Thromboembolic Drugs

Question 1

• long polysaccharide chain
• blocks generation of thrombin
• used in need of rapid onset anticoagulant effects (pulmonary embolism, stroke, massive DVT)
• given parenterally
• highly variable plasma levels requires intensive monitoring via aPTT assay

Answer 1

heparin

Question 2

When is heparin contraindicated?

Answer 2

thrombocytopenia

Question 3

• short polysaccharide
• cannot form tertiary complex with antithrombin III and thrombin
• selectively inhibits factor Xa
• prevents DVT after abdominal surgery, hip/knee replacement
• longer half life than heparin, more expensive
• bleeding is major adverse effect

Answer 3

enoxaparin

Question 4

What is the antidote for bleeding caused by enoxaparin?

Answer 4

protamine

Question 5

• synthetic pentasaccharide
• selectively inhibits factor Xa
• prevents conversion of prothrombin to thrombin
• slightly more effective than enoxaparin, but has increased risk of bleeding
• administered subQ with fixed daily dose
• NOT reversible with protamine***
• does NOT cause heparin-induced thrombocytopenia***

Answer 5

fondaparinux

Question 6

• synthetic 20aa peptide, given IV
• directly blocks thrombin (reversible inhibits)
• can be given in combination to patients undergoing angioplasty
• doesn’t require antithrombin, causes less bleeding
• NO antidote

Answer 6

bivalirudin (parenteral anticoagulant)

Question 7

What is the classic drug given for hepatin-induced thrombocytopenia?

Answer 7

argatroban

Question 8

• directly binds catalytic site of thrombin
• prophylaxis/tx of thrombosis
• efficacy monitored by aPTT
• short half life, given IV

Answer 8

argatroban

Question 9

• vitamin K agonist (inhibits vitK epoxide reductase-1, enzyme that converts K epoxide back to reduced form)
• oldest oral anticoagulant
• decreases production of factors 2, 7, 9, 10, protein C and S
• prevents thromboembolism in patients with mechanical heart valves
• prevents thrombosis in patients with A-fib
• delayed effects (not useful in emergency)
• monitored with prothrombin time ratio (INR)

Answer 9

warfarin

Question 10

What is the most widely used long-term prophylaxis of thrombosis?

Answer 10

warfarin

Question 11

What are the contraindications of warfarin?

Answer 11

• severe thrombocytopenia
• any surgery/procedure
• patients at high risk of bleeding
• PREGNANCY**

Question 12

Why can warfarin cause cutaneous necrosis?

Answer 12

Protein C has a shorter half-life than several other clotting factors, so warfarin can initially cause a pro-coagulant state

Question 13

• direct inhibitor of activated factor X (inhibiting thrombin production)
• rapid onset
• fixed dosage (oral administration)
• lower bleeding risk and fewer drug interactions than warfarin, no INR monitoring needed
• used to prevent DVT and pulmonary embolism after hip/knee replacement

Answer 13

rivaroxaban

Question 14

What are the contraindications of rivaroxaban? adverse effects?

Answer 14

pregnancy! also should not be combined with any other anticoagulants

• epidural hematoma
• major intracranial/retinal bleeds
• GI bleeds
• adrenal bleeds
• interact with CYP3A4

Question 15

• reversible direct thrombin inhibitor
• used in prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrilation
• rapid onset, few drug/food interactions, low risk of bleeding, same dose for all patients (pills are unstable**)

Answer 15

dabigatran

Question 16

What is the antidote for dabigatran?

Answer 16

idarucizumab (Ab fragment that binds dabigatran with high affinity)

Question 17

What are the contraindications for dabigatran?

Answer 17

• for patients with mechanical heart valves (since more likely to experience strokes/MI)

Question 18

• irreversible blockade of P2Y receptors on platelets (that mediate ADP-induced aggregation)
• prevent Gi pathway (decreasing cAMP)
• inhibits platelet aggregation
• is a prodrug*** that must be converted to active form
• generally well tolerated
• risk of bleeding (lower for GI bleeds and intracranial heorrhage than for aspirin)
• often given with proton-pump inhibitors to relieve GI effects

Answer 18

clopidogrel

** the drug to start with**

Question 19

What patient demographics have CPY2C19 variant enzyme that cannot activate clopidogrel?

Answer 19

• 50% of Chinese
• 34% of African Americans
• 25% of Caucasians
• 19% of Mexican Americans

Question 20

• suppresses platelet aggregation by unknown mech
• used in fixed-dose combination with aspirin to prevent recurrent ischemic stroke in patients with past stroke or TIA***

Answer 20

dipyridamole (PDE inhibitor)

Question 21

What are the adverse effects of PDE inhibitors?

Answer 21

• headache
• dizziness
• nausea
• vomiting
• dyspepsia
• diarrhea

Question 22

• type 3 PDE inhibitor (prolongs life of cAMP in platelets and cells)
• platelet aggregation inhibitor
• vasodilator
• causes claudication (leg cramping/pain induced by exercise)
• oral table 2x/day
• metabolized by CYP3A4

Answer 22

cilostazol

Question 23

• purified Fab fragment of monoclonal Ab, reversibly binds GP11b/111a receptors, preventing binding to fibrinogen
• blocks final common pathway of platelet aggregation (inhibiting aggregation cause by all factors)
• used to treat acute coronary syndromes (unstable angina), and percutaneous coronary intervention
• IV administration

Answer 23

abciximab

Question 24

What is the most effective antiplatelet drug?

Answer 24

abciximab

Question 25

• purified glycoprotein of 527 amino acids, with sequence identical to human tissue plasminogen activator
• catalyzes the conversion of clot-bound plasminogen to plasmin
• administered by continuous IV infusion, has a very short half life
• major indications: AMI, acute ischemic stroke, acute massive pulmonary embolism

Answer 25

alteplase (tPA)

** clot buster!

Question 26

What is the most serious concern of tPA?

Answer 26

intracranial hemorrhage, occurs for 2 reasons:

• destroying preexisting clots
• degrades clotting factors, interfering with clot formation

Question 27

What is the clinical application of urokinase (uPA)?

Answer 27

pulmonary embolism

NOTE: is second plasminogen activator, recently back on market

Question 28

What are the complications of uPA?

Answer 28

potentially fatal hemorrhage, easy bruising, nosebleeds, red/pink urine
- anaphylactic shock**