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

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Antimetabolites

– Folic Acid Antagonists – Pyrimidine Analogues – Purine Analogues – Natural Products – Antitumour Antibiotics – Enzymes – Androgen Inhibitors – Anti-oestrogens – Miscellaneous Agents – General Treatment Measures for Anti-cancer Drug Overdoses

Antimetabolites

Folic Acid Antagonists

Methotrexate (MTX)

Folic acid antagonists or antifolates, hold a special place in anticancer chemotherapy, since they were the first to produce striking remissions in leukaemia, and the first cure for a solid tumour (choriocarcinoma). Methotrexate even today remains one of the most important of the antifolates, and is used in the treatment of lymphoma, lymphocytic leukaemia, breast cancer, small cell carcinoma, rheumatoid arthritis, and trophoblastic diseases. Methotrexate or MTX is also used as an immunosup-pressive in organ transplantation.

Methotrexate (MTX) is rapidly absorbed orally if admin-istered in small doses. Large doses are incompletely absorbed, and therefore should be given intravenously. In the latter case, the drug disappears from plasma in a triphasic fashion. The first phase is a rapid distributive phase, which is followed by a second phase of renal clearance (half-life of 2 to 3 hours), and a terminal phase of half-life of 8 to 10 hours. If the terminal phase is unduly prolonged, as in renal failure, there can be severe toxic effects. Renal excretion occurs through a combina-tion of glomerular filtration and tubular secretion. Therefore, concomitant administration of drugs that reduce renal blood flow, or which delay drug excretion, or are nephrotoxic, can lead to severe myelosuppression.

Adverse effects include nausea, vomiting, diarrhoea, fever, anaphylaxis, and hepatic necrosis. Chronic use causes oral and gastrointestinal ulceration (sometimes perforation), bone marrow depression, hepatotoxicity (cirrhosis), renal toxicity, pulmonary fibrosis, osteoporosis, conjunctivitis, alopecia, encephalopathy, infertility, and lymphoma. Intrathecal MTX induces three types of toxic reaction—chemical arachnoiditis (self-limiting), spinal cord and/or nerve damage (may be revers-ible or progressively fatal), and encephalopathy, with dementia, convulsions, coma and death.

Overdose can result in pancytopenia and severe mucositis.

Mortality from high-dose MTX therapy is about 6%, and occurs primarily when the patient is not monitored regularly with MTX levels. Treatment involves gastric lavage if the victim is seen early. Activated charcoal is not effective. Good urinary output (1 to 3 ml/kg/hr) must be maintained, and the urine may be alkalinised with sodium bicarbonate. Folinic acid or leucovorin is the specific antidote for MTX. It reverses bone marrow and GI toxicity, but unfortunately does not resolve neurotoxicity. An initial dose of leucovorin estimated to produce the same plasma concentration as the MTX dose should be given as soon as possible. The toxic threshold for MTX is reported to be 2 × 10-8 mol/L (i.e. 0.02 mmol/L or 20 nmol/L). The dose of leucovorin should be repeated every 3 to 6 hours until the MTX level falls below 1 × 10-8 mol/L. Leucovorin therapy may have to be continued for 12 to 24 doses or longer. In all but the most severe cases of MTX, a leucovorin dose of 100 mg/m2 every 6 hours should be effec-tive. Haemoperfusion and haemodialysis have been reported to be beneficial in MTX overdose. Carboxypeptidase G2 is a new agent capable of inactivating MTX by cleaving its terminal glutamate group. However it can cause hypersen-sitivity reactions because of its bacterial origin. Granulocyte colony stimulating factor (G -CSF) has been used successfully in some patients with MTX overdose. The suggested dosage of G-CSF is 125 mcg/kg/day.

Intrathecal MTX overdose must be treated as follows:

·              CSF drainage—Drainage of 30 ml CSF by lumbar puncture within the first 15 minutes after the overdose can remove upto 95% of the drug. Two hours after the overdose, drainage may remove only about 20% of MTX.

·              CSF washout—With MTX overdoses of more than 100 mg,

·              CSF drainage must be accompanied by ventriculolumbar perfusion.

·              IV pentobarbitone and phenytoin for convulsions.

·              Alkalinise urine to promote urinary excretion of MTX.

·              Administration of high doses of leucovorin IV (upto 1000 mg) may be of benefit.

·              Mannitol for cerebral oedema.

·              Maintain fluid balance.

·              Monitor arterial blood gases.

·              Intubation and mechanical ventilation, if patient is coma-tose.

Pyrimidine Analogues

5-Fluorouracil (5-FU)

The 5-FU requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity. It is generally used to treat patients with metastatic carcinomas of the breast and GI tract. It is also beneficial in hepatoma and carcinoma of ovary, cervix, urinary bladder, pros-tate, pancreas, and oropharyngeal areas. 5-FU is administered parenterally and is subsequently inactivated by dihydropyrimi-dine dehydrogenase, deficiency of which can lead to profound toxicity even with conventional doses.

Toxic effects include anorexia, nausea, stomatitis, diar-rhoea, GI ulceration, shock and death. Chronic adverse effects include myelosuppression (maximal in 2 weeks), alopecia, dermatitis, acute cerebellar syndrome and cardiotoxicity.

Cytarabine (Cytosine arabinoside)

Cytarabine is the most effective antimetabolite used in the treatment of acute myelocytic leukaemia. It has to be first “acti-vated” by conversion to the 5/-monophosphate nucleotide which is catalysed by deoxycytidine kinase. This is then converted to the diphosphate and triphosphate nucleotides which cause potent inhibition of DNA synthesis in cells.

Cytarabine is usually given IV or intrathecally. Less than 10% of the injected dose is excreted unchanged in the urine, while most appears as the inactive, deaminated product arabi-nosyl uracil.

Adverse effects include vomiting, diarrhoea, anaphylaxis, and respiratory distress (high doses). Chronic use can cause bone marrow depression, conjunctivitis, oral ulceration, hepatic damage, fever, pulmonary oedema, neurotoxicity and rhabdomyolysis.

Purine Analogues

Mercaptopurine

Mercaptopurine is an important drug in the treatment of leukaemias, especially acute leukaemia in children. It also has immunosuppressive activity, but its imidazoyl derivative azathioprine is more effective in this regard. Mercaptopurine is usually given orally, though the bioavailability by this route is relatively low.

Adverse effects include bone marrow depression, anorexia, nausea, vomiting, jaundice, hepatic necrosis, pancreatitis, and dermatitis. Overdose results in dizziness, headache, abdominal pain, hepatotoxicity and death.

6-Thioguanine

Thioguanine is especially useful in the treatment of acute granulocytic leukaemia when given along with cytarabine. It is generally administered orally, though absorption is incomplete and erratic by this route. Toxic effects include bone marrow depression, GI distress and hepatic damage.

Natural Products

Vinca Alkaloids

The vinca alkaloids are obtained from the periwinkle plant (Vinca rosea) (Fig 32.6), which is a type of myrtle. Important alkaloids include vinblastine, vincristine, vindesine, and vinorelbine. They are mainly employed in the treatment of lymphomas, Hodgkin’s disease, acute leukaemias, and certain solid tumours. Only vinorelbine can be administered orally, while the others are given IV All the vinca alkaloids are extensively metabolised by the liver, and the metabolites are excreted mainly in the bile.


Vincristine is more neurotoxic than the other alkaloids, but is much less myelotoxic, the incidence of myelosuppres-sion being only about 5 to 10%. The following are the major adverse effects of vinca alkaloids: leukopenia, anaemia, thrombocytopenia, alopecia, constipation, nausea, vomiting, abdominal pain, haemorrhagic enterocolitis, paraesthesia, peripheral neuritis, hypertension, bronchospasm, sterility, and skin vesiculation. 

Occasionally, a syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurs. Overdose results in fever, nausea, vomiting, peripheral neuropathy, muscle weakness, convulsions, hypertension, and bone marrow suppression. Inadvertent intrathecal administra-tion of vincristine has resulted in ascending paralysis and death. Vindesine overdosage leads to severe muscle pain, burning sensation in mouth, tinnitus, diarrhoea, hiccoughs and insomnia.

Treatment involves the administration of leucovorin which is said to be beneficial in ameliorating peripheral neuropathy and myelosuppression. However there is no uniform consensus on this. There have been reports of the utility of glutamic acid, though this matter too has not yet been clearly resolved. Plasmapheresis was successfully employed in one case of vincristine overdose. Dialysis is usually ineffective.

Antitumour Antibiotics

Bleomycin

It is obtained from Strep. verticillus and is actually a mixture of two copper-chelating peptides (bleomycin A 2 and B2). It is mainly used against squamous carcinomas of the head and neck and lungs, lymphomas, and testicular tumours. The cytotoxic action results from its ability to cause fragmentation of DNA. It is usually given parenterally (IM or IV).

Adverse effects include pulmonary toxicity (interstitial pneumonitis, fibrosis), anaphylactoid reactions, hyperpyrexia, rash and vesiculation, hyperkeratosis, alopecia, headache and vomiting.

Dactinomycin (Actinomycin D)

It is also obtained from Streptomyces species, and is mainly used intravenously in the treatment of rhabdomyosarcoma and Wilms’ tumour in children. It is also useful in treating Ewing’s tumour and Kaposi’s sarcoma.

Toxic manifestations include anorexia, nausea, vomiting, haematopoietic suppression with pancytopenia, proctitis, diar-rhoea, ulcerations of oral mcosa, alopecia and dermal changes. 

Mitomycin C

This is obtained from Strep. caespitosus, and is usually given intravenously in the treatment of carcinoma of colon or stomach.

Adverse effects include myelosuppression, vomiting, diarrhoea, dermatitis, fever, pulmonary fibrosis. The most dangerous adverse effect is a haemolytic uraemic syndrome which results in renal failure. Extravasation of the drug while infusing it can cause severe local injury.

Daunorubicin, Doxorubicin, and Idarubicin

These are called anthracycline antibiotics and are produced by the fungus Strep. peucetius var. Caesius. Idarubicin is actu-ally a synthetic derivative. Daunorubicin has been useful in the treatment of acute lymphocytic and granulocytic leukaemias. It is the drug of choice in acute nonlymphoblastic leukaemia (along with cytarabine). Doxorubicin is effective not only in the treatment of acute leukaemias and malignant lymphomas, but is also useful in treating a number of solid tumours.

Toxic effects include myelosuppression, thrombocytopenia, anaemia, GI disturbances, alopecia, conjunctivitis, and severe local reactions if extravasation occurs. A serious adverse effect with all anthracyclines is cardiomyopathy. Cardiac damage may be minimised by concomitant administration of dexrazoxane, an iron chelator.

Enzymes

Bleomycin

Escherichia coli produces two L-asparaginase isozymes, onlyone of which (EC-2) is used as an antineoplastic agent. The purified E.coli enzyme is given IV or IM for the treatment of acute lymphoblastic leukaemia and other lymphoid cancers. Since this enzyme is a foreign protein and causes hypersen-sitivity reactions in 5 to 20% of patients, other sources have been made available including Erwinia chrysanthemi. Also a modified form of the enzyme (PEG-asparaginase) has been developed, which is obtained by conjugating it with polythylene glycol. These are much safer.

Toxic effects include nausea, vomiting, fever with chills, headache, hyperglycaemia, acute haemorrhagic pancreatitis, renal and hepatic toxicity, and coagulation defects. CNS toxicity has been reported, characterised by lethargy, stupor and coma, which is ascribed to a fall in CSF asparagines. “Asparagine rescue” infusions have been evolved to counter such serious adverse effects.

Epipodophyllotoxins

Podophyllotoxin is an extract of the mandrake or mayappleplant (Podophyllum peltatum) (Fig 32.7). Etoposide and temi-poside are semisynthetic glycosides derived from it. Etoposideis more commonly used and is given orally or intravenously for the treatment of malignant lymphomas, acute leukaemias, small cell lung cancer, and some other solid tumours.


Toxic effects include myelosuppression, nausea, vomiting, diarrhoea, alopecia, fever, and allergic reactions. High doses are associated with hepatic damage.

Androgen Inhibitors

Flutamide

Flutamide is a non-steroidal anti-androgen which is adminis-tered orally for prostatic cancer. It acts directly on the target tissues either by blocking androgen uptake or by inhibiting cytoplasmic and nuclear binding of androgen.

Adverse effects include hot flashes, loss of libido (in about 50% of patients), impotence, gynaecomastia, nausea, vomiting, diarrhoea, chest pain, blurred vision, hepatitis, rash, SLE-like syndrome, confusion and depression.

Anti-oestrogens

Tamoxifen

Tamoxifen citrate is an anti-oestrogen that is effective as pallia-tive treatment for patients with advanced breast cancer. It is also used as an adjuvant in postmenopausal women to prevent disease recurrence. Tamoxifen is given orally.

Adverse effects include hypercalcaemia (in patients with bone metastases), thromboembolic events, hot flushes, vaginal bleeding, pruritis vulvae, GI upset, vertigo, and an increased tendency towards endometrial cancer. The last mentioned should be watched for by conducting yearly pelvic examina-tions, and specific enquiries must be made regarding pelvic discomfort for vaginal bleeding.

Miscellaneous Agents

Platinum Co-ordination Complexes (Platinoids)

The cytotoxic effects of the platinum-containing compounds were first discovered in 1965, and since then many such compounds have been synthesised, of which the important ones include cisplatin, carboplatin, and iproplatin. The platinoids are used mainly in the treatment of ovarian and testicular tumours, and also cancers of head and neck, bladder, oesophagus and lung. They are usually given IV.

Common adverse effects include renal dysfunction,auditory impairment, peripheral neuropathy, and myelosup-pression. Overdose results in rapid renal failure and death, due to irreversible acute tubular necrosis. The presence of urinary alanine aminopeptidase and N-acetyl-beta -D-glucosamidase are early indicators of renal tubular damage. Renal dysfunction is usually preceded by encephalopathy, convulsions, visual impairment (negative-type response with electroretinogram), and high-frequency hearing loss.

Treatment involves the following measures:

Chloride diuresis promotes the inactive anionic state of cisplatin and decreases the urine platinum concentration, which is helpful in nephrotoxicity during therapy.

Hydration with 0.9% sodium chloride, and an osmotic diuretic (e.g. mannitol) should be administered to achieve a high urine output (1 to 3 ml/kg/hr), for 6 to 24 hours post-exposure.

Careful assessment of renal function by regular assays of serum BUN and creatinine, glomerular filtration, filtration fraction, and renal plasma flow.

Administration of nephroprotectants post-exposure, e.g. sodium thiosulfate* (IV bolus of 4 gm/m2, followed by infu-sion of 12 gm/m2 over 6 hours), and diethyldithiocarbamate,** i.e. DDTC (4 gm/m2 as a 1.5 to 3.5-hour infusion). Disulfiram is metabolised to DDTC and can be used if the latter is not available.

Plasmapheresis is highly beneficial. Haemodialysis is effec-tive if there is renal failure.

Hydroxyurea

Hydroxyurea causes cell death by specific inhibition of DNA synthesis, and is administered orally in the treatment of chronic myeloid leukaemia and some varieties of solid tumours.

Adverse effects include bone marrow suppression, nausea, vomiting, diarrhoea, stomatitis, drowsiness, convulsions, hallu-cinations, alopecia, fever, chills and renal dysfunction.

Mitoxantrone (Mitozantrone)

Mitoxantrone is an anthraquinone related chemically to the anthracyclines. It is indicated in the treament of advanced breast cancer, lymphoma, and acute lymphocytic leukaemia. It is given IV.

Adverse effects include myelosuppression, cardiotoxicity, vomiting, alopecia, stomatitis, fever, and neurological effects. Urine may be discoloured blue-green. Overdose results in ataxia, nystagmus, loss of vibration sense, paraesthaesia, convulsions, and hepatic dysfunction. Extravasation causes tissue necrosis.

Mesna Preparations

Mesna is usually given as a uroprotectant to prevent haemor-rhagic cystitis resulting from therapy with cyclophosphamide and ifosfamide. It is usually given intravenously. Adverse effects include headache, tachycardia, and hypertension. Overdose can cause vomiting and diarrhoea.

General Treatment Measures for Anti-cancer Drug Overdoses

Stabilisation—­

·              Watch for and manage convulsions (if they occur), with IV diazepam.

·              If there are vital sign abnormalities, establish IV line, cardiac monitor, oxygen, and assisted ventilation (as needed).

·              Correct abnormalities of ventilation and blood pressure.

·              Arrange for complete haematological analysis (RBC, haematocrit, WBC, platelets).

·              If patient is asymptomatic even after 12 hours, discharge can be considered. However, the patient must be subse-quently followed up weekly with blood counts for at least 4 weeks. Cardiovascular follow-up is necessary for several months in the case of anthracycline overdose, on account of frequently delayed onset of cardiotoxicity.

Decontamination—

·              Stomach wash is indicated in oral overdoses. Syrup of ipecac is not advisable since it may provoke convulsions which are frequently encountered with antineoplastic drugs.

Antidotes—There are very few antidotes available for antineoplastic drug overdose. Table 32.7 lists some of the accepted antidotal agents.


Elimination Enhancement—While extracorporeal treat-ment methods such as haemodialysis, haemoperfusion, and exchange transfusion may help in some cases of overdose, they are generally not beneficial because most anicancer drugs possess high volumes of distribution, high protein binding values, and tendency for extensive metabolite formation.

Supportive Care—

·              Treat convulsions with IV diazepam.

·              Unconscious patients, and those with respiratory diffi-culty must be intubated.

·              If there is fever (with or without chills), repeated cultures should be obtained of blood, urine, and sputum. Intravenous antibiotics may be necessary if there is evidence of infection.

·              Electrolyte depletion should be corrected by replace-ment therapy with IV electrolytes. This should be accompanied by careful cardiac and respiratory moni-toring, and periodic arterial blood gas determinations.

·              Oral mucositis necessitates local therapy and parenteral administration of nutrition. One study indicates that topical application of 1 ml of vitamin E oil (400 mg/ml), twice a day for 5 days is effective for chemotherapy-induced mucosal lesions.

·              Conjunctivitis can be managed with saline irrigations and ocular steroids.

·              Chemotherapy-induced vomiting is the most consistent toxic effect of almost every anticancer drug, and may be extremely severe and refractory to treatment. The usual antiemetics employed include phenothiazines (e.g. prochlorperazine), butyrophenones (e.g. droperidol), and substituted benzamides (e.g. metoclopramide). Ondansetron is as effective as metoclopramide in the prevention of chemotherapy-induced vomiting.

·              Antiemetic cocktail: Metoclopramide + Steroids (decadron or methylprednisolone), + Lorazepam.

·              Table 32.8 outlines common treatment regimens for chemotherapy-induced nausea and vomiting.



Dehydration must be managed with IV fluids and moni-toring of CVP.

Nephrotoxicity may require prolonged dialysis.

Treatment of encephalopathy involves periodic EEG, lumbar punctures (for CSF analysis), CAT scan, nuclear magnetic resonance studies, and possible “CSF washout”.

Thrombocytopenia may necessitate platelet transfusion.

Anaemia and low haematocrit may necessitate red blood cell transfusions.

Hypertension can be managed with mannitol or IV sodium nitroprusside.

 

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