Compare and contrast the pharmacology of ibuprofen and paracetamol.
This was a standard compare and contrast question of common analgesic pharmacology and it was generally well answered. The use of a table ensured all areas were covered including class, indications, pharmaceutics, mode of action, pharmacodynamics, pharmacokinetics and adverse effects. The uncertain nature (and possibilities) of the mechanism of action of paracetamol was alluded to in better responses.
Details of the comparative pharmacokinetics were often lacking. Answers should have included a comment on first-pass effect, the significance of the difference in protein binding and the details of metabolism, particularly paracetamol. Metabolism limited to "hepatic metabolism and renal excretion” gained no marks as better responses were more detailed and clearer about the differences between the two drugs. Knowledge of metabolism at therapeutic doses and the effect of overdose were expected. Better answers included potential interactions with other drugs (e.g. warfarin) and contraindications to the use of these drugs.
|Chemistry||Aryl-propionic acid||Para-aminophen derivative|
|Routes of administration||Oral, PR, IV is available in some places||oral, IV, PR|
|Absorption||Rapidly absorbed; oral bioavailability is close to 100%||Rapidly absorbed; oral bioavailability ~ 80%|
|Solubility||pKa 4.9; quite lipid soluble and poorly water soluble||pKa 9.5; moderately soluble (equally badly in water and lipid)|
|Distribution||VOD = 0.1L/kg; 99% protein bound (to albumin)||VOD = 0.9L/kg; 15-20% protein bound|
|Target receptor||COX-1 and COX-2 isoforms of the cycloxygenase enzyme||Molecular targets are uncertain|
|Metabolism||Almost 100% of the dose is metabolised in the liver: oxidation into water-soluble inactive metabolites||Hepatic metabolism: major pathway is glucouronidation and sulfation;
minor pathway involves the formation of a toxic metabolite (NAPQUI) which needs to be detoxified by conjugation with gluathione
|Elimination||All products of metabolism are renally excreted||All products of metabolism are renally excreted|
|Time course of action||Half-life is 1.8 to two hours (duration of COX inhibition is much longer)||Half life of paracetamol is only about 2 hours|
|Mechanism of action||Inhibition of cyclooxygenase enzymes leads to decreased synthesis of prostaglandins, which decreases the vascular regional response to inflammation, and decreases the sensitivity of peripheral nociceptors. COX-1 inhibition also leads to the dysregulation of vascular antihrombotic effects of PGI2 and to the decreased secretion of bicarbonate and mucus in the gastric mucosa||Mechanism of analgesic effect of paracetamol is unclear, and is likely a combination of "effects on prostaglandin production, and on serotonergic, opioid, nitric oxide (NO), and cannabinoid pathways". (Sharma & Mehta, 2014)|
|Clinical effects||COX-1 inhibitor and nonselective NSAID side effects:
GI ulceration (decreased gastric mucosal pH and mucus synthesis)
Acute kidney injury (microvascular renal dysfunction)
COX-2 inhibitor side effects:
Anti-inflammatory activity is mainly due to COX-2 inhibition
Prothrombotic side effects are due to COX-2 inhibition
CCF exacerbation and hypertnesion
|Analgesia; co-anagesic effect with other agents; vasodilation when given IV; antipyrexial effect|
|Single best reference for further information||TGA PI document||TGA PI document|
Bacchi, Simona, et al. "Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review." Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents) 11.1 (2012): 52-64.
Rao, Praveen, and Edward E. Knaus. "Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond." Journal of pharmacy & pharmaceutical sciences 11.2 (2008): 81s-110s.
Day, R. O., G. G. Graham, and K. M. Williams. "Pharmacokinetics of non-steroidal anti-inflammatory drugs." Bailliere's clinical rheumatology 2.2 (1988): 363-393.
Verbeeck, Roger K., Jim L. Blackburn, and Gordon R. Loewen. "Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs." Clinical pharmacokinetics 8.4 (1983): 297-331.
Irvine, Jake, Afrina Afrose, and Nazrul Islam. "Formulation and delivery strategies of ibuprofen: challenges and opportunities." Drug development and industrial pharmacy 44.2 (2018): 173-183.
Day, Richard O., et al. "Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid." Clinical pharmacokinetics 36.3 (1999): 191-210.
Fitzpatrick, F. A. "Cyclooxygenase enzymes: regulation and function." Current pharmaceutical design 10.6 (2004): 577-588.
Hawkey, C. J. "COX-1 and COX-2 inhibitors." Best Practice & Research Clinical Gastroenterology 15.5 (2001): 801-820.