Compare and contrast aspirin and clopidogrel
Both of these commonly used agents are level A in the syllabus and thus a high level of detail was expected. Marks were awarded in the following areas - pharmaceutics, mechanism of action, pharmacokinetics (PK) and side effects. For the PK parameters a general description rather than exact values was sufficient (i.e. ‘high protein binding’ rather than ‘98% protein bound’). It was expected that candidates would mention the fact that clopidogrel is a pro-drug and the factors which influence its conversion to the active form. Additional marks were awarded for well-structured answers which attempted a comparison between the two drugs (helped by the use of a table).
|Class||COX-1 inhibitor||P2Y12 receptor antagonist|
|Routes of administration||Oral||Oral|
|Absorption||Oral bioavailability 50% due to first pass effect(but, well absorbed)||Absorption is poor (50%) and bioavailability is even worse - only 2% of the oral dose is converted to the active metabolite|
|Solubility||pKa 2.97; only slighly water-soluble||pKa 3.5; basically insoluble in water|
|Distribution||VOD=0.1-0.2 L/kg; 58% protein-bound||VOD=550L/kg; 98% protein-bound|
|Target receptor||COX-1 and COX-2 isoforms of the cycloxygenase enzyme||P2Y12 class of ADP receptor|
|Metabolism||80% is metabolised in the liver; active metabolite (salicylic acid) is responsible for much of the analgesic and antiinflammatory effect, but has little antiplatelet activity.||Complex hepatic metabolism,. where most of the absorbed dose is hydrolysed by carboxylesterase 1 into an inactive carboxylic acid metabolite, and onyl 2% is converted to clop-AM, the pharacologically active form of clopidogrel.|
|Elimination||Salicylic acid is eliminated in the urine; renal clearance of aspirin itself becomes more important with overdose||Of the metabolites, 50% are eliminated in the urine, and 50% in the faeces|
|Time course of action||Aspirin half life is only 20 minutes; half-life of salicylic acid can range from 2 to 12 hours, depending on the dose.
Clinical effect duration: 96 hours
|Clopidogrel has a half-life of 6 hours, and the active metabolite has a half-life on only 30 minutes.
Clinical effect duration: 7-10 days
|Mechanism of action||By inhibiting the activity of COX-1 isoenzyme, aspirin decreases the synthesis of trhomboxane-A2, which is a potent platelet activator. The result is a decrease in platelet activation and aggregation. This inhibition is irreversible (acetylation)||By inhibits the binding of ADP to the P2Y12 receptor, clopidogrel prevents platelet activation, and the subsequent ADP- mediated activation of the glycoprotein GPIIb/IIIa complex. Thus, both platelet activation and platelet aggregation are affected. This effect is irreversible|
|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 hypertension.
Also the possibility of causing brinchospasm in asthmatics
|Risk of bleeding (which is serious!), aplastic anemia, thrombocytopenia, and neutropenia|
|Single best reference for further information||Nagelschmitz et al, 2014||TGA PI document|
Patrono, Carlo. "Aspirin as an antiplatelet drug." New England Journal of Medicine 330.18 (1994): 1287-1294.
Li, Chunjian, et al. "Reversal of the anti‐platelet effects of aspirin and clopidogrel." Journal of Thrombosis and Haemostasis 10.4 (2012): 521-528.
Plosker, Greg L., and Katherine A. Lyseng-Williamson. "Clopidogrel." Drugs 67.4 (2007): 613-646.
Savi, P., et al. "Clopidogrel: a review of its mechanism of action." Platelets 9.3-4 (1998): 251-255.