• What factors can influence the absorption and distribution of sedative-hypnotic drugs? What is the clinical significance of this?

The absorption of these drugs in the body is determined by the rate at which these drugs are released into the body and then absorbed. This rate is determined by the fat solubility of the benzodiazepine, in other words the lipophilicity of the drug. Drugs that are highly lipophilic include: Triazolam, Zaleplon and Zolpidem. These drugs are highly lipophilic and therefore will show a rapid onset of action. Drugs such as Oxazepam, Lorazepam, Temazepam and Bromazepam will take longer to be absorbed and cause a reaction in the body because they are less lipophilic drugs. In older people, the activity of oxidative enzymes is greatly delayed, therefore drugs that are directly conjugated (such as Oxazepam, Lorazepam, Temazepam and Bromazepam) will be safer to use.

• What does redistribution mean and what is its significance?

Redistribution is the ability of the body to spread substances that are highly lipophilic to organs in the body such as the heart, brain and kidneys and then to spread to muscles and other tissues. Drugs that are more lipophilic have a longer duration of action in the body.

• How are the BDs metabolized? Give the different steps in the process.

Benzodiazepines are step-transformed by enzymes called “liver microsomals” and are metabolised under normal conditions as follows:

1. Dealkilation (active metabolite)

Oxidation of Cytochrome 450 (active metabolite)

3. Conjugation (Phase 2) of oxidized metabolite with glucuronic acid to then form an inactive metabolite towards the end.

• Which BDs are converted to active metabolites? What is the importance of this?

Diazepam, Chlorasapate, Prazepam, Chlorodiazepoxide and Ketazolam (more lipophilic drugs). This drug undergoes all three steps of the metabolic process and then forms an active metabolite that prolongs the duration of action of these drugs.

• Which BDs are not dependent on the cytochrome P45 oxidative enzymes for metabolism? What are the benefits of this?

Oxazepam, Lorazepam, Temazepam and Lormetazepam (less lipophilic drugs). These drugs are especially beneficial in patients such as the elderly, neonates, patients with liver cirrhosis and patients using therapy with P450 enzyme inhibitors, where the cytochrome P45 activity is delayed or low, because these drugs are not dealkylated or oxidized during metabolism but are immediately conjugated. Metabolism therefore still takes place in full.

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

When the body is exposed to a chemical agent and physiological conditions or conditions, enzyme induction can occur when there is an increase in biosynthesis or catalytically active enzymes occur and thus increase the metabolism of the drug. Drugs known for this are the Barbiturates such as Phenobarbital, Thiopentone and Sodium Thiopentone.