Drug Interactions between Psychoactive Agents and Antiepileptic Agents

Epilepsy & Behavior 2, 92–105 (2001) doi:10.1006/ebeh.2001.0165, available online at http://www.idealibrary.com on

REVIEW Drug Interactions between Psychoactive Agents and Antiepileptic Agents Candace Smith, Pharm.D. St. John’s University College of Pharmacy & Allied Health Professions, Jamaica, New York 11439 Received October 23, 2000; revised February 5, 2001; accepted for publication February 26, 2001

INTRODUCTION

This review focuses on the different potential mechanisms of drug interactions and their clinical significance with special regard to anticonvulsants and psychotropics. Furthermore, the cytochrome P450 isoenzyme system is given special consideration since it is involved in the metabolism and interactions of the majority of the aforementioned pharmacological classes. A drug interaction occurs when the effectiveness or toxicity of a drug is altered by the administration of another drug or substance (3). Mechanisms of drug interactions can be classified as either pharmacokinetic, pharmacodynamic, or a combination. Pharmacokinetic alterations affect drug concentrations by altering drug absorption, distribution, metabolism, and excretion. These pharmacokinetic changes may or may not result in an altered pharmacological response or therapeutic outcome. The most common pharmacokinetic drug interaction involves modifications in bioavailability and drug metabolism. In contrast, pharmacodynamic interactions occur at the site of pharmacological effect and generally do not reflect changes in drug concentrations. Pharmacodynamic interactions are generally related to the pharmacological effects of the administered drugs which may or may not closely parallel pharmacokinetic changes. While some pharmacokinetic interactions are clinically unremarkable and need only careful clinical monitoring, others require prompt dosage adjustment. The clinical importance of any drug interaction depends on factors that are drug, patient, and administration related and the extent varies markedly among individuals depending on age, preexisting medical conditions, and

The evaluation of potential drug– drug interactions in the treatment of psychiatric disorders in patients with epilepsy is necessary due to the increasing use of multiple medications in these two disease states (1). Concomitant administration of psychoactive drugs with antiepileptic drugs (AEDs) provides a compelling reason for gaining an understanding of whether coadministered medications can interact pharmacokinetically or pharmacodynamically. Knowledge of such interactions enables the prescriber to make appropriate treatment decisions so that the risk of adverse effects can be avoided or minimized. Fortunately, knowledge of the mechanisms underlying drug– drug interactions has increased substantially, particularly in the area of pharmacokinetic drug interactions. Drug interactions can occur at any step from absorption to elimination of a drug and can induce adverse as well as beneficial effects. Unfortunately, most drug interactions occur in the form of adverse effects, especially those with a low therapeutic index. However, many patients receiving potentially interacting drugs do not manifest adverse consequences (2). Therefore, one must identify situations where the patient is truly at risk. Knowledge of the interactive properties of drugs and/or determination of plasma drug concentrations can aid in evaluating whether an adverse drug interaction may occur. However, not all drugs have an established therapeutic range, making the use of a plasma concentration invaluable.

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Drug Interactions

possibly dose (4). Generally, a doubling or more in plasma drug concentration has the potential for an enhanced adverse effect or beneficial drug response because the therapeutic range for many drugs is sufficient to allow for a 50% increase. However, less pronounced pharmacokinetic interactions may still be clinically important for drugs with a narrow therapeutic range (e.g., carbamazepine), at the extreme end of the therapeutic range, with metabolites or with nonlinear kinetics (e.g., phenytoin). Interactions may occur under single-dose conditions or only after multiple doses when steady state has occurred. Assessment of a drug interaction may be most apparent when a new drug is added to the regimen of a patient stabilized on the affected drug. Temporal relationships between the administration of a drug and the addition or deletion of a new drug can help determine whether a drug interaction has occurred. The addition or deletion of another drug, whether an AED or psychotropic, may change dosage requirements of either drug. Therefore, serum drug concentration monitoring, when available, is particularly useful in assessing potential drug interactions and in helping to manage combinations of antiepileptic drugs or other concurrent drugs that invariably interact. The majority of known pharmacodynamic interactions occur when drugs with additive, synergistic, or antagonistic pharmacological effects are used therapeutically (i.e., tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)). In other situations, the additive or antagonistic response may produce adverse effects (2). Although many pharmacodynamic drug interactions do not cause serious adverse effects, it is difficult to anticipate which interactions may produce clinical difficulty when a patient is receiving 5–10 drugs for various medical conditions. Therefore, clinicians should know the pharmacokinetic as well as the pharmacodynamic drug interactions to anticipate clinical effects and reduce the risk of toxicity and/or seizure worsening when a drug is added to or withdrawn from the patient’s drug regimen (2).

cesses: the fraction of the dose that is absorbed from the gut and the fraction that does not undergo presystemic metabolism. There are several mechanisms by which a drug may affect the gastrointestinal absorption of another: (1) binding or chelation, (2) changing gastric pH, (3) alteration in gastrointestinal motility, and (4) alteration in gastrointestinal flora (5). Changing gastric pH and alteration in gastrointestinal flora are not mechanisms generally found to interfere with AEDs and psychotropic medications. When a precipitant drug binds with or otherwise inhibits the gastrointestinal absorption of an object drug, the serum concentration of the object drug usually begins to decrease at a rate that is dependent on its elimination half-life. Drug binding in the gastrointestinal tract occurs through mechanisms such as adsorbing drugs onto their surface, and preventing passage of the drug across the wall of the intestine (5). In one study, administration of aluminum hydroxide and magnesium hydroxide simultaneously and within 2 hours of a single dose of gabapentin reduced gabapentin bioavailability by approximately 10 –20% (6). These types of drug interactions can generally be prevented by separating administration times by 2 hours, with the administration of the objective drug prior to the participitant drug. Gastric emptying can be an important determinant of drug absorption rate. Drugs that increase gastric motility (i.e., metoclopramide) can hasten the absorption of drugs whereas drugs such as anticholinergics, for example, antidepressants, that slow gastric emptying can delay the absorption of orally administered drugs. Although the absolute bioavailability may not be affected by altering the rate of absorption, a slowed rate of absorption could be clinically important if a rapid drug response is desired (5). For example, because of phenytoin’s relatively slow and concentration-dependent absorption and the need to achieve high serum concentrations when loading a patient, an alteration in the rate of absorption of phenytoin may lead to a delay in achieving a therapeutic concentration.

Absorption With regard to orally administered drugs, knowledge of the extent of and factors determining the bioavailability of these substrates helps predict changes that could occur to their pharmacokinetics with administration of interfering medications. Oral bioavailability (amount of the dose that reaches the systemic circulation) is determined by two major pro-

Protein Binding Drug interactions related to protein binding result from the displacement of one drug from a protein by another drug with greater affinity (7). Displacement interactions are usually not of clinical significance unless the displaced drug is highly protein bound (ⱖ90%), is slowly eliminated, and has a narrow therCopyright © 2001 by Academic Press All rights of reproduction in any form reserved.

94 apeutic range (i.e., phenytoin) (3). When a displaced drug possesses these properties, the enhanced pharmacological effect may be transient because more unbound drug is available for elimination from the body. For this reason, protein binding displacement interactions may be dose dependent and may be clinically significant only when there is a reduction in the affected drug’s elimination. Phenytoin, valproic acid, and tiagabine are the only highly protein-bound antiepileptic drugs. Protein binding displacement interactions involving phenytoin and valproate depend on the concentration of valproic acid. When the serum concentration of valproic acid is ⬍35 mg/L, the displacement of phenytoin is minimal and no dosage adjustment is required (8). However, when the valproic acid level is ⬎50 mg/L, the extent of phenytoin displacement increases and a dosage adjustment may be required. The interaction can result in the total phenytoin concentration’s increasing, decreasing, or not changing when valproate is added. However, unbound phenytoin concentrations may be changed. Therefore, unbound phenytoin concentrations should be monitored in a patient receiving both valproate and phenytoin to reduce the risk of toxicity. Protein binding displacement interactions may be of greater importance when the displacing drug also reduces the elimination of the object drug (5). For example, valproic acid displaces diazepam from plasma protein binding sites with a concomitant inhibitory effect on diazepam metabolism, leading to increased risk of adverse effects (9). Of the SSRIs, fluoxetine, paroxetine, and sertraline are highly protein bound, while citalopram (80%) and fluvoxamine (77%) are not of clinical importance. Although protein binding raises the issue of displacement interactions, SSRIs are weakly bound to ␣ 1-acid glycoprotein (10). This may explain why SSRIs have not been found to increase the free fraction of concomitantly administered drugs that are also highly protein bound (i.e., TCAs) (11).

Drug Interactions Affecting Metabolism Pharmacokinetic interactions between AEDs and psychotropic agents arise most frequently as a consequence of drug-induced changes in hepatic metabolism. The propensity for AEDs and psychoactive agent to interact with each other depends on their metabolic characteristics and action on drug metabolic enzymes (1, 2) (see Table 1).

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Candace Smith

Biotransformation Before discussing drug interaction examples and their impact on clinical therapy, drug metabolism is reviewed. The chemical reactions involved in drug biotransformations (drug metabolism) are facilitated by enzymes that play an important role in the inactivation and subsequent elimination of drugs not easily excreted by the kidney. Biotransformation reactions are classified as either phase I (nonsynthetic) or phase II (synthetic/conjugation) reactions. Drug elimination via metabolism is normally a multistep process involving both phase I and phase II reactions. However, the structural features of many drugs allow conjugation to occur without previous phase I reactions (12). Phase I reactions include oxidation, reduction, and hydrolysis. Commonly, phase I biotransformation reactions occur first and introduce or expose a functional group on the drug molecule, making it more polar to facilitate biliary and/or renal elimination. Phase II biotransformation generates water-soluble metabolites from parent compounds or phase I metabolites by linking them to their corresponding glucuronides. Other phase II reactions include methylation and acetylation. However, the latter routes of metabolism usually do not enhance water solubility. Among the phase I reactions is the cytochrome P450 microsomal enzyme system, a collective term for a group of related enzymes or isoenzymes that oxidize numerous drugs (13). These metabolic enzymes are a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes, but also are present in high concentrations in enterocytes of the small intestine and, in smaller quantities, in extrahepatic tissues such as the kidney, brain, and lungs (14). As well, uridine diphosphate (UDP) glucuronosyltransferases (UGTs), the enzymes responsible for glucuronidation, are located in the endoplasmic reticulum and therefore form part of the microsomal fraction (13). Although more than 30 human metabolic cytochrome P450 isoenzymes have been identified to date, the major ones responsible for drug metabolism are CYP3A4, CYP2D6, CYP1A2, and CYP2C subfamily (14). Each P450 isoenzyme is encoded by a separate gene and classified according to families and subfamilies based on the degree of similarity in amino acid sequence of the iosenzyme they encode. CYP3A4 is the most abundantly expressed isoenzyme and is responsible for the majority of drug metabolism. Some of the most important factors involved in drug bio-

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Drug Interactions TABLE 1 Metabolic Pathways and Enzyme Effects of AEDs and Psychotropics Drug

Metabolic isoenzyme pathway

Other pathway

Enzymes drug induces

Enzymes drug inhibits

AEDs Carbamzepine

CYP3A4

GT

Ethosuximide Felbamate

CYP3A4 CYP3A4 (minor)

None Hydrolysis

Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Phenobarbital

None Negligible Negligible CYP2C9/19

Renal GT Hydrolysis GT GT

Phenytoin

CYP2C19/C9

None

Tiagabine Topiramate

CYP3A4

None Hydrolysis Hydroxylation Glucuronidation GT ␤-oxidation Acetylation

Valproic acid Zonisamide Antipsychotics

CYP3A4

Quetiapine

CYP3A4, 2C19 2D6 (minor) CYP2D6/3A4 CYP1A2, 2D6 3A4 (minor) CYP1A2, 2C9 2D6 (minor) CYP3A4/2D6 CYP1A2/2D6

Risperidone Clozapine Olanzapine Sertindole Haloperidol Antidepressants Fluoxetine Sertraline

2C9/2D6 3A4

Paroxetine

2D6

Fluvoxamine

2D6

Citalopram

2C19, 3A4, 2D6

Nefazodone

3A4, 2D6 (metabolite) 2D6, 3A4 (metabolite)

Venlafaxine

CYP1A2, 2C9, 3A4 GT None CYP3A4

GT

None GT (minor) None CYP3A4 CYP1A2, 2C, 3A4 GT CYP1A2, 2C, 3A4 GT None CYP3A4

None

None None CYP2C19 ␤ oxidation None None None CYP2C19 None None None CYP2C19

None

CYP2C9 GT None

None

None

Conjugation

2D6, 3A4 2D6, 2C19

Glucuronidation

2D6 (weak)

transformation are age, nutrition, stress, hepatic disease, and genetic polymorphisms (14). Genetic Polymorphism Genetic polymorphism is a functional expression of some CYP450 isoenzymes (i.e.,2D6 and 2C19) that can

34A, 2D6 2D6 2D6, 3A4, 2C9 2D6, 3A4 (weak) 2C 2D6, 3A4 (weak) 1A2 (weak) 2C9 (weak) 1A2, 3A4, 2C9 2D6 (weak) IA2 (weak) 2D6 (weak) 2C19 (weak) 3A4, 2D6 (weak) 2D6 (weak)

contribute to marked interpatient variability in drug metabolism, leading to significant drug interactions (14). The cytochrome P450 2D6, the target of sparteine/debrisoquine oxidation, is a particular isoenzyme that has been extensively studied (13). This isoenzyme occurs in a relatively inactive form in Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

96 5–10% of white persons and in 1–3% of Asians and black persons (13). The wild-type cytochrome P450 2C19 gene is absent in 2– 6% of Caucasian populations and up to 20% of Asian populations (13). Individuals can be characterized as extensive (rapid) or poor (slow) metabolizers depending on whether the enzyme is available to metabolize the drug. Poor metabolizers of CYP2D6- or CYP2C19-dependent drugs may be at increased risk of adverse effects arising from accumulation of the unmetabolized parent compound (15). Poor metabolizers, including the elderly, show greater plasma concentrations, prolonged elimination, and possibly enhanced pharmacological effects (1). The most clinically relevant interaction appears to be the potent inhibition by some of the antipsychotics of the metabolism of the tricyclic antidepressants. Risperidone and sertindole are two antipsychotic agents that demonstrate metabolic changes consistent with CYP2D6 polymorphism. It has been shown that extensive metabolizers convert risperidone rapidly to 9-hydroxyrisperidone, an active metabolite, while poor metabolizers convert it much more slowly, resulting in a change in half-life (3 hours for extensive metabolizers and a 20-hour half-life for poor metabolizers). In addition, coadministration of a drug that inhibits the isoenzyme may lead to phenotypic conversion of an extensive metabolizer to a poor metabolizer. For example, coadministration of fluoxetine, a potent inhibitor of CYP2D6, with risperidone, which also is an inhibitor as well as being metabolized by CYP2D6, may lead to a shift in the distribution of extensive and poor metabolizers (15). In contrast, drugs with multiple metabolic pathways may not demonstrate a significant change in pharmacokinetics in poor versus extensive metabolizers. For example, olanzapine serum concentrations have not been shown to be increased in patients who are poor metabolizers because CYP2D6-mediated oxidation appears to be a minor metabolic pathway for olanzapine and it has multiple metabolic pathways (16). Citalopram, as well, which is metabolized by both CYP2C19 and CYP2D6, may or may not have some interindividual variability in plasma concentrations with Caucasians compared with Asians (17). In general, genetic polymorphisms are clinically significant only if the drug and/or its metabolite are eliminated mainly by CYP2D6 or CYP2C19. With the recommended doses of drugs such as tricyclic antidepressants and some of the neuroleptics, two groups are at risk of developing a drug– drug interaction. The poor metabolizers are at risk of developing toxic plasma concentrations, whereas the rapid extensive Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

Candace Smith

metabolizers may display subtherapeutic plasma concentrations (13). Induction and Inhibition of Metabolism Some of the most important drug– drug interactions are mediated by inhibition or induction of interacting drugs by cytochrome P450 isoenzymes. Induction of new protein synthesis accelerates drug metabolism and decreases the magnitude and duration of drug response, and inhibition results in elevated plasma drug concentrations with increased potential for enhanced beneficial or in most cases adverse effects (4). Many known inhibitors or inducers of metabolism are of uncertain clinical relevance. However, particular attention must be paid to specific drugs or drug classes that are strong inducers or inhibitors of other drugs. There are no known inducers of CYP2D6, but a number of agents induce CYP34A. Specific anticonvulsants and pyschotropics that deserve mention because they are potent inducers of the CYP isoenzymes as well as the UGTs and have been associated with clinically relevant interactions include carbamazepine, phenytoin, and phenobarbital; whereas many of the SSRIs (e.g., fluvoxamine and fluoxetine) and the antipsychotic agents (e.g., risperidone) are strong inhibitors of the cytochrome P450 isoenzymes. The extent of inhibition is more difficult to predict than the type of interaction because it depends on the affinity of the substrate for the enzyme and the dose of the inhibitor. The onset and offset of the drug interaction are frequently rapid, but depend on the half-life of the inhibiting drug and the time needed to achieve a new steady state (four to five half-lives) (18). If the half-life of the inhibiting drug is shorter than that of the substrate, less time is required to revert to a lower steady-state concentration once the inhibitor is discontinued than when the inhibitor was initiated (18). For drugs such as phenytoin, which are concentration dependent, stabilization of a serum concentration following the administration of an inhibitor is quite variable and may take days to occur. In addition, small changes in metabolism by an enzyme inhibitor can lead to clinically significant changes in serum concentrations because of saturable metabolism or Michaelis– Menten pharmacokinetics associated with phenytoin. Unlike competitive inhibition, enzyme induction requires time to develop after the introduction of an inducing agent. The time required depends on both the time to reach steady state of the inducing agent and the de novo synthesis of enzymes (2). The mechanism of induction is generally inducer specific. Clini-

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cally, the consequences are a fall in the plasma concentration of the affected drug and a possible reduction in its therapeutic effect. If the affected drug has an active metabolite, induction can result in increased metabolite formation and potentially an increase in the drug’s therapeutic effect or toxicity (i.e., carbamazepine). The magnitude of the effect is proportional to the dose of the inducing agent (18). In contrast to the dose relationship, induction is not strictly additive when patients are receiving multiple inducers (2). The offset of enzyme induction is also gradual since it depends on elimination of enzyme-inducing drug and an elimination of increased enzyme stores. When the inducer is removed, plasma concentrations of the affected drug increase if the dose is not reduced. In summary, enzyme inducers with long half-lives (e.g., phenobarbital, t 1/2 ⫽ 3–5 days) usually have longer onset and offset than enzyme inducers with shorter half-lives (i.e., carbamazepine, t 1/2 ⫽ 8 hours). Some drugs may be metabolized by more than one isoenzyme, as are many of the psychoactive drugs including amitriptyline, imipramine, and clozapine. When a drug has more than one metabolic pathway, a clinically significant interaction may or may not occur depending on which metabolic pathway is predominant (8). This was demonstrated in a study evaluating the interaction between phenytoin and topiramate where topiramate inhibited the CYP2C19 isoenzyme involved in phenytoin metabolism, but did not inhibit the isoenzyme CYP2C9 (which accounts for 70 –90% of phenytoin clearance), resulting in a small but clinically insignificant change in phenytoin serum concentrations (19). This explains why few significant metabolic interactions occur with phenobarbital, where each elimination pathway is responsible for no more than 20% of its clearance and only drugs affecting more than one pathway are likely to produce clinically relevant effects (2). The metabolism of felbamate appears to be contradictory in terms of the role of CYP34A. The clearance of felbamate can be increased with inducers of the CYP34A isoenzyme, but CYP34A inhibitors have little effect on its pharmacokinetics. This is because under normal conditions the metabolic pathway, CYP3A4, is relatively minor (20). A drug may inhibit or induce the activity of a specific isoenzyme even though it is not a substrate or metabolized by that particular isoenzyme. As an example, phenytoin and phenobarbital, despite being potent inducers of CYP34A, are not metabolized by this isoenzyme but rather by CYP2C9/19 (21). In addition, some drugs can inhibit (e.g., fluoxetine) or induce (e.g., carbamazepine) their own metabolism as

well as others (1). One must not forget metabolite formation and whether the metabolite is active or inactive. Norfluoxetine, the active metabolite of fluoxetine and a more potent inhibitor of CYP3A4, can lead to a persistent drug– drug interaction following the discontinuation of fluoxetine because of the usually long half-life of norfluoxetine (15). In addition, drug may not inhibit the primary metabolic pathway but may reduce the clearance of an active metabolite. Nefazodone is metabolized primarily via CYP3A4 but one of its active metabolites is eliminated via CYP2D6. Therefore, CYP2D6 inhibitors may not affect nefazodone but may increase its active metabolite (22). Summary Some drug classes are relatively homogeneous, and all members of the class interact with other drugs in essentially the same way. However, for most drug classes pharmacokinetic differences can result in differing interaction patterns for individual members of the same class. Therefore, as some of the most notable drug classes for altering drug metabolism are discussed, note the differences in the propensity for one drug to cause an interaction relative to another. In addition as the various drug– drug interactions are being discussed consider the substrate’s therapeutic window (if one exists), the presence of active metabolites and their half-lives, whether genotypic polymorphism exists, and the probability of concurrent use (1).

INTERACTIONS BETWEEN AEDs Clinically significant drug interactions involving hepatic metabolism are observed with all the antiepileptic drugs except gabapentin, levetiracetam, and tiagabine. Of the antiepileptic drugs, felbamate, phenobarbital, phenytoin, and carbamazepine are strong inducers of the P450 enzyme system and, therefore, are involved in many drug interactions. Phenytoin, as well as carbamazepine and phenobarbital, increases the metabolism of drugs that are metabolized by the CYP3A4 and CYP2C9 subfamilies and UGTs; while felbamate and topiramate are only inducers of the CYP3A4 isoenzymes (2). In addition to inducing the same isoenzymes as phenobarbital and phenytoin, carbamazepine induces its own metabolite, via CYP3A4-catalyzed metabolism to carbamazepine 10,11-epoxide. Carbamazepine 10,11-epoxide (CBZ-E) is pharmacologically active and contributes to the therapeutic effects of carbamazepine as well as its Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

98 systemic and neurotoxicity (23). Patients receiving comedications with enzyme-inducing agents such as phenobarbital, phenytoin, and felbamate have an increased ratio of CBZ-E to carbamazepine in the plasma because of the CYP3A4-mediated conversion of carbamazepine to the epoxide metabolite (23, 24 –26). Coadministration of valproic acid or felbamate can lead to a 50% increase in the epoxide metabolite of carbamazepine (27, 28). Increases in the active metabolite carbamazepine epoxide generally cause no change or a small decrease in carbamazepine plasma concentrations with the addition of valproic acid (28). This interaction may be related to valproic acid’s inhibition of expoxide hydrolase, the enzyme responsible for metabolism of the epoxide metabolite. While this interaction is of limited clinical significance, patients may develop adverse neurological effects from the elevated carbamazepine epoxide concentrations, necessitating a decrease in dose. Through felbamate’s induction of CYP3A4 metabolism, carbamazepine concentrations may decrease 15%–30%, while carbamazepine epoxide concentrations increase, leading to variable clinical effects (26). Therefore, one should also consider the effects on the active metabolite of carbamazepine when other enzyme-inducing agents are administered concurrently. Although phenytoin and phenobarbital induce hepatic metabolism, competition at the site of metabolism can occur with other drugs metabolized by the same isoenzyme. Since phenytoin and phenobarbital are metabolized by the same isoenzyme, the combined use of phenytoin and phenobarbital may have a variable response. Individually phenytoin and phenobarbital accelerate the elimination of carbamazepine, probably by stimulating the CYP3A4 isoenzyme, resulting in a significant reduction in carbamazepine concentrations (23). However, adding phenobarbital to patients stabilized on a combination of carbamazepine and phenytoin is of little consequence because the metabolism of carbamazepine is maximally induced (29). Certain drugs can affect the metabolism of some drugs in one way and other drugs in the opposite direction. For example, when carbamazepine and phenytoin are given concurrently, the serum concentrations of both drugs can often be affected in opposite directions. Phenytoin plasma concentrations may either increase, decrease, or remain the same after addition of carbamazepine. While the decrease in phenytoin concentration is probably due to induction of CYP2C9, the mechanism by which carbamazepine increases phenytoin is unclear (30, 31). Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

Candace Smith

Plasma concentrations of felbamate are increased during coadministration with valproic acid and decreased with phenytoin and carbamazepine (24). Furthermore, due to the ability of felbamate to inhibit CYP2C19 and ␤-oxidation, plasma concentrations of phenytoin, phenobarbital, and valproic acid are increased during coadministration with felbamate (24 –26). Maximal induction or deinduction occurs approximately 1–2 weeks after initiation or removal of drug therapy but depends on the drug’s half-life. Some AEDs have the advantage of minor or no interference with the metabolism of other drugs, as is the case for gabapentin, lamotrigine, tiagabine, levetiracetam, and vigabatrin (32). Although lamotrigine and tiagabine are drugs that do not interfere with the metabolism of many drugs, they are strongly induced or inhibited by other AEDs. Because lamotrigine is glucuronidated, drugs such as phenytoin, phenobarbital, carbamazepine, and valproic acid are expected to affect elimination of lamotrigine. In one study, coadministration of the hepatic enzyme-inducing antiepileptic drugs phenytoin and carbamazepine decreased the lamotrigine serum concentration/dose ratio from 65 to 31 and 17 nmol/L/mg, respectively (33). In contrast, the concomitant administration of valproic acid significantly increased the serum concentration/ dose ratio of lamotrigine to 251 nmol/L/mg (33).

INTERACTIONS BETWEEN ANTIDEPRESSANTS AND AEDs With the increasing use of pyschotropic drugs in the treatment of psychiatric disorders associated with epilepsy, potential drug– drug interactions exist because both of these classes of drugs are metabolized primarily by the P450 microsomal enzyme system, with some antiepileptic agents (carbamazepine, phenytoin, felbamate) acting as inducers of metabolism and most of the antidepressants (SSRIs) inhibiting metabolism (34). While members of this pharmacological class are similar in terms of CNS pharmacodynamics, they are quite different in terms of their pharmacokinetic effects and their effects on various cytochrome P450 isoenzymes (11). The capacity of individual SSRIs to cause drug interactions is influenced by their effects on cytochrome P450 enzymes and there is now considerable knowledge of the effects of SSRIs on CYP1A2, CYP2D6, CYP3A4, and CYP2C19. From the data presented in Table 2 it appears that the potential for an individual SSRI or atypical antidepressant to

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Drug Interactions TABLE 2 Potential Interaction of Antidepressant Medications with Antiepileptic Medications Relative rank High

CYP1A a Fluvoxamine

CYP2C a

CYP2D6 a

Fluvoxamine Fluoxetine

Paroxetine Fluoxetine Secondary TCA

Moderate Low to minimal

Substrate

a

Fluoxetine Bupropion Sertraline Paroxetine Citalopram Nefazodone Venlafaxine Carbamazepine (minor)

CYP3A a

Sertraline Paroxetine Nefazodone Venlafaxine

Nefazodone

Sertraline Fluvoxamine Citalopram (metabolite)

Fluvoxamine Fluoxetine (metabolite) Fluoxetine Paroxetine Sertraline

Bupropion Nefazodone Venlafaxine Phenytoin Phenobarbital

Carbamazepine Tiagabine Felbamate Zonisamide Ethosuximide

SSRIs in descending order of magnitude.

inhibit the metabolism of an AED is greatest for fluvoxamine, fluoxetine, and nefazodone and least for sertraline, paroxetine, venlafaxine, and citalopram. On the basis of in vitro studies of human liver preparations, and other studies, the rank order of potency for inhibition of CYP3A4 is nefazodone & fluvoxamine Ⰷ fluoxetine, which can result in clinically meaningful increases in blood levels of many of the AEDs metabolized by this isoenzyme (33). On this basis, concomitant administration of the SSRIs fluvoxamine and fluoxetine with carbamazepine has the potential to increase plasma concentrations of carbamazepine, leading to adverse effects. Case reports have shown variable effects on serum concentrations of carbamazepine or its metabolite, ranging from no effect to 70% increase in serum concentrations when fluvoxamine was coadministered (11, 35, 36). Similar to fluvoxamine, fluoxetine either increased serum concentrations of carbamazepine or had no effect (37–39). Similarly, investigators have described the occurrence of carbamazepine toxicity when nefazodone was added to patients stabilized on carbamazepine therapy (40, 41). Plasma concentrations of carbamazepine increased 23% to threefold, which the authors attributed to inhibition of CYP3A4 by nefazodone. In contrast, neither sertraline nor paroxetine altered carbamazepine concentration, indicating their lack of effect on CYP34A (1, 42). A better recognized IA2 inhibitor, fluvoxamine, exhibits moderate CYP2C enzyme-inhibitory effects, similar to fluoxetine, which can result in phenytoin

toxicity (33, 44). Symptoms of toxicity, including nausea and ataxia, have been reported in patients receiving fluvoxamine and concomitant phenytoin (34). As well, case reports involving patients on phenytoin reported a 67–309% increase in serum concentration with the addition of the inhibitor fluoxetine (43, 44). In several case reports, fluoxetine also increased valproic acid levels to the toxic range (45, 46). Neither paroxetine nor venlafaxine appears to significantly affect the metabolism of carbamazepine, valproic acid, or phenytoin because they inhibit primarily the isoenzyme CYP2D6 (42). In conclusion, it is likely that fluoxetine, nefazodone, and fluvoxamine affect serum concentrations of AEDs to a greater extent than paroxetine, sertraline, venlafaxine, or citalopram because of the pathways used. In contrast to the effect of SSRIs on AEDs, there is little evidence for the influence of TCAs on the pharmacokinetics of AEDs (47). There are few data describing the effects of AEDs on SSRIs or TCAs. There is evidence that phenobarbital and phenytoin may cause a 25% decrease in plasma concentrations of paroxetine by decreasing systemic availability (42), whereas valproic acid may increase plasma paroxetine concentrations. However, these pharmacokinetic alterations were not associated with any observable clinical effects. A pharmacodynamic effect may be observed in patients receiving carbamazepine and fluoxetine. Toxic serotonin syndrome was observed in a patient receiving fluoxetine and Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

100 carbamazepine in one study (48). While fluoxetine serum concentrations were not determined, another study did not show an alteration in fluoxetine or its metabolite when carbamazepine was concurrently administered (1). Because nefazodone and sertraline are substrates of the isoenzyme CYP3A4, there is the theoretical potential for phenytoin, felbamate, topiramate, and carbamazepine to affect these serum concentrations. Many of the TCAs are metabolized by the CYP2D6 isoenzyme and, therefore, are not susceptible to enzyme induction or inhibition by any of the AEDs. However, reports have shown enhanced elimination in patients receiving concurrent enzyme-inducing AEDs such as carbamazepine (47, 67). Therefore, since inadequate serum concentrations can result in therapeutic failures, patients treated with enzyme-inducing AEDs may require therapeutic drug monitoring with subsequent increases in doses of TCAs than when receiving monotherpy (49).

INTERACTIONS AMONG ANTIDEPRESSANTS SSRIs are commonly coadministered with other antidepressants to enhance clinical efficacy in resistant patients (14). Many of the secondary tricyclic antidepressants and antipsychotics (i.e., risperidone, sertindole, clozapine) are metabolized by CYP2D6 and, therefore, form the focus of clinical attention with respect to their potential interactions with SSRIs. Drug– drug interactions involving fluoxetine, sertraline, and paroxetine with desipramine have been described. In normal volunteers, paroxetine 20 mg daily and fluoxetine 20 mg daily demonstrated threefold and fourfold increases in desipramine levels due to significant inhibition of CYP2D6, respectively (50, 51, 77). Additionally, because of the long half-life of norfloxetine (active metabolite of fluoxetine), plasma desipramine concentrations remained elevated for weeks despite discontinuation of fluoxetine. It is suggested that the dosage of a TCA such as desipramine be reduced 75% when fluoxetine is added to a TCA (47). As well, coadministration of desipramine and sertraline resulted in a significant elevation (50%) of plasma desipramine concentrations (52, 53). The lack of a drug interaction between desipramine and fluvoxamine may be because of the minimal effect of fluvoxamine on CYP2D6 (54). Overall, the relative impact of each SSRI on the in vivo clearance of desipramine is as follows: fluoxetine, 380 – 640% increase in desimipraCopyright © 2001 by Academic Press All rights of reproduction in any form reserved.

Candace Smith

mine concentrations; paroxetine, 327– 421% increase; citalopram, 47% increase; sertraline, 0 –37% increase; and fluvoxamine, 14% increase (11). The tertiary tricyclic antidepressant imipramine is demethylated to desipramine via several isoenzymes CYP1A2, CYP2C19, and CYP3A4 and hydroxylated via the CYP2D6 isoenzyme (15). The three- to fourfold increase in imipramine concentration following the addition of fluoxetine illustrates a significant drug interaction potential at multiple isoenzymes. Similarly, because of the ability of fluvoxamine to inhibit CYP3A4, CYPP1A2, and CYP2C19 isoenzymes, elevations in imipramine concentrations are significant (15). A study of 12 healthy subjects taking fluvoxamine for 10 days and a single dose of imipramine (50 mg) and desipramine (100 mg) demonstrated a minimal in vivo pharmacokinetic interaction with desipramine (55). However, fluovoxamine caused significant prolongation of imipramine’s half-life and a marked decrease in clearance, demonstrating that many imipramine pathways were blocked by fluvoxamine. Because of the potent inhibitory effects of fluvoxamine on CYP1A2 reports of increased serum concentrations by varying extents (two- to eightfold over baseline) of other tricyclic antidepressants, particularly those of clomipramine (eightfold increase) and amitriptyline (twofold increase), have been reported (35, 56). Because the potential exists for serotonergic syndrome, a pharmacodynamic interaction with the use of SSRIs and TCAs, patients receiving these combinations should be monitored to avoid toxicity. When pharmacokinetic interactions occur, cardiac arrhythmia, heart block, and sudden death are possible when plasma concentrations of tricyclic antidepressants exceed 450 ␮g/L (15). Although there are few drug– drug interactions where antidepressants influence the elimination of SSRIs, steady-state plasma concentrations of citalopram were elevated by about 36% during coadministration of phenothiazines. These interactions are likely to have considerable clinical significance and require careful monitoring of clinical response when these agents are combined (47).

INTERACTIONS BETWEEN AEDs AND ANTIPSYCHOTIC AGENTS Because of the metabolic induction caused by many of the AEDs, notably carbamazepine, phenytoin, phenobarbital, there is generally an increase in the clearance rate of many of these antipsychotic medications

101

Drug Interactions TABLE 3 Potential AED Drug Interactions with Antipsychotics Object drug

Mechanism

Quetiapine

34A

Risperidone Clozapine

3A4? 1A2, 3A4

Olanzapine Sertindole

1A2, 2C19 (minor) 34A

Haloperidol

1A2

a

Precipitant drug

Effect on object drug

Carbamazepine Phenytoin Phenobarbital Felbamate a Topiramate a Carbamazepine Carbamazepine Phenytoin Phenobarbital Felbamate Topiramate Carbamazepine Phenytoin Carbamazepine Phenytoin a Phenobarbital a Felbamate a Topiramate a Carbamazepine Phenytoin Phenobarbital

Increased metabolism

Increased metabolism Increased metabolism

Increased metabolism Increased metabolism

Increased metabolism

Theoretical.

leading to clinical failure (57). The principal isoenzymes of significance with antipsychotics are CYP2D6, CYP3A4, and CYP1A2. From the data presented in Table 3, potential drug– drug interactions of clinical significance affecting the clearance of the antipsychotic agents might result at the CYP2D6 and CYP34A systems for sertindole; at CYP1A2, CYP34A, for clozapine; at CYP1A2 for olanzapine; at 3A4 for risperidone; at 34A and 2D6 for quetiapine; and at 2D6 for haloperidol (57). For many of the antipsychotics, there may be a twofold increase in the clearance rate if an anticonvulsant such as carbamazepine or phenytoin is coadministered. This means that the patient may require twice as much medication to achieve the same concentration during the drug interaction than without the coadministered medication, or the dose may require reduction when the anticonvulsant is removed. In the presence of carbamazepine, phenytoin, phenobarbital, and possibly the newer anticonvulsants felbamate and topiramate, doses of drugs such as sertindole, clozapine, olanzapine, and quetiapine might need to be increased (54, 58, 59). Valproic acid has caused clozapine levels to either increase or decrease (60, 61). However, in the presence of multiple metabolic pathways, the chance of an inducer or inhibitior causing significant effects is reduced since the alternate pathway can often com-

pensate for the alterations in the primary pathway. For instance, because olanzapine is metabolized by multiple pathways, inhibition of the primary pathway should not cause the same degree of toxicity that would occur with a drug with only one pathway of metabolism. Particularly relevent is the interaction between the CYP1A4 isoenzyme inducers and haloperidol. Several studies have shown that haloperidol plasma levels decrease 50 – 60% after carbamazepine, phenytoin, and phenobarbital coadministration (62, 63). According to some investigators, the dosage of haloperidol should be two- to threefold higher than normal in patients treated with AEDs that interfere with its metabolism (1). Data on the effects of the new antipsychotics on AEDs are lacking. Because most of the AEDs are not substrates of CYP2D6 and many of the psychotropics, olanzapine, sertindole, risperidone, and clozapine, are inhibitors of CYP2D6, there is a low potential for any drug– drug interaction (1, 57, 58). In contrast, the potential exists for a drug– drug interaction between clozapine, a CYP2C19 inhibitor, risperidone or sertindole, a CYP3A4 inhibitor, and phenytoin and carbamazepine, respectively (58). A pharmacodynamic interaction between lithium and carbamazepine has been described in which patients develop a syndrome characterized by somnolence, confusion, disorientation, and ataxia and other cerebellar symptoms (64).

MONAMINE OXIDASE INHIBITORS (MAOIs) AND ANTIPSYCHOTIC AGENTS The ability to cause pharmacodynamic interactions differs from one drug class to another depending on the respective mechanisms of action (1). The risk of a pharmacodynamic interaction increases with an increase in the range of receptors and enzymes affected. Therefore, the risk of a pharmacodynamic interaction decreases as the mechanism of action becomes more specific (47). The greatest pharmacodynamic interactions have been reported with the MAOIs. MAOIs produce their antidepressant effect by blocking monoamine oxidase degradation. The most dangerous drug interaction in pyschiatry is the combination of any SSRI or serotonergic TCA with any MAOI, including phenelzine, trancyclopromine, and selegiline (65). This pharmacodynamic drug interaction, which does not depend on cytochrome P450 inhibition, consists of central nervous system (i.e., seizures, coma), cardiovascular (hypertension), and auCopyright © 2001 by Academic Press All rights of reproduction in any form reserved.

TABLE 4 Potential Drug Interactions Precipitant drugs Antidepressant

Interacts with Antidepressant

AED

Nafazodone Imipramine Amitriptyline Clomipramine

Carbamazepine Phenytoin

Clozapine Haldol Olanzapine MAOIs Lithium Quetiapine

Fluoxetine

Venlafaxine Desipramine Imipramine Trazodone

Phenytoin Carbamazepine Valproic acid

Haldol MAOIs Clozapine Lithium Thioridazine Risperidone Quetiapine Sertindole

Paroxetine

Desipramine Venlafaxine

Clozapine Haldol MAOIs Thioridazine

Citalopram

Desipramine

Lithium MAOIs

Sertraline

Desipramine

SSRIs Fluvoxamine

Atypical Nefazodone Venlafaxine Trazodone MAOIs AED Carbamazepine

Carbamazepine Lamotrigine

MAOIs Clozapine Thioridazine

Carbamazepine

Haldol, MAOIs Haldol

Carbamazepine Phenytoin? All Citalopram

Tiagabine, Topiramate Lamotrigine Valproic acid Ethosuxamide Phenytoin Felbamate Zonisamide

Oxcarbazepine

Lamotrigine Phenytoin

Phenytoin

Tiagabine Topiramate Lamotrigine Phenobarbital Valproic acid Felbamate Zonisamide Carbamazepine

Vigabatrin Valproic acid

Antipsychotic

Phenytoin Phenytoin Ethosuximide Lamotrigine

Desipramine

Lamotrigine

Valproic acid Carbamazepine 102

Haldol Olanzepine Risperidone Quetiapine Clozapine Sertindole

Haldol Sertindole Thioridazine Quetiapine Olanzapine Clozapine

Clozapine

103

Drug Interactions TABLE 4—Continued Precipitant drugs Antidepressant

Interacts with Antidepressant

AED

Antipsychotic

Topiramate

Phenytoin Valproic acid

Phenobarbital

Tiagabine Felbamate Lamotrigine Phenytoin Zonisamide Ethosuximide

Sertindole Quetiapine Clozapine Haldol

Felbamate

Phenytoin Carbamazepine Phenobarbital Valproic Acid Tiagabine Lamotrigine

Clozapine Sertindole a Quetiapine a

Primidone Antipsychotics Sertindole Olanzapine Risperidone Quetiapine Clozapine

Clozapine MAOI

Venlafaxine Fluoxetine

Clozapine

Fluoxetine Fluvoxamine Paroxetine Venlafaxine

Risperidone

tonomic (hyperpyrexia) symptoms due to excessive serotonin activity, known as the serotonin syndrome. Since the effect of irreversible MAOIs persists several days after cessation, a washout period of at least 2 weeks should elapse between discontinuation of a MAOI and initiation of TCA or SSRI therapy. If combination therapy is considered, the drugs should be introduced together at a low dosage. It is generally considered safer to add a MAOI to a TCA than vice versa (47). Tranylcypromine with imipramine or clomipramine should be avoided, since they are considered to be more likely to cause a reaction (47). Particular care should be exercised with fluoxetine due to its long half-life and that of its active metabolite. In this situation, a 5-week washout period is recommended between fluoxetine discontinunation and administration of a MAOI (47). In an attempt to minimize the serious adverse effects of these agents, a new generation of MAOIs have been developed (47). Although a newer, selective, reversible MAOI, moclobemide appears to be devoid of many of the pharmacodynamic effects of the older MAOIs; its metabolic pathway appears to involve CYP2C19, leading to a prolonged clearance in poor

metabolizers (66). CYP2D6 does not appear to play a significant role in the metabolism of moclobemide; therefore, SSRIs that have significant inhibitory effects on this substrate may not affect the clearance of moclobemide. A phenothiazine, for example, thioridazine, which is a potent ␣-adrenergic blocking agent, may produce uncontrollable hypotension when combined with a MAOI antidepressant (65). In contrast, because haloperidol has the least ␣-adrenergic blocking effects and is the least likely to induce hypotension, the potential of an additive interaction with a MAOI is less likely than with other neuroleptics (65).

CONCLUSION A large number of interactions involving AEDs and antipsychotic agents have been reported and many more will be described in the future. Some of these drug– drug interactions are well documented while others have been reported only anecdotally. Pharmacokinetic and pharmacodynamic drug– drug interactions between AEDs and psychotropic agents are imCopyright © 2001 by Academic Press All rights of reproduction in any form reserved.

104

Candace Smith

portant and complex because of the multiple enzyme systems that can be affected. Although it is generally believed that older less specific agents are more likely to cause clinically significant pharmacokinetic and pharmacodynamic interactions, this may not be true in all situations. In considering metabolic drug– drug interactions, it is important not to concentrate on only one isoenzyme system. Many of these agents are metabolized and interact with many isoenzyme systems. Since the presence of multiple metabolic pathways can reduce the chance of an inducer or inhibitor causing significant effects, it is important to understand when one pathway can compensate for the primary pathway. In addition, do not forget whether the drug has an active metabolite. In general, the risk of a serious pharmacodynamic interaction decreases with increasing selectivity (i.e., SSRI vs MAOI) of the the drug action. Table 4 is provided to aid you in evaluating the potential for a drug– drug interaction. However, some general recommendations can be made to minimize the occurrence of an adverse drug interaction in patients with psychiatric disorders and epilepsy. (1) Multiple-drug therapy should be used only where there is a definite clinical indication. (2) Knowledge of the interaction potential of the individual agents is essential. (3) In general, the risk of serious pharmacodynamic interactions decreases with increasing selectivity of the drug. (4) Finally, many adverse effects can be avoided or minimized by appropriate dosage adjustments based on clinical observation and determination of plasma drug concentrations when available. In summary, caution should be advised when prescribing antipsychotic agents with AEDs that are eliminated through the same enzymatic pathway, especially those agents with a narrow therapeutic range.

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