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Session 2 Pharm14
Pharm -14- Anticoagulants
| Question | Answer |
|---|---|
| what is hemostasis | cessastion of blood loss from a damaged vessel |
| what is thrombosis | pathological formation of a hemsostatic plug |
| what is thrombus | a blood clot that forms in a vessel and stays there arterial thrombus- mostly platelets and leukocytes in a fibrin mesh venous thrombus- like a blood clot with a jelly-like red tail |
| What is embolism | all or part of a thrombus that has dislodged and moved to a distant site |
| what is fibrinolysis | process of body to prevent blood coag from growing and causing problems |
| Coagulation generally needs a stimulus to happen what are some signals that stimulate blood coagulation | ADP thromboxane A2 Ca2+ platelet factors |
| what are the two pathways of blood coagulations how are they different | extrinsic and intrinsic estrinsic- begins with release of tissue factor and activations of factor VIIa and Ca2+ Intrinsic Pathway- begins with activation of pro-enzymes (XII or XI) through contact with thrombin (or with glass in laboratory) |
| which coagulation pathway is faster extrinsic or intrinsic | extrinsic faster intrinsic slower |
| What is the result of the coagulation cascade with respect of prothrombin and soluble fibrinogen | prothrombin is converted by proteolytics to thrombin. Solubel fibrinogen is converted by the thrombin to insoluble fibrin forms a mesh network that aggregates platelets to form a thrombus |
| What does anti-thrombin do | antithrombin helps regulate thrombus formation it is a serine protease inhibitor that inactivates thrombin (factor IIa), IXa and Xa gets help from protein C (another anticoagulant) |
| what role does vit K play in coagulation | vit K dependent coag factors won't work if vit K is not present. Vit K has a cycle of being in a reduced active form (hydroquinone) to an oxidized state (Vit K epoxide) Hydroquinone- carries out gamme-carboxylation to activate coag factors in liver |
| what are the three targets of drug therpay in coagulation | prevent blood coagultion fibrin formation target platelet function fibrin removal (fibrinolysis) |
| What type of drug therapy is Heparin and what type of formulations are there | an Indirect thrombin inhibitor low molecular weight heparin unfractionated heparin |
| What is the structure of heparin where is it naturally found in the body | heterogenous mixture of sulfated mucopolysaccharides found in granules of basophils and mast cells |
| What is the MW range of unfractionated heparin vs low molecular weight heparin | UF Heparin- 5000-30000 LMWH- average MW of 6000 |
| What is the MOA of heparin | binds to anti-thrombin and enhances its effects 1000 fold to bind and inactivate thrombin (IIa), IXa and Xa LMWH- doesn't bind thrombin (IIA) but rapidly inactives factor Xa All preps have similar efficacy (UF, LMW, and fondaparinux) |
| What are the theraputic uses of heparin | initiate tx of venous thrombosis and pulmonary embolism. thrombosis on prosthetic heart valve thrombosis and embolization in patients w/ atrial fibrillation myocardial infarction in patients with unstable angina |
| What are the Pharmacokinetics of UFH and LMWH | UFH- IV most rapid, maitenance can be given Sub Q, IM should be avoided, dosing based on weight LMWH- SC (sub q) absorption more predictable than for UFH |
| How is heparin metabolized | cleared by reticuloendothelial system(liver) some active heparin is cleared by the renal system, and exreted in urine |
| what are the s/e of heparin | Bleeding- with toxicity- minimize by tight dosage control, patient selection, and monitoring. Caution in elderly or renal failure more likely to hemorrhage. heparin induced thrombocytopenia (HIT) (don't give heparin to them) |
| what is heparin-induced thrombocytopenia | rare but serious increased risk for thrombosis due to formation of antibodies to heparin and platelet factor 4. gen happens 2-14 days after starting heparin therapy. usually decreased platelet counts, may lead to thrombosis |
| how do you treat a heparin overdose | IV injection of protamine which forms a stable, inert complex. Should calculate protamine based on dose of heparin |
| What are the contraindications of heparin therapy | Hypersensitivity to UFH LMWH- pork products, hypersensitivity to UHF, history of HIT (heparin thrombocytopenia) |
| What is Lepirudin and argatroban | Lepirudin is a bivalent direct thrombin inhibitor Argatroban- monovalent direct thrombin inhibitor |
| what is the difference between lepirudin/argatroban and heparin | heparin is an indirect thrombin inhibitors lepirudin/argatroban- are DIRECT thrombin inhibtors |
| What is the MOA of lepirudin - argatroban- | lepirudin- binds substrate recognition and catalytic site of thrombin (factor IIa) to inhibit the coagulation cascade Argatroban- binds to and blocks the catalytic site on thrombin |
| what are the adverse effects of the direct thrombin inhibitors | hemorrhage is most serious s/e |
| when are direct thrombin inhibitors contra indicated lepirudin- argatroban- | lepirudin- CI in renal insufficiency Argatroban- CI in hepatic insufficiency |
| What is the therputic use of direct thrombin inhibitors | primary use in tx of HIT |
| What is the drug name for warfarin | coumadin |
| What are the pharmacokinetics of warfarin (coumadin) | 100% bioavailability over 99% is bound to plasma albumin. Effects delayed 12-16 hours full effect not seen for 8-16 days. T1/2 is 36 hours |
| what is the MOA of warfarin (coumadin) | blocks Gamma-carboxylation of glutamate residues in prothrombin factors VII, IX, X by inhibiting enzymes that reduce Vit K preventing its action in beta-carboxylation |
| what are the major s/e of warfarin toxicity | hemorrhage of the bowel or brain is the main adverse effect significant variablility in pharmacodyamic response and pharmoacokinetics with warfarin correct dosing requires continual monitoring. |
| Can you give warfarin during pregnancy | no it crosses placenta and causes birth defects |
| What possible drug interactions are common with warfarin therapy | some drugs can decrease metabolism of warfarin increasing risk of bleeding. aspirin or hyperthyroid meds may increase risk of bleeding via altered pharmacodynamic effects Vit K intake can interact with warfarin (green tea, broccoli) |
| How can you treat warfarin overdose | administer Vit K (via fresh frozen plasma, parenteral Vit K) |
| how do heparin and warfarin differ in their clinical uses | heparin is used acutely warfarin is used in prolonged therapy |
| what would you give to PREVENT Deep vein thrombosis Pulmonary embolus Thrombosis and emboli in patients with atrial fib Thrombosis on prosthetic heart valves Clotting in extracorporeal circulations (e.g. during hemodialysis) MI in pt with unstable | Anticoagulants either heparin or warfarin deepending on time frame |
| What are the contraindications to anticoagulation therapy | active bleeding hemophilia severe liver disease severe thrombocytopenia inability to monitor treatment Heparin- hx of HIT Warfarin- Pregnancy |
| What is the fibrinolysis system | gets activated along with caog cascade plasminogen gets converted to plasmin (by tissue plasminogen activator tPA, Urokinase-type plasminogen activator or kallikrein, neutrophil elastase) plasmin helps thrombolysis |
| What fibrinolytic drug was isolated from streptococci and binds to and activates plasminogen to convert it to plasmin has a low fibrin specificity | streptokinase (streptase) |
| What is the MOA of tPA (tissue plasminogen activators) such as streptokinase, reteplase, teneteplas, alteplase | enzymatically convert plasminogen to plasmin |
| How do the t-PAs, alteplase and teneteplase differ from alteplase | reteplase and teneteplase have mutations that give them longer half lives than alteplase. |
| Which t-PA drugs act like endogenous t-PA and have specificity for fibrin bound plasminogen | alteplase and teneteplase considered clot specific drugs |
| What are the contra indications to fibrinolytic therapy via exogenous t-PAs (alteplase, steptokinase, reteplase, teneteplase) | surgery in last 10 days serious GI bleed w/in 3 months hx of HTN active bleeding or hemorrhagic disorder CVA or active intracranial process aortic dissection acute pericarditis |
| what are the therapeutic uses of fibrinolytics | Pulmonary emoblism with hemodynamic instability severe deep venous thrombosis ischemic stroke- fibrin specific over non specific Acute MI (reduce mortality 20%) |
| why would you prescribe or give streptokinase over the better recombinant proteins like reteplase, teneteplase or alteplase | the recombinants costs 12x as much as streptokinase |
| what are the s/e of fibrinolytics | hemorrhage due to lysis of fibrin in physiological thrombi (IE thrombi that formed to stop a bleed) Streptokinase can cause antibody production limiting its long term usage |
| How are platelets kept in the resting state | intact endothelial cells release NO, prostaglandin I2 to keep platelets inactive. (activation of prostacyclin receptor by PGI2, is a Gs coupled receptor increases cAMP and decreases release of CA2+ from ER keeping platelet inactive) |
| What are the receptors on the surface of platelets that bind fibrin | GP IIb and IIIa during inactive state these receptors can't bind fibrin (kept that way by NO, PGI2) |
| How do platelets get activated | injury to enothelium decreases PGI2 release decreases cAMP and you get a release of CA2+ from the ER. Platelet GP receptors are now active. Platelet adhere tightly to damaged basal lamina via von Willebrand factor. Ater this it binds collagen |
| What does binding of collagen by the platelet initiate | initiates intracellular acitivity that activates COX-1 leading to production and release of TxA2, ADP, Ca2+ and other molecule involved in coagulation |
| What is one of the most important signaling molecules for platelet aggregation | ADP- it stimulates P2Y12 receptor mainly found on platelets. Decreases intracellular cAMP |
| What signal apart from stimulating platelet aggregation also stimulates localized vasoconstriction how does it do this | TxA2- stimulates thromboxane receptor (TP), increasing Ca2+ release, |
| what is the MOA of thromboxane A2 | causes platelets to change shape and release granules and aggregate. |
| What is the MOA of Aspirin as a anticoagulant | acetylates active site of COX-1 preventing formation of precursor to thromboxane A2, inhibition of COX-1 is irreversible because enzyme cannot be regenerated |
| What are the therapeutic uses of aspirin | prevents MI by decreasing stickiness of platelets. Used in TIA may be combined with other anticoag drugs to increase benefits because of its different MOA |
| what are the s/e of aspirin | bleeding, salicylism |
| what are the following Clopidogrel (plavix) Prasugrel (effient) new in july 2009 Ticlopidine (Ticlid) | ADP antagonists |
| What is the MOA of the ADP antagonists (clopidogrel, prasugrel, ticlopidine) | irreversibly bind to and inhibit the P2Y12 receptor, the receptor for ADP. Receptor blockade prevents platelet aggregation |
| What is the therpeutic use of ADP antagonists (clopidrogrel, prasugrel, ticlopidine) | used in place of aspirin or along with it (synergistic effect) Clopidogrel- reduces rate of stroke and MI in pt with recent MI, Peripheral art disease, or acute coronary syndrome. Prasugrel- appproved to reduce risk of heart attack following angiopla |
| What are the s/e of ADP antagonists (clopidrogrel, prasugrel, ticlopidine) | Thrombotic Thrombocytopenic purpura- more often in ticlopidine |
| What are Abciximab (reopro) eptifibadine (inegrilin) Tirofiban (aggrastat) | glycoprotein IIB/IIIA receptor blockade anti-platelet agents |
| What is the MOA of glycoprotein IIB/IIIA receptor blockade anti-platelet agents (abciximab(reopro), Eptifibadine (inegrilin), tirofiban (aggrastat)) | prevent interaction of IIb/IIIa to fibrionogen or von willebrand factor. prevent interaction of platelet with foreign surfaces (endothelium) and other platelets. prevents platelet aggregation |
| what are the therapeutic uses of glycoprotein IIB/IIIA receptor blockade anti-platelet agents (abciximab(reopro), Eptifibadine (inegrilin), tirofiban (aggrastat)) | acute coronary syndrome |
| what are the s/e of glycoprotein IIB/IIIA receptor blockade anti-platelet agents (abciximab(reopro), Eptifibadine (inegrilin), tirofiban (aggrastat)) | Bleeding |
| What is the MOA of the anit-platelet agent dipyridamole | phosphodiesterase which prevents the degradation of cAMP, decreasing activation and aggregation of the platelet. |
| What is the therapeutic use of anit-platelet agent dipyridamole | most effective when used with warfarin to prevent formation of emboli originating from prosthetic heart valves |
| What is the tx for hereditary clotting defects (ie hemophilia) | replace the missing factor, VIII, IX or others can be supplied by fresh or concentrated plasma preps. Recombination factors are available but expensive |
| what is the tx for acquired bleeding disorders | most likely in liver disease, vit K defieciency, excessive oral anticoag therapy. -may just need to give Vit K replacement |
Created by:
smaxsmith
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