Factors that affect the absorption and distribution of sedative-hypnotic drugs:

The rate of oral absorption is dependent on the lipophilicity of the drugs. The more lipophilic they are, the more rapidly they are absorbed and distributed in the brain. For example, triazolam is very lipophilic and is absorbed very rapidly. Diazepam and active metabolite of clorazepate are absorbed faster than other benzodiazepines. Some drugs are converted to the active form by acid hydrolysis in the stomach, which are then absorbed much quicker. Barbiturates, older sedative-hypnotic and newer sedative-hypnotic drugs are absorbed very quickly into the blood stream after oral administration. All sedative-hypnotic drugs cross the placental barrier during pregnancy and may be found in breast milk of nursing mothers. This is clinically significant as this factor is responsible for the rapid onset of effects caused by these drugs. It suppresses the central nervous system and may contribute to depression of neonatal vital functions.

 

Redistribution of drugs and the significance thereof:

Drug redistribution refers to drugs that are distributed to the brain, heart, kidney, etc. directly followed by distribution into muscle and fatty tissue and stored there. Once plasma concentration starts decreasing, the drugs are redistributed from the muscle and fatty tissue into the blood so that it can prolong the drugs effect and prevent the plasma concentration from decreasing rapidly.

 

Benzodiazepine metabolism:

Benzodiazepines are metabolised step-by-step by the hepatic microsomal enzymes. The various steps in the process are:

1. Dealkylation: converting the benzodiazepines to active metabolites.
2. Oxidation: of the active metabolites by the cytochrome P450 enzymes.
3. Conjugation: (Phase 2) of the oxidised metabolites with glucuronic acid (endogenous substance) to form inactive metabolites.

However, some benzodiazepines, like oxazepam, lorazepam, temazepam and lormetazepam do not undergo dealkylation and oxidation. These drugs are immediately converted to glucuronide conjugates. All the glucuronide conjugates are hydrophilic and are excreted in the urine.

 

Benzodiazepines converted to active metabolites:

Diazepam, clorazepate, prazepam, chlordiazepoxide and ketazolam are the more lipophilic drugs and they are converted to active metabolites then oxidised and conjugates. The active metabolites contribute to the prolonged duration of action of the drug and cumulative effects occur with multiple doses (as their elimination half-lives are very long).

 

Benzodiazepines not dependent on cytochrome P450 oxidative enzymes:

Oxazepam, lorazepam, temazepam and lormetazepam are the benzodiazepines that do not undergo metabolism by the cytochrome P450 oxidative enzymes. They are the drug of choice in patients that are elderly, neonates, suffer from liver cirrhosis, are using therapy with cytochrome P450 inhibitors. This is advantageous as the metabolism of the drugs will not be affected. For example, if diazepam were to be used, there would be prolonged duration of action and drug accumulation would occur, which could be toxic.

 

Enzyme induction and the significance thereof:

An increase in the number of enzymes as a result of stimulation. Barbiturates increase biotransformation of other pharmacological agents as a result of enzyme induction. This is the potential mechanism underlying drug interaction of barbiturates and other drugs.