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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Gastrointestinal and Endocrinal Drugs

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Antineoplastic Agents

– Classification – Alkylating Agents – Nitrogen Mustards – Ethyleneimine and Methylmelamine Derivatives – Alkyl Sulfonates – Nitrosoureas – Triazenes

ANTINEOPLASTIC AGENTS

Classification

·      Alkylating agents:

o     Nitrogen mustards: chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan.

o     Ethyleneimine and methylmelamine derivatives: hexa-methylmelamine, thiotepa.

o     Alkyl sulfonates: busulfan.

o     Nitrosoureas: carmustine, lomustine, streptozocin.

o     Triazenes: dacarbazine.

·      Antimetabolites:

o     Folic acid antagonists: methotrexate, trimetrexate.

o     Pyrimidine analogues: 5-fluorouracil, floxuridine, cyta-rabine.

o     Purine analogues: 6-mercaptopurine, 6-thioguanine.

o     Adenine analogue: fludarabine-A.

o     Adenosine deaminase inhibitors: pentostatin.

o     Interferons: interferon alfa 2a and 2b.

·      Natural products:

o     Vinca alkaloids: vincristine, vinblastine, vindesine.

o     Antitumour antibiotics: aclarubicin, bleomycin, dactin-omycin (actinomycin D), mitomycin C, 5-azacytidine, daunorubicin, doxorubicin, idarubicin, plicamycin.

o     Enzymes: 6-asparaginase.

o     Epipodophyllotoxins: etoposide, teniposide.

·      Androgen inhibitors: cyproterone acetate, flutamide, leupro-lide acetate.

·      Anti-oestrogen: tamoxifen citrate.

·      Hormones: testolactone, adrenocorticosteroids, oestrogens, progestins, androgens.

·      Miscellaneous agents: platinum co-ordination complexes (cisplatin, carboplatin), hydroxyurea, procarbazine, hexam-ethylmelamine, amsacrine, mitoxantrone, mitotane, leuco-vorin, levamisole, BCG, aminoglutethimide, coumarin, estramustine, mesna.

·              General treatment measures for toxicity arising out of anticancer drug overdoses. The following discussion is centred on the toxicity of specific drugs and special treatment measures.

Alkylating Agents

The era of modern cancer chemotherapy began with the landmark clinical studies of the action of nitrogen mustards on lymphosar-coma in mice in the early 1940s.

The tumouricidal activity of alkylating agents results from the formation of reactive intermediates that bind to nucle-ophlilic moieties on the DNA chain. The capacity of these drugs to interfere with DNA integrity and function in rapidly proliferating tissues provides the basis for their therapeutic applications (and for many of their toxic properties). The alkylating agents are most cytotoxic to rapidly proliferating tissues in which a large proportion of the cells are in division, even though some of these agents have damaging effects on tissues with low mitotic indices, e.g. liver, kidney, and lymphocytes.

Nitrogen Mustards

Mechlorethamine

Mechlorethamine was the first nitrogen mustard introduced into clinical practice, and is invariably administered only intrave-nously. It is used primarily in the combination chemotherapy regimen MOPP (mechlorethamine, oncovin (vincristine), procarbazine, and prednisone), for the treatment of Hodgkin’s disease. It is given intravenously. Adverse effects include nausea, vomiting, diarrhoea, local reaction and phlebitis, bone marrow depression, alopecia, oral ulcers, leukaemia, amenor-rhoea, sterility, hyperuricaemia.

Local reaction to extravasation of mechlorethamine can be severe, and therefore must be treated promptly by infiltration of the affected area with a sterile isotonic soluton of sodium thiosulfae (1/6 M).* This is followed by intermittent application of cold compress for 6 to 12 hours.

Cyclophosphamide

Cyclophosphamide is used in the treatment of lymphomas and chronic leukaemias, and also often in combination with methotrexate or doxorubicin as adjuvant therapy after surgery for breast cancer. It has also been used effectively in the treatment of carcinomas of lung, cervix, and ovary, as well as childhood neoplasms such as neuroblastoma and retino-blastoma. Adverse effects include nausea, vomiting, hyper-sensitivity reactions, visual blurring, and facial burning (from IV use). Chronic use may cause bone marrow depression, alopecia, haemorrhagic cystitis (due to its irritating metabo-lite acrolein), sterility, pulmonary fibrosis, hyponatraemia, leukaemia, bladder cancer, and cardiotoxicity. Inappropriate secretion of antidiuretic hormone sometimes leads to water intoxication.

Overdose results in cardiac arrhythmias, myocarditis, and myocardial necrosis. Deaths have been reported.

The incidence of haemorrhagic cystitis can be greatly reduced by adequate hydration (for dilution), IV administration of MESNA (sodium 2-mercaptoethanesulfonate), and intra-vesical N-acetylcysteine. Treatment of haemorrhagic cystitis, once it has set in, involves any of the following suggested measures: electrocauterisation, systemic vasopressin, and intra-vesical administration of silver nitrate, formalin, prostaglandin F2 alpha, and hydrostatic pressure. 

Chlorambucil

Chlorambucil can be administered orally, and at the recom-mended dosages, it is the slowest-acting nitrogen mustard. It is mainly indicated in the treatment of chronic lympho-cytic leukaemia and primary macroglobulinaemia. Adverse effects include bone marrow depression, pulmonary fibrosis, leukaemia, hepatic toxicity, and sterility. Overdose causes nausea, vomiting, ataxia, convulsions, ECG changes, coma.

Ifosfamide

Ifosfamide is an analogue of cyclophosphamide, and is mainly employed in combination with other drugs in the treatment of germ cell testicular cancer and sarcomas. It is also useful in treating lymphomas and carcinomas, and carcinomas of cervix and lung. Ifosfamide is usually given intravenously. Adverse effects comprise bone marrow depression, haemorrhagic cystitis, alopecia, inappropriate ADH secretion, renal failure, and neurotoxicity (drowsi-ness, blurring of vision, hallucinations). Overdose causes nausea, vomiting, confusion, nephrotoxicity, renal Fanconi’s syndrome, and cardiotoxicity.

Haemorrhagic cystitis can be prevented by adequate hydration and co-administration of MESNA which reacts at acid pH in the urine to detoxify the metabolites of ifosfamide. MESNA is given IV as boluses equal to 20% of the ifosfamide dosages at 4 hourly intervals until a total dose of 60% has been achieved. At least 2 litres of IV fluids (or oral fluids) must also be administered every day. The MESNA treatment can be repeated every 3 to 4 weeks.

Haemodialysis may be effective in treating ifosfamide overdose, since it has a low apparent volume of distribution.

Melphalan

Melphalan can be given orally and intravenously. It is mainly used in multiple myeloma. Adverse effects comprise bone marrow depression (especially platelets), hepatic toxicity, GI ulceration (oral, intestinal), and pancreatitis. Overdose results in vomiting, diarrhoea, and nephropathy. Treatment is symp-tomatic and supportive. Colony stimulating factors (GM-CSF, GCSF) may help in improving the prognosis.

Ethyleneimine and Methylmelamine Derivatives

Thiotepa

Thiotepa is mainly indicated in bladder cancer, and is usually given intravenously. Adverse effects include bone marrow depression, sterility, leukaemia and mucositis.

Alkyl Sulfonates

Busulfan

Busulfan is well absorbed orally and is used for treating chronic granulocytic leukaemia, polycythemia vera, and myelofibrosis. Adverse effects comprise bone marrow depression, pulmonary fibrosis, alopecia, gynaecomastia, ovarian failure, hyperpig-mentation, stomatitis, azoospermia, leukaemia, cataract, and hepatitis. Overdose results in vomiting and convulsions.

Nitrosoureas

The nitrosoureas are very effective against brain tumours and gastrointestinal neoplasms. Carmustine and lomustine are lipophilic and can therefore quite easily cross the blood-brain barrier. Streptozocin has a high affinity for beta cells of the islets of Langerhans and is useful in the treatment of pancreatic (islet cell) carcinoma and malignant carcinoid tumours. While carmustine and streptozocin are administered intravenously, lomustine can be given orally.

With regard to adverse effects, carmustine and lomustine characteristically cause delayed myelosuppression (maximal at 4 to 6 weeks), nausea, vomiting, pulmonary fibrosis, renal failure, and hepatic toxicity. Streptozocin causes renal and hepatic toxicity in about two thirds of patients, but myelosup-pression is relatively infrequent (20%). Overdose can cause pancytopenia.

Triazenes

Dacarbazine

Dacarbazine is used (in combination with other drugs) for the treatment of malignant melanoma, Hodgkin’s disease, and adult sarcomas. It is given intravenously. Toxicity results in nausea, vomiting, flu- like syndrome, myelosuppression, alopecia, hepatotoxicity and neurotoxicity.


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