ANTITUMOR AGENTS and MISCELLANEOUS DRUGS

1. ANTITUMOR AGENTSand MISCELLANEOUS DRUGS Reilly Thomas Class of 2013 rct2013@uw.edu

3. Objectives • To have a basic understanding of cancer and its processes • Types • Causes • What we attempt to do in its treatment • General Information about the chemotherapeutic agents • Method of Action (MOA) • Route of Administration (ROA) • Side effects (SE) • Indications (ID) • Drug- drug interactions (DDI) • Counseling points for patients (CP)

4. Cancer is…. • the uncontrolled growth of abnormal cells in the body. Cancerous cells are also called malignant cells. • There are a number of causes • Chemicals/toxins • Sun exposure • Obesity • Viruses • Genetic factor • Radiation • Some causes are unknown

5. Overview of Carcinogenesis • Types of cancer • Leukemia: Cancer of Blood/lymph cells • ALL – Acute lymphoblastic leukemia • AML – Acute myelogenous leukemia • CLL – Chronic lymphocytic leukemia • CML – chronic myelogenous leukemia

6. Overview Continued • Types of cancer • Multiple Myeloma • Lymphoma • Hodgkin’s • Non-Hodgkin’s • Burkitt’s • Specific Tissue Cancers • Carcinoma • sarcoma

7. Stages of Cancer • The stages of cancer can be seen below, difficultly in treatment and a decrease in good outcomes increase as the mutated cells grow.

8. Example • Melanoma • Asymmetry • Border • Color • Diameter • Elevation/evolution http://skinipedia.org/skin-diseases/skin-cancer-melanoma-in-children3.html

10. Goals for Treatment •  #1 – Cure: Complete remission for more than 5 years • #2 – Disease control: Partial or temporary remission • #3 – Relieve symptoms: Relieve symptoms of the cancer, and includes pallative care

11. Classes of Antitumor Agents • Antimetabolites • Folic acid analogs • Pyrmidine analogs • Purine analogs • Enzymes • DNA Alkylating agent • Nitrogen mustards • Nitrosoureas • Alkyl sulfonates • Triazene/hydrazines/aromatic aminotriazene • Metalating Agents • Platinum Complexes • DNA damaging agents • Peptide antibiotics • Topoisomerase II inhibitors • Antracyclines • Epi-PodoPhyllotoxins • Topoisomerase I inhibitors • Camptothecin • Antimitotics • Vinca Alkaloid • Taxanes • Endocrine agents • Adrenocorticosteroids • Antiestrogens • Gonadotropins • Antiandorgens • Biological Response Modifiers • Glycoprotiens • Recombinant Hematopoietic Growth Factor • Cytokines • Chemoprotectants • Thiol donors/thio-phosphonate • Target agents • Monoconal antibodies (MAB) • MAB’s + radioimmuno conjugate • Tyrosine Kinase inhibitor • Epidermal Growth factor

12. Classes of Antitumor Agents Oral/Topical dosage forms • Antimetabolites • Folic acid analogs • Pyrimidine analogs • Purine analogs • DNA Alkylating agent • Nitrogen mustards

13. Mechanism of antitumor agents

15. Antimetabolites: Folic Acid Analogs Methotrexate • Rheumatrex® and Trexall • MOA: Act by inhibiting the synthesis of DNA by blocking the synthesis of thymidine • ROA: injection or tablets

16. Antimetabolites: Folic Acid Analogs Methotrexate • SE: Bone marrow depression (BMD), Gastrointestinal (GI) Ulceration, kidney damage • ID: ALL, Non-Hodkins Lymphoma, head and neck cancers, breast and lung cancer, there are also non-oncology uses including psoraisis • DDI: • Ciprofloxacin &Cyclosporine • NSAIDs, penicillin, PPIs, and salicylates • CP: Take on an empty stomach, avoid in pregnancy (category X), do not take with alcohol or folic acid supplements

17. Antimetabolites: Pyrmidine Analogs Fluorouracil (5-FU), Capecitabine • Carac, Efudex, Fluroplex • MOA: Inhibits thymidylatesynthetase and incorporates into DNA as an abnormal nucleotide http://www.medscape.com/viewarticle/588189_2 http://www.eu-pharmagate.com/news-dettaglioENG.asp?ID=314&TAB=ultimissime

18. Antimetabolites: Pyrmidine Analogs Fluorouracil (5-FU), Capecitabine • ROA: Injection or topical • SE: • Injection: BMD, GI-ulceration, N/V/D • Topical: Skin irritation • ID: actinic keratoses and superficial basal cell carcinoma • DDI: warfain, cavediolol and phenytion (injection) • CP: Sun sensitivity, wash hands after topical application, and do not cover with occlusive dressing

19. Antimetabolites: Purine Analogs Mercaptopurine (6MP)- Purinethol® Azathioprine- Azasan®; Imuran® • MOA: Interferes with steps in the biosynthesis of purine therefore blocking DNA synthesis • ROA: Tablets http://www.medscape.com/viewarticle/499922_3

20. Antimetabolites: Purine Analogs Mercaptopurine (6-MP), Azathioprine • SE: BMD, anemia, thrombocytopenia, and hepatotoxicity • ID: ALL, Crohn’s disease, ulcerative colitis • DDI: Allopurinol and warfarin • CP: May cause fever, bleeding/bruisingand should be taken on an empty stomach and women of child bearing age should take birth control

21. DNA Alkylating Agents: Nitrogen Mustards Cyclophosphamide- Cytoxan Ifosfamide- Ifex • MOA: Crosslinks DNA • ROA: Injection (cyclo only) and tablets

22. DNA Alkylating Agents: Nitrogen Mustards cyclophosphamide, ifosfamide • SE:BMD, N/V/D, hemorrhagic cystitis, hair loss • ID: lymphoma, CLL, AML, ALL, etc. • DDI: Vaccines, Succinylcholine, Warfarin • CP: Drink lots of water, take dose early, and take with food, do not crush or chew

24.  Estrogen Receptor Antagonist Tamoxifen - Nolvadex® • MOA: Competitively binds estrogen receptors producing a decrease in DNA synthesis and inhibiting estrogen effect. • ROA: Tablet

25.  Estrogen Receptor Antagonist Tamoxifen • SE: Flushing, hypertension, mood changes, skin changes, pain, hot flashes • ID: Treatment and prevention of breast cancer • DDI: CYP2C9 inducers and inhibitors, 2D6 inhibitors and 3A4 inducers and inhibitors • CP: Avoid grapefruit juice, May need to get bone density screening, chest pain, difficulty breathing, rash,

26. Miscellaneous Agents • 5-Alpha reductase inhibitors (BHP and Alopecia) • Retinoic Acid derivatives (acne and skin cancers) • Antigout /Antihyperuricemic agent • Immunosuppressant agents/ Calcineurin inhibitors

27. Objectives General Information about the miscellaneous agents • Method of Action (MOA) • Route of Administration (ROA) • Side effects (SE) • Indications (ID) – what is the disease state each medication treats? • Drug- drug interactions (DDI) • Counseling points for patients (CP)

28. 5-Alpha reductase inhibitors for BPH Finasteride-Propecia®; Proscar® • MOA: Competitive inhibitor of 5-alpha reductase which inhibits conversion of testosterone to dihydrotestosterone • ROA: Tablets http://www.mahalo.com/finasteride/

29. 5-Alpha reductase inhibitors for BPH Finasteride-Propecia®; Proscar® • SE: Rash, swelling reduced libido, hypersensitivity • ID: BPH (5mg dose), Alopecia (1 mg dose) • DDI: None • CP: Women should not handle, medication could take months

31. Retinoic Acid derivatives for Acne Isotretinoin - Amnesteem®; Claravis™; Sotret®, Accutane® • MOA: Decrease in sebaceous gland size and secretion, and regulates skin proliferation and differentiation • ROA: tablets and topical • SE: Pancreatitis, peripheral edema, photosensitivity • ID: Acne and some skin cancers • DDI: Vitamin A derivatives (retinol and Adapalene) and ethanol

32. Retinoic Acid derivatives for Acne Isotretinoin – • CP: • Avoid pregnancy – female patients need to be on 2 effective types of birth control • impaired glucose control – particularly for diabetics • Take with food – decreases N/V, and increase bioavailability • Limit alcohol- can increase triglyceride levels • May require liver function

33. Isotretinoin and iPledge • This system is used with the intention of preventing pregnancy while patient is taking this medication due to the high incidence of birth defects. • Doctor, patient, and pharmacist are required to enter information stating they have finished the prerequisites before the prescription can be filled.

35. Anti-gout Colchicine - Colcrys® • MOA: Reduces urate crystal deposits in the joint • Disrupts cytoskeletal functions by inhibiting tubulin polymerization into microtubules, which inhibits neutrophil migration • ROA: Tablets

36. Anti-gout Colchicines • SE: N/V/D, neuromyopathy, myelosuppression • ID: Gout • DDI: Digoxin, antifungals, macrolides, diltiazem, grapefruit juice • CP: Low purine diet, and adequate hydration

37. Anti-gout - Diet • Low-purine foods and beverages: • Eggs (limit to 3 to 4 per week). • Nuts and peanut butter: limit if trying to lose weight. • Low-fat and fat-free cheeses and ice cream. • Pudding. • Milk: (limit to 24 ounces per day). • Cream-style soups made with low-fat milk. • Soups made without meat extract or broth. • Vegetables not on the lists above • Fruits and juices. • Breads and cereals: low fiber, white flour, or refined grain types. • Pasta and macaroni. • Rice. • Soda, Coffee and tea. • Gelatin. • Cake and cookies in small amounts. • Fats and oils in small amounts. • Sugar, syrup, and other sweets in small amounts.

38. Anti-gout - Diet • Medium-purine foods: • Fish and shellfish not on the high purine list above. • Poultry foods not on the high purine list above. • Beef, lamb, pork, and other red meats not on the high purine list above. • Dried beans, peas, lentils. • Asparagus. • Mushrooms. • Spinach. • Cauliflower. • Green peas. • Oats and oatmeal. • Wheat germ and bran. • Whole grain breads and cereals.

39. Anti-gout - Diet • High-purine foods: • Anchovies. • Roe (fish eggs). • Fish such as herring and mackerel. • Sardines. • Scallops and mussels. • Game meats, like goose, duck, and partridge. • Organ meats: brains, heart, kidney, liver, and sweetbreads. • Meat extracts. • Mincemeat. • Broth, bouillon, and consomme. • Gravy. • Yeast (baker's and brewer's) taken in the form of a supplement.

40. Anti-gout Allopurinol • MOA: Blocks uric acid production by inhibiting xanthineoxidase • ROA: Tablets and injection http://www.thekanjifoundrypress.com/a.html

41. Anti-gout Allopurinol • SE: Rash and puritis, thrombocytopenia, hepatitis and renal failure • ID: Gout • DDI: ACE inhibitors, thiazide diuretics, antacids, and amoxicillin • CP: Report any rash, fever or painful urination, take with food to minimize GI side effects

43. Immunosuppressant agents/ Calcineurin inhibitorsfor Transplant rejection prevention Cyclosporine - Gengraf®, Neoral®, Restasis®, Sandimmune® • MOA: Inhibit interleukin-2 production which leads to inhibition of T-cell differentiation • ROA: Tablet, oral solution, and injection

44. Immunosuppressant agents/ Calcineurin inhibitorsfor Transplant rejection prevention Cyclosporine - SE: Hypertension, headache, tremor • ID: Transplant rejection, Rheumatoid arthritis and psoriasis • DDI: phenytoin, phenobarbital, azoleantifungals, allopurinol, vancomycin, Statins, digoxin • CP: Take dose at same time everyday, mix in glass container, do not take with grapefruit juice

45. Immunosuppressant agents/ Calcineurin inhibitorsfor Transplant rejection prevention Tacrolimus - Prograf®; Protopic® • MOA: same as cyclosporine • ROA: Tablets, topical, and injection • SE: N/V/D, anemia, rash, headache, insomnia • ID: Prevention of organ transplant rejection • DDI: CYP 3A4 inducers and inhibitors • CP: Take dose at same time everyday, do not take with grapefruit juice

46. Oh you wantz to Sleep? We don’t thinkz so.

47. sources • http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267 • http://en.wikipedia.org/wiki/Leukemia • http://en.wikipedia.org/wiki/Multiple_myeloma • http://en.wikipedia.org/wiki/Lymphoma • http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Chemotherapy/ChemotherapyPrinciplesAnIn-depthDiscussionoftheTechniquesanditsRoleinTreatment/chemotherapy-principles-goals-of-chemo • http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001028 • http://www.uptodate.com.offcampus.lib.washington.edu/contents/colchicine-drug-information?source=search_result&selectedTitle=1~131 • http://www.uptodate.com.offcampus.lib.washington.edu/contents/all-trans-retinoic-acid-tretinoin-drug-information?source=search_result&selectedTitle=1~70 • http://www.uptodate.com.offcampus.lib.washington.edu/contents/topical-tretinoin-topical-all-trans-retinoic-acid-drug-information?source=search_result&selectedTitle=4~70

48. Need to know! • What is cancer? • What are the goals of treatment? • What are the classes of drugs we went over? • What drugs are in these classes and what are their MOAs? • Side effects, Drug-drug interactions, and patient counseling points

49. Questions