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

Pharmacokinetics describes what the body does to a drug (Absorption, Distribution, Metabolism, Elimination). 

Lipophilicity is one of the many properties that influences absorption and distribution. With increased lipid solubility comes increased absorption and so the drug is able to reach the brain faster and thus produce an effect faster (quicker onset of action). 

Highly lipid soluble drugs are redistributed from the brain to other tissues (heart, kidneys, muscles, fats) this then proves to us that lipophilicity also plays an important role in distribution. 

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

Redistribution is when highly lipid-soluble drugs are initially distributed to organs with high blood flow (brain, heart, kidneys) and then later on they are distributed to less vascular tissues (muscle and fat). A depo is then formed in these less vascular tissues and the drug is then slowly released from them over time. 

The concept of redistribution prolongs the duration of action of the drug as therapeutic drug levels are maintained for longer. 

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

Benzodiazepines undergo a three step biotransformation by hepatic microsomal enzymes.

STEP 1: DEALKYLATION 

The active metabolite Desmethyldiazepam is formed (it has an elimination half-life of 40hrs)

STEP 2: OXIDATION 

Desmethyldiazepam undergoes oxidation and becomes a new active metabolite known as Oxazepam. 

STEP 3: CONJUGATION 

Oxazepam undergoes glucuronide conjugation to become an inactive metabolite which is now aqueous soluble and can then be excreted in the urine. 

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

Diazepam, Chlorazepate, Prazepam, Chlordiazepoxide, Ketazolam 

Active metabolites contribute to the extended duration of action of benzodiazepines and with multiple doses it is important to note that a cumulative effect can occur. 

This is clinically significant in elderly patients, neonates and patients using cytochrome P450 inhibitors. In elderly patients, there is a chance that their hepatic microsomal enzymes no longer work at capacity and thus there is a risk of metabolite accumulation and an extended duration of action which could have negative side effects. In neonates, if the mother was taking benzodiazepines the baby can be born with CNS suppression which must be corrected. In patients using cytochrome P450 inhibitors, they should rather be prescribed other drugs (Oxazepam, Lorazepam, Lormetazepam) which don’t make use of dealkylation/oxidation reactions and which won't form active metabolites because due to their use of the cytochrome P450 inhibitors they won't be able to break down active metabolites that form and thus the metabolism of the drug is delayed and there is prolonged CNS suppression. 

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

Oxazepam, Lorazepam, Lormetazepam

These drugs don’t depend on hepatic microsomal enzymes for metabolism, they only rely on glucuronide conjugation. As a result, these drugs can then be used in situations where people have decreased hepatic microsomal enzyme activity (elderly, neonates, patients using cytochrome P450 inhibitors) since the drug will still be converted to an aqueous soluble product for excretion and there is no dangerous of accumulation. 

6. 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 and that enzyme then increases the metabolism of the drug. If drug metabolism is increased, then overall drug concentrations will decrease in the bloodstream and so the therapeutic effect is decreased. 

This occurs with certain barbiturates for example phenobarbitone.