Antiepileptic Agents
SODIUM VALPROATE (VALPROIC ACID)
Sodium valproate increases the levels of GABA in the brain and increases the
responses to GABA in the postsynaptic neurons. Also sodium valproate affects potassium flow across the neurons. The result of these effects is inhibition of initiation as well as spread of epileptic activity in the neurons.
Valproate has antiepileptic efficacy in different types of epilepsy. It is therefore sometimes called the broad range antiepileptic drug. It has no significant hypnosedative effects nor does it have respiratory depressant activity. In addition it does not have undesirable effects on blood pressure, heart rate, kidney function and body temperature.
Absorption is rapid and complete. Protein binding is between 80 to 95 percent and the elimination half life is 8 to 22 hours. It is metabolised in the liver and is excreted by the kidney. There is no presystemic metabolism.
Adverse effects include anorexia, nausea, vomiting, diarrhoea and/or constipation, weight gain, skin rash; hair loss, neutropenia, tremors and ataxia are occasionally reported. Valproic acid is contraindicated in liver disease, especially cirrhosis, pregnancy and hypersensitivity.
BENZODIAZEPINES
CLONAZEPAM
It is a benzodiazepine useful in the treatment of petitmal epilepsy, myoclonic seizures and infantile spasms. It is used in the treatment of petitmal epilepsy not responding to ethosuximide and sodium valproate. Clonazepam and diazepam act by increasing the effectiveness of the inhibitory neurotransmitter GABA, within the central nervous system.
Antiepileptic Agents 109 Clonazepam is well absorbed orally and
approximately 85 percent is bound with plasma proteins, completely metabolized in liver and excreted through kidney.
Adverse effects include sedation, lack of concentration, irritability, ataxia and behavioural abnormalities.
The detailed pharmacology of diazepam is discussed in chapter ‘Sedative and hypnotics’.
CLOBAZAM
It is 1, 5 benzodiazepine with a chemical structure slightly different from that of diaz-epam and clonazdiaz-epam. This change in struc-ture results in less sedative and psychomo-tor retardation. Though introduced as an anxiolytic it has been found to be useful in treatment of patients with refractory epilepsy.
Its antiepileptic activity results from its binding to one or more specific GABA recep-tors increasing GABA mediated inhibition.
Adverse reactions include drowsiness, hangover effects, dizziness, weight gain, headache, dry mouth and orthostatic hypotension etc.
PHENYLTRIAZINE DERIVATIVE
LAMOTRIGINE
It is phenyltriazine compound, chemi-cally unrelated to existing antiepileptic drugs. It acts primarily via a dose depen-dent blockade of voltage sensitive sodium channels in their slow inactivated state, thus stabilizing the presynaptic neuronal membrane inhibiting release of excitatory neurotransmitters mainly glutamate.
Lamotrigine is almost completely absorbed after oral administration and metabolized completely in liver.
The adverse effects include headache, rash, nausea, dizziness, somnolence and insomnia.
It is mainly used as adjunctive therapy in patients for simple partial seizures, complex partial seizures, secondary generalised tonic and clonic seizures.
NEWER COMPOUNDS
TOPIRAMATE
It is used as adjunctive treatment of seizures including refractory seizures, simple and complex partial seizures.
It acts by reducing epileptiform discharges generated by blocking the sensitive sodium channel and enhancing the activity of GABA receptors.
It is rapidly absorbed after oral administration and is unaffected by presence of food and excreted mainly through kidney.
Adverse effects include abdominal pain, anorexia, weight loss, impaired concentra-tion, confusion, mood disorders, ataxia, diz-ziness, drowsiness, fatigue and psychotic symptoms.
GABAPENTIN
It is a new anticonvulsant drug and is a structural analogue of GABA. It increases the release of GABA by unknown mecha-nism. It modifies maximal electroshock as well as inhibits pentylenetetrazol induced convulsions.
After oral administration, it is rapidly absorbed and widely distributed into all tissues. It readily crosses blood brain barrier and is not bound to plasma proteins.
It is excreted unchanged in urine. It is mainly used as adjunctive therapy in treatment of partial seizures with or without secondary generalization in adults.
Adverse effects include sedation, dizziness, diplopia, ataxia and fatigue.
VIGABATRIN
It is an inhibitor of GABA transaminase which degrades GABA. It suppresses maximal electroshock and kindled seizures and is used in partial seizure with or without generalization.
It is well absorbed after oral administra-tion and excreted unchanged in urine.
Adverse effects include drowsiness, dizziness, agitation and amnesia.
Muscle Relaxants 111
Skeletal muscle relaxants act peripherally at the neuromuscular junction or centrally in the cerebrospinal axis to reduce muscle tone.
Skeletal muscle relaxation can be achieved by following group of drugs as in table 2.7.1.
NEUROMUSCULAR BLOCKERS
D-TUBOCURARINE
It is an dextrorotatory quarternary a m m o n i u m a l k a l o i d o b t a i n e d f r o m
Chondrodendron tomentosum plant. It ini-tially produced motor weakness fol-l o w e d b y f fol-l a c c i d p a r a fol-l y s i s a f t e r parenteral administration. The paralysis occurs in following order e.g. paralysis of fingers, toes, eyes, ears producing diplopia, speech slurring, difficulty in swallowing; the muscles of neck, limb, trunk, paralysis of diaphragm and death occur due to hypoxia.
In higher doses, d-tubocurarine can produce blockade of autonomic ganglia. It
Table 2.7.1: Classification of skeletal muscle relaxants.
I. Neuromuscular blockers
d-Tubocurarine 0.2-0.4 mg IV
Atracurium 10-15 mg IV
Pancuronium 40-100 µg/kg IV
Vecuronium 0.08-0.1 mg/Kg IV
Succinylcholine 30-50 mg IV
Benzoquinonium 10-15 mg IV
Dantrolene 25 to 100 mg/day
II. Centrally acting muscle relaxants Mephenesin
Chlorzoxazone (MOBIZOX) 250 mg TDS
Methocarbamol (FLEXINOL) 0.l5-1 g/day oral, 100-200 mg IM/IV
Carisoprodol (CARISOMA) 350 mg TDS
Orphenadrine (ORPHIPAL) 100-300 mg/day
Tizanidine (CITANZ) 2-6 mg/day
Baclofen (LIORESAL) 30-75 mg/day
Metaxalone (FLEXURA) 400-800 mg TDS-QID