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anticoagulants
| Question | Answer |
|---|---|
| what is virchows triad? | things that increase your chance of coagulation. Endothelial injury, Abnormal blood flow, and hypercoagulability/ stasis |
| what happens with injury to endothelial cells? | exposes collagen below the cells causing endothelial cells to release VWF |
| what causes endothelial cells to release vwf? | exposure of collagen from damage of endothelial cells |
| what is VWF | protein that attaches to collagen used by the plateletes to bind to VWF |
| how do th eplateletes bind to vwf? | thorugh a glycoprotein called gp1b |
| gp1b | used by plateletes to attach to vwf |
| gp2b3a | allows other plateletes to attach to the initial platelete, it anchors fibrinogen to plateletes forming a true clot |
| what happens when platetes are activated? | they release ADP and TxA2 but this also causes aggregation of platetes |
| what drugs do we know block thromboxaene? | COX inhibitors |
| what are cyclooxygenas einhibtiros? | irreversibly inhibit COX1 in lateltees ex Aspirin |
| example of a cyclooxygenase inhibitors | Aspirin |
| how do cyclooxygenase inhibitors work | blocs the formation of thromboxane which is needed for platelete aggregation |
| aspirin is used for what disorders? | resuce the risk of platleete aggregation in atherosclersis, MI adn stroke |
| how does cox1 inhibitrion work? | blocks cyclooxygenease which placks prostaglanid and thromboxane |
| plateltes expresses which COX? | cox1 |
| what will giving a COX 2 do? | nothing for platleetes, will go down prostglandin pathway and help with inflammation |
| how does thromboxane activate plateletes? | when it is activated it releases TXa2 which binds to thromboxne receptors on plateletes and activate a cascafe whih leads to activation of gp2b3a receptors on that paltelete |
| blocking htomrboxane does what? | block activaiton of ther palteeltes |
| 81mg | minimal dose of aspirin that can block COX1 with les side effects |
| which drug is a phosphodiesterase inhibitor? | dipyridamole |
| how does dipyridamole wokr | increeases levels of cAMP which decreases plalete aggregation |
| cAMP | we want these levels to be high so that inhibit platelte aggregation |
| potency f dipyridamole | weak antoplatete alone givenw it apirin 325 for cerebrovascular ischemia |
| side effect of diparidamole | vasodilation can cause coronary steal= angina |
| what doe sphosphodiesterase dow? | it breaks down cAMP |
| besides phosphodiesterase wha other way can we affect cAMP? | when ADP receptrs are activated on plateletes it decreases levels of cAMP , so if we block these receptors we get more cAMP |
| used with aspirin 325 for cerebral ischemia | dipyridamole |
| wht do adp receptor inhibitors do? | inhibit the ADP pathway of platelte activation |
| examples of adp receptor inhibitors | clopidogre, prasugrel, ticlopidine, ticagrelor |
| drawback of earlier adp receptor inhibitors | clopidogrela dn ticlopidine are prodrugs which means it takes some liver activations before it becomes the active compound and they form a covalant bond |
| increase levels oc cAMP | decreases paltelte aggregation |
| ae of ticlopidine | gi effects like nausea, diarrhea, dyspepsia hemorrhage and leukopenia |
| why do we give clopidogrel insted of ticlopidine? | better tolerated less gi effect but same risk for bleeding |
| drawback to clopidogrel | prodrug - needs 2 liver activations before it becomes active so it is slow to onset and irreversibel becuase of the covalent bond |
| what s a covalent bond? | once its bound its staying there. irreversible |
| what happens with release of adp | it binds to receptors and decrease cAMP inc ells causing platetes to aggregate |
| how do clopidogrel, prasugel and ticlopidine work? | competitive binding to adp receptor so it blcoks adp form getting ot receptos and will block receptor forever. comeptitive covalent |
| benefits of prasugrel? | it is a produrg but only needs 1 liver conversion as opposed to 2 so its more rapid potent consistent blocakde of adp reeptors then clopidogrel |
| prasugrel | potent consistent blocakde of adp reeptors then clopidogrel and possibly better,irreversible |
| this drug is possibly better than clpidogrel with greater prevention of MI | prasugrel |
| ticagelor | reversible, oral given in active form no cype faster mroe consistnet response less unwanted bleeding |
| whats the benefit of a gp2b3a antagonis? | it blocks the final pathway to bringing the plateletes together. as opposed to either adp or txa blockign no matter which way they plateletes are being activated in the end they will not stick |
| gp2b3a receptor anatagonist | eptifibatide, abciximab, tirofiban |
| potency of gp2b3a antagonists | more portent greater chance of bleeding |
| which mab is used for antiplatelte | gp2b3a antagonist abcicimab |
| which gp2b3a is reersible? | tirofibran |
| • etifibitite | • high potency and efficacy but it not easy to reverse and greater chance of bleeding |
| pros and cons of etifibitite | • drawback is parenteral but advantage because you can regulate how much to give |
| used for pt who need top of the line high levels of platelete inhibition | eptifibatide |
| prostacyclin | helps protect platelet to prevent platelet aggregation |
| exaples of anticoagulat | heparin warfarin factor xa inhibitor and direct thrombin inhibitors |
| what 2 things start activation of clotting cascade | • activated by tissue injury blood vessel injury |
| acitvating tissue and activating blood vessels | • You cant get injure a tissue w.o injuring injuring a blood vessel but you can injury a blood vessel without injuring tissue. ex htn, diabetes. this is another reason why you these people are at an increase risk |
| what substance is needed to clot | calcium |
| what happens when facto 10 is activated | • when factor x to xa, it converts prothrombin to thrombin • thrombin works on fibrinogen to fibrin • fibrin can now bind to platelet pug and makes into into blood clot ith help if calcium |
| heparin backgrowund | • big negatively charged acidic compound • its natural we make it in our mast cells as a natural anticoagulant • commercially from bovine- cows • it is a polymer - groups of sugars • negative charge for binding |
| how does body turn of cascade? | uses antithrombin3 |
| how does antithrombin 3a work | • AT3 inactivate Xa and thrombin |
| differences between theheparins | difference between the heparins is that some will enhance both and some will enhance one |
| heparin is a cofactor what does that mean | • a cofactor is something that enhances the activity of an enzyme • in presence of heparin, activity of AT3 is increased x 1000 • no heparin AT3 turns cascade off at its regularly slow paced. |
| what turns clotting factors off? | antithrombin 3/ AT3 |
| 2 ways to shut off clotting cscade? | inhibiting thombin orinhibiting Xa |
| HMWH inactivates what? | • HMWH helps inactivate heparin and Xa |
| lmwh binds where to inhibit clotting? | to AT3 but not so much thrombin • Doesn’t bind well with thrombin. It poorly inactivates thrombin • Enhances the activation of Xa but not thrombin • Thrombin is still running with this • A little less potent but less risk of bleeding |
| what • Selectively increases inactivation of Xa only because it binds poorly to thrombin | LMWH |
| pentsaccaride binds to what? | • Pentasaccaride doesn’t bind whatsoever with thrombin • But it does bind with AT# an inactivates Xa |
| used prpophylactically to prevent thrombus | heparin |
| LMWH | • LMWH have a greater therapeutic index- range and doses between toxic effect and dose • Less risk, safer • Heparin is well tolerated major concern is unwanted bleeding |
| major adverse effect of heparin | HIT in 1-4% of pts |
| whose at risk for HIT | 1-4% of pts treated with UFH for 7 days • Less likely to occur with LOWH and def. not with fondaparintin |
| What is HIT | • This is autoimmune activation and destruction of platelets • This is a thrombotic disorder • Autoimmune destruction of platelets – thrombocytopenia • And activation of platelets |
| what is the mechanism behind HIT | • Platelet and heparin combined in certain % of pts. exposed to heparin overtime will bind to plasma proteins and attach to platelet and become a hapten • When they are attached it turns into a hapten and attract igG which bind to that platel |
| how to reverse heparin | protmaine sulfate |
| what does protamine sulfate work against? | LMWH adn HMWH |
| how was coumadin founded | • Farmers plated sweet clover instead of corn to feed cows • Cows were dying from eating the clover that had spoiled and cause of death was due to hemorrhage |
| • Synthetic cogener of 4 hydroxycoumarin | Coumadin |
| how does warfarin work | • Inhibits regeneration of vitamin K • Which is a cofactor for synthesis of clotting factor in the live • It inhibits an enzyme that’s needed to make clotting factors- vitamin k reductase |
| what is needed to make clotting factors, besides calcium | reduced vitamin K |
| how is reduced vitamin k made | • In liver there is vitamin k reductase that takes vitamin k and reduces it |
| desribe cycle of vitmain k | • Once reduced vitamin k is finished it turns into oxidized vitamin k which cant be sued • It needs to urn back to reduced vitamin k. • Vitamin k reductase does this • Warfarin inhibits vitamin k reductase |
| what happens when we block vitmain k reductase | • If we block vitamin k reductiase the cofactor stays in oxidized state and cant be used in cofactor |
| does warfarin directly inhibit coagulation? | no it • Doesn’t directly inhibit liver enzymes it inhibits regeneration of vitamin k which over enzymes need for clotting • Pts. with no vitamin k wont make clotting factors as well |
| major metabolism of warfarin | CYP2C9 |
| what factors do warfarin inhibit? | 2,7,9,10 |
| why dont we see effects of warfarin right away | • Don’t see an effect of warfarin in 24 hours because we still have clotting factors already made is circulation. They need to be used up first 18-24 hrs. |
| are effects of heparin immediate | yes |
| pros of warfarin | long half life, 100% bioavailable but has a narrow theraputic index |
| drugs that diminish warfarins effect | Cholestyramine, barbiturates, carbamazepine, phenytoin, rifampin, vitamin k reduced |
| how does cholestyramine work with warfarin | inhibits absorption inthe gi tract |
| barbiturates, carbamazepine, pheytoin, rifampin and warfarin | accelerates metabolism by inducing hepatic P450 enzymes |
| vitmain k adn warfarin | bypass warfarins inhibition of epoxide reductase |
| drugs that enhance warfarin effect | chloral hydrate, amiodarone, clopidogrel, ethanol, flucanzale, fluoxitine, metrondiazole, sulfamethoxazole, broad spectrum abs, anabolic steroids (testosterone) |
| chloral hydrate and warfarin | displases it from plasma albumin |
| amiodarone, clopidogrel, ethanol, flucanzale, fluoxitine, metrondiazole, sulfamethoxazole, | decreases metabolism by inhibiting hepatic p450 enzymes |
| broad spectrum ABS and warfarin | eliminates gutbacteria and reducsavailability of vitamin k in gi tract |
| testosterone nad warfarin | inhibit synthesis and increase degredation of coagulation factors |
| pharmacogenetis | how genes effect response to drug • you can have pts. with he right dose but they either under or over coagulate • one possibility is genetics or reductase doesn’t respond as well |
| pharmacogenetis adn warfarin | • cyp2c9-lots of variants out there - so have high rates some have low rate of activity • varying ability of metabolism • other is vitamin k epoxide reductase - varying response to drug |
| absolute Ci of warfarin | pregnancy |
| factor xa inhibitor | Rivaroxaban, ximelagtrasn, dibigatran |
| Rivaroxaban | • approved for prevention of venous thrombosis following hip or knee replace • given oral • fixed dose no monitoring Xa inhibitor, rapid onset hsort hald life for afib and stroke prevention |
| direct thrombin inhibitors | Hirudin, lepirudin, bivalirudin, argatroban, melagatran |
| hirudin | from leech saliva |
| recombinant hirudin is what | lepirudin |
| bivalirudin | • bivalirudin 0 for use during coronary angioplasty |
| direct thrombin given iv | • all but hirudin and recumbent are given IV |
| first oral direct thrombin inhibitor | Ximelagtran removed due to liver tox |
| what do you do if pt gets HIT? | change heparin or change to direct thrombin inhibitor |
| how does body normally get rid of a clot | • plasminogen’s made in liver when clot is formed the body incorporates it into platelet plug • it is inactive hen its in platelet plug • when clot is no longer needed body activatesplasminogen activatorTurns it into plasmin |
| what dissoves fibrin | plasmin |
| naturan plasminogen activator | tPA |
| how does tPa work | converts pasminogen to plasmin |
| why dont we give plasmin but we give plasmingon activator | • we don’t give plasmin we give plasminogen activator • we don’t give plasmin because it is going to digest fibrin any and everywhere • plasminogen activator is only gnna work on plasminogen in the clot • |
| streptokinase | is another tPA from bacteria • powerful but antigenic |
| CI of tPA | recent sroke |
| why is tPA Ci in stroke | • what is most likely stopping a hemorrhage from recent stroke is a clot so we don’t want to lyse that |
| modifeid vriantes of tPA | • tenecteplase and reteplase : modified variants of tpA • genetically modified to be more specific with longer half life and better bioavailability |
| approved for STEMI and PE | Streptokinase |
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Cherry5301
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