List the antiplatelet agents and outline their mechanisms of action, adverse effects, mode of
elimination and duration of action.
Most candidates did reasonably well by including aspirin, ADP receptor blockade and glycoprotein 2b/3a blockade in their answers. The best approach to answer this type of question was to use a table with each anti-platelet agent within a column and headings for the rows such as mechanisms of action, adverse effects, mode of elimination and duration of action. Common omissions included the irreversibility of the blockade of the platelet function by many of tthese agents, renal toxicity and bronchospasm as side effects of aspirin, bone marrow toxicity of ADP receptor blockers, and dipyridamole as an anti-platelet agent. Some candidates classified clopidogrel as a glycoprotein 2b/3a blocker incorrectly and thought clopidogrel has a relative short duration of action on platelet function because of its half-life. Clopidogrel as a prodrug requiring activation by cytochrome P450 and hence significant potential drug interactions were not mentioned by any candidates.
Syllabus: J2a,2d
References: Goodman and Gillman, The Pharmacological basis of therapeutics Chp 55
Antiplatelet agents in common use today are aspirin, clopidogrel, prasugrel, ticagrelor, abciximab and tirofiban, to name just a few. Listing them in the table suggested above would be painful. Instead, one agent from each major class is selected here.
| Name | Aspirin | Clopidogrel | Tirofiban |
| Class | Antiplatelet agent | Antiplatelet agent | Antiplatelet agent |
| Chemistry | Aromatic acetate | Thienopyridine | Tyrosine derivative |
| Routes of administration | Oral | Oral | IV only |
| 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 | 2.2% oral bioavailability (in rats...) |
| Solubility | pKa 2.97; only slighly water-soluble | pKa 3.5; basically insoluble in water | pKa 3.7; slightly soluble in water |
| Distribution | VOD=0.1-0.2 L/kg; 58% protein-bound | VOD=550L/kg; 98% protein-bound | VOD = 0.4-1.0L/kg; 64% protein bound |
| Target receptor | COX-1 and COX-2 isoforms of the cycloxygenase enzyme | P2Y12 class of ADP receptor | GP IIb/IIIa 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. | Minimal metabolism |
| 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 | Cleared renally as unchanged drug |
| 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 |
Half-life about 2 hours. Clinical effect duration:platelet activity returns to normal 4-8 hours after the infusion is ceased |
| 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 | Tirofiban binds to the GPIIb/IIIa receptor which inhibits platelet aggregation by preventing the binding of fibrinogen fibrin and von Willebrand factor, thus preventing platelet crosslinking. This binding is reversible. |
| 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 | Apart from the risk of bleeding (which is serious!), no other major side effects |
| Single best reference for further information | Nagelschmitz et al, 2014 | TGA PI document | TGA PI document |
Nagelschmitz, J., et al. "Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers." Clinical pharmacology: advances and applications 6 (2014): 51.
Jiang, Xi-Ling, et al. "Clinical pharmacokinetics and pharmacodynamics of clopidogrel." Clinical pharmacokinetics 54.2 (2015): 147-166.
Hashemzadeh, Mehrnoosh, et al. "Chemical structures and mode of action of intravenous glycoprotein IIb/IIIa receptor blockers: a review." Experimental & Clinical Cardiology 13.4 (2008): 192.
Teng, Renli, and Juan Maya. "Absolute bioavailability and regional absorption of ticagrelor in healthy volunteers." Journal of drug assessment 3.1 (2014): 43-50.
Karaźniewicz-Łada, Marta, et al. "Clinical pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases." Clinical pharmacokinetics 53.2 (2014): 155-164.
Rosenkranz, B., et al. "Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man." British journal of clinical pharmacology 21.3 (1986): 309-317.
Juneja, Shivani, Kanchan Gupta, and Sandeep Kaushal. "Ticagrelor: an emerging oral antiplatelet agent." Journal of pharmacology & pharmacotherapeutics 4.1 (2013): 78.
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.
Cook, Jacquelynn J., et al. "Tirofiban (Aggrastat®)." Cardiovascular Drug Reviews 17.3 (1999): 199-224.
McClellan, Karen J., and Karen L. Goa. "Tirofiban." Drugs 56.6 (1998): 1067-1080.