Question

During surgery acetylcholine function is blocked to switch off muscle stimulation including of the gastrointestinal tract and urinary bladder. With reference to acetylcholine's structure and stability, suggest why oral administration or intravenous injection of acetylcholine after surgery can not be used to switch back on the muscle stimulation [2 marks] Bethanechol is an acetylcholine agonist that can be used to switch back on muscle 11 stimulation after surgery. Show how bethanechol can act as an acetylcholine agonist AND also provide explanation for why it is orally and intravenously more stable than an acetyleholine [3 marks] Nt H2N bethanechol iii) Profiling of sewage water for illicit drugs and their phase 1 metabolites is a common way of detecting of community wide illicit drug metabolite) use. Common drug metabolites looked for are amphetamine benzoylecgonine (cocaine and and 4-hydroxymethamphetamine (methamphetamine metabolites). Explain how these metabolites are produced from the parent drug [3 marks] OH Cocaine H Benzoylecgonine HO NH2 Methamphetamine Amphetamine 4-Hydroxymethamphetamine 8

Answer 1

i) Oral administration and intravenous injections of acetylcholine are not used for the following reasons -

• Acetylcholine has a very non selective action, it may be injected to restimulate the gastric muscles but may also/or otherwise stimulate the release of noradrenaline or dialate the pupils( other functions of acetylcholine).
• Oral or intravenous administration of acetyl choline may never reach its desired target as the drug would undergo first pass metabolism where it would be broken down in the stomach by gastric juices or the intravenous injection passes through the liver where it is broken down.
• Acetylcholine is also rapidly degraded by cholinesterases present in the body.

ii) An agonist is a substance that enhances the activity of a particular compound, therapeutic or otherwise. Bethanechol is orally and intravenously more stable than acetylcholine because the acetate of acetylcholine is replaced by carbamate while the choline complex is methylated. Therefore it is not degraded by cholinesterases. But other esterases are still able to degrade it. It has a strong muscarinic activity that acts on the smooth muscles of the GI tract.

iii) If we look at the structures of Cocaine and Benzoylecgonine we see that Benzoylecgonine has a few additional Hydrogens added to it. Therefore its a reduction reaction. The transformation occurs due to the Humancarboxyesterase-! (hCE-1) enzyme present in the Liver and GI tract

Methamphetamine is metabolized by Cytochrome P450 2D6 present in the liver to Amphetamine. This enzyme has demethylation and dealkylating properties as well as promotes hydroxylation, which leads to the final product called 4 Hydroxymethampphetamine.