Pharmacology Flashcards
List 4 examples of antiplatelets and their respective classifications
1) Dipyridamole : adenosine uptake and PDE3 inhibitor
2) Aspirin: COX-1 inhibitor
3) Ticagrelor: ADP (P2Y12) receptor inhibitors
4) Clopidogrel: ADP (P2Y12) receptor inhibitors
What do antiplatelets primarily do?
Block platelet aggregation and primary hemostasis
What is the mechanism of action of dipyridamole?
1) Inhibits platelet activation and aggregation by increasing cAMP within platelets through:
Adenosine reuptake inhibitor- increases plasma adenosine activation of A2 receptors on platelets
PDE3 inhibitor- reducing cAMP degradation within platelets
2) Also functions as a vasodilator as it inhibits adenosine reuptake and PDEs in vascular smooth muscle
Dose limiting adverse effects limit clinical antiplatelet efficacy; adjunct antiplatelet given in combination with other antiplatelets or anticoagulants
Infused intravenously as an alternative to exercise for myocardial perfusion imaging
List 5 adverse effects of dipyridamole
S.E from vasodilatory action:
1) Hypotension
2) Headache
3) Dizziness
4) Flushing
GI S.E:
5) gastrointestinal disturbance
6) Diarrhea
7) nausea
8) vomiting
List 2 group of patients to be cautioned against the use of dipyridimole
1) Caution in hypotension
2) Caution in patients with severe coronary artery disease: vasodilatory effects can reduce BP, leading to reflex tachycardia which may lead to angina pectoris and ECG abnormalities & MI
List 3 drug drug interactions for dipyridamole
1) Adenosinergic agents: increase plasma levels and cardiovascular effects of adenosine
2) May counteract the anticholinesterase effect of cholinesterase inhibitors, potentially aggravating myasthenia gravis
3) Caution for bleeding when combined with heparin or other anticoagulants and antiplatelets
Explain the mechanism of action of aspirin as an antiplatelet
Aspirin is an irrevirsible COX inhibitor (COX 1 > Cox 2). Inhibition of COX-1 inhibits platelet production of thromboxane A2 which promotes platelet aggregation
Explain why aspirin is more effective as an antiplatelet at low doses as compared to higher doses
At lower doses, Aspirin has greater selectivity on COX-1 than COX-2. Irreversible inhibition of COX-1 in the platelets, to inhibit the production of TXA2, can only be restored by formation of new platelets, which takes 7-10 days, hence allowing a longer lasting antiplatelet activity.
However at higher doses, there is lesser selectivity, and there is more inhibition of COX-2 enzymes in the endothelial cells which further blocks the production of prostacyclin (PGI2) which is a vasodilator and inhibits platelet aggregation, hence reducing its antiplatelet activity.
Note: Inhibition of COX-2 in the endothelial cells can be restored by synthesis of new COX enzyme which take 3-4 hours.
Explain the mechanism of action of P2Y12 inhibitors (clopidogrel, ticagrelor)
Inhibits ADP from acting on ADP p2Y12 receptors, thereby inhibiting activating GP IIb/IIIa receptors and platelet recruitment and aggregation
Explain the key characteristics of clopidogrel
1) Is a prodrug with an active metabolite: converted to active metabolite by CYP2C19
2) Active metabolite irreversibly binds to ADP binding site on the P2Y12 receptor
3) Delayed onset (peak 6-8h) and interindividual variability due to CYP2C19 mediated metabolism to produce active metabolite
4) Irreversible inhibition: effect on platelet function lasts for lifetime of affected platelets, which is between 7-10 days
Explain the characteristics of ticagrelor
1) Ticagrelor and its metabolites bind reversibly at a different site (not ADP binding site) to inhibit G protein activation and signaling
2) Faster onset and peak effect than clopidogrel
3) Recovery of platelet function depends on serum concentrations of ticagrelor and its active metabolites and takes 2-3 days
List 5 adverse effects of clopidogrel
1) Hemmorhage/bleeding (incl intracranial bleeding)
2) Bruising
3) dyspepsia
4) rashes
5) bronchospasm/dyspnea
6) hypotension
List 2 contraindications to clopidogrel
1) Hypersensitivity
2) CI in patients with active pathologic bleeding
List 2 cautions for clopidogrel use
1) caution in patients at risk of bleeding
2) Variant alleles of CYP2C19 associated with reduced metabolism to active metabolite and diminished antiplatelet response
List 4 DDIs of clopidogrel
1) Antiplatelets/coagulants: warfarin, NSAIDs, salicylates may increase risk of bleeding
2) Macrolides may reduce the antiplatelet effect
3) Strong to moderate CYP2C19 inhibitors: PPIs, fluoxetine, ketoconazole may reduce antiplatelet effect
4) Rifamycin may increase the antiplatelet effect
List 5 adverse effects of ticagrelor
1) Cough- significant, likely due to increased adenosine levels
2) Dyspnea - significant, likely due to increased adenosine levels
3) Hemorrhage/bleeding (incl intracranial bleeding)
4) Bruising
5) Bradycardia
List 5 contraindications with ticragrelor
1) Hypersensitivity
2) Severe hepatic impairment
3) Breast feeding women
4) History of intracranial hemorrhage
5) Active pathological bleeding
List 4 DDIs with ticagrelor
1) Anticoagulants, fibrinolytics, long term NSAIDs may increase bleeding risk
2) Aspirin doses >100mg/day reduce ticagrelor effect but increase bleeding risk
3) CYP3A inducers: dexamethasone, phenytoin etc may reduce ticagrelor level and antiplatelet effect
4) CYP3A strong inhibitors e.g. clarithromycin, ketoconazole etc may increase ticagrelor level and risk of adverse reactions
What is the general action of anticoagulants?
Anticoagulants block activation of fibrin polymerization and secondary hemostasis
List 3 examples of oral anticoagulants and their respective classes
1) Warfarin: vitamin K antagonist
2) Dabigatran: Direct oral anticoagulants - non-vitamin K antagonists
3) Rivaroxaban: Direct oral anticoagulants - non-vitamin K antagonists
List 2 examples of parenteral anticoagulants
1) Heparin
2) Low molecular weight heparin derivatives
Explain the mechanism of action of warfarin
Active vitamin K is oxidized to inactive vitamin K in a step coupled to carboxylation of glutamic acid residues on coagulation factors II, VII, IX and X
Carboxylation functionally activates coagulation factors II VII, IX, X
Warfarin inhibits the vitamin K reductase enzyme that reactivates the oxidized vitamin K
Vitamin K can reverse the effect of warfarin
Explain how genetic variation can affect warfarin response
Genetic polymorphism in CYP2C9 and vit K reductase complex subunit 1 (VKORC1) accounts for most of the variability in response
How is warfarin mainly metabolized?
Hepatic, primarily via CYP2C9
Why is there usually a delay of onset of action in warfarin for about 24-72h?
Delay in onset of action until endogenous vit K is depleted
What are 2 monitoring labs commonly used to monitor warfarin for dose titration?
International normalized ratio (INR) and prothrombin time (PT)
List 3 side effects of warfarin
1) Hemorrhage/bleeding: blood in stools/urine, melena, excessive bruising, petechiae, persistent oozing from superficial injuries, excessive menstrual bleeding
2) Hepatitis: greatest risk in >60 y/o, male, on warfarin < 1 month
3) Cutaneous necrosis and infarction of the breast, buttocks and extremities: possibly due to reduced blood supply to adipose tissue; typically 3-5 days after initiating treatment
List 6 contraindications with warfarin
1) Hypersensitivity
2) Active bleeding, risk of pathologic bleeding, after recent major surgery
3) Severe or malignant hypertension
4) Severe renal or hepatic disease
5) Subacute bacterial endocarditis, pericarditis, or pericardial effusion
6) Pregnancy: teratogenic, can cause hemorrhagic disorder in fetus
List 6 drugs that have DDI with warfarin and could lead to increased risk of bleeding
1) Paracetamol long-term therapy (>2 weeks) at high doses (>2g/day)
2) Allopurinol
3) NSAIDs
4) Salicylates
5) PPIs
6) Metronidazole
List 4 drugs that have DDI with warfarin which can lead to reduced efficacy of warfarin
1) Barbiturates
2) Thiazide diuretics
3) Corticosteroids
4) Spironolactone
List 4 examples of traditional medicine/herbs/supplements that can have interaction with warfarin to increase risk of bleeding
1) Gingko
2) Ginseng
3) Reishi mushrooms
4) Cranberry juice
List 2 examples of supplements/herbs/traditional medicines that interacts with warfarin to reduce the efficacy of warfarin
1) Green tea
2) Vitamin K supplements/ vitamin-k rich foods
Explain the MOA of dabigatran
Dabigatran exists as a prodrug dabigatran etexilate, which is rapidly converted to dabigatran.
Dabigatran and its acyl glucuronide metabolites are competitive reversible non-peptide antagonists of thrombin (factor IIa)
What is the antidote/ reversal agent for dabigatran?
Idarucizumab: humanized monoclonal antibody fragment that binds dabigatran and its acyl glucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin
- indicated for reversal of anticoagulant effects of dabigatran for emergency surgery or urgent procedures and in life-threatening or uncontrolled bleeding
Explain the MOA of rivaroxaban
Competitive reversible antagonist of activated factor X (Xa)
What is the antidote/ reversal agent for rivaroxaban?
Andexanet alfa: recombinant modified human factor Xa decoy protein for reversal of -xabans ( and off-label LMWHs)
What is the difference with regards to the metabolism of dabigatran vs rivaroxaban?
Dabigatran is largely excreted unchanged, while 2/3 of rivaroxaban undergoes metabolism by the liver and 1/3 metabolites cleared by the kidneys
List 5 classes of drugs that could interact with dabigatran to increase risk of bleeding
1) NSAIDs
2) Fibrinolytics
3) Anti-coagulants
4) Antiplatelets
5) Ketoconazole
List 1 drug that could interact with dabigatran to reduce dabigatran level
1) Rifampin
List 4 classes of drugs that can interact with rivaroxaban to increase risk of bleeding
1) Antiplatelets
2) Anticoagulants
3) NSAIDs
4) P-glycoprotein inhibitors
5) CYP3A4 inhibitors
List 2 types of drugs that could interact with rivaroxaban to reduce rivaroxaban levels
1) P-gp inducers
2) CYP3A4 inducers
Explain the MOA of heparin and LMWH
Potentiates the action of antithrombin III (AT III) and thereby inactivates thrombin.
Active heparin molecules binds tightly to AT III and cause a conformational change, which exposes AT III’s active site for more rapid interaction with proteases.
Heparin-AT III complex inactivates a number of coagulation factors:
- inactivates thrombin (factor IIa) and factors IXa, Xa, XIa, XIIa
- thrombin is needed for the conversion of fibrinogen to fibrin
- without fibrin, clot formation is impeded
LWMH are more selective for factor Xa and to a lesser extent factor IIa
List 4 differences between heparin and LWMH
1) Bioavailability: LWMH have higher bioavailability (86-98%) than heparin (30%)
2) Half-life: LWMH have a longer half life (4h) than heparin (1h)
3) Thrombocytopenia: LWMH have a lower risk of thrombocytopenia (<1%) than heparin (<5%)
4) Renal excretion: LWMH are renally excreted ut not heparin
List 3 adverse effects assoc/w parenteral anticoagulants
1) Bleeding: anticoagulant effect disappears within hrs of discontinuation
2) Increased risk of epidural/spinal hematoma and paralysis in patients receiving epidural or spinal anesthesia or spinal puncture
3) Heparin-induced thrombocytopenia (low platelet count): binds to platelet factor 4 on activated platelet surface, igG antibody against heparin-PF4 complex. Lower risk with LMWH
What is the reversal agent/antidote for heparin?
Protamine sulfate: IV infusion; highly basic peptide stably binds to negatively charged heparin and neutralizes anticoagulant properties of heparin. Incomplete reversal for LMWHs
List 3 contraindications for parenteral anticoagulants
1) Hypersensitivity to heparins or pork-products
2) Active major bleeding
3) Thrombocytopenia or antiplatelet antibodies
List 5 classes of drugs that can interact with parenteral anticoagulants to increase risk of bleeding
1) NSAIDs
2) Antiplatelets
3) Anticoagulants
4) Fibrinolytics
5) SSRIs
List 5 food/herbs that can interact with parenteral anticoagulants to increase risk of bleeding
1) Ginger
2) Gingko
3) Ginseng
4) Garlic
5) Fenugreek
6) Chamomile
What clotting factors does warfarin inhibit?
II, VII, IX, X
