Antiepileptic Drugs

Prof. DR. dr. Hadyanto Lim, MKes,SpFK,FESC,FIBA Dept.of Pharmacology, Faculty of Medicine, Methodist University of Indonesia-Medan

Blok 8 Semester IV Neuropsikiatri Kelas A 14 Juni 2011, Selasa, jam 11.00-12.00; Kelas B 14 Juni 2010, Selasa, jam 10.00-11.00

Seizure

• Episodes of abnormal electrical activitiy in the brain that cause involuntary movements, sensations, or thoughts. It can result from : head trauma, stroke, brain tumors, hypoxia, hypoglycemia, fever, alkohol withdrawal, infection, genetic, hyperthermia in children, idiopathic.

• Epilepsy : chronic disorder characterized by recurrent , self limited seizures.

Neurobiology of Seizure

Glu = Glutamate NMDA = N-methyl D-aspartate

Other Mechanisms of Seizure

• Suppression of inhibitory neurotransmission of -aminobutyric acid (GABA).

• Increase in calcium influx via T-type calcium channel in thalamic neuron.

Classification of Seizure• Partial (Focal) seizure : 60% - Originates in one cerebral hemisphere - Does not lose consciousness during the seizure. - In simple partial seizures : consciousness is not altered, in complex partial seizures, altered consciousness and repetitive behaviors (automatism)• Generalized seizure : 40% - Arises in both cerebral hemispheres and involves loss of consciousness.

Generalized Seizures• Tonic-clonic seizures : grand mal seizures A brief tonic phase that is followed by a clonic phase

with muscle spasms lasting 3 to 5 minutes.• Absence seizures : petit mal seizures - abrupt loss of consciousness - decreased muscle tone.

Partial and Generalized Seizures

Cellular and Synaptic Mechanisms Generating Seizures

Mechanisms of Antiepileptic Drugs

• Inhibition of the sodium or calcium influx responsible for neuronal depolarization.

• Augmentation of inhibitory GABA neurotransmission.

• Inhibition of excitatory glutamate neurotransmission.

Action of Phenytoin on

Na+ Channel

By prolonging the inactivated state of the Na+ Channel. Thereby, reducing the likelihood of repetitive action potentials

Drugs for Partial and Generalized Tonic-Clonic Seizures

• Phenytoin - A hydantoin derivative formerly called diphenylhydantoin. - Phenytoin is converted to an inactive hydroxylated metabolite by cytochrome P 450 enzymes. - Interferes with folate metabolism, and can lead to megaloblastic anemia. - Adversely affects collagen metabolism and thereby contributes to gingival hyperplasia.

Phenytoin

• Impairing cerebellar function, and can cause ataxia, diplopia, nystagmus, and slurred speech.

• It can cause hirsutism (excessive hair growth). Thus, phenytoin use in children should be avoided.

Drugs for Partial and Generalized Tonic-Clonic Seizures

• Carbamazepine - Adequately absorbed after oral administration. - Biotransformed to an active metabolite, carbamazepine epoxide. - Excreted as metabolites in the urine and feces. - Cause drowsiness, ataxia and CNS depression. - Drug of choice for trigeminal neuralgia.● Phenobarbital

Phenobarbital

• Well absorbed from the gut (usus)• Can cause ataxia, dizziness (pusing

kepala/pening), drowsiness, and cognitive impairment.

• In excessive doses, it can depress respiration.• Onset of action is slow, but long duration.• Second line drug for partial and generalized

tonic-clonic seizures.