Pharmacology

Question 1

List 4 examples of antiplatelets and their respective classifications

Answer 1

1) Dipyridamole : adenosine uptake and PDE3 inhibitor
2) Aspirin: COX-1 inhibitor
3) Ticagrelor: ADP (P2Y12) receptor inhibitors
4) Clopidogrel: ADP (P2Y12) receptor inhibitors

Question 2

What do antiplatelets primarily do?

Answer 2

Block platelet aggregation and primary hemostasis

Question 3

What is the mechanism of action of dipyridamole?

Answer 3

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

Question 4

List 5 adverse effects of dipyridamole

Answer 4

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

Question 5

List 2 group of patients to be cautioned against the use of dipyridimole

Answer 5

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

Question 6

List 3 drug drug interactions for dipyridamole

Answer 6

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

Question 7

Explain the mechanism of action of aspirin as an antiplatelet

Answer 7

Aspirin is an irrevirsible COX inhibitor (COX 1 > Cox 2). Inhibition of COX-1 inhibits platelet production of thromboxane A2 which promotes platelet aggregation

Question 8

Explain why aspirin is more effective as an antiplatelet at low doses as compared to higher doses

Answer 8

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.

Question 9

Explain the mechanism of action of P2Y12 inhibitors (clopidogrel, ticagrelor)

Answer 9

Inhibits ADP from acting on ADP p2Y12 receptors, thereby inhibiting activating GP IIb/IIIa receptors and platelet recruitment and aggregation

Question 10

Explain the key characteristics of clopidogrel

Answer 10

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

Question 11

Explain the characteristics of ticagrelor

Answer 11

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

Question 12

List 5 adverse effects of clopidogrel

Answer 12

1) Hemmorhage/bleeding (incl intracranial bleeding)
2) Bruising
3) dyspepsia
4) rashes
5) bronchospasm/dyspnea
6) hypotension

Question 13

List 2 contraindications to clopidogrel

Answer 13

1) Hypersensitivity
2) CI in patients with active pathologic bleeding

Question 14

List 2 cautions for clopidogrel use

Answer 14

1) caution in patients at risk of bleeding
2) Variant alleles of CYP2C19 associated with reduced metabolism to active metabolite and diminished antiplatelet response

Question 15

List 4 DDIs of clopidogrel

Answer 15

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

Question 16

List 5 adverse effects of ticagrelor

Answer 16

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

Question 17

List 5 contraindications with ticragrelor

Answer 17

1) Hypersensitivity
2) Severe hepatic impairment
3) Breast feeding women
4) History of intracranial hemorrhage
5) Active pathological bleeding

Question 18

List 4 DDIs with ticagrelor

Answer 18

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

Question 19

What is the general action of anticoagulants?

Answer 19

Anticoagulants block activation of fibrin polymerization and secondary hemostasis

Question 20

List 3 examples of oral anticoagulants and their respective classes

Answer 20

1) Warfarin: vitamin K antagonist
2) Dabigatran: Direct oral anticoagulants - non-vitamin K antagonists
3) Rivaroxaban: Direct oral anticoagulants - non-vitamin K antagonists

Question 21

List 2 examples of parenteral anticoagulants

Answer 21

1) Heparin
2) Low molecular weight heparin derivatives

Question 22

Explain the mechanism of action of warfarin

Answer 22

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

Question 23

Explain how genetic variation can affect warfarin response

Answer 23

Genetic polymorphism in CYP2C9 and vit K reductase complex subunit 1 (VKORC1) accounts for most of the variability in response

Question 24

How is warfarin mainly metabolized?

Answer 24

Hepatic, primarily via CYP2C9

Question 25

Why is there usually a delay of onset of action in warfarin for about 24-72h?

Answer 25

Delay in onset of action until endogenous vit K is depleted

Question 26

What are 2 monitoring labs commonly used to monitor warfarin for dose titration?

Answer 26

International normalized ratio (INR) and prothrombin time (PT)

Question 27

List 3 side effects of warfarin

Answer 27

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

Question 28

List 6 contraindications with warfarin

Answer 28

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

Question 29

List 6 drugs that have DDI with warfarin and could lead to increased risk of bleeding

Answer 29

1) Paracetamol long-term therapy (>2 weeks) at high doses (>2g/day)
2) Allopurinol
3) NSAIDs
4) Salicylates
5) PPIs
6) Metronidazole

Question 30

List 4 drugs that have DDI with warfarin which can lead to reduced efficacy of warfarin

Answer 30

1) Barbiturates
2) Thiazide diuretics
3) Corticosteroids
4) Spironolactone

Question 31

List 4 examples of traditional medicine/herbs/supplements that can have interaction with warfarin to increase risk of bleeding

Answer 31

1) Gingko
2) Ginseng
3) Reishi mushrooms
4) Cranberry juice

Question 32

List 2 examples of supplements/herbs/traditional medicines that interacts with warfarin to reduce the efficacy of warfarin

Answer 32

1) Green tea
2) Vitamin K supplements/ vitamin-k rich foods

Question 33

Explain the MOA of dabigatran

Answer 33

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)

Question 34

What is the antidote/ reversal agent for dabigatran?

Answer 34

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

Question 35

Explain the MOA of rivaroxaban

Answer 35

Competitive reversible antagonist of activated factor X (Xa)

Question 36

What is the antidote/ reversal agent for rivaroxaban?

Answer 36

Andexanet alfa: recombinant modified human factor Xa decoy protein for reversal of -xabans ( and off-label LMWHs)

Question 37

What is the difference with regards to the metabolism of dabigatran vs rivaroxaban?

Answer 37

Dabigatran is largely excreted unchanged, while 2/3 of rivaroxaban undergoes metabolism by the liver and 1/3 metabolites cleared by the kidneys

Question 38

List 5 classes of drugs that could interact with dabigatran to increase risk of bleeding

Answer 38

1) NSAIDs
2) Fibrinolytics
3) Anti-coagulants
4) Antiplatelets
5) Ketoconazole

Question 39

List 1 drug that could interact with dabigatran to reduce dabigatran level

Answer 39

1) Rifampin

Question 40

List 4 classes of drugs that can interact with rivaroxaban to increase risk of bleeding

Answer 40

1) Antiplatelets
2) Anticoagulants
3) NSAIDs
4) P-glycoprotein inhibitors
5) CYP3A4 inhibitors

Question 41

List 2 types of drugs that could interact with rivaroxaban to reduce rivaroxaban levels

Answer 41

1) P-gp inducers
2) CYP3A4 inducers

Question 42

Explain the MOA of heparin and LMWH

Answer 42

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

Question 43

List 4 differences between heparin and LWMH

Answer 43

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

Question 44

List 3 adverse effects assoc/w parenteral anticoagulants

Answer 44

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

Question 45

What is the reversal agent/antidote for heparin?

Answer 45

Protamine sulfate: IV infusion; highly basic peptide stably binds to negatively charged heparin and neutralizes anticoagulant properties of heparin. Incomplete reversal for LMWHs

Question 46

List 3 contraindications for parenteral anticoagulants

Answer 46

1) Hypersensitivity to heparins or pork-products
2) Active major bleeding
3) Thrombocytopenia or antiplatelet antibodies

Question 47

List 5 classes of drugs that can interact with parenteral anticoagulants to increase risk of bleeding

Answer 47

1) NSAIDs
2) Antiplatelets
3) Anticoagulants
4) Fibrinolytics
5) SSRIs

Question 48

List 5 food/herbs that can interact with parenteral anticoagulants to increase risk of bleeding

Answer 48

1) Ginger
2) Gingko
3) Ginseng
4) Garlic
5) Fenugreek
6) Chamomile

Question 49

What clotting factors does warfarin inhibit?

Answer 49

II, VII, IX, X