Heme/Onc Flashcards
Heparin
Mechanism: Activates antithrombin -> decreases thrombin and factor Xa. Short half life
Clinical use: Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT; used during pregnancy since doesn’t cross placenta.
Toxicity:
- Bleeding - follow PTT
- thrombocytopenia (HIT: ab-heparin-PF4 complex activates platelets -> thrombosis and thrombocytopenia)
- Osteoporosis
Antidote= protamine sulfate (+charged binds -charged heparin)
Low molecular weight heparins (enoxaparin, dalteparin) and fondaparinux
act on Xa > thrombin, better bioavailability, 2-4x longer half life, administered subQ w/out lab monitoring. Not easily reversible
Argatroban, bivalirudin, dabigatran
Mechanism: Related to hirudin (leech anticoagulant); Directly inhibits thrombin (no effect on Xa)
Use: Alternative to heparin for patients with HIT
Warfarin
Mechanism: Inhibits epoxide reductase -> vitamin K cannot activate -> interferes w gamma-carboxylation of vitamin K clotting factors: II, VII, IX, X, C, S. Metabolism affected by polymorphisms in gene for vitamin K epoxide reductase complex (VKORC1)
Clinical use: Chronic anticoagulation, not used in pregnant women since crosses placenta
Toxicity: Bleeding - follow PT/INR Teratogeneic Skin/tissue necrosis C and S have shorter half-lives -> early transient hypercoaguability with warfarin -> use heparin early
Reversal agent- vitamin K; rapid reversal: fresh frozen plasma
Direct factor Xa inhibitors
Apixaban, rivaroxaban
Mechanism: Directly inhibits Xa
Clinical use: Treatment and prophylaxis for DVT and PE (rivaroxaban); stroke prophylaxis in patients with a. fib.
Toxicity:
Bleeding (no reversal agent)
Thrombolytics
Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA)
Mechanism: Directly or indirectly aids in conversion of plasminogen to plasmin -> cleaves thrombin and fibrin clots.
Increases PT and PTT, no change in platelet count or bleeding time
Clinical use: Early MI, early ischemic stroke, direct thrombolysis of severe PE
Toxicity:
Bleeding
Contraindicated: active bleeding, hx of intracranial bleeding, recent surgery, known bleeding diatheses, severe HTN
Treat toxicity: aminocaproic acid (fibrinolysis inhibitor). FFP and cryoprecipitate to correct factor deficiencies
Aspirin
Mechanism: Anti-platelet drug. Irreversible inhibition of COX-1 and 2 by covalent acetylation -> decreased TXA2 and prostaglandins -> Increases bleeding time. platelets can’t synthesize new enzyme –> effects last until new platelets (8-10d)
Clinical use: Antipyretic, analgesic, anti-inflammatory, anti-platelet (decreased aggregation)
Toxicity:
Gastric ulceration
tinnitus (CN VIII)
Chronic use -> acute renal failure, interstitial nephritis and upper GI bleed
Reye syndrome in children w viral infection
Overdose- hyperventilation and respiratory alkalosis but becomes mixed metabolic acidosis-respiratory alkalosis
ADP receptor inhibitors
Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine
Mechanism: Inhibits platelet aggregation by irreversibly blocking ADP receptors. Prevents expression of glycoproteins IIb/IIIa on platelet surface
Clinical use: Acute coronary syndrome (STEMI, NSTEMI, unstable angina), coronary stenting, decreases incidence/recurrence of thrombotic stroke
Toxicity:
Neutropenia (ticlopidine) -> clopidogrel preferred
TTP
Cilostazol, dipyridamole
Mechanism: PDE3 inhibitor-> increases constant cAMP in platelets -> inhibits platelet aggregation (pulsatile cAMP increases aggregation); vasodilates
Clinical use: Intermitten claudication, coronary vasodilation, prevent stroke or TIA (combined w aspirin), angina prophylaxis
Toxicity: Nausea HA Facial flushing hypotension Abdominal pain
GPIIa/IIIb inhibitors
Abciximab, eptifibatide, tirofiban
Mechanism: binds GPIIb/IIIa preventing aggregation. Abciximab made from monoclonal Fab fragments (mechanism mimics Glanzmann thrombasthemia)
Clinical use: Unstable angina, percutaneous transluminal coronary angioplasty
Toxicity:
Bleeding and thrombocytopenia
Azathioprine, 6-mercaptopurine (6MP), 6-thioguanine (6TG)
Mechanism: purine analog -> decrease de novo purine synthesis (S phase). Activated by HGPRT. Azathioprine metabolized to 6MP
Clinical use: Prevent organ rejection, RA, IBD, SLE; Used to wean patients off steroids and treat steroid-refractory chronic disease
Toxicity:
Myelosuppression, GI, liver
Azathioprine and 6MP metabolized by XO -> increased toxicity with allopurinol or febuxostat
6TG is not metabolized by XO-> can use with allopurinol etc
Cladribine (2-CDA)
Mechanism: Purine analog ->multiple mechanism (inhibit DNA polymerase, DNA strand breaks etc) (S phase)
Clinical use: Hairy cell leukemia
Toxicity: Myelosuppression, nephrotoxicity and neurotoxicity
Cytarabine (arabinofuranosyl cytidine)
Mechanism: Pyrimidine analog -> inhibits DNA polymerase (S phase)
Clinical use: Leukemias (AML), lymphomas
Toxicity:
CYTarabine causes panCYTopenia: leukopenia, thrombocytopenai, megaloblastic anemia
5-fluorouracil (5-FU)
Mechanism: Pyrimidine analog bioactivated to 5F-dUMP which covalently complexes folate -> complex inhibits thymidylate synthase -> can’t convert dUMP to dTMP -> decreased DNA synthesis (S phase)
Clinical use: Colon cancer, pancreatic cancer, basal cell carcinoma (topical)
Toxicity:
Myelosuppression which is not reversible with leucovorin (folinic acid); can give thymidine to bypass drug effect
Methotrexate (MTX)
Mechanism: Folate analog that competitively inhibits dihydrofolate reductase -> can’t convert DHF to THF -> decreased dTMP -> decreased DNA synthesis (S phase)
Clinical use:
- Cancers: leukemias (ALL), lymphomas, choriocarcinoma, sarcomas
- Non-neoplastic: ectopic pregnancy, medical abortion (w/ misoprostol), RA, psoriasis, IBD, vasculitis
Toxicity: Myelosuppression reversible with leucovorin (folinic acid) Hepatotoxicity Mucositis (mouth ulcers) *Pulmonary fibrosis
Bleomycin
Mechanism: Induces free radical formation -> breaks in DNA strands -> prevents progression from G2
Clinical use: Testicular cancer, Hodgkin lymphoma
Toxicity: Pulmonary fibrosis*, skin hyperpigmentation, mucositis, minimal myelosuppression
