Antiepileptic drugs

Antiepileptic drugs

Seizure

Transient alteration of behavior due to disordered synchronous and rhythmic firing of population of brain neurons.

Epilepsy

Refers to disordered brain function characterized by periodic and unpredictable occurrence of seizure.

Seizure

1.       Partial seizure – status epilepticus

2.       Generalized seizure – Absence seizure

Mechanism of seizure and anti seizure drugs

For excitation to abnormally predominate over inhibition, one of at least four possible events is likely to occur.

1.        Increased availability of excitatory neurotransmitter (Glutamate) due to either increased    production and release or impaired metabolism or reuptake.

2.       Decreased availability of inhibitory neurotransmitters such as GABA, the most potent inhibitory neurotransmitter in the CNS.

3.       Altered neuronal membrane function that can lead to excessive depolarization (alteration of the Na⁺ - K⁺ pump).

4.       There may be increased calcium concentration inside the cell. This facilitates the initiation and spread of seizure.

Classification

Classified according to their chemical structure,

1.       Barbiturates – Phenobarbitone

2.       Deoxybarbiturates – Primidone

3.       Hydantoins – Phenytoin

4.       Benzodiazepines – Diazepam, clonazepam

5.       Aliphatic carboxylic acid – Valproic acid

6.       Bromides – Potassium bromide and sodium bromide

7.       Succinimide – Ethosuximide

8.       Newer agents – Gabapentin, Vigabatrin, Lamotrigine

9.       Miscellaneous – Carbamazepine

Mechanism of action

1.       Sodium channel  – Prolongation of the inactivation state of the sodium channel. Drugs acting –  

                                  Phenytoin, Valproate, Carbamazepine.

2.       Chloride channel – Facilitation of GABA mediated chloride channel opening. Drugs acting –  

                                         Barbiturates, Benzodiazepine, Valproate, Vigabatrin, Gabapentin .

3.       Calcium channel – Closing of T- type calcium channel – Ethosuximide, Valproate.

Hydantoins

Phenytoin

·         Antiseizure activity without causing general depression.

·         It slows the rate of recovery of voltage activated Na⁺ channels from inactivation.

·         Enhancement of response to GABA.

·         It is an enzyme inducer.

·         Frequently used in human epileptic patients.

·         In Veterinary medicine use of phenytoin for long term treatment  is diminished due to its undesirable pharmacokinetic profile in animals i.e., moderate oral absorption, short half life and induction of micorsomal enzymes contribute to difficulty in achieving effective serum levels of phenytoin in dogs even when high doses are administered.

·         Prolonged effect of phenytoin observed in cat over some of the other species may be related to its decreased ability to conjugate with glucuronic acid and this can lead to accumulation and toxicity.  

·         On over dosage, sedation, ataxia and anorexia and gingival hyperplasia noticed.

·         Phenytoin may decrease pharmacological effects of concurrently administered drugs like glucocorticoids, doxycycline, etc., by enhancing their metabolism.

Clinical use

·         Use of phenytoin for control of epilepsy in veterinary medicine has declined due to lack of efficacy and undesirable pharmacokinetic profile

·         It remains, however, as an alternative or adjunctive therapy in dogs that have not responded to or have developed severe adverse reactions from either phenobarbitone or primidone.

Barbiturate

1.Phenobarbitone

·         First effective organic anticonvulsant drug and is still one of the more effective and widely used drugs.

·         Potentiate GABAergic inhibition by increasing the lifetime of chloride channel opening induced by GABA (GABA mimetic action)

·         Antiseizure activity is noticed at low dose than required for hypnosis.

·         Anticonvulsant dosage causes some drowsiness and CNS depression

·         It is capable of increasing the rate of metabolism of other drugs (digitoxin, phenylbutazone, glucocorticoids etc.,) and its own rate of metabolism

·         Phenobarbitone is more suitable drug for long term treatment of epilepsy

·         Not useful to stop ongoing seizures because of low lipid solubility blood level slowly increased.

·         Contadindicated in hepatic impairment , pregnant and nursing mothers.

2.Primidone

·         2- deoxy analogue of phenobarbitone approved for use in dogs for control of convulsions associated with epilepsy, virus encephalitis, distemper etc.,

·         It is metabolized in liver to phenobarbitone

·         Indicated for seizure control in dogs.

Benzodiazepines

1.Diazepam

·         Has strong anticonvulsant action

·         Enhance inhibitory effects of GABA in both brain and spinal cord

·         It enhance the frequency of chloride channel opening induced by GABA (GABA facilitatory action)

·         Well studied for intravenous treatment as it crosses the blood brain barrier faster than any other drugs.

·         It is metabolized to nordiazepam and oxazepam which has only about 1/3^rd anticonvulsive property

·         Within 1-2 weeks tolerance developed and hence not suitable for long term treatment.

·         Drug of choice for the treatment of status epilepticus in dogs and cats and for emergency control of convulsions induced by tetanus, toxicity etc.,

2. Clonazepam

·         Extremely potent drug.

·         Orally well absorbed.

·         Used primarily as an adjunct anticonvulsant in dogs, especially when seizures not controlled with other standard therapies

·         Not suitable for long term treatment.

Valproate

·         In dogs valproic acid is effective in controlling seizures when given orally, but its short half life makes it impractical for long term use.

·         It is a second to fourth line anticonvulsant, that may be useful as an adjunctive treatment in some dogs.

·         Its clinical usefulness in cats has not been evaluated.

·         Adverse effect – hepatotoxicity

Potassium bromide

·         It is hypothesized that bromide ion enters neurons via chloride ion channels resulting in hyperpolarizaition of the neuronal membrane

·         Used orally to treatment of refractory seizures in dogs. The use in cats is not recommended as it evokes severe asthma in this species.

·         Used in combination with Phenobarbital to terminate refractory generalized tonic-clonic convulsions in dogs.

Ethosuximide

·         Routinely used in human medicine for control of absence seizures that is rare in animals.

Gabapentin

·         Synthetic GABA analogue that crosses blood brain barrier to exert anticonvulsant effect.

·         GABA content in neurons is increased by gabapentin

·         It also inhibits calcium channels.

·         Useful as adjunctive therapy for refractory or complex partial seizures or in treatment of chronic pain in dogs and cats

·         Administered orally

Vigabatrin

·         At present proved only for adjuvant medication in humans.

Carbamazepine

·         Used in human medicine for treatment of partial and clonic tonic seizures

·         In addition it has antidiuretic and effect in mood disorders.

·         In dogs very rapidly eliminated and cannot be maintained even when high dose administered.

·         Hence it is ineffective in dogs and occupies minor position in veterinary medicine.