Monitoring of Suspected Adverse Drug Reactions in Oncology Unit ...

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International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 It is believed that a number of these are active cytotoxic agents and that the pharmacological effects of these drugs are still felt long after the parent drug is gone. Vincristine is eliminated much more slowly than the other two vinca alkaloids. Despite close similarity in structure the different vinca alkaloids have quite different therapeutic uses. Vincristine is used mainly in combination therapy for the induction of remission in childhood acute leukemias. Vincristine together with prednisone is the main therapy for induction of ALL. Complete remissions are obtained in 80 to 90% of patients. It is also used for the treatment of Hodgkin's and non- Hodgkin's lymphoma where it is part of several complex protocols. Here again vincristine therapy is very successful. On the other hand the most important clinical use of vinblastine is for metastatic testicular tumors where it is combined with bleomycin and cisplatin. Beneficial responses have also been obtained in the treatment of Hodgkin's and non-Hodgkin's lymphoma. In Hodgkin’s disease it has been used in place of vincristine providing similar antitumor activity with less neurotoxicity. Vindesine, the newest of the vinca alkaloids, has significant activity in the treatment of acute leukemia, blast crisis of CML and Hodgkin’s and non-Hodgkin’s lymphomas. Toxicity: Like the therapeutic uses the toxicities of these drugs is different. The dose limiting toxicity of vincristine is mainly peripheral neuropathy and other neurological toxicities. The most common symptom is a depressed Achilles tendon reflex which is usually followed by paresthesias in the extremities. Autonomic neuropathy often occurs early in the course of therapy resulting in abdominal pain, constipation, paralytic ileus, urinary retention and orthostatic hypotension. Unlike most antineoplastic agents, vincristine usually does not cause significant bone marrow suppression. Therefore it is often found in combination therapies with other drugs that are myelosuppressive. Gastrointestinal symptoms are also common with this vinca alkaloid. Unlike vincristine the other vinca alkaloids produce mainly bone marrow depression. Myelosuppression (primarily neutropenia) is the major toxicity of vinblastine while lymphopenia is the dose limiting toxicity of vindesine but neurotoxicity also occurs frequently. The neurotoxicity produced by these drugs is similar to vincristine but less common and less severe. Paclitaxel and docetaxel are taxane derivatives. Paclitaxel was first isolated from the bark of the Pacific Yew tree (Taxus brevifolia). Docetaxel is a more potent analog that is produced semisynthetically. In contrast to other microtubule antagonists, the taxanes disrupt the equilibrium between free tubulin and microtubules by shifting it in the direction of assembly, rather than disassembly. As a result, taxol treatment causes both the stabilization of microtubules and the formation of abnormal bundles of microtubules. The binding site for taxol is apparently distinct from the binding sites for colchicine, vinblastine and podophyllotoxin. Paclitaxel is usually given IV, preferably in 24 hour infusions, in order to prevent certain severe hypersensitivity reactions from occurring. Taxol binds extensively to plasma proteins. It undergoes significant cytochrome P 450 enzyme mediated hepatic metabolism to hydroxylated metabolites and this is believed to be the major mechanism of elimination. Taxanes have significant activity against ovarian cancer, breast cancer, carcinoma of the lung and head and neck carcinoma. Response rates in these cancers are fairly high. Toxicity: The major toxicity of these drugs is bone marrow depression with neutropenia the common doselimiting toxicity. Hypersensitivity reactions are also common. They are characterized by dyspnea, urticaria and hypotension. It is not clear at this time whether they are due to the vehicle in which taxol is given or the drug itself. Avoidance of bolus injections and short infusions can minimize this toxicity as can pretreatment with steroids or antihistamines. Mucositis is also common and is manifested as ulcers of the mouth and throat. Taxol also causes some reversible neurotoxicities, most often numbness and paresthesias in the hands and feet. Chromatin function inhibitors These constitute a class of drugs that owe their antitumor effects to disruption of chromosomal dynamics. Chromosomes are complex structures which undergo many changes in conformation and Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 18
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 intracellular position during the cell cycle. Drugs that interfere with the proteins responsible for these changes are selectively toxic to proliferating cells. The topoisomerase inhibitor epipodophyllotoxins, etoposide (VP-16) and teniposide (VM-26), are semisynthetic glycosidic derivatives of podophyllotoxin, a natural compound produced in the roots of the May Apple (Podophyllum peltatum) plant. DNA in eukaryotic cells must be packed very efficiently to be able to fit into the nucleus. As a result, chromosomal DNA is twisted extensively and the activities of enzymes called topoisomerases are needed to permit selected regions of DNA to become sufficiently untangled and relaxed to allow transcription, replication, and other essential functions to proceed. To do this topoisomerases have the ability to break DNA strands and then to reseal these breaks after the topological changes have occurred. The clinically useful drugs in this class are inhibitors of topoisomerase II as they break both strands of DNA. The two drugs work similarly although teniposide is taken up by cells more rapidly and retained to a greater extent than etoposide. This may be because teniposide is more lipophilic than etoposide. These drugs form complexes with the topoisomerase II enzyme. This complex produces inhibition of the enzyme along with production of double stranded breaks in the DNA. Removal of the drug results in a rapid return of normal topoisomerase function. Arrest of cells occurs during the G 2 phase of the cell cycle. Early studies with these drugs led investigators to believe that their action was due to inhibition of microtubules. Although these drugs bind to tubulin they have no effect on microtubular function or structure at therapeutic concentrations. They are usually given IV as oral administration usually results in variable absorption. Approximately 30-50% of etoposide is recovered as unchanged drug. Almost all of this is found in the urine with a small amount excreted in the bile. As much as 20% is recovered as metabolites. Both drugs are extensively bound to plasma proteins. Etoposide has shown activity against a variety of tumor types. Its greatest effectiveness is in the treatment of testicular tumors where it is effective against tumors resistant to treatment with other drugs. It is most effective when combined with bleomycin and cisplatin. Etoposide also has an important role in the treatment of small cell lung carcinomas where it is often combined with cisplatin. Teniposide appears to be effective for the treatment of ALL and childhood neuroblastomas as well as brain tumors in adults. Toxicity: The principal dose-limiting toxicity of these drugs is bone marrow depression, primarily leukopenia and thrombocytopenia. Nausea and diarrhea are common but not severe. Mucositis can be severe at higher doses. Other toxic effects seen include fever, chills, erythema. Allergic reactions have been noted in some patients. The camptothecins are a new class of chemotherapeutic agents with a novel mechanism of action targeting the nuclear enzyme topoisomerase I. The parent compound was isolated from the bark of a Chinese tree. This drug and its derivatives are inhibitors of topoisomerase I. Camptothecin itself is poorly soluble and causes significant toxicity. Several more soluble and less toxic derivatives are now available. One derivative with a lot of promise is irinotecan. It is one of the most active compounds available for the treatment of non-small cell lung cancer. Leukopenia and diarrhea are the most severe toxicities seen. Nausea and vomiting are common but manageable. Topotecan is a more recent introduction. Other anticancer drugs L-asparaginase was developed after it was noted that guinea pig serum suppressed the growth of lymphosarcomas in mice. The active serum component was found to be L-asparaginase, an enzyme that hydrolyzes L-asparagine to L-aspartate. The enzyme is effective because a few neoplastic cells have low levels of asparagine synthetase activity and require L-asparagine for growth. The use of L-asparaginase in cancer chemotherapy is limited to ALL to induce remission. Resistance rapidly develops to in most cancer cells. Hydroxyurea inhibits DNA synthesis. Specifically, it inhibits ribonucleotide reductase to block deoxyribonucleotide formation and DNA synthesis. This enzyme is closely related to proliferative status in cancer cells. It is involved in the de novo synthesis of all the precursors used in DNA synthesis. It converts ribonucleotide diphosphates to deoxyribonucleotides. Hydroxyurea is an S phase specific drug. Resistance is due to changes in the ribonucleotide reductase. The drug is well absorbed from the gastrointestinal tract Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 19
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