromuscular blockers Nondepolarizing

Depolarizing

Succinylcholine

Interacting Drug Class

Barbiturates Inhalant anesthetics Benzodiazepines Opioids Metociopramide Fentanyl and halothane Epinephrine Propranolol ACE inhibitors (Enalapril) Added epinephrine Tricyciical antidepressants Aminoglycosides Amphotericin B Clindamycin Magnesium (parenteral) Vancomycin Polymixin Calcium channel blockers Inhalant anesthetics Local anesthetics Cholinesterase inhibitors Theophylline Inhalant anesthetics Magnesium Cholinesterase inhibitors Local anesthetics Calcium channel blockers Nondepolarizing neuromuscular blockers Cyclophosphamide Digoxin

Result

t

Mechanism

References

Pharmacodynamic

11,52

Unknown Pharmacokinetic Unknown Pharmacokinetic Unknown

39 11 26 11 11

Pharmacokinetic Unknown

11 11

Potentiation of blockade

Many

20,41

Antagonism of blockade Antagonism of blockade Potentiation of blockade

Pharmacokinetic Unknown Many

20,41

Antagonism of blockade

Pharmacodynamic

Potentiation of blockade i Arrhythmias

Unknown Unknown

CNS depression

j Induction dose of propofol j Concentrations of propofol i Arrhythmias j Propranolol concentrations, severe hypotension j Duration i Arrhythmias

20,41

ACE = angiotensin converting enzyme; MAO = monoamine oxidase; SSRI = selective serotonin reuptake inhibitors; MAC = minimal alveolar concentration; CNS = central nervous system;

= increased; ! = decreased.

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has been included as a quick reference for many clinically relevant drug interactions.

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26. Kamibayashi T, Hayashi Y, Suikawa K, et a!: Enhancement by propofol of epinephrineinduced arrhythmias in dogs. Anesthesiology 75:1035, 1991 27. Kaplan JA, Cooperman LH: Alarming reactions to ketamine in patients taking thyroid medication: Treatment with propranolol. Anesthesiology 35:229, 1971 28. Klotz U: Delayed clearance of diazepam due to cimetidine. N Eng! J Med 302:1012, 1980 29. Lasser EC, Elizondo-Marte! G, Granke RC: Potentiation of pentobarbital anesthesia by competitive protein binding. Anesthesiology 24:665, 1963 30. Martinez EA, Mealey KL, Woolridge AA, et a!: Pharmacokinetics, effects on renal function, and potentiation of atracurium-induced neuromuscular blockade after administration of high dose gentamicin in isoflurane-anesthetized dogs. Am J Vet Res 57:1623, 1996 31. Maze M, Mason DM, Kates RE: Verapamil decreases MAC for halothane in dogs. Anesthesiology 59:327, 1983 32. Mazze RI, Woodruff RE, Heerdt ME: Isoniazid-induced defluorination in humans. Anesthesiology 57:5, 1982 33. McAuliffe MS, Hartshorn EA: Anesthetic drug interactions. Certified Registered Nurse Anesthetists 8:116, 1997 34. Meyer D, Halfin V: Toxicity secondary to meperidine in patients on monamine oxidase inhibitors: A case report and critical review. Clinical Psychopharmacology 1:319, 1981 35. Most JA, Markle BG: A nearly fatal hepatoxic reaction to rifampin after halothane anesthesia. Am J Surg 127:593, 1974 36. Nies AS, Spielberg SP: Principles of therapeutics. In Hardman JG, Limbird LE (eds): The Pharmacological Basis of Therapeutics, ed 9. New York, McGraw-Hill, 1996, p 43 37. Olkkola KT, Backman JT, Neuvonen PJ: Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacal Ther 55:481, 1994 38. Overll KL: Pharmacologic treatments for behavior problems. Vet Clin North Am Small Anim Pract 27:637, 1997 39. Page VJ, Chipa JH: Metoclopramide reduces the induction dose of propofol. Acta Anaesth Scand 41:256, 1997 40. Pfeiffer RF: Antiparkinsonian agents. Drug interactions of clinical significance. Drug Sa£ 14:343, 1996 41. Ransom ES, Mueller RA: Safety considerations in the use of drug combinations during general anaesthesia. Drug Sa£ 16:88, 1997 42. Rosow CE: Anesthetic drug interaction: An overview. JClin Anesth 9(suppl):27S, 1997 43. Schlanz KD, Myre SA, Bottorff MB: Pharmacokinetic interactions with calcium channel antagonists (Part 1). Clin Pharmacokinet 21:448, 1991 44. Smith DJ, Bouchal RI, de Sanctis CA, et a!: Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology 26:1253, 1987 45. Spiss CK, Smith CM, Maze M: Halothane-epinephrine arrhythmias and adrenergic responsiveness after chronic imipramine administration in dogs. Anesth Analg 63:825, 1984 46. Sprung J, Schoenwald PK, Levy P, et a!: Treating intraoperative hypotension in a patient on long-term tricyclic antidepressants: A case of aborted aortic surgery. Anesthesiology 86:990, 1997 47. Stambaugh JE, Wainer IW: Drug interaction: Meperidine and chlorpromazine, a toxic combination. J Clin Pharmacal 21:140, 1981 48. Stambaugh JE, et a!: A potentially toxic drug interaction between meperidine and phenobarbitone. Lancet 197(suppl):69S, 1984 49. Stoelting RK: Drugs used in treatment of psychiatric disease. In Stoelting RK (ed): Pharmacology and Physiology in Anesthetic Practice. Philadelphia, JB Lippincott, 1987, pp 347-364 50. Tucker WK, Rackstein AD, Munson ES: Comparison of arrhythmic doses of adrenaline, metaraminol, ephedrine and phenylephrine during isoflurane and halothane anaesthesia in dogs. Br J Anaesth 46:392, 1974 51. Usubiaga JE, Wikinski JA, Morales RL, et a!: Interaction of intravenously administered

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procaine, lidocaine, and succinylcholine in anaesthetized subjects. Anesth Analg 46:39, 1967 52. Vuyk J: Pharmacokinetic and pharmacodynamic interactions between opioids and propofol. J Clin Anesth 9(suppl):23S, 1997 53. Yeates RA: Interaction between midazolam and clarithromycin: Comparison with azithromycin. Int J Clin Pharmacol Ther 34:400, 1996 54. Zomberg GL, Bodkin JA, Cohen BM: Severe adverse interaction between pethidine and selegiline. Lancet 337:246, 1991

Address reprint requests to Katrina A. Mealey, DVM, PhD Department of Veterinary Clinical Sciences Washington State University Pullman, WA 99164-6610