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

Lipophilicity. This affects the onset of action of the drug as well as the extent of the effect on the central nervous system. Drugs that have a high lipophilicity have a rapid onset of action hence a great effect on the CNS, whereas drugs with a lower lipophilicity have a slow onset of action and does not yield a great effect on the CNS because it cannot cross the blood brain barrier.

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

Drug redistribution happens when drug that is absorbed into the systemic circulation gets distributed to other tissues into the body, e.g. the lipophilic tissue. This can in turn prolong the duration of action of the drug.

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

Benzodiazepines are metabolized by the hepatic microsomal enzymes in a three step process:

• Dealkylation to active metabolites.
• Oxidation via the CYP-P450 enzymes to active metabolites.
• Conjugation with glucuronic acid to form inactive, water-soluble metabolites.  

 

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

 

Benzodiazepines converted to the active metabolite desmethyldiazepam include: diazepam, chlorazepate, prazepam, chlordiazepoxide and ketazolam. The formation of active metabolites can increase the duration of action of the drugs (advantage) and can also cause cumulative effects with multiple doses (disadvantage).

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

Benzodiazepines that are not dependent of the CYP-P450 enzyme for metabolism include: oxazepam, lorazepam, temazepam, lormetazepam. These drugs provide an advantages for patients with liver cirrhosis, elderly patients, neonates as well as patients that use CYP-P450 enzyme inhibitors for these drugs do not affect the levels of CYP-P450 in the body because it does not require the enzyme to elicit its effect.

• 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 increases the production of a certain enzyme that then increases the rate of metabolism of the drug. Enzyme induction is seen more often with the older barbiturates (especially phenobarbital) and meprobamate. Enzyme induction, as previously stated, increases the rate at which drugs are metabolized and that then causes a decrease in the level of the drug in the systemic circulation which decreases the therapeutic effect of the drug.