Table 25.2 Time to steady-state and therefore maximum therapeutic outcome consequent to an inhibitory interaction of those antiepileptic drugs (AEDs) which are known to be affected b y inhibitory interactions Half-life (hours) a Affected AED Steady-state (days) achieved after 5 half-lives (values are rounded up or down for clarity) Carbamazepine 8 \200\22320 2 \200\2234 2 \200\2237 (7 \200\22310) b Clobazam 10 \200\22330 Ethosuximide 40 \200\22360 8 \200\22312 Felbamate 16 \200\22322 3 \200\2235 Lamotrigine 15 \200\22335 3 \200\2237 Phenobarbitone 70 \200\223140 15 \200\22329 Phenytoin 30 \200\223100 6 \200\22321 Ru \201 namide 6 \200\22310 1 \200\2232 Valproic acid 11 \200\22320 2 \200\2234 a Values are in the absence of interacting medication (9). b Includes time to steady-state for pharmacologically active metabolite Stiripentol inhibits CYP1A2, CYP2C19, and CYP3A4 and con- sequently can decrease the cleara nce of carbamazepine, clobazam, N-desmethyl-clobazam. oxford textbook of epilepsy and epileptic seizures 272 good example of this effect is that of primidone when phenytoin or carbamazepine are co-pre scribed. Because primidone is metab- olized partly to phenobarbital, stimulation of metabol ism may actually result in enhanced production of the phenobarbital metab- olite and theref ore an increased pharmacological effect. Another example relates to valproic acid the metab olism of which is typi- cally enhanced by carbamazepine, phenytoin, and phenobarbital resul ting in decreased plasma concentrations and decreased effec- tiveness of valproic acid Howe ver, this interaction may also lead to increased formation of hepatotoxic metabolites and m ay explain why patients taking these AEDs are more susceptible to valproate- induced liver toxicity ( 25 ). phenobarbital, phenytoin, primidone, and valproic acid ( 7 ). The inhibition of clobazam me tabolism is associated with a concur- rent and even more potent inhibition of the pharmacol ogically active metabolite, N-desmethylclobazam, so that stiripentol increases clobazam pla sma levels and N-desmethylclobazam plasma levels severalfold ( 22 ). Felbamate inhibits CYP 2C19 and epoxide hydrolase so that plasma concentration of carbamazepine- 10,11-epoxide, N- desmethyl-clobazam, phenobarbital, phenytoin and valproic acid are increased. Oxcarbazepine is a weak inhibitor and topiramate is a modest inhibitor of CYP2C19. Conseque ntly, oxcarbazepine, particularly when used at high dosages ( > 1800 mg/day), can increase plasma phenytoin concentrations by up to 40 % and to a lesser extent phe- nobarbital ( 23 ) . Topiramate can increase plasma phenytoin con- centrations in a small subset of patients b y 25 % . Ru \201 namide can decrease the clearance of phenobarbital and phenytoin by less than 20 % and increase their plasma concentrations ( 24 ). Other inhibi- tory drug interact ions caused by AEDs also occur but these are less common and are usually of modest clinical signi \201 cance. An interesting interaction is that between phenytoin and the angiotensin-receptor blocker l osartan. While phenytoin increases plasma concentrations of losartan by 17 % , it decreases the plasma concentrations of the active carboxylic acid metabolite E3174 by 63 % through i nhibition of its CYP2C9-mediated formation clear- ance. Therefore, a reduced antihypertensi ve effect may be antici- pated ( 29 ). Induction interactions resulting in decreased AED concentration Most AEDs (e.g. gabapentin, lacosamide, lamotrigine, levetira- cetam, pregabalin, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide) are not associated with enzyme-inducing effects on the metaboli sm of concurrently administered AEDs. In con- trast, carbamazepine, phenytoin, phenobarbita l, and primidone are potent inducers of various CYP isoenzymes and they also induce UGT and epoxide hydrolases ( 3 ). Consequently, these AEDs stimulate the metabolism and decrease t he plasma concen- trations of numerous AEDs, including clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine and its active monohydroxy-metabolite, rufinamide, st iripentol, tiagabine, topiramate, valproic acid, and zonisamide. Rufinamide can decrease pl asma concentrations of carbamazepine and lamotrigine, probably via hepatic induction of met abolism ( 24 ). In addition, phenobarbital, phenytoin, and primidone can markedly induce th e metabolism of carbamazepine so that mean plasma carbamazepine concentrations are decrease d by 33 % , 44 % , and 25 % respectively ( 25 ). Co-medication of valproic acid with carbam azepine, pheno- barbital, or phenytoin can reduce mean plasma valproic acid con- centration s by 66 % , 76 % , and 49 % respectively ( 26 ). In addition, the metabolism of lamotrigine is signi \201 cantly enhanced by oxcar- bazepine ( 27 ) and methsuximide ( 28 ). Pharmacodynamic interactions Pharmacodynamic interactions are less well described because t hey occur at the site of action in the brain and are usually inferred by default when a cha nge in the clinical status of a patient cannot be attributable to a pharmacokinetic change in plasma concentra- tions. These interactions, which can be additive (when they equal the sum of the effects of the individual drugs), synergistic (when the combined effects are gre ater than expected from the sum of individual drugs) or antagonistic (when the combined eff ects are less than additive), are more common than previously thought and in order that a r ational approach to the use of AED combinations in the management of epilepsy can occur we must enhance our understanding of this type of interaction. A mechanistic approach, in which combinations of drugs acting via different mechanisms coul d be co-prescribed and thus facilitate the use of rational AED polytherapy is highly desira ble ( 30 ). Indeed, although our current knowledge of AED pharmacology is insuf \201 - cie nt universally to take this approach, there is some evidence that certain AED combinations (e.g. valproate plus lamotrigine and valproate plus ethosuximide) are associated with bene \201 cial inter- actions at the pharmacodynamic level ( 31 , 32 ). Such AED combi- nations act synergistically and are associated with seizure control in patients previously unrespo nsive to the highest tolerated dose of either drug given alone. Unfortunately, additive neu rotoxicity can also occur when AEDs that share a common mechanism of action (e.g. blockage of voltage-dependent sodium channels) are co-pre- scribed ( 33 ). These effects have been m ore commonly associated with the combinations of lamotrigine plus carbamazepine, lamot- rig ine plus valproate and oxcarbazepine plus carbamazepine ( 23 , 28 , 34 ). In some patients, these interactions have modest clinical conse- quences because the loss o f ef \201 cacy resulting from the decreased concentration of the affected drug is compensa ted for by the inde- pendent anticonvulsant effect of the enzyme-inducing AED. In other pat ients, however, the decrease in plasma concentration of the affected drug impacts adversely on seizure control, and an increase in dosage is then required. Drugs whose dosage require - ments are most signi \201 cantly increased in the presence of enzyme- inducing AEDs incl ude carbamazepine, valproic acid, tiagabine, and lamotrigine. Interactions between AEDs and other drugs Inhibition interactions resulting in increased AE D concentration There are many drugs that are used to treat other conditions in patients wi th epilepsy that are potent inhibitors of CYP isoenzymes resulting in elevated plasma AED c oncentrations and toxicity. Most such interactions have been reported for carbamazepine, The consequence of enzyme induction is complicated when AEDs are associated with pharmacolo gically active metabolites (e.g. carbamazepine-epoxide of carbamazepine, various metabo- li tes of valproic acid, phenobarbital of primidone, and N-desmethyl- clobazam of clobazam). T here can be a paradoxical outcome and a CHAPTER 25 drug interactions 273 phenytoin and phenobarbital, and new AEDs appear to be rarely affected. This can be attribu ted in part to the fact that many new AEDs undergo little or no hepatic metabolism but also because there is limited clinical experience with the newer AEDs. pregabalin, or vigabatrin), which are not metabolized by CYP isoenzymes or have CYP enzyme inhibiting effects and thus have an insigni \201 cant propensity to interact at the metabo lic level (Table 25. 1 ) ( 2 ). Many antimicrobial agents are potent inhibitors of CYP isoen- zymes. The imidazole antifung als ketoconazole and \202 uconazole can inhibit CYP3A4 and, if co-prescribed in patients taking car- bamazepine, signi \201 cant increases in plasma carbamazepine con- centration (up to 29 % ) can occur resulting in carbamazepine intoxication. Likewise, the CYP2C9 inhib itors miconazole and \202 uconazole can signi \201 cantly increase plasma phenytoin conc entra- tions 2 \200\2234-fold. In contrast, itraconazole increases phenytoin levels by only 10 % ( 25 ). Isoniazid, used as an antituberculosis agent, inhibits the metabolism of carb amazepine, ethosuximide, pheny- toin, and valproic acid, resulting in increased plasma conc entrations and associated toxicity. Induction interactions resulting in decreased AED concentration Oral hormonal contraceptive steroids can induce the metabolism of UGT1A4 and enhance the metabolism of lamotrigine and decrease plasma lamotrigine concentrations by 50 % ( 41 ). This is considered to be the co nsequence of the estrogen component of the combined contraceptive pill and in some women a reduction in seizure control occurs ( 42 ). Valproic acid, which is in part metabo- lized v ia UGT1A3 and UGT2B7 isoenzymes, is also affected by intake of contraceptive steroids so th at the mean clearance of total and unbound plasma valproic acid concentrations increased by 21.5 % and 45.2 % respectively ( 43 ). Similar induction of metabo- lism may occur with ox carbazepine and eslicarbazepine acetate, both of which undergo metabolism via UGT isoenzyme s. Some macrolide antibiotics are potent inhibitors of CYP3A4 and can signi \201 cantly incre ase plasma carbamazepine concentrations ( 35 ). Particularly potent inhibitors are erythrom ycin and trolean- domycin, with some patients experiencing serious carbamazepine toxicity c onsequent to up to 2 \200\2234-fold increases in plasma car- bamazepine concentrations. There are various additional interactions resulting in clinically important decreases in pl asma AED concentrations. For example, the antineoplastic agent cisplatin and methotrexate d ecrease plasma valproic acid concentrations, whilst cisplatin, in addition decreases plasma carbamazepine concentrations. Also, the antitu- berculosis agent rifampicin acts as a pote nt enzyme inducer and can signi \201 cantly decrease phenytoin, carbamazepine, valproic ac id, ethosuximide, and lamotrigine plasma concentrations ( 4 ). The use of carbapenem antibi otics (e.g. meropenem and ertapenem) in combination with valproic acid is contraindicated b ecause plasma valproic acid concentrations are decreased by more than 80 % as a result of i nduction of valproic acid glucuronidation ( 44 ). The antiulcer drugs cimetidine and omeprazole can inhibit CYP2C19 and thus decrease the met abolic clearance of phenytoin so that phenytoin plasma concentrations are increased by 20 % and 25 % , respectively ( 36 , 37 ). Similarly cimetidine and omeprazole can increase plas ma carbamazepine concentrations through an action on CYP3A4. Danazol, a synthetic estrogen used in the management of endometriosis, is a potent inhibitor of car- bamazepine metabolis m and has been observed to increase plasma carbamazepine concentrations by 50 \200\223100 % ( 38 ). Psychotropic drugs are frequently co-prescribed to patients with epilepsy and thus several clinically important drug interactions have been described with these drugs. Some antidepre ssants includ- ing \202 uoxetine, \202 uvoxamine, sertraline, trazodone, viloxazine and , possibly, imipramine exert an inhibitory effect on the metabolism of phenytoin ( 25 ). Ca rbamazepine metabolism can be inhibited by viloxazine, trazodone, nefazodone and, possibly, \202 uoxetine and \202 uvoxamine so that plasma carbamazepine concentrations are incre ased. The concentrations of valproic acid and lamotrigine may be increased by sertraline. I n contrast, carbamazepine plasma concentrations are unaffected by paroxetine and sertraline and in addition plasma concentrations of valproic acid and phenytoin are unaffected by par oxetine. Some antipsychotic drugs, for example risperidone can increase plasma carbamazepin e concentrations by 20 % whilst co-medication with thioridazine and chlorpro- mazine has be en associated with precipitating signs of phenytoin toxicity ( 39 ). Inhibition interactions resulting in increased concentration of the other drug Inhibition i nteractions in which AEDs increase the plasma concen- trations of drugs used for other cond itions are rare and primarily involve valproic acid. Valproic acid can inhibit the metaboli sm of a variety of drugs including amitriptyline, aripiprazole clomi- pramine, chlorpromazi ne, etoposide, lorazepam, nortriptyline, nitrosurea, paroxetine, and zidovudine. With regar ds to amitriptyl- ine and nortriptyline, their plasma concentrations can increase by 50 \200\22360 % and lead to symptoms of toxicity, including worsening or precipitation of seiz ures. Topiramate can increase plasma haloperi- dol concentration by 28 % and its pharmacolo gically active metab- olite by 50 % ( 45 ). Induction interactions resulting in decreased concentration of the other drug Because enzym e-inducing AEDs (carbamazepine, phenytoin, phe- nobarbital, and primidone) are extensively prescribed there are many interactions described in which decreases in drug plasma concentr ations occur and most can be of clinical signi \201 cance (Table 25.3 ). Of particular con cern are those involving drugs that undergo extensive \201 rst-pass metabolism since thei r plasma con- centrations are decreased to such an extent that treatment failure is common. Examples of such drugs include the antifungals itracona- zole and ketoconazole; the antimi crobials metronidazole and dox- ycycline; the antihelmintics albendazole and praziquantel ( 46 ); the antiviral agents nevirapine, efavirenz, delaverdine, indinavir, ritonavir, and s aquinavir. In one report, the plasma concentration Special care is needed when AEDs are co-prescribed with antine- oplastic and antiviral agen ts because many of these drugs inhibit drug metabolizing enzymes and increase plasma AED co ncentra- tions. Indeed the antineoplastic agents doxi \202 uridine, 5- \202 uorour- acil, tamoxifen, and UFT (a mixture of uracil and the 5- \202 uorouracil prodrug tegafur) can i nhibit phenytoin metabolism and cause phenytoin intoxication whilst ritonavir, an antiviral agent, pro- foundly inhibits carbamazepine metabolism resulting in a 2 \200\2233-fold incr ease in plasma carbamazepine concentrations ( 4 , 40 ). Therefore, for patients treated wit h antineoplastic or antiviral agents, it would be best to select AEDs (e.g. gabapentin, lac osamide, levetiracetam, oxford textbook of epilepsy and epileptic seizures 274 Table 25.3 Enzyme-inducing AEDs (carbamazepine, phenobarbital, phenytoin, and primidone) an d their enhancement of metabolism resulting in decreased plasma concentrations of various d rugs Antimicrobials Phenytoin: Albendazole, delaverdine, doxycycline, efavirenz, erythromycin, indinavir, itrac onazole, ketoconazole, mebendazole, nel \201 navir, nevirapine, praziquantel, ritonavir, s aquinavir, voriconazole, zidovudine Carbamazepine: Albendazole, delaverdine, doxycycline, e favirenz, erythromycin, indinavir, isoniazid, itraconazole, ketoconazole, mebendazole, nel \201 navir, nevirapine, praziquantel, ritonavir, saquinavir, zidovudine Phenobarbital: Alb endazole, chloramphenicol, delaverdine, doxycycline, efavirenz, indinavir, itraconazole, ke toconazole, metronidazole, nel \201 navir, nevirapine, praziquantel, ritonavir, saquinavir , zidovudine Primidone: Delaverdine, efavirenz, indinavir, nel \201 navir, nevirapine, rit onavir, saquinavir, zidovudine Antineoplastic agents Phenytoin: 9-aminocampthotecin, busulphan, cyclophosphamide, docetaxel, etoposide, ifofosfa mide, irinotecan, methotrexate, paclitaxel, procarbazine, teniposide, topotecan, vincristin e Carbamazepine: 9-aminocampthotecin, docetaxel, methotrexate, paclitaxel, procarbazine, te niposide, vincristine Phenobarbital: 9-aminocampthotecin, docetaxel, etoposide, ifofosfamid e, methotrexate, paclitaxel, procarbazine, teniposide, vincristine Cardiovascular drugs Phenytoin: Amiodarone, dicoumarol, digoxin, disopyramide, felodipine, losartan a , mexileti ne, nimodipine, nisoldipine, quinidine, verapamil, warfarin b Carbamazepine: Amiodarone, di coumarol, felodipine, nimodipine, nivadipine, phenprocoumon, warfarin Phenobarbital: Alpren alol, dicoumarol, felodipine, nifedipine, nimodipine, propranolol, quinidine, verapamil, wa rfarin Primidone: Dicoumarol Immunosuppressants Phenytoin: Cyclosporine A, sirolimus, tacrolimus Carbamazepine: Cyclosporine A Phenobarbita l: Cyclosporine A Primidone: Cyclosporine A Psychotropic drugs Phenytoin: Alprozolam, amitriptyline, citalopram, clobazam, clomipramine, clonazepam, cloza pine, desipramine, desmethylclomipramine, diazepam, \202 uphenazine, haloperidol, imipram ine, mianserin, midazolam, mirtazapine, nefazodone, nortriptyline, olanzapine, paroxetine, protriptyline, quetiapine, risperidone, thioridazine, ziprasidone Carbamazepine: Alprozolam , amitriptyline, citalopram, clobazam, clomipramine, clonazepam, clozapine, desipramine, de smethylclomipramine, diazepam, doxepin, \202 uphenazine, haloperidol, imipramine, mianser in, midazolam, mirtazapine, nefazodone, nortriptyline, olanzapine, paroxetine, protriptylin e, quetiapine, risperidone, sertraline, thioridazine, ziprasidone Phenobarbital: Alprozolam , amitriptyline, citalopram, clobazam, clomipramine, clonazepam, chlorpromazine, clozapine, desipramine, desmethylclomipramine, diazepam, \202 uphenazine, haloperidol, imipramine, mianserin, midazolam, nefazodone, nortriptyline, olanzapine, paroxetine, protriptyline, que tiapine, risperidone, ziprasidone Primidone: Alprozolam, amitriptyline, citalopram, clobaza m, clomipramine, clonazepam, desipramine, desmethylclomipramine, diazepam, \202 uphenazin e, haloperidol, imipramine, midazolam, nefazodone, nortriptyline, olanzapine, paroxetine, p rotriptyline, quetiapine, risperidone, ziprasidone a Only pharmacologically active carboxylic acid metabolite (E3174) is affected. b A biphasi c interaction occurs whereby initially phenytoin acts as an inhibitor and subsequently indu ction prevails. CHAPTER 25 drug interactions 275 of indinavir was decreased to insigni \201 cant levels upon addition of carbamazepine ( 47 ). (e.g. mianserin, nomifensine, bupropion, nefazodone, citalopram and paroxetine) are readily decreased by enzyme inducing AEDs. Higher dosages of these antidepressants may be required for clini- cal ef \201 cacy. The interactions between antipsychotics (chlorpro- mazine, c lozapine, haloperidol, olanzapine, risperidone, quetiapine and ziprasidone) and enzyme-indu cing AEDs are similar to those described for antidepressants and are often of clinical sign i \201 cance. There are nine AEDs (carbamazepine, phenytoin, phenobarbi- tal, primidone, f elbamate, oxcarbazepine, ru \201 namide, eslicar- bazepine acetate, and topiramate) which enhance the metabolism of estrogen component of the contraceptive pill so as to decrease es trogen blood concentrations and therefore decrease the ef \201 cacy of steroid oral contra ceptives (Table 25. 4 ) ( 54 , 55 ). With regards to topiramate, the interaction appears to be minimal or absent at topiramate daily dosages of 200 mg or less. Women taking these AED s should be prescribed an oral contraceptive containing 50 micrograms of ethinyloestradiol and if breakthrough bleeding occurs, ethinyloestradiol doses may need to be increased to 75 or 100 micrograms. In contrast, there are 12 AEDs which do not affect the metabolism of or al contraceptives (Table 25. 4 ). With lamot- rigine the interaction occurs in reverse and oral contraceptives induce the metabolism of lamotrigine and decrease its plasma con- centr ation by 40 \200\22365 % , potentially leading to worsened seizure control or signs of toxi city when the contraceptive is discontinued ( 41 ). Oxcarbazepine and valproic acid plasma concentrations are similarly decreased (by \210 20 % ) due to induction of glucuronidation . Enzyme inducing AEDs increase the metabolism of many antin- eoplastic agents including busu lfan, cyclophosphamide, etoposide, ifosfamide, methotrexate paclitaxel, and teniposide and some vinca alkaloids. Overall, these interactions would be expected to result in decreased ef \201 cacy of the affected drug, even though for drugs that have active metabolites (e.g . ifofosfamide and cyclophosphamide) enzyme induction could theoretically potentiate drug e ffects. Other examples, whereby the increased formation of a pharmacologically active metab olite can complicate the therapeutic outcome of an induction interaction, include amiodaron e, disopyramide and bupropion. Enzyme inducing AEDs can increase the metabolism of hypo- tensive agents such as -adreno ceptor blockers (e.g. propranolol, metoprolol), alprenolol, dihydropyridine calcium antagon ists (e.g. nifedipine, felodipine, nimodipine and nisoldipine), and other such agents (e.g. verapamil). In the case of most dihydropyridine calcium antagonists, the magnitude of the interaction and its high inter-patient variability practically negate the use of these agen ts in patients co-medicated with enzyme inducing AEDs ( 48 ). Phenytoin can induce the metabolism of numerous lipid lower- ing agents (e.g. atorvastatin, lovastatin, simvastatin), via an action on CYP3A4, and reduces their effectiveness. A simi larly interaction occurs between carbamazepine and simvastatin and in these set- tings high er statin doses need to be prescribed ( 49 ). The anticoagulant effects of dicoumarol and warfarin can be reduced by carbamazepine and ot her enzyme-inducing AEDs, pos- sibly via an induction of CYP2C9 ( 50 ). The interaction bet ween phenytoin and warfarin, however, is more complex and initially inhibition of CYP2C9 oc curs (with enhancement in anticoagulant action) followed after 1 \200\2232 weeks by inducti on of CYP2C9 (with decreased anticoagulant action) ( 51 ). Because anticoagulants have a na rrow therapeutic index, it is advisable to always monitor the INR whenever a signi \201 ca nt change in AED dosage or therapy occurs. Pharmacodynamic interactions Most pharmacodynamic interactions between AEDs and other drugs relate to increased toxicity. For example, the combination Table 25.4 Oral contraceptive steroids and interactions with antiepileptic drugs (AEDs) Patients that require immunosuppression with cyclosporine A, tacrolimus or sirolimus and ha ve seizures their seizures are best treated with AEDs devoid of CYP enzyme inducing activit y, such as gabapentin, lacosamide, lamotrigine, levetiracetam, tiagabine, or vigabatrin. Th e metabolism of cyclosporine A, a substrate of CYP3A4, is enhanced by carbamazepine, phenob arbital, phenytoin and primidone so that plasma cyclosporine A concentrations are decreased and an increase in the dosage of the immunosuppressant is usually required to prevent ther apeutic failure ( 52 ). A similar effect can occur with oxcarbazepine whereby plasma cyclos porine A concentrations are decreased. Tacrolimus, which is also prima- rily metabolized by CYP3A, is also susceptible to induction inter- actions by phenytoin and carbamazepine and typically tacrolimus dose increments of up to 1.4-fold can be needed in order to main- tain adequate therapeutic tacrolimus blood concentrations. Finally, phenytoin can enhance the m etabolism of sirolimus by up to 4-fold via an action on CYP3A4/5. AEDs that do not interfere with the metabolism of oral contraceptives AEDs that enhance the metabolism of oral contraceptives and compromise contraception contro l Clobazam Carbamazepine Clonazepam Eslicarbazepine acetate Ethosuximide Felbamate Gabapentin Oxcarbazepine Lacosamide Phenobarbital Lamotrigine a Phenytoin Levetiracetam Primidone Pregabalin Ru \201 namide Retigabine Topiramate ( > 200 mg/day) Tiagabine Vigabatrin Because psychiatric disorders are commonly associated with epi- lepsy, the concomitant admi nistration of AEDs and psychotropic drugs can result in several clinically important drug i nteractions ( 39 , 53 ). Indeed, plasma concentration of many tricyclic antide- pressants ( e.g. amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, desmethylclomipra mine, protriptyl- ine, and doxepin), and of many newer generation antidepressants Zonisamide a Although lamotrigine is without effect overall, it does enhance the progesterone component of the pill so that blood concentrations are reduced by \210 10 % and this effec t may be clinically signi \201 cant in patients taking the progesterone-only contraceptive pill. The interaction between stiripentol and oral contraceptive steroids is not known. Ho wever, its clinical indication is such that it is unlikely that it would be prescribed to w omen of childbearing potential. oxford textbook of epilepsy and epileptic seizures 276 17. Schaf \202 er L , Bourgeois BFD , Luders HO . Rapid reversibility of autoinduction of carbamazepine metabolism upon temporary discontinuation . Epilepsia 1994 ; 35 : 195 \200 \223 8 . of nitroso-urea-cisplatinum-based chemotherapy with valproic acid has been associated with increased hematological toxicity whilst the concurrent use of lithium and valproic acid has been associated with additive adverse reactions such as weight gain, sedation, gastrointes tinal complaints, and tremor. The increased incidence of neurotoxicity when lithium and car bamazepine are used concurrently may also be the consequence of a pharmacody- namic interac tion. The combination of carbamazepine with cloza- pine is generally contraindicated due to a pharmacodynamic interaction which results in additive adverse hematological adverse effe cts ( 25 ). 18. Pisani F , Fazio A , Oteri G , Ruello C , Gitto C , Russo F , Perucca E . Sodium valpro ate and valpromide: Differential interactions with carbamazepine in epileptic patients . Ep ilepsia 1986 ; 27 : 548 \200\223 52 . 19. 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HW , Jung W . Phenytoin and carbamazepine decrease oral bioavailability or praziquentel . N eurology 1992 ; 42 : 492 \200\223 6 . This page intentionally left blank CHAPTER 26 The Pharmacokinetics and Clinical Therapeutics of the Antiepileptic Drugs Mark Cook and Sim on Shorvon Pharmacokinetics of antiepileptic drugs Pharmacokinetics is the study of drug absorption, d istribution, metabolism, and elimination. A working knowledge of the pharmacology, pharmaco kinetics, indications, and common and serious side effects are important for appropriate us e of the anti- convulsant medications, which are summarized in this chapter. when unexpected toxicities may result paradoxically through reduction of the enzyme-inducin g agent. Other drugs are more rarely given including acetazolamide, piracetam, and adrenocorticotrop ic hormone (ACTH), and these agents are not discussed here. Basic pharmacokinetic parameters are shown in Tables 26. 1 and 26. 2 . Between 1989 \200\2232011, 15 new antiepileptic drugs (AEDs) were licensed ( 1 , 2 ). These are eslicarbazepine felbamate, gabapentin, lacosamide lamotrigine, levetiracetam, oxcarbaz epine, pregabalin, retigabine, ru \201 namide, stiripentol, tiagabine, topiramate, viga- b atrin, and zonisamide ( 3 ). Generally these new AEDs are licensed as \200\230add-on \200 \231 therapies, at least for initial use, after which there may be scope for conversion to monotherapy. Because they are used in combination, pharmacokinetic interactions can be of i mpor- tance. Such interactions include those relating to protein-binding displacement from albumin in blood, and metabolic inhibitory and induction interactions occurring in the live r. Overall, the newer AEDs are less prone to be involved in interactions because their phar macokinetics are more favorable and many are mini- mally or not bound to blood albumin (esl icarbazepine, felbamate, gabapentin, lacosamide levetiracetam, ru \201 namide, topiramate, and vigabatrin) and are primarily renally excreted or metabolized by non-cytochrome P450 o r uridine glucoronyl transferases (e.g. gabapentin, lacosamide levetiracetam, ru \201 nami de, topiramate, and vigabatrin). Gabapentin, lacosamide, levetiracetam, pregaba- lin, retig abine, and vigabatrin have few clinically significant pharmacokinetic interactions. Of the new AEDs, lamotrigine and topiramate have the greatest range of signi \201 cant interactio ns ( 4 \200\2236 ). The pharmacokinetics of the various agents may be signi \201 cantly altered by metabolic d ysfunction, age, and pregnancy. The reader is directed to the relevant chapters of this boo k for the speci \201 c details of these situations.