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

Lipophilicity is an important factor which affect the absorption and distribution of sedative-hypnotic drugs.

Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS. This property is responsible for the rapid onset of action/ effects of Triazolam (a benzodiazepine) , thiopental (a barbiturate) as these drugs are rapidly absorbed into surrounding tissues.

Usually highly lipid soluble drugs are redistributed from the brain to other tissues including the heart, kidneys, muscles and fatty tissues.

 All sedative-hypnotics cross the placental barrier during pregnancy due to their lipophilic nature. If given during the predelivery period, it could lead to depression of neonatal vital functions. It can also enter into the breast milk and so forth cause depressant effects in the nursing infant.

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

Due to high lipophilicity of the drugs, they initially distribute to highly vascularized tissues/ areas such as the brain, heart and kidneys. Thereafter the quickly distribute to surrounding tissues (muscle and fats). Redistribution from brain to other tissues. The drugs often move to fatty tissues where it causes the depot effect resulting in the slow and controlled release of the drug.  Thiopentone, a barbiturate is the most lipid soluble drug and used as induction anesthetic.

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

Benzodiazepine undergo 3 step biotransformation by hepatic microsomal enzymes.

The 3 steps are as follows:

1. Dealkylation 
   1. Active metabolite, Desmethyldiazepam is formed (elimination half-life = 40hours)
2. Microsomal oxidation
   1. Phase 1 reactions; 
   2. Catalysed by liver cytochrome P450 enzymes; especially CYP3A4.
   3. Active metabolite Desmethyldiazepam undergoes oxidation and a new active metabolite, Oxazepam is  formed
3. Conjugation 
   1. Phase II reactions; 
   2. Conjugation of oxidised metabolites with glucuronic acid to form inactive metabolite
   3. Oxazepam undergoes glucuronide conjugation to become an inactive metabolite known as glucuronides.
   4. The glucuronides are water-soluble and is excreted in urine.

The drugs Diazepam, Clorazepate, Prazepam, Chlordiazepoxide, Ketazolam all undergo all 3 of the metabolic steps: Dealkylation, Oxidation and Conjugation.

Exceptions on the above metabolic biotransformation of benzodiazepines include the drugs Oxazepam, Lorazepam, Temazepam & Lormetazepam. They do not undergo dealkylation or oxidation. It immediately undergoes a conjugation reaction where it forms inactive metabolites, Glucuronide, that are water-soluble  and thus excreted into urine for elimination. NO ACTIVE METABOLITES ARE FORMED

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

The drugs Diazepam, Clorazepate, Prazepam, Chlordiazepoxide, Ketazolam all undergo all 3 of the metabolic steps: Dealkylation, Oxidation and Conjugation.  After dealkylation of the above-mentioned drugs it forms the active metabolite Desmethyldiazepam. This drug has a very long elimination half-life of 40hours. This is then further oxidised to Oxazepam (active metabolite) which is then conjugated to become water-soluble for excretion in urine.

The formation of the active metabolites contribute to the extended duration of action/ prolonged CNS suppression of the drugs.

The formation of active metabolites are of great importance in the following instances:

1. Elderly people ,neonates and patients suffering from liver cirrhosis tend to have reduced enzymatic effectivity or activity. The drugs mentioned above all require biotransformation hepatic microsomal enzymes. If these enzymes are not functioning at full capacity, it could lead to the accumulation of the sedative-hypnotic drugs as it is not able to be metabolised at full potential. THis could be very dangerous as it could lead to an extended duration of action of these drugs and cause several side effects.
2. People using cytochrome P450 enzyme inhibitors such as Erythromycin, Ketoconazole or Cimetidine j will inhibit the enzymes from metabolising the above mentioned drugs. Thus, the drug concentrations will elevate in the body due to decreased metabolism of the drug. Once again, accumulation of the drugs occur which could be very dangerous.

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

The drugs Oxazepam, Lorazepam, Temazepam and Lormetazepam do not undergo dealkylation or oxidation. It immediately undergoes a conjugation reaction where it forms inactive metabolites, Glucuronide, that is water-soluble  and thus excreted into urine for elimination. No active metabolites are formed. Because these above mentioned drugs are not metabolised by the CYP450 enzymes, it is the drugs of choice for people who have reduced CYP450 activity.

People with reduced CYP450 activity: Elderly, neonates, liver cirrhosis patients and patients using CYP450 inhibitors.

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

Enzyme induction occurs when chemicals/ drugs cause an increase in synthesis and activity of enzymes, thereby increasing the metabolism of drugs that are catalysed by those enzymes. If drug metabolism is increased, it will decrease the overall drug concentrations in the body which could dampen the therapeutic effects of the specific drug being metabolised.