Lamotrigine This drug was \201 rst licensed for use in 1991. It has since established a p lace as a useful \201 rst- and second-line therapy in a broad spec- trum of epilepsies. I t acts by a variety of mechanisms, most impor- tant being sodium channel conduction blockad e, like phenytoin and carbamazepine. Given the very long serum half-life, particularly with co- It has complex pharmacokinetics, is metabolized in the liver, and has drug interactions, wh ich complicate its use. The most important interaction is with valproate, co-medication wit h which can result in a very marked elevation of lamotrigine levels. Serum lamotrigine leve ls are reduced by many drugs including enzyme inducing antiepileptic drugs (e.g. carbamazep ine, phenytoin, phenobarbital), rifampicin, combined steroid contraceptives. Lamotrigine ma y reduce the serum levels of levonorgestrel. In the later stages of pregnancy, the levels o f lamotrigine can fall greatly. administration of valproate, the dosing interval is 1 \200\2232 times/day. Blood level monitoring is of limited usefulness, it may have particular utility in establis hing an effective target range prior to pregnancy, when the dose may need to be increased 5 0 \200\223100 % in the last trimester through increased clearance ( 13 ). The usual target range is generally considered 2.5 \200\22315 mg/L, but much higher levels are often tolerat ed very well. Levetiracetam The drug was licensed in 1999/2000 in the USA/Europe and is a powerful antiep ileptic compound, which has rapidly gained an important place in clinical practice both in monotherapy and poly- therapy. It acts by binding to the synaptic vesicle (SV2A) protein an d this is a unique mode of action not shared by other widely used antiepileptics ( 14 ). Important or common side effects include rash and hypersensi- tivity reaction involving fev er, hepatic dysfunction, blood dyscra- sias, disseminated intravascular coagulation, and mu ltiorgan failure. A troublesome side effect is an allergic rash which can be occasionally s evere or progress to a Stevens \200\223Johnson syndrome. The frequency of skin rash is high er in children than in adults. Early reports suggested that 1 in 50 children developed a po ten- tially life-threatening rash, but the incidence has fallen since the recognition that slow incrementation \200\224 particularly in patients co- medicated with valproate \200 \224 greatly reduces the risk. Headache can be marked, and aseptic meningitis is recognized ( 11 ). Ataxia, asthe- nia, fatigue, diplopia, nausea, vomiting, dizziness, somnolence, in somnia, depression, psychosis, tremor, movement disorder, other neurological and psychiatri c effects, arthralgia, lupus-like syndrome, and photosensitivity have all been reported. It has excellent pharmacokinetics and is metabolized largely by hydrolysis and only 24 % of the drug is metabolized in the liver. Co-medication with levetiracetam does not affect lev els of other drugs. Levetiracetam levels can fall by up to 20 \200\22330 % on co-medi- cati on with enzyme-inducing AEDs. It is generally very well tolerated without the usual sedative effects of other AEDs or the typical central nervous system side effects of the sodium channel-blocking antiepileptics. Its main drawback is its tendency in susceptible individuals to cause marked irritability and occasionally aggressive or psychotic behavior ( 15 , 16 ). It can paradoxically increas e seizure frequency in occasional patients especially at high doses. Other important or com mon side effects include behavioral change, irritability, aggression, mood change, depressi on, anxiety, and psychosis. Other side effects include headache, unsteadiness, tremor and h yperkinesis, memory In spite of all this, the impact of side effects in routine practice is generally low and t he drug is generally well tolerated, although some side effects such as insomnia can limit its use. Its main disadvantages relate to the need to individualize dose according to co-medication and the need for a slow introduc- tion of therapy. Its main advantages are its broad spectr um and oxford textbook of epilepsy and epileptic seizures 284 headache, fatigue, nausea, and gastrointestinal disturbances. Other side effects include an orexia, alopecia, pancreatic disturbance, lupus-like syndrome, cardiorespiratory disturbanc e, and other cognitive and neurological symptoms. and attention disturbance, somnolence, asthenia, visual distur- bance, gastrointestinal dis turbance, infection, itching, rash, alopecia, blood dyscrasia, myalgia, pancreatic and hepa tic distur- bance, and cough. Its usual indication is as a \201 rst- or second-line treatment in partial and secondaril y generalized seizures, in both adults and children. It is easy to use in clinical practice and has a broad-spectrum activity in epilepsy, controlling generalized and partial seizures. Its current licensing is as adjunctive therapy for partial seizures in adults and children from 4 years of age; adjunctive therapy for myoclonic seizures in adults and adolescents wi th juvenile myoclonic epilepsy from 12 years of age; as adjunctive therapy for primary gene ralized tonic \200\223clonic seizures in adults and adolescents with idiopathic generalized epilepsy from 12 years of age in Europe and from 6 years of age in the US; initial monothe rapy for partial seizures in adults, in Europe but not the US. Available preparations are tablets of 150, 300, 600 mg size, and oral suspension. The usual adult dosage initially is 600 mg/day, with maintenance doses of 900 \200\2232400 mg/day. I n children the usual dosage is initially 4 \200\2235 mg/kg/day, increased by increments of 5 mg/ kg/day weekly, with a maintenance dose of 20 \200\22345 mg/kg/day. Dosing intervals are 2 times/day. Serum level monitoring may be useful in some cases. The t arget range 3 \200\22335 mg/L. The usual indication for use is as \201 rst line and adjunctive therapy of partial-onset seizures and of generalized tonic \200\223clonic seizures and myoclonic seizures in IGE. Le vetiracetam may also be useful for other generalized seizure types. Phenobarbital Phenobarbital is a remarkable compound, introduced into practice in 1912, and still, in volume terms, the most commonly prescribed AED in the world. It is by far the ch eapest of the AEDs commonly available. It is highly effective with an ef \201 cacy that ge nerally speak- ing has not been bettered by any subsequent drug. It is extensively metaboli zed in the liver and is involved in a number of drug inter- actions, although these are usu ally minor. It has a very long half- life and a tendency to accumulate. Its main disadvanta ges relate to its cerebral side effects and its tendency to cause sedation, but this is sel dom a problem at low doses. In children, there is a strong ten- dency to cause hyperexcitib ility and behavioral change, which often limits its use. Its main mechanism of action is en hancement of GABA A receptor activity, but it also depresses glutamate excita- bility and a ffects sodium, potassium, and calcium conductance. Usual preparations include tablets of 250, 500, 750, 1000 mg size, oral solution (100 mg/mL ), and an IV preparation (500 mg/5mL) The usual adult dosage is initially 125 \200\223250 m g/day, with increments of 125 \200\223250 mg every 2 weeks. Maintenance doses are typically 750 \200\2233000 mg/day. Dosage needs to be reduced in renal disease. In children the initial dosage is 10 \200\22320 mg/kg/day with incre- ments of 10 \200\2232 0 mg/kg/day every 2 weeks, and maintenance of 20 \200\22360 mg/kg/day. The dosing interval is 2 times/day Serum level monitoring is not routinely available in mos t centers, and only occasionally useful. The target range is 12 \200\22346 mg/L. Phenobarbital is a potent hepatic enzyme inducer and stimulates the metabolism of many othe r drugs including antiepileptics. Serum phenobarbital levels are also reduced due to induct ion by many other drugs, and increased due to inhibition by co-adminis- tration of drugs su ch as valproate. Oxcarbazepine Oxcarbazepine is the 10-keto analog of carbamazepine. It was introduced into clinical practice in Denmark in 1990, but licensed in other EU countries in 1999 and in the US in 2000. Oxcarbazepine is metabolized \201 rst by reduction, avoiding the oxidative s tep that carbamazepine undergoes and thus the production of the oxidative metabolite of car bamazepine (CBZ-epoxide), which is responsible for some carbamazepine side effects. The pha rmacological action of oxcarbazepine is exerted almost exclusively through its active 10-mo nohydroxy derivative metabolite (MHD). Its antiepileptic effects are very similar to those of carbamazepine, and its mode of action is identical Common and important adverse events include rash and other idiosyncratic reactions. Other s ide effects include sedation, leth- argy, somnolence, headache, dizziness, diplopia, ataxia , rash, hyponatraemia, weight gain, alopecia, nausea, gastrointestinal dis- turbance. Neuro psychiatric side effects can occur including depres- sion, aggressiveness, cognitive dysfun ction, impotence, reduced libido, paradoxical hyperkinesis and behavioral change in chil- d ren (which can be severe). Cognitive effects including memory and attentional disturbances, folate and vitamins D and K de \201 - ciency, Dupuytren \200\231s contracture, frozen sho ulder, other connec- tive tissue and cosmetic effects, osteopenia, and osteomalacia are als o reported. It has generally fewer and less marked drug interactions than carbamazepine. Other enzyme i nducing antiepileptic drugs reduce the serum levels of the active metabolite MHD. Oxcarbaze pine co- medication increases serum levels of phenytoin and phenobarbital, and reduces seru m levels of oral contraceptives. The primary indication is as \201 rst- or second-line therapy for par- tial or generalize d seizures (including absence and myoclonus), Lennox \200\223Gastaut syndrome, and other ch ildhood epilepsy syn- dromes. It has also been extensively used in febrile convulsions and neonatal seizures. Side effects are also similar to those of carbamazepine. It has however a more marked prope nsity to cause hyponatraemia, which can be severe. Although the risk of serious rash is low er that with carbamazepine, a mild skin rash is relatively common (about 5 \200\22310 % of all patients). About 25 \200\22330 % of those experiencing a seri- ous rash or hypersensiti vity on carbamazepine will also experience similar symptoms on oxcarbazepine. It may share the link described earlier with the HLA-B * 1502 and carbamazepine ( 17 ). Other side effec ts are dizziness, unsteadiness, diplopia, ataxia, somnolence, Available preparations tablets of 15, 30, 50, 60, 100 mg strength, liquid (15 mg/5mL), and injection (200 mg/mL). Usual dosage for adults is initially 30 mg/day, with increments of 30 mg every 2 weeks. Mai ntenance doses are typically 30 \200\223180 mg/day. CHAPTER 26 the pharmacokinetics and clinical therapeutics of the antiepileptic drugs 285 Serum level monitoring is mandatory when establishing therapy. Usual dosage for neonates is 3 \200\2234 mg/kg/day, and for children Target range is 40 \200\22380 mol/L (10 \200\22320 mg/L) 3 \200\2238 mg/kg/day. Dosing interval is 1 \200\2232 times/day. Serum level monitoring may be useful in some pati ents, with a Pregabalin Pregabalin was licensed as an antiepileptic drug in 2004 for adjunc- tive use in partial seizures in adults, both in the US and in Europe. In addition to its epilepsy indi cations, it is licensed as an analgesic for neuropathic pain. It is structurally similar to gabapentin and acts in the same way, by modulating neurotransmitter release by binding to the 2 subunit of voltage-gated calcium channels. However, its binding is stronger and it has greater ef \201 cacy than gabapentin. It has excellent pharmacokinetics, with a lo w potential for drug interaction and is excreted largely unchanged. These are signi \201 c ant advantages in many clinical situations. It also has a mild anxiolytic effect. Its main side effects are weight gain and CNS effects such as sedation, and these tend to be dose-re lated and may be dose-limiting. It is a powerful antiepileptic and a useful addition to sec ond-line therapy, though its most common use is in pain management. target range of 10 \200\22340 mg/L. Phenytoin Phenytoin was introduced into clinical practice in 1938. Although no longer consi dered \201 rst-line therapy in Europe, it remains one of the most widely used AEDs in the world because of its low cost and strong antiepileptic effect. It has dif \201 cult pharmacokinetic properties, with non-linear kinetics, extensive hepat ic metabolism, and many drug interac- tions. Because of this, its use requires regular seru m level monitor- ing especially when changing therapy. However, once a satisfactory phenyto in dosage regimen has been achieved in a particular patient, it will rarely be necessary to alter the regimen over many years. The list of side effects is long but most patients on c hronic therapy do not experience marked side effects, and there is no strong evidence of an y general difference in tolerability between phenytoin and other old (or new) drugs. It is now usually reserved as a drug of second choice in partial and secondarily generalized seiz ures, and also in primary generalized tonic \200\223clonic seizures. Its major mecha- nism of action, as with carbamazepine, is mediated by inhibition of voltage-dependent sodium cha nnels. Common or important side effects include dizziness, somno- lence, ataxia, asthenia, increas ed appetite and weight gain, visual disturbances, tremor, memory and attentional de \201 c it, confusion and other cognitive effects, psychiatric disturbance, change in sexual functi on, blurred vision, peripheral oedema, dry mouth, gastrointestinal disturbances (particular ly constipation), \202 atu- lence, cardiorespiratory disturbance, myalgia, joint pains, h epatic and pancreatic disturbance. Rare cases of hypersensitivity have been reported includ ing severe skin reactions and blood dyscrasia. There are many common and important drug interactions. Phenytoin is a strong enzyme inducer and reduces the serum levels of many other drugs. Similarly, numerous drugs interfere with phenytoin absorption, plasma protein binding, and metabolism. It has no important drug interactions. Primary indications for use are as second-line thera py for partial A hypersensitivity reaction to phenytoin is rare but can be severe and can take various for ms including rash, fever, hepatic and renal disturbance, a lupus-like syndrome, lymphadenop athy or blood dyscrasias. Other side effects include: ataxia, dizziness, lethargy, sedation , psychiatric disturbance including depression and anxiety and psychosis, headache, dyskine sia, acute encephalopathy (pheny- toin intoxication), insomnia, tremor, psychological chang es includ- ing memory and attentional defects, connective tissue alterations, gingival hype rplasia, coarsened facies, hirsutism, osteopenia and osteomalacia, vitamins D and K and fol ate de \201 ciency, megaloblastic anemia, hypocalcaemia, hormonal dysfunction, loss of lib ido, pseu- dolymphoma, hepatitis, coagulation defects, bone marrow hypopla- sia, gastrointe stinal disturbance including nausea and vomiting and anorexia, weight change. seizures with or without secondary generalization in adults. The preparations available are capsules: 25, 50, 75, 100, 150, and 300 mg size. The usual a dult dosage is initially 50 mg/day, with increments of 50 mg every 2 weeks. Maintenance dos es are 150 \200\223600 mg/day. Dosing interval is 2 times/day. Serum level monitoring is not routinely needed or useful. Primidone Primidone is a \200\230pro-drug \200\231 of phenobarbital, introduced into clini cal practice in 1952, and its action is probably entirely due to the derived phenobarbital. It has no clinical advantage (and signi \201 - cant disadvantages) compared to phenobarbi tal, although it is not, like phenobarbital, a drug of abuse and therefore not subject to s pecial controls. The side effects are the same as those of phenobar- bital, with the additi onal problem of a propensity to intense dizzi- ness, nausea and sedation at the onset of th erapy (sometimes after only one tablet) if the dose started is too high. These effects are probably due to the initially high concentration of the parent drug and disappear after a w eek or so. Because of this reaction it is always advisable to start primidone at a very low dose. The drug interac- tion pro \201 le of primidone is that same as that of phenobarbit al. Primary indications for use are partial and primary and second- arily generalized seizures (excluding myoclonus and absence). Available preparations include capsules: 25, 30, 50, 100 , 200 mg; chewtabs: 50 mg; liquid suspension (30 mg/5 mL, 125 mg/50 mL), and injection (250 mg/5 mL). The usual adult dosage initially is 300 mg at night, with mainte- nance doses of 200 \200 \223500 mg/day (higher doses can be used; guided by serum level monitoring). The non-linear kinetics of the drug mean 25 \200\22350 mg increments and decrements of the dose are usual ly appropriate when near the target range, and conversely that rela- tively small changes i n the dose can cause large changes in serum levels. Usual indications are as for phenobarbital. The available prepara- tions are a tablet, 250 mg, and suspension: 50 mg/mL. The usual adult dosage is initially 62.5 \200\223125 mg/day. Increasing by 125 \200\223250 mg incre- ments every 2 weeks to a maintenance dose of 500 \200\2231500 mg/day. In children the usual maintenance dose is 10 mg/kg/day. Again, The usual dosage in children initially is 50 mg increased gradu- higher doses can be used; guided by serum level monitoring. ally to a maintenance dose of 10 \200\22325 mg/kg/day. Dosing interval is 1 \200\2232 times/day. oxford textbook of epilepsy and epileptic seizures 286 levels through a decrease in hepatic metabolism. Ru \201 namide can decrease serum levels of carbamazepine and lamotrigine, and may increase serum levels of phenobarbital and phenyt oin. Ru \201 namide may also increase the clearance of ethinyloestradiol and norethin- dro ne and consequently impair the ef \201 cacy of the oral contracep- tive. No dosage adjustm ent is needed in the presence of renal dysfunction, but it is not recommended for use in pa tients with hepatic impairment. Haemodialysis may reduce serum concentra- tions by approxim ately 30 % . Dosing interval is 2 times/day. Serum level monitoring is useful to measure the derived phe no- barbital levels. Retigabine Retigabine was licensed in Europe in 2011. It has a completely novel mechanism o f action and thus its use in epilepsy was eagerly awaited. Retigabine acts primarily by ope ning neuronal potas- sium channels (KCNQ2 [Kv7.2] and KCNQ3 [Kv7.3]) and thus stabilizing t he resting membrane potential and controlling the sub- threshold electrical excitability in neurons ( 18 ). This seems to be its only action and this action is not shared by other an tiepileptic drugs. The indication for use currently is as adjunctive treatment of sei- zures in Lennox \200 \223Gastaut syndrome in patients 4 years and older. The recommended starting dose for adults is 400 \200\223800 mg/day. The dose may be increas ed by 400 \200\223800 mg/day increments every 2 days to a maximum dose of 3200 mg/day. The recommended starting dose in children is 10 mg/kg/day, increasing by 10 mg/kg every 2 days up to a dose of 45 mg/kg/day or 3200 mg/day. The drug is absorbed only to about 60 % . It is approximately 80 % bound to plasma protein over the concentration range of 0.1 to 2 micrograms/mL. It is extensively metabolized in th e liver eventu- ally to N-glucuronides, and is excreted largely via the kidney. It does not induce or block liver enzymes and retigabine does not signi \201 cantly alter the levels of other AEDs, although phenytoin and carbamazepine can reduce retigabine systemic exposure by about one-third. Stiripentol Stiripentol was licensed in Europe in 2008, again though the orphan drug progra m. Its precise mechanism of action is unknown, other than that it enhances the effect of GA BA ( 19 ). The drug is rapidly absorbed after oral ingestion, but its bioavailability has n ot yet been determined. It is 99 % bound to serum proteins. Stiripentol is extensively meta bolized, and only traces detectable unchanged in the urine. The most common side effects are dizziness, fatigue and somno- lence. Other side effects ar e weight gain, confusion, psychotic dis- orders, hallucinations, disorientation and anxiety . The usual neurological side effects of antiepileptic drugs have been reported including: diplopia, blurred vision, memory disturbance, unsteadi- ness, vertigo, paraesthesia, tremor , speech disturbance and malaise. Gastrointestinal disturbance and peripheral oedema have b een reported. Because of its mode of action, dif \201 culty with micturition and even urin ary retention have been reported as an unusual but troublesome side effect. Stiripentol is a potent hepatic enzyme inhibitor, and can increase serum levels of phenytoi n, carbamazepine, phenobarbital, valproic acid, and clobazam. Enzyme-inducing agents such a s car- bamazepine, phenobarbital, phenytoin and primidone induce the metabolism of stiripen tol, and may lower stiripentol serum levels. No signi \201 cant interactions between stiri pentol and other non-AEDs have been reported, but it is a potent inhibitor of hepatic enzym es and the potential exists for interactions with other medications metabolized by the live r. It is not currently known to have any sig- ni \201 cant effect on sex hormones or oral contraceptive agents. The drug has shown striking ef \201 cacy. The licensed indication currently is as adjuncti ve treatment for partial onset seizures with or without secondary generalization in adults aged 18 years and above. The only current licensed indication for stiripentol is as adjunc- tive treatment of seizur es in children with severe myoclonic epi- lepsy in infancy (Dravet syndrome)( 20 ). Availab le preparations are a capsule, 250 and 500 mg size; and powder also 250 and 500 mg. The ini tial dose is 50 mg/kg/day, increasing up to 100 mg/kg per day, with a maximum of 4g. The usual starting dose is 50 mg 3 times a day. This is increased every week or two by 50 m g, 3 times a day until an effective mainte- nance dose of between 600 \200\2231200 mg is re ached. The maximum licensed dose currently is 400 mg, 3 times a day. In severe renal or hep atic failure the dose should be halved, but there is no requirement to change the dose in m ild or moderate renal or hepatic failure. The dosing interval is 2 \200\2233 times daily. Because of its potential for interactions, the doses of other anticonvulsants may have to be reduced, and potential interactions with other hepatically metabo- lized agents will need to be careful monitored. Retigabine is available as 50, 100, 200, 300, and 400 mg tablets. The recommended dosing intervals are three times a day. Serum level monitoring is not required Ru \201 namide Ru \201 namide was licensed in Europe in 2007 through the European Orphan Drug Program. It is a triazole derivative structurally unre- lated to any other current ant iepileptic drugs. Ru \201 namide \200\231s exact mechanism of action is unknown, though it is thought to modulate sodium channels and produce membrane stabilization. Tiagabine Tiagabine was introduced into clinical practice in 1998 as adjunc- tive therapy i n refractory patients with partial or secondarily gen- eralized seizures, in adults and in children over the age of 12 years. It is a GABA reuptake blocker, and acts by enhancing GAB Aergic transmission. This is a similar mechanism of action to that of viga- batrin, but tia gabine does not carry the risk of psychosis and depression, or visual \201 eld defects, w hich are major side effects of vigabatrin. It is metabolized by the hepatic cytochrome CYP3 A4 enzymes, is 96 % protein bound and has a half-life of 5 \200\2239 hours but which is red uced to 2 \200\2234 hours in co-medication with enzyme- inducing drugs. Its use however is complicated by the need to The absorption is slow but complete, with bioavailability of 85 % . It is 34 % protein boun d. Ru \201 namide is metabolized in the liver, primarily by hydrolysis, and the pharmacolo gically inactive metab- olite is excreted in urine. The half-life is 6 \200\22312 hours. Carbamazepine, phenobarbital, phenytoin, primidone and viga- batrin can signi \201 cantly decrease ru \201 namide serum levels through increased clearance. Valproic acid can increa se ru \201 namide serum CHAPTER 26 the pharmacokinetics and clinical therapeutics of the antiepileptic drugs 287 Common and important adverse events include dizziness, ataxia, headache, paraesthesia, trem or, somnolence, visual blurring, cog- nitive dysfunction (especially dif \201 culties with memory, attention, language and word \201 nding) confusion, agitation, amnesia, depres- sion, anxiety, psychosis, emotional lability, diplopia, loss of appe- tite and weight loss (which can be marked), nausea, abdominal pain, taste disturbance, dyspepsia, acidosis, and alopecia. Open- angle glaucoma is rarely reported. titrate slowly, the potential for drug interactions that result in the need for dose change s, and the frequent need for 3 or even 4 times a day dosing. It should always be taken with food, and preferably at the end of meals, to avoid rapid rises in plasma concentrations \200\224 and the giving with food will greatly improve tolerability. Individual dosing 4 ti mes daily may also be helpful, at least with higher doses. Minor dose-related side effects are common but the frequency of idiosyncratic drug-related reactions, including cutaneous r eac- tions, is very low. It has a tendency to exacerbate seizures in the generalized epilep sies, and to provoke non-convulsive status ( 21 ). Most enzyme-inducing AEDs increase tiaga bine clearance by stimulating its metabolism and dose changes are often needed under these circumstances. The usual indications for use are as adjunctive therapy or mono- therapy in partial and sec ondarily generalized seizures. It is also useful for Lennox \200\223Gastaut syndrome and pr imary generalized tonic \200\223clonic seizures in adults and children over 2 years of age. Preparations available include tablets: 25, 50, 100, 200 mg size and sprinkles of 15 and 25 mg size. The usual adult dosage is initially 25 \200\22350 mg/day, increasing in 25 mg inc rements every 2 weeks. Maintenance doses are 100 \200\223500 mg/day. Usual dosage in childr en initially is 0.5 \200\2231 mg/kg/day, and maintenance doses 2 \200\2239 mg/kg/day. It is often poorly tolerated, and common or adverse events include dizziness, tiredness, ne rvousness, tremor, diarrhea, nausea, headache, ataxia, confusion, psychosis, depression, wo rd- \201 nding dif \201 culties and other cognitive effects, emotional lability, \202 u-like symptoms, gastrointestinal disturbances, and exacerbation especially of myoclonic an d absence seizures and the precipitation of non-convulsive status epilepticus. Dosing interval is 2 times/day. Serum level monitoring can be helpful in occasional cases. The target level 5 \200\22320 mg/L. The usual indications for use are as adjunctive therapy in partial and secondarily generali zed seizures in patients over 12 years of age, but it has generally only a small role in co ntemporary therapy. Usual preparations are tablets 2.5, 5, 10, 15 mg size in Europe: 2, 4, 12, 16, and 20 mg in the US and Canada. The usual adult dosage initially is 4 \200\2235 mg/ day, then slow increase by increments of 4 \200\2235 mg/week. Maintenance doses are 15 \200 \22335 mg/day (30 \200\22350 mg/ day in co-medication with enzyme-inducing drugs). Valproate Valproate was licensed in Europe in the early 1960s and then in the US in 1978. I t is marketed as a sodium, magnesium, or calcium salt, an acid, and also as sodium hydrogen divalproate. Its mechanisms of action have not been fully established, but it has effects on GABA and glutaminergic activity, calcium (T) con- ductance, and potassium conductance. S odium valproate is the usual form in the UK and depakote in Europe. Valpromide (dipro- pyla cetamide), a prodrug of valproate, is also marketed, as is a delayed release formulation of sodium valproate. The term val- proate is usually adopted to refer to all these forms. Alt hough properties vary to some extent, none of these formulations has been shown to confer a ny real superiority over the others. Valproate is still one of the most commonly used antie pileptics throughout the world. It is a drug of \201 rst choice in all seizure types (abs ence, myoclonus, tonic \200\223clonic) in idiopathic generalized epilepsy and is strikingly more effective than lamotrigine, topiram- ate and barbiturate drugs in this syndrome. Whet her levetiracetam can compete with its effectiveness is not yet clear. It is also a drug of \201 rst choice in the Lennox \200\223Gastaut syndrome where it controls atypical absenc e and atonic seizures better than most other \201 rst line drugs. It is also a drug of \201 rst choice in the syndromes of myoclonic epilepsy and the progressive myoclonic epilep sies, and for epilepsies with photosensitivity and/or generalized spike wave electrographic ally. In partial and secondarily generalized epilepsy, carbamazepine is usually tried befor e valproate, although there is no real evidence that valproate is less effective in new or mild cases. Dosing interval is 3 times a day. Serum level monitoring is not needed. Topiramate Topiramate was licensed in the UK in 1994, and subsequently in the US, Europe, a nd many countries worldwide. It is a sulfamate- substituted monosaccharide with multiple me chanisms of action, which include inhibition of voltage-gated sodium channels, poten- tiati on of GABA-mediated inhibition at the GABA A receptor, reduction of AMPA receptor activity, inhibition of high voltage calcium channels and carbonic anhydrase activity. Its pharmacok i- netic properties are generally favorable, although it is metabolized in the liver and ca n be involved in drug interactions, albeit usually of a minor nature. It has gained a reput ation as a powerful antiepi- leptic drug, effective in some patients in whom all other medi ca- tions have failed. It is effective in a broad spectrum of epilepsies, but has a particu lar place in the treatment of resistant focal sei- zures, and symptomatic generalized epile psies. The early clinical trials were carried out at higher doses than are now currently re c- ommended, and although these studies showed marked ef \201 cacy, the rate of neurologic al and cognitive side effects was also high. However, subsequent experience shows that lowe r doses are also effective and confer better tolerability, and in routine practice now, the rate of side effects is lower than initially feared. The risk of side effects can also be greatly reduced by starting the drug at a very low dose and titrating upwards slowly. Side effects remain a problem. Weight gain is common and often problematic. Other side effe cts, such as the neurotoxic effects and effects on hair growth are also common, but often o nly slight and usually are not a reason for drug withdrawal. In female patients, the possib ility that valproate increases the frequency of polycystic ovaries, cause menstrual irregul arities and reduce fertility are enough for many to avoid its use although scienti \201 c evidence on these points is generally slight. Valproate teratogenicity is a major Drug interactions are generally slight. However, topiramate levels can be lowered by co-med ication with carbamazepine, phe- nobarbital and phenytoin. Topiramate co-medication can inc rease phenytoin levels. oxford textbook of epilepsy and epileptic seizures 288 available AED. It also has other signi \201 cant side effects, including depression and ps ychosis. It has a strong effect in infantile spasms, and is often effective in cases resist ant to ACTH, and because of this has become a drug of \201 rst choice in this small indic ation. It is particularly effective in cases in which the infantile spasms are due to tuber ous sclerosis. concern and is a further reason for avoiding valproate in female patients where pregnancy i s an issue. Its use in young children, especially those under 2 years of age, carries a sma ll but de \201 nite risk of hepatic failure and where other drugs are available, these ten d now to be used. It is contraindicated in the presence of hepatic or pancreatic disease. V alproate pharmacokinetics are complex and there are many and varied interactions. It slight ly inhibits the metabolism of other AEDs, usually without consequence, but does cause major rises in lamotrigine levels when given as co-medica- tion. Imipenem antibiotics profoundly lower valproate levels and should not be used in co-medication. Valproate concentra- tions are lowered by co-medication with commonly used antineo- plastic drugs and elevated by co- medication with commonly used antidepressant and psychotropic drugs. Other drugs, such as i soni- azid, can increase valproic acid levels. Valproic acid inhibits the metabolism of a n umber of drugs, most notably phenobarbital, lamotrigine, and ru \201 namide. Valproic acid displaces phenytoin from plasma protein binding sites and can also inhibit phenytoin metab olism. Apart from the visual \201 eld restrictions and the psychiatric effects, other common and important side effects of vigabatrin include nausea, abdominal pain, drowsiness, dizziness , encephalopathy, stupor, confusion, visual \201 eld restriction, weight gain, headache, tremor, and paraesthesia. Vigabatrin has no important or common drug interactions. The usual indication for use is as adjunctive therapy in partial epilepsy, but only in exceptional circumstances and where su per- vised by a specialist, and infantile spasm. The available prepara- tions are tablets 5 00 mg size, and powder 500 mg/sachet. The usual adult dosage is initially 500 mg, increasin g by 500 mg increments to 2 \200\2233 g/day. The usual dosage in children is: 10 \200\22315 kg: 0.5 \200\2231 g/ day; for children 15 \200\22330 kg: 1 \200\2231.5 g/day; and for chil dren 30 \200\22350 kg: 1.5 \200\2233 g/day. Common and important side effects include nausea, vomiting, hyperammonaemia and other metab olic effects, endocrine effects, weight gain, severe hepatic toxicity, gastrointestinal dis tur- bance, pancreatitis, drowsiness, cognitive disturbance, aggressive- ness, tremor, atax ia, weakness, encephalopathy, extrapyramidal symptoms, oedema, thrombocytopenia, neutropeni a, platelet and coagulation dysfunction, aplastic anemia, hair thinning and hair loss, poly cystic ovarian syndrome, Fanconi syndrome, and hyponatraemia. Dosing interval is 2 times/day. Serum level monitoring is not useful. Zonisamide Zonisamide is a chemically distinctive sulfonamide drug, with striking effective ness in a wide spectrum of partial and generalized seizures. It has been licensed in Japan for some years, although has become available in Europe only since 2002. It has multiple po ten- tial mechanisms of action, and inhibits the voltage-gated sodium channel and T-type ca lcium channel currents, acts to enhance the benzodiazepine GABA A receptor, is a carbonic a nhydrase and also has actions on excitatory glutaminergic transmission. It is prone to caus e various side effects and tolerability can be improved by slow introduction. The risk of r enal stones has been a concern particu- larly in Europe and the US, but less so in Japan, a nd patients should be advised to remain well hydrated when taking this drug. It has about 5 0 % protein binding, and a very long half life (50 \200\22370 hours) but this is signi \201 cantly reduced (25 \200\22340 hours) by co-medication with enzyme-inducing AEDs and do se changes when co- medicating are appropriate. Vaproate is indicated in all forms of epilepsy at all age groups. The usual preparations ar e enteric-coated tablets: 200, 500 mg; crushable tablets: 100 mg; capsules: 150, 300, 500 m g; solution or syrup: 200 mg/5 mL, 250 mg/5 mL; sustained-release tablets: 200, 300 500 mg; sustained-release microspheres, sachets: 100, 250, 500, 750, 1000 mg; divalproex tablets: 125, 300, 500 mg (as valproic acid equivalents); divalproex tablets delayed release: 125, 2 50, 500 mg (as valproic acid equivalents); divalproex sprinkles, 125 mg (as val- proic acid equivalents); divalproex tablets extended release: 250, 500 mg (as valproic acid equivalen ts); solution for intravenous injection: 100 mg/mL The usual adult dosage initially is 200 \200\223500 mg/day increasing by 200 \200\223500mg increments every 2 weeks to maintenance doses of 600 \200\2232000 mg/day. The usual dosage in children initially is 15 mg/ kg/day (children <20 kg); and 40 mg/kg/day (children > 20 k g). Maintenance doses in children < 20kg: 20 \200\22340 mg/kg/day, and in children > 20 kg: 20 \200\22330 mg/kg/day. Dosing intervals is 2 times/day. Blood levels show marked diurnal variation, but serum level monitoring can be useful in occasional cases. The target range is 50 \200\223100 mg/L. It should be noted that the drug can be very effective at low serum levels, and as with other agents clinical parameters should be used to guide therapy where ver possible. Serum zonisamide levels are markedly lowered by carbamazepine, phenytoin, and barbiturates. Zonisamide co-medication does not usually signi \201 cantly in \202 uence levels of othe r drugs. Common and important adverse events are somnolence, ataxia, dizziness, insomnia, headache, attention and concentration dif \201 culties, memory impairment, irritability, confusion, depres- sion, impaired concentration, mental slowing, speech distur- bance, fatigue, nausea , vomiting, weight loss, anorexia, itching, abdominal pain, hyperthermia, nephrolithiasis, acidosis, pyrexia, renal impairment, oligohidrosis and risk of heat stroke. Rash and other manifestations of a hypersensitivity are rare but can be serious. Vigabatrin Vigabatrin is a GABA agonist, which was introduced in 1989 for the treatment of partial seizures. It was then discovered in 1997 to cause visual \201 eld constriction, a side effect which is now known to occur in over 40 % of treated patients ( 22 ). Because o f this, its use has become severely limited to a very small number of patients with partial epilepsy whose seizures are controlled with no other Usual indications include adjunctive therapy in partial and generalized epilepsy, Lennox \200\223Gastaut syndrome, West syndrome, and progressive myoclonic epilepsy. It is licensed in Europe, Japan and Asia in children and adults. It is licensed in the US only for refrac tory partial epilepsy in patients 16 or more years of age The usual preparations are capsules 25, 50, 100 mg size, tablets 25 and 100 mg size, and po wder: 20 % . Initial dose in adults is CHAPTER 26 the pharmacokinetics and clinical therapeutics of the antiepileptic drugs 289 50 mg/day, increased by 50 mg increments each 2 weeks, to a main- tenance dose of 200 \200 \223500 mg/day. In children the initial dose is 2 \200\2234 mg/kg/day, and maintenance 4 \200\2238 mg/kg/day. 9. Ng YT , Conry JA , Drummond R , Stolle J , Weinberg MA , OV-1012