Treatment of Thrombolytic Disorders

Question 1

Vascular Injury: Arteries vs. Veins

Answer 1

Vascular injury = exposes collagen and vWF causing platelet release, adhesion, recruitment, activation, and aggregation to form a thrombus; tissue factor exposure causes activation of coagulation cascade, thrombin generation, fibrin formation, and thrombus formation

Venous thrombosis will be clotting activation and arterial thrombosis will mostly be platelet aggregation

Question 2

Coumadin/Warfarin

Answer 2

Coumadin/warfarin = inhibits actions of VIIa, X, IX, II
Warfarin/Coumadin mechanism: does not directly work on clotting protein, but interferes so you don’t get proteins 7, 9, and 10

Inhibits synthesis, so if have already formed then won’t work as well to cause immediate effects

Warfarin Antidote: fresh frozen plasma

Question 3

Heparin

Answer 3

Heparin products (fondaparinux, danaparoid, LMWH, and UFH) = fewer drug interactions

LMWH is more effective on Xa, but also works on IIa (thrombin)

Fondaparinux only works on Xa, no action on thrombin

Heparin: doesn’t do anything by itself; with antithrombin, will neutralize thrombin or factor X aka increases rate of anti-thrombin

Heparin has an antidote

Question 4

DTIs

Answer 4

DTIs: directly bind to thrombin (IIa) and inhibit activation; direct thrombin inhibitors

DTIs: lepirudin, bivalirudin, argatroban, and dabigatran

DTI: no antidote

Question 5

Heparin vs. Warfarin

Answer 5

Heparin (often as LMWH) is used acutely and Warfarin for prolonged therapy

Question 6

Mechanism of Thrombus Formation

Answer 6

Plaque disruption causing platelet activation and adhesion with release of thromboxane A2 and ADP to cause conformational activation of GPIIb/IIIa receptors thus causing platelet aggregation

Question 7

Aspirin

Answer 7

Cyclooxygenase (COX-1)
Irreversible inhibition of COX-1 blocks TXA2 mediated platelet activation

At higher doses aspirin inhibits COX-2 in endothelial cells and thereby blocks synthesis of PGI2, a potent inhibitor of platelet aggregation, by elevating platelet cyclic AMP levels

NSAIDs + aspirin = drug interaction and aspirin will not work; if need to take both, take aspirin 8 hours before or after

Side Effects: Bleeding, Gastro-Intestinal complications including Gastric ulcers

Question 8

Clopidogrel

Answer 8

ADP (P2Y12)-receptor
Irreversible antagonism of P2Y12 blocks platelet aggregation

Irreversible and prodrug (must be metabolized to become active); patients may not respond

Side Effects: Bleeding; Rash; Neutrocytopenia; Thrombocytopenia; TTP

Question 9

Prasugrel

Answer 9

ADP (P2Y12)-receptor
Irreversible antagonism of P2Y12 blocks platelet aggregation

Irreversible and prodrug (must be metabolized to become active); patients may not respond

Side Effect: Bleeding

Question 10

Ticlopidine

Answer 10

ADP (P2Y12)-receptor
Irreversible antagonism of P2Y12 blocks platelet aggregation

Irreversible and prodrug (must be metabolized to become active); patients may not respond

Side Effects: Bleeding; Gastro-Intestinal complications; Rash; TTP Neutrocytopenia; Thrombocytopenia

Question 11

Ticagrelor

Answer 11

ADP (P2Y12)-receptor
Reversible antagonism of P2Y12 blocks platelet aggregation

Direct acting and reversible

Side Effects: Bleeding, Dyspnea, and Bradyarrhythmia

Question 12

Dipyridamole

Answer 12

Cyclic nucleotide phosphodiesterase (PDE)
Adenosine uptake
Inhibition of PDE and adenosine uptake prevents platelet activation by increasing cyclic AMP levels

Side Effects: Bleeding, Headache; Dizziness; Dizziness; Rash; Pancytopenia

Question 13

Cilostazol

Answer 13

Cyclic nucleotide phosphodiesterase 3 (PDE3)
Inhibition of PDE 3 prevents platelet activation by increasing cyclic AMP levels in vascular tissue thus causing vasodilation

Side Effects: Bleeding; Headache; Diarrhea Dizziness; Rash; Pancytopenia

Question 14

Abciximab

Answer 14

Integrin aIIbb3-receptor
Inhibition of fibrinogen binding to integrin aIIbb3 prevents platelet aggregation

Do not give patients for prevention of MI or stroke, and only given intravenously during surgery or in hospital

Side Effects: Bleeding and thrombocytopenia

Question 15

Eptifibatide

Answer 15

Integrin aIIbb3-receptor
Inhibition of fibrinogen binding to integrin aIIbb3 prevents platelet aggregation

Do not give patients for prevention of MI or stroke, and only given intravenously during surgery or in hospital

Side Effects: bleeding and thrombocytopenia

Question 16

Tirofiban

Answer 16

Integrin aIIbb3-receptor
Inhibition of fibrinogen binding to integrin aIIbb3 prevents platelet aggregation

Do not give patients for prevention of MI or stroke, and only given intravenously during surgery or in hospital

Side Effects: bleeding and thombocytopenia

Question 17

Adenosine and PGI2

Answer 17

Adenosine: works on A2 receptor; increase cAMP

PGI2: works on AC receptor; increase cAMP

Question 18

Clinical Use of Antiplatelet Drugs

Answer 18

Patients with acute myocardial infarction
Patients who have recovered from myocardial infarction
Patients with symptoms from atherosclerosis, including angina, transient cerebral ischemic attacks, intermittent claudication

Following coronary artery bypass grafting
Following coronary artery angioplasty and stenting
Acute thrombotic stroke
Atrial fibrillation in patients who have a contraindication to oral anticoagulation

Question 19

Fibrinolytic Drugs

Answer 19

Streptokinase
Urokinase
Tissue plasminogen activators (t-PA)
Reteplase
Tenecteplase

All convert plasminogen to plasmin to cause breakdown of fibrin
More specific for fibrin where clot is: t-PA
Streptokinase is cheaper but not as specific – so effective everywhere; from bacterium so higher risk of reactions
Urokinase: like streptokinase

Question 20

Clinical Use of Fibrinolytic Drugs

Answer 20

Acute myocardial infarction, within 12 hours of onset
Acute thrombotic stroke within 3 hours of onset
Deep vein thrombosis, pulmonary embolus, clearing thrombosed shunts and cannulae, acute arterial thromboembolism

Question 21

Treatment of Peripheral Arterial Disease

Answer 21

Antiplatelet drugs
ACE inhibitors
β-blockers
Statins
Cilostazol

Question 22

Class of Evidence for Claudication Therapies

Answer 22

Class I: Evidence and general agreement or both that treatment is beneficial, useful and effective

Class IIb: Conflicting evidence or divergence of opinion about efficacy or usefulness

Class III: Evidence and general agreement or both that treatment is not beneficial, useful and effective

Question 23

Level of Evidence for Claudication Therapies

Answer 23

Level A: Data derived from multiple trial or meta analysis

Level B: Single randomized trial or non-randomized studies

Level C: Consensus opinion of experts, case studies or the standard of care

Question 24

Class I

Answer 24

Cilostazol

Class A

Contraindicated in heart failure; headache, diarrhea, palpitations, dizziness

Question 25

Class IIb

Answer 25

Pentoxifylline: A; Sore throat, dyspepsia, nausea, diarrhea

Arginine: B; GI distress, decrease in hematocrit

Propionyl levocarnitine: B; none or mild

Ginkgo biloba: B; none or mild

Question 26

Class III

Answer 26

Prostaglandins: A; Headache, flushing, GI distress

Vitamin E: C; none or mild

Chelation EDTA: A ; Hypocalcemia, renal failure, proteinuria, GI distress

Question 27

Cilostazol Pharmacokinetics

Answer 27

Cilostazol is given orally.

Cilostazol extensively binds to plasma albumin.

It is metabolized in liver.

Its metabolites are pharmacologically active.

Cilostazol is eliminated via kidneys (75%) and in feces (20%).

Question 28

Pentoxifylline

Answer 28

Pentoxifylline, a synthetic molecule related to caffeine, inhibits platelet aggregation by inhibiting breakdown of cyclic AMP by phosphodiesterase.

Pentoxifylline has been shown to reduce blood viscosity.

Evidence for the effectiveness of Pentoxifylline for claudication is classified as Class IIb

Question 29

Pentoxifylline Pharmacokinetics

Answer 29

Orally administered Pentoxifylline is well absorbed and undergoes significant first-pass metabolism.

Peak levels are seen in two to four hours.

Pentoxifylline is eliminated via kidneys with a T1/2 of less then an hour.

Renal impairment decreases its rate of elimination.

Question 30

Anticoagulant and Antiplatelet Therapies in Peripheral Arterial Disease

Answer 30

In patients with peripheral arterial disease, the combination of an oral anticoagulant and antiplatelet therapy is not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and is associated with an increase in life-threatening bleeding

Question 31

Clopidogrel + Aspirin Therapy

Answer 31

Clopidogrel and aspirin combined is not more effective than aspirin alone if patient is not undergoing surgical procedure or active MI/stroke, if so then combination may be helpful