cofactor for the activation of antithrombin leading to decreased thrombin and factor Xa
Use of Heparin
immediate anticoagulation for PE, acute coronary syndrome, MI, DVT **Follow PTT
Heparin can be used during pregnancy bc...
it does not cross the placenta. Warfarin cannot be used in pregnancy.
Toxicity of Heparin
-bleeding -HIT -osteoporosis
For rapid reversal of Heparin, use...
protamine sulfate (which is a positively charged molecule that binds negatively charged heparin).
Low-molecular weight heparins (2)
1. Enoxaparin 2. Dalteparin
Low-molecular weight heparins act more on...
factor Xa, have better bioavailablity and 2-4x longer half life.
Heparin Induced Thrombocytopenia (HIT)
-development of IgG antibodies agaisnt heparin bound to platelet factor 4 (PF4) -Ab-heparin-PF4 complex activates platelets leading to thrombosis and thrombocytopenia
Argatroban, Bivalirudin MOA
Inhibit thrombin directly
Argatroban and Bivalirudin are used...
instead of heparin for anticoagulating pts with HIT.
-interferes with normal synthesis and gamma-carboxylation of vitamin-K dependent clotting factors II, VII, IX and X and proteins C and S
Warfarin is metabolized by...
In lab assays, Warfarin has an effect on the...
extrinsic pathways and increases PT.
Use of Warfarin
-chronic anticoagulation (after STEMI, venous thromboembolism prophylaxis, stroke prevention) **Follow PT/INR values.
Toxicity of Warfarin
-bleeding -teratogenic -skin/tissue necrosis
For reversal of warfarin overdose
-give vitamin K -if rapid reversal is necessary, give FFP
Apixaban and Rivaroxaban MOA
bind and directly inhibit activity of factor Xa
Use of Apixaban and Rivaroxaban
-treatment and prophylaxis of DVT and PE (rivaroxaban) -stroke prophylaxis
1. Alteplase (tPA) 2. Reteplase (rPA) 3. Tenecteplase (TNK-tPA)
MOA of thrombolytics (tPA, etc)
directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots -increases PT and PTT
Use of thrombolytics
-MI -ischemic stroke -directy thrombolysis of severe PE
Thrombolytics are contraindicated in...
pts with active bleeding, hx of intracranial bleed, recent surgery, known bleeding diathesis or HTN.
Treat thrombolytic toxicity with...
aminocaproic acid (inhibitor of fibrinolysis).
irreversibly inhibits COX1 and COX2 by covalent acetylation; platelets cannot synthesize new enzyme so the effects last until new platelets are produced
-increased bleeding time -decreased TXA2 and prostaglandins -no effect on PT or PTT
Use of Aspirin
-antipyretic -analgesic -anti-inflammatory -antiplatelet (decreased aggregation)
Toxicity of aspirin
-gastric ulceration -tinnitus -reye syndrome in children with viral infxn
Chronic use of aspirin can lead to...
acute renal failure, interstitial nephritis and upper GI bleeding.
Overdose of aspirin causes....
respiratory alkalosis initially which is then superimposed by metabolic acidosis.
ADP receptor inhibitors (4)
1. Clopidogrel 2. Ticlopidine 3. Prasugrel 4. Ticagrelor
MOA of ADP recpetor inhibitors
inhibit platelet aggregation by irreversibly blocking ADP receptors; inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa binding
Use of ADP receptor inhibitors
-acute coronary syndrome -coronary stenting (decreased risk of thrombotic stroke)
Toxicity of ADP receptor inhibitors
-Neutropenia (Ticlopidine) -may see TTP/HUS
Cilostazol and Dipyridamole MOA
phosphodiesterase III inhibitors leading to increased cAMP in platelets, thus inhibiting platelet aggregation vasodilators
Use of Cilostazol and Dipyridamole
-intermittent claduication -coronary vasodilation -prevention of stroke/TIA/angina
GP IIb/IIIa inhibitors (3)
Abciximab Eptifibatide Tirofiban
GpIIb/IIIa inhibitor MOA
bind to the glycoprotein receptor IIb/IIIa on activated platelets, inhibiting aggregation
Abciximab is made from...
monoclonal antibody Fab fragments.
Use of GP IIb/IIIa inhibitors
-unstable angina -percutaneous transluminal coronary angioplasty
1. Metotrexate 2. 5-Fluorouracil 3. Cytarabine 4. Azathioprine 5. 6-Mercaptopurine 6. 6-Thioguanine *all are S-phase specific
folic acid analog that inhibits dihydrofolate reductase leading to decreased dTMP, DNA and protein synthesis.
Cancer uses of methotrexate
-leukemias/lymphomas -choriocarcinoma -sarcomas
Non-neoplastic uses of methotrexate
-abortion/ectopic pregnancy -RA -psoriasis -IBD
Toxicity of Methotrexate
-Myelosuppression -Macrovesicular fatty change in liver -mucositis -teratogenic
Myelosuppression from methotrexate is reversible with...
pyrimidine analog bioactivated to 5F-dUMP which covalently complexes folic acid; this complex inhibits thymidylate synthase leading to decreased dTMP, DNA and protein synthesis
Clinical uses of 5-FU
-colon cancer -pancreatic cancer -basal cell carcinoma
Toxicity of 5-FU
-myelosuppression (not reversible w/ leucovorin; use uridine) -photosensitivity
-pyrimidine analog leading to inhibition of DNA polymerase
Clinical use of Cytarabine
Pancytopenia (thrombocytopenia, leukopenia, megaloblastic anemia)
Azathioprine, 6-MP and 6-TG MOA
purine analogs that decrease de novo synthesis of purines; activated by HGPRT
Clinical uses of azathioprine, 6-MP and 6-TG
-preventing organ rejection -RA -SLE (azathioprine) -Leukemia/IBD (6-MP, 6-TG)
Toxicity of Azathioprine, 6-MP and 6-TG
-bone marrow, GI and liver
Azathioprine and 6-MP are metabolized by...
xanthine oxidase and thus both have increased toxicity with allopurinol.
Antitumor antibiotics (3)
1. Dactinomycin 2. Doxorubicin, Daunorubicin 3. Bleomycin
intercalates in DNA
Use of Dactinomycin
-Wilms tumor -Ewing sarcoma -Rhabdomyosarcoma
Toxicity of Dactinomycin
Doxorubicin, Daunorubicin MOA
generate free radicals; intercalate DNA decreasing replication
Clinical use of Doxorubicin
solid tumors lymphomas/leukemias
Toxciity of Doxorubicin
-Cardiotoxicity (DCM) -myelosuppression -alopecia
When giving Doxorubicin, cardiotoxicity can be prevented with...
induces free radical formation which causes breaks in DNA
Uses of Bleomycin
-testicular cancer -Hodgkin lymphoma
Toxicity of Bleomycin
-pulmonary fibrosis -skin changes -mucositis
1. Cyclophosphamide, Ifosfamide 2. Nitrosoureas (Carmustine, Lomustine, Semustine, Streptozocin) 3. Busulfan
Cyclophosphamide and Ifosfamide MOA
covalently X-link (interstrand) DNA at guanine N-7; requires activation by liver
Clinical uses of cyclophosphamide/Ifosfamide
-solid tumors -leukemia/lymphomas -some brain tumors
Toxicity of Cyclophosphamide/Ifosfamide
-myelosuppression -hemorrhagic cystitis
Hemorrhagic cystitis from cyclophosphamide and Ifosfamide can be partiall prevented with...
mensa which binds toxic metabolites.
Nitrosureas (carmustine, lomustine, semustine, streptozocin) MOA
cross BBB and cross-links DNA; requires activation
Use of Nitrosurease (carmustine, lomustine, semustine, streptozocin)
brain tumors (including glioblastoma multiforme)
Toxicity of Nitrosureas
Clinical use of Busulfan
CML -and to ablate pts bone marrow before BMT
Toxicity of Busulfan
-severe myelosuppression -pulmonary fibrosis -hyperpigmentation
1. Vincristine/Vinblastine 2. Paclitaxel (-taxols)
MOA of Vincristine/Vinblastine
vinca alkaloids that bind beta-tubulin and inhibits its polymerization into microtubules, thereby preventing mitotic spindle formation (m-phase arrest)
Clinical use of Vincristine/Vinblastine
-solid tumors -leukemias/lymphomas
Toxicity of Vincristine/Vinblastine
-myelosuppression (vinblastine) -neuotoxicty, pralytic ileus (vincristine)
hyperstabilizes polymerized microtubules in M-phase so that mitotic spindle cannot break down preventing anaphase
Use of Paclitaxel
-ovarian cancer -breast cancer
Toxicity of Paclitaxel
-myelosuppression -alopecia -hypersensitivity
Cisplatin and Carboplatin MOA
Cisplatin and Carboplatin Use
testicular, bladder, ovary and lung carcinomas
Cisplatin and Carboplatin toxicity
-nephrotoxicity -acoustic nerve damage
Nephrotoxicity from cisplatin and carboplatin can be prevented with...
amifostine and chloride diuresis.
Etoposide and Teniposide MOA
inhibits topoisomerase II leading to increased DNA degradation
Clinical use of Etoposide and Teniposide
-solid tumors (esp. testicular, small cell lung) -leukemias/lymphomas
Toxicity of Etoposide/Teniposide
-myelosuppression -GI irritation -alopecia
Irinotecan and Topotecan MOA
inhibit topoisomerase I and prevent DNA unwinding and replication
Use of Irinotecan and Topotecan
-colon cancer (irinotecan) -ovarian and small cell lung (topotecan)
Toxicity of Irinotecan and Topotecan
-severe myelosuppression -diarrhea
inhibits ribonucleotide reductase leading to decreased DNA synthesis
Use of Hydroxyurea
-melanoma -CML -sickle cell
Toxicity of Hydroxyurea
-myelosuppression -GI upset
MOA of Prednisone and Prednisolone
may trigger apoptosis
Use of Prednisone and Prednisolone
-most commonly used glucocorticoids in cancer chemo -used in CLL, non-Hodgkins -also as immunosuppressants
Toxicity of Prenisone and Prednisolone
Tamoxifen and Raloxifene MOA
selective estrogen reuptake modulators (SERMs) - receptor antagonists in breast and agonists in bone
Use of tamoxifen and raloxifene
-breast cancer treatment (tamoxifen) -osteoporosis prevention (raloxifene)
partial agonist in endometrium which increases risk of endometrial cancer
monoclonal Ab against HER-2, a tyrosine kinase receptor; helps kill breast cancer cells through inhibition of HER2 cellular signaling and Ab-dependent cytotoxicity
Use of Trastuzumab
HER2 + breast and gastric cancer
Toxicity of Trastuzumab
tyrosine kinase inhibitor of bcr-abl and c-Kit
-CML (bcr-abl) -GI stromal tumors (c-Kit)
monoclonal antibody agaisnt CD20 which is found on most B-cell neoplasms
Use of Rituximab
-Non-hodgkins -RA -ITP
Toxicity of Rituximab
-incrneased risk of progressive multifocal leukoencephalopathy
inhibitor of forms of B-Raf kinase with V600E mutation
Use of Vemurafenib
monoclonal Ab against VEGF; inhibits angiogenesis
Use of Bevacizumab
solid tumors (colorectal, RCC)
Toxicity of Bevacizumab
-hemorrhage -impaired wound healing