• What factors may affect the absorption and distribution of sedative-hypnotic drugs? What is the clinical significance thereof?

Benzodiazepines' fat solubility (Lipophilicity) is determined by the rate of absorption. This is of importance so that you can decide whether to administer a short-acting or long-acting drug.

A more lipophilic drug will be rapidly distributed and absorbed by the CNS, where a less lipophilic drug will spread more slowly and will only be absorbed after a long period of time.

• What is meant by redistribution and what is the significance thereof?

Redistribution means substances that are highly fat-soluble (lipophilic) that reach the brain, heart, kidneys, etc. These substances are distributed for the previously mentioned organs and then distributed directly thereafter to the muscles and tissues

The importance of redistribution is due to these drugs that are so widely distribute. The rate at which these drugs leave the body is prolonged, thus prolonging the duration of action.

• How are the BDs metabolized? Name the various steps in the process.

BDs are biotransformed by liver microsomal enzymes:

• Dealkylation - formation of active metabolites
• Oxidation – the liver is oxidized by cytochrome P450 and active metabolites can be formed
• Conjugation - (Phase II) of oxidized metabolites with glucuronic acid (endogenous substance) to form an inactive metabolite. Which is water soluble and can be excreted as urine.

• Which BDs are converted to active metabolites? What is the significance thereof?

BDs that are converted to active metabolites are: Diazepam, Chlorazepate, Prazepam, Chlorodiazepoxide and Ketazolam.

These active metabolites contribute to the prolonged duration of the action of the drugs.

• Which BDs are not dependent on the cytochrome P450 oxidative enzymes for metabolism? What are the advantages thereof?

BDs not dependant on the cytochrome P450 oxidative enzymes for metabolism are: Oxazepam, Lorazepam, Temazepam and Lormetazepam. Advantages of these drugs are: Because the drugs are not metabolized by the liver microsomal enzymes, they act as choice drugs, where the benzodiazepines must be used in the conditions where the activity of the liver microsomal enzyme is reduced.

• What is enzyme induction? Which of the sedative hypnotic drugs are known for this? What is the clinical significance of enzyme induction?

Enzyme induction is when a drug accelerates / increases the production of a certain enzyme, it will lead to an increased metabolism of the drug. Examples of the drugs are: Barbiturates (Phenobarbital) & Meprobamate. An increase in metabolism causes a decrease in the duration of action in the body/ therapeutic effect.