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

Lipophilicity plays a major role in the absorption and distribution of sedative-hypnotic drugs. The more lipophilic the drug is, the quicker it is absorbed into the CNS and the faster it spreads throughout the CNS. Thus, the drug will have a rapid onset of action when it is lipophilic. 

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

Redistribution occurs when drugs have a high lipophilicity. These drugs are fat soluble and therefore spread to surrounding tissues,  usually fatty tissues, where it causes a depot effect resulting in the slow release of the drug. 

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

Benzodiazepines are metabolised by hepatic microsomal enzymes in three steps.

Step 1: Dealkylation (can form active metabolites)

Step 2: Microsomal oxidation (Phase 1 reactions, catalysed by cytochrome P450 enzymes especially CYP3A4, active metabolites can also be formed here)

Step 3: Conjugation (Phase 2 reactions where the oxidised metabolites conjugate with endogenous substances in the body, usually glucuronic acid, to form an inactive metabolite which is excreted in the urine.) 

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

Diazepam, Chlorazepate, Prazepam, Chlordiazepoxide and Ketazolam are all converted to active metabolites. These drugs have prolonged action, and should therefore be used with caution when given to older people, neonates or people on CYP450 inhibitor drugs. 

These patient’s liver function could be reduced and with the already prolonged action, the break down would be slowed as well and the metabolites will build-up.

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

Oxazepam, Lorazepam, Temazepam and Lormetazepam are not dependent on the cytochrome P450 enzymes. Therefore they are the drug of choice for people who have reduced CYP450 activity. This includes the elderly, neonates or people on CYP450 inhibitor drugs. 

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 the action of the enzymes is promoted. This means that the enzyme will metabolize the drugs much quicker into inactive metabolites. Enzyme induction will reduce the duration of action of these drugs.

Sedative-hypnotic drugs that are known for this include Phenobarbital and Meprobamate.