Seizure is defined as transient neurological dysfunction resulting from excessive depolarization of cerebral neurons. Predisposition to recurrent unprovoked seizures are called epilepsy.
Classification of seizures
Seizures are classified into partial and generalized. Again the partial seizures are subdivided into simple and complex.Generalized seizures are subdivided into absence, myoclonic, tonic, clonic, tonic-clonic and atonic.
Mechanisms of epilepsy
Seizure can be due to abnormal neuronal circuits(e.g. thalamocortical circuit in absence seizures), chanellopathies, increased excitation (increased Na+ influx, reduced K+ efflux, increased Ca2+ influx) or due to reduced inhibition (reduced GABA activity).
Antiepileptic drugs: mechanisms
All antiepileptic drugs depend on 3 mechanisms, they are to reduced glutamate activity, increase GABA activity and ion channel blockade.
Antiepileptic drugs
Phenobarbitone (1912)
Phenytoin (1938)
Ethosuximide (1953)
Carbamazepine (1963)
Sodium valproate (1968)
Clonazepam (1975)
Clobazam (1986)
Lamotrigine (1991)
Gabapentin (1993)
Topiramate (1995)
Phenytoin
Phenytoin is a use dependent Na+ channel blocker.It has slow absorption from GIT and bioavailability is about 85%. But its bioavailability is unpredictable after i.m injection.Phenytoin metabolized by the liver and T1/2 at low doses 12-36 h.
The main adverse effect of phenytoin is cosmetic problems such as gum hyperplasia, acne, hirsutism, facial coarsening. It also cause cognitive impairment, osteomalacia, megaloblastic anemia, teratogenicity, drowsiness, diplopia, dysarthria, ataxia and act as CYP-450 inducer.
Carbamazepine is a Na+ channel blocker (use-dependent) and its oral bioavailability is about 80%.It is metabolized by liver and T1/2 is about 8-24 h.Carbamazepine is also a CYP-450 inducer and has autoinduction (pharmacokinetic tolerance) property.
Carbamazepine is known to cause skin rash, most are maculopapular but rarely cause Stevens Johnson syndrome. Other side effects include drowsiness, imbalance, diplopia, agranulocytosis and hyponatraemia.
Phenobarbitone is the oldest antiepileptic drug. It is a potentiats GABA receptor activator. Its oral bioavailability is about 95% and it is metabolized by liver; 25% excreted unchanged. Its T1/2 72-144 h. Phenobarbitone is also a CYP-450 inducer. Side effects of phenobarbitone includes sedation, changes in cognition, mood & behavior problems.
This blocks T-type Ca++ channels in thalamic neurons. Its oral bioavailability is 95% and it is metabolized by liver; 25% excreted unchanged. Ethosuximide has a T1/2 of 20-60 h. Adverse effects of ethosuximide includes,dyspepsia, Ataxia and imbalance.
Sodium valproate known to cause dyspepsia, tremor, weight gain, hair loss, hepatotoxicity and teratogenicity(Neural tube defects - reduced by folic acid).
Clonazepam enhances GABA receptor activation. Its oral bioavailability is 80% and metabolized by the liver. Sedation is a common side effect of clonazepam.
This blocks Na+ > T-type Ca++ channels. Recommendation is to use monotherapy / adjunctive therapy in partial or generalized tonic-clonic seizures. It is well absorbed from GIT and metabolized by the liver. It has longer T1/2 of 25 h. Adverse effects includes headache, nausea, vomiting and rash (more likely with high doses & valproate).
Gabapentin inhibits glutamate release by blocking high-voltage-activated Ca2+ channels. It uses as adjunctive therapy for partial seizures. Gabapentin is well absorbed from GIT and eliminated unchanged in urine. Its T1/2 is 6 h and has adverse effects such as sedation, fatigue and weight gain.
Topiramate blocks Na+ channels, act as glutamate antagonist and has property of GABA potentiation. It is well absorbed from GIT and 70% eliminated unchanged in urine. The T1/2 is 21 h and has adverse effects such as sedation, fatigue, renal calculi and weight loss.
Antiepileptic drugs and pregnancy
Exposure to antiepileptic drugs in first trimester increases risk of congenital malformations.
- Valproate – neural tube defects
- Phenytoin – cleft palate
- Phenobarbitone – cardiac malformations
Polytherapy increases the risk further and Carbamazepine is a (if appropriate) relatively safe drug to use during pregnancy.
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