Antiplatelets, Anticoagulants & Fibrinolytics Flashcards
Which class of haematological drugs inhibits primary haemostasis?
Antiplatelet drugs
What are the processes involving blood cells that occur during primary haemostasis?
Platelet activation and aggregation are the first stages of hemostasis, activated during primary haemostasis. Antiplatelet drugs block this early stage of haemostasis and clot formation.
List FIVE mechanisms or classes of antiplatelet drugs.
(1) Adenosine uptake and PDE3 inhibitors(2) Irreversible cyclooxygenase-1 (COX-1) inhibitors(3) P2Y12 ADP receptor inhibitors(4) Glycoprotein IIb/IIIa receptor inhibitors (also known alpha-IIb/beta-3 integrin inhibitors) (5) Prostacyclin (PGI2) and analogues
Name ONE example of an adenosine uptake and PDE3 inhibitor antiplatelet agent.
Dipyridamole
How fast is the onset of clinically useful antiplatelet actions after administration of dipyridamole?
Fast onset after oral administration (20-30 min) and peak effect (2 to 2.5 hours).
Why is dipyridamole often administered in a modified- or extended-release preparation?
Dipyridamole has a short half-life resulting in a short duration of action of about 3 hours. It is, therefore, often administered in a modified- or extended-release preparation.
What is the clinical mechanism of action of dipyridamole as an antiplatelet agent?
Dipyridamole inhibits platelet activation and aggregation by ↑cAMP within platelets by being a/an:(1) Adenosine reuptake inhibitor → ↑ plasma adenosine activation of A2 receptors on platelets.(2) Phosphodiesterase 3 (PDE3) inhibitor reducing cAMP degradation within platelets.
What is the major dose-limiting side effect of dipyridamole?
By increasing cAMP levels through inhibiting phosphodiesterases (PDEs) and adenosine reuptake, dipyridamole is also a smooth muscle relaxant in vascular smooth muscle. Vasodilation results in dose-limiting side effects. Dipyridamole is therefore usually used as an adjunct or add-on with other antiplatelet agents.
List at least FOUR common adverse effects of dipyridamole when used as an antiplatelet agent.
Headache, hypotension, dizziness, flushing (due to vasodilator effect)Gastrointestinal (GIT) disturbance, diarrhoea, nausea, vomiting (due to effects on GIT smooth muscle).
List TWO cautions over the use of dipyridamole as an antiplatelet agent.
Caution in hypotension or severe coronary artery disease.
List THREE drug-drug interactions of dipyridamole when used as an antiplatelet agent.
(1) Increases levels of adenosine: Increases cardiac adenosine levels and effects.(2) Reduces activity of cholinesterases inhibitors: May aggravate myasthenia gravis.(3) Caution for bleeding when combined with heparin or other anticoagulants and antiplatelets.
Name ONE example of an irreversible cyclooxygenase-1 (COX-1) inhibitor used as an antiplatelet drug.
Aspirin
Explain how aspirin works as an antiplatelet drug.
Aspirin is an irreversible cyclooxygenase-1 (COX-1) inhibitor in platelets. Thus aspirin inhibits the production of thromboxane A2 (TXA2), which promotes platelet aggregation.
Why are the antiplatelet effects of aspirin stronger when it is used at a low dose than when it is used at a high dose?
Aspirin inhibits both COX-1 and COX-2. Aspirin inhibits COX-1 more than COX-2, but as the dose increases, the COX-2 inhibition is sufficient to have clinical consequences. COX-1 is present in platelets, producing thromboxane 2 (TXA2), which promotes platelet aggregation. COX-2 is present in other cells, including the endothelial cells of the blood vessel walls, where it produces prostacyclin (PGI2), which inhibits platelet aggregation. Thus, higher doses of aspirin inhibit COX-2-dependent PGI2 production more, counteracting the antiplatelet effect of inhibiting COX-1-dependent TXA2 production.
Why are the antiplatelet effects of aspirin stronger when it is used once daily than when it is used three to four times daily?
Aspirin irreversibly inhibits both COX-1 and COX-2. COX-1 is present in platelets, producing thromboxane 2 (TXA2), which promotes platelet aggregation. Platelets have no nucleus so when COX-1 is irreversibly inhibited by aspirin, new platelets need to be produced to replace platelets with functional COX-1. It takes from 7 to 14 days to replace platelets. COX-2 is present in other cells, including the endothelial cells of the blood vessel walls, where it produces prostacyclin (PGI2), which inhibits platelet aggregation. These cells have nuclei and can start to make new COX-2 protein within 3 to 4 hours. Thus, once-daily dosing has a stronger antiplatelet effect because it is sufficient for prolonged inhibition of COX-1 in platelets, but allows COX-2-dependent production of antiplatelet PGI2 to recover in other vascular cell types with nuclei.
How fast is the onset of the clinically useful antiplatelet effect of aspirin on once daily dosing?
(1) Onset within 3-4 hours (once COX-2-dependent PGI2 production has recovered).(2) Peak-effect 2 to 3 days as it takes a few days to achieve steady state maximal irreversible inhibition of COX-1 in the population of platelets.
How long does the antiplatelet effect of aspirin last after discontinuation of dosing?
7 to 10 days as aspirin is an irreversible COX-1 inhibitor and it takes time to replace platelets with functional COX-1.
List the TWO adverse effects of aspirin when used as an antiplatelet agent.
(1) Upper gastrointestinal (UGI) events (e.g., gastric ulcers, bleeding) due to inhibition of COX-1 production of protective prostaglandin in the stomach. Even low-dose aspirin for cardioprotective effects is associated with a two- to fourfold increase in UGI events.(2) Increased risk of bruising and bleeding.
What is the major caution over the use of aspirin?
Use with caution in patients with platelet and bleeding disorders (especially active upper gastrointestinal tract bleeding).
What is the major caution over drug-drug interactions for aspirin?
Caution for bleeding when combined with other antiplatelets and anticoagulants.
Name at least TWO examples of ADP P2Y12 receptor inhibitors used as antiplatelet drugs.
ClopidogrelTicagrelor
What is the major pharmacological difference between clopidogrel and ticagrelor?
Clopidogrel is a prodrug with an active metabolite that irreversibly binds to the ADP binding site on the P2Y12 receptor.Ticagrelor and its metabolites bind reversibly at a different site (not the ADP binding site) on the P2Y12 receptor.
How fast is the onset of clinically useful antiplatelet action after administering clopidogrel?
Onset of the clinical effect of clopidogrel takes about 2 to 4 hours as it is a prodrug metabolised to active metabolites. The peak effect takes about 6 to 8 hours.
How long does it take for platelet function to recover after discontinuation of clopidogrel?
About 7 to 10 days. Clopidogrel causes irreversible inhibition of the ADP P2Y12 receptors on platelets. It takes 7 to 10 days to replace new platelets with functional ADP P2Y12 receptors.
How fast is the onset of clinically useful antiplatelet activity after administering ticagrelor?
Approximately 20 to 30 minutes after oral administration with a peak effect after 2 to 3 hours.
How fast does platelet activity recover after discontinuation of ticagrelor?
Approximately 2 to 3 days due to the half-life of ticagrelor and its active metabolites.
List at least THREE contraindications or cautions when using clopidogrel.
(1) Contraindicated in patients with hypersensitivity to the drug(2) Contraindicated in patients with active pathologic bleeding(3) Caution in patients at risk of bleeding (e.g., risk of intracranial haemorrhage, trauma, surgery).(4) Variant alleles of CYP2C19 (4 % to 40 %) are associated with reduced metabolism to active metabolite and diminished antiplatelet response
List examples of drug-drug interactions with clopidogrel that increase the antiplatelet effect and risk of bleeding.
(1) Warfarin, NSAIDs, and salicylates may increase the risk of bleeding (pharmacodynamic interactions)(2) Rifamycins may increase the antiplatelet effect (pharmacokinetic interactions)
List examples of drug-drug interactions with clopidogrel that reduce the antiplatelet effect.
Strong to moderate CYP2C19 inhibitors (e.g., proton pump inhibitors, fluoxetine, ketoconazole, etc.) may reduce the antiplatelet effect by reducing the conversion of clopidogrel to its active metabolite.
List at least THREE contraindications or cautions when using ticagrelor.
(1) Contraindicated in patients with hypersensitivity to the drug, severe hepatic impairment, and in breast-feeding women(2) Contraindicated in patients with a history of intracranial haemorrhage or active pathologic bleeding (e.g., bleeding peptic ulcer)(3) Caution in patients at risk of bleeding (e.g., peptic ulcer, trauma, surgery), elderly, and moderate hepatic failure
List examples of significant drug-drug interactions with ticagrelor.
(1) Anticoagulants, fibrinolytics, & long-term NSAIDs may increase the bleeding risk (pharmacodynamic effects)(2) Aspirin doses >100 mg/day recude the ticagrelor effect but increase the bleeding risk (largely pharmacodynamic interactions)(3) CYP3A inducers (e.g., dexamethasone, phenytoin, etc) may reduce the ticagrelor level and antiplatelet effect (pharmacokinetic interactions)(4) CYP3A strong inhibitors (e.g., clarithromycin, ketoconazole, etc.) may increase the ticagrelor level and risk of adverse reactions (pharmacokinetic interactions).
What class of drugs inhibits secondary haemostasis?
Anticoagulants block secondary haemostasis.
What processes during secondary haemostasis are blocked by anticoagulants?
Anticoagulants block the activation of clotting factors and the resulting activation of fibrin polymerization in secondary haemostasis.
Name THREE classes of oral anticoagulant drugs.
(1) Vitamin K antagonists(2) Direct oral anticoagulant (DOAC) thrombin/factor IIa inhibitors: the “gatrans”.(3) Direct oral anticoagulant (DOAC) factor Xa inhibitors: the “xabans”
Name ONE example of a vitamin K antagonist anticoagulant drug.
Warfarin
Name ONE example of a thrombin/factor IIa inhibitor direct oral anticoagulant drug (DOAC).
Dabigatran (or any other “gatran”)
Name ONE example of a factor Xa inhibitor direct oral anticoagulant drug (DOAC).
Rivaroxaban (or any other “xaban”)
How long is the onset of the anticoagulant action of oral warfarin?
24-72 hours to onset of anticoagulant action and 5-7 days to achieve the peak effect on continuous administration. Although the plasma peak occurs within 2 - 8 hours after oral administration of warfarin, it takes time to deplete reserves of activated vitamin K.
How long does it take to reverse the anticoagulant effect of warfarin on discontinuation of the drug?
Duration of action 2-5 days. Due to the long half-life of some of the coagulation factors. (e.g. Factor II, t1/2 = 50 h) and the long elimination half-life of warfarin (20-60 hours).
