Hematology and Oncology Drugs Flashcards
What is the MOA of heparin? Does heparin have a short or long half-life?
Heparin is an activator of anti-thrombin (thrombin is what cleaves fibrinogen to fibrin to form clot), which will decrease thrombin and decrease factor Xa.
Heparin has a short half-life
When do you use heparin? How do you monitor heparin?
immediate anticoagulation for pulmonary embolism, acute coronary syndrome, MI, DVT. Unlike warfarin, it is not teratogenic so used during pregnancy. You monitor heparin by looking at partial thromboplastin time (PTT: normal: 25-35 secs)
List some side effects associated with heparin use
- bleeding b/c it’s an anticoagulant
- heparin-induced thrombocytopenia -develop IgG Abs against heparin-bound platelet factor 4 (PF4). Ab-heparin PF4 complex will activate platelets leading to thrombosis and since you’re using up platelets, you will get thrombocytopenia.
- osteoporosis
- drug-drug interactions
Explain how heparin can cause heparin-induced thrombocytopenia
heparin use can cause production of autoantibodies against heparin bound platelet factor 4. Antibody+heparin-bound platelet factor 4 complex can activate platelets leading to thrombosis. Since platelets are being used up, can lead to thrombocytopenia.
How to treat a heparin toxicity? what’s the charge on the molecule?
Use protamine sulfate (a positively charged molecule) that will bind heparin which is negatively charged
List 2 LMW heparin and the synthetic heparin. How do they compare to regular heparin?
- LMW heparin: enoxaparin, dalteparin
- synthetic heparin: fondaparinux
- act more on factor Xa than thrombin
- better bioavailability
- 2-4x higher half-live
- can be administered subcutaneously (heparin is iv and sc)
- no need to monitor labs
- **but no antidote if there’s toxicity so not easily reversible
People who need immediate anticoagulation with heparin, but get heparin induced thrombocytopenia have what other alternatives?
-argatroban, bivalirudin, dabigatran are DIRECT thrombin inhibitor that can be used as alternatives to heparin in cases of HIT.
List the 3 direct thrombin inhibitors that can be used for immediate anticoagulation if heparin is contraindicated like in cases of HIT. Which one is related to hirudin, an anticoagulant used by leeches
- argatroban
- bivalirudin -related to hirudin, an anticoagulant used by leeches
- dabigatran
What’s the mech of action of warfarin aka coumadin? How is warfarin use monitored?
Warfarin interferes with y-carboxylation of vitamin K-dependent clotting factors II, VII, IX and X, and proteins C and S.
Warfarin use is monitored by prothrombin time/INR, affecting the extrinsic coagulation cascade.
How’s the half-life of warfarin?
long half-life
Warfarin metabolism can be affected by polymorphisms in the gene for?
Vitamin K epoxide reductase complex (VKORC1)
What are the clinical uses of warfarin?
-chronic anticoagulation (venous thromboembolism ppx, and prevention of stroke in atrial fibrillation)
AF is assoc with increased clotting b/c of disturbed blood flow so to prevent clots, warfarin is used ppx.
Warfarin or heparin cannot be used in pregnant ppl b/c of its teratogenicity?
Warfarin cannot be used in pregnancy b/c can cause dandy-walker malformation (cerebellar hypoplasia), blindess and intellectual disability.
What are some side effects assoc with warfarin?
- bleeding b/c it’s an anticoagulant
- teratogenic
- skin/tissue necrosis due to small vessel microthromboses
- “warfarin skin necrosis” -due to already shorter half-lives of proteins C and S (anti-coagulants) than factors II, VII, IX, X so in the beginning of warfarin treatment can be hypercoagulable
- drug-drug interactions
How to reverse Warfarin toxicity (too much bleeding)?
- give Vitamin K
- but for rapid reversal, give fresh frozen plasma.
Explain the need for “heparin bridging” during anticoagulation with warfarin.
- heparin is freq used when starting warfarin
- heparin activates anti-thrombin which decreases thrombin and factor Xa –> anti-coagulable state
- early warfarin use is assoc with hypercoagulability b/c proteins C, S (anticoaguants) < factors II, VII, IX, X = transient hypercoagulable state
*this reduces risk of recurrent venous thromboembolism and skin/tissue necrosis
Compare structure of heparin and warfarin.
heparin is large and negatively charged polymer (which is why its antidote protamine sulfate is + charged)
warfarin is small, amphipathic molecule.
Compare route of administration of heparin and warfarin
heparin is parenteral (IV, SC)
warfarin is oral (po)
Compare site of action of heparin and warfarin.
heparin = blood by activating antithrombin warfarin = liver by inactivating vit K epoxide reductase (enzyme in the liver)
Compare onset of action of heparin and warfarin.
heparin = rapid (secs) warfarin = slow, limited by half-lives of clotting factors that are already formed
Compare duration of action of heparin and warfarin.
heparin = acute (hrs) -short t1/2 (t1/2 = .7Vd/Cl) warfarin = chronic (days)
Compare if heparin and warfarin can inhibit coagulation in vivo
heparin = yes b/c works on the blood to activate anti-thrombin III warfarin = no b/c works on the LIVER
Direct thrombin (IIa) inhibitors = argatroban, bivalirudin, dabigatran. What are the 2 direct factor Xa inhibitors? What do you use them clinically for? Toxicity?
direct factor Xa inhibitors = Apixaban, rivaroxaban so they bind to and directly inhibitor factor Xa used as treatment and PPX for DVT and PE (rivaroxaban); stroke PPX in pts with AF (like warfarin)
given orally; and do not usu require coagulation monitoring. There’s a risk of bleeding and there’s no reversal agent.
List the 5 thrombolytics.
- tPA/tissue plasminogen activato (alteplase)
- rPA (reteplase)
- streptokinase
- TNK-tPA (tenecteplase)
What’s the mech of action of thrombolytics? What is the drug’s effect on PTT, PT, and platelet count?
- directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots
- clot buster –> increase bleeding –> increase PTT and increase PT; no effect on platelet count
What’s the clinical use for thrombolytics (clot busters)?
- Early MI (used within 3 - 4.5 hrs of onset of symptoms)
- early ischemic stroke (used w/in 3 - 4.5 hrs of onset of symptoms)
- direct thrombolysis of SEVERE PE
Thrombolytics are clot busters assoc with risk of bleeding. Thrombolytics (tPA, reteplase, streptokinase, tenectplase) are contraindicated in?
- pts with active bleeding
- h/o of intracranial bleeding
- h/o of stroke or head trauma within past 3 months
- known bleeding diastheses
- severe HTN (syst > 185, diastolic > 110)
- PLT count < 100,000
- age < 18
How to treat toxicity with thrombolytics? ALso, what can be used to correct factor deficiencies.
antidote for toxicity with thrombolytics = aminocaproic acid (inhibitor of fibrinolysis = prevent fibrin breakdown = preserve clot)
to restore factor deficiencies, you can give FFP and cryoprecipitate (source of fibrinogen)
Aspirin is an NSAID that irreversibly inhibits COX-1 and COX-2 via covalent acetylation. How long will the effect of aspirin last?
The plts cannot synthesize new COX until new platelets are made and then they can synthesize COX.
What are changes to PT, PTT, bleeding time, TXA2, prostaglandings, and leukotrienes when someone is on aspirin?
aspirin inhibits COX-1 and COX-2 which are enzymes responsible for making prostaglandins and thromboxanes. So a person will have lower levels of TXA2 and prostaglandins. No effect on leukotriene levels b/c those are produced by lipooxygenase.
PT, PTT are unaffected b/c aspirin doesn’t affect extrinsic or intrinsic coagulation pathway. Bleeding time will increase b/c TXA2 is impt in plt aggregation so lower TXA2 = lower plt aggregation = increase bleeding time
