Cytotoxic Drug.pptx

pharmacology

1. CYTOTOXIC DRUGS

2. CYTOTOXIC DRUG ( sometimes known as antineoplastics ) describe a group of medicines that contain chemicals which are toxic to cells, preventing their replication or growth, and so are used to treat cancer. Combination therapy – the use of two or more chemotherapy agents to treat cancer – was adopted and led to improved response rates and increased survival times. Chemotherapy is used as the only treatment of cancer, or it may used in conjunction with other modalities such as radiation, surgery, and biologic response modifiers (BRMs ). WHAT?

3. 01 ALKYLATING DRUGS

4. WHAT? Alkylating Drugs One of the largest groups of anticancer drugs . It damage the cell’s DNA by cross-linkage of DNA strands, abnormal base pairing, or DNA strand breaks, thus preventing the reproduction of cancer cells. They are used to treat many different types of cancer including leukemia, lymphoma, multiple myeloma, sarcoma, and solid tumors such as those of the breast, ovary, uterus, lung, bladder, and stomach.

5. 2 5 CLASSES OF ALKYLATING DRUGS

6. 1 Nitrogen Mustards 2 4 3 Alkyl Sulfonates 5 classes of Alkylating Drugs 5 Nitrosoureas Triazines Ethylenimines

7. General Adverse Reactions Adverse Reactions Bone Marrow Suppression/ Myelosuppression Low RBC count (anemia) Low WBC count (leukopenia) Low platelet count (thrombocytopenia) Gastrointestinal Disturbances Anorexia Nausea and vomiting Diarrhea Mucositis (stomatitis) Other Alopecia Fatigue infertility

8. NITROGEN MUSTARDS 01

9. WHAT? Nitrogen Mustards it is not found naturally in the environment HN-1 originally was designed to remove warts but later on, it was identified as a potential chemical warfare agent. HN-2 was designed for military agent but was later used in cancer treatment.

10. MECHLORETHAMINE The first clinically used nitrogen mustard and is the most reactive of the drugs in this class. It is used topically for treatment of CTCL as a solution that is rapidly mixed and applied to affected areas. It has been largely replaced by cyclophosphamide, melphalan , and other more stable alkylating agents.

11. MECHLORETAMINE ROUTE AND DOSAGE USES AND CONSIDERATIONS HODGKIN DISEASE : A: IV: 0.2 mg/kg or 6 mg/m2 as single dose FOR HODGKIN DISEASE, LEUKEMIAS, SOLID TUMORS AND EFFUSION CAUSED BY CANCER. This drug is contraindicated in patients with active infections PB: 94% - 96 % t½: 40 min CLL: A: IV: 6 mg/m2 q4wk CML: A: IV: 0.4 mg/kg or 6 mg/m2 monthly Other dosing regimen and routes are available

12. CYCLOPHOSPHAMINE An analogue of nitrogen mustard and has activity against many neoplastic diseases such as Hodgkin and non-Hodgkin lymphoma (NHL), acute and chronic lymphocytic leukemia (CLL) and etc. Used for immunologic disorders such as lupus nephritis, and has been shown to prevent progressive renal scarring, preserve renal function, induce renal remission and decrease end-stage renal failure.

13. CYCLOPHOSPHAMIDE (Cont.) This drug is a severe vesicant, that causes tissue necrosis if it infiltrates into the tissues. Given orally or intravenously A prodrug that is activated and extensively metabolized by the liver. 5% or 25% of the drug is eliminated by the kidney as unchanged, and its elimination half life is 3-12 hours. Patients should report all medications they are taking, including over-the-counter (OTC) medicines and herbal supplements. Patient should be hydrated while taking the drug to prevent hemorrhagic cystitis

14. Sodium 2- mercaptoethanesulfonate A chemoprotectant drug often given with high-dose cyclophosphamide to inactivate urotoxic metabolites to reduce the incidence of hemorrhagic cystitis.

15. almost exclusively used in treating CLL The cytotoxic effects of chlorambucil on the bone marrow, lymphoid organs, and epithelial tissues are similar to those observed with other nitrogen mustards. As an orally administered agent, chlorambucil is well tolerated in small daily doses and provides flexible titration of blood counts. Nausea and vomiting may result from single oral doses of 20 mg or greater. CHLORAMBUCIL

16. CHLORAMBUCIL ROUTE AND DOSAGE USES AND CONSIDERATIONS Palliative CLL, Hodgkin Disease, and NHL : A: PO: 0.1-0.2 mg/kg/d (4-10 mg/d) for 3-6 weeks FOR CLL AND NHL: Monitor for bone marrow suppression or pancytopenia PB: 99 % t½: 1.5 h

17. IFOSFAMIDE Ifosfamide is an analogue of cyclophosphamide . Ifosfamide is approved for treatment of patients with relapsed germ cell testicular cancer and is frequently used for first-time treatment of pediatric or adult patients with sarcomas It is a common component of high dose chemotherapy regimens with bone marrow or stem cell rescue

18. IFOSFAMIDE ROUTE AND DOSAGE USES AND CONSIDERATIONS A: IV: 1.2-2g/m2/d for 5 d in combination with MESNA; repeat every 3 wk after recovery from hematologic toxicity. Mesna is usually given concomitantly to prevent hemorrhagic cystitis FOR TESTICULAR CANCER: Monitor for hemorrhagic cystitis PB: negligible t½: 7-15 h

19. BENDAMUSTINE approved for treatment of CLL and non-Hodgkin lymphoma. rapidly degraded through sulfhydryl interaction and adduct formation with macromolecules; less than 5% of the parent drug is excreted in the urine intact The parent drug has a plasma t 1/2 of about 30 min.

20. BENDAMUSTINE ROUTE AND DOSAGE USES AND CONSIDERATIONS CLL: A: IV: 100 mg/m2 on days 1 and 2, repeated q28d for up to 6 cycles FOR CLL AND NHL: Monitor for bone marrow depression Assess for tumor lysis syndrome and skin reactions PB: 94% - 96 % t½: 40 min NHL: A: IV: 120 mg/m2 on days 1 and 2, repeated q21d for up to 8 cycles

21. MELPHALAN used to treat multiple myeloma and, less commonly, in high-dose chemotherapy with bone marrow transplantation. The general pharmacological and cytotoxic actions of melphalan are similar to those of other bifunctional alkylators . The drug is not a vesicant . may be used in myeloablative regimens followed by bone marrow or peripheral blood stem cell reconstitution

22. MELPHALAN ROUTE AND DOSAGE USES AND CONSIDERATIONS MULTIPLE MYELOMA : A: PO: 6 mg daily for 2-3 wks ; maint; 2 mg/d; adjust 1-3 mg/d based on hematologic response A: IV: 16 mg/m2 q2wk for 8 doses; maint; 16 mg/m2 q4wk FOR MULTIPLE MYELOMA AND OVARIAN CANCER : Do not confuse with alkeran with Leukeran or Myleran PB: 20% -30 % t½: 1.25- 1.5 h OVARIAN CANCER : A: PO: 200 mcg/kg/d for 5 d; repeat q4-5wk based on hematologic response

23. ESTRAMUSTINE ROUTE AND DOSAGE USES AND CONSIDERATIONS A: PO: 14 mg/kg/d or 600 mg /m2/d in 3-4 divided doses FOR PALLIATIVE TREATMENT OF PROSTATE CANCER. Gynecomastia and impotence may occur PB: UK t½: 20-24 h

24. NITROSOUREAS

25. WHAT? Nitrosoureas H ave an important role in the treatment of brain tumors and find occasional use in treating lymphomas and in high-dose regimens with bone marrow reconstitution. They function as bifunctional alkylating agents but differ from conventional nitrogen mustards in both pharmacological and toxicological properties . Cross-blood barrier, making them useful in the treatment of brain cancer.

26. CARMUSTINE (BCNU) its ability to cross the blood-brain barrier, an important property in the treatment of brain tumors. u sed in the treatment of malignant gliomas . An implantable carmustine wafer is available for use as an adjunct to surgery for recurrent glioblastoma multiforme

27. CARMUSTINE (BCNU) ROUTE AND DOSAGE USES AND CONSIDERATIONS A: IV: 150-200 mg/m2 single dose q6wk or 75-100 mg/m2/d for 2 days q6wk FOR HODGKIN DISEASE, NHL, MULTIPLE MYELOMA, AND BRAIN TUMORS. Monitor for bone marrow suppression and pulmonary symptoms PB: UK t½: 5-30 mins

28. STREPTOZOCIN used in the treatment of human pancreatic islet cell carcinoma and carcinoid tumors. has a methylnitrosourea moiety attached to the 2-carbon of glucose. It has a high affinity for cells of the islets of Langerhans and causes diabetes in experimental animals.

29. STREPTOZOCIN ROUTE AND DOSAGE USES AND CONSIDERATIONS A: IV: 500 mg/m2/d for 5 d q4-6 wk ; doses above 500 mg/m2 are not recommended FOR PANCREATIC CANCER. Do not confuse with streptomycin PB: UK t½:30-45 mins

30. LOMUSTINE (CCNU) ROUTE AND DOSAGE USES AND CONSIDERATIONS FOR HODGKIN DISEASE AND MALIGNANT GLIOMA: A:PO: 100-130 mg/m2 q6wk FOR HODGKIN DISEASE AND MALIGNANT GLIOMA . Monitor for bone marrow suppression and liver function PB: UK t½: 16 h – 2 d

31. ALKYL SULFONATES

32. BUSULFAN the initial oral dose of busulfan varies with the total leukocyte count and the severity of the disease primarily used in high-dose regimens, in which pulmonary fibrosis, GI mucosal damage, and hepatic VOD are important toxicities.

33. BUSULFAN ROUTE AND DOSAGE USES AND CONSIDERATIONS A: PO: 4-8 mg/d FOR MYELOCYTIC CANCER Monitor for seizures and cerebral hemorrhage PB: 32% t½: 2.5 h

34. TRIAZINES

35. DACARBAZINE (DTIC) a methylating agent after metabolic activation to the monomethyl triazeno metabolite MTIC. It kills cells in all phases of the cell cycle. Resistance has been ascribed to the removal of methyl groups from the O6-guanine bases in DNA by MGMT . The primary clinical indication for dacarbazine is in the chemotherapy of Hodgkin disease

36. DACARBAZINE (DTIC) ROUTE AND DOSAGE USES AND CONSIDERATIONS MELANOMA: A: IV: 250 mg/m2/d for 5 d; repeat q3wk for 2 more cycles FOR HODGKIN DISEASE AND MALIGNANT MELANOMA : Monitor hepatic function PB: minimal t½: 5 h HODGKIN DISEASE : A: IV: 375 mg/m2 on day 1 q2wk for 12 cycles

37. ETHYLENIMINES

38. ALTRETAMINE Its precise mechanism of cytotoxicity is unknown, although it can alkylate DNA and proteins. It is a palliative treatment of patients with persistent or recurrent ovarian cancer following cisplatin -based combination therapy The drug undergoes rapid demethylation in the liver

39. ALTRETAMINE ROUTE AND DOSAGE USES AND CONSIDERATIONS A: PO: 260 mg/m2/d on 4 divided doses after meals and at bedtime for 14-21 d in 28-d cycles; Drug holiday for > 14 d then restart at 200 mg/m2/d FOR OVARIAN CANCER: PB: weakly t½: 4.7-10.2 h

40. 3 PLATINUM COORDINATION COMPLEXES

41. PLATINUM COORDINATION COMPLEXES Platinum coordination complexes have broad antineoplastic activity and have become the foundation for treatment of ovarian, head and neck, bladder, esophagus , lung, and colon cancers Although cisplatin and other platinum complexes do not form carbonium ion intermediates like other alkylating agents or formally alkylate DNA, they covalently bind to nucleophilic sites on DNA and share many pharmacological attributes with alkylators

42. CISPLATIN Cisplatin is used to treat various types of cancer. It is a chemotherapy drug that contains platinum. It is used to slow or stop cancer cell growth.

43. CISPLATIN (cont.) Cisplatin , in combination with bleomycin , etoposide , or with ifosfamide and vinblastine, cures 90% of patients with testicular cancer. Used with paclitaxel, cisplatin or carboplatin induces complete response in the majority of patients with carcinoma of the ovary. Cisplatin produces responses in cancers of the bladder, head and neck, cervix, and endometrium; all forms of carcinoma of the lung; anal and rectal carcinomas; and neoplasms of childhood. The drug also sensitizes cells to radiation therapy and enhances control of locally advanced lung, esophageal, and head and neck tumors when given with irradiation.

44. CISPLATIN ROUTE AND DOSAGE USES AND CONSIDERATION BLADDER CANCER A: IV: 50-70 mg/m2 q3-4wk FOR BLADDER, OVARIAN AND NSCLC. Monitor for CNS function Reversible posterior leukoencephalopathy may occur PB: 90 % t½: 30-100 h, dose related OVARIAN CANCER A: IV: 50-75 mg/m2 q21d TESTICULAR CANCER A: IV: 20 mg/m2 for 5d; repeat q3wk for 2 more cycles

45. CARBOPLATIN carboplatin is much less reactive than cisplatin , the majority of drug in plasma remains in its parent form, unbound to proteins. Most drug is eliminated via renal excretion

46. CARBOPLATIN (cont.) Carboplatin and cisplatin are equally effective in the treatment of patients with suboptimally debulked ovarian cancer, non–small cell lung cancer, and extensive-stage small cell lung cancer; however, carboplatin may be less effective than cisplatin in the treatment of patients with germ cell, head and neck, and esophageal cancers. Carboplatin is an effective alternative for responsive tumors in patients unable to tolerate cisplatin because of impaired renal function, refractory nausea, significant hearing impairment, or neuropathy, but doses must be adjusted for renal function. may be used in high-dose therapy with bone marrow or peripheral stem cell rescue

47. CARBOPLATIN ROUTE AND DOSAGE USES AND CONSIDERATION NEW CANCER A: IV: 300 mg/m2 in combination with cyclophosphamide q4wk for 6 cycles FOR ADVANCED OVARIAN CANCER. Usually given as combination therapy PB: UK t½: 1.5-2.5 H RECURRENT CANCER A: IV: 360 mg/m2 q4wk

48. OXALIPLATIN has a short t½ in plasma, probably as a result of its rapid uptake by tissues and its reactivity exhibits a range of antitumor activity (colorectal and gastric cancer) that differs from other platinum agents. Oxaliplatin’s effectiveness in colorectal cancer is perhaps due to its MMR- and HMG-independent effects.

49. OXALIPLATIN ROUTE AND DOSAGE USES AND CONSIDERATION A: IV: 85 mg/m2 on day 1 q2wk for 12 cycles FOR METASTIC COLORECTAL CANCER . Used with 5-FU (fluorouracil) and leucovorin (FOLFOX4) Assess for pulmonary complication PB: >90% t½: 391 h

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