Assoc. Prof. Ivan Lambev e-mail: itlambev@mail.bg

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

Antiseizure(antiepileptic)

drugs(Abstract)

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).

EEG

Cortex:F – frontalO – occipitalT – temporal

Classification of seizures

Rang et al. Pharmacology– 5th Ed. (2003)

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.

ANTI

SEIZ

URE

DR

UGS

1. Carboxamides (enzyme inductors – CYP450): Carbamazepine (+ neuropathic pain – n. trigeminus, postherpetic pain, etc.), Oxcarbazepine 2. Hydantoins: Phenytoin (enzyme inductor), used in digitalis intoxication too3. 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, Nitrazepam7. GABA analogues: Gabapentin, Tiagabine8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam, Pregabalin (partial seizures, peripheral neuropathic pain), Topiramate, Vigabatrin

MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGSAntiepileptics 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 blockGABA transaminase and tiagabine blocks reuptake of GABA.(2) Reducing cell membrane permeability to voltage-dependentsodium channels: carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate.(3) Reducing cell membrane permeability to calcium T-channels: valproate, ethosuximide; the result is diminishing of the generationof action potential.(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.

CarbamazepineLamotrigineOxcarbazepinePhenytoinTopiramateValproate

EthosuximideLevetiracetamPregabalinValproate

BarbituratesBenzodiazepinesGabapentinLevetiracetamTiagabineTopiramateValproateVigabatrin

Na+ Ca2+

GABA

Antiseizure drugsenhanced

GABAsynaptic

transmission

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

Antiseizure drugs, enhanced Na+ channel inactivation

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

Antiseizure drugs, induced reduction of current through T-type Ca2+ channels.

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

Effects of three antiseizure drugs on sustained high-frequency firing of actionpotentials 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 theentire duration of the current pulse. Phenytoin, carbamazepine, andsodium valproate all markedly reduced the number of action potentialselicited by the current pulses.

Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)

INDIVIDUAL ANTIEPILEPTICS

▼CARBAMAZEPINE blocks voltage-dependent sodium ion channels,reducing membrane excitability. The t1/2 of the drug falls from 35 to20 h over the first few weeks of therapy due to the induction of hepaticenzymes 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 offirst choice for focal and secondary generalized epilepsy but aggravates myoclonic and absence seizure. It is useful for thetreatment of trigeminal neuralgia, postherpetic pains, etc. Adverse reactions (ARs): reversible blurring of vision, diplopia, dizziness, ataxia, depression of AV conduction, skin rashes, liver, andkidney dysfunction.

▼VALPROIC ACID (Sodium valproate) acts by inhibiting GABAtransaminase 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, febrileconvulsion and post-traumatic epilepsy. ARs can be troublesome: weight gain, teratogenicity, polycysticovary syndrome, and loss of hair which grows back curly. Nausea can be a problem, rarely, liver failure (risk maximal at2–12 weeks). Ketone metabolites may cause confusion in urinetesting in diabetes mellitus.

▼PHENYTOIN (t1/2 6–24 h) has saturation kinetics. It is extensivelyhydroxylated in the liver and this process becomes saturated at the doses needed for therapeutic effect (therapeutic plasma concentrationrange 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 metabolisminclude: valproic acid, cimetidine, co-trimoxazole, isoniazid, chloram-phenicol, some NSAIDs, disulfiram. Phenytoin is 90% bound to plasmaalbumin 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 toprefer carbamazepine and valproate), sedation, hirsutism, skin rashes, gum hyperplasia (due to the inhibition of collagen metabolism),hyperglycemia, anaemia, osteomalacia.

Saturation kinetics. Phenytoin is extensively hyd-roxylated in the liver and this process becomessaturated at about the doses needed for therapeuticeffect. Thus phenytoin at low doses exhibits first-order kinetics but saturation or zero-order kineticsdevelop as the therapeutic plasma concentrationrange (10–20 mg/L) is approached, i.e. the doseincrements of equal size produce disproportional risein steady-state plasma concentration.

Nonlinear relationship of phenytoin dosage and plasma concentrations.Five different patients (identified by different symbols) received increasingdosages of phenytoin by mouth, and the steady-state serum concentrationwas 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)

▼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 ona long-term basis, although it is not considered very effective inthis application, probably because of the rapid development oftolerance. A rectal gel is available for refractory patients who needacute 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 epilepticusand is preferred by some experts.

•Clonazepam (t1/2 25 h) is a benzodiazepine used as asecond line drug for treatment of primary generalized epilepsyand status epilepticus.

ClBarbitu-rate sate

GABAA-site

GABA

BDZs

site+

+

Clonazepam, Clorazepate,Diazepam, Lorazepam,Nitrazepam

Barbiturates

+GABAA-benzo-diazepinereceptorcomplex

By Bennett and Brown (2003)

▼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 arestill used for generalized seizures; sedation is usual.

Primidone and its active metabolites

Basic & Clinical Pharmacology – 10th Ed. (2007)

▼LAMOTRIGINE (t1/2 6–24 h) inhibits excitory neurotransmitterglutamate. Lamotrigine is effective for the treatment of partial and secondarily generalized tonic-clonic seizure. It is generally welltolerated but may cause serious ARs of the skin, includingStevens–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.

Stevens–Johnson syndrome

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).

MAIN INDICATIONS OF ANTIEPILEPTIC DRUGS

Anticonvulsive drugs of choiceGrand 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 orvalproateAlternative – Phenytoin, Lamotrigine, Vigabatrin, Topiramate

Status epilepticus: I choice – Diazepam or Lorazepam (i.v.)Alternative – Phenobarbital (i.m./i/v.)

Patient in opisthotonus (grand mal)

Treatment of status epilepticus in adults

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 canbe controlled on one drug (monotherapy).(3) Anticonvulsant drug therapy should be appropriate to the typeof seizure.(4) The choice of drugs is also determined by the patient’s ageand sex.(5) If the attempt to control epilepsy by use of a single drug is unsuccessful, it should be withdrawn and replaced by a secondline drug, though these are effective in only 10% of patients.

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 withabout 20% relapse during withdrawal and a further 20% relapseover the following 5 years. It is recommended that the antiepi-leptic drug be withdrawn over a period of 6 months. If a fitoccurs during this time, full therapy must begin again until thepatient has been free from seizure for a further 2–3 years.

Alternative methodsfor treatment of epilepsy:

• Neurosurgery + laser therapy