Antiepileptics 2

PHENOBARBITONE [Since 1912; first antiepileptic]

Increases seizure threshold limits spread . ¯kindled siezures

Mechanism of action: differ from CNS depression

[1] Quantitative diff in GABA-facilitatory, GABA mimetic, Anti glutamate, Ca++ entry reduction exist between anticonvusant & CNS depressant action of Barbiturates

[2] GABAA mediated synaptic inhibition à most important

[3] Sedation decreases with continued use; but anticonvulsant action persists

Kinetics:

Slow oral absorption; long T1/2 [80 –120hr]; 60 mg TID; Steady state: 2-3 weeks; Important ADR: sedation

Indications: gtc, sps & cps [not absence siezures]

PRIMIDONE

Converted to phenobarbitone + phenyl ethyl malonamide in liver; both active metabolites. Useful in refractory gtc / sps / cps & myoclonic seizures. Also adjunct to phenytoin / carbamazepine. ADRs similar to phenobarb; 250 – 500 mg BD

PHENYTOIN: [used since1938; major drug]

Limits spread of siezure; abolishes MES tonic phase. PTZ threshold not raised; decreases tonic clonic phase;

Mechanism of action

Increases Na+ channel inactivation à decreases repetitive high frequency firing of neurons à Stabilizes neurons, Normal synaptic transmission not impaired [therefore useful in Cardiac arrhythmia & Trigeminal Neuralgia too]

Kinetics:

Oral absorption slow; 80-90% plasma protein bound. Metabolism in liver by hydroxylation & glucuronic acid conjugation. Saturation kinetics; 1st order à 0 order at > 10 mcg/ml. T1/2 increases from 12 – 24 hrs to 60 hrs at > 10 mcg/mlàTDM

ADRs of Phenytoin

Gum hypertrophy[common [20%] more in younger. Hirsutism, coarsening of facial features, acne. Hypersensitivity: rashes, neutropenia. Decreases folate absorption & increase excretionà Megaloblastic anaemia. Interferes with Ca++ metabolism à Osteomalacia. Decreases insulin release à hyperglycemia. Teratogenic: fetal hydantoin syndrome: cleft palate. Large doses à Cerebellar /vestibular effects: ataxia, vertigo

Drug Interactions with Phenytoin

Phenytoin + Barbiturates à mutual inhibition of metabolism + enzyme inductionà complex

Valproate & acidic drugs displaces protein bound phenytoin

Chloramphenicol, INH, Cimetidine & Warfarin à Decreases metabolism à increase toxicity. Phenytoin àincreases enzymes à oral contraceptive failure. Phenytoin à decreases tolbutamide metabolism à hypoglycemia. Sucralfate binds phenytoin à decreases absorption

Uses of Phenytoin

GTC, sps, cps ineffective in absence seizures. i.v. injection for status epilepticus [occasionally used]. Trigeminal neuralgia, digitalis induced cardiac arrhythmia . Dose: 100 mg BD, maximum 400 mg / day

CARBAMAZEPINE: [1960]: Abolishes MES; ­ PTZ threshold; inhibits kindling

Mechanism of action:

Similar to phenytoin; increases Na+ channel inactivation, but action profile on brain & neurons different. Useful in mood disorders. Increases ADH action on renal tubules

Kinetics:

Low aq solubility àvariable oral absorption; 75% plasma protein bound; Metabolism in liver to active metabolite, T ½: 20 –40 hrs for acute doses;

Chronic doses à Auto-induction à T½ reduces to 10 –20 hrs

ADRs of carbamazepine

Dose related neurotoxicity. E.g. Sedation, vertigo, diplopia, ataxia. Increase dose; Vomiting & diarrhoea; increases seizures. Acute intoxication à coma, convulsion, CVS collapse. Hypersensitivity: Rashes, photosensitivity; lupus, agranulocytosis & aplastic anaemia are rare. Increased ADH action à water retention, hyponatremia in old. Fetal malformations, [increases teratogenicity with valproate]

Drug Interaction with carbamazepine

Enzyme inducerà increases metabolism of phenobarb, phenytoin, and valproate & vice versa. Also reduces haloperidol action & increases contraceptive failure.

Erythromycin à reduces metabolism of carbamazepine

Uses of carbamazepine

Best for cps; as good as phenytoin for gtc & sps. Trigem neuralgia. Alternate to Lithium in manic depressives. Dose: 200 – 400 mg TDS

ETHOSUXIMIDE

Blocks PTZ siezure; Effective only in absence seizures. Not MES / Kindling

Mechanism of action

Decreases T type Ca++ current à decreases reciprocal thalamo-cortical impulses à selective against absence seizures

Kinetics

Slow but complete oral absorption; Metabolised by liver by hydroxylation & glucuronidation; T ½ 48 for adults & 32 for children

ADRs:

GIT problems, agitation, headache, drowsiness, Hypersensitivity: rashes, rarely DLE,

Blood dyscrasias

Use: Only absence seizures [valproate is first choice]. Dose:20-30mg/kg/dy upto 1.5g/dy

VALPROIC ACID [1960; broad spectrum anticonvulsant]

Blocks PTZ better than MES; + prevents kindling

Mechanism of action: Multiple mechanisms

1. Increases Na+ channel inactivation .2. Decreases Ca++ T current

3. Inhibits GABA transaminase à increases GABA nergic action

Kinetics:

Good oral absorption; 90% plasma protein Bound. Metabolism by liver [oxidation & glucuronidation]. T ½ 10-15 h

ADRs of Valproate:

Toxicity more in Indians than in West. Anorexia, vomiting, drowsiness, ataxia, tremor: dose related. Alopecia, increases blood Ammonia; thrombocytopenia, rashes. Rarely fulminant hepatitis only in children. Avoid in pregnancy à fetal defects: Dose 200mg TDS

Uses of Valproate

Drug of choice in absence, myoclonic & atonic. Also alternative/adjunct for gtc/sps /cps; 2nd line for bipolar disease

Drug Interactions with Valproate

Inhibits phenobarb metabolism; displaces phenytoin + decreases metabolism; Mutually increases metabolism with carbamazepine; valproate + clonazepam à absence status. Valproate + carbamazepine à increase in fetal abnormalities

CLONAZEPAM

Blocks PTZ siezure, decreases kindling but not MES; Ineffective in gtc

Mechanism of action:

Indirect action via BZD receptor à stimulates GABA Receptor on Cl- channelàCl- influxàCNS depression. Large doses like Phenytoin à decreases high frequency Discharges

Kinetics:

Good oral absorption; 85% plasma protein bound; Metabolism by liver; T ½ = 24 h

ADRs:

Sedation [therefore start with low doses], irritability, behavior abnormalities in children, ataxia,

Uses

Absence siezures; Adjunct in myoclonic & akinetic, infantile spasm. Tolerance in 6 monthsàreduce the use

DIAZEPAM

Rapid tolerance. Drug of choice in :Status epilepticus, tetanus, eclampsia, Drug poisoning induced convulsion: 0.2 - 0.5 mg/Kg slow i.v.; repeat doses: max100 mg/day

LAMOTRIGINE

Reduces PTZ & MES; [similar to carbamazepine]; stabilises presynaptic membrane à reduces glutamate; does not block NMDA receptors. [Metabolism: liver; T ½ 24 h]

Use:

Adjunct for refractory partial and secondarily generalized. Dose: start 50 mg /day can increase up to 300 mg

ADRs:

sleepy, dizzy, ataxia, diplopia, vomiting

GABAPENTIN

[GABA analog crosses BBB] à increases GABA release; no action on GABA receptor;Reduces PTZ & MES; adjunct for refractory cases; Dose up to 300-600 TDS

VIGABATRIN

g Vinyl GABA; Inhibits GABA transaminase. Decreases GABA breakdown;

Adjunct only; Dose 2 – 4 g daily

Category: Pharmacology Notes