anticoagulants Flashcards
heparin (unfractionated) physical properties
1, heterogenous mixture of sulfated polysaccharides
2, highly negatively charged because of multiple sulfate and carboxylic acid residues
3, comes from porcine intestine
MOA heparin
- no intrinsic anticoagulant properties
- catalyzes antithrombin, the inhibition of several coagulation factors
- antithrombin- from liver is the protease that inhibits thrombin, Xa, IXa, a suicide substrate 1:1 ratio
- binding of heparin induces a conformational change in antithrombin, making reactive site more accessible
- heparin increases the rate of thrombin-antithrombin rxn 1000 fold. Thrombin has an active site and 2 secondary binding exosites. Exosite 1 is the dock for substrates such as fibrin to promote orientation for active site binding, exosite 2 is the heparin binding domain
- does not affect the synthesis of clotting factors
low molecular weight heparin
less effective catalyst to inhibit thrombin by anti thrombin
both heparin and LMWH catalyze the inhibition of Xa by anti thrombin
absorption and metabolism of heparin
not absorbed from the GI tract (due to size an polarity), given IV or SubQ
does not cross the plasenta, so anticoagulatnt of choice in pregnancy
immediate onset of action when given IV- more variable with subQ.
t.5 in plasma depends on dose administration
cleared by reticuloenothelial system and liver
activated PTT should be 1.5 to 2.5 times
adverse reactions
bleeding major adverse reaction
Heparin- induced thrombocytopenia (higher in surgical patients with venous thromboembolism, IgG antibodies develop against heparin-IV, heparinIV bind to FcIIa receptor-> platelet aggregation
contraindication of heparin
Active bleeding, recent surgery-intracranial/sp cd/eye, severe uncontrolled hypertension
therapeutic/clinical indications of heparin
- initial treatment of deep venous thrombosis or pulmonary embolism
- initial management of unstable angina or acute MI during or after coronary angioplastyl or stent placement, or during surgery requiring cardiopulmonary bypass
- low dose heparin used prophylactically to prevent DVT and thromboembolism
- hemodialysis in blood samples drawn for lab analysis and to maintain patency of indwelling arterial catheters
- anticoagulation during pregnancy
enoxaparin
low molecular weight heparin
MOA: no intrinsic anticoagulant property, LMWH potentiates Xa inhibition by antithrombin than thrombin inhibition bc of the length
Pharmacokinetics: not absorbed, given parenternally, abbsorbed more uniformly when SubQ, longer half life 4-6 hrs, cleared almost exclusively by kidney (contra indicated in renal impairment)
Adverse E: bleeding is less, thrombocytopenia
Contraindicated: active bleeding, recent surgery (intracranial, sp cd, eye), severe uncontrolled HTN, reneal impairment
Clinical use- acute DVT, prophylaxis of DVT, acute unstable angina and MI, hip replacement surgery
fondaparinux
selective factor Xa inhibitor
MOA: no intrinsic anticoagulant properties, synthetic pentasaccharide that causes antithrombin mediated selective inhibition of Xa
Pharmacokinetics: sub Q, reaches peak in 2 hours excreted in urine, t.5- 17hr, contraindicated in renal failure
Adverse effectsL bleeding, hemorrage,but less likely than heparan, less likely to induce thrombocytopenia
ContX: active bleeding, recent surgery, sever uncontrolled HTN, renal impairment
Clinical use: prophylaxis of DVT for hip surgery, knee surgery, abdominal surg, pulmonary embolism, acute DVT without PE and given to pts with a Hx of heparin-induced thrombocytopenia
bivalirudin
direct thrombin inhibitor
MOA: occupies catalytic site of thrombin, occupies exosite 1, thrombin slowly cleaves bivalirudin so thrombin will slowly regain activity
Pharmacokinetics: IV and excreted by kidney, t.5=25 min
Adverse effects: bleeding, ConX in renal failure, active bleeding recent surg, seever uncontrolled HTN
used as an alternative to heparin in pts undergoing coronary angioplasty or cardiopulmonary bypass surgery
advantage of using bivalirudin compared to lmwh and heparin: activation of circulating and fibrin bound thrombin
protamin sulfate
heparin antagonist
- low molecular weight, positively charged derived from fish sperm
- high affinity for negative heparin (1:1 ratio)- inactive heparin
- weak anticoagulant properties if used alone in high doses
- may cause anaphylactic reaction w/ bradycardia, cutaneuous vasodilation and hypotension. seen in pt with fish hypersensitivty, previous protamine exposure in insulin products
- may result in severe pulmonary HTN
- used most commonly to reverse heparin following cardiopulmonary bypass
warfarin physical properties
Physical properties: fat soluble derivative of hydroxycoumarin, structural naolog of vitK
warfarin MOA
vitamin k antagonist
reduced Vitamin k is required for activating 2, 7, 9, 10 via y carboxylation–> Ca binding site
vitamin k comes from diet to liver
reduced vitamin k-> oxidized vitamin k-> y carbosylation
Warfarin interferes w/ post translational modification of vitamin k-dependent clotting factors (2,7,9,10) by inhibiting VKORC1, trapping vit K in oxidized form (cant be recycled to reduced form)
competitive inhibition via vitamin k infusion
therapeutic effect of warfarin
delayed for several hours to days
circulating clotting factors are not affected, results in an altered balance between rate of inhibition of modification and rate of degradation of factor 2 7 9 10
kinetics of pharmacological effect is dependent on the half lives of existing clotting factors
absorption and metabolism of warfarin
rapidly and completely absorbed after oral admin, bound to albumin, converted to inactive metabolites by liver cyp 450 mediated
adverse reactions and contraindications of warfarin
bleeding (increases with intensity and duration)
CYP2C9 polymorpphisms
genetic variations in vitamin K receptor variation
crosses the placenta, contraindicated in pregnancy
liver or kidney disease or vit K deficiency
warfarin-induced skin necrosis (rare)
reversal of warfarin
minor bleeding may treated w/ discontinuation
vitamin k administration (can take a few days bc factor 2 7 9 10 must be synthesized)
immediate reversal of warfarin requires admin of active clotting factors
reversal of anticoagulant effects of warfarin is correlated with reestablishment of normal clotting factor activity (not warfarin concentration)
food interaction of INR
increase INR: cranberries, grapefruit juice, alcohol, vitamin E
decreased INR: green leafy veg, green rea, soybean, vit K
inr= time for blood to coagulate
indication of warfarin
long term trt of venous thromboembolitic disease
prophylaxis against thromboembolis in A-fib, pts w/ prosthetic heat valves or w/ dilated cardiomyopathy
genetic poly morphisms of warfarin
cyp2c9 affect warfarin pharmacokinetics (*2 and *3 need reduced dose)
vkorc1 variants affect warfarin pharmacodynamics (A clade need lower warfarin bc have less VKORC1) (B clade have higher expression and need higher dose)
Dabigatran
MOA: prodrug converted invivo
a specific reversible direct thrombin inhibitor (inhibits both free and fibrin bound thrombin)
inhibits coagulation by preventing thrombin-mediated effects (cleavage of fibrinogen to fibrin, activation of 5 8 11 and 13, and inhibition of thrombin induced platelet aggregation
the ability to inhibit fibrin bound thrombin is an advangtage of dabigatran over the heparin (bound thrombin can continue to trigger thrombus expansion)
dabigatran has little effect on prothrombin time or INR even at therapeutic concentration
pharmacokinetics of dabigatran and adverse effects, antidote, uses
orally active prodrug, esterases activate it, plasma peak at 2 hrs, t.5= 14-17 hrs
eliminated mainly by kidney (80% drug excreted unchanged)
dont coadminister with inducers of pgp. will decrease dabigatran
SE: bleeding for renal function
antidote: idarucizumab
not metabolized by cyp450 so not many interactions
indicated: post op thomboprophylaxis total hip or knee surgery, prevention of stroke and systemic embolism in pt with nonvalvular atrial fibrilation
Rivaroxaban
and apixaban
riva: inhibits free and clot associated factor Xa platelet and fibrin formation are supressed
a small molecule that binds directly and reversibly to 10 a has 4 subpockets (S1 is the major component)
factor Xa catalyzes the conversion of prothrombin to thrombin
apixaban- inserts into s1 and s4, f=.5, plasma peak 1-3 hour, cleared kidney unchanged amd hepatic 3a4, dose reduced in 80ys, >60 kg, serum creatinine of 1.5 mg/dl or higher, uses P-gp
Rivaroxaban: plasma peak 2-4 hours after oral admin and t.5=5-9 hours, dual elimination (unchanged by kidney, and 2/3 hepatic CYP 3a4 and metabolized in urine and feces) dose reduction with decreased renal function, uses P-gp transproter
SE of both: bleeding, lower than other anticoagulants, Pgp inducers/inhibitors caution
use for risk of stroke and systemic embolism in pt with nonvalvular atrial fibrilation, prohylaxis of DVT in pt w/ hip or knee replacement
no antidote
