Term
| fibrin network - 2 actions? |
|
Definition
stabilizes the platelet plug
is major component of red thrombi |
|
|
Term
|
Definition
| formed in veins or other areas of slow blood flow, made by the fibrin network |
|
|
Term
| two pathways that lead to fibrin formation? which is faster? |
|
Definition
| intrinsic & extrinsic systems...extrinsic is faster |
|
|
Term
| two main regulators of the blood coagulation cascade? |
|
Definition
| protein C & TFPI (tissue factor pathway inhibitor) |
|
|
Term
| the blood coagulation cascade is initiated when ____ comes into contact with ____. |
|
Definition
tissue factor (in SM cells, e.g.)
blood |
|
|
Term
| in the coag cascade, pro____ is converted to _____, which converts _____ogen to ______ (the CLOT!) |
|
Definition
(pro)thrombin
thrombin
fibrin(ogen)
fibrin |
|
|
Term
| protein C becomes activated in the presence of __ (3 things)? |
|
Definition
| fibrin, thrombomodulin, & endothelial cells |
|
|
Term
| activated protein C inactivates what two factors? |
|
Definition
|
|
Term
| TFPI forms a complex with what two factors to cause their inactivation? |
|
Definition
|
|
Term
| the main proteolytic enzyme of the fibrinolytic pathway that breaks down fibrin into various products |
|
Definition
|
|
Term
| is plasmin specific for fibrin? |
|
Definition
| NOPE, but it does cleave & break down the fibrin network |
|
|
Term
| three main anticoagulants |
|
Definition
| heparin, thrombin inhibitors, warfarin |
|
|
Term
| very negatively charged mucopolysaccharide found naturally in mast cells but also commercially made today |
|
Definition
|
|
Term
| 4 pharmacological actions of heparin |
|
Definition
1. immediate anticoag effect
2. activates antithrombin III
3. reduces fibrin formation
4. reduces thrombin levels (inhib platelet aggregation) |
|
|
Term
| a plasma glycoprotein that neutralizes several coag factors, esp thrombin & factor X. activated by heparin. |
|
Definition
|
|
Term
| three factors inhibited by heparin |
|
Definition
| factors IXa, Xa and IIa (thrombin) |
|
|
Term
what drug?
a. can't cross plasma membranes (bc FAT & negative), so can't be given orally
b. no IM injxn bc of hematomas
c. degraded by heparinase in the liver |
|
Definition
|
|
Term
| heparin's usual administration |
|
Definition
| deep subcutaneous injxn at low doses...action is delayed 20-60 mins |
|
|
Term
| 2 MAIN clinical uses of heparin |
|
Definition
| venous thromboembolism, coronary artery disease |
|
|
Term
| heparin is used prophylactically for what two conditions? what are some risk factors for these conditions? |
|
Definition
DVT, PE
atrial fibrillation, orthopaedic surgery |
|
|
Term
| how do you treat DVT with heparin? (administration) |
|
Definition
| IV bolus then infusion at high concentrations (more than for prophylaxis) |
|
|
Term
| three coronary artery disease conditions for which you would use heparin? |
|
Definition
unstable angina
acute MI
after thrombolytic therapy or angioplasty |
|
|
Term
| two forms of heparin? which is more active? |
|
Definition
1. high molecular weight heparin, unfractionated
2. low molecular weight heparin, aka Enoxaparin, *more active form |
|
|
Term
| Enoxaparin (LMW heparin) has a greater affect on? |
|
Definition
| factor X (more than for thrombin)...gives it enhanced anti-thrombotic activity |
|
|
Term
| which form of heparin has the LOWER relative risk for death, MI, or recurrent angina in pts following ST-elevation MI? |
|
Definition
|
|
Term
| 3 main side effects of heparin |
|
Definition
1. bleeding
2. thrombocytopenia
3. activation of lipoprotein lipase |
|
|
Term
| heparin antagonist that rapidly terminates it's action in a bleeding situation |
|
Definition
|
|
Term
| protamine's charge? action on heparin? problem? |
|
Definition
-positively charged
-forms a complex with heparin & neutralizes it
-can be an anticoagulant itself |
|
|
Term
| heparin induced thrombocytopenia: what does heparin bind/how do you get thrombocytopenia?,what should you monitor? |
|
Definition
| heparin binds platelets - an antibody administered to remove the heparin-platelet complexes can induce thrombocytopenia. monitor platelet counts |
|
|
Term
| heparin's activation of lipoprotein lipase can increase the risk of ______ via increased levels of ______. |
|
Definition
arrhythmias
fatty acids (they think) |
|
|
Term
| heparin associated risk of major bleeding is _____-dependent. |
|
Definition
| AGE! older peeps more likely to bleed! |
|
|
Term
| group of drugs based on hirudin (present in salivary glands of leeches) |
|
Definition
|
|
Term
what drug?
a. synthetic 20 AA polypeptide that binds thrombin
b. used as alt. therapy for tx of unstable angina
c. has potential advantages over unfractionated (HMW) heparin |
|
Definition
|
|
Term
| bivalirudin potential advantages over UF heparin? (4) |
|
Definition
1. predictable pharmacokinetics
2. not inhibited by plasma proteins
3. doesn't activate platelets
4. not associated with thrombocytopenia |
|
|
Term
| bleeding as a side effect is greater with which treatment: bivalirudin OR heparin + GP IIb/IIIa inhibitor? |
|
Definition
| heparin + GP IIb/IIIa inhibitor |
|
|
Term
| cattle who ate clover developed a hemorrhagic condition...this was due to the clover ingredient called ____. |
|
Definition
|
|
Term
| first developed as a rat poison, this oral anticoagulant's clinical trials began after someone's suicide attempt with this drug failed. |
|
Definition
|
|
Term
pharmacological actions of warfarin:
a. anticoag effect is ______
b. therapeutic effects are ______ |
|
Definition
a. indirect
b. delayed, 8-12 hours |
|
|
Term
Fill in the blanks:
Warfarin indirectly blocks the ___________ reaction of factors ___, ___, ___, and ___ by inhibiting ___________. |
|
Definition
gamma carboxylation
II, VII, IX, and X
Vitamin K reductase |
|
|
Term
| why are the actions of warfarin delayed? |
|
Definition
| it has to do with it's MOA: the factors coming off the ribosome are inactive...they must be converted to their active state & new proteins must be formed in order for warfarin to have it's effects. ....? |
|
|
Term
| inactive vitamin K (epoxide) is reduced to _______ via warfarin. |
|
Definition
|
|
Term
| emergency!: your pt has a stroke. you have warfarin and heparin. which do you give & why? |
|
Definition
| heparin, it has an immediate effect. |
|
|
Term
| vitamin K is the cofactor for what reaction in the coagulation cascade? |
|
Definition
|
|
Term
| coagulation factors inhibited by warfarin |
|
Definition
|
|
Term
| warfarin + this gastric acid secretion inhibitor (_____) = ______. why? |
|
Definition
-cimetidine
-increased prothrombin time
-cimetidine blocks the CYP2C9 that metabolizes warfarin |
|
|
Term
| 3rd generation cephalosporins + warfarin = ______. why? |
|
Definition
-increased prothrombin time
-the cephs eliminate the bacteria in the gut responsible for some vitamin K synthesis |
|
|
Term
| warfarin + inflammatory agents ____ or ____ = _____. why? |
|
Definition
-phenylbutazone or sulfinpyrazone
-increased prothrombin time
-these drugs inhibit the CYP2C9 responsible for warfarin metabolism |
|
|
Term
| drug-drug interactions involving warfarin that cause increased prothrombin time are usually due to inhibition (by the added drug) of _____. |
|
Definition
| Cytochrome 2C9 or CYP2C9 - responsible for warfarin's metabolism |
|
|
Term
| 10 drugs that increase prothrombin time when mixed with warfarin (drug-drug interaction!) [mnemonic: A Cool Dude Mo Fo Pelted Self Tanner At Candace] |
|
Definition
| 1. Amiodarone, 2. Cimetidine, 3. Disulfiram, 4. Metronidazole, 5. Fluconazole, 6. Phenylbutazone, 7. Sulfinpyrazone, 8. Trimethoprim-sulfamethoxazole, 9. high doses of Aspirin, 10. 3rd gen. Cephalosporins |
|
|
Term
| 5 drugs that DECREASE prothrombin time when mixed with warfarin (drug-drug interaction) |
|
Definition
barbituates
rifampin
cholestyramine
diuretics
vitamin K |
|
|
Term
| warfarin + barbituates or rifampin = _____. why? |
|
Definition
decreased prothrombin time
they induce CYP2C9 (responsible for warfarin metabolism) |
|
|
Term
| warfarin + cholestyramine = ____. why? |
|
Definition
decreased prothrombin time
the drug complexes with warfarin & eliminates it |
|
|
Term
| diuretics affect levels of _______, allowing for a _____ prothrombin time when used in conjunction with warfarin. |
|
Definition
clotting factors
decreased |
|
|
Term
| name the warfarin stereoisomers, what are they metabolized by? which stereoisomer is more active? |
|
Definition
| R & S forms - metabolized by CYP2C9; S form is more active |
|
|
Term
| Warfarin R is converted to _____ via CYP2C9. What drug inhibits this conversion? |
|
Definition
secondary alcohol
cimetidine |
|
|
Term
| Warfarin S is converted to _____ via CYP2C9. what drugs inhibit this conversion? |
|
Definition
7-hydroxy warfarin
phenylbutazone, sulfinpyrazone |
|
|
Term
| which drugs have a greater effect on warfarin: cimetidine OR anti-inflammatories (like phenylbutazone, sulfinpyrazone? why? |
|
Definition
| anti-inflammatories - because they act on the S form of warfarin, which is more active |
|
|
Term
| 6 clinical uses of warfarin |
|
Definition
DVT (tx & prevention)
prosthetic heart valves
atrial fibrillation
dilated cardiomyopathy
angina
advanced myocardial infarction |
|
|
Term
|
Definition
| start with heparin (for immediate effect), then move to warfarin |
|
|
Term
| warfarin vs. aspirin: which drug reduces strokes & cardiovascular events in pts with atrial fibrillation better? |
|
Definition
|
|
Term
following a stroke, a pt with atrial fibrillation should be given:
a. high dose warfarin
b. aspirin
c. low dose warfarin
d. nothing |
|
Definition
| a. high dose warfarin - reduces mortality substantially (more so than low dose warfarin or aspirin, which have about the same affect) |
|
|
Term
warfarin side effect?
how do you treat this?
what should you monitor during the treatment? |
|
Definition
hemorrhage
withdraw warfarin & give vitamin K
monitor prothrombin time |
|
|
Term
| you want the prothrombin time to be within a certain range when giving warfarin in order to avoid what two potential adverse effects? |
|
Definition
stroke & intracranial hemorrhage
you want to dose warfarin so that both of these adverse effects are minimized & the pt is in a stable situation |
|
|
Term
| platelet aggregation step one: platelet adheres to damaged endothelium via _____. |
|
Definition
|
|
Term
| a platelet bound to damaged endothelium will release ____ or ____, which will promote platelet aggregation. |
|
Definition
|
|
Term
| platelet aggregation involves the interaction of two platelets with _____ and _____ (the peanut butter). |
|
Definition
| glycoprotein IIb/IIIa (on each platelet) & fibrinogen |
|
|
Term
| what stabilizes the platelet plug? |
|
Definition
|
|
Term
| the 3 main factors released from the platelet that will act on receptors of adjacent platelets to promote aggregation |
|
Definition
thromboxane A2
ADP
serotonin (5-HT) |
|
|
Term
| released from endothelial cells & inhibits platelet aggregation |
|
Definition
|
|
Term
| activation of these regulate aggregation: increase calcium, increase phosphorylation, exposing the glycoprotein IIb/IIIa |
|
Definition
|
|
Term
| antiplatelet therapy is the CORNERSTONE in the management of what two conditions? |
|
Definition
| unstable angina & non-ST segment myocardial infarction |
|
|
Term
| as the number of platelets in the blood are elevated, adverse effects of non-ST sgement MI ____. (increase, decrease, or stay the same?) |
|
Definition
|
|
Term
| a drug, acting through prostaglandins, that regulates platelet aggregation. (by inhibiting cyclooxygenases) |
|
Definition
|
|
Term
| in the prostaglandin biosynthetic pathway, products made are usually either _____ OR ______ are readily available. these products are often tissue or cell specific. |
|
Definition
| intrinsically unstable OR degrading enzymes |
|
|
Term
| agents that promote platelet aggregation often activate phospholipase A2, which cleaves phospholipids, leaving the product ______. |
|
Definition
|
|
Term
| arachidonic acid (in the platelet aggregation pathway), is converted to cyclic endoperoxides (PGG2, PGH2) via _____. |
|
Definition
|
|
Term
|
Definition
| involved in anti-platelets, can cause GI irritation |
|
|
Term
| COX-2 inhibitors & their major problem |
|
Definition
| involved in inflammation; knock out inflammatory response & lack GI affects, but have serious problems with cardiovascular disease (VIOXX was one drug of this class) |
|
|
Term
| this drug should routinely be one of the first agents administered after an MI |
|
Definition
|
|
Term
| 3 main drugs that affect platelet aggregation by modulating cAMP & ADP |
|
Definition
dipyridamole
eicosapentenoic acid
clopidogrel |
|
|
Term
what drug?
a. inhibits phosphodiesterase > raises cAMP > promotes phosphorylation of VASP
b. potentiates prostacyclin > activates AC
c. only recommended for pts with prosthetic heart valves |
|
Definition
|
|
Term
| phosphorylation of VASP inhibits platelet aggregation by inhibiting activation of _____. this phosphorylation is done by _____. |
|
Definition
glycoprotein IIb/IIIa
cAMP-dependent kinase |
|
|
Term
what drug?
a. becomes incorporated into phospholipids of platelets, alters thromboxane and prostacyclin synthesis, is converted to IP3 (antiaggregating), AND does not appear to alter bleeding when combined with clopidogrel or aspirin
b. found in high levels in the eskimo diet, in fish supplements |
|
Definition
| eicosapentenoic acid (omega 3) |
|
|
Term
| the MAJOR drug to inhibit ADP-mediated platelet aggregation by affecting both the rate & extent of aggregation |
|
Definition
|
|
Term
| what two receptors does ADP react with & what do they do? |
|
Definition
P2Y1 - increases Ca++, aggregates
P2Y12 - inhibits AC, affects cAMP levels, affects VASP |
|
|
Term
| how is clopidogrel activated? what does it do to cAMP levels? what does it do to platelet aggregation? |
|
Definition
via CYP34A or CYP2C19
increases cAMP levels > promotes phosphorylation of VASP > inhibits GP IIb/IIIa > reduces platelet aggregation |
|
|
Term
| 4 therapeutic uses of clopidogrel |
|
Definition
1. reduce strokes
2. maintains revascularization following angioplasty and in combo with stents
3. inhibits occlusion of bypass graft following coronary bypass surgery
4. MI |
|
|
Term
| your patient has myocardial ischemia and you want to reduce relative risk of bad outcomes. if you only care about drug effectiveness, would you prescribe aspirin or clopidogrel? if your pt is poor, which drug would you recommend? |
|
Definition
clopidogrel is more effective & more expensive
aspirin is recommended more often bc it is cheap |
|
|
Term
| what drug is often given after placement of a stent, even if the stent is coated with another drug? |
|
Definition
|
|
Term
| do all pts respond to clopidogrel? |
|
Definition
|
|
Term
| potential causes of low responsiveness to clopidogrel? (5) |
|
Definition
1. inadequate generation of active drug metabolite (CYP3AY polymorphism?)
2. polymorphism of P2Y12 receptor
3. insufficient intestinal absorption
4. diabetes
5. drug-drug interactions (Ca++ channel blockers, proton pump inhibitors) |
|
|
Term
| carriers of the allele for unresponsiveness to clopidogrel (mutated CYP2C19) have _____ rate of stent thrombosis and risk of bad outcomes |
|
Definition
|
|
Term
| how does diabetes affect clopidogrel responsiveness? |
|
Definition
| affects Ca++ transport (Ca++ plays a role in platelet aggregation), also affects prostaglandin synthesis |
|
|
Term
| 4 clopidogrel side effects |
|
Definition
1. bleeding
2. neutropenia
3. TTP-HUS (rare)
4. withdrawal of the drug following an MI or after revascularization therapy can increase the risk of MI |
|
|
Term
| 3 drugs affecting GP IIb/IIIa |
|
Definition
Abciximab
tirofiban
Eptifibatide |
|
|
Term
| monoclonal Ab fragment with high affinity for GP IIb/IIIa; inhibits platelet aggregation for a long period of time (50% inhib after 24-48hrs) |
|
Definition
|
|
Term
| abciximab therapeutic uses (2) |
|
Definition
revascularization following angioplasty
reduce MI and mortality in pts w evidence of MI |
|
|
Term
| abciximab adverse effects (2) |
|
Definition
1. bleeding (if severe thrombocytopenia, give platelets)
2. can promote thrombotic effects |
|
|
Term
| tirofiban mechanism of action? |
|
Definition
| binds GP IIb/IIIa after it has undergone some conformational change |
|
|
Term
| abciximab vs. tirofiban: better effectiveness? better cost? |
|
Definition
abciximab has better outcome
tirofiban is cheaper |
|
|
Term
| goals of revascularization therapy? (3) |
|
Definition
reestablish coronary patency
salvage myocardium
improve survival |
|
|
Term
| which is more effective at reducing mortality? stent placement or thrombolytic drugs |
|
Definition
|
|
Term
| Individual thrombolytic agents |
|
Definition
| streptokinase, urokinase, TPA, anistreplase |
|
|
Term
| streptokinase interacts with _____ > conversion to _____ > a proteoltyic activity that can attack fibrin |
|
Definition
|
|
Term
| is streptokinase fibrin specific? |
|
Definition
|
|
Term
| how do you make streptokinase more fibrin specific? |
|
Definition
| complex it with anisoylated plasminogen = APSAC or Anistreplase |
|
|
Term
|
Definition
1. more stable in plasma (can be admin as a bolus)
2. more potent in dissolving old clots
3. fibrin specific! interacts w fibrin in hemostatic plugs or thrombus |
|
|
Term
what drug?
a. is a serine protease
b. is fibrin specific bc it has higher specifity for fibrin-plasminogen complex than free plasminogen
c. unstable with t 1/2 of 5 mins - admin IV infusion
d. is active in endothelial cells & an agent that regulates fibrinolysis |
|
Definition
| tissue plasminogen activator (t-PA!) |
|
|
Term
| when ____ binds plasminogen, it converts it to plasmin. plasmin cleaves _____. |
|
Definition
|
|
Term
| t-PA is used for ________. this occurs more quickly/effectively with less severe occlusion. |
|
Definition
|
|
Term
what drug?
a. precursor of a fibrin specific serine protease
b. has a C-terminal region similar to t-PA
c. secreted by endothelial cells |
|
Definition
| single chain urokinase type plasminogen activator |
|
|
Term
| therapeutic uses of the thrombolytic drugs (2) |
|
Definition
1. reduce damage caused by an occlusion (stroke, MI, PE)
2. reduce occlusion following angioplasty |
|
|
Term
| treatment of a PE with thrombolytic agents (any) can reduce the size of the PE by about ____%. |
|
Definition
|
|
Term
| what is one problem with thrombolytic agents? |
|
Definition
| can see reocclusion after some time...about 7-10% have strokes associated with these |
|
|
Term
| ____ used in conjunction with t-PA can increase ST segment resolution, help with revascularization/myocardial perfusion |
|
Definition
|
|
Term
| streptokinase and _____ both reduce mortality following MI. combining the two gives an even better outcome. |
|
Definition
|
|
Term
| streptokinase side effects (3) |
|
Definition
1. bleeding
2. reocclusion
3. ALLERGIC REACTIONS |
|
|
Term
| what thrombolytic agent could cause a frank anaphylactic reaction in your pt? |
|
Definition
| streptokinase - bc of its source (streptococcus) |
|
|
Term
| which thrombolytic agent is most effective at increasing patency (quickest)? |
|
Definition
*accelerated* t-PA
accelerated = give t-PA bolus initially then infuse |
|
|
Term
| which thrombolytic agent will have the greatest patency % at 5-7 days? |
|
Definition
| all thrombolytic agents are equal at 5-7 days |
|
|
Term
| early improvement in patency can affect _____ (of the heart) in a positive way |
|
Definition
| contractile function or ejection fraction |
|
|
Term
| what genetically synthesized thrombolytic agent is not even considered for use in canada due to its high cost? |
|
Definition
|
|
Term
| accelerated t-PA decreases mortality, but shows a slightly increased risk of _____ as compared to streptokinase. |
|
Definition
|
|
