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Benzodiazepines as Antiepileptics

Benzodiazepines acting as antiepileptics are:

  1. Clonazepam
  2. Nitrazepam
  3. Diazepam
Mechanism of action

Mainly act for control of seizures on three parts of brain:

  1. Cerebral cortex
  2. Thalamus
  3. Limbic area

Have GABAergic effect.

1. Bind benzodiazepine receptors

Receptors are present in complex on cell membrane, the supramolecular complex, which also contains binding sites for GABA receptors, barbiturates, and chloride receptors.

These are present post synaptically on cell membrane.

When bind own receptors, activation occurs, resulting in displacement of protein GABA modulin.

This protein normally prevents binding of GABA with receptors. When displaced, more binding of GABA with receptors occurs, leading to increased frequency of opening of chloride channels, leading to hyperpolarization, producing inhibitory effect.

2. In high doses increases calcium dependent potassium conductance

3. Increases accumulation of adenosine which has inhibitory effect.

Benzodiazepines Barbiturates
Increase frequency of opening of chloride channels Increased duration of opening of chloride channels
Pharmacokinetics
  1. Well absorbed after oral administration
  2. Peak plasma concentration is achieved after 1-4 hours.
  3. Redistribution occurs as well (person feels drowsy all day)
  4. Plasma protein binding ranges between 85-90% especially in diazepam
  5. Metabolism is mainly by three processes:
  • Desalkylation
  • Hydroxylation
  • Conjugation

Diazapem is first converted by desalkylation into active metabolite, desmethyl diazepam. Then hydroxylated to active metabolite, oxyzepam. It is then conjugated to inactive metabolite.

Uses

Epilepsy

Clonazepam has a wide range of actions. It is the 2nd line drug in petit mal epilepsy. Also used for myoclonic seizures and in partial seizures.

Diazepam is specifically used in treatment of status epilepticus, when given I/V. it is not used routinely as produces tolerance. It is given only in emergency.

Clonazepam may be used on daily basis.

Adverse Effects
  1. Drowsiness
  2. Sedation
  3. Lethargy
  4. Unlike phenobarbitone, respiratory depression and circulatory collapse are rare, only when used I/V or with other sedative hypnotics.
  5. Muscle relaxant effect, hypotonia
  6. Dysarthria
  7. Anorexia and hyperphagia
  8. In children paradoxical effects, but are rare and include:
  • Restlessness
  • Anxiety
  • agitation
  1. Increase in bronchial, salivary secretions
  2. If patient is taking for prolonged periods, and withdrawn abruptly, may lead to status epilepticus, so tapered gradually.
  3. In given in pregnancy, may lead to floppy baby syndrome (hypotonia, difficulty in suckling)
Drug interactions

Can potentiate the effects of sedative hypnotics and alcohols.

Effective plasma concentration of clonazepam is 5-70 ng/ml.

Used for control of emergency.

Dose

Clonazepam 1.5-20 mg daily

Diazepam 5-10 mg I/V for control of status epilepticus, repeated after 4-6 hours, even after 15 min but not more than 100 mg in 24 hours.

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