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Pharmacokinetics of New Anticonvulsants in Psychiatry

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Pharmacokinetics of New Anticonvulsants in Psychiatry PSYCHIATRY SUPPLEMENT Pharmacokinetics of new anticonvulsants in psychiatry HAROLD H. MORRIS, MD ince bromide was used for catamenial necessitating multiple daily doses can undermine seizures and hysteria by Locock in the mid- patient compliance with several of the agents.2 1800s, antiepileptic drugs (AEDs) have been High protein binding associated with some of the utilized in the treatment of various psychi- drugs may also result in drug interactions.3 In addi- S 1 tion, active metabolites of carbamazepine, valproic atric disorders. Today, valproate and carbamazepine are important therapies for treatment of mania and acid, and primidone alter the safety profile of sev- bipolar disorder. Now, a number of newer anticon- eral compounds; hepatic metabolism and clearance vulsant agents—including gabapentin, lamotrigine, complicate the use of most older AEDs. All of the topiramate, and tiagabine—with improved pharma- older AEDs are known to interact with other cokinetic profiles are being investigated for psychi- drugs. atric indications as well. In addition, the range of The newer AEDs have an improved pharmaco- their psychiatric utility has been expanded, and the logic profile providing greater anticonvulsant activ- effect of AEDs is currently being considered not ity while improving patient tolerability and safety. only in bipolar disorder but in panic and social pho- The pharmacokinetic properties of the ideal AED bia and in the treatment of neuropathic pain and have been described by Gram (Table J).4 Do the detoxification. newer available anticonvulsant agents used in psy- The mechanisms by which these agents influence chiatry fit this profile of an ideal drug? mental status and pain perception is unclear, but a review of their pharmacologic properties may reveal some potential mechanisms of action. In addition, TABLE 1 an outline of their metabolism, drug interactions, PHARMACOKINETICS OF THE IDEAL AED and adverse effects will help to establish their most appropriate administration guidelines and most High oral bioavailability effective application in the psychiatric arena. No/low protein binding Long half-life IMPROVING THE PHARMACOLOGIC PROFILE Linear kinetics Several pharmacologic features of the older No active metabolites AEDs have complicated their use. A short half-life Renal elimination No enzyme induction From the Department of Neurology, Section of Epilepsy and No/few drug interactions Sleep Disorders, The Cleveland Clinic Foundation. Address reprint requests to H.H.M., Department of Adapted with permission from Gram." Neurology, M52, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. VOLUME 65 • SUPPLEMENT I CLEVELAND CLINIC JOURNAL OF MEDICINE SI-15 Downloaded from www.ccjm.org on September 27, 2021. For personal use only. All other uses require permission. PHARMACOKINETICS • MORRIS Although protein bind- TABLE 2 ing is low (approximately PHARMACOKINETIC CHARACTERISTICS OF THE NEWER AVAILABLE AEDs 25%), felbamate is nonetheless associated Drug Peak Bioavailability T,0(h) Protein Absorption (%) Binding with substantial drug (h) (%) interactions, particularly when combined with Felbamate 2-6 > 90 15-23 25 other AEDs. Polytherapy Gabapentin 2-3 35-60 6-7 0 including felbamate has Lamotrigine 1-3 98 15-70 55 been shown to increase Topiramate 1-4 > 80 18-23 15 plasma concentrations of phenytoin,9,10 valproate,11 Tiagabine 1-2 100 5-8 96 and carbamazepine epox- ide and to decrease carba- Adapted from Gram. 4 mazepine plasma lev- els.9,10,12-14 In addition, comedication with pheny- toin and carbamazepine 15 CURRENTLY MARKETED AEDS USED IN PSYCHIATRY reduces the felbamate concentration ; valproate may increase it." The pharmacokinetic characteristics and inter- Felbamate is nonsedating, but complaints of actions of the newer AEDs are summarized in Tables insomnia, nausea, anorexia, and weight loss are 2 and 3. The benefit to be gained from these sec- common, and there have been reports of anxiety ond-generation agents will be evaluated for their and psychosis.16,17 Use of felbamate in the treatment pharmacokinetic profiles, reduced incidence of of epilepsy significantly declined when it was adverse effects, and limited drug-drug interactions. reported to cause aplastic anemia and hepatic Many of the newer agents do, indeed, have simpler necrosis.18,19 Its use will be limited in psychiatry as pharmacokinetics and fewer drug interactions than well because of these same complications. the older AEDs. These parameters will be described in greater detail in the following sections. Gabapentin Gabapentin was developed by integrating Felbamate GABA into a lipophilic cyclohexane moiety, in Felbamate is a dicarbonate derivative that order to transport GABA across the blood-brain appears to potentiate the action of y-aminobutyric barrier. The goal was for this analogue molecule to acid (GABA) and to elicit postsynaptic blockade of inhibit seizures by binding to the GABA receptor. the N-methyl-D-aspartate (NMDA) receptor.5 It is Gabapentin does have anticonvulsant activity but, the only one of the newer agents that is approved in fact, does not adhere to the GABA receptor; currently for use as monotherapy in the treatment of instead, it is believed to bind to a novel site that has epilepsy. not been well characterized.20 Felbamate is rapidly and completely absorbed in The starting dose of gabapentin is 300 mg qd, a linear fashion after oral administration, reaching increasing to 300 mg bid on day 2 and to 300 mg maximum concentrations in 2 to 5 hours; it exhibits tid on day 3, with subsequent increases as needed. a high bioavailability (> 90%)." The half-life has Gabapentin is rapidly absorbed (2 to 3 hours) fol- been estimated at approximately 20 hours,6,7 which, lowing oral single-dose administration. Food has theoretically, should allow for qd or bid administra- no effect on absorption. The bioavailability, esti- tion. High doses frequently result in gastrointestinal mated at 60%, can be variable due to the drug's complaints, so patients may tolerate it only when dose-dependent absorption kinetics over the dose divided into three daily doses. Felbamate is metabo- range 100 to 900 mg.21 This dose dependence is lized in the liver. There is no evidence that felba- probably related to the mechanism of absorption mate induces liver enzymes, but it does inhibit the from the gut, which functions via a saturable L-sys- clearance of some other drugs. tem transporter for neutral amino acids.22 The SI-16 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 65 • SUPPLEMENT I Downloaded from www.ccjm.org on September 27, 2021. For personal use only. All other uses require permission. PHARMACOKINETICS • MORRIS TABLE 3 INTERACTIONS OF THE NEWER AEDS Parent Induces Metabolism Inhibits Metabolism Induces Parent Inhibits Parent of These Drugs of These Drugs Drug Metabolism Drug Metabolism Felbamate CBZ CBZ-E, PHT, PB, VPA PHT, PB, CBZ None Gabapentin None None None None Lamotrigine None None PHT, PB, CBZ VPA Topiramate Oral contraceptives None PHT, PB, CBZ None Tiagabine None None PHT, PB, CBZ None CBZ=carbamazepine, CBZ-E=carbamazepine epoxide, PB=phenobarbital, PHT=phenytoin, VPA=valproic acid. Adapted from Gram.4 nonlinear absorption profile is unique among the Lamotrigine AEDs. This saturable transport mechanism may Lamotrigine is a phenyltriazine derivative that reduce the symptoms from overdose because the inhibits voltage-gated sodium channels and reduces maximum drug absorption results in a lower plas- the release of glutamate. The anticonvulsant spec- ma level. trum of this drug, however, is far broader than that The serum half-life of gabapentin is relatively of phenytoin and carbamazepine, which also work short, at 6 to 7 hours. In the central nervous system at the sodium channels. In addition, its psychiatric (CNS), however, the effect of the drug appears to be activity suggests additional mechanisms play a role longer than the serum half-life would suggest. Thus, in its clinical activity. the CNS efficacy is sustained beyond the duration Lamotrigine is rapidly (1 to 3 hours) and com- of peak serum levels,23 probably because of accumu- pletely absorbed, with almost 100% bioavailabili- lation of gabapentin in the neurons. Gabapentin ty.29"31 It has moderate protein binding (56%) that is does not undergo hepatic metabolism in man and is unaffected by other AEDs.32 In monotherapy it has excreted unchanged in the urine. Dose adjustments a half-life of 25 hours, but when administered with may be necessary in renally impaired patients.24 metabolism-inducing agents such as phenytoin or Hemodialysis does increase clearance in anuric carbamazepine, the half-life drops to < 15 hours.30,33 patients.25 The absence of hepatic metabolism and When combined with a drug that inhibits its metab- zero protein binding prevents significant drug inter- olism, such as valproic acid, the half-life can reach actions, although alterations in gabapentin renal 60 hours.33 This potential for drug interaction com- clearance have been observed with cimetidine,21 plicates its titration schedule (Table 4). Lamotrigine and reduced absorption has been related to use of has no significant effect on plasma concentrations aluminum/magnesium hydroxide antacids.26 There of other AEDs or on oral contraceptive efficacy. 21 are no interactions with oral contraceptives. Lamotrigine is conjugated in the liver. It follows The most common adverse effects of gabapentin linear kinetics, but to some extent has been shown are somnolence, ataxia, dizziness, and fatigue.
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