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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Anti-Infectives

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Mefloquine, Halofantrine, Endoperoxidases, Pyrimethamine, Mepacrine - Antimalarial Drugs

1. Mefloquine 2. Halofantrine 3. Endoperoxidases 4. Pyrimethamine 5. Mepacrine (Quinacrine)

Other Antimalarial Drugs

1.  Mefloquine

It is an antimalarial agent which is a blood schizontocide. It is a 4-quinolone-methanol developed in the 1960s to combat drug-resistant strains of Plasmodium falciparum. It is admin-istered orally, and plama levels rise in a biphasic manner to reach their peak in about 15 to 17 hours. Mefloquine is widely distributed and highly protein-bound (98%). Excretion is mainly by faecal route.

Therapeutic doses are usually well tolerated, but may occa-sionally cause abdominal pain, vomiting, diarrhoea, and vertigo. Higher doses result in ataxia, headache, bradycardia, prolonga-tion of the QTc interval, hypoglycaemia, psychosis, anxiety, depression, agitation, nightmares, hallucinations, paranoia and audiovisual disturbances. Women may be more susceptible to mefloquine-induced neuropsychiatric effects. Other effects reported include skin rashes, pruritus and urticaria, hair loss, muscle weakness, myalgia, liver function disturbances, and occasionally thrombocytopenia and leucopenia. Rare compli-cations include encephalopathy and seizures. Concomitant administration of quinine or chloroquine enhances the risk of convulsions as well as cardiotoxicity. Since mefloquine has a long elimination half-life (13 to 24 days), adverse effects may persist for several weeks after drug cessation. A post-malaria neurological syndrome has been reported, consisting of confu-sion, psychosis, seizures, or tremor developing after treatment for malaria.

Treatment of acute toxicity is on general lines with special attention directed towards control of seizures. All patients with mefloquine overdose should be admitted and observed with continuous cardiac monitoring, along with neurologic and psychiatric assessment, for at least 24 hours. Activated charcoal can be administered or stomach wash done, if decontamination is applicable in a given case. Atropine, dobutamine, or pacing can control bradycardia. Phenytoin, lignocaine, or amiodarone may be required for ventricular arrhythmias. Methods of extra-corporeal elimination are unlikely to be of benefit because of the large volume of distribution and extensive protein binding of mefloquine.

Spontaneous abortions and an increased number of stillbirths were seen in women who received mefloquine for malaria prophylaxis early in pregnancy. Animal experiments suggest that mefloquine is teratogenic.

2. Halofantrine

It is a phenanthrene methanol which is sometimes used as an alternative to quinine and mefloquine for the treatment of drug-resistant falciparum malaria. It is a blood schizontocide with no apparent activity against the sporocyte, gametocyte, or hepatic stages of the infection.

Side effects include vomiting, diarrhoea, and abdominal pain. Syncope, dizziness, pruritus, and convulsions may also occur. High doses induce cardiotoxicity (QTc interval prolon-gation and ventricular arrhythmias). Halofantrine should be taken on an empty stomach. Food, especially food high in fat content, increases the absorption of halofantrine, which may increase its toxicity.

Although not reported, overdose of halofantrine might also be expected to cause cardiotoxicity (ECG abnormalities and ventricular arrhythmias) and gastrointestinal toxicity (nausea, vomiting, diarrhoea, and abdominal pain).

Treatment of halofantrine overdose is mainly symptomatic and supportive. Activated charcoal and/or gastric lavage may be of help in the initial stages. Monitor fluid and electrolytes in cases of severe vomiting and diarrhoea, and ECG for ventricular arrhythmias. Antiarrhythmic agents (lignocaine, phenytoin, amiodarone, etc.) may be required. Convulsions can be controlled with benzodiazepines. Liver function tests should be monitored in symptomatic patients.

3. Endoperoxidases

They are recent entrants in the field of antimalarial therapy, and are represented mainly by qinghaosu (a sesquiterpene lactone discovered in China), and its derivatives artemether and artesunate. They are used in the treatment of drug-resistant falciparum malaria. They are generally well tolerated, but can occasionally cause gastrointestinal distress and cardiotoxicity.

4. Pyrimethamine

It is a dihydrofolate reductase inhibitor, and is used in combination with sulfadoxine (a long -acting sulfonamide), or trimethoprim, for the treatment of chloroquine-resistantfalciparum malaria. This drug combination is also recom-mended for the therapy of toxoplasmosis. Adverse reactions include severe cutaneous eruptions, DIC, blood dyscrasias, anaphylactoid reactions, peripheral neuritis, ataxia, vertigo, and renal/hepatic damage. Use of trimethoprim at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/ or megaloblastic anaemia.

Most serious cases of pyrimethamine overdose have been reported in children under three years old. Symptoms include vomiting, rashes, CNS depression, convulsions, hyperpyrexia, tachycardia, respiratory rate changes, and jaundice. Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression.

Treatment of overdose with either agent is supportive in nature. Haemodialysis is moderately effective in eliminating trimethoprim. Due to higher protein binding, it is not likely that haemodialysis will be very effective for the elimination of pyrimethamine.

5. Mepacrine (Quinacrine)

It is an acridine derivative which was formerly used widely as an antimalarial drug, but is unpopular today owing to severe side effects including vertigo, headache, ataxia, vomiting, yellowish discolouration of skin and urine, bluish-black discol-ouration of palate and nails, psychosis, convulsions, ocular toxicity, exfoliative dermatitis, liver damage, and aplastic anaemia. It is incompatible with alcohol and can produce a disulfiram-like reaction. Mepacrine has been banned in the USA and most other Western countries since the early 1990s. That it is still available in India is a sad reflection of govern-mental apathy towards the sale of dangerous and obsolete drugs.


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