First Aid Hematology and Oncology-Pharmacology

Heparin MOA
Cofactor for activation of antithrombin. Decreases thrombin and factor Xa.

Clinical use, heparin
Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT. Used during pregnancy (doesn’t cross placenta). Follow PTT.

Toxicity, heparin
Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions.

Antidote, heparin?
Antidote=protamine sulfate (positively-charged, binds negatively-charged drug)

Enoxaparin, dalteparin
Low weight molecular heparins

Low molecular weight heparins (enoxaparin, dalteparin)
Heparins that act more on factor Xa, have better bioavailability and longer half life. Can be given subQ and no lab monitoring necessary. Not easily reversible.

Heparin induced thrombocytopenia (HIT)
Development of IgG abs against heparin bound to platelet factor 4 (PF4). Antibody-heparin PF4 complex activates platelets–>thrombosis and thrombocytopenia

Lepirudin, bivalirudin
Derivatives of hirudin, the anticoagulant used by leeches; inhibit thrombin. Alternative to heparin for anticoagulating patients with HIT.

Warfarin MOA
Interferes with normal synthesis and gamma carboxylation of vitamin K dependent clotting factors II, VII, IX and X and proteins C and S. Metabolized by cytochrome P-450 pathway. In lab, has effect on extrinsic pathway and increases PT (The EX-PresidenT went to war(farin)).

Use, warfarin
Used in chronic anticoagulation. Not used in pregnant women because can cross the placenta.

PT/INR values, warfarin
What labs should be followed during warfarin ttmt?

Toxicity, warfarin
Bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions

Reversal of warfarin
Reversal: vitamin K
Rapid reversal of severe overdose: fresh frozen plasma

Alteplase
A thrombolytic, tPA

Reteplase
A thrombolytic, rPA

Tenecteplase
Thrombolytic, TNK-tPA

Alteplase, reteplase, tenecteplase
Name the thrombolytics

Thrombolytics
Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. Increased PT and PTT, no change in platelet count.

Uses of thrombolytics?
Uses: Early MI, early ischemic stroke, direct thrombolysis of severe PE

Toxicity, thrombolytics?
Toxicity=bleeding
Contraindicated in pts with active bleeding, hx of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension.

Ttmt of toxicity, thrombolytics?
Ttmt of toxicity=aminocaproic acid (an inhibitor of fibrinolysis)

Aspirin, MOA
Irreversibly inhibits COX1 and 2 via covalent acetylation. Platelets can’t make new enzyme, so effect lasts until new platelets are made. Increases bleeding time, decreases TXA2 and prostaglandins. No effect on PT or PTT.

Clinical use, aspirin
Use: antipyretic, analgesic, anti-inflammatory, antiplatelet (decreased aggregation).

Toxicity, aspirin
Toxicity: gastric ulceration, tinnitus (CN VIII). Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding. Reye’s syndrome in children with viral infection.

What does OD on aspirin cause
OD causes respiratory alkalosis and metabolic acidosis

ADP receptor inhibitors?
Clopidogrel, ticlopidine, prasugrel, ticagrelor

MOA, ADP receptor inhibitors?
Inhibit platelet aggregation by irreversibly blocking ADP receptors (ADP its receptor on surface of platelet causes GP IIb/IIIa insertion on the membrane, receptor for fibrinogen). Inhibits fibrinogen binding by preventing glycoprotein IIb/IIIa from binding to fibrinogen.

Toxicity, ADP receptor inhibitors (ticlopidine)
Toxicity: neutropenia

Phosphodiesterase inhibitors
Cilostazol is what type of drug?

ADP receptor inhibitor
Ticlopidine=?

ADP receptor inhibitor
Prasugrel=?

ADP receptor inhibitor
Clopidogrel=?

ADP receptor inhibitor
Ticagrelor=?

Phosphodiesterase III inhibitor
Dipyridamole=?

Phosphodiesterase III inhibitors
Cilostazol, dipyridamole are this type of drug

GP IIb/IIIa inhibitor
Abciximab is what type of drug?

GP IIb/IIIa inhibitor
Eptifibatide=?

GP IIb/IIIa inhibitor
Tirofiban=?

GP IIb/IIIa inhibitors
Abciximab, eptifibatide, tirofiban=what type of drugs?

Cilostazol, dipyridamole MOA
Phosphodiesterase III inhibitor, increase cAMP in platelets, thus inhibiting platelet aggregation; vasodilators.

Clinical use, cilostazol, dipyridamole?
Use: Intermittent claudification, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), angina prophylaxis

Toxicity, cilostazol, dipyridamole?
Tox: nausea, headache, facial flushing, hypotension, abdominal pain.

MOA, abciximab, eptifibatide, tirofiban
MOA: bind to glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Abciximab made from monoclonal Ab Fab fragments.

Clinical use, abciximab, eptifibatide, tirofiban?
Use: acute coronary syndromes, percutaneous transluminal coronary angioplasty.

Toxicity, abciximab, eptifibatide, tirofiban?
Toxicity: bleeding, thrombocytopenia

Act on S phase, antimetabolites
Antimetabolites act at what phase in the cell cycle?

Act on S phase, G2 phase
Etopiside acts on which phases on cell cycle?

G2 phase
Bleomycin acts on which phase of the cell cycle?

M phase
Vinca alkaloids and taxols work at which phase of the cell cycle?

Methotrexate, MOA
MOA:Folic acid analog that inhibits dihydrofolate reductase
-v dTMP, v DNA, and v protein synthesis

Methotrexate, clinical use
Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas
Non-neoplastic: abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis

MTX, toxicity
Toxicity: myelosuppression reversible with leucovorin (folinic acid) rescue)
-Macrovesicular fatty change in liver
-Mucositis
-Teratogenic

5-fluorouracil MOA
Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thymidylate synthase–> vdTMP–>v DNA and v protein synthesis

5-fluorouracil uses
Uses: Colon cancer, basal cell carcinoma

5-fluorouracil toxicity
Myelosuppresion which isn’t reversible via leucovorin.
Photosensitivity

Antidote for 5-FU OD?
Antidote=thymidine

MOA, cytarabine (arabinogfuranosyl cytidine)
MOA: pyrimidine analog–>inhibition of DNA polymerase

Clinical use, cytarabine
Clinical use: leukemias, lymphomas

Tox, cytarabine
Toxicity: leukopenia, thrombocytopenia, megaloblastic anemia

MOA, azathioprine, 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG)
MOA: purine (thiol) analogs–>v de novo purine synthesis. Acitvated by HGPRT.

Clinical use, azathioprine, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG)
Use: Leukemias

Azathioprine, 6-mercaptopurine, and 6-thioguanine toxicity
Tox: bone marrow, GI, liver
Metabolized by xanthine oxidase; thus increases toxicity with allopurinol

Antitumor antibiotics
What do dactinomycin (actinomycin D), doxorubicin, daunorubicin, and bleomycin have in common?

Dactinomycin MOA
Antitumor abx that intercalates in DNA

Dactinomycin clinical use
Use: wilm’s tumor
-Ewing’s sarcoma
-Rhabdomyosarcoma
-Used for childhood tumors (children ACT out)

Dactinomycin, toxicity
Tox: myelosuppression

Doxorubicin, daunorubicin MOA
MOA: generate free radicals. Noncovalently intercalate in DNA–>breaks in DNA–>decrease replication

Doxorubicin, daunorubicin use
Use: solid tumors, leukemias, lymphomas

Doxorubicin, daunorubicin tox
Tox: cardiotoxicity (dilated cardiomyopathy)
-Myelosuppression
-Alopecia
-Toxic to tissues following extravasation

Doxorubicin, daunorubicin antidote
Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity

Bleomycin MOA
MOA: induces free radical formation, which causes breaks in DNA strands

Bleomycin uses
use: testicular cancer, lymphoma

Bleomycin tox
Tox: pulmonary fibrosis, skin changes. Minimal myelosuppression.

Alkylating agents
Cyclophosphamide
Ifosfamide
Nitrosureas (carmustine, lomustine, semustine, streptozocin)
Busulfan

Cyclophosphamide, ifosfamide MOA
MOA: covalently X-link (interstrnad) DNA @ guanine N-7. Require bioactivation by liver.

Uses, cyclophosphamide, ifosfamide
Uses: solid tumors, leukemia, lymphomas, and some brain cancers.

Tox, cyclophosphamide, ifosfamide
Tox: myelosuppression
-Hemorrhagic cystitis

Mesna (thiol group binds toxic metabolite)
Substance that can be used to prevent hemorrhagic cystitis caused by cyclophosphamide, ifosfamide

Nitrousoureas
Carmustine, lomustine, semustine, streptozocin are?

MOA, nitrousureas
MOA: require bioactivation, cross BBB–>CNS

Uses, nitrousureas
Uses: brain tumors (including glioblastoma multiforme)

Toxicity, nitrousureas?
Tox: CNS toxicity (dizziness, ataxia)

MOA, busulfan
MOA: alkylates DNA

Uses, busulfan
Uses: CML, also used to ablate pt’s bone marrow before bone marrow transplantation.

Toxicity, busulfan:
Tox: pulmonary fibrosis, hyperpigmentation

Microtubule inhibitors
Vincristine, vinblastine
Paclitaxel, other taxols

MOA: vincristine, vinblastine
MOA: alkaloids that bind to tubulin in M phase and block polymerization of microtubules so that mitotic spindle cannot form “Microtbules are the VINes of your cells

Tox, vincristine
Tox: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus

Tox, vinblastine
Tox: bone marrow suppress

Vinblastine BLASTS Bone marrow

MOA, paclitaxel, other taxols
MOA: hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur). “it is TAXing to stay polymerized”

Toxicity, paclitaxel and other taxols
Tox: myelosuppression and hypersensitivity

MOA, cisplatin and carboplatin
MOA: cross-link DNA

Tox, cisplatin and carboplatin
Tox: nephrotoxicity and acoustic nerve damage.

Amifostine (free radical scavenger) and chloride diuresis
How to prevent nephrotoxicity with cisplatin and carboplatin?

MOA, etopiside, teniposide
MOA: inhibit topoisomerase II–>increase DNA degradation

Tox, etopiside, teniposide
Tox: myelosuppression, GI irritation, alopecia

MOA, hydroxyurea
MOA: inhibits ribonucleotide reductase–>v DNA Synthesis (S phase specific)

Tox, hydroxyurea
TOx: bone marrow suppression, GI upset

MOA, prednisone, prednisolone
MOA: may trigger apoptosis, may even work on non-dividing cells

Toxicity, prednisone, prednisolone
Tox: Cushing-like sx, immunosuppression, cataracts, acne, osteoporosis, htn, peptic ulcers, hyperglycemia, psychosis

MOA: tamoxifen, raloxifene
MOA: SERMs, receptor antagonists in breast and agonists in bone. Block the binding of estrogen to estrogen receptor-positive cells.

Toxicity, tamoxifen
Tox: partial agonist in endometrium, which increases the risk of endometrial cancer; hot flashes

Tox, raloxifene
Tox: no increase in endometrial CA because it’s an endometrial antagonist

Trastuzumab (Herceptin) MOA
MOA: monoclonal Ab vs HER-2 (c-erb B2), a tyrosine kinase. Helps kill breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity.

Toxicity, trastuzumab
Tox: cardiotoxicity

MOA, Imatinib (gleevec)
MOA: Philadelphia chromosome bcr-abl tyrosine kinase inhibitor

Uses, imatinib
Use: CML, GI stromal tumors

Tox, imatinib
Fluid retention=tox

Rituximab MOA
MOA: monoclonal Ab vs. CD20, which is found on most B cell neoplasms

Vemurafenib MOA
MOA: small molecule inhibitor of forms of the B-Rag kinase with the V600E mutation.

Vemurafenib use
Use: metastatic melanoma

Bevacizumab MOA
MOA: monoclonal ab vs VEGF. Inhibits angiogenesis.

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