BENZODIAZEPINES.pptx

Pharmacology of benzodiazepines

1. BENZODIAZEPINES

2. MECHANISM OF ACTION Benzodiazepines bind to a regulatory site (benzodiazepine receptor), on the GABA A receptor. As a result, there is increase in the frequency of opening of γ-aminobutyric acid (GABA)-activated chloride channels. Consequently there is increased chloride ion conductance which facilitates the inhibitory actions of GABA.

3. PHARMACOKINETICS ABSORPTION AND DISTRIBUTION Benzodiazepines are well absorbed when given orally, usually giving a peak plasma concentration in about 1 hour. Some (e.g. oxazepam, lorazepam) are absorbed more slowly. They bind strongly to plasma protein. Their high lipid solubility causes many of them to accumulate gradually in body fat.

4. METABOLISM AND EXCRETION Hepatic breakdown accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines go through microsomal oxidation (phase I reactions), including N- dealkylation and aliphatic hydroxylation catalyzed by cytochrome P450 isozymes, especially CYP3A4. The metabolites are then conjugated (phase II reactions) to form glucuronides that are excreted in the urine.

5. DURATION OF ACTION Benzodiazepines vary greatly in duration of action and based on this, they are divided into the following; Short acting compounds (t 1/2 of <5 hours) – e.g. Midazolam and Triazolam Medium acting compounds (t 1/2 of 5-24 hours) – e.g. Alprazolam, Clonazepam, Estazolam, Lorazepam, Oxazepam and Temazepam. Long acting compounds (t 1/2 of >24 hours) – e.g. Chlordiazepoxide, Clorazepate, Diazepam, Flurazepam, Prazepam and Quazepam. This variability in duration of action determines the therapeutic utility of the compound

6. THERAPEUTIC USES Treatment of anxiety disorders Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder, generalized anxiety disorder, social anxiety disorder, performance anxiety, posttraumatic stress disorder, obsessive compulsive disorder, and the extreme anxiety sometimes encountered with specific phobias. Muscular relaxants Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy. Induction of anterograde amnesia The shorter-acting agents are often used as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty.

7. Treatment of seizures Clonazepam is occasionally used in the treatment of certain types of epilepsy. Diazepam and lorazepam are the drugs of choice in ending grand mal epileptic seizures and status epilepticus. Chlordiazepoxide, clorazepate, diazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and decreasing the risk of withdrawal-related seizures. Induction of sedation, hypnosis and treatment of sleep disorders Not all benzodiazepines are useful as hypnotic agents, although all have sedative or calming effects. In treatment of insomnia, they tend to decrease the latency to sleep onset and increase Stage II of non-rapid eye movement (REM) sleep

8. ADVERSE EFFECTS Daytime drowsiness, sedation, and ataxia impair judgment and interfere with motor skills, particularly in the elderly. In the elderly, overuse of benzodiazepines is the most common cause of reversible confusion and amnesia as well as a cause of blurred vision, hypotension, tremor, and constipation. Respiratory depression at higher than hypnotic doses, which is exaggerated in patients with COPD or obstructive sleep apnea. When given IV, it may decrease blood pressure and heart rate in patients with impaired cardiovascular function. On rare occasions they cause paradoxical excitement.

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