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

Lipophilicity is a factor that affects the rates of oral absorption of sedative-hypnotics. For example, triazolam’s absorption is very rapid, and the absorption of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, which is a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam) by acid hydrolysis in the stomach. Most of the barbiturates and older sedative-hypnotics, as well as eszopiclone, zaleplon and zolpidem (newer hypnotics) are absorbed fastly into the blood after oral administration.

Lipid solubility plays a big role in determining the rate at which a certain sedative-hypnotic enters the CNS. This property causes a rapid onset of effects of triazolam, thiopental and newer hypnotics.

All the sedative-hypnotics cross the placenta barrier during pregnancy. If they are given during the predelivery period, they can cause depression of neonatal vital functions. They are also detectable in breast milk and can cause depressant effects in the nursing infant (Katzung, 2018: 388).

What is meant by redistribution and what is the significance thereof? / Wat beteken herdistribusie en wat is die belang daarvan?

Herdistribusie van die brein na ander weefsel vind plaas. ‘n Middel soos tiopentoon wat hoogs lipiedoplosbaar is en as induksie narkose middel gebruik word, beweeg baie vinnig va die bloed na die brein; beweeg dan ook weer baie vinnig uit die brein uit. Dit word nie dadelik geëlimineer nie, maar kan versprei na vetweefsel waar dit ‘n depot kan veroorsaak en vandaar vrygestel word (Brand, 2021).

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

Biotransformation by hepatic microsomal enzymes (step-by-step):

Step 1: Dealkylation – active metabolites are formed

Step 2: Oxidation – (Cytochrome P450) active metabolites are formed

Step 3: Conjugation (Phase II) of oxidised metabolite with glucuronic acid takes place and inactive metabolite is formed (Brand, 2021).

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

• Diazepam
• Chlorazepate
• Prazepam
• Chlordiazepoxide
• Ketazolam

Active metabolites cause an extended duration of action and cumulative effects can occur with multiple doses (Brand, 2021).

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

• Lorazepam
• Oxazepam
• Lormetazepam
• Temazepam

When Cytochrome P450 activity is reduced, these are the drugs of choice and can be used for older patients, neonates, liver cirrhosis and therapy with P450 enzyme inhibitors like cimetidine, ketoconazole, erythromycin and fluvoxamine (Brand, 2021).

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 the enhancement of the rate of its synthesis or the reduction in its rate of degradation (Katzung, 2018:59).

The following sedative hypnotic drugs are affected by enzyme-inducers:

• Flurazepam and zolpidem (Some inducers= barbiturates, carbamazepine, glucocorticoids, phenytoin...) (Katzung, 2018:63).

Induction leads to accelerated substrate metabolism and usually in a decrease in the pharmacologic action of the inducer and also of co-administered drugs. When drugs are metabolically transformed to reactive metabolites, enzyme induction may intensify metabolite-mediated toxicity (Katzung, 2018: 59).

References

Brand, L. 2021. Pharmacology FKLG312 2021 Inleiding. Leergedeelte 1.1. [PDF]. Ongepubliseerde lesing notas op eFundi, FKLG312. Potchefstroom: NWU.

Brand, L. 2021. Pharmacology FKLG312 2021 Inleiding. Leergedeelte 1.1. [Video]. Ongepubliseerde lesing notas op eFundi, FKLG312. Potchefstroom: NWU.

Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14th ed. New York: McGraw-Hill Education.