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Pharm-Block 3
Antithrombotics, antiplatelets, fibrinolytics
| Question | Answer |
|---|---|
| Heparin | UFH; prevent venous thrombosis, Tx PE or AMI; antithrombotic; speedy onset/quick recovery; antithrombin changes conformation and accelerates inactivation of coagulation factors thrombin (IIa) and Xa; doesn't cross placenta; binds PF-4, causes HIT |
| Enoxaparin (lovenox) | LMWH; antithrombotic; speedy onset/quick recovery; selectively accelerates interaction of antithrombin with factor Xa (NOT thrombin)! convenient SC wt-based injection that can be done at home; doesn't cross placenta; doesn't bind PF-4, rarely causes HIT |
| Dalteparin (fragmin) | LMWH; antithrombotic; speedy onset/quick recovery; selectively accelerates interaction of antithrombin with factor Xa (NOT thrombin)! convenient SC wt-based injection that can be done at home; doesn’t cross placenta; doesn't bind PF-4, rarely causes HIT |
| Tinzaparin (innohep) | LMWH; antithrombotic; speedy onset/quick recovery; selectively accelerates interaction of antithrombin with factor Xa (NOT thrombin)! convenient SC wt-based injection that can be done at home; doesn’t cross placenta; doesn't bind PF-4, rarely causes HIT |
| Fondaparinux (arixtra) | factor Xa inhibitor; antithrombotic; pentasaccharide UFH/LMWH sequence binds AT (not thrombin) and inhibits Xa; NO ptn or PF-4 binding; no monitoring, no HIT; 1xSC dose qd; long halflife |
| Warfarin (coumadin) | antithrombotic; inhibits vit K carboxylation of coagulation protein factors II, VII, IX, X (1972); red anticoag ptns C and S; *net effect is anticoag (paradox, can cause necrosis or purple toes);* admin w/other drug till existing factors degrade (5d-2wk) |
| Lepirudin (refludan) | direct thrombin inhibitor; antithrombotic; IV infusion; aPTT monitoring (may inc PT/INR); renal clearance; irreversible |
| Bivalirudin (angiomax) | direct thrombin inhibitor; antithrombotic |
| Argatroban | direct thrombin inhibitor; antithrombotic; IV infusion; aPTT monitoring (inc PT/INR); Hepatic clearance; reversible |
| Ximelagatran (exanta) | direct thrombin inhibitor; antithrombotic; NOT on market |
| Aspirin | antiplatelet |
| Clopidegrol (plavix) | ADP receptor blocker; antiplatelet |
| Ticlopidine (ticlid) | ADP receptor blocker; antiplatelet |
| Abciximab (ReoPro) | glycoprotein IIb/IIIa inhibitor; antiplatelet |
| Eptifibatide (integrilin) | glycoprotein IIb/IIIa inhibitor; antiplatelet |
| Tirofiban (aggrastat) | glycoprotein IIb/IIIa inhibitor; antiplatelet |
| Streptokinase (streptase) | fibrinolytic; 1-hr infusion; 18-23hr half-life; Ab production; hepatic clearance; Group A Strep origin |
| Alteplase (activase, tPA) | fibrinolytic; bolus + 90min infusion; 3-8hr half-life; no Ab production; hepatic clearance; recombinant |
| Reteplase (retavase, rPA) | fibrinolytic; 2 bolus doses 30min apart; 15-28hr half-life; no Ab production; renal clearance; recombinant |
| Tenecteplase (TNKase, TNK) | fibrinolytic; single bolus; no Ab formation; 18-20hr half-life; hepatic clearance; recombinant |
| Adverse effects of UFH | hypersensitivity, bleeding, thrombocytopenia (HAT, HIT), osteoporosis (suppress osteoclasts, activate osteoclasts) |
| How do normal endothelial cells prevent clotting? | via secretion of prostacyclin (prostaglandin I2) that binds platelet receptors, increases intracellular cAMP to stabilize inactive GPIIIb/IIa and inhibit granule release of Ca and aggregation agents |
| What happens when endothelial cells are damaged? | less prostacyclin is released; platelet receptors remain unbound and the intracellular cAMP is low; this leads to platelet aggregation; platelets also adhere to exposed collagen of subendothelium, triggering platelet activation |
| Platelet membrane receptors | prostacyclin (PG-I2); thrombin, thromboxane, exposed collagen...when bound they activate the platelet and trigger aggregation |
| Regulation of clot formation | ptn C activated at hi [thrombin]; w/cofactor ptn S they degrade factors Va & VIIIa; C also stim release of t-PA (tissue plasminogen activator); antithrombin (AT) inhibits thrombin & factors IXa, Xa, XIIa |
| Clot dissolution | must be removed to resume blood flow; vascular endothelium releases tPA after injury in response to ptn C stim; tPA is activated by fibrin binding; epithelial (pro)urokinase + tPA convert plasminogen to plasmin which digests fibrin and dissolves clots |
| What can we do to stop the clot formation? | coagulation cascade ==> antithrombics OR platelet AAA ==> antiplatelets |
| What can we do to break the clots already formed? | fibrinolytics |
| Heparin vs. (LMWH) | IV half-life: 2hrs (4hrs); anticoagulant response: variable (predictable); bioavailability: 20% (90%); adverse effects: freq bleeds (less bleeds); Tx setting: hospital w/aPTT 1.5-2.5x normal (hospital or outpatient); endothelial cells/MQs degrade (renal) |
| Thrombocytopenia | platelet count <150x10^9cells/L; can be caused by UFH therapy as Heparin-associated thrombocytopenia or Heparin-induced thrombocytopeina |
| Heparin-associated thrombocytopenia (HAT) | aka: HIT type 1; benign slight drop in platelets in 25% using UFH; w/in 5days of Tx; platelet count recovers with continued therapy |
| Heparin-induced thrombocytopenia (HIT) | aka: HIT type 2; *immune mediated* can lead to thrombotic complications (Venous: DVT, PE; Arterial: stroke, MI, gangrene, skin lesions); hi morbidity/mortality if not treated; Dx by presentation; lab findings take too long to confirm |
| Pathogenesis of HIT | activated platelets release PF-4; binds heparin; antigenic complx stimulates IgG; gG complex activates platelets (IIIa/IIb receptor exposed); platelet aggregation causes thrombocytopenia (paradox); excess PF-4 binds endothelium releasing tissue factor |
| Diagnosis of HIT | >50% drop in platelets; unexplained thrombosis; 4-14 days following injection of UFH (need time to develop Ab); Detection of heparin Ab (can be from previous UFH exposure); pts can lose limbs |
| Limitations of UFH | variable response d/t ptn and cell binding; dose dependent clearance (less predictable); inability to inactivate thrombin/factor Xa w/in a clot; IV admin; difficult monitoring; adverse effects |
| LMWH Special Considerations | may need to monitor anti-Xa activity in renal failure pts (CrCl <60mL/min d/t dose-dependent renal clearance); obesity >190kg (unsure about distribution in adipose); Pregnancy (not sure what Vd and weight to use)...if anti-Xa is unavailable, used UFH |
Created by:
bscaryp