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 629

630 MEALEY & MATTHEWS

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.

DRUG INTERACTIONS DURING ANESTHESIA 631

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

632 MEALEY & MATTHEWS

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

Alfentanil Bupivicaine Acepromazine Diazepam Fentanyl Lorazepam Midazolam Sufentanyl Temazepam Propofol Thiopental

Protein Bound (%)

92 95 99 98 84 91 95 93 97 98 85

DRUG INTERACTIONS DURING ANESTHESIA 633

Table 2. DRUGS THAT INDUCE OR INHIBIT CYTOCHROME P450 ENZYMES

Inducers

Barbiturates Primidone Rifampicin

Inhibitors

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-

634 MEALEY & MATTHEWS

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

DRUG INTERACTIONS DURING ANESTHESIA 635

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-

636 MEALEY & MATTHEWS

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

DRUG INTERACTIONS DURING ANESTHESIA 637

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

Methoxyflurane

Halothane

Opioids

Meperidine and pentazocine

Alfentanil

Benzodiazepines

Midazolam

Interacting Drug Class

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

Barbiturates

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

Erythromycin Cimetidine Phenothiazines Barbiturates Opioids Clarithromycin, erythromycin,

azole Antifungals, B blockers, SSRis

Result

t MAC

t MAC

Renal toxicity

Risk of cardiac arrhythmias

t CNS depression, t respiratory suppression

t Opioid concentrations Serotonin syndrome

t Alfentanil concentrations

t CNS depression

t Midazolam concentrations

Mechanism References

Pharmacodynamic 11, 20, 31, 41

Unknown CNS catecholamine

concentration Metabolism to 20

nephrotoxicants Unknown 14, 19, 50

Pharmacodynamic 11, 20, 31, 47, 48

Pharmacokinetic Pharmacodynamic 11, 25

Pharmacokinetic 11,20

Pharmacodynamic 11,20

Pharmacokinetic 11, 20, 53

Diazepam Omeprazole, i3 blockers, j Diazepam concentrations Pharmacokinetic 20, 21, 28 cimetidine, fluoroquinolones, azole antifungals, SSRis

Intravenous preparations Metronidazole Vomiting Metronidazole inhibits 20 containing ethanol aldehyde

dehydrogenase Alpha2 agonists Phenothiazines Additive hypotensive effects Pharmacodynamic 20

Butyrophenones Calcium channel blockers Arrhythmias Unknown 20 Opioids Potentiates analgesia Pharmacodynamic 42 Phenothiazines i CNS depression Pharmacodynamic 20,42 Barbiturates Benzodiazepines

Dissociatives Ketamine Thyroid hormone Hypertension and tachycardia Unknown 27

Theophylline, aminophylline Seizures Unknown 23 Naloxone May reduce analgesic effects Pharmacodynamic 44

Barbiturates Opioids i CNS depression Pharmacodynamic 11,20 Benzodiazepines Phenothiazines Alpha2 agonists

Thiopental Adrenergic drugs t Risk of arrhythmias Unknown 11 Propofol, inhalant anesthetics Synergistic anesthetic effects Pharmacodynamic 11 Halothane j Thiopental concentration Pharmacokinetic 11

(halothane decreases thiopental volume of distribution)

Phenothiazines Benzodiazepines j CNS depression Pharmacodynamic 11,20 Opioids Barbiturates Alpha2 agonist i3 blockers j Phenothiazine Pharmacokinetic

concentrations, additive Pharmacodynamic hypotension

Alpha2 agonists Additive hypotension Pharmacodynamic Tricyclical antidepressants j Concentration of tricyclical Pharmacokinetic 17

antidepressants

0\ Table continued on following page (JJ \D

a-oj;>. Q

Table 3. INTERACTIONS INVOLVING DRUGS USED IN ANESTHESIA Continued

Interacting Anesthetic Drug Drug Class Result Mechanism References

Propofol Barbiturates t CNS depression Pharmacodynamic 11,52 Inhalant anesthetics Benzodiazepines Opioids Metociopramide Unknown 39 Fentanyl and halothane j Induction dose of propofol Pharmacokinetic 11 Epinephrine j Concentrations of propofol Unknown 26 Propranolol i Arrhythmias Pharmacokinetic 11 ACE inhibitors (Enalapril) j Propranolol concentrations, Unknown 11

severe hypotension Local anesthetics Added epinephrine j Duration Pharmacokinetic 11

Tricyciical antidepressants i Arrhythmias Unknown 11 Neuromuscular blockers

Nondepolarizing Aminoglycosides Potentiation of blockade Many 20,41 Amphotericin B Clindamycin Magnesium (parenteral) Vancomycin Polymixin Calcium channel blockers Inhalant anesthetics Local anesthetics Cholinesterase inhibitors Antagonism of blockade Pharmacokinetic Theophylline Antagonism of blockade Unknown

Depolarizing Inhalant anesthetics Potentiation of blockade Many 20,41 Magnesium Cholinesterase inhibitors Local anesthetics Calcium channel blockers Nondepolarizing Antagonism of blockade Pharmacodynamic

neuromuscular blockers Succinylcholine Cyclophosphamide Potentiation of blockade Unknown 20,41

Digoxin i Arrhythmias Unknown

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

DRUG INTERACTIONS DURING ANESTHESIA 641

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

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