Question 20

Compare and contrast the pharmacology of aspirin and clopidogrel.

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College Answer

Both agents are principally used as anti-platelet agents. Aspirin however has wider clinical applications. Mechanism of action of both agents involves irreversible inhibitions of enzymes  and/or receptors. The inability of platelets to regenerate these means that physiological effects can not be fully explained by pharmacodynamics or pharmacokinetics alone.Candidates who followed a traditional template for pharmacology answers scored better, 
providing answers that covered the breath of the topic.


Name Aspirin Clopidogrel
Class COX-1 inhibitor P2Y12 receptor antagonist
Chemistry Aromatic acetate Thienopyridine
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.