Pharmacology of Hemostasis Flashcards

Terms Definitions
Arterial thrombosis
turbulent flow, endothelial damage leads to adherence of platelets to collagen in the vessel walls.  Secondary activation of platelets leads to further aggregation.
venous thrombosis
Stasis of blood, inflammation, or factors from damaged cells directly activates the coagulation cascade leading to thrombosis
arterial thrombosis occurs most commonly due to damage of endothelium of arteries by:
atherosclerotic plaques
surgical injury to vessels
Glycoprotein IIb/IIIa inhibitors
acute inhibition of platelet aggregation by blockade of platelet membrane fibrinogen receptors
 
used to prevent thrombosis following PCI and to treat ACS
Glycoprotein IIb/IIIa inhibitors: mechanism of action
fibrinogen has two IIb/IIIa binding sites
Gp IIb/IIIa is an integrin w/ αIIb/β3 chains
inihibition blocks fibrinogen binding and results in immediate blockade of platelet fxn
Must be given parenterally (too large to be absorbed)
Abciximab
monoclonal antibody
binds to IIb/IIIa and sterically interferes w/ fibrinogen binding
given by bolus injection followed by infusion
immediate onset of action, persists for 1-2 days
prevent PCI thrombosis and unstable angina
bleeding is the main complication
Eptifibatide
peptide
binds to IIb/IIIa and competes w/ fibrinogen
parenterally by bolus + infusion
rapid onset of action but cleared so rapidly it is only effective during infusion
used in both PCI and unstable angina
bleeding is main side effect
Low dose aspirin therapy
most commonly used strategy for reducing risk of arterial thrombosis in patients at risk for MI and stroke
Aspirin (mechanism of Action)
irreversible inhibitor of COX, when low dose it preferentially blocks platelet production of thromboxane A2 w/o inhibiting endothelial prostacyclin I2
net effect: inhibit platelet activation and decrease platelet function
endothelial cells have nucleus so can regenerate COX de novo, but platelets cannot
aspirin indications
once-a-day low dose for inc risk of arterial thrombi
coronary artery disease
cerebral artery atherosclerosis (TIA risk)
arterial prosthesis or damaged endothelium
aspirin pharmacokinetics
60-160 mg per day
ASA anti-platelet activity lasts for 1-2 weeks
Clopidogrel
anti-platelet drug for patients w/ ACS, vascular disease and PCI
Clopidogrel facts
inhibits ADP receptor thus ADP-dependent platelet aggregation
used as an alternative or in combo w/ ASA
SE: bleeding when used in combo w/ ASA
ORAL for long term therapy
For acute situations, give a loading dose
Fibronolytic therapy indications
For acute arterial thrombosis
must be given by IV infusion and only lasts for an hour or so
 
Frequently used in combo w/ anti-platelets/coags
tPA
protease normally produced by endothelium
binds to fibrin and activates plasminogen
selective for plasminogen bound to fibrin
used for acute MI and stroke
IV prep
cleared in 5-10 mins, can stay bound to fibrin clot for hours
SE: hemorrhage!
Streptokinase
produced by b-hemolytic strep that promotes activation of plasminogen
binds to free or bound plasminogen and auto-activates it
increases risk of hemorrhage
Many patients have antibodies to it so must give a loading dose then IV infusion
40-80 min half life
Antistreplase
combo of streptokinase + modified plasminogen that preferentially binds to fibrin clots
Urokinase
plasminogen activator secreted by renal epithelial cells
 
non-selective and expensive
Aminocaproic acid
antidote to excessive fibrolysis
 
inhibits plasminogen binding to fibrin
Heparin: structure and source
sulfated proteoglycan
produced by mast cells
high molecular weight polymers
heparin: mechanism of action
binds to anti-thrombin, increasing its activity
causes immediate inhibition of coagulation cascade
blocks extrinsic (IXa, Xa, IIa)
blocks intrinsic (XIa, XIIa, kallikrein
heparin: pharmacokinetics
given parenterally (LMWH via subcutaneous)
onset is immediate, cleared rapidly
does NOT cross the placenta
Goal of therapy is 1.5 - 2.5x normal PTT
heparin side effects
hemorrhage is most common
immune thrombocytopenia in longterm therapy
low molecular weight heparins
fondaparinux - synthetic heparin that blocks factor Xa inhibition --> good for long-term prophylaxis
Enoxaparin - improved thrombokinetics
Subcutaneous admin used prophylactically in hospitalized patients
Factor Xa antagonists
Rivaroxaban is a direct inhibitor
 
given ORALly for long-term anti-coagulation
 
prevents DVT
Warfarin
anti-coagulant used in long-term management
Warfarin: structure and source
Vit K is a co-factor in synthesis of several coagulation factors.  Warfarin is an inhibitor of Vit K activity.
Warfarin: mechanism of action
Factors VII, IX, X, II are modified by adding γ-carboxy groups to glutamate residues
Vitamin K is a co-factor in this reaction
after rxn vit K needs to be converted back by a reductase enzyme
Warfarin is a competitive inhibitor of this reductase
depletes active vitamin K
Warfarin: pharmacokinetics
taken ORALly for long-term therapy
onset of delay, so full effects not present til a week after starting therapy
goal is to increase INR to 2-3x goal
crosses the placenta
warfarin: drug metabolism
metabolized by CYP2C9
 
some patients have variants that make them more or less susceptible to therapy so need to do a diagnostic test before giving medicine
Warfarin: drug interactions
bad interaction if taking drugs that effect vit K, protein binding, or warfarin metabolism
antibiotics deplete Vit K, thus ↑warfarin action
drugs that increase hepatic microsomal enzymes (barbiturates) decrease warfarin anti-coagulation
if they displace warfarin from proteins it will increase warfarin activity
Warfarin: indications
Long term anti-coagulation
pulmonary embolism 2° to thrombophlebitis
chronic a-fib
prosthetic valves, stents, vessel grafts
it is TERATOGENIC
Warfarin: side effects
hemorrhage and necrotic ulcers of skin
warfarin: antidote
reversed by administration of vitamin K
 
in emergency can infuse fresh plasma or clotting factors
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