Anticoagulation Drugs Flashcards
Serine proteases
cleave down-stream factors to activate them or cleave factors Va and VIIIa
Examples of serine proteases that cleave down-stream factors
Factors XII, XI, X, IX, VII, II (procoagulants)
Examples of serine proteases that cleave factors Va and VIIIa
protein C (anticoagulant)
Glycoproteins
co-factors for activation of proteases and they bind to and inhibit thrombin
Cofactors for activation of proteases
Factors VIII, V, III (tissue factor), Protein S
Glycoproteins that bind to and inhibit thrombin
Anti-thrombin III
Ca2+
links certain factors to anionic lipids
Transglytaminase
cross-links fibrin fibers (Factor XIII)
Fibrinogen/Fibrin
ultimately, the substrate protein for factor IIa (thrombin) that polymerizes to form clot
Hemophilia A
deficiency in factor VIII (males)
Hemophilia B
deficiency in factor IX (males)
Factor V Leiden
resistance to activated protein C
Where are clotting factors produced?
all except for von Willebrand factor are made in the liver; vWF is produced in the endothelium, subendothelium, and megakaryocytes; Factor VIII is also produced in the endothelium
Extrinsic pathway
requires a factor (Tissue Factor) extrinsic to the blood; important when vessel is damaged and blood leaks out
Intrinsic pathway
triggered when collagen is exposed on the wall of the blood vessel
Intrinsic pathway is initiated by
contact with negatively charged collagen of diseased or injured vessels; blood in test tube clots by this mechanism
Extrinsic pathway relies on
factors outside bloodstream for activation; release of tissue thromboplastin initiates pathway
Describe the steps in the activation of the extrinsic pathway to coagulation
- TF is expressed on the surface of cells outside of but near blood vessels
- Factor VII normally resides in blood
- TF binding to factor VII activates it
- Factor VIIa binds and cleaves factor X
Describe the steps in the activation of the intrinsic pathway to coagulation
- Factor XIIa cleaves prekallikrein to kallikrein and Factor XI to XIa
- Kallikrein activates more Factor XII molecules to XIIa
- HMWK anchors kallikrein and Factor XIa to damaged surface
- Factor XIa cleaves HMWK, diffuses into circulation, and activates Factor IX
- Factor IXa binds Factor VIIIa on the surface of platelets and activates Factor X
What does thrombin do?
Thrombin converts fibrinogen into long strands of insoluble fibrin; activates factor XIII which then cross-links fibrin to form a stable clot incorporated into platelet plug
Prothrombin time (PT)
recalcified blood + thromboplastin - clots in 12-14 sec; used to monitor oral anticoagulant therapy
Activated partial thromboplastin time (aPTT)
recalcified blood + phospholipid - clots in 24-36 sec; used to monitor heparin therapy
Bleeding time
time taken for a standardized skin puncture to stop bleeding; measured in minutes (2-9 minutes); abnormal when defect in platelet numbers of function
Slow PT (prolonged time) means
defect in extrinsic or common coagulation pathways (oral coagulants)
Slow aPTT (prolonged time) means
defect in intrinsic or common coagulation pathways (heparin)
INR
standardization of PT - International Normalization Ratio
Equation for INR
(Patient PT/Control PT) ^C
C is the international sensitivity index (isi); corrects for different thromboplastin reagents
Therapeutic range for the INR
PT ratio of 1.35 - 1.6 = INR of 2-3
Why use anticoagulants?
prevent excessive clotting that can lead to occlusion of blood vessels: stroke, post MI, unstable angina, DVT, PE, artificial surfaces
Oral anticoagulant drugs
Warfarin (Coumadin) and Anisindione
Indandione anticoagulants
orally active; exhibit significant side effects; rarely used clinically
MOA of oral anticoagulants
inhibit reduction of vitamin K
Vitamin K is essential for
post-translation modification of clotting factors VII, IX, X, prothrombin (II) and anticoagulation proteins C and S
Action of Vitamin K
Vitamin K carboxylase catalyzes the gamma-carboxylation of Glu in prothrombin; Vit K is oxidized in the process
Coumarins inhibit
Vit K epoxide reductase, thus blocking reduction of Vit. K epoxide back to its active form
Warfarin onset of action
delayed onset of action; must deplete the pool of circulating clotting factors; maximal anticoagulant effect is not observed until 3-5 days after initiation of therapy
Loading/Maintenance dose of Warfarin
Loading dose: 5 mg/day
Maintenance dose: 2.5 or 5 mg/day
What happens after discontinuing warfarin therapy
factors must be re-synthesized to return to normal PT (several days)
Metabolism of warfarin
metabolized in liver by CYP2C9 (S-warfarin)
Termination of action of warfarin is related to
termination of action is not correlated with plasma warfarin levels, but reestablishment of normal clotting factors
Overdose of warfarin therapy
Iatrogenic hemorrhage; discontinue warfarin therapy; administer Vit K
What can high levels of Vit K do?
can activate warfarin-inhibited reductase
Warfarin use during pregnancy
contraindicated in women who are or may become pregnant; warfarin passes freely thru placenta; increased incidence of spontaneous abortions; fetal hemorrhage; birth defects
Fetal warfarin syndrome
nasal hypoplasia and abnormal bone formation
Vitamin K involved in the post-translation modification of
prothrombin, factors VII, IX, and X
Uses of Vitamin K (Phytonadione)
individuals with abnormalities of fat absorption (vit K deficiency); all newborns receive an injection to prevent hemorrhagic disease; reverse anticoagulant effect of excess warfarin
Parenteral anticoagulants
heparin (unfractionated heparin); low molecular weight heparins; non-heparinoids
MOA of heparin
heparin binds to a positively charged region of antithrombin III; (AT) heparin binding greatly increases the rate at which AT interacts with plasma protease clotting factors; heparin then dissociates from complex and can interact with more AT
What does binding of heparin do?
enhances the rate of inhibition of clotting factors
Antithrombin III (AT) can inactivate
thrombin and factors Xa, VIIa, and IXa
Administration of heparin
effective immediately; intermittent IV injection; continuous IV infusion - easiest to control SC injection
When do you adjust heparin dosing based on
adjust dosing according to coagulation tests
Adverse effects of heparin
Iatrogenic hemorrhage; thrombocytopenia; osteoporosis
Risk factors for iatrogenic hemorrhage
patients over 50, ulcer patients, severe hypertension, antiplatelet drugs
Treatment for iatrogenic hemorrhage due to heparin
stop heparin; protamine sulfate - binds tightly to heparin to neutralize the anticoagulant action
Protamine sulfate
binds tightly to heparin to neutralize the anticoagulant aciton
Thrombocytopenis and heparin
develops 7-12 days after starting therapy; antibodies develop to platelet (PF4) - heparin complex
Osteoporosis and heparin
associated with extended therapy (3-6 months)
Low molecular weight heparins
Dalteparin, Enoxaparin, Tinzaparin, Danaparoid
Compare standard heparin to LMWH
equal efficacy; LMWH has increased bioavailability from SQ site of administration (only route); LMWH has less frequent dosing and a longer half life; no monitoring of clotting needed with LMWH
MOA of LMW heparins
binding to AT is sufficient for Factor Xa inhibition; preferentially inhibit Factor Xa; only slightly affect thrombin activity; PT and aPTT are insenstivie measures of activity
Advantages of LMWH
more predictable pharmacokinetic profile; good bioavailability fro SQ injection site; less protein binding/more uniform dosing; longer half life; lower incidence of thrombocytopenia and osteoporosis
Fondaparinux sodium
Factor Xa inhibitor; synthetic sulfated pentasaccharide
Fondaparinux sodium MOA
indireclty inhibits factor Xa by selectively binding AT
Uses of Fondaparinux sodium
venous thromboembolism; acute DVT; PE; prophylaxis in patients undergoing hip fracture surgery, hip replacement, knee replacement or abdominal surgery
Thrombocytopenia and fondaparinux sodium
low potential for thrombocytopenia; action not reversed by protamine sulfate!!
Rivaroxaban (Xarelto)
Factor Xa inhibitor; treatment/prevention of VT and PE; prevention of thrombosis in NV atrial fibrillation
Apixaban (Eliquis)
Factor Xa inhibitor; prevention of thrombosis in NV atrial fib
Both Rivaroxaban and Apixaban need dose reduction in which patients?
dose reduction in patients with impaired renal function; increased risk of stroke upon discontinuation
Edoxaban (Savaysa) used for
treatment of VT and PE after 5-10 days with parenteral anticoagulant; prevention of thrombosis in NV atrial fib
Edoxaban is not used in patients with
impaired renal excretion; patients with creatinine clearance greater than 95 ml/min
Risks with Edoxaban
increased risk of ischemic events upon premature discontinuation; risk of hematoma/paralysis in patients undergoing spinal puncture or epidural anesthesia
Direct thrombin inhibitors/Non-heparinoid parenteral agents inhibit
free thrombin and fibrin-bound thrombin; do not act through AT-III
Hirudin
peptide from saliva gland of medicinal leach
Desirudin (Iprivask)
recombinant hirudin grown in yeast; highly specific direct irreversible inhibitor of thrombin; no effect on AT; aPTT values increase dose-dependently; can produce hypersensitivity reactions
Bivalirudin (Angiomax)
direct thrombin inhibitor; reversible binding to catalytic site of thrombin; given IV during PCI; eliminated by renal excretion; low risk of bleeding doesn’t induce antibody formation
Argatroban
direct thrombin inhibitor; binds reversibly to the active site of thrombin; doe snot require AT for activity; can inhibit free and clot-associated thrombin; metabolized in liver (CYP3A4/5)
Argatroban is approved for
prophylaxis or treatment in patients with heparin-induced thrombocytopenia
Dabigatran (Pradaxa)
orally adminstered direct thrombin inhibitor; indicated for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
What is Dabigatran etexilate
the prodrug that gives rise to dabigatran upon ester hydrolysis
