Heme-Onc

drugs that decrease the formation of FIBRIN clots.

• -Oral anticoagulants (Warfarin) --> decrease hepatic synthesis of II, VII, IX, X
• -Heparin--> inhibits activity of activated clotting factors (esp. IIa, Xa)
• -Endogenous anticoagulants (Protein C, S)--> proteolyze V, VIII

• anticoagulant
• -mix of large sulfated polysacch, water-soluble (Parenteral!)
• -cofactor for Antithrombin III (ser-protease inhibitor)-->breakdown II,IX,X,XI, XII (intrinsic path!)
• -works both in vivo, in vitro
• -short half-life. Does NOT cross placenta (safe in pregnancy)
• -monitor w/ PTT

USE- immediate anticoagulation for Pulm embolism, stroke, acute coronary syndrome, MI, DVT, DIC, unstable angina, (safe in pregnancy)

• SE- bleeding, Osteoporosis, Heparin-induced thrombocytopenia (type II)- anti-heparin-PF4 IgG
• (actually thrombosis!)
• Antidote for HIT- Protamine sulfate
• Alternative- Argatroban, Lepirudin, Bivalirudin

• low molecular weight heparin
• -bind, activate thrombin

Protamine sulfate

• - + charged molecule, bind and block Heparin
• -fast onset

(ex) Enoxaparin

• Advantages over unfractionated Heparin:
• -longer half life, better bioavailability
• -LESS heparin-induced thrombocytopenia
• -better action against Thrombin (Xa)
• -can be given SubQ
• -no need to monitor

• Disadvantages:
• -Not easily reversible.

• Thrombin-specific anticoagulant
• -Hirudin
• -directly inhibit Thrombin
• -does NOT need antithrombin (like Heparin does)

USE- alternative to Heparin for anticoagulating patients with HIT!

Bivalirudin- use with Aspirin in unstable angina when doing PTCA.

• Long term Anticoaglant
• -small, lipid soluble, vit-K derivative
• -inhibit liver epoxide reductase--> prevent gamma carboxylation of vit-K dependent coag factors (II, VII, IX, X, Protein C, S)
• -more effect on Extrinsic pathway (b/c VII shortest half life)
• -works only in vivo
• -long half life, PO
• -HIGH protein binding, metabolized by Cyps
• -CROSS placenta! teratogenic!
• -monitor w/ PT/INR (intrinsic)

USE- long-term anticoagulation (ambulatory) for thromboses, emboli, post-MI, heart valve, atrial arrhythmias

SE- Bleeding, Hemorrhagic skin necrosis! (low protein C initially), Teratogenic, drug interactions (Cyp-inducers decrease efficacy, Cyp inhibitors increase toxicity), Cholestyramine (trap bile salt) decrease absorption!, Displaced by other drugs (ASA, sufonamides, phenytoins--> incr PT)

Antidote or overdose- Vit K (takes time), FFP (immediate reversal)

• Warfarin inhibits syn of II, VII, XI, X, Protein C, S
• -VII, protein C have the shortest half lives.

-Warfarin initially cause transient deficiency of Protein C b/c protein C has shorter half life than others, first one to decrease--> inactivate extrinsic pathway, Protein C but intrinsic coag path remain active for a few more days--> hypercoagulability--> vascular thrombosis, skin necrosis!

• RX- start the patient on Heparin and very small dose of Warfarin initially.

• Highly protein bound, but weakly bound, so can be displaced by other highly protein bound drugs:
• -Phenytoin
• -Sulfonamides
• -ASA

• Broken down by Cyps
• Decrease efficacy w/ Cyp inducers:
• -Phenobarbital
• -Phenytoin
• -Rifampin
• -Carbamazapine

• Increase toxicity with Cyp blockers:
• -Cimetidine
• -Amiodarone
• -Metronidazole
• -TMP-SMX
• note: many A-fib patients on both Amiodarone + Warfarin!

• Warfarin is PO, lipid soluble, so absorbed via Bile micellization like Fat soluble vitamins:
• -Cholestyramine decrease GI absorption of Warfarin!

• Break thrombi by catalyzing formation of endogenous fibrinolytic plasmin (serine protease)!!
• -enhance Plasminogen---> Plasmin--> degrade Thrombin, Fibrinogen, Fibrin.
• -increase PT, PTT, no change in Plts!

• Drugs:
• -Alteplase- recombinant tPA
• -Streptokinase (bacterial)
• -Urokinase

USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke (tPA)- but SCAN it first to rule out Hemorrhagic stroke!

• -Effectiveness depends on TIMING for MI!
• must give within 4 hrs! (when still reversible)
• -ASA, beta-blockers, nitrates further decrease mortality
• -Adenosine decrease infarct size

SE- bleeding, intracerebral hemorrhage

Antidote: treat toxicity w/ Aminocaproic acid, Tranexamic acids

• Thrombolytic/ fibrinolytic
• -derived from bacteria (beta-hemolytic streps)
• -Act on both bound and free plasminogen (not clot specific)--> deplete circulating plasminogen and V, VIII.
• -Bind plasminogen to activate it to plasmin
• -increase PT, PTT, no change in plts

USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke- but SCAN it first to rule out Hemorrhagic stroke!

• SE- antigenic! (strep antibodies may decrease efficacy), bleeding, intracerebral hemorrhage
• DO NOT use in patients with active bleeding, hx of intracranial bleeding, severe HTN

Rx toxicity w: Aminocaproic acid, Tranexamic acid

• Thrombolytic/ Fibrinolytic
• -recombinant tPA
• -catalyze Plasminogen--> Plasmin
• -increase PT, PTT, no change in Plts
• -Clot specific! acting mainly on Fibrin-bound plasminogen
• -natural activator, so NO allergy problems!
• -expensive!

USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke (tPA)- but SCAN it first to rule out Hemorrhagic stroke!

• SE- bleeding, intracranial hemorrhage.
• DO NOT use in patients with active bleeding, hx of intracranial bleeding, severe HTN

Rx toxicity w: Aminocaproic acid, Tranexamic acid

• Platelet aggregation:
• Increase by:
• -ADP, 5-HT, TXA2, Thrombin, Alpha-2 agonists

• Decrease by:
• -PGI2, cAMP, ASA, Ticlopidine, Clopidogrel
• gP IIb/IIIa blockers

• Antiplatelet
• -acetylate, irreversibly inhibit Cox-1 and Cox-2 (at high dose)--> prevent TXA2--> increase bleeding time
• -NO effect of PT, PTT.

• USE- low dose prevent MI, recurrence
• -prophylaxis in atrial arrhythmias
• -antipyretic, analgesic, anti-inflammatory, anti-platelet

• SE- gastric ulcer (decr PGE2), Bleeding, Hyperventilation, Reye's syndrome, Tinnitis (CN VIII)
• Salicylim (very high dose)- vertigo, tinnitis, hearing loss, stimulate respiratory drive--> hyperventilate--> resp alkalosis plus salicilate metabolic acidosis

Samter's triad: Asthma, aspirin hypersensitivity (nasal, bronchospasm, flushing), nasal polyposis (b/c increase leukotriens!!)

• Antiplatelet
• -irreversibly block ADP-receptor-->block platelet activation/ aggregation (decrease gP IIb/IIIa expression)

• USE- acute coronary syndrome, coronary stenting!
• -alternative to ASA in TIA, post-MI, unstable angina (decrease recurrence of thrombotic stroke)

• SE- Hemorrhage,
• Ticlopidine--> Neutropenia!! (fever, mouth ulcers, neutropenia, ITP (do CBC every 3 weeks initially)

• Antiplatelet
• -monoclonal antibody block gp IIb/IIIa (fibrinogen receptor) on activated platelets--> decrease plt aggregation

USE- Acute coronary syndromes, PTCA, Post angioplasty (mainly hospital use)

SE- bleeding, thrombocytopenia

• Synthetic vasopressin analog
• -also release vWF and VIII from endothelium!

• USE- Central Diabetes Insipidus
• -Hemophila A, von-Willebrand disease

• Log kill-therapy
• -cytotoxic actions of anticancer drugs follow 1st-order kinetics
• -Kill fixed Percentage of tumor cells, NOT fixed number
• -why used in combo

• Growth fraction
• -More effective against tumors w/ high growth fraction
• -So normal cells with high growth fractions (bone marrow, GI mucosa) more sensitive to anticancer drugs

• -all screw up the microtubule
• Vinblastin
• Vincristine
• Paclitaxel

• Alkylating agents
• -Cyclophosphamide
• -Ifosfamide
• -Nitrosoureas (Carmustine, Lomustine, Semustine, Streptozocin)
• -Busulfan
• -Cysplatin
• Antitumor antibiotics
• -Dactinomycin
• -Daunorubicin

• Antimetabolites
• -Methotrexate
• -5-Fluorouracil
• -6-Mercaptopurine
• -6-thioguanine
• -Cytarabine

-Etoposide (antitumor antibiotic)

• antitumor antibiotics
• -Etoposide
• -Bleomycin

• S-phase anticancer drug
• -antimetabolite
• -Folic acid analog
• -block Dihydrofolate reductase--> decrs dTMP--> block DNA, protein synthesis

• USE- Leukemia, Lymphoma, Choriosarcoma
• Non-cancer- Abortion, ectopic pregnancy, Rheumatoid arthritis, Psoriasis

• SE- Marrow suppression (reverse with Leucovorin- folinic acid), Macrovesicular fatty change in liver
• -Mucositis, Teratogenic!

• Purine analog
• -resistant to degradation by adenosine deaminase
• -can reach high conc in cell

USE- hairy cell leukemia

• fever
• apthous ulcers
• pancytopenia

• S-phase anticancer drug
• -antimetabolite
• -Pyrimidine analog
• -activated to 5F-dUMP-->complex w/ folic acid--> block Thymidylate synthase--> decr dTMP--> block DNA, protein synthesis

• USE- Colon cancer, solid tumors
• -topical for basal cell carcinoma
• -synergy with Methotrexate!

• SE- Marrow suppression (NOT rescued by Leucovorin!) rescue w/ Thymidine
• -Photosensitivity

• S-phase anticancer drug
• -antimetabolite
• -Purine analog
• -block de novo purine synthesis
• -activated by HGPR transferase (Leish-Nayan)
• -metabolized by Xanthine oxidase

• USE- Leukemias, Lymphomas (NOT CLL or Hodgkins)
• -immunosuppression

• SE- Marrow suppression, GI, Liver
• -increased toxicity with Allopurinol!

• S-phase anticancer drug
• -antimetabolite
• -Purine analog
• -block de novo purine synthesis
• -activated by HGPR transferase (Leish-Nayan)

USE-ALL

• SE- Marrow suppression, liver
• but you CAN give with allopurinol (unlike 6-Mercaptopurine!)

• S-phase anticancer drug
• -antimetabolite
• -Pyrimidine antagonist--> block DNA polymerase!

USE- AML, ALL, high grade non-Hodgkin's lymphoma

USE- Leukopenia, thrombocytopenia, megaloblastic anemia!

• Anticancer drug
• -antitumor antibiotic
• -intercalate into DNA!
• USE-Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma
• -for childhood tumors!

SE- Marrow suppression

• Anticancer drug
• -antitumor antibiotic
• -gen free radicals, noncovalently intercalate into DNA--> break DNA--> block replication
• -inhibit topoisomerase

USE- Hodgkin's lymphoma, Myeloma, Sarcoma, solid tumor ( Breast, Ovary)

• SE- Cardiotoxic! delayed CHF (Dexrazoxane- antidote!- Fe-chelating agent prevent FR form)
• Marrow suppression, alopecia
• -toxic to tissues with extravasation.

• Anticancer drug
• -antitumor antibiotic
• -gen free radicals, noncovalently intercalate into DNA--> break DNA
• --> block replication
• -inhibit topoisomerase

USE- Hodgkin's lymphoma, Myeloma, Sarcoma, solid tumor ( Breast, Ovary)

SE- Cardiotoxic! delayed CHF (Dexrazoxane- antidote!- Fe-chelating agent prevent FR form) Marrow suppression, alopecia-toxic to tissues with extravasation.

• Anticancer drug
• -G2 block!
• -antitumor antibiotic
• - complex w/ Fe, O2, free radical formation--> break DNA strands
• -NO marrow suppression!

USE- Testicular cancer, Hodgkins lymphoma

• SE- Pulmonary fibrosis, Skin changes,
• no marrow suppression!!

• Anticancer drug
• -S and G2 block!
• -antitumor antibiotic
• -block topoisomerase II--> increase DNA breakdown!

• USE- small cell carcinoma of lung, prostate,
• testicular carcinoma

SE- Marrow suppression, GI, alopecia

same as Etoposide, but used for genital warts!

• Anticancer drug
• -alkylating agent!
• -Covalently crosslink DNA at guanine N-7
• -must be activated by liver--> Acrolein

USE- Non-hodgkin's lymphoma, breast, ovarian carcinoma, Neuroblastoma

• SE- Marrow suppression, Hemorrhagic cystitis!
• (prevent w/ Mesna- thiol group bind toxic metabolite)

-similar: Ifosfamide

Carmustine, Lomustine, Semustine, Streptozocin

• Anticancer drug
• -Alkylating agents
• -must be activated--> cross BBB--> CNS!!

USE-Brain tumors! (Glioblastoma multiform)

SE- CNS toxicity (dizziness, ataxia)

• Anticancer drug
• -Alkylate DNA

• USE-CML
• -also for ablating bone marrow before bone marrow transplantation

SE- Pulmonary fibrosis, Hyperpigmentation

• Anticancer drug
• -Alkylate DNA--> crosslink DNA
• -NO marrow suppression!, but severe nausea, vomiting!

USE- Testicular cancer, Bladder cancer, Lung cancer

• SE- Nephrotoxicity (antidote= Amifostine), VIII nerve damage -deafness!
• Severe Nausea, vomiting (give w/ Ondensetron)
• NO marrow suppression!!

• Anticancer drug
• -M-phase!
• -block microtubules, block polymerization--> block mitotic spindle formation
• -NO marrow suppression!

USE- Hodgkin's lymphoma , Wim's tumor, Choriocarcinoma

• SE- Neurotoxicity- areflexia, peripheral neuritis
• NO marrow suppression!

• Anticancer drug
• -M-phase!
• -block microtubules, block polymerization--> block mitotic spindle formation

USE-Hodgkin's lymphoma, Kaposi sarcoma, testicular cancer

SE-Marrow suppression, GI, Alopecia

• Anticancer drugs
• -M-phase!
• -block Microtubule depol (breakdown)! --> anaphase cannot occur!

USE- Ovarian, breast cancer

SE- Marrow suppression, hypersensitivity

• anti-gout drug
• also block microtubules

• Anticancer drug
• -S-phase!
• -block Ribonucleotide reductase--> block DNA synthesis

USE- melanoma, CML, sickle cell disease--> increase HbF

SE- Marrow suppression, GI upset

• USE- most commonly used glucocorticoid in cancer chemotherapy
• -used in CLL, Hodgkins's lymphoma
• -immunosuppressant used in autoimmune diseases

• SE- Cushing-like syptoms, immunosuppression, cataracts, acne, osteoporosis, HTN, peptic ulcer, hyperglycemia, psychosis.
• may rigger apoptosismay even work on nondividing cells

• anticancer drug
• -receptor antagonists in breast and agonist in bone
• -block binding of Estrogen to Estrogen receptor + cells

• USE- breast cancer
• -also useful to prevent osteoporosis

• SE- may increase risk of endometrial carcinoma via partial agonist effects (hot flashes)
• NO increased risk with Raloxifene (b/c endometrial antagonist)

• anticancer antibody
• -monoclonal antibody against HER-2 (erb-B2)
• -kill breast cancer cells that overexpress HER-2
• (via antibody-dependent cytotoxicity?)

USE- Metastatic breast cancer

SE- cardiotoxicity

• anticancer antibody
• -philadelphia chromosome Bcr-abl Tyr-kinase inhibitor

USE- CML, GI stromal tumors

SE- fluid retention

• anticancer antibody
• monoclonal antibody against CD-20 (on most B-cell neoplasms)

USE- Non-hodgkin's lymphoma. Rheumatoid arthritis (w/ methotrexate)

• Cisplatin
• Bleomycin
• Vincristine

• Cisplatin
• Methotrexate

• Doxorubicin
• Daunorubicin

• Vincristine
• Cisplatin

• 6-Mercaptopurine
• Busulfan
• Cyclophosphamide

• Bleomycin
• Busulfan
• Procarbazine

• Cyclophosphamide
• Methotrexate

inhibit 5-HT3 receptors in GI, area postrema, SNT

USE - nausea, vomiting after chemotherapy

Cytoprotective FR scavenger

• USE-decrease nephrotoxicity assoc. w/ platinum containing and alkylating chemotherapy drugs
• -decrease xerostomia

• G-CSF
• -increase granulocytes

USE- marrow recovery

• GM-CSF
• increase granulocytes, macs

USE- marrow recovery

USE- anemia esp assoc w/ renal failure

USE-thrombocytopenia

note- can also use IL-11 increase platelet formation

• IL-2
• increase lymphocyte differentiation, NK cells

USE- renal cell cancer, metastatic melanoma