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Assoc. Prof. Ivan Lambev e-mail: itlambev@mail.bg Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology Antiseizure (antiepileptic) drugs (Abstract)
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EPILEPSY affects 5–10‰ of the general population. It is due to sudden, excessive depolarization of some or all cerebral neurons. This may be: localized (focal or partial seizure); spread to cause a secondary generalized seizure; may affect all cortical neurons simultaneously (primary generalized seizure).
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EEG Cortex: F – frontal O – occipital T – temporal Classification of seizures Rang et al. Pharmacology – 5th Ed. (2003)
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HISTORY Bromides (1857) Phenobarbital (1912) Phenytoin (1938) Later: Ethosiximide, Carbmazepine New anticonvulsants (in the last 15–20 years): vigabatrin, gabapentin, lamotrigine, topiramate, oxcarbazepine, levetiracetam, pregabalin etc.
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ANTISEIZURE DRUGS 1. Carboxamides (enzyme inductors – CYP450): Carbamazepine (+ neuropathic pain – n. trigeminus, postherpetic pain, etc.), Oxcarbazepine 2. Hydantoins: Phenytoin (enzyme inductor), used in digitalis intoxication too 3. Barbiturates (Phenobarbital – enzyme inductors) and their analogues (Primidone – prodrug) 4. Succinimides: Ethosuximide (casp. 250 mg – petit mal) 5. Valproates (enzyme inhibitors): Sodium valproate (Depakin®) 6. Benzodiazepines: Clonazepam, Clorazepate, Diazepam t1/2 43 h, amp. 10 mg/2 ml i.m./i.v., Lorazepam, Nitrazepam 7. GABA analogues: Gabapentin, Tiagabine 8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam, Pregabalin (partial seizures, peripheral neuropathic pain), Topiramate, Vigabatrin
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MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS Antiepileptics inhibit the neuronal discharge or its spread in one or more of the following ways: (1) Enhancing GABA synaptic transmission: barbiturates, benzo- diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira- mate, valproate; the result is increased permeability to chloride ion, which reduces neuronal excitability. Valproate and topiramate block GABA transaminase and tiagabine blocks reuptake of GABA. (2) Reducing cell membrane permeability to voltage-dependent sodium channels: carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate. (3) Reducing cell membrane permeability to calcium T-channels: valproate, ethosuximide; the result is diminishing of the generation of action potential. (4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.
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Carbamazepine Lamotrigine Oxcarbazepine Phenytoin Topiramate Valproate Ethosuximide Levetiracetam Pregabalin Valproate Barbiturates Benzodiazepines Gabapentin Levetiracetam Tiagabine Topiramate Valproate Vigabatrin Na+ Ca2+ GABA
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Antiseizure drugs enhanced GABA synaptic transmission Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
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Antiseizure drugs, enhanced Na+ channel inactivation Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
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Antiseizure drugs, induced reduction of current through T-type Ca2+ channels. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
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Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by cultured neurons. Intracellular recordings were made from neurons while depolarizing current pulses, approximately 0.75 s in duration, were applied (on-off step changes indicated by arrows). In the absence of a drug, a series of high-frequency repetitive action potentials filled the entire duration of the current pulse. Phenytoin, carbamazepine, and sodium valproate all markedly reduced the number of action potentials elicited by the current pulses. Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)
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INDIVIDUAL ANTIEPILEPTICS ▼CARBAMAZEPINE blocks voltage-dependent sodium ion channels, reducing membrane excitability. The t1/2 of the drug falls from 35 to 20 h over the first few weeks of therapy due to the induction of hepatic enzymes that metabolize it as well as other drugs (including adrenal corticosteroids, hormonal contraceptives, theophylline and warfarin. Standard tablets are taken twice a day. Carbamazepine is a drug of first choice for focal and secondary generalized epilepsy but aggravates myoclonic and absence seizure. It is useful for the treatment of trigeminal neuralgia, postherpetic pains, etc. Adverse reactions (ARs): reversible blurring of vision, diplopia, dizziness, ataxia, depression of AV conduction, skin rashes, liver, and kidney dysfunction.
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▼VALPROIC ACID (Sodium valproate) acts by inhibiting GABA transaminase and increases the concentration of inhibitory neuro- transmitter GABA at its receptors. Valproic acid has t1/2 13 h and 90% bound to plasma albumin. It is a nonspecific inhibitor of meta- bolism, and inhibits its own metabolism, and that of lamotrigine, phenobarbital, phenytoin and carbamazepine. Valproic acid is effective for treatment of generalized and partial epilepsy, febrile convulsion and post-traumatic epilepsy. ARs can be troublesome: weight gain, teratogenicity, polycystic ovary syndrome, and loss of hair which grows back curly. Nausea can be a problem, rarely, liver failure (risk maximal at 2–12 weeks). Ketone metabolites may cause confusion in urine testing in diabetes mellitus.
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▼PHENYTOIN (t1/2 6–24 h) has saturation kinetics. It is extensively hydroxylated in the liver and this process becomes saturated at the doses needed for therapeutic effect (therapeutic plasma concentration range is 10–20 mg/L). Phenytoin is a potent inducer of hepatic metabo- lizing enzymes affecting itself and other drugs (carbamazepine, war- farin, adrenal and gonadal steroids, thyroxine, tricyclic antidepressant, doxycycline, vitamin D, folate). Drugs that inhibit phenytoin metabolism include: valproic acid, cimetidine, co-trimoxazole, isoniazid, chloram- phenicol, some NSAIDs, disulfiram. Phenytoin is 90% bound to plasma albumin and small changes in binding will result in a higher concentra- tion of free active drug. It is used to prevent all types of partial seizure, generalized seizure, and st. epilepticus. It is not used for absence attacks. ARs: impairment of cognitive function (which has led many physicians to prefer carbamazepine and valproate), sedation, hirsutism, skin rashes, gum hyperplasia (due to the inhibition of collagen metabolism), hyperglycemia, anaemia, osteomalacia.
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Saturation kinetics. Phenytoin is extensively hyd- roxylated in the liver and this process becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits first- order kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (10–20 mg/L) is approached, i.e. the dose increments of equal size produce disproportional rise in steady-state plasma concentration.
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Nonlinear relationship of phenytoin dosage and plasma concentrations. Five different patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is storable. Note also the marked variation among patients in the serum levels achieved at any dosage. Basic & Clinical Pharmacology – 10th Ed. (2007)
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▼BENZODIAZEPINES Diazepam given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic- clonic status epilepticus. The drug is occasionally given orally on a long-term basis, although it is not considered very effective in this application, probably because of the rapid development of tolerance. A rectal gel is available for refractory patients who need acute control of bouts of seizure activity. Lorazepam appears in some studies to be more effective and longer-acting than diazepam in the treatment of status epilepticus and is preferred by some experts. Clonazepam (t1/2 25 h) is a benzodiazepine used as a second line drug for treatment of primary generalized epilepsy and status epilepticus.
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Cl- Barbitu- rate sate GABAA- site GABA BDZs site + + Clonazepam, Clorazepate, Diazepam, Lorazepam, Nitrazepam Barbiturates + GABAA- benzo- diazepine receptor complex By Bennett and Brown (2003)
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▼BARBITURATES (enzyme inducers) Antiepilepsy members include phenobarbital (phenobarbitone – ( t1/2 100 h), methylphenobarbital and primidone (which is largely metabolized to phenobarbital, i.e. it is a prodrug). They are still used for generalized seizures; sedation is usual. Primidone and its active metabolites Basic & Clinical Pharmacology – 10th Ed. (2007)
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▼LAMOTRIGINE (t1/2 6–24 h) inhibits excitory neurotransmitter glutamate. Lamotrigine is effective for the treatment of partial and secondarily generalized tonic-clonic seizure. It is generally well tolerated but may cause serious ARs of the skin, including Stevens–Johnson syndrome and toxic epidermal necrolysis. ▼TOPIRAMATE (t1/2 21 h) is used as adjunctive treatment for partial seizure, with or without secondary generalization. ARs: sedation, weight loss, acute myopia, raised intraocular pressure. ▼ETHOSUXIMIDE (t1/2 55 h) blocks T-type calcium ion channels. It is active in absence seizures (petit mal). ARs: gastric upset, CNS effects and allergic reactions.
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Stevens–Johnson syndrome
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PRINCIPLES OF MANAGEMENT (Clinical Parmacology – 9th Ed., 2003) Any causative factor must be treated (cerebral neoplasm etc). Educate the patient about the disease, duration of treatment and need for compliance. Avoid precipitating factor (alcohol, sleep deprivation, emotional stress, and caffeine). Anticipate natural variation: fits may occur around menstrual periods in women – catamenial (monthly) epilepsy. Give antiepileptics only if seizure type and frequency require it (e.g. more than one fit every 6–12 months).
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MAIN INDICATIONS OF ANTIEPILEPTIC DRUGS
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Anticonvulsive drugs of choice Grand mal: I choice – valproate or Lamotrigine Alternative – Carbamazepine, Topiramate or Phenytoin Petit mal: I choice – Ehosuximide or valproate Alternative – Clonazepam or Lamotrigine Partial seizures: I choice – Carbamazepine or valproate Alternative – Phenytoin, Lamotrigine, Vigabatrin, Topiramate Status epilepticus: I choice – Diazepam or Lorazepam (i.v.) Alternative – Phenobarbital (i.m./i/v.)
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Patient in opisthotonus (grand mal) Treatment of status epilepticus in adults
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GENERAL GUIDE TO ANTIEPILEPSY PHARMACOTHERAPY (1) The decision whether or not to initiate drug therapy after a single seizure remains controversial since approximately 25% of patients may not have another seizure. (2) Therapy should start with a single drug (70% of patients can be controlled on one drug (monotherapy). (3) Anticonvulsant drug therapy should be appropriate to the type of seizure. (4) The choice of drugs is also determined by the patient’s age and sex. (5) If the attempt to control epilepsy by use of a single drug is unsuccessful, it should be withdrawn and replaced by a second line drug, though these are effective in only 10% of patients.
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There is little evidence that 2 or 3 drugs are better than one, but more drugs often mean more ARs. (6) Effective therapy must never be stopped suddenly, only gradually. (7) After a period of at least 2–3 years free from seizures, with- drawal of anticonvulsants can be considered. In general, dis- continuing the antiepileptic drug therapy is associated with about 20% relapse during withdrawal and a further 20% relapse over the following 5 years. It is recommended that the antiepi- leptic drug be withdrawn over a period of 6 months. If a fit occurs during this time, full therapy must begin again until the patient has been free from seizure for a further 2–3 years.
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Alternative methods for treatment of epilepsy: Neurosurgery + laser therapy