A-30. Drugs used in coagulation disorders II: Anticoagulant drugs Flashcards
What is Unfractionated Heparin and Low Molecular Weight Heparin
A negatively-charged glycosaminoglycan naturally produced by mast cells; endothelial cells release heaprin sulfate, the molecule with more in vivo action
MOA of Unfractionated Heparin and Low Molecular Weight Heparin
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
Kinetics of LMWH and UFH
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
Indication of LMWH and UFH
- ) DVT, PE and other arterial emboli
- ) Prophylaxis- post-op to prevent venous thrombosis or recurrence of thromboemboli
- ) ACS- for acute MI (after or without thrombolysis) and angina
- ) Pregnancy- anticoagulant prophylaxis (warfarin is strictly contraindicated in pregnancy)
- ) Extracorporeal circulation
What is measured when taking LMWH and UFH
aPTT to measure intrinisic coagulation pathway function
- With UFH, the goal is 1.5-2.5x normal aPTT
- aPTT in not prolonged by LMWH
Side effects with LMWH and UFH
Less frequent with LMWH
- ) Bleeding- more with IV therapy, major bleeding 5% of the time and lethal in 1% of the time
- ) 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 - ) Rare effects: hair loss, allergy, liver transaminase increased
- ) At high doses: impaired aldosterone synthesis
- ) WIth long-term treatment (3-6 months): osteoporosis
Heparin-induced thrombocytopenia cause? HIT-II mechanism
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
How to reverse heparin action?
Protamine sulfate
A high basic positively charged protein which neutralizes heparin and partly neutralizes LMWH
What is Fondaparinux and how does it work?
A synthetic pentasaccharide that binds antithrombin III leading to factor Xa inactivation only
Kinetics and indication of Fondaparinux
Parenteral only (S.C. injection with 100% bioavailability; 16 hour half-life) Indicated for DVT
Side effects of Fondaparinux
Bleeding (no HIT, but also no protamine reversibility)
Analogue druge of Fondaparinux and how often is it given?
Indraparinux, given once a week via S.C. injection
Heparinoid drug
Danaparoid
What is Danaparoid
A mixture of heparin sulfate, dermatan sulfate, and chondroitin sulfate
Danaparoid MOA and kinetics
Stimulation of AT-III action leading to factor Xa inactivation
Kinetics: parenteral admin, s.c. injection; 100% bioavailable; 25 hr half-life
Danaparoid indication and side effects
Indication: similar to heparin, for patients with HIT type II
Side effects: bleeding (not protamine-reversible)
Direct Thrombin Inhibitor drugs (4)
Hirudin
Desirudin
Bivalirudin
Argatroban
Hirudin and Desirudin MOA Kinetics Indication Side effects
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)
Bivaliruidn structure and MOA?
What is the difference?
synthetic hirudin-like compound with same MOA
Faster onset, shorter DOA, only given IV for PCI procedures; cleared by proteolytic cleavage; kidney-independent elimination
Argatroban details (4)
Synthetic thrombin inhibitor
short half-life; hepatic elimination; give IV in case of HIT type II
Novel Oral Anticoagulants (NOACs)
Dabigatran etexilate, Apixaban, Rivaroxaban, Edoxaban
Dabiatran etexilate
MOA?
Kinetics?
Antidote?
MOA: direct thrombin inhibition; orally-active prodrug converted to dabigatran
Kinetics: given 1-2x/day
Antidote: idarucizumab
Apixaban, Rivaroxaban, Edoxaban MOA Kinetics Indications Antidotes
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
Coagulation Factor Synthesis Inhibitors
Warfarin + related compounds ( all 4-OH-coumarin derivatives differing onl in potency and DOA)
MOA of Warfarin
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
How long does coumarin derivatives delay lasts and antidote and may be required in severe cases
8-12 hour delay in their anticoagulant effet
Vitamin K can reverse the drug
fresh frozen plasma or factor concentrates in severe cases
Kinetics of Warfarin
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
Half lives of…
Acenocoumarol?
Warfarin?
Phenprocoumon?
Acenocoumarol-16 hours
Warfarin- 40 hours
Phenprocoumon- 150 hours
Indications of coumarin
- ) Continuation of heparin therapy- heparin given first, then taper off when warfarin takes effect
- ) Thromboembolism prophylaxis- as in atrial fibrilllation
Coumarin dosing and goal for PT/INR
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)
Side effects of Coumarin
- ) Bleeding
- minor in 10-20%; major in <5%; lethal in <1%;; high risk in INR>4 - ) Fetal malformation/death
- y-carboxylation reactions are important in bone formation; coumarins are stricly contraindications in pregnancy - ) 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
Interactions of coumarin
- )Dietary/GI flora-produced vitamin K (affects serum vit K+ thus coumarin therapy)
- )Antacids/Cholestyramine (inhibits coumarin absorption)
- ) NSAIDS (compete for albumin binding)
- ) CYP inhibitors (decrease coumarin metabolism)
- ) CYP inducers
- ) Pharmacodynamics interactions
- ) Coumarin resistance (rare, due to VKOR mutation)
- ) Coumarin sensitivity (polymorphorism of CYP2C9 causes decreased metabolism and higher serum coumarins, more prevelant in caucasians)
CYP inhibitors decreasing coumarin metabolism
phenylbutazone, sulfinpyrazone, metronidazole, fluconazole, sulfonamide, amiodarone, disulfiram, and cimetidine
CYP inducers increasing coumarin metabolism
barbiturates, refampin, carbamazepine, phenyton, griseofulvin
Contraindications of coumarin
pregnancy, nurse, active bleeding or increased bleeding risk
