Question

Q 1Using paracetamol as your example, explain THREE reasons why different formulations of the same drug might be desirable for administration through different routes. Your answer should describe the pathway of drug absorption to elimination for each route.

Answer 1

ANALGESIC EFFICACY: There is good evidence to show paracetamol as an analgesic is effective and safe.

The paracetamol can be administered as oral, intravenous or suppository.

Paracetamol plasma concentrations were observed for the first 80 minutes after administration of either 1g or 2g oral paracetamol or 2g intravenous propacetamol. Intravenous paracetamol provided an average concentration within the therapeutic range after 20 minutes.

Rectal absorption of paracetamol is more faster, with bioavailability between 24-98%. The variability in the rate and extent of absorption of suppositories is thought to be due to several factors.

After being taken by mouth, paracetamol is rapidly absorbed by the gastrointestinal (GI) tract.

Paracetamol is metabolized primarily in the liver, into toxic and nontoxic products. Three metabolic pathways are notable.

· Glucuronidation (45–55%)

· Sulfation (sulfate conjugation) (20–30%)

· N-hydroxylation and dehydration, then glutathione conjugation, (less than 15%).

The hepatic cytochrome P450 enzyme system metabolises paracetamol (mainly CYP2E1), forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzoquinone imine) (also known as N-acetylimidoquinone) NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.

All three pathways yield final products that are inactive, nontoxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an example of toxication.

Intavenous routes of administration of Acetamenophen or paracetamol causes direct absorption of drug. It has high bioavailability, with only 13% to 21% of the dose being lost during absorption.

The rectal administration shows a lower absolute bioavailability (of about 30-40%) substantially independent of dose in the range under consideration.Rectal absorption is variable and depends largely on the vehicle base. After oral administration, peak levels are reached in 30 to 60 minutes. The plasma half-life is approximately 2 hours, and its duration of action is approximately 4 hours.