Drug-Drug Interactions in the Elderly with Epilepsy: Focus on Antiepileptic, Psychiactric, and Cardiovascular Drugs

Special Issue - October 2004

The goal of this educational activity is to review the current and potential interactions among antiepileptic drugs and select psychiatric and cardiovascular drugs that are frequently used in the geriatric patient with epilepsy.

Sponsored by the

Continuing Medical Education Accreditation Statement

The University of Minnesota is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The University of Minnesota designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit actually spent on the educational activity. Credits are available until the expiration date of October 15, 2005.

This CME activity was produced under the supervision of Ilo E. Leppik, MD, Professor, College of Pharmacy; Adjunct Professor, Department of Neurology, University of Minnesota; Director of Research, MINCEP Epilepsy Care.

Continuing Medical Education Policy on Faculty and Sponsor Disclosure

It is the policy of the University of Minnesota that the faculty and sponsor disclose real or apparent conflict of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/unapproved use of drugs or devices that are included in their article(s). Detailed disclosure is provided below.

Statement of Need

The goal of this educational activity is to review the current and potential interactions among antiepileptic drugs and select psychiatric and cardiovascular drugs that are frequently used in the geriatric patient with epilepsy.

Target Audience

This activity is designed for neurologists, emergency department physicians, and primary care providers.

Learning Objectives

Upon completion of this educational program, the participant should be able to:

• Understand the pharmacology of drug-drug interactions
• Identify the pathways and isoenzymes involved in drug-drug interactions
• Evaluate the current and possible drug-drug interactions among antiepileptic, psychiatric, and cardiovascular drugs and adjust treatment protocol accordingly

Release date: October 15, 2004; Expiration date: October 15, 2005

Faculty

Carol Collins, MD
Research Associate
Department of Pharmaceutics
University of Washington

Rene Levy, PhD
Chair
Department of Pharmaceutics
School of Pharmacy
University of Washington

Full Disclosure Policy Affecting CME Activities

As a sponsor accredited by the ACCME, it is the policy of the University of Minnesota to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation.

The faculty reported the following:

Off-Label Product Discussion

The faculty members have disclosed that their articles will not include unlabeled/unapproved uses of pharmaceuticals or devices.

Grant Support

This educational activity has been supported by an unrestricted educational grant from UCB Pharma, Inc.

Introduction

Geriatric patients with epilepsy are particularly vulnerable to drug-drug interactions because they are often prescribed many other medications for their concurrent acute and chronic diseases.¹  Additional challenges in the treatment of this population are that elderly patients may be more sensitive to side effects, especially cognitive and cardiac, and that they experience age-related changes in protein binding and clearance, which increase the propensity for drug-drug interactions.² 

Geriatric patients with epilepsy are likely to have coexisting cardiovascular disease and/or psychiatric disorders such as dementia and/or depression. The most common known etiology of seizures in the elderly is stroke^3-6  with ischemic stroke being the most frequent cause. Ischemic strokes are associated with cardiovascular risk factors such as atrial fibrillation, carotid artery stenosis, hypertension, and coronary heart disease.⁷ 

An increased incidence of Alzheimer's disease has been found in individuals who have had a stroke.⁸  Independently, there is a 9% to 17% incidence of seizures among patients with dementia.^4-6,9-11  Furthermore, the prevalence of depression in patients with Alzheimer's disease has been estimated to be 30% to 50%.¹²  There is a known increase in the incidence of depression in individuals after a stroke¹³  and in individuals diagnosed with epilepsy.¹⁴  Although the etiology is not clear, patients with depression are more likely to have a stroke.^15,16  The risk of developing cardiovascular disease¹⁷  and epilepsy¹⁴  also is higher among individuals with depression.

This monograph focuses on the current and potential interactions among antiepileptic drugs and some psychiatric and cardiovascular drugs that are frequently used in the geriatric patient with epilepsy. The scope of this review will concentrate on alterations in drug metabolism due to the presence of other drugs.

The Food and Drug Administration (FDA) has published guidances (http://www.fda.gov/cder/guidance/clin3.pdf and http://www.fda.gov/cder/guidance/2635fnl.pdf) that provide recommendations for assessment of whether an agent is likely to alter the clearance of other drugs and for predicting the magnitude of that alteration. These guidances include recommendations on the utility of in vitro studies and the interpretation of specific in vivo clinical studies with probe substrates. They also provide very specific labeling guidelines for prescribing information on drug-drug interactions.

The Metabolism and Transport Drug Interaction Database^TM (http://depts.washington.edu/didbase) was the primary source of information for this monograph. It is a relational database that includes over 4500 published articles on drug interactions in humans. It includes pharmacokinetic parameters from both in vitro and in vivo data. MEDLINE^TM, MICROMEDEX^TM, international Pharmaceutical Abstracts,^TM and prescribing information were also utilized.

Chapter One
Pharmacology of Drug-Drug Interactions

The efficacy of a drug depends on the extent to which it reaches its site of action and its ability to produce a biological effect at that target. The science of pharmacokinetics describes the absorption, distribution, and clearance of a drug. Many factors can modify these parameters, altering a drug's systemic concentration.

Drug-drug interactions occur when one therapeutic agent either alters the concentration (pharmacokinetic interactions) or the biological effect of another agent (pharmacodynamic interactions). Pharmacokinetic drug-drug interactions can occur at the level of absorption, distribution, or clearance of the affected agent. Pharmacodynamic drug-drug interactions are more difficult to evaluate than pharmacokinetic interactions due to alterations in drug metabolism and thus will be discussed only briefly. Key principles important for an understanding of drug-drug interactions and their clinical implications will be discussed.

An important pharmacokinetic property is the relationship between dose and plasma concentration. This relationship may be described as linear or nonlinear. When a drug's pharmacokinetic properties are linear, there is a proportional and predictable relationship between dose and plasma concentration. For example, doubling the dose of the drug will result in a doubling of the plasma level. Drugs with nonlinear pharmacokinetic properties have a dose-plasma concentration relationship where a doubling of the dose results in an increase in plasma concentration, which may be more than double for some drugs (such as those with saturable metabolism) or less than double for others (such as those that exhibit autoinduction). This is critical for drugs with narrow therapeutic windows where small increases in plasma concentrations may result in toxic side effects. Phenytoin is an example of an agent that exhibits both saturated metabolism and a narrow therapeutic window.

Many drugs exhibit altered bioavailability in the geriatric population. Drugs that have nonlinear kinetics and altered bioavailability in the elderly can be especially challenging because the plasma concentrations cannot be accurately predicted. The concentration of a drug in the systemic circulation is a very important factor in terms of both its efficacy and its toxic side effects. Two terms that describe the drug concentrations achieved after administration of a known dose of drug are the maximum concentration observed and the area under the curve, which describes the overall relationship of drug concentration over time. Clinical studies in drug-drug interactions typically will compare the concentration of the drug being acted upon (substrate) given by itself to the concentration observed by giving the same dose in the presence of another drug (precipitant).

The final pharmacokinetic concept that needs to be stressed in drug-drug interactions is elimination of drug from the body. Some terms used to quantify elimination are clearance and half-life. The classic definition of clearance is the volume of blood cleared per unit time of the drug in question by the various processes of elimination. This volume is related to the blood flow of the organs (typically liver and kidney) responsible for the clearance of the drug.

Half-life is the time needed for elimination of one half of the total amount of drug in the body. This term is easier to conceptualize than clearance, but it is not measured in some studies evaluating drug bioavailability.

Many drugs are eliminated by metabolism. Drugs are metabolized by Phase I catalytic reactions such as oxidation, reduction, and hydrolysis or Phase II conjugation reactions, such as glucuronidation and sulfation.

The Phase I microsomal reactions that have been studied the most in the past 20 years involve the cytochrome P (CYP) 450 family of enzymes. These enzymes are large heme-containing proteins that exhibit substrate-binding properties not dissimilar to the oxygen-binding properties of hemoglobin. The P450 isoenzymes are distributed throughout the body, but the ones that are most important in drug metabolism are located in the endoplasmic reticulum in the cytoplasm of cells found in the intestinal wall and the liver.

Although there are many enzymes in this family, only a few are responsible for the majority of metabolic reactions involving drugs. These include the isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Table 1).

		Table 1. Enzymes Responsible for Majority of Metabolic Drug Reactions
		Isoforms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4

The drug-drug interactions involving Phase II conjugation reactions have not been studied as extensively as those pertaining to the P450 system. Of these Phase II drug-drug interactions, those involving glucuronidation are the best characterized. The enzymes responsible for glucuronidation (uridine diphosphate glucuronosyltransferases [UGTs]) are also located in the endoplasmic reticulum of the liver.

Enzyme inhibition refers to the decrease in metabolic enzyme activity due to the presence of an inhibitor. Inhibitors generally affect the binding of the substrate to the enzyme or form inactive complexes.

Inhibition of enzyme activity may result in higher concentrations and/or prolonged half-life of the substrate drug. The increase in concentrations or prolongation in half-life of the substrate enhances the potential for toxic side effects. The clinical significance of a specific drug-drug interaction depends on the degree of accumulation of the substrate and the therapeutic window of the substrate.

In general, the onset of metabolic inhibition is rapid, a matter of hours or days. The degree of inhibition will increase in relationship to the dose of the inhibitor until maximal inhibition occurs. This maximum state of inhibition may require the inhibitor to reach its own steady state. For some inhibitors, such as fluoxetine, it may take several days to reach steady-state inhibition. After introduction of the inhibitor, the concentration of the affected drug will rise until it reaches a new higher steady-state plasma concentration. The enzyme inhibition will continue as long as the two drugs are given together. If the inhibitor is withdrawn, its effect on enzyme activity will decrease based in part on the half-life of the inhibiting drug and in part on the mechanism by which the drug caused the enzyme inhibition.

Inhibitors can be evaluated and ranked as to the strength of inhibition by comparing their effects on known substrates of a given isoezyme. Another general characteristic of enzyme inhibition is that it is specific for an isoenzyme but independent of the substrate. Thus, an inhibitor should decrease the metabolism of all substrates of a given isozyme but would not be expected to alter the metabolism of drugs not metabolized by the specific isoenzyme.

Enzyme induction is associated with an increase in enzyme activity. For drugs that are substrates of the isoenzyme induced, the effect is to lower the concentration of these substrates. Generally, the effects of enzyme induction occur more gradually than those of inhibition. The mechanism of induction involves the increased synthesis of new enzyme. It may take 2 to 4 weeks to develop full induction. This slower time course is governed by the time needed to synthesize new enzyme and the time needed to reach steady state of both the inducing agent and the induced substrate.

The clinical consequence of the presence of an inducing agent and the resultant decrease in concentration of the substrate may be loss of efficacy. For some drugs this may be countered by increasing the dose. For other drugs, where the therapeutic plasma concentration has not been established or where efficacy is not easily determined, dosage adjustment cannot easily be accomplished.

The inducing effect on enzyme activity will continue at a new steady state as long as the two drugs are given simultaneously. If the inducing agent is stopped, enzyme activity will gradually decrease based in part on the half-life of the isozyme and in part on the half-life of the inducing drug. Clinically, it is important to remember that plasma concentration of the substrate may rise dramatically after withdrawal of an inducer. For substrates with a narrow therapeutic window, this may result in toxic side effects (Table 2).

		Table 2. Key Terms in Metabolic Enzyme Activity
		Enzyme inhibition = Decrease in metabolic enzyme activity due to the presence of an inhibitor   = May result in higher concentrations and/or prolonged half-life of the substrate drug, increasing the potential for toxic side effects Enzyme induction = Associated with an increase in enzyme activity   = The effect is to lower the concentration of these substrates of the isoenzyme induced   = May result in loss of efficacy

The optimal situation in avoidance of metabolic drug-drug interactions is selection of drugs that are not metabolized by the liver and that do not alter the activity of the enzymes involved in hepatic metabolism. Only a few drugs match these criteria. For drugs that do not meet these criteria, the most desirable substrate would be metabolized by multiple enzymes. If a drug is metabolized by multiple enzymes, inhibition of one enzyme is not likely to have a clinically significant effect unless there are extenuating circumstances, such as drugs with very narrow therapeutic indices or in patients who are lacking the enzymes needed for the alternative pathways. However, a drug that is metabolized by multiple enzymes may have clinically significant interactions with agents that induce enzyme activity. Induction of a pathway that normally accounts for a small portion of the elimination of a drug can result in clinically significant decreases in drug concentration because of a marked increase in isoenzyme activity. This is a particularly important consideration with drugs that will be used concomitantly with the antiepileptic drugs that are known to be inducers of enzyme metabolism (carbamazepine, phenobarbital, and phenytoin). Examples of drugs exhibiting clinically significant induction via a minor pathway include citalopram and metoprolol.

Prodrugs present even more complex situations. Many drugs are administered in a pharmacodynamically inactive form referred to as a prodrug. There are many reasons why an entity would be administered as a prodrug. One of the most common reasons is that the active entity is poorly absorbed or unstable. Prodrugs are dependent on metabolism in order to convert them into the pharmacodynamically active forms.

Addition of an inhibitor or an inducer to a prodrug may produce an apparently paradoxical change in the pharmacokinetics of the prodrug. For example, the addition of an enzyme inhibitor will block the conversion of a prodrug to its active form and may result in a loss of efficacy rather than an accumulation of the active form. Similarly, the addition of an enzyme inducer may result in an increased concentration of the active form and lead to toxicity.

Pharmacogenomics

There are known inter-ethnic differences in the enzyme activity of many of the isoforms. Ethnic differences are most dramatic with CYP2C19 where approximately 20% to 30% of Asians have markedly reduced enzyme activity compared with 3% of Caucasians and 5% of African Americans. CYP2C9 activity is absent in about 1% of both Caucasians and African Americans. For CYP2D6, there is little enzyme activity in 7% of Caucasians and African Americans. For the isozymes CYP1A2 and CYP3A4, there are large variations in enzyme activity between individuals but these differences cannot be separated into ethnic characteristics at this point.

The ability to genotype patients is now becoming more widespread. Patients who exhibit apparently anomalous responses to drugs can undergo testing that allows for tailoring drug regimens to patients with known metabolic defects in P450 enzymes.

Review of P450 Isoenzymes

CYP1A2
This isoenzyme metabolizes caffeine but otherwise metabolizes only a relatively small proportion of drugs. It is induced by the antiepileptic drugs carbamazepine, phenobarbital, phenytoin, and cigarette smoking. There are large variations in CYP1A2 activity between individuals.

CYP2C9
Substrates of CYP2C9 include phenytoin, S-warfarin, nonsteroidal anti-inflammatory drugs, sulfonylureas, oral hypoglycemia agents, and cyclooxygenase-2 inhibitors. This isoenzyme is induced by carbamazepine and phenobarbital. It has a variable response to phenytoin. A small percentage (1%) of Caucasians and African Americans have low CYP2C9 activity.

CYP2C19
Relatively few drugs are metabolized by this isoenzyme. Substrates include phenytoin and proton pump inhibitors. Carbamazepine has a variable effect on CYP2C19 activity. This enzyme is notable for the marked ethnic differences in activity. Up to 30% of Asians have low CYP2C19 activity while 3% of Caucasians and 5% of African Americans have markedly reduced activity.

CYP2D6
Substrates include beta-blockers and the selective serotonin reuptake inhibitors. This isoenzyme does not appear to be susceptible to induction. There is marked ethnic variability in CYP2D6 activity. About 7% to 10% of Caucasians are classified as poor metabolizers and about 5% are classified as ultrarapid metabolizers.

CYP3A4
The CYP3A isozymes (CYP3A4 and CYP3A5) metabolize the largest proportion of therapeutic agents. This includes carbamazepine, the antiepileptic agent zonisamide, calcium channel blockers, statins, and benzodiazepines. It is induced by carbamazepine, phenytoin, and phenobarbital. It is found in high concentrations in both the liver and the small intestine. There is a large variation in the activity of CYP3A4 between individuals.

Geriatric Pharmacokinetics

Very little is known about how the pharmacokinetics in elderly differ from younger adults. The processes that affect bioavailability may be profoundly altered in the elderly. In addition, geriatric patients may manifest an altered pharmacodynamic response to a drug. The situation is further complicated by the fact that the degree to which a drug's pharmacokinetic and pharmacodynamic properties are altered can certainly be a factor of the absolute age of the individual, but there is also the potential for remarkable variability based on the individual's underlying liver and renal function and the presence of comorbid diseases.

In general, the Phase I reactions are reduced in the elderly more than Phase II reactions. One consequence of the reduction in P450 enzyme activity in the elderly is that they may actually be less susceptible to enzyme induction by compounds such as carbamazepine, phenytoin, and phenobarbital.

Chapter Two
Antiepileptic Drugs

		Table 3. Enzymes Involved in Metabolism of Antiepileptic Drugs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

First- and Second-Generation Antiepileptic Drugs

Carbamazepine
Carbamazepine has a black box warning for aplastic anemia and agranulocytosis.¹⁸  It should not be used in patients with a history of bone marrow suppression.¹⁸  This drug is structurally related to the tricyclics and should not be used in patients who are sensitive to tricyclics.¹⁸  Its use with monoamine oxidase inhibitors is not recommended.¹⁸ 

Carbamazepine is associated with rare but serious dermatologic reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome. Prescribing information also recommends monitoring renal and liver function and periodic eye examinations. Hyponatremia has been reported in association with carbamazepine use.¹⁸  Signs of carbamazepine toxicity include drowsiness, dizziness, nausea, and vomiting.

Plasma levels of carbamazepine may fluctuate at a given steady dosage level and there may be marked variability between individuals.¹⁹  Side effects appear to be correlated with higher plasma levels. Carbamazepine exhibits nonlinear kinetics at higher doses; plasma levels are less than would be predicted from dosage increases. This is thought to be due to autoinduction. The clearance of carbamazepine in the elderly is reduced.^20-22 

Carbamazepine is extensively metabolized by CYP3A4 to its pharmacologically active metabolite, carbamazepine-10,11-epoxide. This metabolite is also responsible for the neurotoxic side effects of carbamazepine. There are minor contributions by CYP2C8 and CYP1A2.

Carbamazepine is an inducer of CYP1A2, CYP2C9, and CYP3A4. It also induces glucuronidation. Carbamazepine has a variable effect on CYP2C19.

Carbamazepine induces many drugs including sildenafil. It induces its own metabolism. Full autoinduction occurs 3 to 5 weeks after start of dosing. Carbamazepine metabolism may also be induced by phenytoin, phenobarbital, and St. John's Wort.

The metabolism of carbamazepine is inhibited by CYP3A4 inhibitors (such as the antibiotics erythromycin and clarithromycin and grapefruit juice). Coadministration of the antiepileptic drug valproate has resulted in increased plasma concentrations for carbamazepine-10,11-epoxide. It is thought the mechanism for valproate inhibition is due to inhibition of the enzyme epoxide hydrolase.

Gabapentin
Gabapentin is a gamma aminobutyric acid (GABA) analog. The mechanism by which gabapentin exerts its antiepileptic action is not known.²³  Gabapentin bioavailability is not dose proportional (ie, the bioavailability decreases with increasing dose).²³  This drug is not metabolized and it is excreted unchanged in urine. Gabapentin clearance is reduced by renal impairment. No dosage adjustment is necessary in elderly patients with normal renal function.²³ 

Because gabapentin is not metabolized, no interactions with known inhibitors or inducers of the P450 isozymes would be expected. In vitro testing did not demonstrate any inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 by gabapentin. Further, coadministration with carbamazepine, phenobarbital, phenytoin, and valproate did not demonstrate a change in gabapentin concentrations.²³ 

Lamotrigine
Lamotrigine blocks voltage-sensitive sodium channels in vitro and it is hypothesized that this effect in turn prevents the release of excitatory neurotransmitters including glutamate. It also is a weak blocker of serotonin reuptake.

Lamotrigine does carry a black box warning due to the incidence of severe rashes including Stevens-Johnson syndrome.²⁴  Rash is the most frequent reason for withdrawal of lamotrigine but severe reactions are rare. The risk of developing a rash is hypothesized to be somewhat dose related.

The dose-concentration relationship for lamotrigine is linear. No pharmacokinetic differences were observed in a trial of elderly volunteers²⁴ ; however, there were not sufficient numbers of subjects over the age of 65 years to make this determination with confidence. The prescribing information does recommend that the dose selection for an elderly patient should be cautious.

Lamotrigine is metabolized mainly by glucuronidation (>70%). About 10% of the lamotrigine dosage is excreted unchanged in the urine. Inducers of glucuronidation (carbamazepine, phenytoin, phenobarbital, and corticosteroids) are known to increase the metabolism of lamotrigine. The antiepileptic drug oxcarbamazepine also induces lamotrigine metabolism to a lesser extent. Valproate is known to inhibit lamotrigine metabolism.

Lamotrigine does not affect phenytoin, phenobarbital, and valproate concentrations. It would not be expected to alter the clearance of other antiepileptic drugs.

Levetiracetam
Levetiracetam is also structurally unrelated to other antiepileptic drugs and its mechanism of action in preventing seizure activity is not known. Its dosage-concentration relationship is linear. A small clinical study in subjects over 60 years of age demonstrated that clearance decreased by 38% and half-life was slightly longer compared with younger subjects.²⁵ 

Approximately 66% of a dose of levetiracetam is excreted by the kidney unchanged.²⁶  Another 24% is metabolized by hydrolysis of the acetamide group by a non-P450-dependent enzyme. Approximately 2.5% of a dose is thought to be metabolized by CYP enzymes. The metabolism of levetiracetam is not altered by other antiepileptic agents.

In vitro studies have suggested that clinically relevant concentrations of levetiracetam do not alter P450, epoxide hydrolase, or UDP-glucuronidation enzyme activity.²⁷  Clinical drug-drug interaction studies demonstrated that levetiracetam did not affect the pharmacokinetics of phenytoin, valproate, and the anticoagulant warfarin.

Oxcarbazepine
Oxcarbazepine is a 10-keto derivative of carbamazepine. This modification is significant because it prevents the formation of the epoxide metabolite that is associated with some of the adverse side effects of carbamazepine. Oxcarbamazepine is structurally related to carbamazepine, and approximately 25% to 30% of patients who have experienced hypersensitivity reactions to carbamazepine will have hypersensitivity reactions to the administration of oxcarbazepine.²⁸ 

Oxcarbamazepine is a prodrug that is converted to its active monohydroxy derivative (MHD) by cytosol arylketone reductase. Approximately 50% of the monohydroxy derivative is then glucuronidated. The steady-state pharmacokinetics of MHD are linear.²⁸  The plasma concentrations of MHD were 30% to 60% higher in elderly subjects compared with younger subjects.²⁸ 

Oxcarbazepine is a weaker inducer of CYP3A4 than carbamazepine. It is not known to produce autoinduction. The addition of oxcarbazepine would not be expected to have a clinically significant effect on most drugs that are CYP3A substrates. It does not have an appreciable inductive effect on other P450 isozymes, but it is a weak inducer of glucuronidation. Oxcarbazepine is a weak inhibitor of CYP2C19, and it may elevate phenytoin concentrations.

Oxcarbazepine is associated with a higher incidence of hyponatremia than carbamazepine. The incidence of hyponatremia is highest in elderly patients. Prescribing recommendations for oxcarbazepine include monitoring serum sodium levels when the patient is receiving other medications known to decrease sodium levels. Symptoms consistent with hyponatremia include nausea, malaise, headache, lethargy, confusion, and obtundation.

Phenobarbital
Phenobarbital is a long-acting barbiturate with significant sedating properties. Elderly patients may be more susceptible to its sedating effects compared with younger adults. Its half-life is also increased in the geriatric population.

Common side effects of phenobarbital are drowsiness, ataxia, and respiratory depression. Rare but severe side effects of phenobarbital include blood dyscrasias such as thrombocytopenic purpura, megaloblastic anemia, leukopenia, and agranulocytosis. Since phenobarbital is a barbiturate, withdrawal should be very gradual.

Phenobarbital is predominantly metabolized by CYP2C9 with minor contributions by CYP2C19 and CYP2E1. The major metabolite of phenobarbital is pharmacologically inactive. Valproate inhibits phenobarbital metabolism and the concomitant use of these medications is associated with excessive sedation.

Phenobarbital is also known to induce CYP1A2, CYP2C9, CYP3A4, and glucuronidation.

Phenytoin
Phenytoin is structurally related to barbiturates. This drug inhibits the sodium channel and has nonlinear pharmacokinetics within the standard dosing range. Dosages need to be reduced in the elderly. The prescribing information also contains warning about skin rashes and osteomalacia.²⁹ 

Phenytoin is predominantly metabolized by CYP2C9 (80%) with a minor contribution by CYP2C19 (20%). Its metabolism may be induced by carbamazepine and phenobarbital and conversely inhibited by valproate and oxcarbazepine. Phenytoin has a narrow therapeutic index and nonlinear pharmacokinetics. The addition of an inhibitor may produce a disproportionately large and clinically significant change in phenytoin levels. Phenytoin is known to induce CYP1A2, CYP3A4, and glucuronidation. The effect of phenytoin on CYP2C9 activity is variable.

Topiramate
Topiramate is a sulfamate-substituted monosaccharide.³⁰  The proposed mechanism of antiseizure activity for topiramate is not known but it is probably associated with multiple effects. It is known to block voltage-sensitive sodium channels and it also inhibits carbonic anhydrase. In contrast to many of the antiepileptic drugs, topiramate is associated with weight loss. More infrequent side effects include glaucoma, kidney stones,³¹  and renal tubular acidosis.³² 

Topiramate is primarily (70%) excreted without metabolism.³⁰  It exhibits linear pharmacokinetics. Topiramate clearance in the elderly is reduced only to the extent that renal function is reduced.³⁰ 

The isoenzymes involved in the metabolism of topiramate are unknown but it is susceptible to induction by carbamazepine, phenytoin, and phenobarbital.

Topiramate itself is a weak inducer of CYP3A4 but it does not exhibit autoinduction. It is also a weak inhibitor of CYP2C19 in vitro. In vivo, the effect of topiramate on the metabolism of other drugs is limited.

Valproate
Valproate is a branched chain fatty acid that is structurally similar to GABA and it is hypothesized to decrease seizure activity via GABAergic actions. It also blocks sodium channels.

Valproate has a black box warning for hepatotoxicity, teratogenicity, and pancreatitis.³³  The relationship between dose and plasma concentration is nonlinear. Clearance of valproate was reduced by approximately 40% in patients over the age of 68 years and it is recommended that the initial dosage be reduced in the elderly.³³ 

The predominant metabolic pathways for valproate metabolism are mitochondrial beta-oxidation and glucuronidation. Valproate is glucuronidated by UGT isoforms UGT1A6, UGT1A9, and UGT2B7. Less than 20% of metabolism occurs through other pathways including CYP2C9, CYP2C19, and CYP2E1. Valproate metabolism is susceptible to induction by carbamazepine, phenytoin, and phenobarbital.

Valproate is a weak inhibitor of CYP2C9. Valproate is known to inhibit the metabolism of carbamazepine, phenytoin, and phenobarbital. It also inhibits epoxide hydrolases and glucuronidation. It inhibits lamotrigine metabolism, and there is an increased risk of lamotrigine-associated serious skin reactions with combination therapy.

Zonisamide
Zonisamide is an analog of sulfonamide. Its use is contraindicated in patients with hypersensitivity to sulfonamides.³⁴  Rare side effects associated with the sulfonamide entity include Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant heptic necrosis, agranulocytosis, and aplastic anemia. Due to the association with serious skin reactions, the manufacturer recommends that consideration should be given to discontinuing zonisamide in patients with an unexplained rash.

Zonisamide blocks sodium and T-type calcium channels. It is a weak inhibitor of carbonic anhydrase and it is associated with a low incidence of renal calculi.

Zonisamide demonstrates a linear relationship between dose and plasma concentration in the range of 200 to 400 mg, but the concentration increases more than proportionately to dose at 800 mg.³⁴  Single-dose pharmacokinetic parameters were not different between young adults and elderly subjects; however the manufacturer does recommend caution when dosing elderly patients.³⁴  Common side effects include somnolence and fatigue.

Approximately 35% of a zonisamide dose is excreted in the urine unchanged. The predominant P450 isoenzyme responsible for metabolism of zonisamide is CYP3A4 with CYP2C19 being a minor pathway.³⁵  Zonisamide is induced by carbamazepine, phenobarbital, and phenytoin.

Zonisamide did not inhibit P450 enzymes in vitro. Zonisamide did not alter the pharmacokinetics of phenytoin, carbamazepine, lamotrigine, or valproate in clinical trials. It is not expected to interfere with the metabolism of other drugs.

Chapter Three
Antidepressants and Drugs Used to Treat Dementia

		Table 4. Enzymes Involved in Metabolism of Antidepressants and Dementia Drugs Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT ANTIDEPRESSANTS Fluoxetine     Minor** Minor** Major*** Minor** ? Paroxetine         Major**     Sertraline   Minor Minor Minor Major** Minor   Citalopram       Minor Major* Minor ? Escitalopram       Minor Major* Minor   Venlafaxine     Minor Minor Major* Minor   Duloxetine Minor       Major*     Mirtazapine Minor       Major Minor Minor DEMENTIA DRUGS Donepezil         Major Minor Minor Galantamine         Major Minor Minor Rivastigmine               Tacrine Major             Memantine               AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; *** = moderately potent inhibitors; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; ‡ = moderate inducer..

Antidepressants and Drugs Used to Treat Dementia

Although many antidepressants are used clinically, this monograph focuses on some antidepressants recommended for use in the elderly including fluoxetine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, and mirtazapine. The first five drugs covered are selective serotonin reuptake inhibitors (SSRIs); the last three are dual serotonin and norepinephrine reuptake inhibitors (SNRIs). These antidepressants have improved tolerability compared with tricyclic and some atypical antidepressants. They have broader therapeutic indices resulting in patients exhibiting fewer toxic side effects with overdose or metabolic inhibition. Although all antidepressants seem to increase the likelihood of seizures and this would be of particular concern in the epileptic patient, the antidepressants to be discussed here have less of this tendency than some other antidepressants. They also exhibit less anticholinergic side effects. In addition, these drugs have more favorable cardiotoxicity profiles and are less likely to precipitate cardiovascular effects such as tachycardia, hypertension, and cardiac conduction abnormalities. The cytochromes contributing to the metabolism of these antidepressants are not established in detail, although the predominant CYP pathways are known for these medications.

The five SSRIs reviewed in this monograph have similar affinities for serotonergic receptor sites (although citalopram and escitalopram do have the highest affinity), similar clinical efficacy, and similar side-effect profiles. Some of the common side effects for this therapeutic class include nausea, diarrhea, insomnia, jitteriness, headache, somnolence, and dry mouth. Other notable side effects are sexual dysfunction and weight gain.

There are marked differences in pharmacokinetic properties, especially half-lives.

Many antidepressants are inhibitors of CYP2D6, and the degree of CYP2D6 inhibition in vitro can be ranked from greatest to least: paroxetine> fluoxetine> sertraline> citalopram> venlafaxine.^36,37  Some antidepressants such as fluoxetine, paroxetine, venlafaxine, and duloxetine have the unique characteristic of being both substrates and inhibitors of the same CYP isoenzymes. The differences in pharmacokinetics between antidepressants contribute markedly to the clinical significance of their drug-drug interactions.

Selective Serotonin Receptor Inhibitors

Fluoxetine
The half-lives of fluoxetine and its active metabolite, norfluoxetine, have been reported as 4 to 6 days and 16 days, respectively, with some individuals having prolonged half-lives for fluoxetine up to 10 to 13 days and half-lives of norfluoxetine of up to 22 days.^38-40  The half-lives of fluoxetine and norfluoxetine have been reported to increase in healthy elderly subjects.⁴¹ 

Fluoxetine's major pathway of metabolism to norfluoxetine in vitro is by CYP2D6.^42,43  Minor metabolic pathways are mediated by CYP2C9, CYP2C19, and CYP3A4.^42-45 

Although fluoxetine is a less powerful inhibitor of CYP2D6 than paroxetine in vitro,^36,37  clinically its role as a CYP2D6 inhibitor is significant because fluoxetine and its metabolite, norfluoxetine (which also inhibits CYP2D6), have long half-lives.^38,39,46  CYP2D6 metabolism has been reported to remain inhibited for several weeks after discontinuation in young healthy subjects.^38,47  This effect may be more pronounced in the elderly.

Many of the drugs discussed in this review are metabolized by CYP2D6 and there is clinical evidence that the concomitant use of fluoxetine can result in inhibition of: lipophilic beta-blockers,^48,49  antiarrhythmics,⁵⁰  and calcium channel blockers.⁵¹ 

Fluoxetine inhibits CYP2C19 in vivo and CYP2C9 in vitro.^37,52-54  There are multiple case reports of phenytoin toxicity developing with concomitant administration of fluoxetine.^55-58  A compilation of 23 cases reported a 161% increase in phenytoin concentration and a mean time to onset of toxic symptoms of 13.8 days.⁵⁸  It is not known if the coadministration of phenobarbital and fluoxetine would result in excessive phenobarbital levels.

The predominant pathway for warfarin metabolism is CYP2C9. There are several case reports of increased bleeding when fluoxetine was administered concomitantly with warfarin.^59-62 

Fluoxetine is a weak inhibitor of CYP3A4 in vitro.^63-65  There are case reports and clinical studies that demonstrate increased carbamazepine levels with fluoxetine administration.^66-69  Zonisamide is metabolized by CYP3A4 but it also has a minor pathway catalyzed by CYP2C19. In addition, zonisamide demonstrates linear pharmacokinetics in the lower portion of its dosing range (200 to 400 mg) and it has a wider therapeutic index. It is less likely that concomitant administration of fluoxetine and zonisamide would result in zonisamide toxicity.

There are three case reports of increased valproate levels and neurotoxicity after the addition of fluoxetine in patients on valproate therapy.^70-72  The mechanism responsible for increased valproate levels remains unknown.

Paroxetine
Paroxetine has a different pharmacokinetic profile than fluoxetine especially clearance parameters. The half-life of paroxetine is 21 hours and steady-state paroxetine concentrations are achieved in about 8 to 10 days.^73,74  Clearance is decreased in the elderly.^73,74  Trough concentrations of paroxetine in the elderly were 70% to 80% greater than in younger adults and therefore the prescribing information recommends that the initial dosage in the elderly should be reduced.⁷³ 

Paroxetine is predominantly metabolized by CYP2D6.^75,76  A clinical study with coadministration of phenytoin decreased the plasma levels of paroxetine by about 50%.⁷³  In addition, a clinical study using a 14-day course of phenobarbital and paroxetine in healthy subjects reported that paroxetine levels decreased by 24%.⁷⁷  This suggests the presence of an inducible minor pathway. Nonetheless, it is clear that paroxetine metabolism is susceptible to induction and an increase in paroxetine clearance would be expected to occur in the presence of carbamazepine.

Paroxetine is an inhibitor of CYP2D6.^36,37,78-80  A clinical study using a 10-day course of a relatively modest dose (30 mg/day) of paroxetine in patients on chronic carbamazepine, phenytoin, or valproate therapy did not show any alterations in plasma concentrations of these drugs.⁸¹  Paroxetine coadministration did not alter the pharmacokinetics of diazepam or cimetidine.⁸²  However, in this same study, coadministration of warfarin and paroxetine resulted in mild bleeding, but this bleeding was not associated with an increase in prothrombin time.⁸²  Prescribing information for paroxetine recommends that the concomitant administration of paroxetine and warfarin should be undertaken with caution.⁷³ 

Sertraline
Sertraline has a half-life of 26 hours.⁸³  Sertraline is metabolized to desmethylsertraline, which is pharmacodynamically inactive. Desmethylsertraline has a much longer half-life than sertraline (2.5 times longer), and it exhibits a time-related increase in concentration up to 14 days.⁸³  Clearance in elderly patients was approximately 40% lower than in young adults.⁸³ 

The predominant metabolic pathway for sertraline metabolism is CYP2D6. Multiple other CYP enzymes including CYP2B6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 have been found to metabolize sertraline in vitro.^84-86  This raises the possibility that sertraline efficacy would be decreased in the presence of carbamazepine, phenytoin, and phenobarbital. This is supported by case reports of markedly decreased plasma sertraline levels concurring with lack of efficacy observed in two patients treated with sertraline and carbamazepine.⁸⁷  In addition, a retrospective comparison of sertraline levels between patients treated with either carbamazepine or phenytoin versus a control group not taking these antiepileptic agents found significantly reduced sertraline levels in the patients on carbamazepine and phenytoin.⁸⁸  Phenobarbital would also be expected to induce sertraline metabolism.

There are case reports of carbamazepine and phenytoin toxicity occurring when sertraline was administered concomitantly.^89,90  Prospective clinical studies performed in healthy subjects using a 200-mg dosage of sertraline for 10 days did not alter either carbamazepine or phenytoin pharmacokinetics.^91,92  Neither of these studies would have allowed desmethylsertraline levels to build up to the levels encountered in clinical cases. Therefore, these studies need to be interpreted judiciously because the inhibitory profile of desmethylsertraline is not well known, and there was no information on the genotypes of these patients.

There are also case reports of lamotrigine and valproate toxicity after administration of sertraline.^93,94  The mechanism of this inhibition is more difficult to explain based on existing data but may be based on sertraline inhibition of glucuronidation.

In a clinical study comparing prothrombin time before and after 21 days of sertraline administration there was a small but statistically significant increase in prothrombin time and a slight delay in normalization of prothrombin time after sertraline withdrawal.⁹⁵  Prescribing information suggests that patients be carefully monitored especially during addition or withdrawal of sertraline when patients are concomitantly receiving warfarin, propafenone, and flecainide.⁸³ 

Citalopram
Citalopram is the most selective inhibitor of serotonin reuptake among the SSRIs. Citalopram concentration was increased by 23% and 30% in elderly subjects and the prescribing information recommends a dosage of 20 mg/day for most elderly patients.⁹⁶  A recent review of 1344 subjects on citalopram found that at the dosage of 20 mg/day the only side effect elderly patients experienced more frequently than younger patients was bradycardia (2.4% versus 0.2%).⁹⁷ 

Citalopram is metabolized by CYP2C19, CYP3A4, and CYP2D6 to desmethylcitalopram in vitro.^98,99  Desmethylcitalopram is further metabolized by CYP2D6.⁹⁹  Carbamazepine administration in depressed patients not responding to citalopram decreased the plasma concentrations of S-citalopram and R-citalopram by 27% and 31%, respectively.¹⁰⁰  Phenytoin and phenobarbital administration would be expected to have a similar effect on citalopram concentrations. Oxcarbazepine would be expected to have a less significant effect on citalopram levels since it is a weak inducer. This is supported by a case report of increased citalopram levels after switching from carbamazepine to oxcarbazepine.¹⁰¹ 

Citalopram is a weak inhibitor of CYP1A2, CYP2C19, and CYP2D6 in vitro.^96,102  Citalopram would not be expected to alter the pharmacokinetics of any antiepileptic agents, and this is supported by a report that steady-state levels of carbamazepine were not changed by the addition of citalopram.¹⁰³ 

Administration of citalopram did not affect the pharmacokinetics of warfarin, and the prothrombin time was increased by 5%.⁹⁶  Coadministration of citalopram resulted in a two-fold increase in the plasma concentrations of metoprolol, but there were no clinically significant changes in blood pressure or heart rate.⁹⁶ 

Escitalopram
Escitalopram is the S-enantiomer of citalopram. It is more than twice as potent an inhibitor of 5-HT uptake as citalopram. Escitalopram concentrations and half-life were increased by 50% in elderly subjects and the prescribing information recommends that the 10-mg dose be used in elderly patients.¹⁰⁴ 

Escitalopram is metabolized by CYP3A4, CYP2D6, and CYP2C19 in vitro. It would be predicted that carbamazepine, phenytoin, and phenobarbital would induce escitalopram metabolism.

In vitro studies of escitalopram did not reveal an inhibitory effect of escitalopram on CYP1A2, CYP2C9, CYP2C19, or CYP3A4.¹⁰⁵  It is a weak inhibitor of CYP2D6 in vitro, and it does appear to inhibit CYP2D6 activity in vivo. Administration of escitalopram in healthy volunteers resulted in an 82% increase in plasma concentrations of metoprolol; however, there were no clinically significant effects on blood pressure or heart rate.¹⁰⁴  Escitalopram would not be expected to have a clinically significant effect on the metabolism of most drugs.

Serotonergic and Norepinephrine Antagonists

Venlafaxine
Venlafaxine is both a serotonin reuptake inhibitor and a norepinephrine reuptake inhibitor. It has a short half-life (5 hours).¹⁰⁶  Plasma levels were not altered in elderly patients.¹⁰⁶  A 12-month open-label clinical trial in patients 65 years and older was well tolerated with few cardiovascular side effects.¹⁰⁷ 

Venlafaxine's metabolism to its major active metabolite, O-desmethylvenlafaxine, is mediated by CYP2D6.^108,109  Minor pathways of venlafaxine metabolism are metabolized by CYP2C9, CYP2C19, and CYP3A4.¹¹⁰  Administration of carbamazepine, phenytoin, and phenobarbital would be anticipated to induce venlafaxine metabolism and decrease efficacy due to these minor but inducible pathways.

Given the inhibitory profile of venlafaxine, clinically significant inhibitions of antiepileptic drugs would not be expected to occur. This is supported by a clinical study that did not demonstrate a statistically significant change in carbamazepine pharmacokinetics.¹¹¹ 

Duloxetine
Duloxetine is a dual serotonin and norepinephrine inhibitor. It was issued an approvable letter for treatment of depression by the FDA in September 2003, and it is expected to be introduced in the US market in 2004. A limited amount of information is available on the pharmacokinetic profile of duloxetine. Age-related dose adjustments in duloxetine dosing are not required.¹¹²  There is little information that suggests that duloxetine would produce clinically significant alterations in the metabolism of antiepileptic agents.

Mirtazapine
Mirtazapine is a combined adrenergic and serotonergic antagonist that does not inhibit the reuptake of these neurotransmitters. It is structurally related to the tricyclics. Mirtazapine is also a potent histamine antagonist and has significant sedating properties compared with other antidepressants.¹¹³  It is sometimes used in elderly patients with insomnia because of demonstrated improvements in sleep architecture.¹¹⁴  Mirtazapine is associated with more weight gain than some of the other antidepressants. A rare but serious side effect is agranulocytosis.

Clearance of mirtazapine was reduced by 40% in elderly subjects, and the prescribing information recommends caution when administering mirtazapine in elderly patients. It, however, does not give specific recommendations for dose adjustment.^113,115  Steady-state conditions are attained in 4 days in younger adults and 6 days in elderly patients.¹¹⁶  Carbamazepine, phenytoin, and phenobarbital would be expected to induce the metabolism of mirtazapine because of the contribution of CYP3A4, CYP1A2, and UGT to mirtazapine metabolism.^113,116,117  This is supported by a clinical study in which coadministration of phenytoin with mirtazapine decreased the concentration of mirtazapine by 46%.¹¹⁸  Another study reported that coadministration of carbamazepine with mirtazapine in healthy subjects decreased the concentration of mirtazapine by 63%.^118-121 

In vitro studies have not indicated that mirtazapine inhibits any CYP isoenzymes.¹¹³  This is further supported by clinical trials in healthy subjects where mirtazapine had no effect on the steady-state pharmacokinetics of carbamazepine, cimetidine, paroxetine, or phenytoin.^118-121 

Pharmacodynamic Issues with Antidepressants

Both antidepressants and antiepileptic agents have considerable central nervous system side effects including drowsiness and fatigue. The simultaneous use of these agents could increase the risk of these side effects especially during initiation of treatment.

The SSRIs and the SNRIs are associated with hyponatremia.^122-130  Although there is little information on the propensity of the newer agents, escitalopram and duloxetine, to induce hyponatremia, it appears to be a class-related side effect and no one agent appears to have a predilection for causing hyponatremia over the other agents. The elderly are more at risk for development of hyponatremia with the use of antidepressants than younger adults.^{122,124,128,130} 

Carbamazepine and oxcarbazepine are associated with hyponatremia. Coadministration of either of these agents with the SSRIs or SNRIs would be expected to increase the risk of hyponatremia. Thiazide diuretics are commonly used in this population, and they also are associated with an increased risk of hyponatremia. A patient in whom the combination of carbamazepine or oxcarbazepine plus an antidepressant and a thiazide diuretic was used could be at particular risk for hyponatremia.

Drugs Used to Treat Dementia

The drugs used in the treatment of dementia include cholinesterase inhibitors and memantine. For drugs in this therapeutic class, efficacy has been determined by a decrease in rate of deterioration in cognitive performance. Therapeutic ranges for drug levels for this therapeutic class have not been determined. Unlike the dose titration commonly used in antidepressants or antihypertensives, titrating a dose to reach efficacy with this therapeutic class would be difficult.

Donepezil
Donepezil is a reversible inhibitor of acetylcholinesterase. It reaches steady-state concentrations within 15 days.¹³¹  No formal pharmacokinetic studies have been conducted in the elderly, but retrospective analysis suggests that no dosage adjustments need to be made in elderly patients.

Donepezil is metabolized by CYP2D6, CYP3A4, and glucuronidation. Inducers of CYP3A4 and glucuronidation (eg, carbamazepine, phenytoin, and phenobarbital) would be expected to increase the rate of elimination of donepezil, however, formal pharmacokinetic studies to evaluate the potential for enzyme induction of donepezil have not been conducted.¹³¹ 

In vitro studies show that at therapeutic plasma concentrations of donepezil there is little likelihood that donepezil will inhibit CYP2D6 or CYP3A4.¹³¹  Donepezil is not expected to alter the clearance of antiepileptic agents.

Galantamine
Galantamine is a reversible inhibitor of acetylcholinesterase. Galantamine concentrations were 30% to 40% higher in patients with Alzheimer's disease compared with young healthy subjects.¹³² 

Galantamine is metabolized primarily by CYP2D6 and CYP3A4. It also undergoes glucuronidation. Carbamazepine, phenytoin, or phenobarbital would be expected to induce the metabolism of galantamine and thereby reduce its efficacy. Galantamine did not alter the activity of CYP1A2, CYP2C, CYP2D6, CYP3A4, or CYP2E1 in vitro. Galantamine is not expected to alter the metabolism of any antiepileptic drugs. A clinical study of galantamine coadministration did not alter the pharmacokinetics of warfarin or prothrombin time.¹³² 

Rivastigmine
Rivastigmine is also a reversible cholinesterase inhibitor. Clearance was 30% lower in elderly subjects compared with clearance in younger subjects.¹³³ 

It is not known if carbamazepine, phenytoin, or phenobarbital induce the metabolism of rivastigmine.

In vitro studies have demonstrated that rivastigmine did not alter the activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.¹³³  Rivastigmine is not expected to alter the pharmacokinetics of antiepileptic agents.

Tacrine
Tacrine is a less potent and less specific acetylcholinesterase inhibitor than the other agents in this therapeutic class. In addition, tacrine has some clinically relevant disadvantages compared with other cholinesterase inhibitors including its short half-life, which requires administration four times a day. No dose adjustment is required for age.¹³⁴ 

Tacrine is metabolized predominantly by CYP1A2. It would be expected that carbamazepine, phenytoin, and phenobarbital would induce tacrine metabolism. Tacrine would not be expected to alter the metabolism of antiepileptic drugs.

Memantine
Memantine is an N-methyl-D-aspartate receptor antagonist. The pharmacokinetics of memantine are not altered by age.¹³⁵ 

Memantine is predominantly eliminated without being metabolized. Antiepileptic drugs would not be expected to alter the pharmacokinetics of memantine.

In vitro studies have shown that memantine produces minimal inhibition of CYP1A2, CYP2C9, CYP2D6, and CYP3A4.¹³⁵  Memantine would not be expected to affect the metabolism of antiepileptic drugs.

Chapter Four
Cardiovascular Agents

		Table 5. P450 Enzymes Involved in the Metabolism of Warfarin and Antiplatelet Agents Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT CARDIOVASCULAR AGENTS Warfarin Minor   Major Minor   Minor   Clopidogrel     *     Major   Cilostazol       Minor Minor Major*   Ticlopidine       *** *** ?   AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; *** = moderately potent inhibitors; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

Anticoagulants

Warfarin
The use of warfarin is a significant concern in the elderly population because warfarin has a narrow therapeutic index. Secondly, there is a significant age-related decline in warfarin metabolism.¹³⁶  Finally, elderly patients may have a higher risk of serious bleeding complications, especially those over the age of 80 years.^137-140 

Warfarin has an average half-life of 36 to 42 hours. Although there are minimal changes in clearance of warfarin in the elderly, there is a decrease in dosage requirement.

Warfarin is a racemic mixture of two enantiomers. The more potent S-warfarin enantiomer is metabolized primarily by CYP2C9. Minor enzymatic pathways for S-warfarin metabolism are catalyzed by CYP3A4 and CYP2C19. R-warfarin is a substrate of CYP1A2 and CYP3A4. Minor pathways for R-warfarin metabolism include CYP2C9 and CYP2C19.^141-142 

The propensity of carbamazepine and barbiturates to reduce warfarin levels and decrease prothrombin time is well documented. There are several case reports and clinical studies documenting a reduction in warfarin levels and decrease in prothrombin time during coadministration of carbamazepine.^143-147  Withdrawal of carbamazepine led to an increase in prothrombin time and in some cases bleeding occurred.

Phenobarbital also decreases prothrombin times. In one clinical study, phenobarbital decreased the half-life of warfarin by 50%.¹⁴⁸  In another, the clearance of R-warfarin was increased by 38%, and the clearance of S-warfarin was increased by 40%.¹⁴⁹  Finally, a third study demonstrated a decrease in average prothrombin time by 2.6 seconds.¹⁵⁰ 

Phenytoin apparently has a more complex effect on anticoagulation. There are case reports of increased prothrombin times or increased international normalized ratios (INRs) with concomitant administration.^151-154  Another case report that is frequently cited is from a patient who demonstrated a biphasic change in prothrombin time after the addition of phenytoin.¹⁵⁵  This observation is based on a limited number of data points observed in this one patient, but it leads to speculation in regards to the role of phenytoin as an inducer versus its potential for inhibition of CYP2C9.

Since valproate is a weak inhibitor of CYP2C9, it is not surprising that there is a case report of increased INRs in a patient on concomitant valproate and warfarin.¹⁵⁶  Conversely, since oxcarbazepine is only a weak inducer it would not be expected to alter warfarin metabolism. This is supported by a clinical study in which prothrombin times were unchanged when oxcarbazepine was administered with warfarin for a 7-day time course to healthy volunteers.¹⁵⁷  Levetiracetam would not be expected to have any effect on warfarin pharmacokinetics. A clinical study using therapeutic levels of levetiracetam concomitantly with warfarin did not demonstrate any pharmacokinetic or pharmacodynamic interaction between warfarin and levetiracetam.¹⁵⁸  Similarly, lamotrigine, gabapentin, and topiramate would not be expected to alter warfarin metabolism.

Clinically significant interactions with warfarin have been reported for other drugs covered in this chapter including: fluoxetine,⁵¹  gemfibrozil,¹⁵⁹  fluvastatin,¹⁶⁰  and lovastatin.¹⁶¹  Clearly, INRs need to be monitored when warfarin is being used with drugs that alter its pharmacokinetics, especially when these agents have been added or removed.

Antiplatelet Agents

Clopidogrel
Clopidogrel is a prodrug.¹⁶²  Its pharmacologically active metabolite, which irreversibly modifies platelet receptors, actually represents a small portion of the clopidogrel dosage. Plasma concentrations of the predominant metabolite (which is pharmacodynamically inactive) were significantly higher in the elderly compared with young healthy volunteers. No differences in platelet aggregation or bleeding times occurred though.¹⁶² 

In vitro studies have demonstrated that it is metabolized by CYP3A4 to its active metabolite.¹⁶³  Since the predominant metabolite is inactive, it is not clear what the effect of comedication with carbamazepine or phenytoin would be on the pharmacodynamics of clopidogrel. Clopidogrel was not influenced by the coadministration of phenobarbital.¹⁶² 

In high concentrations in vitro, clopidogrel inhibits CYP2C9, and therefore, the manufacturer cautions that clopidogrel may interfere with the metabolism of phenytoin, warfarin, and fluvastatin.¹⁶²  Since phenobarbital is also metabolized by CYP2C9, this caution should be extended to include phenobarbital. Clopidogrel is a weak inhibitor of CYP1A2 and CYP2C19 in vitro¹⁶⁴ ; however, clopidogrel did not alter the pharmacokinetics of theophylline, a CYP1A2 substrate, in vivo.¹⁶² 

Cilostazol
Cilostazol inhibits phosphodiesterase III. Cilostazol's mechanism of action is not known. Cilostazol is contraindicated in congestive heart failure and this warning is black boxed. Clearance was not significantly different in patients over the age of 50 years of age.¹⁶⁵  Cilostazol is primarily metabolized by CYP3A4 with minor pathways metabolized by CYP2D6 and CYP2C19.^165,166  It is predicted that cilostazol metabolism would be induced in the presence of carbamazepine, phenobarbital, or phenytoin. Cilostazol has little effect on CYP enzymes.¹⁶⁵  Coadministration of cilostazol with the CYP3A4 substrate, lovastatin, resulted in a 1.6-fold increase in total plasma lovastatin concentrations.¹⁶⁷  Concomitant administration with a single dose of warfarin did not alter the pharmacokinetics of warfarin.¹⁶⁸ 

Ticlopidine
Ticlopidine binds irreversibly to platelets and duration of platelet inhibition continues for the duration of the platelet lifespan. Ticlopidine has a black box warning for neutropenia, agranulocytosis, thrombotic thrombocytopenic purpura, and aplastic anemia. Plasma concentrations were doubled in the elderly in comparison with concentrations in younger adults.¹⁶⁹ 

Ticlopidine is a prodrug and is metabolized to several metabolites. The metabolic pathways for these metabolites have not been identified. The pharmacologic effects of ticlopidine were not affected by chronic administration of phenobarbital.¹⁶⁹  Ticlopidine is a moderate inhibitor of both CYP2C19 and CYP2D6 in vitro.^164,170,171  It also inhibits CYP1A2.¹⁶⁹  There are multiple case reports of phenytoin toxicity and a clinical study reporting inhibition of phenytoin metabolism by ticlopidine.^172-176  Prescribing information reports that several cases of elevated phenytoin plasma levels with associated somnolence and lethargy have been reported with concomitant administration.¹⁶⁹  Elevated carbamazepine levels have also been reported.¹⁷⁷ 

Chapter Five
Beta-Blockers

		Table 6. P450 Enzymes Involved in the Metabolism of Beta-blocking Agents Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT ANTIHYPERTENSIVES Acebutolol         ?     Atenolol               Bisoprolol         Major Minor   Carvedilol Minor   Major Minor Major Minor Minor Metoprolol         Major**     Propranolol Minor       Major**     Sotalol               Timolol         Major     AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

Beta-Blockers

Acebutolol
Acebutolol is a somewhat ß1-selective beta-blocker that is considered hydrophilic but it exhibits many of the characteristics of lipophilic beta-blockers, including extensive hepatic metabolism and a short half-life (3 to 4 hours). In geriatric patients, the bioavailability of acebutolol and its pharmacodynamically active metabolite is increased approximately twofold. Elderly patients may require a lower maintenance dose.¹⁷⁸ 

The mechanisms involved in the elimination of acebutolol are not well delineated. Sufficient information is not available to determine whether carbamazepine, phenobarbital, or phenytoin would induce acebutolol metabolism.

There is little information on the propensity of acebutolol to alter CYP enzyme activity. The prescribing information states that no significant interactions have been observed with warfarin.¹⁷⁸ 

Atenolol
Atenolol is a hydrophilic ß1-selective blocker. Atenolol clearance is correlated to renal function. Because elderly hypertensive patients often exhibit some decrease in renal function, it is suggested that a lower initial dosage should be used in the elderly.^179-181 

Atenolol is highly hydrophilic and it undergoes minimal hepatic metabolism in humans (about 10%).¹⁷⁹  Since it undergoes minimal hepatic metabolism, no metabolic drug interactions would be expected between atenolol and antiepileptic agents.

Atenolol would not be expected to alter the metabolism of other therapeutic agents.

Bisoprolol
Bisoprolol is a lipophilic highly ß1-selective agent that has a long half-life in comparison to other beta-blockers (10 to 12 hours).¹⁸²  In elderly subjects, mean plasma concentrations were increased. This was attributed to decreased creatinine clearance. Approximately 50% of an absorbed dose of bisoprolol is excreted by the kidneys unchanged and the remainder undergoes hepatic metabolism. Bisoprolol metabolism is predominantly catalyzed by CYP2D6, with a minor pathway catalyzed by CYP3A4.¹⁸²  Carbamazepine, phenobarbital, and phenytoin would be expected to induce the metabolism of bisoprolol. Bisoprolol would not be expected to alter the pharmacokinetics of antiepileptic agents.

Carvedilol
Carvedilol is a nonselective highly lipophilic beta-blocking agent with vasodilating activity. Plasma concentrations are about 50% higher in the elderly.¹⁸³  Carvedilol is extensively metabolized, with the primary isoenzymes responsible for metabolism being CYP2D6 and CYP2C9 with lesser contributions by CYP3A4, CYP2C19, and CYP1A2.¹⁸³  In vitro tests with human recombinant microsomes have demonstrated that carvedilol is also glucuronidated by UGT1A1, UGT2B4, and UGT2B7.¹⁸⁴  In clinical trials, total carvedilol concentrations were reduced by about 70% in the presence of the broad-spectrum inducer, rifampin.¹⁸³  There is a potential for carbamazepine, phenytoin, and phenobarbital to induce carvedilol metabolism.

There is little information on the potential for carvedilol to alter the metabolism of antiepileptic agents.

Metoprolol
Metoprolol is a ß1 blocker with no alpha-adrenergic activity. The prescribing information suggests that dose selection in the elderly should be cautious.^185,186 

Metoprolol is moderately lipophilic and predominantly metabolized by CYP2D6. Metoprolol clearance is inhibited by CYP2D6 inhibitors in vivo.¹⁸⁷  Case reports and clinical studies with coadministration of CYP2D6 inhibitors, including fluoxetine and paroxetine, have resulted in increased metoprolol concentrations.

Although metoprolol is predominantly metabolized by CYP2D6, it has been demonstrated that pentobarbital and rifampin do induce its metabolism. Therefore, metoprolol metabolism would be expected to increase in the presence of carbamazepine, phenytoin, or phenobarbital.

Metoprolol is a weak inhibitor of CYP2D6 in vitro and in vivo. Metoprolol is not known to alter the pharmacokinetics of antiepileptic agents.

Propranolol
Propranolol is a highly lipophilic nonselective ß1 and ß2 blocker. Higher plasma concentrations are noted in elderly patients compared with those in young healthy volunteers.¹⁸⁸ 

Propranolol is metabolized to an active metabolite, 4-hydroxy-propranolol. In vitro studies in human liver microsomes found that both CYP2D6 and CYP1A2 resulted in oxidation to 4-hydroxy-propranolol.¹⁸⁹  There were large racial differences in the proportions metabolized by these isoenzymes.¹⁸⁹  Due to the contribution of CYP1A2 to propranolol metabolism, there is a potential for induction by carbamazepine, phenytoin, and phenobarbital.

Propranolol is a weak inhibitor of CYP2D6.¹⁸⁸  Propranolol would not be expected to alter the metabolism of antiepileptic drugs.

Sotalol
Sotalol is a nonselective beta-blocker that is classified as a Class III antiarrhythmic. About 80% of a sotalol dose is excreted by the kidneys without metabolism.¹⁹⁰  The pharmacokinetics of sotalol are not altered by age. Metabolic drug-drug interactions are not expected between sotalol and antiepileptic agents.

Timolol
Timolol is a lipophilic nonselective beta-blocker. The prescribing information suggests that dose selection for an elderly patient should be cautious.¹⁹¹ 

Although a portion of a timolol dose is excreted by the kidneys, it undergoes hepatic metabolism by CYP2D6. A clinical study demonstrated that a 7-day course of phenobarbital induced timolol metabolism.¹⁹²  Timolol would also be expected to undergo increased metabolism in the presence of phenytoin and carbamazepine.

The effect of timolol on CYP enzymes is not well delineated. Timolol is not expected to alter the metabolism of antiepileptic agents.

Chapter Six
Diuretics

		Table 7. P450 Enzymes Involved in the Metabolism of Diuretics Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT DIURETICS Hydrochlorothiazide               Furosemide             Minor AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

Diuretics

Hydrochlorothiazide
Thiazide diuretics are frequently used to treat hypertension; however, relatively sparse formal pharmacokinetic data on these agents are available. Dosage titration should be cautious in the elderly.

Hydrochlorothiazide is not metabolized. Metabolic drug-drug interactions would not be expected between hydrochlorothiazide and antiepileptic agents.

Hydrochlorothiazide is associated with hyponatremia, especially in the elderly. Severe hyponatremia associated with the combined use of thiazide diuretics and selective serotonin reuptake inhibitors and carbamazepine has been reported.^193,194  The coadministration of oxcarbazepine would also be expected to increase the risk of hyponatremia.

Furosemide Furosemide is a short-acting loop diuretic. There is no requirement for dosage adjustment in the elderly.

Furosemide is predominantly eliminated by the kidneys without metabolism. It does undergo glucuronidation.^195,196  Since carbamazepine, phenobarbital, and phenytoin induce glucuronidation, the presence of these agents would be expected to lower the efficacy of furosemide. Furosemide is not expected to affect the metabolism of antiepileptic agents.

Chapter Seven
Angiotensin-Converting Enzyme (ACE) Inhibitors

		Table 8. P450 Enzymes Involved in the Metabolism of ACE Inhibitors Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT ACE INHIBITORS Benazepril               Captopril               Enalapril               Lisinopril               Perindopril             Minor Ramipril             Minor Quinapril               Trandolapril               AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

ACE Inhibitors

Benazepril
Benazepril is a prodrug that is converted by hepatic esterases to its active metabolite, benazeprilat. The pharmacokinetics of benazepril and benazeprilat do not appear to be influenced by age.¹⁹⁷ 
Benazepril and benazeprilat are cleared predominantly by renal excretion. The metabolism of benazepril to benazeprilat is not catalyzed by P450 enzymes. Metabolic drug-drug interactions would not be expected with concomitant use of benazepril and antiepileptic agents.

Captopril
Unlike the majority of drugs in this therapeutic class, captopril is not a prodrug. Dosage adjustment is required in renal impairment but not in elderly patients with normal renal function.¹⁹⁸ 

Captopril is excreted renally without metabolism. Metabolic drug-drug interactions with antiepileptic drugs are not expected.

Enalapril
The active metabolite of enalapril is enalaprilat, and there is no evidence of other metabolites.¹⁹⁹  The total plasma concentrations of enalaprilat were increased by 29% in healthy elderly subjects compared with those in healthy young subjects.²⁰⁰  There is a case report that coadministration of the inducer, rifampin, did not change the serum concentrations of enalapril but reduced the plasma concentrations of enalaprilat by 31%.²⁰¹  This suggests that carbamazepine, phenytoin, and phenobarbital may also decrease plasma concentrations of enalaprilat and reduce efficacy. Enalapril is not expected to alter the pharmacokinetics of antiepileptic agents.

Lisinopril
The half-life of lisinopril is longer than some other angiotensin-converting enzyme inhibitors (12 hours).²⁰²  Older patients on average, have a twofold higher total plasma concentration than younger patients.²⁰² 

Lisinopril is cleared renally and does not undergo metabolism. It is not expected to undergo metabolic drug-drug interactions with antiepileptic agents.

Perindopril
Perindopril is the prodrug of perindoprilat. Perindopril has an average half-life of 0.8 to 1.0 hours, and it does not accumulate with a once-a-day dosing regimen.²⁰³  Plasma concentrations of both perindopril and perindoprilat are approximately twice as high in patients older than 70 years of age.²⁰³ 

Perindopril is also glucuronidated²⁰³  and is cleared predominantly by the kidneys. It is not known if induction of glucuronidation by carbamazepine, phenytoin, or phenobarbital would result in a clinically significant alteration in perindopril pharmacokinetics.

Perindopril is not expected to alter the metabolism of antiepileptic agents.

Quinapril
Quinapril is a prodrug, which is de-esterified to the active metabolite, quinaprilat. It is not clear if dosage adjustments should be made in the elderly because there were not sufficient subjects to determine conclusively that pharmacokinetics were altered in this population. The prescribing information recommends that dose selection for an elderly patient should be cautious.²⁰⁴ 

Quinaprilat is excreted renally. Metabolic drug-drug interactions would not be expected with quinapril and antiepileptic agents.

Ramipril
Ramipril is a prodrug. It is de-esterified in the liver to its active metabolite, ramiprilat. Total plasma concentrations for ramiprilat are higher in older patients.^205,206  In addition to the de-esterification of ramipril, both ramipril and ramiprilat undergo glucuronidation into inactive metabolites. It is not known if induction by carbamazepine, phenobarbital, or phenytoin would alter the efficacy of ramipril. Ramipril is not expected to affect the metabolism of antiepileptic agents.

Trandolapril
Trandolapril is an ester prodrug of trandolaprilat. The plasma concentration of trandolapril is higher in elderly patients, while the plasma concentration of trandolaprilat was similar between young and elderly patients.²⁰⁷ 

Trandolaprilat is the predominant metabolite of trandolapril. Coadministration of trandolapril with cimetidine, which is a broad-spectrum inhibitor of P450 enzymes, resulted in a 44% increase in peak concentrations of trandolapril but no difference in the pharmacokinetics of trandolaprilat. It is not known if carbamazepine, phenytoin, or phenobarbital would alter the metabolism of trandolapril.

Trandolapril is not known to alter the metabolism of other drugs. This is supported by a clinical study in which the concomitant administration of trandolapril did not affect the pharmacodynamic effects of warfarin.^207,208 

Chapter Eight
Angiotensin Receptor Antagonists

		Table 9. P450 Enzymes Involved in the Metabolism of ARBs Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT ANGIOTENSIN RECEPTOR ANTAGONISTS Candesartan     ?         Irbesartan     Major     Minor   Losartan     Major   Minor     Olmesartan               Telmisartan             Minor Valsartan               AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

Angiotensin Receptor Antagonists

Candesartan
Candesartan cilexetil is a prodrug that undergoes ester hydrolysis to its active metabolite, candesartan, in the gastrointestinal tract. Total plasma concentrations were 80% higher in elderly subjects.²⁰⁹ 

Candesartan is predominantly eliminated by renal excretion without further metabolism. There is a potential for induction by carbamazepine, phenobarbital, or phenytoin.

Candesartan is not known to alter the activity of P450 enzymes, and it is not expected to alter the pharmacokinetics of antiepileptic agents.

Irbesartan
Irbesartan is a long-acting angiotensin II receptor antagonist. Plasma concentrations were about 20% to 50% greater in elderly subjects.²¹⁰ 

Irbesartan is metabolized by CYP2C9 and glucuronidation.^210,211  There is a minor CYP3A4 pathway. Carbamazepine, phenytoin, and phenobarbital would be expected to induce irbesartan metabolism.

Irbesartan is a mild inhibitor of CYP2C9 in vitro.²¹²  A clinical study revealed that concomitant administration of irbesartan did not alter the concentrations of warfarin.²¹³  Irbesartan would not be expected to alter the metabolism of antiepileptic agents.

Losartan
Losartan is a pharmacodynamically active compound but its active metabolite E3174 is 63% more active than losartan. Plasma concentrations were similar between young and older individuals.²¹⁴ 

Losartan is metabolized by CYP2C9 with a minor contribution of CYP3A4. Rifampin, a potent inducer, decreased the total plasma concentration of losartan by 35% and the concentration of losartan's active metabolite by 40%.²¹⁵  Carbamazepine and phenobarbital are less potent inducers than rifampin and their effects on losartan pharmacokinetics would be expected to be less dramatic. This is supported by a clinical study investigating the concomitant use of phenobarbital that found a small but statistically significant decrease in concentration of both losartan and its metabolite.²¹⁶ 

The effect of phenytoin on losartan metabolism is more complex. In a clinical study performed in healthy subjects, administration of phenytoin increased the concentration of losartan by 17% and reduced the concentration of the active metabolite by 63%.²¹⁷  This reduction in active metabolite levels was not associated with changes in blood pressure.

Olmesartan
Olmesartan is a prodrug that undergoes ester hydrolysis for bioactivation. Plasma concentration was 33% higher in elderly patients.²¹⁸ 

Olmesartan is not metabolized by the P450 system. Metabolic drug-drug interactions with antiepileptic agents are not anticipated.

Telmisartan
Telmisartan is the most lipophilic of the angiotensin receptor blockers. The pharmacokinetics of telmisartan do not differ between elderly and younger patients.²¹⁹ 

More than 97% of telmisartan is eliminated unchanged through biliary excretion.²¹⁹  A potential for glucuronidation of telmisartan to be induced by carbamazepine, phenytoin, or phenobarbital exists. The clinical significance of this induction cannot be predicted.

Telmisartan is a weak inhibitor of CYP2C19 in vitro but did not alter the activity of other CYP enzymes.²¹⁹  Telmisartan slightly decreased the mean warfarin trough plasma concentration but did not change INRs.²¹⁹  Drug-drug interactions between telmisartan and antiepileptic agents are not expected.

Valsartan
Total plasma concentration of valsartan is increased by 70% in elderly patients.²²⁰  Valsartan undergoes little hepatic metabolism in humans (about 20%).²²⁰  The inhibitory or induction potential of valsartan on CYP 450 enzymes is not known.²²⁰  Sufficient information is not available to predict the propensity for drug-drug interactions between valsartan and antiepileptic agents at this time.

Chapter Nine
Calcium Channel Blockers

		Table 10. P450 Enzymes Involved in the Metabolism of Calcium Channel Blockers Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT CALCIUM CHANNEL BLOCKERS Verapamil Minor       (?) Major***   Diltiazem         Minor? Major***   Amlodipine           Major   Felodipine           Major   Nimodipine           Major ? AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

Calcium Channel Blockers

Verapamil
Verapamil exhibits decreased clearance in the elderly.²²¹  Verapamil has three active metabolites, the most potent of which is norverapamil. Verapamil is metabolized by CYP3A4 and CYP1A2. Since it is a substrate of both CYP1A2 and CYP3A4, it would be expected that carbamazepine, phenobarbital, and phenytoin would induce verapamil metabolism. There are reports of increased clearance of verapamil after induction by phenobarbital.²²²  There is also a case report of decreased verapamil concentrations with administration of phenytoin.²²³ 

Verapamil is a weak inhibitor of CYP3A4 and an even weaker inhibitor of CYP2D6 in vitro.^224,225  However, in vivo verapamil is a moderately potent inhibitor and there are multiple reports of clinically significant drug-drug interactions between verapamil and CYP3A4 substrates. There are case reports of increased carbamazepine levels with neurotoxicity with verapamil.^226-228  Verapamil decreased the plasma levels of the monohydroxy metabolite of oxcarbazepine by 20%.²²⁹  Although zonisamide is metabolized by CYP3A4, it is unlikely that verapamil will affect its metabolism since there are no reports of elevations of zonisamide concentrations in the presence of CYP3A4 inhibitors.

Diltiazem
Clinical studies of diltiazem did not include sufficient numbers of elderly subjects to determine if the pharmacokinetics of diltiazem are altered.²³⁰ 

Diltiazem is predominantly metabolized by CYP3A4 with a minor pathway by CYP2D6.^231,232  There is a potential for induction of diltiazem metabolism by carbamazepine, phenytoin, or phenobarbital.

Diltiazem is a less potent inhibitor of CYP3A4 activity than verapamil. Nonetheless, there are multiple case reports of carbamazepine inhibition with associated neurotoxicity by diltiazem.^233-238  A case report illustrated elevated phenytoin levels with concomitant use of diltiazem.²³⁷  There is little risk of drug-drug interactions between diltiazem and zonisamide.

Dihydropyridines

Amlodipine
Elderly patients have a decreased clearance of amlodipine with a resulting increase in total plasma concentration of approximately 40% to 60%.²³⁹ 

The metabolic pathways of amlodipine are not well described, but it is a CYP3A4 substrate. Carbamazepine, phenytoin, and phenobarbital would be expected to induce amlodipine metabolism.

Amlodipine is a weak inhibitor of CYP2C9, CYP2D6, and CYP3A4 in vitro.²³⁹  There is a small potential for drug-drug interactions with carbamazepine.

Felodipine
Plasma concentrations of felodipine increase with age. The average clearance of felodipine in elderly hypertensives was only 45% of that in young healthy volunteers.²⁴⁰ 

Felodipine is metabolized by CYP3A4. This drug's concentrations were reduced in patients taking carbamazepine, phenobarbital, and phenytoin.^240,241  Although oxcarbazepine is a much weaker inducer of CYP3A4 than carbamazepine, a study in healthy volunteers found that a 7-day treatment with oxcarbazepine reduced felodipine levels by 34%.²⁴² 

Felodipine is a weak inhibitor of CYP3A4 and CYP2C9 in vitro.²²⁶  There is a small probability that felodipine would produce a clinically significant inhibition of carbamazepine in vivo.

Nimodipine
Nimodipine concentrations were twofold higher in elderly subjects, and dosing in elderly patients should be cautious.²⁴³ 

Nimodipine is a CYP3A4 substrate. A clinical trial comparing single-dose pharmacokinetics of nimodipine between control subjects and patients receiving chronic carbamazepine, phenobarbital, or phenytoin reported that nimodipine concentrations were lowered by about sevenfold in patients taking enzyme-inducing anticonvulsants.²⁴⁴  In this same study, nimodipine levels were about 50% higher in patients taking valproate compared with control subjects. This suggests that valproate inhibits nimodipine metabolism via glucuronidation since valproate is known to inhibit glucuronidation and is not known to inhibit CYP3A4.

Chapter Ten
Statins

		Table 11. P450 Enzymes Involved in the Metabolism of Statins Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT STATINS Atorvastatin           Major* Minor Fluvastatin     Major**     Minor   Lovastatin           Major*   Pravastatin     ?         Rosuvastatin     Minor Minor       Simvastatin           Major* Minor AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

Statins

Atorvastatin
Total plasma concentrations of atorvastatin are approximately 30% higher in healthy elderly subjects.²⁴⁵  Atorvastatin exhibits nonlinear pharmacokinetics, and it has a markedly longer half-life than lovastatin and pravastatin (20.7 hours versus 2.8 and 2.7 hours).²⁴⁶  The inhibitory effect of atorvastatin on HMG CoA reductase is closer to 30 hours because atorvastatin metabolites are also pharmacologically active.

Atorvastatin is metabolized by CYP3A4 and glucuronidation. It would be predicted that carbamazepine, phenytoin, and phenobarbital would induce atorvastatin metabolism. This is supported by a case report of loss of efficacy with the addition of phenytoin.²⁴⁷  Increasing the dose of atorvastatin to offset induction cannot be advocated since the degree of induction of CYP3A4 in the elderly is variable and there are no clinical data or product labeling to support this action.

Atorvastatin is considered a weak inhibitor in vitro, but clinical studies have demonstrated that it inhibits the CYP3A4 substrates midazolam and terfenadine.²⁴⁸  Since carbamazepine is metabolized by CYP3A4 and it has a narrow therapeutic index, carbamazepine levels should be closely monitored if atorvastatin is added.

Fluvastatin
Plasma concentrations of fluvastatin do not vary as a function of age.²⁴⁹  About 75% of fluvastatin metabolism is attributed to CYP2C9 with minor contributions by CYP3A4 (~20%) and CYP2C8 (~5%).²⁴⁹  Due to the contribution of CYP3A4 to fluvastatin metabolism, it would be predicted that fluvastatin metabolism would be induced by carbamazepine or phenobarbital. The prescribing information reports that concomitant administration of fluvastatin and phenytoin increased the total plasma levels of phenytoin by 20% and total fluvastatin concentrations by 40%.²⁴⁹ 

Fluvastatin is a moderate inhibitor of CYP2C9 in vitro. However, its effect in vivo is modulated because of its short half-life. There are multiple case reports of interactions between fluvastatin and warfarin.²⁵⁰ 

Lovastatin
Lovastatin is a prodrug that is hydrolyzed into its active form in the liver. Plasma concentrations were increased approximately 45% in elderly patients.²⁵¹ 

Lovastatin is metabolized by CYP3A4.^251,252  It would be predicted that carbamazepine, phenytoin, or phenobarbital would induce the metabolism of lovastatin and decrease its efficacy.

Lovastatin is a weak inhibitor of the CYP3A4 substrates midazolam and terfenadine. Since it is a weak inhibitor and has a short half-life, lovastatin would not be expected to alter the metabolism of most CYP3A4 substrates.

Pravastatin
Pravastatin concentrations were 27% and 46% higher in elderly subjects.²⁵³  The metabolic pathways for pravastatin are not established; however, in vitro studies suggest that CYP3A4 is a minor pathway for pravastatin metabolism.²⁵³  The potent inducer, rifampin, decreased the plasma concentrations of pravastatin by 31%. Therefore, there is a potential for a reduction in pravastatin concentrations and efficacy in the presence of carbamazepine, phenytoin, and phenobarbital.

Rosuvastatin
There were no differences in plasma concentrations of rosuvastatin between elderly and younger adults.²⁵⁴ 

About 90% of rosuvastatin is eliminated unchanged by the kidneys. The remaining 10% is metabolized by CYP2C9 and CYP2C19. Carbamazepine, phenytoin, and phenobarbital would be predicted to induce rosuvastatin metabolism.

Rosuvastatin is not anticipated to alter the metabolism of other drugs. Coadministration of warfarin with rosuvastatin did not change warfarin plasma concentration but resulted in clinically significant rises in INR.²⁵⁰  In addition, there is one case report of increased INR in a patient receiving both medications.²⁵⁵ 

Simvastatin
Simvastatin is an analogue of lovastatin and is also a prodrug. It has a very short half-life (2 hours).

Simvastatin is a CYP3A4 substrate. In addition, simvastatin is metabolized by glucuronidation. It would be predicted that carbamazepine, phenytoin, or phenobarbital would induce the metabolism of simvastatin. This is supported by a clinical study where a 14-day course of carbamazepine decreased the total simvastatin concentration by 75% and a case report of decreased efficacy when coadministered with phenytoin.²⁵⁶ 

Simvastatin is a weak inhibitor of CYP3A4. Since it is a weak inhibitor and it has a very short half-life, simvastatin would not be expected to produce clinically significant inhibition of most CYP3A4 substrates.

Chapter Eleven
Fibrates and Nonfibrates

		Table 12. P450 Enzymes Involved in the Metabolism of Fibrates and NonFibrates Compared with AEDs: Pathways and Inducing and Inhibiting Properties
		CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 UGT FIBRATES AND NONFIBRATES Gemfibrozil     ***       Major Ezetimibe             Major AEDS Carbamazepine Minor **/   Major Gabapentin               Lamotrigine             Major/? Levetiracetam               Oxcarbazepine       **   Minor Phenobarbital Minor Major Minor   Phenytoin Major*/ Minor   Topiramate             Valproate     **       Major** Zonisamide       Minor   Major   AEDs = antiepileptic drugs; CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase (glucuronidation); Major = major pathways; Minor = minor pathways; ** = weak inhibitors; * = very weak inhibitors; = weak inducer; = moderate inducer.

Fibrates

Gemfibrozil
Gemfibrozil is glucuronidated. Since carbamazepine, phenytoin, and phenobarbital induce glucuronidation, there is a potential for induction of gemfibrozil metabolism with concomitant administration.

Gemfibrozil is a moderately potent inhibitor of CYP2C9 in vitro.^257,258  It also inhibits CYP2C19, CYP2C8, and UGTs. There is a potential for inhibition of phenytoin metabolism, but there are no reports in the literature. The potential also exists for inhibition of valproate or lamotrigine glucuronidation. The most serious drug interactions reported to date with gemfibrozil have involved inhibition of statin metabolism with resultant rhabdomyolysis.²⁵⁹ 

Nonfibrates

Ezetimibe
Ezetimibe inhibits the absorption of cholesterol at the level of the brush border of the small intestine. Its mechanism of action differs from the bile acid sequestrants and fibrates. Total plasma concentrations for ezetimibe were about twofold higher in subjects over the age of 65 years.²⁶⁰ 

Ezetimibe is primarily metabolized by glucuronidation. It is predicted that ezetimibe metabolism would be induced by carbamazepine, phenytoin, and phenobarbital.

The concomitant administration of ezetimibe did not alter warfarin metabolism.²⁶⁰  Ezetimibe is not expected to alter the metabolism of antiepileptic agents.

Conclusions

The antidepressants recommended for use in the elderly with epilepsy have favorable safety profiles. Little potential exists for antiepileptic agents to inhibit the metabolism of antidepressants resulting in toxic side effects. There is, however, a propensity for the inducing antiepileptic agents to induce the metabolism of these antidepressants and reduce their efficacy.

Marked differences were shown in the potential for antidepressants to inhibit the metabolism of some antiepileptic agents. The antidepressants with the least potential for altering metabolism are citalopram, escitalopram, venlafaxine, duloxetine, and mirtazapine.

The use of carbamazepine, phenytoin, and phenobarbital may reduce the levels of donepezil and galantamine. There is little potential for these cholinesterase inhibitors to alter the metabolism of antiepileptic agents. Memantine is predominantly eliminated without being metabolized; therefore, there is little potential for drug-drug interactions. A significant risk of drug-drug interactions exists between antiepileptic agents and warfarin. Carbamazepine, phenytoin, and phenobarbital have been reported to decrease prothrombin time. Other drugs covered in this issue have been associated with increased prothrombin time and hemorrhage including fluoxetine, gemfibrozil, fluvastatin, and lovastatin. There is a potential for induction of the clearance of antiplatelet agents by carbamazepine, phenobarbital, and phenytoin. Several reports of ticlopidine coadministration illustrated resulting carbamazepine and phenytoin toxicity.

Among the therapeutic classes of antihypertensives, metabolic drug-drug interactions would not be expected with angiotensin-converting enzyme inhibitors, ARBs, hydrophilic beta-blockers, and thiazide diuretics. Data show a moderate risk for carbamazepine, phenobarbital, and phenytoin to decrease levels and efficacy of lipophilic beta-blockers. A significant risk is that carbamazepine, phenobarbital, and phenytoin will decrease the concentrations of calcium channel blockers. Further, there is a significant risk of elevated levels of carbamazepine and phenytoin when diltiazem and verapamil are administered.

There is evidence to suggest that carbamazepine, phenobarbital, and phenytoin would reduce the efficacy of most statins and other lipid-lowering agents.

In summary, among the drugs commonly prescribed in geriatric patients with epilepsy there is a significant potential for drug-drug interactions with first-generation AEDs particularly carbamazepine, phenytoin, and phenobarbital. These metabolic drug-drug interactions should be taken into account when prescribing comedications, and drug levels may need to be monitored more closely. Newer antiepileptic agents such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate are less likely to alter the metabolism of other drugs.

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162. Plavix^TM [prescribing information]. New York, NY: Sanofi-Synthelabo, Inc; 2003.
163. Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos 2003;31(1):53-59.
164. Richter T, Murdter TE, Heinkele G, et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 2004;308(1):189-197.
165. Pletal^TM [prescribing information]. Rockville MD: Otsuka American Pharmaceutical, Inc; 1999.
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177. Brown RI, Cooper TG. Ticlopine-carbamazepine interaction in a coronary stent patient. Can J Cardiol 1997;13(9):853-854.
178. Acebutolol hydrochloride [prescribing information]. Spring Valley, NY: Par Pharmaceutical, Inc; 2002.
179. Tenormin^TM [prescribing information]. Wilmington, DE: AstraZeneca Pharamceuticals, LP; 2000.
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182. Horikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci 1998;87(3):289-294.
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184. Ohno A, Saito Y, Hanioka N, et al. Involvement of human hepatic UGT1A1, UGT2B4, and UGT2B7 in the glucuronidation of carvedilol. Drug Metab Dispos 2004;32(2):235-239.
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186. Toprol-XL^TM [prescribing information]. Wilmington, DE: AstraZeneca AB; 2002.
187. Hemeryck A, De Vriendt CA, Belpaire FM. Metoprolol-paroxetine interaction in human liver microsomes: stereoselective aspects and prediction of the in vivo interaction. Drug Metab Dispos 2001;29(5):656-663.
188. Park BK. Prediction of metabolic drug interactions involving beta-adrenoceptor blocking drugs. Br J Clin Pharmacol 1984;17 (suppl 1):3S-10S.
189. Johnson JA, Herring VL, Wolfe MS, Relling MV. CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences. J Pharmacol Exp Ther 2000;294(3):1099-1105.
190. Betapace AF^TM [prescribing information]. Wayne, NJ: Berlex Laboratories; 2003.
191. Blocadren^TM [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; 2002.
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193. Rosner MH. Severe hyponatremia associated with the combined use of thiazide diuretics and selective serotonin reuptake inhibitors. Am J Med Sci 2004;327(2):109-111.
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195. Soars MG, Riley RJ, Findlay KA, Coffey MJ, Burchell B. Evidence for significant differences in microsomal drug glucuronidation by canine and human liver and kidney. Drug Metab Dispos 2001;29(2):121-126.
196. Soars MG, Burchell B, Riley RJ. In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharmacol Exp Ther 2002;301(1):382-390.
197. Lotensin^TM [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2003.
198. Capoten^TM [prescribing information]. Spring Valley, NY: Par Pharmaceutical, Inc; 2003.
199. Vasotec^TM [prescribing information]. Morrisville, NC: Biovail Pharmaceuticals Inc; 2002.
200. Todd PA, Heel RC. Enalapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure. Drugs 1986;31(3):198-248.
201. Kandiah D, Penny WJ, Fraser AG, Lewis MJ. A possible drug interaction between rifampicin and enalapril. Eur J Clin Pharmacol 1988;35(4):431-432.
202. Zestril^TM [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.
203. Aceon^TM [prescribing information]. Marietta, GA: Solvay Pharmaceuticals, Inc; 2003.
204. Accupril^TM [prescribing information]. New York, NY: Parke-Davis; 2003.
205. Altace^TM [prescribing information]. Bristol, TN: Monarch Pharmaceuticals; 2003.
206. Meisel S, Shamiss A, Rosenthal T. Clinical pharmacokinetics of ramipril. Clin Pharmacokinet 1994;26(1):7-15.
207. Mavik^TM [prescribing information]. North Chicago, IL: Abbott Laboratories; 2001.
208. Meyer BH, Muller FO, Badenhorst PN, Luus HG, de la Rey N. Multiple doses of trandolapril do not affect warfarin pharmacodynamics. S Afr Med J 1995;85(8):768-770.
209. Atacand^TM [prescribing information]. Wilmington, DE: AstraZeneca LP; 2003.
210. Avapro^TM [prescribing information]. New York, NY: Sanofi-Synthelabo, Inc; 2002.
211. Bourrie M, Meunier V, Berger Y, Fabre G. Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes. Drug Metab Dispos 1999;27(2):288-296.
212. Taavitsainen P, Kiukaanniemi K, Pelkonen O. In vitro inhibition screening of human hepatic P450 enzymes by five angiotensin-II receptor antagonists. Eur J Clin Pharmacol 2000;56(2):135-140.
213. Mangold B, Gielsdorf W, Marino MR. Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin. Eur J Clin Pharmacol 1999;55(8):593-598.
214. Cozaar^TM [prescribing information]. Whitehouse Station, NJ: Merck and Co, Inc; 2004.
215. Williamson KM, Patterson JH, McQueen RH, et al. Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1998;63(3):316-323.
216. Goldberg MR, Lo MW, Deutsch PJ, Wilson SE, McWilliams EJ, McCrea JB. Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. Clin Pharmacol Ther 1996;59(3):268-274.
217. Fischer TL, Pieper JA, Graff DW, et al. Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers. Clin Pharmacol Ther 2002;72(3):238-246.
218. Benicar^TM [prescribing information]. Parsippany, NJ: Sankyo Pharma Inc; 2003.
219. Micardis^TM [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2003.
220. Diovan^TM [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2002.
221. Calan^TM [prescribing information]. Chicago, IL: Pharmacia Corporation; 2003.
222. Rutledge DR, Pieper JA, Mirvis DM. Effects of chronic phenobarbital on verapamil disposition in humans. J Pharmacol Exp Ther 1988;246(1):7-13.
223. Woodcock BG, Kirsten R, Nelson K, Rietbrock S, Hopf R, Kaltenbach M. A reduction in verapamil concentrations with phenytoin. N Engl J Med 1991;325(16):1179.
224. Wang YH, Jones DR, Hall SD. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos 2004;32(2):259-266.
225. Bennett MA, Prueksaritanont T, Lin JH. Drug interactions with calcium channel blockers: Possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos 2000;28(2):125-130.
226. Macphee GJ, McInnes GT, Thompson GG, Brodie MJ. Verapamil potentiates carbamazepine neurotoxicity: A clinically important inhibitory interaction. Lancet 1986;1(8483):700-703.
227. Price WA, DiMarzio LR. Verapamil-carbamazepine neurotoxicity. J Clin Psychiatry 1988;49(2):80.
228. Beattie B, Biller J, Mehlhaus B, Murray M. Verapamil-induced carbamazepine neurotoxicity. A report of two cases. Eur Neurol 1988;28(2):104-105.
229. Kramer G, Tettenborn B, Flesh G. Oxcarbazepine-verapamil drug interaction in healthy volunteers. Epilepsia 1991;32(suppl 1):70-71.
230. Cardiazem LA^TM [prescribing information]. Morrisville, NC: Biovail Pharmaceuticals; 2001.
231. Sutton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in human hepatic diltiazem N-demethylation: Inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther 1997;282(1):294-300.
232. Molden E, Asberg A, Christensen H. CYP2D6 is involved in O-demethylation of diltiazem. Eur J Clin Pharmacol 2000;56(8):575-579.
233. Eimer M, Carter BL. Elevated serum carbamazepine concentrations following diltiazem initiation. Drug Intell Clin Pharm 1987;21(4):340-342.
234. Brodie MJ, Macphee GJ. Carbamazepine neurotoxicity precipitated by diltiazem. Br Med J 1986;292(6529):1170-1171.
235. Ahmad S. Diltiazem-carbamazepine interaction. Am Heart J 1990;120(6, pt 1):1485-1486.
236. Gadde K, Calabrese JR. Diltiazem effect on carbamazepine levels in manic depression. J Clin Psychopharmacol 1990;10(5):378-379.
237. Bahls FH, Ozuna J, Ritchie DE. Interactions between calcium channel blockers and the anticonvulsants carbamazepine and phenytoin. Neurology 1991;41(5):740-742.
238. Maoz E, Grossman E, Thaler M, Rosenthal T. Carbamazepine neurotoxic reaction after administration of diltiazem. Arch Intern Med 1992;152(12):2503-2504.
239. Norvasc^TM [prescribing information]. New York, NY: Pfizer Labs; 2003.
240. Plendil^TM [prescribing information]. Wilmington, DE: AstraZeneca LP; 2000.
241. Capewell S, Freestone S, Critchley JA, Pottage A, Prescott LF. Reduced felodipine bioavailability in patients taking anticonvulsants. Lancet 1988;2(8609):480-482.
242. Zaccara G, Gangemi PF, Bendoni L, Menge GP, Schwabe S, Monza GC. Influence of single and repeated doses of oxcarbazepine of the pharmacokinetic profile of felodipine. Ther Drug Monit 1993;15(1):39-42.
243. Nimotop^TM [prescribing information]. West Haven, CT: Bayer Pharmaceuticals Corporation; 2003.
244. Tartara A, Galimberti CA, Manni R, et al. Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients. Br J Clin Pharmacol 1991;32(3):335-340.
245. Lipitor^TM [prescribing information]. Morris Plains, NJ: Parke-Davis; 2001.
246. Cilla DD, Whitfield LR, Gibson DM, Sedman AJ, Posvar EL. Multiple-dose pharmacokinetics, pharmcodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin Pharmacol Ther 1996;60(6):687-695.
247. Murphy MJ, Dominiczak MH. Efficacy of statin therapy: Possible effect of phenytoin. Postgrad Med J 1999;75(884):359-360.
248. Mc Donnell CG, Harte S, O'Driscoll J, et al. The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam. Anaesthesia 2003;58(9):899-904.
249. Lescol^TM [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2003.
250. Andrus M. Oral anticoagulant drug interactions with statins: Case report of fluvastatin and review of the literature. Pharmacotherapy 2004;24(2):285-290.
251. Altocor^TM [prescribing information]. Weston, FL: Andrx Laboratories; 2003.
252. Jacobsen W, Kirchner G, Hallensleben K, et al. Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 1999;27(2):173-179.
253. Pravachol^TM [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2003.
254. Crestor^TM [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.
255. Barry M. Rosuvastatin-warfarin drug interaction. Lancet 2004;363(9405):328.
256. Ucar M, Neuvonen M, Luurila H, Dahlqvist R, Neuvonen PJ, Mjorndal T. Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Eur J Clin Pharmacol 2004;59(12):879-882.
257. Lopid^TM [prescribing information]. New York, NY: Pfizer Inc; 2003.
258. Wen X, Wang JS, Backman JT, Kivisto KT, Neuvonen PJ. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos 2001;29(11):1359-1361.
259. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol 1998;81(3):368-369.
260. Zetia^TM [prescribing information]. North Wales, PA: Merck/ Schering-Plough Pharmaceuticals; 2003.



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Post Test

Click the button next to the correct answer for each question and then press the Score Test button to view your test results.
1. Which of the following isoenzymes is apparently not susceptible to induction?
	a) CYP2C19
	b) CYP2C9
	c) CYP2D6
	d) CYP3A4
2. Which enzyme is responsible for metabolizing the largest portion of therapeutic agents?
	a) CYP2C9
	b) CYP2C19
	c) CYP2D6
	d) CYP3A4
3. Which enzyme has the highest percentage of poor metabolizers in the Caucasian population?
	a) CYP2C9
	b) CYP2C19
	c) CYP2D6
	d) CYP3A4
4. Which of the following antiepileptic agents induce CYP3A4?
	a) Carbamazepine, phenobarbital, phenytoin, oxcarbazepine, and gabapentin
	b) Carbamazepine, phenobarbital, phenytoin, oxcarbazepine, and levetiracetam
	c) Carbamazepine, phenobarbital, phenytoin, oxcarbazepine, and topiramate
	d) Carbamazepine, phenobarbital, phenytoin, oxcarbazepine, and zonisamide
5. Which of the following agents is expected to increase INRs in a patient taking warfarin?
	a) Lamotrigine
	b) Levetiracetam
	c) Oxcarbazepine
	d) Valproate
6. Which of the following antiepileptic drugs did not demonstrate decreased clearance in elderly patients?
	a) Zonisamide, valproate, oxcarbazepine
	b) Topiramate, oxcarbazepine, gabapentin
	c) Gabapentin, levetiracetam, topiramate
	d) Gabapentin, topiramate, zonisamide
7. Which of the following agents used in the treatment of Alzheimer's disease is least likely to be induced by carbamazepine?
	a) Donepezil
	b) Galantamine
	c) Rivastigmine
	d) Memantine
8. Which of the following antidepressants is most likely to decrease the clearance of phenytoin?
	a) Fluoxetine
	b) Citalopram
	c) Venlafaxine
	d) Mirtazapine
9. Withdrawal of phenytoin in a post-stroke patient who has not experienced further seizures is most likely to increase the concentration of which of the following antihypertensives?
	a) Amlodipine
	b) Satalol
	c) Lisinopril
	d) Olmesartan
10. Which cholinesterase inhibitor is least likely to exhibit a decreased clearance in an elderly patient already taking lamotrigine, fluoxetine, warfarin, hydrochlorothiazide, amlodpine, and atorvastatin?
	a) Donepezil
	b) Galantamine
	c) Rivastigmine
	d) All of the above

Course Evaluation

1.	Upon completion of this educational activity, the participant was able to (1 = strongly disagree/poor rating; 5 = strongly agree/excellent rating):
a.	Understand the pharmacology of drug-drug interactions
	1   2   3   4   5
b.	Identify the pathways and isoenzymes involved in drug-drug interactions
	1   2   3   4   5
c.	Evaluate the current and possible drug-drug interactions among antiepileptic, psychiatric, and cardiovascular drugs and adjust treatment protocol accordingly
	1   2   3   4   5
2.	How current was the information presented in this activity?
	1   2   3   4   5
3.	This educational activity was objective, balanced, and free of commercial bias.
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4.	Please indicate your overall evaluation of this activity.
	1   2   3   4   5
5.	Do you intend to make changes in your practice as a result of this activity?
	1   2   3   4   5
6.	What aspects of this activity were of most interest to you?
7.	Do you have any comments or suggestions for this or future activities?
8.	Enter the number of hours it took you to complete this course. Hours:

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