Adverse Drug Interactions in Anesthesia

James G. Bovill, MD, PhD, FFARCSI* Department of Anaesthesiology, University Hospital Leiden, Leiden, Netherlands.

Anesthesia often involves the administration of several drugs belonging to different classes. In addition, many patients will be taking a number of drugs related to their surgical condition or for other medical diseases. Thus, there is a considerable potential for drug interactions in the perioperative period, some of which may be potentially harmful to patients. The most common interactions involve changes in the pharmacokinetics or pharmacodynamics of one drug caused by induction or inhibition of the enzyme system by another drug. Other important interactions involve monoamine oxidase inhibitors, some antibiotics, and the tricyclic and tetracyclic . These adverse interactions are the subject of this review. © 1997 by Elsevier Science Inc.

Keywords: Anesthesia; drug interactions: adverse reactions; enzyme induction; enzyme inhibition.

Introduction Anesthesia for anything but the most minor procedures may involve the administration of up to ten or more drugs. In addition, many patients will be taking a number of drugs related to their surgical condition or for other medical diseases. Because the probability of an adverse drug interaction increases exponentially with the number of drugs a patient receives,1 there is considerable potential for such reactions in the perioperative period. Indeed, the potential for drug interactions is probably greater in anesthesia than in other areas of medicine. Drug interactions result when the effect of one drug is altered by the concurrent administration of another. In some cases the interactions may be beneficial, for example, the synergistic interactions between many hypnotics and . Unfortunately, many drug interactions are potentially harmful to patients. These adverse interactions are the subject of this review. The mecha- nisms involved in drug interactions may be one of three types: pharmaceutical, pharmacokinetic, or pharmacodynamic.

Pharmaceutical Interactions Pharmaceutical interactions refer to direct chemical combinations between drugs or their absorption into the material of their containers. A common example of a direct chemical interaction is the precipitation that occurs when a solution of thiopental (highly alkaline) is mixed with acidic solutions such as *Professor of Anaesthesiology succinylcholine or . When thiopental and vecuronium are adminis- tered consecutively, a white precipitate of thiopental acid forms, which is Address correspondence to Professor Bovill insoluble in plasma and which may occlude intravenous (IV) tubing.2 Aminogly- at the Department of Anaesthesiology, Uni- cosides and penicillin should never be mixed in the same container because the versity Hospital Leiden, P.O. Box 9600, 2300 penicillin inactivates the aminoglycoside to a significant degree. Glyceryl trini- RC Leiden, Netherlands. trate is inactivated by binding to polyvinyl chloride, and insulin can adhere to Received for publication February 3, 1997; the surface of glass or plastic syringes. The net result is that the patient receives revised manuscript accepted for publication a lower than expected dose of the drug, with a reduction in clinical effect. The March 31, 1997. antagonism of the anticoagulant effects of heparin by protamine results from

Journal of Clinical Anesthesia 9:3S–13S, 1997 © 1997 by Elsevier Science Inc. 0952-8180/97/$17.00 655 Avenue of the Americas, New York, NY 10010 PII S0952-8180(97)00119-0 Adverse drug interactions in anesthesia: Bovill the formation of an inactive chemical complex between Table 1. Drugs that Inhibit or Induce Cytochrome P450 the two substances. This is a therapeutic pharmaceutical Enzymes interaction. In general, however, pharmaceutical interac- tions are seldom a problem in anesthesia if sensible Inhibitors Inducers precautions are taken. Problems are more likely to arise in the intensive care unit (ICU). Antibiotics Barbiturates macrolides Antiepileptics troleandomycin carbamazepine Pharmacokinetic Interactions erythromycin phenytoin fluoroquinolones primidone Pharmacokinetic-related drug interactions are a much isoniazid Rifampicin more common source of adverse reactions associated with Azole antifungal drugs Dichloralphenazone anesthesia. Pharmacokinetic interactions occur when the ketoconazole Ethanol administration of one drug alters the disposition of an- itraconazole Tobacco smoke other drug, changing the pharmacodynamics of the sec- Calcium entry blockers ond drug. Pharmacokinetic interactions may arise because diltiazem of alterations in drug absorption, distribution, metabo- verapamil lism, elimination, or excretion. Of these, interactions Omeprazole Cimetidine affecting distribution and metabolism are the most impor- Propofol tant for anesthesiologists. Grapefruit juice

Absorption The absorption of an orally administered drug from the biotransformation in the liver. Phase I biotransformations gastrointestinal tract may be influenced by gastric and are oxidation, hydrolysis, or reduction processes. Oxida- intestinal pH, speed of gastric emptying, the pKa of the tion is usually catalyzed by one or more of the cytochrome drug, its lipid solubility, and the particular pharmaceutical P450 enzymes. More than 60 isoforms of this hemoprotein formulation. An example of a drug absorbed from the enzyme have been described, and each individual isoform stomach is salicylic acid, and absorption is much greater at possesses a unique cytochrome system whose characteristics low than at high pH. Most drugs, however, are absorbed reflect genetic makeup and environmental and drug expo- from the upper small intestine, and their absorption will sure. P450 enzymes have been grouped into three families, be more influenced by gastric and intestinal motility. CYP 1, CYP 2, and CYP 3, on the basis of the degree of Premedication with opioids and anticholinergics will delay similarity of their amino acid sequences. Each of these gastric emptying and drug absorption, while metoclo- families is divided into subfamilies, denoted by a capital pramide, which increases the rate of gastric emptying, may letter. Within each subfamily specific enzymes are denoted increase the rate of diazepam absorption.3 This could be by an Arabic numeral. CYP 3A4 is probably the most impor- relevant where these drugs are combined with oral drugs tant cytochrome P450 isoform for drug metabolism. It has a for premedication such as benzodiazepines. Within the very wide substrate specificity and mediates the metabolism gut, interaction between drugs can have important effects of approximately 65 different drugs. It is the isoform with on absorption. For example, the tetracycline antibiotics highest expression in the human liver, and it is also present can chelate with a number of divalent and trivalent in high concentrations in the intestine.4,5 CYP 3A4 is involved metallic ions such as the calcium, aluminium, and bismuth in the metabolism of midazolam6 and alfentanil.7 A wide present in dairy products and antacids to form complexes range of chemical compounds, including many drugs, can that are not only poorly absorbed but have reduced interact with the cytochrome P450 system, causing either an antibacterial effect. increased activity (enzyme induction) or enzyme inhibi- tion (Table 1). Both enzyme inhibition and induction can Distribution be responsible for adverse drug interactions. Phase II reactions involve conjugation of the metabolites or the The extent of the distribution of a drug within the body parent drug with a water-soluble ligand such as glucuro- depends on several factors, including tissue blood flow, nide or sulphate. These conjugates are more polar and lipid solubility, and protein binding. Inhalational and IV thus more readily excreted in the bile and urine. Phase II anesthetics often produce significant hemodynamic metabolism is not mediated by P450 enzymes and is less changes that may profoundly affect peripheral blood flow commonly involved in drug interactions. and perfusion. In addition to changes in distribution, a reduction in liver and renal blood flow will also affect the Enzyme Induction clearance of most drugs. Enzyme induction is an adaptive response that involves the Metabolism and Elimination accumulation of specific mRNAs and increased expression of the associated enzymes. It may be a regulatory mecha- Drugs are eliminated from the body by several processes, nism that has evolved to protect against the accumulation of which by far the most important for IV drugs is of foreign compounds to levels that may cause toxic

4S J. Clin. Anesth., vol. 9, September 1997 Adverse drug interactions in anesthesia: Bovill effects.8 Enzyme induction most commonly occurs when drugs are given at relatively high doses, although in humans a number of drugs can induce P450 enzymes at therapeutic doses (eg, rifampicin, barbiturates, phenytoin, and carbamazepine). Some compounds are selective and induce only specific families of P450 enzymes, while others are multifunctional, inducing several isoforms. Ethanol and cigarette smoke cause relatively selective induction of the cytochrome P450 isoenzymes CYP 2E1 and CYP 1A, respectively.9 In addition to induction of P450, these substances may also induce other systems such as those involved in glucuronidation. There is indirect evidence that rifampicin, phenobarbital, and some anticonvulsants can induce glucuronyl transferase (UDPGT) in humans. The half-life of the anticonvulsant lamotrigine, which is eliminated mainly by glucuronidation, is reduced from 29 hours to 15 hours by concomitant administration of carbamazepine, phenytoin, or pentobarbital.10,11 In contrast to enzyme inhibition, enzyme induction has been responsible for fewer adverse reactions in anesthesia, although it has been implicated in a number of adverse events. CYP 2E1 is probably the major enzyme responsible for the metabolism of the fluorinated volatile anesthetics. Biotransformation of these drugs results in the formation of products that can cause either renal or hepatic toxicity. Figure 1. Plasma concentrations (means Ϯ SEM) of midazo- Enzyme induction by the antituberculosis drug rifampicin lam after a 15 mg oral dose following pretreatment with was implicated in a near fatal hepatoxicity in a patient placebo or 600 mg rifampicin once daily for 5 days in 10 given this drug immediately following anesthesia with healthy subjects. Open circles ϭ after placebo; closed cir- .12 Rifampicin is a potent inducer of P450 cles ϭ after rifampicin. From Backman et al.21 with permis- enzymes both in the liver and the intestine.5,13 Halothane sion. undergoes oxidative metabolism to form trifluoroacetyl halide (TFA), a pathway metabolized mainly by CYP 2E1.14 Most TFA is excreted by the kidneys but a small percent- tration-time curve (AUC) of oral midazolam by 96% age binds covalently to lipoproteins and proteins, includ- (Figure 1). The elimination half-life was also reduced, from ing P450 enzymes, to form a TFA-hapten, which, in 3.1 Ϯ 0.2 hours to 1.3 Ϯ 0.2 hours. The lesser reduction in susceptible individuals, is thought to be responsible for half-life compared with the AUC suggests that there was halothane hepatitis. This pathway is enhanced by induc- also considerable induction of CYP 3A4 in the gut wall and tion of P450, and it is therefore advisable to avoid using that this may be even more important in this interaction halothane in patients taking potent enzyme inducers. than hepatic enzyme induction. Substantial concentrations Cimetidine, which is an inhibitor of cytochrome P450 of CYP 3A4 are found in the wall of the proximal small enzymes, decreases the incidence and severity of liver intestine.5,22 The pharmacodynamic effects of midazolam damage in animal models of halothane hepatitis.15 were significantly less following pretreatment with rifam- Chronic isoniazid therapy induces the metabolism of picin, consistent with the reduced bioavailability (Figure 2). It enflurane and , markedly increasing the peak is likely that other potent inducers of CYP 3A4 will cause a fluoride concentrations.16,17 There are several reports of similar interaction. The almost total loss of the pharmacody- increased metabolism of methadone in patients treated namic effect of midazolam in the presence of enzyme with rifampicin, with significantly lower (33% to 68%) induction has obvious clinical implications for the use of plasma concentrations during treatment than when treat- benzodiazepines in patients taking enzyme inducers. ment was stopped.18 There is little data about interactions Phenobarbital was one of the earliest drugs to be between rifampicin and other opioids, but it would seem recognized as an enzyme inducer. Other drugs used for reasonable that the metabolism of fentanyl or other the treatment of epilepsy, especially carbamazepine and opioids is also increased.19 This would result in a need for phenytoin, also have this property. Both are commonly higher doses than normally required to reach a desired prescribed antiepileptic drugs, and carbamazepine is also effect. used in the treatment of trigeminal neuralgia and, in Midazolam undergoes extensive metabolism in the psychiatry, for the treatment of depression. Carbamaz- liver, mainly by CYP 3A3, CYP 3A4, and CYP 3A5,6,20 and epine and phenytoin are potent inducers of cytochrome less than 1% is excreted unchanged in the urine. Its oral P450 enzymes, in particular the CYP 3A isoforms, although availability is between 30% and 70% in healthy subjects. carbamazepine also induces other isoforms, as well as Backman et al.21 showed that pretreatment with rifampicin glucuronyl-transferases.23 The oxidation of cyclosporin A, 600 mg once daily decreased the area under the concen- which is catalyzed by CYP 3A enzymes, is increased by

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were confirmed by a variety of tests of the pharmacody- namic responses to midazolam. Carbamazepine, phenyt- oin, and the barbiturates also enhance the metabolism of opioids that rely on hepatic metabolism. Obviously, these pharmacokinetic and pharmacodynamic changes need to be taken into account when administering drugs metabo- lized by P450 enzymes to patients on chronic antiepileptic therapy.

Inhibition of Drug Metabolism Because many of the drugs used in anesthesia are metab- olized by hepatic cytochrome P450 isoenzymes, any inhi- bition of these enzymes can have important consequences. Although the number of compounds that inhibit enzyme activity is less than that producing enzyme induction, their potential for causing serious adverse reactions related to anesthesia is probably much greater.

Antibiotics A number of antibiotics, most notably the macrolides and azole antifungal drugs, have been implicated in significant enzyme inhibition resulting in adverse interactions with anesthetic-related drugs. Nearly all interactions with mac- rolide antibiotics appear to result from a dose-dependent Figure 2. Changes in the Digital Symbol Substitution Test inhibition of the cytochrome P450 isoform CYP 3A4. CYP (DSST) and Maddox wing test (heterophoria) after oral 3A4-mediated metabolism of these drugs results in the midazolam in subjects from the same study as Figure 1. Open formation of a stable complex with the haem of the circles ϭ after placebo; closed circles ϭ after rifampicin. enzyme, rendering it inactive.30 Troleandomycin and From Backman et al.21 with permission. erythromycin both bind to P450 to form inactive com- plexes, although the degree of complex formation is lower with erythromycin.31 Coadministration of erythromycin phenytoin24 and carbamazepine.25 These interactions re- with midazolam or alfentanil, which are also metabolized sult in lowered plasma concentrations of the immunosup- by CYP 3A,6,7,32,33 has resulted in delayed excretion and pressant, with the attendant risk of transplant rejection. prolonged effects. The elimination half-life of alfentanil Carbamazepine and other antiepileptic drugs accelerate increased from 84 Ϯ 8.2 minutes to 131 Ϯ 43 minutes, and the metabolism of warfarin26 and dicoumarol,27 thereby clearance decreased from 3.9 Ϯ 0.8 ml/kg to 2.9 Ϯ 1.2 reducing the anticoagulant effect. ml/kg, in six subjects after a 7-day course of erythromycin These drugs also stimulate the biotransformation of (Figure 3).34 There are a number of case reports describing benzodiazepines, including diazepam28 and midazolam.29 prolonged respiratory depression following alfentanil in In the case of diazepam, the interaction with carbamaz- patients treated with erythromycin.34,35 Erythromycin does epine is associated with increased plasma concentrations not appear to inhibit the metabolism of sufentanil,36 when of the pharmacologically active metabolite nordiazepam28 studied in subjects who had participated in a previous so that there may not necessarily be a decrease in thera- study with alfentanil.34 This finding is at first difficult to peutic efficacy. Because midazolam does not have active explain, because the enzyme CYP 3A4 responsible for the metabolites, enzyme induction will result in a decrease in N-dealkylation of sufentanil (and fentanyl) is the same as pharmacologic effect. Backman et al.29 studied the phar- that which metabolizes alfentanil and erythromycin.33,37 A macokinetics and pharmacodynamics of a single dose of possible explanation may be the differences in hepatic oral midazolam 15 mg in six patients with epilepsy taking clearance between alfentanil and sufentanil. Sufentanil either carbamazepine or phenytoin, or a combination of has a much greater intrinsic hepatic clearance than alfen- both drugs. The control group consisted of volunteers tanil38,39 and therefore will be more dependent on matched by age and gender. In the patients, the AUC of changes in hepatic blood flow than hepatic metabolism, so midazolam was only 5.7%, and the peak midazolam con- that it is less likely to be affected by enzyme inhibition than centration was 7.4% (5.2 ng/ml vs. 70.4 ng/ml) of the alfentanil. values in the control subjects. The elimination half-life of The biotransformation of midazolam is mediated by at midazolam in the patients was 42% of that in the controls. least three P450 isoenzymes, CYP 3A3, CYP 3A4, and CYP Most patients had no sedative effects after oral midazolam, 3A5,6 and erythromycin inhibits midazolam metabolism in whereas there was a clear sedative effect lasting 2 to 4 animals and humans.40–44 Hiller et al.40 reported deep hours in each of the control subjects. These differences unconsciousness and exceptionally high midazolam con-

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kinetic effects of erythromycin were much less following IV than orally administered midazolam. Both erythromy- cin and troleandomycin reduce the metabolic clearance of triazolam, which, like midazolam, is metabolized by CYP 34A.43,45 In volunteers, erythromycin increased peak plasma triazolam concentrations by 100% and prolonged its half-life.30,46

Antifungal Drugs The common mechanism of action of the azole antifungal drugs is inhibition of a fungal cytochrome P450. However, these drugs are not selective and they also inhibit human microsomal enzymes from all three P450 enzyme fami- lies.30 Inhibitory activity is greatest against CYP 3A4, fol- lowed by CYP 1A2, and weakest for CYP and CYP 2D. Ketoconazole is the most potent inhibitor, followed by itraconazole (10 times less potent) and then fluconazole (500 times less potent).47 The best documented interac- tion is the inhibition of cyclosporin metabolism by keto- conazole, both in vitro48 and in animals and humans.49 Indeed, it has been suggested that concomitant adminis- tration of ketoconazole could be used to reduce the dose, and thus the cost, of cyclosporin treatment.50 In vitro, ketoconazole and itraconazole are potent inhibitors of midazolam hydroxylation.43 Pretreatment of volunteers with these antimycotics for 4 days increased the AUC after oral triazolam 22- to 27-fold and the elimination half-life 6- to 7-fold.51 The higher concentrations of tria- zolam during treatment with antimycotics was associated with profound pharmacodynamic effects, measured using a battery of psychomotor tests. The same group also found similar interactions with oral midazolam. Both ketocon- azole and itraconazole increased the AUC following oral midazolam 7.5 mg from 10- to 15-fold and the mean peak plasma midazolam concentration three to four times compared with a placebo.52 Psychomotor tests were signif- icantly disturbed until at least 6 hours after the ingestion of midazolam.

Calcium Channel-Blockers Figure 3. Plasma alfentanil concentrations in a subject who had taken no drugs (control) and after erythromycin 500 mg The calcium channel-blockers diltiazem and verapamil for 1 or 7 days. From Bartkowski et al.34 with permission. interact with a variety of drugs including propanolol, carbamazepine, cyclosporine, and benzodiazepines.53–55 Diltiazem and probably also verapamil are metabolized by centrations in a child being treated with IV erythromycin CYP 34A,56 and both drugs are potent inhibitors of this given oral midazolam as premedication. In a 61-year-old enzyme.43,57 They significantly increased the bioavailabil- man receiving erythromycin for suspected Legionnaires’ ity of midazolam and triazolam and prolonged the elimi- disease, midazolam 300 mg IV given over 14 hours in- nation half-life.55,58 These changes in the pharmacokinet- duced sleep lasting 6 days.43 The measured half-life of ics were associated with profound and prolonged sedative midazolam in this patient was 24.8 hours (normally 1.5 to effects. 2.5 hours). In a controlled study in volunteers, pretreat- ment with erythromycin 500 mg three times daily for one Grapefruit Juice week resulted in an almost threefold increase in the Cmax of midazolam and more than a four-fold increase in AUC Grapefruit juice is not a substance usually associated with values for oral midazolam.41 These changes, caused by an anesthesia. However, in recent years it has been the object increase in oral bioavailability and a decrease in plasma of considerable pharmacologic interest because of its clearance of midazolam, were accompanied by excessively ability to increase the bioavailability of a number of drugs, long-lasting hypnotic and amnesic effects. The pharmaco- especially the dihydropyridine calcium channel-block-

J. Clin. Anesth., vol. 9, September 1997 7S Adverse drug interactions in anesthesia: Bovill ers,59–62 cyclosporine,63 and the terfena- half-life and mean residence time in the extensive metabo- dine.64 All of these compounds are metabolized by cyto- lizers.76,77 It is worth noting that diazepam is subject to chrome P450 isoenzyme CYP 3A4, and the inhibitory dual routes of metabolism, with approximately 40% to effect of grapefruit juice is thought to result from inhibi- 50% of N-demethylation being mediated by CYP 2C19 and tion of CYP 3A4.65 This effect is found only with grapefruit the remainder probably mediated by CYP 3A.78 Whether juice and not with other citrus fruits, and it is thought to this interaction between omeprazole and diazepam has be caused by flavinoids and other ingredients of the clinical relevance remains to be established. However, in grapefruit. Of more direct relevance to anesthetic practice view of the wide therapeutic safety index of diazepam, the are the changes produced by drinking this juice on the changes produced are unlikely to cause serious adverse pharmacokinetics of oral benzodiazepines.66,67 Pretreat- effects. Surprisingly, lansoprazole did not affect the ment with grapefruit juice resulted in a 56% increase in plasma concentrations of diazepam,79 perhaps because peak plasma midazolam concentrations and an increase in the affinity of lansoprazole for CYP 2C19 is low in com- bioavailability from 24% (control) to 35% (grapefruit parison to that of diazepam.71 Pantoprazole also does not juice). However, intake of grapefruit juice did not affect seem to have a major affect on diazepam metabolism.80 the pharmacokinetics of midazolam given intravenously.67 Midazolam is commonly given orally for premedication of H -receptor Antagonists children, and the concomitant drinking of grapefruit juice 2 could result in a more profound sedative effect than The H2-receptor antagonist cimetidine binds to the cyto- anticipated. chrome P450 enzymes, inhibiting their activity and thus impairing the hepatic metabolism of a large number of Propofol drugs. Cimetidine is a potent inhibitor of the hepatic cytochrome P450 enzymes responsible for the phase I Propofol, which is widely used in anesthesia and for metabolism of many drugs, including opioids, benzodiaz- sedation of patients in ICUs, undergoes oxidative metab- epines, lidocaine, and warfarin. Inhibition of P450 en- olism in the liver by cytochrome P450 enzymes. As such, it zymes will cause a greater than expected plasma drug has the potential to interact with other drugs metabolized concentration and thus more pronounced clinical effect, by this enzyme system. Propofol impaired the intrinsic which also may be prolonged. The inhibition of P450 by clearance of ,68 which is a P450 substrate, and cimetidine results from an interaction directly with the inhibited the enzymatic degradation of alfentanil and P450 haem iron through one of the nitrogen atoms of the sufentanil by isolated human and pig liver microsomes in imidazole nucleus. Ranitidine, which contains a furan ring vitro.69 The mechanism for this latter interaction is un- in place of imidazole, does not inhibit P450, although it clear. Whereas alfentanil and sufentanil are metabolized does form a complex with hepatic cytochrome P450, but by cytochrome P450 CYP 3A enzymes, current evidence more weakly than cimetidine. As far as is known, neither suggests that the P450 isoforms responsible for the bio- famotidine nor nizatidine inhibits P450 enzymes. transformation of propofol are primarily CYP 2A1 and Klotz et al.81 compared the effect of cimetidine and CYP 2B1.68,70 ranitidine on the steady-state plasma concentrations of mi- dazolam given as an IV bolus infusion technique to healthy Proton Pump Inhibitors volunteers. Cimetidine significantly increased the mean (Ϯ SD) steady-state plasma concentration of midazolam The proton pump inhibitors omeprazole, lansoprazole, from 56.7 Ϯ 7.8 ng/ml to 71.3 Ϯ 19.6 ng/ml. In contrast, and pantoprazole are used for the treatment of peptic the steady-state plasma midazolam following ranitidine did ulcers and other hypersecretory conditions. They undergo not differ significantly from that after placebo. As of this extensive metabolism in the liver, mediated by the poly- writing, only one study has reported a significant increase morphically expressed enzyme CYP 2C19,71 and this ac- in oral bioavailability of midazolam when given in combi- counts for a pronounced interindividual variability in their natin with ranitidine.82 One explanation for this unex- pharmacokinetics. Other substrates for CYP 2C19 include pected finding is that it might have resulted from an increase S-mephenytoin, propranolol, diazepam, and a number of in the pH-dependent absorption of midazolam.81 Cimetidine tricyclic antidepressants. Population studies on CYP 2C19 coadministered with diazepam causes a 62% rise in diaz- polymorphism indicate that 2% to 6% of white Europeans epam concentration, with only minimal clinical effects.83 and Americans are poor metabolizers of S-mephenytoin, the prototype substrate for CYP 2C19, whereas in Asian Interactions with Monoamine Oxidase Inhibitors populations the proportion of poor metabolizers is signif- icantly higher, from 12% to 20%.72 In poor metabolizers Monoamine oxidase (MAO) is an enzyme that catalyzes of S-mephenytoin, diazepam is more slowly metabolized the oxidative deamination of over 15 monoamines in the than in subjects who are extensive metabolizers.73,74 Ome- body, including important neurotransmitters or neuro- prazole had no effect on the pharmacokinetics of diaze- modulators such as adrenaline, noradrenaline, , pam in the poor metabolizers, because these individuals and (5-HT). There are two subtypes of MAO, are deficient in CYP 2C19,75 and the conditions for an MAO-A and MAO-B, which differ in substrate preference, interaction therefore do not exist.74,76 However, it signifi- inhibitor specificity, and tissue distribution.84 MAO-A pref- cantly decreased the mean clearance and increased the erentially deaminates 5-HT, noradrenaline, and adrena-

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terminals, and administration of an indirectly-acting sym- pathomimetic will cause an exaggerated release of nor- adrenaline and a potentially fatal hypertensive response. Thus, in patients treated with MAOIs, the use of indirectly acting sympathomimetic drugs should be avoided. Direct- ly-acting drugs (eg, adrenaline, , methox- amine, or ) are safe to use in these patients. (meperidine) is the most commonly associated with an adverse reaction with MAOIs. Although only a proportion of patients taking MAOIs will react adversely to pethidine, there is no sure way of predicting the small group in whom the combination could produce severe, life-threatening reactions. These reactions can present in two distinct forms. The excitatory form is characterized by sudden agitation, delirium, headache, hypotension or hypertension, rigidity, hyperpyrexia, con- Figure 4. Metabolic pathways in the biotransformation of vulsions, and coma. It is thought to be caused by an noradrenaline involve the enzyme monoamine oxidase increase in cerebral 5-HT concentrations as a result of (MAO). Inhibition of MAO by the class of inhibition of MAO. This is potentiated by pethidine, which drugs known as MAO inhibitors can lead to important and blocks neuronal uptake of 5-HT.87 The depressive form, potentially life-threatening adverse drug interactions. CNS ϭ which is frequently severe and fatal, presents as respiratory central nervous system; COMT ϭ catechol-o-methyl trans- and cardiovascular depression and coma. It is the result of ferase; HMMA ϭ 4-hydroxy 3-methoxy mandelic acid; a reduced breakdown of pethidine due to the inhibition of MHPG ϭ methoxy-hydroxy phenyl ethelene glycol. hepatic N-demethylase by MAOIs, leading to accumula- tion of pethidine. There is evidence that the risk of adverse reactions to pethidine is more likely with drugs line, whereas MAO-B preferentially deaminates nonpolar that inhibit both MAO-A and MAO-B,88 and the risk may aromatic amines such as 2-phenyl-ethylamines and benzyl be less with newer, specific MAO-A inhibitors. Interactions amine. Tyramine and dopamine are substrates for both.85 with other opioids such as morphine and pentazocine The monoamine oxidase inhibitors (MAOIs), developed have been reported, but they are much less common. in the 1950s as the first effective antidepressant drugs, Other opioids appear to be safe in combination with bind irreversibly with MAO-A and MAO-B by the forma- MAOIs, with the possible exception of phenopiperidine, tion of covalent bonds. Because the generation of fresh which is metabolized to pethidine, norpethidine, and MAO is a slow process, the potential for drug interactions . with these drugs persists for up to 2 weeks after stopping Prolongation of the action of succinylcholine has been the drug. The newer generation of MAOIs, in contrast, are reported with phenelzine.89,90 This seems to be a specific competitive inhibitors of MAO and produce a reversible interaction with phenelzine, which decreases pseudocho- inhibition of MAO-A (RIMAs). Specific MAO-B inhibitors linesterase concentration. The use of nondepolarizing such as selegiline (I-deprenyl) have been developed, but muscle relaxants is not contraindicated in the presence of are less efficient than MAO-A inhibitors as antidepres- MAOIs, although pancuronium should be used with care sants. Selegiline is marketed for the treatment of Parkin- because of its ability to release noradrenaline. son’s disease.86 Because of the widespread inhibition of MAO and other enzyme systems by MAOIs, there is Pharmacodynamic Interactions considerable potential for adverse interactions with other drugs as well as other substances, including certain foods Pharmacodynamic interactions are those in which the such as cheese and yeast extracts that contain tyramine. Of effects of one drug are altered by the presence of another most concern to anesthetists has been interactions with drug at its site of action, or where the concentration of one sympathomimetic drugs and opioids. drug is changed by, for example, displacement from Indirectly acting sympathomimetic drugs such as am- binding sites on plasma or tissue proteins by a second phetamine, , and act partly by drug. The possibilities for this type of interaction is more stimulating the release of endogenous noradrenaline limited than for pharmaceutical or pharmacokinetic inter- from sympathetic nerve terminals. Within these terminals, actions. noradrenaline is stored in a stable pool, and in a mobile Adverse drug interactions can occur when two drugs pool ready for immediate release. Following reuptake of acting at the same or a related receptor are given concom- noradrenaline into the nerve terminal, it is metabolized by itantly. For example, ␤-adrenoceptor antagonists diminish the enzymes MAO and catechol-o-methyl transferase the effectiveness of ␤-agonists such as or ter- (COMT) (Figure 4). MAO acts to limit the size of the stable butaline. On other occasions interactions involve drugs pool by mediating a constant turnover of noradrenaline. with quite different mechanisms. For example, the inhibi- During treatment with MAOIs, large amounts of nor- tion of prostaglandin production by nonsteroidal antiin- adrenaline accumulate in the brain and in the sympathetic flammatory drugs (NSAIDs) can sometimes cause marked

J. Clin. Anesth., vol. 9, September 1997 9S Adverse drug interactions in anesthesia: Bovill loss of antihypertensive control in patients receiving treat- and volume of distribution that may mitigate the expected ment with ␤-adrenoceptor antagonists, diuretics, or angio- increase in free drug concentration. Concomitantly ad- tensin-converting enzyme (ACE) inhibitors.91 ministered drugs can compete with one another for binding sites on plasma proteins, resulting in displace- Antidepressants ment interactions that may lead to increased pharmaco- logic effect and the possibility of toxicity. Drugs likely to be The tricyclic and tetracyclic antidepressants act by specif- involved in displacement interactions are those that are ically blocking the reuptake of endogenous cat- highly protein bound, have a small volume of distribution, echolamines and serotonin into nerve terminals, by com- a high clearance, and a narrow therapeutic range of peting for the active transport mechanism. In patients concentrations.94 One of the best documented examples receiving these drugs, the circulatory effects of adrenaline is the displacement of warfarin and other anticoagulants are potentiated two to three times, and that of noradren- that are highly bound to albumin, by acidic drugs such as aline by up to nine times.92 A marked increase in hyper- chloral hydrate, phenylbutazone, mefenamic acid, and tensive effect will also occur with other directly acting sulphinpyrazole.95–97 However, although such displace- sympathomimetics. Pancuronium and also in- ment can result in increased anticoagulation, the effect is hibit the neuronal reuptake of catecholamines and should usually transient. Other mechanisms probably are equally be used with caution in patients taking these drugs. important, inhibition of metabolism, in particular. Indirectly acting vasoconstrictors such as ephedrine act by The pharmacodynamics of the coumarin anticoagu- causing the release of noradrenaline from adrenergic lants also is increased by some antibiotics such as the nerve terminals. In the presence of tricyclic and tetracyclic aminoglycosides and cephalosporins. The mechanism is antidepressants, the uptake of these drugs into the neu- not well understood, but one possibility is that the reduc- rons is partially or completely prevented, so the release of tion in bacteria in the gut responsible for producing noradrenaline is inhibited leading to a diminished effect. vitamin K reduces production of the vitamin. However, this is normally not an essential source of vitamin K, and a Electrolyte Disturbances more likely explanation is that vitamin K absorption is reduced by the antibiotics as part of a general antibiotic- Electrolyte disturbances caused by diuretics, for example, induced malabsorption syndrome. can result in important pharmacodynamic interactions. The incidence of toxic effects of the cardiac glycosides is Interactions with Muscle Relaxants increased by potassium depletion brought about by potas- sium-depleting diuretics. Hypokalemia caused by diuretics Several classes of antibiotics possess neuromuscular block- may potentiate the activity of nondepolarizing muscle ing actions, including the aminoglycosides, tetracyclines, relaxants leading to prolonged paralysis. The elimination polymixins, and linocosamides. Most of the aminoglyco- of lithium occurs almost entirely by the kidney, and sides are comparatively potent in their ability to potentiate lithium clearance is reduced by thiazide diuretics so that muscle relaxants. Gentamycin, neomycin, and streptomy- plasma lithium concentrations can rise to toxic levels. cin, but not tobramycin, are capable of producing a Diuretic-induced sodium depletion also may result in dose-dependent neuromuscular block alone in the rat lithium toxicity due to compensatory increases in proxi- isolated phrenic nerve-diaphragm preparation.98 Potenti- mal tubular reabsorbtion of lithium. Clinically important ation of neuromuscular block by the aminoglycosides can increases in lithium levels have been reported in patients occur with relatively small doses of the drugs, and enough taking ACE inhibitors. The mechanism is unclear but may can be absorbed from irrigation of the intrapleural space, involve altered sodium reabsorption.93 Lithium toxicity peritoneal cavity, or even a wound to give rise to clinical also has been associated with calcium entry blockers, problems. The only aminoglycoside that has not been NSAIDs, tricyclic antidepressants, and a wide variety of implicated in this type of interaction is netilmicin, which antipsychotic drugs such as , phenothiazines, does not seem to have any neuromuscular action.99 Ami- and . Interactions with antipsychotics usually noglycosides inhibit neuromuscular transmission by pre- involve some form of neurotoxic reaction ranging from venting the presynaptic release of acetylcholine; tetracy- extrapyramidal symptoms to the neuroleptic malignant clines inhibit this transmission by chelating extraneuronal syndrome. calcium. These drugs can prolong the recovery of nonde- polarizing muscle relaxants, with the possible exception of 100 Protein Binding and Pharmacodynamics atracurium. Aminoglycoside-induced block may be overcome by calcium salts and 4-aminopyridine, but the Changes in protein binding are generally only clinically block caused by the other groups cannot reliably be important for highly bound drugs. A reduction in binding reversed by pharmacologic means. from 95% to 90% represents a 100% increase in unbound Chronic therapy with antiepileptic drugs, phenytoin, (free) fraction of drug, whereas a reduction from 35% to carbamazepine, or sodium valproate has been associated 30% corresponds to only a 7.7% increase in free fraction. with resistance to the nondepolarizing muscle relax- It is the free fraction of a drug that is responsible for the ants.100–103 There is an increase in the dose of muscle pharmacologic effect. The effects of altered protein bind- relaxant required to achieve a given degree of block and a ing are complex and often involve changes in clearance reduction in the duration of action. There is potentiation

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