A30. Drugs used in coagulation disorders II: Anticoagulant drugs

Question 1

What is the MOA of Heparin?

Answer 1

Heparin binds to antithrombin-III, accelerating its activity 1000x. AT-III is serpine (serine protease inhibitor), inactivates thrombin and factor Xa and IXa. Heparin in long chains inactivates both thrombin and factor Xa equally, but LMWH inactivates mostly factor Xa. Heparine is therefore more reliable.

Question 2

List the Anticoagulants.

Answer 2

1. Heparin
2. LMWH
3. Enoxaparin + Dalteparin

Question 3

Name the drug that inhibits COX-1.

Answer 3

Aspirin

Question 4

List the Platelet aggregation inhibitors.

Answer 4

1. COX-1 Inhibitor: Aspirin
2. Phosphodiesterase inhibitors: Dipyridamole, cilostazol
3. P2Y12 inhibitors: clopidogrel, ticagrelor, ticlopidine, prasugrel
4. GPIIb/IIIa inhibitors: Abciximab, Eptifibatide, Tirofiban.

Question 5

List the Thrombolytics.

Answer 5

1. Alteplase
2. Reteplase
3. Tenecteplase
4. Urokinase
5. Streptokinase (Antidote?: aminocaproic acid and tranexamic acid)

Question 6

List the indirect inhibitors of factor X.

Answer 6

1. Bivalent: Bivalirudin and Desirudin
2. Univalent: Argatroban and Dabigatran

Question 7

List the direct inhibitors of factor X.

Answer 7

1. Apixaban
2. Rivaroxaban

Question 8

What are the side effects of taking Heparin?

Answer 8

Side effects less with LMWH than UFH.

1. Bleeding
2. HIT- Heparin induced thrombocytopenia: usually reversible (HIT type I), but some cases can be very dangerous w/ antibody-mediated thrombocyte aggregation (HIT type II) → paradoxical thromboembolic complications.
3. Rarely: hair loss, allergic rxn, mild transaminase elevation, high doses → impaired aldosterone synthesis and osteoporosis w/ long-term therapy.

Question 9

What is the general MOA of Anticoagulant drugs?

Answer 9

1. They bind to coagulation factors and inactive them either as part of inactivation complex - indirectly (e.g. heparin, LMWH, danaparoid, fondaparinux) or directly (hirudin, dabigatran, rivaroxaban, bivalirudin, argatroban).
2. Or they inhibit coagulant factor synthesis (warfarin, other oral anticoagulants).

Question 10

What are the contraindications for Coumarins?

Answer 10

1. Pregnancy
2. Nursing women
3. Active bleeding

Question 11

Is there an antidote for Heparin and if so what is it?

Answer 11

Antidote is protamine sulfate. It is highly basic (positive charge) protein that neutralizes heparin in blood (only partially to LMWH).

Question 12

What is the antidote for Coumarin overdose?

Answer 12

Antidote here is more vitamin K, but it’s also not immediate. Have to make normal clotting factors.

Question 13

What are the side effects of coumarins?

Answer 13

1. “Warfarin necrosis”: necrosis in s.c tissue of skin or mucous membranes. Inhibition of protein C might be in the background.
2. Teratogenic
3. Bleeding
4. Allergic reactions
5. GI symptoms
6. Alopecia
7. “Purple toe syndrome”

Question 14

What is the MOA of Coumarins?

Answer 14

Coumarins are anticoagulants that work via inhibiting factor synthesis. Vitamin K is converted from hydroquinone to epoxide form for the steps of clotting factor formation, then converted back to hydroquinone form. Warfarin blocks this re-conversion step. Protein C and S are also affected by this, not just the pro-coagulant factors. Don’t have an immediate action… delay of about 10 hours.

Question 15

What is the MOA of Fondaparinux?

Answer 15

Fondaparinux is a synthetic part of heparin that activates antithrombin III + inactivates only factor Xa.

Question 16

Name coumarin drugs.

Answer 16

1. Warfarin
2. Acenocoumarol
3. Phenprocoumon

Question 17

List the Low molecular weight heparin.

Answer 17

Only need to know 1 or 2 names.

1. Enoxaparin
2. Certoparin
3. Dalteparin
4. Ardeparin
5. Nadroparin
6. Reviparin
7. Tinzaparin

Question 18

What is the MOA of Warfarin?

Answer 18

Warfarin is an anticoagulant drug normally used to prevent blood clot formation as well as migration. Although originally marketed as a pesticide (d-Con, Rodex, among others), Warfarin has since become the most frequently prescribed oral anticoagulant in North America. Warfarin does not actually affect blood viscosity, rather, it inhibits vitamin-k dependent synthesis of biologically active forms of various clotting factors in addition to several regulatory factors.

Question 19

How is aPTT affected by LMWH?

Answer 19

aPTT is not prolonged by LMWHs, their effect can be monitored by aPTT but usually not needed due to their more predictable pharmacokinetics.

Question 20

What are the side effects of Warfarin?

Answer 20

Warfarin has several properties that should be noted when used medicinally, including its ability to cross the placental barrier during pregnancy which can result in fetal bleeding, spontaneous abortion, preterm birth, stillbirth, and neonatal death. Additional adverse effects such as necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions have also been documented with warfarin use.

Question 21

How are the Pharmacokinetics of Coumarins?

Answer 21

1. Well-absorbed from GI tract, binds albumin in plasma, crosses the placenta so could be teratogenic and maybe affect breast milk too (?)
2. Metabolized in liver, glucoronidation. Excreted mainly with urine, partly with bile.
3. Half-life: strong individual variations! Warfarin T1/2 is 25-60 hours (Acenocoumarol is shorter but still about 9-24 hours, Phenprocoumon has very long half-life, 130-160 hours)
4. INR really important to measure. Goal 1.5 to 3. prophylactically may be only slight more than 1 though.
5. Doses: in the first few days, give 2x these doses. Warfarin 2-10 mg. Acenocumarol 1-12 mg
6. Interactions: diet / intestinal bacterial flora affecting vit K concentration.
7. Absorption: inhibited by antacids, cholestyramine.
8. Albumin binding: inhibited by several drugs, e.g. NSAIDs.
9. Metabolism: Enzyme inhibition for phenylbutazone, sulfinpyrazone, metronidazole, fluconazole, sulfonamides, amiodarone, disulfiram, cimetidine. Enzyme inducers of barbiturates, rifampin, carbamazepine, phenytoin, griseofulvin
10. Increased coagulation: heparin, ASA, liver disease, hyperthyroidism, certain cephalosporins with N-methyl-thiotetrazol substitution (cefamandole, cefoperazone)
11. Decreased coag: vit K, hypothyroidism, strong diuretic therapy, corticosteroids.
12. Many Caucasians have ↓ metabolism (CYP2C9) → more sensitive

Question 22

What are the indications for Fondaparinux?

Answer 22

Fondaparinux can be used for DVT. It doesn’t cause HIT (Heparin induced Thrombocytopenia), but can cause bleeding, not reversible by protamine.

Question 23

What are the pharmacokinetic parameteres of Unfractionated heparin?

Answer 23

Uncertain pharmacokinetics: unsure about how person will respond. aPTT needs to be monitored. should be 1.5-2.5x times longer than controlled value.

Question 24

What are the indications of Unfractionated heparin?

Answer 24

1. DVT, acute PE and arterial emboli
2. Prophylaxis of post-op venous thrombi and recurrent thromboembolism
3. MI and unstable angina
4. Anticoag therapy during pregnancy
5. Extracorporeal circulation

Question 25

What is a longer acting analouge than Fondaparinux?

Answer 25

Idraparinux - one s.c. injection/week