Pharmacology-Anticoagulants and antiplatelet drugs and thrombolitics Flashcards
What is hemostasis?
includes mechanisms which inhibits the loss of blood from damaged vessels
what are the physiological consequences of coagulation?
wound repair and healing, integrity of hte circulatory system, and prevention of exsanguination ((blood loss)
what are the pathological consequences?
cardiovascular disease, vascular injury and tissue trauma
this pathway is rapid and massive in response due to?
- proteolytic positive feedback that enhances factor activation
- normally high plasma concentration of prothrombin and fibrinogen
what is fibrinolysis modulated by?
plasminogen activatior inhibiotr-1 which inhibits t-PA, and by a2-antiplasmin
what are the therapeutic options?
prevent the formation of pathologic thromubs
-destroy formed pathological thrombus
How do you prevent the formation of pathologic thrombi?
- traditional approach– anticoagulant drugs (heparin and warfarin)
- newer approach– prevention of arterial damage, and inhibiton of platelet aggregation (asprin or ticlopidine)
How do you destroy formed pathological thrombi?
dissoling preformed closts is difficult to achieve w/o causing bellding but fibrinolytic drugs like sreptokinase, rtPA, retalplase adn ASPAC can be used in emergency
What is the mechanism of heparin?
binds to antithrombin III and increases its affinity for its clotting factors, that are serine proteases, X, Thrombin
what is the pathophys of HIT?
platelet factor 4 binds to heparin and when a patient is no heparin for 5-10 days
Abs can form against the complex of heparin-PF4 and can :
-activate platelts to form clots in arteries,
-release more PF4 from their alpha granules which cross react with heparin-PF4 complex on endothelial cells and destroys the endothelial cells
What is the clinically useful coumarins?
warfarin
what is the molecular action of warfarin?
binds to the vit k epoxide reductase and block its activity
what are warfarin’s pharmacokinetics?
-oneset, considerably delayed (36-72 hrs)
(due to long t1/2 of warfarin adn the fact htat pre-existing clotting factors are slowly cleared from the blood)
-duration: prolonged (proportional to the elimination T1/2 (25-60Hs)
When is warfarin used?
- over lap with heparin therapy to avoid long delay in onset of action
- DVT
- PE
- Arterial fib
- Rheumatic hrt disese
- Mechanical and prosthetic hrt valves
What is warfarin’s therapeutic window?
narrow
is there a variablility in dose of warfarin?
considerable inter-indicidaul and intra-indivdual variability
Is monitoring required for warfarin?
yes,
what is the saftey profile for warfarin?
difficut in maintaining pts within therapeutic w/in the target theraptuitc range (INR 2-3)
-contributes to and increased risk of bleeding
What are the low molecular weight heparins?
Enoxaparin, Danaproid
- smaller, active pieces of regular heparin
- greater anti-Xa activity, less antiplatelet activity
What are LMWH used for?
prophylaxis of DVT associated with hip and abdominal surger
What is the differnce b/t LMWH versus Heperain?
longer duration, simpler kinetis, clotting test not usally required
Is there cross reaction with HIT with use of LMWH?
yes!!!
what are the limitation of heparins?
parenteral administration only
risk of heparin-induced thrombocytopenia
need for lab monitoring (platelet cound)
what are the limitations of Warfarin?
narrow therapeutic window
significant interaction with food and other drugs
need for frequent lab monitoring and dose adjustment
What are the direct thrombin inhibitors?
hirudin
leprirudin
Argatroban
Dabigatran
what is hirudin?
- found in slaivary glands of medicinal leech
- direct thrombin inhibitor (doesn’t require ATIII
- can be used in pts with heparin-induced thrombocytopenia
What is lepirudin?
A recombinant derivative of hirudin
- shorter half life (80min)
- renal elimination
- HIT approved
- IV
what is the mechanism of DTIs?
-Block both circulating and clot-bound thrombin!!!!
the bind directly to thrombin and inhibit the active site
-have potential for greater anticoagulant action than heparin. further, the direct throbin inhibitors that bind reversibly may also avoid any increase in bleeding risk
Which DTIs inhibit thrombin reversible and which are irreversible?
hirudin, lepirudin is irreversible at the active site
argatroban and dabigatran bind reversibly at active site
what are the characteristics of DTIs?
- specific adn potent direct inhibiton of thrombin, independent of antithrombin III
- inhibit thrombin-mediated activation of clotting factors (V,VIII,XI,XIII,) and platetlets
- action against free (soluble) and clot-bound thrombin
- unaffected by factors that neutralize heparin
- don not induce immune-mediated thrombocytopenia
What are the PK charcteristics of dabigatran?
oral
t1/2- 12 hrs
renal elimination
What are the PK charcteristics of argatroban?
iv
t1/2- 45min
liver elimination
What are the PK charcteristics of hirudins?
iv and subcu
t1/2 iv-60 min subcu- 120 min
renal elimination
what is the problem with dabagatran if od?
no antidote
venous thrombosis
acute: heparin
Chronic: warfarin
TIA, thrombotic strok
acute: heparin, aspirin
chronic: aspirin, clopidogrel
Unstable angina
acute; heparin, aspirin, GpIIb/IIIa inhib
chronic: aspirin, clopidigrel
MI
acute: thrombolytic, heparin, aspirin,
chronic: aspirin
atrial fib
acute: heparin
Chronic: warfarin (aspirin)
Angioplasty/ stent
acute: heparin, GpIIb/IIIa inhib
Chronic: aspirin, clopidigrel
what are arterial thromboisis?
stroke
MI
peripheral artery occlusion
Endothelium (damaged- atherosclerosis, HTN, homocystine etc)
Platelets (adhere to vessel wall and to each other)
what are venous thromboisis?
DVT
PE
other sites (intracrania, intra-abdominal/ plevic upper extremities)
What are arterial clots?
white thrombi, pale on one end
cause death in 40% of events
cause maj disability in 20%
What are venous clots?
red chrombus
-cause death in 6% of events
after effects (post phlotic sysntrome, veins are dammaged by the clots, edema, breakdown of tissue ets)
What are the consequences of arterial thrombosis>
ischemic injury/ death of tissue (infarcation)
what are the actue management of arterial thrombi?
thrombectomy, mechanical removeal of clot
stent placement (make vessle wider)_
-thrombolysis
-follow with anti-platelet adn anticoagulant drugs
How do platelets reduce reactivity?
- block thromboxane production (ASA)
- Block IIb IIIa receptors (abciximab, eptifibatide)
- reduce thrombin production (heparin)
- Block receptors for ADP (clopidogrel)
What favor venous thromboemoblic disease?
immobility- DVT in 10-40% hospital admissions -DVTs in 40-60% orthopedic admission thrombophilia -deficiency of PC, PS, AT, V liden etc procoagulant states -acquired (CA, prg, trauma, etc) -congential (high VIII, abnormal I, etc)
What are the symptoms of DVT?
pain in calf swelling calf/ entire leg homans sing (pull up on toes-- pain) none of the above sudden death
What are the symptomps of PE?
SOB pleuritic chest pain hemoptysis shock none of the above sudden death
What is the txment of PE?
anticoagulation
thrombolysis
what are the reasons for antivoagulation?
prevent extension of clot form calf into thigh
prevent PE
prevent recurrence
prevent post-phlebitic syndrom
-precent emboli form atrial fib and mechanical hrt valves
What are the drugs we use to try and dissovel clots (thrombolytics)
tissue plaminogen activator (t-PA)
urokinase
thrombectomy
what are the drugs we use to anticoagulate?
heparin LMWH warfarin Lepirudin aragatroban dabigatran fondaparinus rivaroxban
what determines if heparin dose needs to be changed?
the PTT
how can the effect of heparin be reversed?
UFH- protamine sulfate (IV)
LMWH - protamine sulface only partially effective)
what is the desired INR for warfarin?
for txment and prophylaxis DVT ~ 2.5
-for protectiono f mechanical hrt valves ~3.0
What reversed the effect of warfarin?
vit K
prothombin comple concentrate
FFP
What occur with an IM injection during warfarin toxicity?
hematomas!!!!!!! have to give antidote by mouth, or subcu!
what are the side effects of anticoagulants?
bleeding
coumarin necrosis (big blisters, swelling and necrosis)
HIT syndrome (can cause gangrenous fingers and other appendices)
osteopenia
brusing, intracranial bleeding w/o head bump
what are most effective at preventing arterial thrombosis?
antiplatelet drugs (asprin and clopidogrel)
antiplatelet drugs (asprin and clopidogrel) an less effective at preventing what?
venous thrombosis
what to thrombolytic drugs lyse?
arterial and venous thrombi
what is asprin?
a cox inhibitor (1 and 2)
what is dypyridaole?
a PEI
what is clopidogrel and prasugrel?
platelet receptory inhibiotrs (ADP r antagonists)
what are eptifibidate adn abciximab?
glycoprotein IIb/IIIa receptor antagonists
Whata are streptokinase, urokinase, TPA, and reteplase?
thrombolytic drugs
what does the inhibition of COX1 prevent?
synthesis of pro-aggregatory prostaglandin and thrombozane (TBX)
what is the half-life of aspirin?
4-7 days
what are the adverse effects of aspirin?
GI bleeding
hemorrhagic stroke
asthma (leukotrines)
what is contraindicated with aspirin?
coumarin anticoagulants (increases risk of bleeding) peptic ulcer disease, aspirin hypersensitivity (asthma)
What is prostacyclin?
IDK!
how does aspirin bind and what about the other cox inhibitors?
asprin acetylates cox, and the other NSAIDS do not! not hey are reversible
What should you use for antiplatelet effect?
asprinin or clopidogret
what is the mechanism of action for PDIs?
inhibit enxyme that degrades cAMP in cells, –> ^ platelte cAMP in response to prostacyclin inhibits aggregation. also activates platelet adenylate cyclase by inhibiting adensonine uptake
what are the properties of dpyridamole?
-weak antiplatelet effect used alone
-evidance of added benefit in combo with asprin in pts with cerebrovascular disease
-reduces thromboembolic events combined with warfarin in pts with prosthetic hrt valves
-potent vasodilator, used IV to induce coronary steal in cardiac studies
(inhibits PD and reuptake of adenosine)
what are the adverse effects of dipyridamole?
headache
dizziness
GI upset
What is the efficacy of combo asprin with dypyridamole in cerebrovascular disease?
additon of extened release dypyridamole ot asprinin prvides added benifit in pts with cerebrovascular disease
-blocking more than one effect
what are the properties of clopidogrel?
- a produrg! metabolized by Cype2C19 to become biologically acitve
- higher dose needed in poor metabolizers (2-14% of population)
- CYP2C19 inhibiotrs (omeprazole) may interfere with formation active metabolite of clopidogretl and reduce efficay
what are the propterites of prasugrel?
prodrug, but activeated by CYP3A4 adn CYP2B6
-consider in ptns with CYP2C19 gene polymorphisms
what is prasugrel more at risk for than clopidogrel?
slightly higher bleeding risk
is clopidogrel offer additional benefit over asprin alone?
not siginifcatly in gerneral population
if had periferal vascular disease saw an improvment so in the pts yes…
what are the benifits of clopidogrel + aspirin?
with pts unstable angiina - saw and inreask bleeding complication whith CABG
- in percutaneous coronary intervention - reduced cardiovascular endpoints
- no evidance of benifit = ^ bleeding risk
what is the mechanism of eptifibidate
?
synthetic polypeptide (6aa) -prevents binding of fibrinogen, vWF to GpIIb/IIIa-R
What is the mechanism of abciximab?
rab fragment of chimeric human-murine monoclonal antibody 7E3
-blocks Gp IIb/IIIa receptor, vitronnectin R
What are the benifit of admistering glycoprotein IIb/IIIa recetpor inhibitor prior to cardiac catherization oand angioplasty?
prevent in-stent thrombosis/stenosis
what is the drug that can rescue failed angioplasty?
abciximab!
what is the mechanism of ation for fibrinolytic drugs?
promote firbrinolysis by convesion of incative plasma zymogen, plasminogen to active fibrinolytic enzyme plasmin
- plasmin degrades fibrin in thromus
- plasmin also degrades fibrinogen in plasma and can induce sysytemic lytic state which may increase risk of bleeding
what are the therapeutic uses of fibrinolytic drugs?
MI, PE, DVT, other arterial or venous thrombosis, thrombotic stroke
what is systemic lytic state and how does it occur>
when plasmin degrades fibrinogen in plasma, and casues and increased risk for bleeding
what are the maj toxicity for throbolytic therpy?
systemic lytic state
serious hemorrhage occur in 2-4%
most serious side effect is intracranial hemorrhage
what occured when strptokinase and asprine were given together?
additive effect
what are the first generation thrombolytics?
streptokinase
urokinase
what are the properties of strptokinase?
- isolated from strptococci
- unique mehcanism – forms activator comples with plasminogen (in intrisnis protease activety)
- activates circulating and fibrin-bound plasminogen indiscriminantly, producing systemic lytic state
what is the problem of streptokinase?
can only be give once!!
stronly immunogenic, due to antistreptokinase anibodies adn causes serum sickness etc
What are the properties of urokinase?
-produced from human fetal kindey cells
-trypsin-like serine protease, directly cleaves plasminogen to plasmin
-nonspecific degradation of fibrin, fibrinogen and other plasma proteins (systemic lytic state)
-not antigenic - no allergic response!!!
indicated for txmetn of acute massive or hemodynamically usntable pulmonary embolism
what are the second generation thrombolyics?
tissue-type plasminogen activator (t-PA)
what are the properties of (t-PA)?
- naturally-occuring protein relesaed by vascular endothelial cells (serine protease)
- produced by recombinant technology
- relatiely firin specific
- -t-PA fibrin, and plasminogen form a ternary complex, localizes plasminogen activation to fibrin clot
waht is t-PA indicated for?
acute MI
pe
acute ischemic stroke
what are the thrid generation thrombolytics?
reteplase r-PA
what are theproperties of reteplase?
deletion variant of t-PA contianing only the kringle-2 and serine protease domains
prolonged 1/2 life, can be admisiter by bolus injection rather than bolus/infusion
shrot-term mortality comparable to that with strptokinase (^iincidence of hemorrhagic stroke)
what is aminocaproic acid?
A fibrinolytic inhibitor
inhibits plasmin, and analogue of lysine,
treats excessive bleeding from systemic hyperfibrinolysys and urinary fibrinolysys
