antiamoeba and other protozons drugs.pptx

Antiamebic drugs may be classified into three groups: luminal, tissue, and mixed amebicides. The most frequently used amebicides with luminal action are diiodohydroxyquinoline (650 mg orally 3 times daily for 20 days), diloxanide furoate (500 mg orally 3 times daily for 10 days) and paromomycin (500 mg orally 3 times daily for 5–10 days).

1. Anti-amoeba and others anti-protozoal drugs Dr. Liaqat Hussain

2. Entamoeba histolytica The infection is encountered around the world, but more often in warmer climates. Approximately 500 million people are thought to harbour the disease, with 40 000–100 000 deaths occurring each year as a result. It is considered to be the second leading cause of death from parasitic diseases worldwide. The organism has a simple life cycle, and humans are the chief hosts. Infection, generally spread by poor hygiene, follows the ingestion of the mature cysts in water or food that is contaminated with human faeces . The infectious cysts pass into the colon, where they develop into trophozoites. These motile organisms adhere to colonic epithelial cells, utilising a galactose-containing lectin on the host cell membrane. Here, the trophozoites feed, multiply, encyst and eventually pass out in the faeces , thus completing their life cycle. Some individuals are symptomless ‘carriers’ and harbour the parasite without developing overt disease, but cysts are present in their faeces and they can infect other individuals. The cysts can survive outside the body for at least a week in a moist and cool environment.

3. The trophozoite lyses the colonic mucosal cells (hence ‘histolytica’) using proteases, amoebapores (peptides that form pores in cell membranes) or by inducing host cell apoptosis. The organism then invades the submucosa, where it secretes factors to modify the host response, which would otherwise prove lethal to the parasite. It is this process that produces the characteristic bloody diarrhoea and abdominal pain, although a chronic intestinal infection may be present in the absence of dysentery. In some patients, an amoebic granuloma ( amoeboma ) may be present in the intestinal wall. The trophozoites may also migrate through the damaged intestinal tissue into the portal blood and hence the liver, giving rise to the most common extra-intestinal symptom of the disease – amoebic liver abscesses.

4. AMEBIASIS Amebiasis is infection with Entamoeba histolytica . This organism can cause asymptomatic intestinal infection, mild to moderate colitis, severe intestinal infection (dysentery), ameboma, liver abscess, and other extraintestinal infections. The choice of drugs for amebiasis depends on the clinical presentation. Treatment of Specific Forms of Amebiasis 1. Asymptomatic intestinal infection Asymptomatic carriers generally are not treated in endemic areas, but in nonendemic areas they are treated with a luminal amebicide. A tissue amebicidal drug is unnecessary. Standard luminal amebicides are diloxanide furoate, iodoquinol, and paromomycin. Each drug eradicates carriage in about 80–90% of patients. Therapy with a luminal amebicide is also required in the treatment of all other forms of amebiasis.

5. 2. Amebic Colitis Metronidazole plus a luminal amebicide is the treatment of choice for amebic colitis and dysentery. Tetracyclines and erythromycin are alternative drugs for moderate colitis but are not effective against extra-intestinal disease. Dehydro-emetine or emetine can also be used, but are best avoided because of toxicity. 3. Extraintestinal Infections The treatment of choice for extra-intestinal infections is metronidazole plus a luminal amebicide . A 10-day course of metronidazole cures over 95% of uncomplicated liver abscesses. For unusual cases in which initial therapy with metronidazole has failed, aspiration of the abscess and the addition of chloroquine to a repeat course of metronidazole should be considered. Dehydroemetine and emetine are toxic alternative drugs.

6. METRONIDAZOLE & TINIDAZOLE Metronidazole, a nitroimidazole is the drug of choice in the treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections. Tinidazole, a related nitroimidazole, appears to have similar activity and a better toxicity profile. It offers simpler dosing regimens. Pharmacokinetics & Mechanism of Action Oral metronidazole and tinidazole are readily absorbed and permeate all tissues by simple diffusion. Intracellular concentrations rapidly approach extracellular levels. Peak plasma concentrations are reached in 1–3 hours. Protein binding of both drugs is low (10–20%); the half-life of unchanged drug is 7.5 hours for metronidazole and 12–14 hours for tinidazole

7. Metronidazole and its metabolites are excreted mainly in the urine. Plasma clearance of metronidazole is decreased in patients with impaired liver function. The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antiprotozoal and antibacterial activity. The mechanism of tinidazole is assumed to be the same .

8. Clinical Uses 1. Amebiasis— Metronidazole or tinidazole is the drug of choice in the treatment of all tissue infections with E histolytica . Neither drug is reliably effective against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection. 2. Giardiasis— Metronidazole is the treatment of choice for giardiasis. The dosage for giardiasis is much lower than that for amebiasis, and the drug is thus better tolerated. Efficacy after a single treatment is about 90%. Tinidazole is at least equally effective, and can be used as a single dose. 3. Trichomoniasis— Metronidazole is the treatment of choice. A single dose of 2 g is effective. Metronidazole-resistant organisms can lead to treatment failures. Tinidazole may be effective against some of these resistant organisms.

9. Adverse Effects & Cautions Nausea, headache, dry mouth, and a metallic taste in the mouth occur commonly. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesia's, encephalopathy, and neutropenia. Taking the drug with meals lessens gastrointestinal irritation. Pancreatitis and severe central nervous system toxicity (ataxia, encephalopathy, seizures) are rare. Metronidazole has a disulfiramlike effect, so that nausea and vomiting can occur if alcohol isingested during therapy. The drug should be used with caution in patients with central nervous system disease. Intravenous infusions have rarely caused seizures or peripheral neuropathy. The dosage should be adjusted for patients with severe liver or renal disease.

10. Tinidazole has a similar adverse-effect profile, although it appears to be somewhat better tolerated than metronidazole. Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, whereas cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole. Metronidazole and its metabolites are mutagenic in bacteria and tumorigenic in mice. Data on teratogenicity are inconsistent. Metronidazole is thus best avoided in pregnant or nursing women, although congenital abnormalities have not clearly been associated with use in humans.

11. IODOQUINOL Iodoquinol ( diiodohydroxyquin ), a halogenated hydroxyquinoline, is an effective luminal amebicide. Pharmacokinetic data are incomplete but 90% of the drug is retained in the intestine and excreted in the feces. The remainder enters the circulation, has a half-life of 11–14 hours, and is excreted in the urine as glucuronides. Iodoquinol is effective against organisms in the bowel lumen but not against trophozoites. Infrequent adverse effects include diarrhea—which usually stops after several days—anorexia, nausea, vomiting, abdominal pain, headache, rash, and pruritus. Some halogenated hydroxyquinolines can produce severe neurotoxicity with prolonged use. Iodoquinol is not known to produce these effects at its recommended dosage, and this dosage should never be exceeded. Iodoquinol should be taken with meals to limit gastrointestinal toxicity.

12. It should be used with caution in patients with optic neuropathy, renal or thyroid disease, or nonamebic hepatic disease. The drug should be discontinued if it produces persistent diarrhea or signs of iodine toxicity (dermatitis, urticaria, pruritus, fever). It is contraindicated in patients with intolerance to iodine. DILOXANIDE FUROATE Diloxanide furoate is a dichloroacetamide derivative. It is an effective luminal amebicide but is not active against trophozoites. In the gut, diloxanide furoate is split into diloxanide and furoic acid; about 90% of the diloxanide is rapidly absorbed and then conjugated to form the glucuronide, which is promptly excreted in the urine. The unabsorbed diloxanide is the active antiamebic substance. Diloxanide furoate is not available commercially in the USA but can be obtained from some compounding pharmacies. It does not produce serious adverse effects.

13. Flatulence is common, but nausea and abdominal cramps are infrequent and rashes are rare. The drug is not recommended in pregnancy. PAROMOMYCIN SULFATE Paromomycin sulfate is an aminoglycoside antibiotic that is not significantly absorbed from the gastrointestinal tract. It is used as a luminal amebicide and has no effect against extraintestinal organisms. Paromomycin appears to have similar efficacy and less toxicity than other luminal agents; in one study it was superior to diloxanide furoate in clearing asymptomatic infections. As it is readily available, paromomycin can be considered the antiamebic luminal agent of choice in the USA. Adverse effects include occasional abdominal distress and diarrhea. Parenteral paromomycin is now used to treat visceral leishmaniasis

14. EMETINE & DEHYDROEMETINE Emetine, an alkaloid derived from ipecac, and dehydroemetine , a synthetic analog, are effective against tissue trophozoites of E histolytica , but because of major toxicity concerns their use is limited to unusual circumstances in which severe amebiasis requires effective therapy and metronidazole cannot be used. Dehydroemetine is preferred because of its somewhat better toxicity profile. The drugs should be used for the minimum period needed to relieve severe symptoms (usually 3–5 days) and administered subcutaneously (preferred) or intramuscularly in a supervised setting. Adverse effects, which are generally mild with use for 3–5 days but increase over time, include pain, tenderness, and sterile abscesses at the injection site; diarrhea, nausea, and vomiting; muscle weakness and discomfort; and minor electrocardiographic changes. Serious toxicities include cardiac arrhythmias,heart failure, and hypotension.

15. TRYPANOSOMIASIS AND TRYPANOCIDAL DRUGS Trypanosomes belong to the group of pathogenic flagellate protozoa. Two subtypes of Trypanosoma brucei ( rhodesiense and gambiense ) cause sleeping sickness in Africa (also called HAT – human African trypanosomiasis ). In South America, another species Trypanosoma cruzi causes Chagas’ disease (also known as American trypanosomiasis). Almost eliminated by 1960, HAT has re-emerged. In 2009 WHO estimated about 30 000 cases, with about 70 million people at risk of contracting sleeping sickness. The disease caused by T . b. rhodesiense is the more aggressive form. Civil unrest, famine and AIDS encourage the spread of the disease by reducing the chances of distributing medication or because patients are immunocompromised, but despite this the incidence appears to be dropping. Related trypanosome infections also pose a major risk to livestock and thus have a secondary impact on human health and well-being.

16. The vector HAT is the tsetse fly. In both types of disease, there is an initial local lesion at the site of entry, which may (in the case of T. b. rhodesiense ) develop into a painful chancre (ulcer or sore). This is followed by bouts of parasitaemia and fever as the parasite enters the haemolymphatic system. The parasites and the toxins they release during the second phase of the disease cause organ damage. This manifests as ‘sleeping sickness’ when parasites reach the CNS causing somnolence and progressive neurological breakdown. Left untreated, such infections are fatal. T. cruzi is spread through other blood-sucking insects, including the ‘kissing bugs’. The initial phases of the infection are similar but parasites damage the heart, muscles and sometimes liver, spleen, bone and intestine. Many people harbour chronic infections but the cure rate is good if treatment begins immediately after infection.

17. Kissing bug

18. The main drugs used for HAT are suramin , with pentamidine as an alternative, in the haemolymphatic stage of the disease, and the arsenical melarsoprol for the late stage with CNS involvement and eflornithine. All have toxic side effects. Nifurtimox , eflornithine and benznidazole are used in Chagas’ disease: however, there is no totally effective treatment for this form of trypanosomiasis. SURAMIN Suramin was introduced into the therapy of trypanosomiasis in 1920. The drug binds firmly to host plasma proteins, and the complex enters the trypanosome by endocytosis, then liberated by lysosomal proteases. It inhibits key parasite enzymes inducing gradual destruction of organelles, such that the organisms are cleared from the circulation after a short interval. The drug is given by slow intravenous injection. The blood concentration drops rapidly during the first few hours and then more slowly over the succeeding days. A residual concentration remains for 3–4 months.

19. It tends to accumulate in mononuclear phagocytes, and in the cells of the proximal tubule in the kidney. Unwanted effects are common. Suramin is relatively toxic, particularly in a malnourished patient, the main organ affected being the kidney. Many other slowly developing adverse effects have been reported, including optic atrophy, adrenal insufficiency, skin rashes, haemolytic anaemia and agranulocytosis. A small proportion of individuals have an immediate idiosyncratic reaction to suramin injection that may include nausea, vomiting, shock, seizures and loss of consciousness.

20. PENTAMIDINE Pentamidine has a direct trypanocidal action in vitro . It is rapidly taken up in the parasites by a high-affinity energy-dependent carrier and is thought to interact with their DNA. The drug is administered intravenously or by deep intramuscular injection, usually daily for 10–15 days. After absorption from the injection site, it binds strongly to tissues (especially the kidney) and is eliminated slowly, only 50% of a dose being excreted over 5 days. Fairly high concentrations of the drug persist in the kidney, the liver and the spleen for several months, but it does not penetrate the blood–brain barrier. It is also active in Pneumocystis pneumonia. Its usefulness is limited by its unwanted effects – an immediate decrease in blood pressure, with tachycardia, breathlessness and vomiting, and later serious toxicity, such as kidney damage, hepatic impairment, blood dyscrasias and hypoglycaemia

21. MELARPROSOL This is an organic arsenical compound that is used mainly when the CNS is involved. It is given intravenously and enters the CNS in high concentrations, where it is able to kill the parasite. It is a highly toxic drug that produces many unwanted effects including encephalopathy and, sometimes, immediate fatality. As such, it is only administered under strict supervision EFLORNITHINE Eflornithine inhibits the parasite ornithine decarboxylase enzyme. It shows good activity against T. b. gambiense and is used as a back-up for melarsoprol , although unfortunately it has limited activity against T. b. rhodesiense . Side effects are common and may be severe, but are readily reversed when treatment discontinue.

22. LEISHMANIASIS Leishmania organisms are flagellate protozoa and leishmaniasis , the infection that they cause, is spread by the sandfly . According to the WHO (2013 figures) the incidence of the disease is increasing with some 1.3 million new cases and 20 000–30 000 deaths recorded each year. With increasing international travel, leishmaniasis is being imported into new areas and opportunistic infections are now being reported (particularly in AIDS patients). The vector is the female sandfly . The parasite exists as a flagellated form (promastigote) in the gut of the infected insect, and a phagocytes of the infected mammalian host. Within these cells, the parasites thrive in modified phagolysosomes. By deploying an array of counter measures, they promote the generation of Th2 cytokines and subvert the macrophage’s microbiocidal systems to ensure their survival. The amastigotes multiply, and eventually the infected cell releases a new crop of parasites into the haemolymphatic system, where they can infect further macrophages and possibly other cells. Different species of Leishmania exist in different geographical areas and cause distinctive clinical manifestations.

23. Typical presentations include: a cutaneous form , which presents as an unpleasant chancre (‘oriental sore’, ‘Chiclero’s ulcer’ and other names) that may heal spontaneously but can leave scarring. This is the most common form and is found in the Americas, some Mediterranean countries and parts of central Asia; a mucocutaneous form (‘espundia’ and other names), which presents as large ulcers of the mucous membranes of the mouth, nose and throat; most cases are seen in South America; a serious visceral form (‘kala-azar’ and other names), where the parasite spreads through the bloodstream and causes hepatomegaly, splenomegaly, anaemia and intermittent fever. This manifestation is encountered mainly in the Indian subcontinent and in west Africa.

24. The main drugs used in leishmaniasis are pentavalent antimony compounds such as sodium stibogluconate and pentamidine as well as amphotericin which is sometimes used as a follow-up treatment. Miltefosine , an antitumour drug, is also used in some countries (not UK), as is meglumine antimoniate . Sodium stibogluconate is given intramuscularly or by slow intravenous injection in a 10-day course. It is rapidly eliminated in the urine, 70% being excreted within 6 h. More than one course of treatment may be required. Unwanted effects include anorexia, vomiting, bradycardia and hypotension. Coughing and substernal pain may occur during intravenous infusion. Reversible hepatitis and pancreatitis are common. The mechanism of action of sodium stibogluconate is not clear, but the drug may increase production of toxic oxygen free radicals in the parasite.

25. Miltefosine ( hexadecylphosphocholine ) is also effective in the treatment of both cutaneous and visceral leishmaniasis. The drug may be given orally and is well tolerated. Side effects are mild and include nausea and vomiting. In vitro , the drug induces DNA fragmentation and apoptosis in the parasites Other drugs, such as antibiotics and antifungals, may be given concomitantly with the above agents. They may have some action on the parasite in their own right, but their main utility is to control the spread of secondary infections. Resistance to current drugs, particularly the pentavalent antimonials (possibly caused by increased expression of an antimonial efflux pump), is a serious problem.

26. TRICHOMONIASIS The principal Trichomonas organism that produces disease in humans is T. vaginalis . Virulent strains cause inflammation of the vagina and sometimes of the urethra in males. The main drug used in therapy is metronidazole although resistance to this drug is on the increase. High doses of tinidazole are also effective, with few side effects. GIARDIASIS Giardia lamblia colonizes the upper gastrointestinal tract in its trophozoite form, and the cysts pass out in the faces. Infection is then spread by ingestion of food or water contaminated with faecal matter containing the cysts. It is encountered worldwide, and epidemics caused by bad sanitation are not uncommon. Metronidazole is the drug of choice, and treatment is usually very effective. Tinidazole or mepacrine may be used as an alternative.