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

More documents

Recommendations

Info

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 Dactinomycin is used mainly in the treatment of pediatric solid tumors (e.g. Wilm's tumor, rhabdomyosarcoma). It is also an alternative drug for choriocarcinoma when methotrexate can't be used because of resistance. The treatment of several solid tumors utilizes combination therapy with dactinomycin and radiotherapy. There seems to be an improved antitumor effect when the two are used in combination. Toxicity: The primary and dose limiting toxicity of dactinomycin is bone marrow depression. The leukocyte count and usually the platelet count are depressed with a trough after one to two weeks. Also nausea, vomiting, malaise, ulceration of the oral mucosa and gastrointestinal tract and acneiform eruptions of the skin occur. The nausea, vomiting and malaise begin several hours after treatment and last for as long as a day. If given to a patient who has had radiation treatment, a ‘recall’ effect may be observed i.e. when the drug is administered, the patient may develop a reaction in normal appearing tissue that was included in the field of radiation. The anthracycline antibiotics, like doxorubicin, daunorubicin, idarubicin and epirubicin, are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemias. They all contain a four-membered anthracycline nucleus attached to a sugar molecule. Daunorubicin and doxorubicin are identical except for the presence of a hydrogen or hydroxyl at the 14 position of the anthracycline ring. Idarubicin is 4-demethoxy-daunorubicin. This minor structural modification at position 4 of the chromophore ring makes the drug more lipophilic giving it a longer half-life. The anthracyclines all bind to double-stranded DNA. In human chromosome preparations treated with anthracyclines the bound drug is observed as well-defined, orange-red fluorescent bands. This interaction with DNA is by intercalation. If the structure of the anthracyclines is modified so that the binding to DNA is altered their is usually a decrease or loss of antitumor activity. However, the pathways leading to cytotoxicity are not all that clear. Inhibition of DNA and RNA synthesis is not though to be critical for cytotoxicity as it only occurs at high drug concentration. Breakage of the DNA strand can occur. This is believed to be mediated either by the enzyme DNA Topoisomerase II or by the formation of free radicals. Inhibition of the enzyme topoisomerase II, for example, can lead to a series of reactions leading to double strand breaks in the DNA. Temporary doublestrand breaks are induced by topoisomerase II in the course of its normal catalytic cycle, by formation of a cleavable complex. Disruption of this complex, which results in a permanent double-strand break, occurs infrequently in the absence of drugs. Inhibitors of topoisomerase II cause the cleavable complex to persist, thereby increasing the probability that the cleavable complex will be converted to an irreversible doublestrand break. Anthracyclines can also cause the formation of reactive oxygen species that then cause predominantly single-strand breakage. The anthracycline chromophore contains a hydroxyquinone, which is a well-described iron chelating structure. The drug-iron-DNA complex catalyzes the transfer of electrons from glutathione to oxygen, resulting in the formation of active oxygen species. All three anthracyclines are administered IV since the glycosidic bond would be split in the gastrointestinal tract making these drugs inactive if given orally. The anthracyclines are very irritating to tissue on extravasation. Thus, they are usually given into the tubing of a rapidly flowing IV infusion. These drugs are rapidly cleared from the plasma. The metabolic pathways of the anthracyclines are very similar. They are eliminated by metabolic conversion to a variety of less active or inactive metabolites by liver enzymes. A major pathway is conversion to the alcohols daunorubicinol and doxorubicinol which also have cytotoxic activity like their parents. This reduction is catalyzed by cytoplasmic NADPH-dependent reductase. Daunorubicin is a better substrate for this enzyme than is doxorubicin; thus after a few hours the alcohol is the principal circulating form of this drug while with doxorubicin the parent drug is the principal circulating form. Glycosidases also act on the parent drugs as well as the metabolites. Since the anthracyclines are detoxified in the liver, patients with impaired hepatic function risk severe toxicity and the dosage must be reduced. Daunorubicin has limited use. It is employed in treatment of ALL and AML. Doxorubicin has a much broader range of use. It is most active against solid tumors, particularly breast cancer. Other solid tumors against which it has good activity are ovary, bladder, and lung carcinomas. It is also active in the treatment of Non-Hodgkin's lymphoma and Hodgkin's disease. Idarubicin appears to be as effective as daunorubicin in combination treatment of AML with perhaps more efficacy in patients less than 60 years old. Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 14
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 Toxicity: The toxic effects of the anthracyclines are similar. They frequently cause nausea and vomiting and patients may experience anorexia and diarrhea. The drugs and their metabolites may color the urine red for one or two days after administration. Bone marrow depression is dose-limiting and occurs in 60%-80% of patients. This is seen primarily as leukopenia which reaches a low point at approximately one to two weeks. Thrombocytopenia and anemia may also occur but is not as severe. Stomatitis is dose related and may be severe. Alopecia also occurs in most patients but reverses when therapy is stopped. The anthracyclines potentiate the effects of radiation and enhancement of radiation reactions and radiation recall effects on normal tissues have been seen. Cardiac toxicity is a peculiar adverse effect observed in both adults and children. Two types of reactions are observed: a) early, transient electrocardiographic changes, and b) a delayed progressive cardiomyopathy. Acute changes in the ECG, including tachycardia, extrasystolic contractions, and ST-T wave alterations, may occur in the week following drug administration. Arrhythmias generally reverse within a few hours, and the ST segment and T-wave abnormalities usually reverse in 1 or 2 weeks after a single dose. Pathological studies of patients who have died of congestive heart failure show a decrease in the number of cardiac muscle cells and signs of degeneration in the remaining cells. It is thought that the sarcoplasmic reticulum is the critical site of anthracycline induced damage within the myocardial cell. The cardiomyopathy is usually fatal. There is now a great deal of evidence that the myocardial damage produced by these drugs is due to production of reactive oxygen species, in particular the hydroxyl radical. These radicals are generated from redox cycling of the anthracycline quinone, which can undergo one electron reduction to the semiquinone or two electron reduction to the corresponding dihydroquinone derivative. The semiquinone reacts rapidly with oxygen to generate superoxide anion. Superoxide anion can dismutate to peroxide, which reacts with a number of species to produce hydroxyl ion. The heart may be especially prone to anthracycline toxicity because it contains lower levels of critical detoxifying enzymes (e.g. catalase and superoxide dismutase) than other organs such as the liver. It has been shown that doxorubicin administration leads to lipid peroxidation in cardiac tissue and that this process can be blocked by free radical scavengers such as alphatocopherol. However, free radical scavengers were found to be unsuccessful at controlling cardiac toxicity in humans. More successful in humans were agents that acted as iron chelators, the rational being that anthracycline induced lipid peroxidation required iron. Dexrazoxane has recently been approved to prevent anthracycline induced cardiac toxicity. Anthracenediones like mitoxantrone are analogs of the anthracyclines. They lack the sugar moiety of the anthracyclines but retain the planar polycyclic aromatic ring structure that permits intercalation into DNA . They have shown impressive clinical activity but appear to cause less cardiac toxicity, most likely because they cannot produce quinone type free radicals. Mitoxantrone interacts with DNA by a high-affinity intercalation. It also produces a lower affinity binding as a result of electrostatic interactions. Intercalation of mitoxantrone into DNA interferes with the strand-reunion reaction of topoisomerase II, resulting in production of protein-linked double-strand DNA breaks. Although mitoxantrone is cytotoxic to cells throughout the cell cycle , cells in late S phase are more sensitive. Tumor cells resistant to mitoxantrone may show cross resistance to other natural products. The drug is given by IV infusion. It undergoes extensive binding to several different tissues and has been detected in tissues of patients who died several weeks to several months after receiving the last dose. Mitoxantrone has a much narrower range of therapeutic activity than the anthracyclines. It is used mainly for treatment of the leukemias (mainly AML) and lymphomas as well as advanced breast cancer. Toxicity: The primary acute toxicity is nausea and vomiting which is mild to moderate and occurs in about 40% of patients. It causes less nausea and vomiting and alopecia than does doxorubicin. Its major toxicities are bone marrow depression and mucositis. The bone marrow depression is of a delayed nature with the lowest counts being seen at one to two weeks. Patients should be warned of a possible blue-green coloration of the sclerae and nails as well as the urine. The bleomycins are a group of antitumor agents isolated from Streptomyces verticillus. The drug employed clinically is a mixture of compounds of complex structure containing about 70% bleomycin A 2 . Bleomycin is a metal binding water soluble glycopeptide antibiotic. Bleomycins have attracted interest Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 15
Page 1 and 2: International Journal of Research i
Page 13: International Journal of Research i

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

Create successful ePaper yourself

Delete template?

Save as template?