This chapter is relevant to Section Q2(i) of the 2017 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:
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
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.
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.
|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.
|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.
|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.
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.
|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.
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|
|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.
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)
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: