Lecture 29 - 3rd Asessment - Anti-convulsant Drugs

ANTI-CONVULSANT DRUGS

CAUSES OF EPILEPSY - Genetic Factors - Antenatal and birth factors – congenital abnormalities - Infection – meningitis, viral encephalitis - Toxic factors – lead and mercury poisoning - Drug withdrawal – abrupt cessation of CNS depressants - Cerebral injury - Metabolic disorders - Hypoxia, hyperpyrexia, hypoglycemia

TYPES OF SEIZURES • TONIC-CLONIC - Generalized seizures usually start with tonic and thereafter progress to clonic rhythmic contractions. Clonic subsides after several min. Regain consciousness. • MYOCLONIC - Rapid, brief contractions, usually of the upper extremities. • ATONIC OR PSYCHOMOTOR - Loss of muscular contraction arrest of activity with hallucinations, alteration of consciousness and affective behaviour • PARTIAL or FOCAL - May be motor (Jacksonian) or sensory and are confined to groups of muscles or parts of the body

Major Seizure Types I. Partial (focal, local) seizures B. Simple partial seizures - Seizures may be limited to a single limb or muscle group, may show sequential involvement of body parts. Consciousness is usually preserved; B. Complex partial - seizures (psychomotor epilepsy, temporal lobe epilepsy) Impairment of consciousness, may have autonomic activity such as pupil dilation, flushing, piloerection, etc. C. Partial seizures (evolving to secondary generalized seizures) - May generalize to tonic, clonic, or tonic-clonic

II. Generalized seizures B. Absence seizures (petitmal epilepsy) - Brief loss of consciousness, with or without motor involvement; occurs in childhood with a tendency to disappear following adolescence B. Myoclonic seizures - Sudden, brief, shocklike contractions of musculature (myoclonic jerks) C. Clonic seizures - Repetitive muscle jerks D. Tonic seizures - Rigid, violent muscular contraction with limbs fixed

II. Generalized seizures E. Tonic-clonic seizures (grand mal epilepsy)Loss of consciousness; sudden sharp tonic contractions of muscles, falling to ground, followed by clonic convulsive movements; often postictal depression and incontinence F. Atonic seizures (astatic) - Sudden diminution in muscle tone affecting isolated muscle groups, or loss of all muscle tone; may have extremely brief loss of consciousness

STATUS EPILEPTICUS Prolonged seizures

Mechanism of action of anticonvulsant drugs 3. Reduce excitability of cell membranes via usedependent block of sodium channels 2. Enhance inhibitory GABAergic transmission 3. Inhibition of calcium channels

PHENYTOIN This is the oldest non-sedative anticonvulsant drug and is still one of the most widely used. Mechanism of action: At therapeutic levels, the main action of phenytoin is to block sodium channels and inhibit the generation of repetitive action potentials.

PHENYTOIN Pharmacokinetics: Effective after oral administration. Absorption is almost complete in most patients. It is highly bound to plasma proteins. Metabolism in the liver is by hydroxylation followed by conjugation with glucuronic acid. The metabolites are excreted in the urine.

PHENYTOIN Uses: 2. Treatment of generalized tonic-clonic seizures and partial seizures 2. Treatment of disturbed psychotic patients without epilepsy 3. Cardiac arrhythmias Side effects: These are usually dose-related. 9. Gingival hyperplasia, hirsutism, nystagmus, ataxia 2. Coarsening of facial features and osteomalacia 3. Blood dyscrasias eg aplastic anaemia

CARBAMAZEPINE Acts by blocking voltage-gated sodium channels (binds to sodium channels in the inactive state). It is orally active and bound (75%) to plasma proteins. It has antidepressant properties.

CARBAMAZEPINE

Uses:

Carbamazepine is used for tonic clonic and partial seizures. It is also used in pain and manic depression

Side effects include

6. induction of liver enzymes 7. ataxia 8. diplopia 9. aplastic anaemia (not very common

VALPROIC ACID Valproic acid acts by: 2. Hyperpolarizing neuronal membranes through an action on potassium channels. 2. Blocking sodium channels (in the inactive state). 3. Increasing GABA levels by inhibiting GABA-T

VALPROIC ACID It is used for tonic-clonic and partial seizures Side effects include: 3. ataxia 4. diarrhea 5. induction of liver enzymes and hepatic failure 6. Gastric irritation 7. teratogenicity

ETHOSUXIMIDE Inhibits T-type calcium channels. Used in absence seizures. Side effects include: 4. headache 5. lethargy 6. diarrhea 7. drowsiness 8. leukopenia

BARBITURATES/BENZODIAZEPINES Potentiate inhibitory GABAergic transmission increasing the duration or frequency of chloride channel opening. They are used for the treatment of status epilepticus. Treatment must be initiated rapidly. Intravenous diazepam is the treatment of choice. Other possibilities if benzodiazepines fail include intravenous phenytoin, Phenobarbital or general anaesthesia.

NEWER ANTICONVULSANT DRUGS Lamotrigine: Suppresses repetitive action potentials by blocking sodium channels in a usedependent manner. It also inhibits the release of glutamate. It is used for tonic-clonic and partial seizures. Side effects include dizziness, ataxia, blurred vision and GIT upset. Tiagabine: This drug prevents reuptake of GABA thus raising GABA levels. It is used for partial Seizures.

NEWER ANTICONVULSANT DRUGS Vigabatrin: Acts as an irreversible inhibitor of GABA-T and therefore prevents degradation of GABA leading to elevated levels of GABA. It is used for Partial and infantile seizures. Gabapentin: Increases neuronal release of GABA. It is used as an adjunct in patients with partial seizures. Side effects include ataxia, dizziness and fatigue.

NEWER ANTICONVULSANT DRUGS All produce ataxia and skin rash as side effects