Pharm: Heparin Anticoagulants Flashcards
Describe where heparin is found naturally within the body
Found in mast cell granules with histamine and serotonin
Describe the chemical structure of heparin
Strongly acidic mucopolysaccharide with repeating units of sulfated glucuronic acid and sulfated glucosamine
Describe the size of heparin
Heterogenous
Molecular weight varies between 2kDa and 40kDa
What is the mechanism of action of heparin?
Inhibits action of Xa, IIa, XIIa, Xia (2,10,11,12)
by binding to ATIII and increasing ATIII affinity for these factors
What are the actions of heparin?
Plasma clearing
Neutralization of vascular lining
Release of tissue factor pathway inhibitor (TFPI)
What is the route of administration of heparin?
IV or subcutaneous
Not absorbed orally or rectally
How is heparin therapy monitored?
Heparin therapy is carefully monitored using APTT
Target APTT is 2-2.5x baseline
How is heparin metabolized?
25% excreted in urine
Some metabolized in liver by heparinases
Mast cells take up heparin
Endothelium binds heparin
Describe the pharmacokinetics of heparin
PK of heparin is dose dependent
Higher doses, longer half life
What are the endogenous modulators of heparin action?
ATIII
Heparin cofactor II
Tissue factor pathway inhibitor (TFPI)
Platelet factor 4 (PF4)
What are the side effects of heparin?
Hemorrhagic complications
Heparin induced thrombocytopenia
Osteoporosis –> fracture risk
Alopecia (loss of hair)
What are the clinical uses of heparin?
Therapeutic, surgical and prophylactic ANTICOAGULATION
Unstable angina
Adjunct therapy with thrombolytic drugs
Thrombotic and ischemic strokes
What is the antagonist of heparin?
Protamine: very basic protein derived from fish sperm
Combines with heparin to form stable salt with no anticoagulant activity
1:1 antagonism
Describe the structure of chemically synthesized heparin
Composed of pentasaccharide
Mimics the sequence repeats found in natural heparin in order to maintain ATIII interaction
How does the bioavailability of LMW heparin differ from native heparin?
LMW heparin has 100% bioavailability unlike native heparin which has ~30% bioavailability
What are the clinical advantages of LMW heparin
Better bioavailability, longer duration of action, less bleeding, lesser thrombocytopenia
What are the clinical uses of LMW heparin
DVT: Prophylaxis and treatment
Acute coronary syndromes management
Anticoagulation during procedures
What are antithrombin concentrates clinically used for?
Congenital antithrombin deficiency
Sepsis and DIC
What is hirudin?
A thrombin inhibitor derived from leaches
Used for anticoagulation in thrombocytopenic patients
What is argatroban?
A synthetic anti-thrombin agent used as an anticoagulant alternative to heparin for patients with heparin induced thrombocytopenia
What is bivalirudin?
A synthetic antithrombin that is a combination of hirudin and a tripeptide
used for anticoagulation during stent placement and angioplasty
What is fondaparinux?
Pentasaccharide
Complexes with ATIII in order to inhibit factor Xa
Used for management of DVT
What is the most common side effect of heparin and related drugs?
Bleeding
What is the mechanism of action of argatroban, bivalirudin and hirudin?
Directly inhibits IIa (thrombin)
What is the main oral anticoagulant prescribed in the US?
Warfarin
What are the clinical uses of warfarin?
Prophylaxis for thrombotic disorders
Treatment of established thrombus
What class of drugs does warfarin belong to?
Vitamin K antagonists (VKAs)
What coagulation factors does warfarin act on?
II, VII, IX, X
Warfarin is an analogue of _________
Vitamin K
Warfarin and Vit K have similar chemical structures
What is the mechanism of action of warfarin?
Inhibit II, VII, IX, X by preventing carboxylation of glutamic acid, thus preventing Ca2+ binding
What is the route of administration for warfarin?
Oral
Is warfarin plasma bound?
Yes, 97% bound to albumin
This gives warfarin a long half life
How is warfarin metabolized?
Liver: hydroxylated in hepatic ER into inactive compound
What lab test is used to monitor warfarin therapy?
PT is used to monitor warfarin and its effect on the extrinsic pathway
How is INR calculated?
INR is a normalized PT value
INR = PT_patient / PT_normalcontrol
What factors effect the dose of oral anticoagulants?
Nutrition, anemia, liver disease, biliary obstruction, drugs
What are the main drug-drug mechanisms leading to potentiation of warfarin’s effect?
Causing vit K deficiency (ABX) Displacing warfarin from albumin Decreasing clotting factor synthesis Decreasing metabolism Antiplatelet aggregating properties
What are the main drug-drug mechanisms leading to inhibition of warfarin’s effect?
Decreasing absorption of warfarin
Increasing metabolism of warfarin
What are the main side effects of warfarin?
Bleeding due to hypoprothrombinemia (ecchymoses, purpura, hematuria, hemorrhage)
Is warfarin safe to give to pregnant women?
No. Warfarin passes the placental barrier and can cause fetal malformation
How does warfarin cause necrosis?
Impaired functionality of protein C due to inhibition of gamma carboxylation of glutamic acid
What is the treatment of warfarin overdose?
- Replacement of factors II, VII, IX, X via whole fresh blood infusion or frozen plasma
- Recombinant factor VIIa
- Vitamin K
What are the therapeutic uses of vitamin K?
- Antidote for drug-induced hypoprothrombinemia
- Intestinal disorders and surgery
- Hypoprothrombinemias in newborns
What are the anti-Xa drugs?
Apixaban
Edoxaban
Rivaroxaban
What are the interactions with anti-Xa drugs?
Anti-Xa drugs are potent CYP3A4 inhibitors
What is the target of Dabigatran?
Factor IIa (thrombin)
Do the new oral anticoagulants require coagulation monitoring?
No.
What is a contraindication for dabigatran?
Renal failure
Dabigatran is 100% cleared by the kidney
What class of drugs does dabigatran interact with?
Proton pump inhibitors
What are the indications for the anti-Xa drugs?
Stroke prevention in AFib patients
Prophylaxis of DVT
What is the indication for dabigatran?
Stroke prevention in AFib patients
