A-30. Drugs used in coagulation disorders II: Anticoagulant drugs

Question 1

What is Unfractionated Heparin and Low Molecular Weight Heparin

Answer 1

A negatively-charged glycosaminoglycan naturally produced by mast cells; endothelial cells release heaprin sulfate, the molecule with more in vivo action

Question 2

MOA of Unfractionated Heparin and Low Molecular Weight Heparin

Answer 2

binds to antithrombin III which accelerates its activity 1000x and bridges it with coagulation factors to facilitate thrombin and factor Xa inactivation
UFH (>18 monosaccharide units) inactivates both factors
LMWH (<18 monosaccharide units) inactivates mostly factor Xa

Question 3

Kinetics of LMWH and UFH

Answer 3

Both have poor oral absorption so Pareneral only, IV or SC
LMWH has a higher SC bioavailability and more stable serum levels
UFH binds endothelium, macrophages + plasma proteins so it has to bind these steady state (LMWH binds less)
Neither cross the placenta
UFH has 60-90 min half-life; LMWH 2-4 hours

Question 4

Indication of LMWH and UFH

Answer 4

1. ) DVT, PE and other arterial emboli
2. ) Prophylaxis- post-op to prevent venous thrombosis or recurrence of thromboemboli
3. ) ACS- for acute MI (after or without thrombolysis) and angina
4. ) Pregnancy- anticoagulant prophylaxis (warfarin is strictly contraindicated in pregnancy)
5. ) Extracorporeal circulation

Question 5

What is measured when taking LMWH and UFH

Answer 5

aPTT to measure intrinisic coagulation pathway function

• With UFH, the goal is 1.5-2.5x normal aPTT
• aPTT in not prolonged by LMWH

Question 6

Side effects with LMWH and UFH

Answer 6

Less frequent with LMWH

1. ) Bleeding- more with IV therapy, major bleeding 5% of the time and lethal in 1% of the time
2. ) Heparin-induced Thrombocytopenia (HIT)
   - Type I- occurs in 5-10%; reversible and transient in first 4 days of treatment
   - Type 2- Occurs in 0.5-3% of patients and is lethal in 20-30% of cases
3. ) Rare effects: hair loss, allergy, liver transaminase increased
4. ) At high doses: impaired aldosterone synthesis
5. ) WIth long-term treatment (3-6 months): osteoporosis

Question 7

Heparin-induced thrombocytopenia cause? HIT-II mechanism

Answer 7

antibody-mediated platelet aggregation leading to thromboemboli
HIT-II mechanism is where heparin binds PF4 from platelet surface and is bound by IgG leading to Ab-heparin-PF4 comple binding platelet Fc receptor and activating the platelet tills its removal by splenic macrophages

Question 8

How to reverse heparin action?

Answer 8

Protamine sulfate

A high basic positively charged protein which neutralizes heparin and partly neutralizes LMWH

Question 9

What is Fondaparinux and how does it work?

Answer 9

A synthetic pentasaccharide that binds antithrombin III leading to factor Xa inactivation only

Question 10

Kinetics and indication of Fondaparinux

Answer 10

Parenteral only (S.C. injection with 100% bioavailability; 16 hour half-life)
Indicated for DVT

Question 11

Side effects of Fondaparinux

Answer 11

Bleeding (no HIT, but also no protamine reversibility)

Question 12

Analogue druge of Fondaparinux and how often is it given?

Answer 12

Indraparinux, given once a week via S.C. injection

Question 13

Heparinoid drug

Answer 13

Danaparoid

Question 14

What is Danaparoid

Answer 14

A mixture of heparin sulfate, dermatan sulfate, and chondroitin sulfate

Question 15

Danaparoid MOA and kinetics

Answer 15

Stimulation of AT-III action leading to factor Xa inactivation
Kinetics: parenteral admin, s.c. injection; 100% bioavailable; 25 hr half-life

Question 16

Danaparoid indication and side effects

Answer 16

Indication: similar to heparin, for patients with HIT type II
Side effects: bleeding (not protamine-reversible)

Question 17

Direct Thrombin Inhibitor drugs (4)

Answer 17

Hirudin
Desirudin
Bivalirudin
Argatroban

Question 18

Hirudin and Desirudin 
MOA
Kinetics
Indication
Side effects

Answer 18

MOA is direct thrombin binding and inactivation
Kinetics: parenteral s.c. 100% bioavailable; kidney elimination; 1-1.5 hour half life
Indications: similar to heparin, for patients with HIT type II
-monitor with aPTT (target is 1.5-3x normal aPTT)
Side effect: bleeding (not protamine-reversible)

Question 19

Bivaliruidn structure and MOA?

What is the difference?

Answer 19

synthetic hirudin-like compound with same MOA
Faster onset, shorter DOA, only given IV for PCI procedures; cleared by proteolytic cleavage; kidney-independent elimination

Question 20

Argatroban details (4)

Answer 20

Synthetic thrombin inhibitor

short half-life; hepatic elimination; give IV in case of HIT type II

Question 21

Novel Oral Anticoagulants (NOACs)

Answer 21

Dabigatran etexilate, Apixaban, Rivaroxaban, Edoxaban

Question 22

Dabiatran etexilate
MOA?
Kinetics?
Antidote?

Answer 22

MOA: direct thrombin inhibition; orally-active prodrug converted to dabigatran
Kinetics: given 1-2x/day
Antidote: idarucizumab

Question 23

Apixaban, Rivaroxaban, Edoxaban
MOA
Kinetics
Indications
Antidotes

Answer 23

MOA: direct Xa inhibitors
Kinetics: given orally 2x/day
Indications
-DVT/PE prophylaxis- for knee/hip surgeries
-DVT/PE acute/chronic treatment
-Stroke/Embolism prevention- in patients with non-valvular atrial fibrillation
2 potential antidotes: adexanet-alfa (recombinant Xa) and ciraparantag

Question 24

Coagulation Factor Synthesis Inhibitors

Answer 24

Warfarin + related compounds ( all 4-OH-coumarin derivatives differing onl in potency and DOA)

Question 25

MOA of Warfarin

Answer 25

Inhibition of vit K epoxide reducation so factors II, VII, IX, and X can’t undergo y-carboxylation of Glu residues which is necessary for Ca2+ binding and incorporation into phospholipid membranes

Question 26

How long does coumarin derivatives delay lasts and antidote and may be required in severe cases

Answer 26

8-12 hour delay in their anticoagulant effet
Vitamin K can reverse the drug
fresh frozen plasma or factor concentrates in severe cases

Question 27

Kinetics of Warfarin

Answer 27

100% oral absorption, high plasma protein binding
crosses the placenta but doesn’t enter break milk
Liver metabolism via glucuronide conjugation with mostly urinary, partly bile, excretion

Question 28

Half lives of…
Acenocoumarol?
Warfarin?
Phenprocoumon?

Answer 28

Acenocoumarol-16 hours
Warfarin- 40 hours
Phenprocoumon- 150 hours

Question 29

Indications of coumarin

Answer 29

1. ) Continuation of heparin therapy- heparin given first, then taper off when warfarin takes effect
2. ) Thromboembolism prophylaxis- as in atrial fibrilllation

Question 30

Coumarin dosing and goal for PT/INR

Answer 30

Double doses are given for the first few days, then single for continuing therapy
Effects are monitored by prothrombin time with values given as INR (goal is 1.5-3 INR, or as low as 1.2 in prophylactic use)

Question 31

Side effects of Coumarin

Answer 31

1. ) Bleeding
   - minor in 10-20%; major in <5%; lethal in <1%;; high risk in INR>4
2. ) Fetal malformation/death
   - y-carboxylation reactions are important in bone formation; coumarins are stricly contraindications in pregnancy
3. ) Subcutaneous Tissue Necrosis
   - rare; may affect breast, fat, intestines, + limbs
   - synthesis of proteins C and S (have anticoagulant effects; also need on y carboxylation) is inhibited first due their short half-lives leading to early local thromboembolic complications

Rare side effects: allergy, GI symptoms, alopecia purple toe syndrome

Question 32

Interactions of coumarin

Answer 32

1. )Dietary/GI flora-produced vitamin K (affects serum vit K+ thus coumarin therapy)
2. )Antacids/Cholestyramine (inhibits coumarin absorption)
3. ) NSAIDS (compete for albumin binding)
4. ) CYP inhibitors (decrease coumarin metabolism)
5. ) CYP inducers
6. ) Pharmacodynamics interactions
7. ) Coumarin resistance (rare, due to VKOR mutation)
8. ) Coumarin sensitivity (polymorphorism of CYP2C9 causes decreased metabolism and higher serum coumarins, more prevelant in caucasians)

Question 33

CYP inhibitors decreasing coumarin metabolism

Answer 33

phenylbutazone, sulfinpyrazone, metronidazole, fluconazole, sulfonamide, amiodarone, disulfiram, and cimetidine

Question 34

CYP inducers increasing coumarin metabolism

Answer 34

barbiturates, refampin, carbamazepine, phenyton, griseofulvin

Question 35

Contraindications of coumarin

Answer 35

pregnancy, nurse, active bleeding or increased bleeding risk