Amoebic Liver Abscess - Management - Amoebicidal Drugs

Amoebicidal Drugs

The treatment of invasive amoebiasis should be directed to all sites where E. Histolytica may be present. Hence the ideal amoebicide should be able to act within the intestinal lumen, in the intestinal wall, and systemically, particularly in the liver. Systemic amoebicidal drugs include emetine, dehydroemetine, chloroquine diphosphate, metronidazole, and tinidazole.

Emetine: Ipecac or ipecacuanha consists of the dried rhizome and roots of Cephaelis ipecacuanha. The medical virtues of ipecac are almost entirely due to the action of its alkaloids-emetine and cephaline. Till today, emetine remains one of the best drugs for treating amoebic liver abscess. It has a direct action on the trophozoites. Its greater concentration and duration of action in the liver as compared to that in the intestinal wall explains its high efficacy in amoebic liver abscess and also its low parasitic cure rate for intestinal amoebiasis. The drug is detoxicated and eliminated slowly. It may, therefore, produce cumulative effects. In man, emetine poisoning is characterized by muscular tremors, weakness and pain in the extremities which tend to persist until drug administration is stopped.Gastro-intestinal symptoms include nausea, vomiting and bloody diarrhoea. The latter may be mistaken for a recurrence of amoebic dysentery. Many clinicians fear the occurrence of cardiac toxicity due to this drug and hence avoid using it. Serious cardiac toxicity, however, is rare. In more than twenty years' experience, I have seen only two patients who developed an enlarged heart with congestive cardiac failure. Both recovered with the treatment for heart failure and withdrawal of emetine. One patient who was given fifteen injections of emetine in a dose of 60 mgm. per day, died. Overdosage of emetine produces focal necrosis of cardiac muscle resulting in cardiac failure and sudden death. Emetine, like digitalis may produce mild ST and T wave changes in the electrocardiogram which does not necessarily mean serious toxicity. In fact, they are encountered, though less commonly, after the use of chloroquine and metronidazole as well. Toxic effects on the myocardium have been described even in doses generally considered safe. These are rise in pulse rate, fall in systolic blood pressure and ST-T changes in the electrocardiogram. The other rare E.C.G. changes include deformity of QRS complexes, prolongation of PR interval, atrial premature beats, and atrial tachycardia. In adults, fatal cases have been reported with a total dose of 0.6 G. or less. The incidence of toxic heart damage greatly increases in patients with anaemia. In patients having myocardial disease or marked hypertension, emetine can be used for amoebic liver abscess, as the benefits from it may outweigh possible hazards. This situation is unlikely to arise these days, as equally good alternative drugs like metronidazole are available. Patients receiving emetine should be monitored for changes in pulse, blood pressure and electrocardiography. Absolute bed rest during and several days after emetine therapy has been recommended, although we have often seen patients in whom no untoward reactions have occurred in spite of neglecting the above precaution. Theoretically the use of emetine in children is not advised. However, in practice it has been used as discussed elsewhere. It should not be administered during pregnancy unless absolutely necessary. Although emetine is undeniably moderately toxic, the risk of using it would be worth accepting in such a serious illness were it not for the fact that less toxic drugs like chloroquine and metronidazole are now available. In practice, emetine still produces a more dramatic clinical response thanchloroquine or metronidazole. This point would score in favour of emetine in places where facilities for a proper diagnosis are not available and a therapeutic test remains as the only weapon with a practitioner. Emetine should always be given deep intramuscularly or deep subcutaneously but never intravenously. The total dose in amoebic liver abscess should not exceed 650 mg. or 10 mg/kg. This should be given over a period of 10 days in a dose of 6G65 mg. daily. A relapse rate of 7% follows one such course. Therefore, the treatment could be repeated after a period of 2–6 weeks. Of late such a need does not arise, as drug combinations are commonly used. When parenteral emetine is combined with oral chloroquine or two courses of emetine are given, the relapse rate can be brought down to 1 percent.

Dehydroemetine: It is a synthetic compound developed by Osbond et al. and Brossi et al. in 1959. It is as effective as emetine in its amoebicidal properties. Given parenterally dehydroemetine is surprisingly painless. Oral tablets have been introduced. But for some reason, these tablets have not become popular. A high cure rate can be obtained with this drug. Compared to emetine, its concentration in the heart is less. Electrocardiographic changes are not seen so often. When present, they are more transient than with emetine. Dehydroemetine is excreted by the kidneys, heart and the other organs more rapidly than emetine. Therefore, a daily dose of 1.25 mg or 1.5 mg/kg body weight is necessary. The total daily dose should not exceed 90 mg. The course should not be repeated in less than 14 days.

Chloroquine: The introduction of cinchona into therapeutics was due to the discovery of its efficacy in malaria. In 1921, John used quinine hydrochloride, an alkaloid of cinchona in the treatment of amoebic liver abscess. Later when synthetic derivatives of quinine were introduced, chloroquine phosphate, a 4-aminoquinoline was found to be less toxic than the parent drug. The drug was first quoted in the treatment of this condition in very early reports by Conan (1948)15, Murgatroyd and Kent (1948). It is absorbed rapidly and completely from the gastrointestinal tract. It is found to be very effective in invasive amoebiasis although the drug is a weaker amoebicide when compared to emetine. It is only feebly amoebicidal in the intestinal lumen. The high concentration in the liver parenchyma and the lung allows the drug to act upon E. Histolytica in cases of amoebic liver abscess and pleuropulmonary amoebiasis. It is usually well tolerated, but in some individuals it may cause mild headache, itching, nausea, vomiting or blurred vision. Rarely incoordination, convulsions, peripheral neuritis and bleaching of hair can occur. Diminution of T waves has been noticed on routine electrocardiographic recordings. Retinopathy does not occur with the usual dosage for amoebic liver abscess. Psychic disturbances though rare may interfere with the safe operation of machines and vehicles. The drug may be toxic to children in large doses18 and causes deafness in the foetus. Each 0.5 G. tablet contains chloroquine diphosphate equivalent to 0.3 G. of the base. For the treatment of amoebic liver abscess, it is administered in doses of 0.6 G. base per day in 2 to 3 divided doses orally for 2 days followed by 0.15 G. base twice daily for 2 to 3 weeks. However, Plorde recommends that it be given as 0.6 G. base initially, 0.3 G. base six hours later and then 0.3 G. base twice daily for fourteen to twenty eight days.19 Chloroquine is also available in an injectable form. Since it is quite toxic by this route, it should not be used for more than 24–48 hours after which oral therapy should be continued. Rarely, when patients of amoebic liver abscess are vomiting, injection chloroquine can be used in a dose of 0.3–0.6 G. base in 24 hours not exceeding 0.9 G.). Chloroquine given alone is a safer drug than emetine in amoebic liver abscess, but unfortunately the relapse rate is almost 25%. Rarely repetition of the course may induce a dramatic response.

Ambilhar: Until 1964, all available amoebicides were selective in their sites of action. The development of newer nitro-imidazole derivatives led to Niridazole. It was given in a daily dose of 25–30 mgm. per kg to 50 patients for seven days. The cure rate was found to be 84% with serious side effects in one patient. An Indian study of 30 patients on this drug revealed that it acted as a contact amoebicide and also against the invasive forms.23 The therapeutic action of Ambilhar was found to be significantly better than that produced by a combination of dehydroemetine and chloroquine.

Metronidazole: This is another derivative of the parent drug and its results are better than niridazole. This amoebicide acts directly on the trophozoites of E. Histolytica. Studies showed that because of very high concentration in the liver extremely small amounts of the drug were effective in amoebic liver abscess, but with such low doses, eradication of amoebae in the bowel was uncertain. The drug is quickly absorbed, partly metabolized, and rapidly excreted without any cumulative effect. It is more active in the tissues than in the gut lumen. It follows that a higher dosage is needed in the cure of luminal than systemic infection. The side effects of metronidazole are infrequent. Gastro-intestinal symptoms and headache occur occasionally. Heavy coating of tongue, brownish urine, metallic taste, dry mouth, and nausea occur more often. Vertigo, incoordinate ataxia, and paraesthesias have been reported on rare occasions. Tsai et al. observed psychosis which usually disappeared within a day or two after metronidazole was withdrawn, but tremors and muscle spasm lasted for several days. It has an antabuse-like action and alcohol should be avoided during its use. A transitory leucopenia may occur. Cardiovascular symptoms are rare. Treatment should be discontinued promptly if ataxia or any other symptoms of C.N.S. involvement occur. Only a few years ago when metronidazole was introduced it was considered to be the last word in the therapy of amoebiasis. However, the recent evidence that this drug is carcinogenic and possibly mutagenic in animals is disturbing. Due to such reports the use of the drug remains controversial, especially as metornidazole is a very widely and commonly-used antibiotic. The potential risk in human beings must be weighed against the severity of the disease. The oral dose of 400 mg. thrice daily for 5 days suffices for the treatment of amoebic liver abscess. Adams29 in his analysis of 2,074 cases of liver abscess preferred metronidazole to other amoebicidal agents. A single oral dose of 2.5 G. metronidazole combined with closed aspiration has also produced dramatic response and cure in patients with amoebic liver abscess. Recently the use of intravenous preparation of metronidazole has been reported. Studies by Lazarachick et a revealed presence of anaerobic bacteroides in as many as 26% cases of amoebic liver abscess with so called 'sterile' pus. Intravenous metronidazole is a drug of choice for anaerobic infections Therefore it may be of extra advantage, if used in amoebic liver abscess. Metronidazole should not be used as a single agent for the eradication of bowel infection.33 When used alone, a few cases are known to have developed amoebic liver abscess, months after apparently successful cure of dysentery. Cases refractory to metronidazole have been occasionally described.

Tinidazole: This nitroimidazole compound, like metronidazole, has shown a marked therapeutic response in amoebic liver abscess.Occasional side effects include nausea and dizziness. Tinidazole is not widely available though it is more effective than metronidazole. Zuberi and Ibrahim found tinidazole to be effective in 86.7% cases of intestinal amoebiasis and in 100% cases of amoebic liver abscess. Luminal amoebicides like halogenated oxyquinolines, e.g. diiodohydroxyquinoline in a dose of 0.6 G. thrice daily for 3 weeks, diloxanide furoate 0.5 G. three times a day for 10 days and sometimes tetracyclines 1-2 G./day for 5 days should be used concurrently with any of the above drugs as adjuncts to eliminate intestinal infection.

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