Anti- Epileptic drugs

It is a collective term applied for a group of convulsive disorders

The common features of epilepsy are

Loss or disturbance of consciousnesses

Characteristic body movements (usually, but not always)

CLASSIFICATION

1. Hydantoins

Phenytoin

2. Barbiturates

Phenobarbitone

Primidone

3. Iminostilbbenes

Carbamazepine

4. Succinimides

Ethosuximided

5. Aliphatic carboxylic acid

Sodium valproate

6. Benzodiazepines

Clonazepam

Clobazam

Diazepam

7. Newer antiepileptic

Lamotrigine

Gbapentine

8. Miscellaneous

Trimethadione

Acetazolamide

Phenytoin

Phenytoin was synthesized in 1908, but its anticonvulsant property was discovered only in 1938

It is effective in suppressing tonic-clinic and partial seizures and  is a drug of choice for initial therapy, particularly in treating adults

Mechanism of action

Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and stabilizes the neuronal membrane

It inhibits the generation of repetitive action potentials

At much higher concentrations , phenytoin can block voltage-dependent calcium channels and  interfere with the release of monoaminergic neurotransmitters

Pharmacological action

Phenytoin exerts antiseizure activity without causing general depression of the CNS

It is one of the most effective drugs against generalized tonic-clonic seizures and partial seizures

Phenytoin reduces the propagation of abnormal impulses in the brain

Pharmacokinetics

Phenytoin is poorly water soluble  hence absorption is slow

It is 90% bound to plasma proteins

It is metabolized in liver

Phenytoin is enzyme inducer

Therapeutic uses

Phenytoin is highly effective for all partial seizures ( simple and complex), for tonic-chronic seizures and in the treatment of status epileptics

Phenytoin is not effective for absence seizures, which often may worsen if treated with this drug

Adverse effects

It depend dose , duration and route

Nausea, vomiting, epigasric pain, anorexia

Nystagmus, diplopia, ataxia are common

Gingival hyperplasia is more common in children on prolonged use

Peripheral neuropathy

Phenytoin inhibits insulin release and produces hyperglycemia

Decreases the release of ADH

Osteomalacia , hypocalcaemia due to altered metabolism of vitamin D and inhibition of intestinal absorption of Ca

Hypersensitivity  - Rashes , SLE, hepatic necrosis , and neutropenia

Megaloblastic anemia – Phenytoin decreases absorption and increases excretion of folates

Teratogenicity

When taken by the pregnant lady, phenytion produces foetal hydantion syndrome characterized by hypo plastic phalanges, cleft palate,  and harelip

Drug interactions

Phenytoin is an enzyme inducer

Phenytoin given with phenobarbitone , both increases  each other metabolism

Phenytoin and carbamazepine enhance each others metabolism

Valproate displaces protein bound phenytoin

Cimetidine and chloramphenicol  inhibit the metabolism of phenytioin  resulting in toxicity

Antacids decreases the absorption of phenytoin

Phenobarbitone

Phenobartitone was the first effective antiepileptic drug to be introduced in 1912. It still remains one of the widely used drugs

It has antiepileptic activity and raises the seizure threshold

Mechanism of action

Barbiturates enhances the inhibitory neurotransmission in the CNS by enhancing the activation of GABA receptors and facilitating the GABA mediated  opening of chloride ion channels

Pharmacokinetics

It is well absorbed orally

The drug freely penetrates  the brain

Approximately 75 % of the drug is inactivated by the hepatic mocrosomal system, whereas the examining drug is excreted unchanged by the kidney

It is a potent inducer of the cytochrome P450 system and when given chronically, it enhances the metabolism of their agents

Therapeutic uses

It provides favorable response for simple partial seizures, but it is not very effective for complex partial seizures

The drug had been regarded as the first choice in treating recurrent seizures in children, including febrile seizures

It also used to treat recurrent tonic-clonic seizures, especially in patients who donot respond to diazepam plus phenytoin

It also used as  a mild sedative to relieve anxiety, nervous tension and insomnia

Adverse effects

Sedation, ataxia, vertigo , nausea and vomiting

Agitation and confusion occur  at high doses

 

Rebound seizures can occur on discontinuance of Phenobarbital

Primdone

It structurally related to Phenobarbital and it resembles Phenobarbital in its anticonvulsant activity

It is an  alternative choice in partial seizures and tonic – clonic seizures

It has more efficacy due to the its metabolites Phenobarbital and phenyl-ethyl-malonamide which have longer half- lives than the parent drug

It is effective against tonic-clinic and simple partial seizures and phenyl-ethy-lmalonamide is effective against complex partial seizures

Primidone is often used with carbamazepine and phenytoin

It is well absorbed orally

It exhibits poor protein binding

These drug has the same adverse effects as those seen with Phenobarbital

 

Benzodiazepines

Several of the benzodiazepines show antiepileptic activity

Diazepam and lorazepam are the drugs of choice in the acute treatment  whereas Clonazepam and clorazepate and clorazepate are used for chronic treatment of status epilepticus

Clonazepam

It suppresses seizure spread from the epileptogenic focus and is effective in absence and myoclonic seizures , but tolerance develops

Clonazepate

Clorazepate is effective in partitial seizures when used in conjunction with other drugs

Diazepam

It is effective against

Petitmal epilepsy

Mylclonic seizures

Status epilepsy

It is drug of choice for status epilepticus

Lorazepam

 Lorazepam and diazepam  are both effective in interrupting the repetitive seizures of status epilepticus.

Lorazepam has a longer duration of action and is preferred by some clinicians

All of the antiepileptics, the benzodiazepines are the safest and most free from severe side effects

All benzodiazepines have sedative properties

Side effects

Drowsiness,

Somnolence,

Fatigue,

Ataxia,

Dizziness and behavioral changes

Respiratory depression and cardiac depression may occur when given intravenously in acute situations

Ethosuximide

It reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting t- type calcium channels in a manner similar to the action of phenytoin on sodium channels

It is the first choice in absence seizures

It is well absorbed orally and is not bound to plasma proteins

About 25% of the drug is excreted unchanged in the urine and 75% is converted to inactive metabolites in the liver by the microsomal cytochrome P450 system

It does not induce P450 enzyme synthesis

The drug is irritating to the stomach and nausea and vomiting may occur on chronic  administration

Drowsiness, lethargy, dizziness , restlessness , agitation , anxiety and the inability to concentrate are often observed

Valproic Acid

It is a broad spectrum anticonvulsant

It has multiple actions , including sodium channel blockade and enhancement of GABAergic transmission

It is the most effective agent available for treatment of myoclinec seizures

It also diminishes absence seizures, but because of its hepatotixic potential, it is a second choice

It also reduces the incidence and severity of tonic-clonic  seizures

The drug is effective orally and is rapidly absorbed

About 90% is bound to the plasma proteins ,only 3%  of the drug is excreted unchanged, the rest is converted into active metabolites by the liver

It is metabolized by cytochrome P450 enzymes

Metabolites are excreted by kidney

It can cause nausea, vomiting ,sedation, ataxia and tremor are common

It inhibits the metabolism of a number of antiepileptic drugs , including Phenobarbital, carbamazepine and ethosuximide

Carbamaepines

Actions

It reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potential in the epileptic focus and preventing their spread

ADME

It is absorbed slowly following oral administration

It enters the brain rapidly because of its high lipid solubility

It induces the drug metabolizing enzymes in the liver

The enhanced hepatic cytochrome p450 system activity also increases the metabolism of many drugs including other antiepileptic drugs

It is an inducer of the cytochromep450  isozyme  cyp3a4, which decrease                                                      the effects of drugs that are metabolized by his enzyme

Therapeutic uses

It is effective in Temporal lobe epilepsy

Trigeminal neuralgia

Used in post hepatic pain

Adverse effects

Chronic administration of carbamazepine can cause stupor, coma and respiratory depression

It also produces drowsiness, vertigo, ataxia, and blurred vision

The drug is irritating to the stomach and nausea and vomiting may occur

Drug interaction

The hepatic metabolism of carbamazepine is inhibited by several drugs

Toxic symptoms may arise if the dose is not adjusted