Antiplatelet agents

This chapter is relevant to Section Q2(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to "understanding of the pharmacology of anti-coagulants, anti-platelet drugs, thrombolytic drugs and anti-fibrinolytic drugs". Specifically, the topic is antiplatelet drugs, which need their own room because they are at least as beloved by the CICM examiners as heparin is. So great is the examiners' fascination with these substances that it has even extended to the Second Part exam, where First-Part-styler questions (eg. "briefly outline the mode of action and half life of aspirin, tirofiban and clopidogrel") were still being asked in 2015. For this reason, a brief summary of antiplatelet agents is also available in the Fellowship exam preparation section.

First Part SAQs involving antiplatelet drugs have mainly been interested in aspirin and clopidogrel, and so it would have been completely reasonable to limit the discussion to these:

  • Question 12 from the second paper of 2017 (aspirin vs. clopidogrel)
  • Question 20 from the second paper of 2015 (aspirin vs. clopidogrel)
  • Question 3 from thw second paper of 2013 (mechanism, and also aspirin)
  • Question 20 from the second paper of 2011 (clopidgrel)
  • Question 5 from the second paper of 2010 (mechanism)
Name Aspirin Clopidogrel
Class Antiplatelet agent Antiplatelet agent
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

Chemical properties of antiplatelet agents

This is a group consisting of several chemically diverse members which stretch all the way across the spectrum of molecular properties sizes and shapes. For example, aspirin (acetylsalicylic acid) is an organic acid, most specifically an acetoacetate. It's obviously going be completely different to clopidogrel, a thienopyridine. Ticagrelor, sounding like it should be related to them (because grel) is in fact a cyclo-pentyltriazolo-pyrimidine, usually listed as a "nucleoside analog" or "adenosine analog", and again has completely different chemical properties. Tirofiban is different again, as a non-peptide piperidine derived from L-tyrosine (where a butylsulfonyl group and a 4-(piperidin-4-yl)butyl group are grafted to the tyrosine body). Lastly, abciximab is the most different of all, being the Fab fragment of a monoclonal antibody.  

Pharmacokinetics of antiplatelet drugs

The pharmacokinetics of these drugs are rather more boring than their mechanisms of action, and so only the absolute minimum of the reader's time will be wasted with discussions of these properties.

Absorption and bioavailability

Name Absorption
Aspirin Oral bioavailability 50% due to first pass effect(but, well absorbed)
Clopidogrel Absorption is poor (50%) and bioavailability is even worse - only 2% of the oral dose is converted to the active metabolite
Prasugrel Rapidly and completely absorbed; 80% bioavailability
Ticagrelor Incompletely absorbed (about 60% of the dose is recovered in the faeces); erratic bioavailability, 25-65%
Abciximab Zero oral bioavailability
Tirofiban 2.2% oral bioavailability (in rats...)

Aspirin is well absorbed and has about 50% bioavailability because of a solid first-pass effect (carboxylesterases in plasma and the liver  tend to deacetylase a major proportion of it during the first pass). In contrast, clopidogrel almost doesn't even look like a drug which is supposed to be given orally, as it is only 50% absorbed, and of what is absorbed, only about 2% ever gets converted into a pharmacologically active form. Clopidogrel is a pro-drug which has basically no activity of its own, and needs be turned into "clop-AM" by CYP450 enzymes.

In contrast, prasugrel is rapidly and completely absorbed, and has 80% bioavailability, whereas the bioavailability of ticagrelor is somewhat erratic and seems to depend on gut motility (as its absorption in the intestine is quite poor). Obviously, abciximab and tirofiban have basically nil oral bioavailability, and are intended as IV-only formulations.

Solubility and pKa

Name Absorption
Aspirin pKa 2.97; only slighly water-soluble
Clopidogrel pKa 3.5; basically insoluble in water
Prasugrel pKa 5.1; basically insoluble in water
Ticagrelor pKa 12.9; basically insoluble in water
Abciximab pKa unknown; probably betwen 6.4 and 8. Good water solubility.
Tirofiban pKa 3.7; slightly soluble in water

Of these drugs, the only pharmacokinetically interesting factoid about solubility is about aspirin. It is a weak acid, which means that it increases in water solubility with higher pH. This makes it more lipid-soluble in the environment of the stomach (all the better to absorb), and water soluble in the more alkaline intestine. In massive overdose, with much of the ingested aspirin in the small intestine, the onset of maximum toxicity may be delayed by this effect. It has other toxicological implications for salicylate overdose: raising the urine pH from 5 to 8 can increase total salicylate excretion by twenty times by an "ion trapping" effect, where filtered salicylate will no longer be lipid-soluble enough to reabsorb back out of the tubule.

Distribution and protein binding

Name Distribution
Aspirin VOD=0.1-0.2 L/kg; 58% protein-bound
Clopidogrel VOD=550L/kg; 98% protein-bound
Prasugrel VOD = 1L/kg; 98% protein-bound (mainly to albumin)
Ticagrelor VOD = 1.2L/kg; 99.8% protein-bound
Abciximab VOD = 0.07L/kg (effectively confined to the circulating volume); minimally protein bound
Tirofiban VOD = 0.4-1.0L/kg; 64% protein bound

The two standouts here are aspirin and clopidogrel. Aspirin, i.e. salicylic acid, is basically confined to the circulating volume and binds plasma proteins only with reluctance. On the other hand, clopidogrel and its active metabolites have a massive apparent volume of distribution (Karaźniewicz-Łada et al, 2014), and are extensively bound to plasma and tissue proteins. Prasugrel and ticagrelor are also very highly protein-bound. 

Metabolism and elimination

One curisority of these drugs is the fact that the majority of antiplatelet agents have active metabolites. Aspirin is mainly metabolised in the liver (80%), being converted into salicylic acid, which is still a pharmacologically active metabolite, but which does not appear to have any antiplatelet activity (Rozencrantz et al , 1986). Aspirin itself is therefore the main mediator of antiplatelet activity. Clopidogrel and prasugrel on their own have basically no antiplatelet effect, and rely on hepatic metabolism to produce active daughter molecules.

Name Metabolism Elimination
Aspirin 80% is metabolised in the liver; active metabolite (salicylic acid) is responsible for much of the analgesic and anti-inflammatory effect, but has little antiplatelet activity. Salicylic acid is eliminated in the urine; renal clearance of aspirin itself becomes more important with overdose
Clopidogrel 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 pharmacologically active form of clopidogrel. Of the metabolites, 50% are eliminated in the urine, and 50% in the faeces
Prasugrel A pro-drug: converted to an active metabolite in the liver by CYP450 enzymes 68% of the metabolites are excreted in the urine, the rest in the faeces
Ticagrelor Extensively metabolised by hepatic CYP3A enzymes; only one active metabolite (but the parent drug itself has pharmacological activity) Inactive metabolites are renally excreted; the main active metabolite undergoes biliary excretion
Abciximab Does not undergo any hepatic metabolism. Eliminated (probably) by the reticuloendothelial system Metabolites are fragments of amino acids, and are generally cleared by being reincoporated into proteins
Tirofiban Minimal metabolism Cleared renally as unchanged drug

In contrast, ticagrelor has some activity of its own (and an active metabolite). The parenterally infused antiplatelet drugs stand alone as far as metabolism is concerned. Specifically, tirofiban is unique, as it appears to undergo no metabolism whatsoever, and is eliminated entirely by renal mechanisms. 

Half life and duration of meaningful antiplatelet activity

The most important concept is the massive difference in the half life of the drug itself and the clinical effect of platelet inhibition, which is due to the effect of the drugs on their molecular target. Most of them disable it in some irreversible way, which means you either need to produce new enzymes, or (more likely) just make new platelets. 

Name Half life Duration of activity
Aspirin Aspirin half life is only 20 minutes; half-life of salicylic acid can range from 2 to 12 hours, depending on the dose. 96 hours
Clopidogrel Clopidogrel has a half-life of 6 hours, and the active metabolite has a half-life on only 30 minutes. 7-10 days
Prasugrel Half life of the active metabolite is about 5-7 hours 7-10 days
Ticagrelor 7-8.5 hrs;
 
48-72 hours
Abciximab Half life is about 10-30 minutes, as a free circulating form, though abciximab-platelet complexes can be recovered from the blood up to ten days later. 48 hours
Tirofiban 2 hours 4-8 hours

The exceptions to this rule are the drugs that bind their receptor in a politely competitive way. Ticagrelor does not bind irreversibly, but its affinity for the ADP receptor is so clingy that it still takes 48 hours for the effect to wear off. According to Juneja et al (2013), after stopping it, on day three you are in the same place as you would be on day 5 after stopping clopidogrel, in terms of platelet function. 

Mechanisms of action of antiplatelet drugs

Three main effects need to be discussed:

COX inhibitor effects: Aspirin, as well as all of its COX-1 inhibiting friends, has the effect of decreasing thromboxane A2 synthesis by inhibiting the synthesis of all eicosanoids. TXA2 is synthesised locally, by the activated platelets themselves, using their own COX-1. As they have none of the machinery necessary to produce new COX enzymes after the old ones have been disabled, the effects of aspirin end up being particularly long-lasting.

Still, aspirin-disabled platelets are still functionally normal in every other respect. They can;t make TXA2 themselves, but if presented with exogenous TXA2, they should still activate as normal. And as your marrow is capable of cranking out enough platelets to completely turn them over every 8-10 days, after stopping aspirin there should soon be enough new working platelets to donate enough TXA2 to their aspirin-crippled siblings. Both sets of platelets will then activate and aggregate as per usual. This is what was discovered by Li et al (2012), who found that the effects of aspirin were basically abolished if there was at least 30% non-aspirinated platelets in the mix. The upshot of this is that with aspirin therapy, you only need to have ceased the doses for 3-4 days before the clotting is functionally normal enough for major surgery.

ADP receptor antagonist effects by clopidogrel prasugrel and all the other 'grels is a pharmacodynamically different animal. These drugs bind to the P2Y12 class of ADP receptor, a Gi-protein coupled receptor. Normally, ADP binding to this receptor produces intracellular calcium increase, degranulation and the activation of the GPIIb/IIIa complex allowing platelets to bind fibrinogen and Von Willebrand Factor. Without it, platelet aggregation cannot occur normally; the platelets will simply not respond to released ADP. Savi et al (2001) mention that "reversible ADP-induced aggregates obtained using platelets from the clopidogrel-treated donors contained small numbers of loosely-attached platelets with few contact points". In short, they lose all interest in binding to each other, even though they will still shapeshift and produce pseudopodia. 

Like aspirin, the union between clopidogrel and the receptor is irreversible, but unlike with aspirin, the addition of fresh platelets or more ADP reagent has minimal effect on the clotting function. Without functioning ADP receptors, the affected platelets remain useless, even if they are surrounded by functioning peers. In fact they are worse than useless, as they get in the way and prevent other fully functional platelets from binding to each other. 

Again from Li et al (2012), it appears that 90% of the platelets in the mixture would need to be non-clopidogrelated (clopidogrelled? Clopidogrelized? Clopped?). This accounts for the longer period of waiting (7 days) which is required to restore normal clotting function since the last dose of clopidogrel.

GPIIb/IIIa receptor antagonists  abciximab and tirofiban are competitive, reversible inhibitors of the most important component of platelet aggregation. The GPIIb/IIIa receptor binds to fibrin, fibrinogen and Von Willebrand factor; other platelets bind to the other end of the same molecules, and become attached to each other in the process. If this function is inhibited, platelet aggregation cannot proceed normally. For tirofiban, this is a transient process - it dissociates from the receptor with a very short half life. For abciximab, the duration of action is prolonged because of its high affinity binding (Hashemzadeh et al, 2008)

Reversal of antiplatelet agent effects

This occasionally comes up in exams, and- let's face it - in real life. How do you undo these crimes against platelets? Here is a selection of options:

  • Wait for a while. The non-urgent reversal of an antiplatelet drug always involves patience. The patient will grow some new platelets eventually, and the effect will wear off. When one has the luxury of time, this is almost always the better option. A drug like tirofiban has the benefit of being rather rapidly cleared, and so could be stopped on the morning of the CABG.
    What's the risk, you ask? The patient is taking these drugs for a reason. It is usually a really good reason. For example, they may have a very high risk of re-thrombosing a recently stented coronary artery, now full of dangerous bare metal. In fact, . According to an overview piece by Filipescu et al (2020) which may not represent any specific guidelines or local policy, "P2Y12 inhibitor therapy should be discontinued for the minimum amount of time possible and aspirin monotherapy continued" unless the risk is "prohibitive", i.e. you're operating on the brain of the unit director's mother in law. You could potentially just operate, and take the risk of bleeding. The risk of surgical haemorrhage is increased approximately 20% by aspirin or clopidogrel alone, and 50% by dual antiplatelet therapy, i.e your risk of having to give a couple of bags of red cells has increased. On the other hand, if you stop preventative DAPT within the first twelve months of a stent, you increase the risk of postoperative myocardial infarction and death five-to-tenfold.
  • Give DDAVP (desmopressin). This is a strategy sufficiently exciting to merit its own entry; here it will suffice to summarise that DDAVP  acts on storage sites in vascular endothelium, rapidly releasing stored vWF and Factor VIII, and increases the density of platelet surface glycoprotein receptors. The result should be an increase in the aggregation of even lazy disabled platelets
  • Reverse them with platelets. This has the greatest merit if the agent involved is mainly aspirin, but realistically, in any scenario where the platelets have been irreversibly disabled, sometimes the only solution is to add actual working platelets into the bloodstream. Do not be concerned about those platelets being affected by the residual clopidogrel, that's not how it works. The free clopidogrel is long gone, its half life is only six hours; and the platelet-bound clopidogrel is unlikely to hop from platelet to platelet because of the 

References

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.

Filipescu, Daniela C., et al. "Perioperative management of antiplatelet therapy in noncardiac surgery." Current Opinion in Anesthesiology 33.3 (2020): 454-462.

Thiele, T., et al. "Platelet transfusion for reversal of dual antiplatelet therapy in patients requiring urgent surgery: a pilot study." Journal of Thrombosis and Haemostasis 10.5 (2012): 968-971.