Anti-protozoal drugs

1. Anti-protozoal drugs • The unicellular protozoa are eukaryotes and it is difficult to treat them compared to bacteria which are prokaryotes. • Most of the protozoal infections are due to unhygienic conditions.

2. Anti-protozoal drugs Trypanosomiasis : Caused by Trypanosoma • African sleeping sickness Tryp brucei gambiense – slow to enter CNS Tryp brucei rhodesiense – invade CNS early. • American sleeping sickness – Chagas disease -- tryp cruzi - cardiomyopathy

3. Anti-protozoal drugs Suramin: Trypanosomiasis • Used in the early treatment and prophylaxis of African trypanosomiasis. • It acts by inhibiting enzymes of energy metabolism including glycerol phosphate dehydrogenase – for trypanocidal activity

4. Anti-protozoal drugs Melarsoprol : Trypanosomiasis • Trivalent arsenical • Mainly used to treat trypanosoma infections with CNS involvement. • The drug acts by reacting with SH groups of various enzymes

5. Anti-protozoal drugs Pentamidine Trypanosomiasis • Active against: • Trypanosoma • leshmaniasis • fungus - pneumocystis jiroveci • Pentamidine interfere with synthesis of RNA, DNA and proteins. • Administered IV or aerosol • Nephrotoxicity is the limitation.

6. Anti-protozoal drugs Nifurtimox : Trypanosomiasis Chagas disease • Used in the treatment of Trypanosoma cruzi infection. • It acts by generating superoxide and hydrogen peroxide radicals – toxic as they lack catalase. • Orally well absorbed

7. Anti-protozoal drugs Leishmaniasis : transmitted by the bite of sandflies • Cutaneous • Mucocutaneous • Visceral ( Liver and Spleen) - Kala Azar

8. Anti-protozoal drugs Leshmaniasis : • Antimonials - Sodium stibogluconate • Pentamidine • Amphotericin

9. Anti-protozoal drugs Sodium stibogluconate :Leshmaniasis • It acts by inhibiting glycolysis and fatty acid oxidation • It is administered i.m or i.v • Cardiac arrhythmia and nephrotoxicity are adverse effects.

11. Anti - Ameobic Drugs • E. histolytica is a water-borne pathogen transmitted by the fecal-oral route. • E. histolytica exists in two forms • Cysts – Infective and can survive outside the body • Trophozoites – Non-infective and do not persists outside the body but invasive.

12. Anti-amebic drugs • A person becomes infected with E. histolytica as follows : • First, the cyst is ingested by the host. • As it travels through the small intestine, E. histolytica excysts and divides into 8 trophozoites. • The trophozoites multiply and either invade and ulcerate the mucosa of the large intestine or feed on the intestinal bacteria.

13. Anti - ameobic drugs • The trophozoites are carried towards the rectum, where they return to the cyst form and are excreted in feces. • Large amount of trophozoites within the colon can lead to systemic infection. • The trophozoites descend into the intestine, they make a flask shaped abscess.

14. Anti - ameobic drugs • The trophozoites can also enter the blood stream and travel to other parts of the body—most commonly the liver, but sometimes the lungs or brain and can cause abscesses. • In tissues, only trophozoites are present.

17. Anti - Ameobic Drugs METRONIDAZOLE : Mixed amebicidal • Broad spectrum cidal activity against --- Protozoa – E. histolytica, T. vaginalis, G. lamblia • Anaerobic bacteria – B.fragilis, C.perfringes, H.pylori, Cl. difficile G. lamblia T. vaginalis

18. Mechanism of action Metronidazole Nitroimidazoles (R-NO2) are activated by the parasite via a reduction to an anion radical. This highly reactive anion radical will then damage DNA and proteins resulting in parasite death. Metronidazole appears to be specifically reduced by ferredoxin in Giaridia, Entamoeba, and Trichomonas.

19. Pharmacokinetics : • Well absorbed from the intestine • Widely distributed in the body secretions – semen, saliva and CSF

20. Anti - Ameobic Drugs Metronidazole : adverse effects : • Nausea and metallic taste are most common • Seizures at high dose Contra-indications : • First trimester of pregnancy • Chronic alcoholism

21. Anti - Ameobic Drugs MIXED : LUMINAL / SYSTEMIC AMEBICIDAL DRUGS : • Metronidazole, Tinidazole, Secnidazole, Ornidazole • Emetine SYSTEMIC AMEBICIDAL DRUGS : • Chloroquine LUMINAL AMEBICIDAL DRUGS : • Diloxanide furoate, Iodoquinol, Tetracycline, Paramomycin.

22. Metronidazole : Uses • Ameobiasis – with luminal amebicidal • Giardiasis • Trichomonas vaginalis – both partners !! • Anaerobic infections • Pseudo-membranous enterocolitis • Ulcerative gingivitis • Helicobacter pylori

23. Emetine ipecac root • Inhibit protein synthesis by blocking chain elongation. • It is administered by i.m injection. • Adverse effects • cardiotoxicity • neuromuscular weakness.

24. Iodoquinol • Amebicidal against luminal trophozoites and cysts • Adverse effects • peripheral neuropathy • optic neuritis: the inflammation of the optic nerve cause a complete or partial loss of vision.

25. Anti - Ameobic Drugs Diloxanidefuroate : • Effective luminal ameobicidal – kills trophozoites • High cure rates in mild intestinal amoebiasis and asymptomatic cyst passers

26. Anti - Ameobic Drugs Paromomycin : • Aminoglycosides which is not absorbed from GIT. • Effective against luminal forms of E. Histolytica – directly • It acts indirectly by reducing the intestinal flora also.

28. Anti-malarial drugs • Malaria is caused by the four species of protozoa – Plasmodium • Plasmodium vivax • Plasmodium falciparum • Plasmodium malariae • Plasmodium ovale

30. Anti-malarial drugs • Chloroquine – most common • Quinine – Chloroquine resistant • Pyrimethamine / Sulfonamides • Primaquine – Radical cure • New drugs - Mefloquine, Artimisinin, Halofantrine

31. Anti-malarial drugs • Drugs for the Exo-erythrocytic phase (liver) and gametocytes : • Primaquine • Drugs to suppress erythrocytic phase / Schizontocides / Clinical cure : • Chloroquine, Quinine, Pyrimethamine, Mefloquine, Artemisinin

32. Anti-malarial drugs • Radical cure : Exoerythrocytic phase (hypnozoites) with the clinical cure thus achieve total eradication of parasite • Primaquine + Chloroquine

33. Chloroquine • It is rapidly acting erythrocytic schizontocide against all species of plasmodium • No effect on exo-erythrocytic phase • It is concentrated by intraerythrocytic plasmodia • Conversion of toxic heme to non-toxic hemozoin is inhibited. • Heme damages plasmodia.

34. Being alkaline, the drug reaches high concentration within the food vacuoles of the parasite and raises its pH. It is found to induce rapid clumping of the pigment. Chloroquine inhibits the parasitic enzyme heme polymerase that converts the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite.

35. Chloroquine is active against entameoba histolytica and giardia lamblia • It has anti-inflammatory and local irritant • It is used for the treatment of malaria in pregnancy

36. Pharmacokinetics : Chloroquine • Oral absorption is excellent • It has high affinity for melanin (retina) and concentrated in liver, spleen, kidney • Metabolized by liver and excreted in urine • Half life ~ 3-10 days

37. Adverse effects : Chloroquine • Nausea , vomiting and epigastric pain • Parenteral administration – hypotension and cardiac arrhythmia, convulsions • Prolonged treatment ( as in RA) causes retinal damage • Loss of hearing, mental disturbances, rashes

38. Uses : Chloroquine • Clinical cure and prophylaxis in malaria • Extra-intestinal ameobiasis • Rheumatoid arthritis • Lepra reactions

39. Anti-malarial drugs Quinine : • It is a levo-rotatory alkaloid from cinchona bark ( dextro isomer – Quinidine) • It is an erythrocytic schizontocide • It is basic and gets concentrated in acidic schizonts and kills by inhibiting heme polymerase

40. Anti-malarial drugs Quinine : • It is orally well absorbed • It has antipyretic action, affects hearing and vision at high dose • High intravenous dose can cause hypotension and cardiac depression

41. Anti-malarial drugs Quinine : adverse effects • Cinchonism – ringing in ears, nausea , difficulty in hearing, visual defects • Hypersensitivity reactions • Hemolysis – can result in hemoglobinuria

42. Anti-malarial drugs Primaquine : • Primary indication is radical cure of malaria. • It is more active against exo-erythrocytic phase of vivax and ovale. • It is highly active against non-growing forms - gametocytes and hypnozoites.

43. Anti-malarial drugs Primaquine : adverse effects • Dose limiting side effect is hemolysis, methemoglobinemia and cyanosis (dose > 60 mg/day) • Neutropenia rarely with large dose • Avoided in pregnancy & G6PD

44. Anti-malarial drugs Mefloquine • It is rapidly acting erythrocytic schizontocide • Effective against even chloroquine resistant strains of plasmodia • It appears to damage the plasmodia membranes

45. Anti-malarial drugs Mefloquine • Oral absorption is good • Concentrated in liver, lungs and intestine • Metabolized in liver and excreted in bile • QT interval prolongation (arrhythmia) when given with halofantrine or quinine • Seizures at high dose.

46. Anti-malarial drugs Artemisinin derivatives : Artemether / Arteether / Artesunate • It is a potent and rapidly acting blood schizontocide and have peroxide configuration – responsible for its action. • ST segment and QT prolongation –conduction defects

47. Anti-malarial drugs Halofantrine : • It is highly active against P. falciparum resistant to chloroquine • Prolonged QT interval and increased liver enzymes

49. Novel Anti-protozoal Drugs: Nitazoxanide

50. Nitazoxanide • Treatment for: » Intestinal protozoa • Cryptosporidium • Giardia • Mechanism of Action: » Metabolized rapidly to active form tizoxanide » May be due to interference with the pyruvate: ferredoxin oxidoreductase enzyme-dependent electron transfer reaction essential for anaerobic metabolism