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).
| 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.