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

The main factor that affects the absorption and distribution of sedative-hypnotics is the lipophilicity of the drug. The lipophilicity affects the rate of drug absorption as well as distribution. The rapid onset of action and the effect on the CNS is also influenced. Drugs that have a high lipophilicity shows a rapid onset of action and a greater effect on the CNS compared to the drugs with a lower lipophilicity.

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

Redistribution happens when a drug gets absorbed into the systemic circulation and is distributed from the brain to the other tissues. Highly lipid soluble drugs are distributed to the brain, heart kidney etc followed directly by fat and muscle. The redistribution process prolongs the duration of action of the drug.

How are BD metabolised? Name the various steps in the process.

Benzodiazepines gets metabolised by the hepatic microsomal enzymes in the liver and this process includes:

1. Dealkylation to active metabolites.
2. Oxidation by the cytochrome P450 enzymes to an active metabolite.
3. Conjugation (Phase II) of the oxidised metabolite with glucuronic acid to form an inactive metabolite.

Which BD’s are converted to active metabolites? What is the significance thereof?

Benzodiazepines converted to Desmethyldiazepam includes: Diazepam, Cholarazepam, Prazepam, Chlorodiazepoxide, ketazolam. Active metabolites contribute towards the extended duration of action.

Which BD’s are not dependent on cytochrome P450 oxidative enzymes for metabolism? What are advantages thereof?

These drugs include Oxazepam, Lorazepam, Temazepam, Lormetazepam. These drugs bring great advantage to patients that suffer from liver cirrhosis, elderly , neonates and patients that make use of CYP-P450 inhibitors, due to the drugs not having an effect on the levels of CYP-P450 because it does not require the enzyme to produce an 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 an enzyme and leads to the  increase in the rate of metabolism. Barbiturates (phenobarbital,secobarbital,etc) and meprobamate are known to be potent enzyme inducers. This increases the metabolism of a drug, which causes a decrease of the drug in the systemic circulation, thus a decrease in the therapeutic effect.