B3.087 - Anticoagulant Therapies COPY Flashcards
why do clots form
- turbulence in blood flow
- abnormalities of surface in contact with blood
- abnormalities in clotting factors
what are conditions with abnormal clotting factors
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
antiphospholipid antibody syndrome
what are the general classes of drugs that treat hemostasis disorders
platelet inhibitors
anticoagulants
thrombolytic drugs
Drugs for bleeding disorders
what do TxA2 and ADP do in primary hemostasis
platelet granule release reaction
what are the antiplatelet drugs
Abciximab Tirofiban Aspririn Ticlopidine Clopidogrel
what is acetylsalicylic acid
aspirin
what does aspirin do
inhibits synthesis of thromboxane A2 by irreversible acetylation of cyclooxygenase COX 1 in platelets
what does thromboxane A2 do
potent mediator of platelet aggregation and degranulation and promotes vasoconstriction
what is aspirin used for
prevents and reduces risk of MI and recurring transient ischemic attacks
how does aspirin work
irreversibly inactivates COX-1; TXA2 end product causes platelet activation and vasoconstriction which is prevented here
what does COX2 do
is in endothelial cells and is inhibited by aspirin and by COX 2 inhibitors; PGI2 causes platelet inhibition and vasodilation
when do you see effects of aspirin
1-2 days after administration and lasts the duration of the platelet life span (7-10 days)
why does wiping out the COX1 affect platelets more than other cell types
they have no nucleus so they cant make new proteins in response, so the effects are seen until the platelets die and are replaced
what type of drug is ticlopidine and how does it work
ADP antagonist, inhibits ADP receptors on platelets which prevents activation of GPIIb-IIIa
what is ticlopidine indicated for
alternative to aspirin to prevent an initial or recurrent thromboembolic stroke and MI thromboembolic stroke
how is ticlopidine administered
orally, bioavailability 80%
adverse effects of ticlopidine
nausea, dyspepsia, diarrhea in 20% of patients, hemorrhage in 5%
what is ticlopidine associated with (AEs that are more severe)
TTP (thrombotic thrombocytopenia purpura)
Severe bone marrow toxicity
what does clopidogrel do
similar mechanism to ticlopidine (ADP antagonist) but lower incidence of adverse effects
what is clopidogrel used for
patients with a history of recent stroke, MI or established peripheral vascular disease, pts with stents
what is an important AE of clopidogrel
many drug drug interactions because requires activation by CYP2C9
what are other drugs metabolized by 2C9 and what drug can cause interactions with these
Clopidogrel causes interactions Fluvastatin NSAIDs Phenytoin tamoxifen tolbutmide warfarin
when would ticlodipine be preferred over clopidogrel
if drug drug interactions are difficult to manage
where is clopidogrel metabolized
liver
how does abciximab work
inhibits platelet aggregation by preventing binding of fibrinogen to glycoprotein receptor IIb/IIIa on activated platelets
how is abciximab administered
IV to high risk pts undergoing coronary angioplasty and pts undergoing angioplasty, atherectomy and stent placement often with clopidogrel
downsides to Abciximab including AEs
Expensive
Bleeding most common AE
what does Tirofiban do
small molecule that with short half life that works similar to Abciximab, has to be continually infused bc of short half life
How does dipyridamole work
inhibits phosphodiesterase which leads to increased cAMP levels, inhibiting platelet activation
what does phosphodiesterase do normally
breaks down cAMP
what effects does dipyridamole do
coronary vasodilator that also inhibits platelet aggregation
what is dipyridamole used for
in combo with warfarin, inhibits embolism from prosthetic heart valves (main use)`
what is dipyridamole combined with aspirin to treat
patients with thrombotic disease, reduces thrombosis
what do calcium chelators do
inhibit blood coagulation in vitro
what do heparins do
accelerate the action of antithrombin III to neutralize thrombin and other coagulation factors
what do rudins do
direct thrombin inhibitors
what do coumarin derivatives do
interfere with the hepatic synthesis of functional vitamin K dependent clotting factors
what are calcium chelators used for and why cant you use them in the body
for lab draws to prevent coagulation
cant use them in the body because calcium is used on so many function
structure of standard heparin
sulfated mucopolysaccharide (acidic molecule)
route of admin for standard heparin
NOT ORAL OR IM
infusion pump or intermittent Subcutaneous
onset of action of standard heparin
immediate
mechanism of action of standard heparin
heparin binds to antithrombin III and stimulates complex formation with antithrombin III
Main mech is heparin-antithrombin III complex inactivates factor IIa (thrombin) and Xa
heparin AEs
endothelial cell/protein binding
Clearance is dose dependent
therapeutic goal of standard heparin
prolong PTT to 1.5-2.5x normal
contraindications of standard heparin
bleeding disorders, hemorrhage
liver, kidney disease, HT, certain infections
indications of standard heparin
preferable to other anticoagulants during pregnancy due to lack of placental transfer
how does the indication of heparin differ from warfarin
preferable during pregnancy due to lack of placental transfer
AEs of standard heparin
bleeding/hemorrhage
allergic reaction
osteoperosis
HIT (heparin induced thrombocytopenia)
what is type I HIT
transient and rapidly reversible heparin induced thrombocytopenia
Abs generated against platelets –> decrease in platelet count
what is type II HIT
severe heparin induced thrombocytopenia
Ab decrease platelet count
Ab also activate platelets–>thormboembolism which may be life threatening
standard heparin antidote
protamine sulfate
what does protamine sulfate do
antidote to heparin, binds to heparin (anion/cation interaction)
why must excessive protamine sulfate be avoided when used as a heparin antidote
its an anticoagulant
what is a disadvantage of LMWH (low molecular weight heparin)
protamine sulfate is less capable of reversing its effects
what are the LMWHs
Enoxaparin
Dalteparin
Tinzaparin
what are LMWHs used for
less sticky than bigger molecules so not as dose dependent more convenient (sub q, dont have to check PTT as much)
how do you monitor LMWH
an anti-Xa activity assay
how does fondaparinux work
it exerts antithrombotic activity as a result of ATIII-mediated selective inhibition of factor Xa
what is the half life of fondaparinux
18 hours, allows once daily dosing, given subc
warfarin is a derivative of what
coumarin
what does the nature of warfarin plasma protein binding mean for its distribution
it has extensive binding which accounts for low volume of distribution, long half life
describe metabolism of warfarin
metabolized by liver by CYP2C9, site of numerous drug interactions
which has activity in vitro heparin or warfarin?
heparin
describe the route of heparin and warfarin
heparin - parenteral
warfarin - oral
onset of heparin v warfarin
heparin - immediate
warfarin - 1-3 days
how do you monitor heparin
PTT
how do you monitor warfarin
PT (INR)
where are the rudins derived from
leeches
who is lepirudin approved for
its a recombinant yeast driven form of hirudin patients with HIT
what can argatroban be used for
its a rudin that is approved for HIT patients and cleared by liver so can be used in pts with end stage renal disease
how do rudins work
direct thrombin inhibitors
what is the main rudin
hirudin (thrombin inhibitor)
what are the oral direct thrombin inhibitors
Dabigatran etexilate
Rivaroxaban
what is a problem with the oran direct thrombin inhibitors
theres not a way to reverse their effects
what is apixaban
FXa inhibitor
what is praxbind
the first reversal agent for the oral anticoagulants
how does praxbind work
binds and sequesters dabigatran and dabigatran glucuronides
what do thrombolytics do
activate plasminogen to be converted to plasmin which degrades fibrin and lyses thrombi
why cant you use plasmin for thrombolytic therapy?
circulating antiplasmins
how is urokinase used as a thrombolytic
its made in the kidney and plasma doesnt have inhibitors to it but it can break down clots
how does streptokinase work
facilitates thrombolysis through formation of activator complex with plasminogen results in formation of plasmin
what is a major AE of streptokinase
hypersensitivity
what are the recombinant thrombolytics
Alteplase
Reteplase
Tenecteplase, TNK-t-PA
what is Alteplase
Biosynthetic recombinant form of human tissue plasminogen activator
what is Reteplase
recombinant plasminogen activator
what is tenecteplase
modified human t-PA, prolonged half life compared to alteplase
when do you use thrombolytic agenst
when you already have a clot
how do you rule out intracranial bleeding and why is it important
CT scan, because you need to be sure its a clot not a bleeding episode
thrombolytic therapy should be followed with what
anticoagulant therapy with heparin and then warfarin
contraindication of thrombolytics
surger, GI bleeidng, hx of hypertension
what is vitamin K used for
gamma carboxylation of glutamate residues in PT factors VII, 9, 10
how fast does vitamin K restore clotting function
days
if you need clotting function faster than vitamin K can provide what can you do
plasma fractions/clotting factors
recombinant factors
what discourages the use of plasma fractions in treatments of patients with hemophilia
AIDS and viral hepatitis
what is aminocaproic acid
fibrinolytic inhibitor
what isomoer is the most active of warfarin
S isomer
describe distribution of warfarin
extensive plasma protein binding accounts for low volume of distribution and a long half life
how is warfarin metabolized
CTP2C9, site of numerous drug interactions
target of warfarin
vitamin K epoxide reductase
speed of onset of warfarin
slow, t1/2 is 1.5 days
antidote to warfarin
large doses of vitamin K and fresh frozen plasma
drugs that diminish warfarin absorption
cholestyramine (also affects Vit K absorption)
what drugs can interfere with hepatic microsomal enzymes needed for warfarin metabolism
antoconvulsants Barbiturates carbamazepine phenytoin primidone rifampin St. Johns Wort
what hormone can interfere with warfarin from stimulation of clotting factor synthesis
estrogens
which drugs inhibit anticoagulant mechanism (warfarin) and are selective for S warfarin
Metronidazole
fluconazole
therapeutic goal of warfarin
prolonged PT time
what is an important factor to consider when prescribing warfarin in women
its a teratogen
contraindicated in pregnancy (category X)
compare and contrast heparin and warfarins mechanism
heparin - accelerates action of ATIII to neutralize thrombin
Warfarin - decreases vit K dependent clotting factors
compare and contrast heparin and warfarin route of admin
heparin - PE
warfarin - oral
compare and contrast heparin and warfarin onset
heparin - immediate
warfarin - gradual (1-3 days)
compare and contrast heparin and warfarin duration
heparin - 4 hours
warfarin - 2-5 days
compare and contrast heparin and warfarin monitoring tests
heparin - PTT
warfarin - PT (INR)
compare and contrast heparin and warfarin treatment of overdose
heparin - protamine sulfate
warfarin - vit k; fresh frozen plasma
