Heme Drugs Flashcards
Heparin
Activates antithrombin-> decreases thrombin and factor Xa; short half life
Use: immediate anticoagulation for PE, acute coronary syndrome, MI, DVT,
Used in pregnancy; Follow PTT
Tox: bleeding, thrombocytopenia (HIT), osteoporosism drug-drug interaction
Antidote for tox: Protamin Sulfate (positively charged bind neg charged Heparin)
Enoxaparin, Dalteparin (LMWH) and fondaparinux
Act on Factor Xa, better bioavailability, longer half life than Heparin
No need lab monitoring, administered SubQ
HIT
IgG antibodies against Heparin bound platelet factor 4. This complex activates platelets -> thrombosis and thrombocytopenia
Argatroban, bivalirudin, dabigatran
leeches; inhibit thrombin directly
Alternative to Heparin if have HIT
Warfarin
Interefers with gamma carboxylation of Vitamin K dependent clotting factors (Factor 2, 7, 9, 10, C and S)
Labs: follow PT (increased) - extrinsic and common pathway. Long half life
Use: anticoagulation (venous thromboembolism prophylaxis), prevent stroke in A fib
CI: pregnant women
Warfarin toxicity
Bleeding, teratogenic, skin/tissue necrosis due to small vessel microthrombosis, drug-drug interaction
Protein C and S have shorter half lives -> early transient hypercoagulability with warfarin use
Warfarin antidote
Vitamin K
Rapid reversal: Fresh frozen plasma
Heparin bridging - to prevent transient hypercoaguable state and skin/tissue necrosis
Heparin V. warafarin
Heparin - large, anionic molecule; IV or SC; site of action: blood, onset: rapid - seconds, MOA: activates antithrombin -> decrease Xa and thrombin action; Duration: hours - acute; Reversal agent: protamin sulfate; follow PTT
Warfarin: small molecule, oral route, liver - site of action, onset of action: slow; MOA: inhibit activation of Vit K dependent factors; duration: chronic (days), reversala gent: Vitamin K, fresh frozen plasma; follow PT; teratogenic
Apixaban, Rivaroxaban
Direct Factor Xa inhibitors
Use: Tx and prophylaxis for DVT and PE, Stroke prophylaxis in A fib patients
No monitoring needed;
Tox: bleeding (no reversible agent)
Thrombolytics
Alteplase, tPA, streptokinase, tenecteplase
Direct or indirect conversion of plasminogen to plasmin-> cleaves thrombin and fibrin clots -> increased PT and PTT; no change in PC
Use: early MI, early ischemic stroke, severe PE
Toxicity of Thrombolytics and toxicity reversal
Bleeding, CI in patients with active bleeding, hx of intracranial bleed, recent surgery, bleeding diathesis or severe HTN
Toxicity tx: Aminocaproic acid (inhibits fibrinolysis), fresh frozen plasma and cryoprecipitate (to correct factor deficiencies)
Aspirin
Irreversible inactivates COX1 and 2 by covalent acetylation. Effect last until new platelets are produced-> increased BT, decreased TXA2 and PGs. No PT and PTT effects
Use: antipyretic, analgesic, anti-inflamamtory and anti-platelet
Tox: Gastric ulceration, tinnitis (CNVIII). Chronic use: Acute renal failure, interstitial nephritis and upper GI bleeding
Reye syndrome.
Overdose initially causes hyperventilation and respiratory alkalosis => mixed metabolic acidosis and respiratory alkalosis
ADP receptor inhibitors
Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine
Inhibit platelet aggregation by IRREVERSIBLY blocking ADP receptors and prevent GpIIb/IIIa receptors on platelets
Use: ACS, coronary stenting. decrease recurrence of thrombotic stroke
Tox: neutropenia, TTP
Cilostazol, Dipyramidole
Inhibits PDEIII -> increases cAMP in platelets -> inhibits platelet aggregation; vasodilators
Use: intermittent claudication, coronary vasodialtion, prevent stroke or TIA (combined with Aspirin), angina prophylaxis
Tox: Nausea, HA, facial flushing, hypotension, abdominal pain
GpIIb/IIIa inhibitors
Abciximab, eptifibatide, tirofaban
Prevent aggregation by direct inhibition of activated platelets
Abciximab - from monoclonal Ab Fab fragments
Use: unstable angina, coronary angioplasty
Tox: Bleeding thrombocytopenia
Antimetabolites
Azathioprine, 6-MP, Cladribine, Cytarabine, 5-fluouracil, MTX
Azathioprine, 6-MP, 6-thioguanine
Purine analog -> decreased de novo purine synthesis, activated by HGPRT.
Azathioprine metabolized to 6-MP
Use: prevent organ rejection, RA, IBD, SLE; wean patients off steroids in chronic disease
Tox: Myelosuppression, GI, liver.
Aza and 6-MP metabolized by Xanthine Oxidase; so CI with allopurinol or febuxostat
Cladribine
Purine analog -> inhibit DNA polymerase or DNA strand break
Use: Hairy Cell leukemia
Tox: Myelosuppression, nephrotoxicity, neurotoxicity
Cytarabine
Pyrimidine analog-> inhibits DNA polymerase
use: Leukemia (AML), Lymphomas
Toxicity: Leukopenia, Thrombocytopenia, Megaloblastic anemia, panCYTopenia
5-FU
Pyrimidine analong -> 5F-dUMP -> covalently complexes folic acid; complex inhibits thymidylate synthase-> decreased dTMP -> decreased DNA synthesis
Use: Colon cancer, Pancreatic cancer, Basal cell carcinoma (topical)
Tox: Myelosuppression, not reversible with leucovorin (folinic acid)
MTX
Folic acid analog competitive inhibits of dihydrofolate reductase -> decreased dTMP -> decreased DNA synthesis
Use: leukemia (ALL), lymphomas, choriocarcinoma, sarcomas
Ectopic pregnancy, medical abortion (with misoprostol), RA, psoriasis, IBD and vasculitis
MTX toxicity
Myelosuppression reversible with leucovorin
hepatotoxicity, mucositis, pulmonary fibrosis
Bleomycin
Free radical formation -> breaks DNA strands
Use: Testicular cancer, Hodgkin lymphoma
Tox: Pulmonary fibrosis, skin hyperpigmentation, mucositis, myelosuppression
Dactinomycin
Intercalates in DNA
Use: Wilm’s tumor, Ewing sarcoma, rhabdomyosarcoma
childhood tumors
Tox: myelosuppression
Doxorubicin
Generate free radicals, intercalate in DNA -> breaks DNA -> decrease replication
Use: Solid tumors, leukemias, lymphomas
Tox: Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia, toxic to tissues
