Anti- platelet drugs

Question 1

Learning outcomes

Answer 1

• Contrast the different anti-platelet drugs in terms of mode of action, efficacy and side effect profile
• Discuss evolving UK guidelines regarding the use of anti-platelet drugs in different clinical scenarios
• Evaluate the current place for fibrinolytic drugs in the initial management of acute myocardial infarction

Question 2

Haemostasis

Answer 2

•Processes involved
–vessel wall constriction (short-term)
–platelet adhesion to sub-endothelial collagen, degranulation (releasing ADP and TXA2), aggregation, plug formation–blood coagulation (fibrin mesh formation)
–[white cell infiltration]–[growth factors, tissue repair]–[fibrinolysis (breakdown of clot by plasmin)

Haemostasis: arrest of haemorrhage e.g. after tooth extraction or surgical procedure

Thrombosis:pathological formationof a ‘haemostatic’ plug within the vasculature in the absence of bleeding

Question 3

Virchow’s triad

Answer 3

Stasis of blood flow
Endothelial injury
Hypercoagulability

• injury to vessel wall (ruptured atheromatous plaque), mainly arterial
• stasis of flow (in legs during long immobility), mainly venous
• abnormal coagulability, acquired (pregnancy, oral contraceptives) or inherited (thrombophilia)

Question 4

Rationale for Antiplatelet drugs

Answer 4

Critical role for platelets in development of arterial thrombi- particularly in arterial circulation (faster/ greater pressure circulation, less time for fibrin network to occur)
•Damaged endothelium activates platelets which respond by adhering to endothelium and aggregating
•Release of thromboxane A2 and ADP amplifies this process
•Thrombin production via the coagulation cascade is also accelerated with thrombus stabilised by conversion of fibrinogen to fibrin
•Different drugs interfere with this process at different points in the cascade

Question 5

Anti- platelet agents

Answer 5

•Cyclo-oxygenase inhibitors (Aspirin)
•ADP receptor pathway inhibitors (Clopidogrel, others)
•Phosphodiesterase inhibitors (Dipyridamole)
•(Glycoprotein IIb/IIIa membrane receptor antagonists)
Anti-platelet Agents

*Anti-platelet drugs decrease platelet aggregation and inhibit thrombus formation in the arterial circulation, because in faster-flowing vessels, thrombi are composed mainly of platelets with little fibrin.
Evidence of benefit not convincing in venous circulation- thrombus associated with more extensive fibrin mesh network

Question 6

Aspirin mechanism of action

Answer 6

Aspirin inactivates COX-1 (by acetylation of serine residue)
Low dose (75mg) aspirin selectively and irreversibly inhibits cyclo-oxygenase (COX-1) which catalyses production of prostaglandins and thromboxanes

•Irreversible COX-1 (and COX-2 at higher doses) inhibitor–[other NSAIDS reversible, shorter duration, poor anti-platelet agents]
•reduced levels of TXA2 result in reduced platelet aggregation, increased bleeding time, vasodilatation
-TXA2 causes aggregation and vasoconstriction
-PGI2 causes vasodilationand reduces aggregation aspirin

Question 7

Aspirin- mechanism of action contd

Answer 7

•Platelets do not contain nuclei and cannot regenerate new COX-1
•Anti-aggregatory effect is irreversible for lifespan of platelet (7-10 days)
•Daily generation of 10-14% new platelets
–so recovery of most of the platelet function by 4-5 days after drug cessation
•[Inhibition of COX-2-dependent endothelial PGI2 synthesis recovers and is less marked due to selectivity of aspirin for COX-1>COX-2at low maintenance dose ~75mg]

Question 8

Clinical indications of aspirin

Answer 8

•secondary prevention in those with:
–ischaemic stroke/TIA
–angina pectoris (prevention of ischaemic events)
–acute coronary syndrome (reduce mortality)
–post myocardial infarction (long-term)
–following coronary bypass/stents (prevents occlusion)
–peripheral arterial disease/claudication
–atrial fibrillation (only if warfarin contra-indicated)?

•primary prevention of fatal and non-fatal cardiovascular events in patients at very high cardiovascular risk?-use declining (even in diabetes) –no longer recommended
–unproven benefit, risk (bleeding) > benefit

Question 9

Aspirin- adverse effects and drawbacks

Answer 9

•gastric irritation /bleeding
–interactions with NSAIDs, corticosteroids, anticoagulants, other anti-platelet agents increase risk
•hypersensitivity reactions [skin, airways]
•Reye’s Syndrome in children –rash, vomiting, with damage to brain, liver

Drawbacks
•lack of response in some patients (aspirin resistance) –rare, often related to poor drug adherence
•irreversible platelet inhibition –continued bleeding risk for some time after stopping the drug

Question 10

ADP and platelet activation

Answer 10

• key role in platelet activation
• ADP binding to (inhibitory) G protein coupled (inhibits cAM, reduce platelet activation) purinergic P2Y12 receptors on platelets unmasks glycoprotein GPIIb/IIIa receptors that become exposed to fibrinogen enhancing platelet aggregation
• Thienopyridines (clopidogrel and prasugrel) selectively and irreversibly inhibit ADP-mediated platelet activation and aggregation

Question 11

Clopidogrel- mechanism of action and clinical indications

Answer 11

•pro-drug given orally, metabolised by liver
–after absorption 85% is hydrolysed by esterases to inactive carboxylic acid
–15% undergoes 2-step oxidation activation principally by CYP2C19 enzymes in the liver

•active metabolite is selective and irreversible inhibitor of ADP-dependent platelet activation
–platelet function remains inhibited for 7-8 days after cessation of drug

Clinical indications
•secondary prevention in patients intolerant of aspirin

•with aspirin for 3 months after acute coronary syndrome and after procedures to coronary arteries [such as CABG, stenting] to prevent thrombosis

Question 12

Clopidogrel- adverse effects and potential drawbacks

Answer 12

• gastro-intestinal irritation and bleeding–especially with aspirin
• dyspepsia, gastrointestinal upset
• hypersensitivity reactions –skin, liver

Potential Drawbacks
•Pro-drug: delayed onset of action–steady state platelet inhibition = 5 days –partially overcome by giving loading dose of 300 mg (antiplatelet action 2-3 hours)
•Genetic variation of liver enzymes responsible for metabolism and activation so response varies between individuals
•Drug-drug interactions–proton pump inhibitors influence liver enzymes that metabolise clopidogrel
•Irreversible inhibition of P2Y12 receptor–bleeding risk for 7-8 days on stopping drug

Question 13

Prasugrel

Answer 13

• prodrug but different chemical structure permits conversion to active metabolite in liver –less dependence on cytochrome P450 enzymes than clopidogrel (one step oxidation to form active metabolite)
• also an irreversible inhibitor of platelet P2Y12 receptor but greater absorption and higher active metabolite bioavailability gives more predictable antiplatelet response than clopidogrel but >risk of bleed
• used in acute coronary syndromes–particularly if undergoing percutaneous coronary intervention or coronary angiography

Question 14

Ticagrelor

Answer 14

• cyclopentyl-triazolo-pyrimidine that does not bind to ADP binding site but a separate site on P2Y12 receptor to inhibit G-protein signalling•reversibleinhibitor of platelet P2Y12 receptor with rapid onset and offset of action–by comparison clopidogrel and prasugrel exhibit slow onset and offset–although fast offset of action, circulating ticagrelor may inhibit platelets infused to patients who are bleeding
• more potent than clopidogrel but > bleeding risk
• used in patients with acute coronary syndrome undergoing PCI when thrombosis > bleed risk

Question 15

Cangrelor

Answer 15

• REVERSIBLE inhibitor of platelet P2Y12 receptor with very rapid onset and offset of action
• IV administration for immediate potent inhibition (alongside oral aspirin) during PCI in high risk patients then switch to oral P2Y12 receptor antagonist

Question 16

Dyprimadole- mechanism of action and clinical indications

Answer 16

• thromboxane synthase inhibitor, may also enhance prostacyclin synthesis
• phosphodiesterase inhibitor [↑cAMP]
• inhibits reuptake and metabolism of adenosine
• collectively these mechanisms attenuate platelet adhesion and aggregation, and promote vasodilatation

Clinical indications
•given with oral anticoagulants for prevention of thromboembolism in patients with prosthetic heart valves•given with aspirin for secondary prevention of ischaemic stroke, TIA

Question 17

Dipyridamole- adverse effects

Answer 17

• gastro-intestinal irritation /bleeding–interaction with other anti-platelet agents and anticoagulants increases risk
• dizziness, flushing and headache
• myalgia
• chest pain
• hypersensitivity reactions [skin, kidney]

Question 18

Anti- platelet drugs: summary of group side-effects

Answer 18

•bleedingis the most important side-effect
–less so with low dose aspirin than other antiplatelet agents
–risk of bleeding increases with use of drugs that also influence platelet function or haemostasis (such as warfarin, NSAIDS)
•need to stop drugs before elective procedures
–usually 1 week for clopidogrel, 4-5 days for aspirin, preferably 2 days for ticagrelor, see specific protocols/guidance
•other common class side-effects–dyspepsia, altered bowel habit, headache, dizziness
•hypersensitivity reactions, bone marrow suppression, thrombocytopenia, hepatic damage
 –more likely with other agents than with low dose aspirin

Question 19

Reversal strategies

Answer 19

• may be needed if acute bleed or an urgent surgical procedure could result in high bleed
• increased risk with irreversible agents
• no reversal agents currently available (ticagrelor antibody fragment in development)
• platelet rich plasma transfusion may be required for timely reversal

Question 20

Summary of recent therapeutic use

Answer 20

•aspirin in secondary prevention
–especially post MI, still widely used for this indication

•clopidogrel monotherapy for occlusive vascular events
–post stroke, peripheral vascular disease

• prasugrel / ticagrelor use limited to acute coronary syndromes (STEMI/NSTEMI)
• antiplatelet agents NOT useful in atrial fibrillation?

Question 21

Fibrinolytic drugs

Answer 21

•activate conversion of plasminogen to plasmin which dissolves fibrin strands of clot

•examples:
–streptokinase, from haemolytic bacteria
–alteplase (tissue plasminogen activator)