1. 1 ANTI PROTOZOAL DRUGS

2. INTRODUCTION They are eukaryotes and have metabolic processes closer to those of human host. Protozoal infections are common among people in underdeveloped tropical and subtropical countries where sanitary conditions, hygienic practices and control of the vectors of transmission are inadequate. 2

3. Are less easily treated than bacterial infections Many of the antiprotozoal drugs cause serious toxic effects in the host, particularly cells showing high metabolic activity, e.g., neuronal, renal tubular, intestinal and bone marrow stem cells 3

4. Overview of antiprotozoal drugs Chemotherapy for amebiasis Chemotherapy for malaria Chemotherapy for trypanosomiasis Chemotherapy for leishmaniasis Chemotherapy for toxoplasmosis Chemotherapy for giardiasis 4

5. 5 Malaria-Overview Plasmodium vivax Plasmodium malariae Plasmodium ovale Plasmodium falciparum

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8. 8 Transmitted through female anopheles mosquito. Plasmodium falciparum is the most dangerous. High fever, erythrocytosis, capillary obstruction & death.

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10. 10 Antimalarial agent efficacy species life-cycle stage-dependencies Parasitic Life Cycle Sporozoites Exoerythrocytic stage Forming tissues schizonts Merozoites Gametocytes

11. 11 Tissue schizonticides PRIMAQUINE SITE : EXO ERYTHROCYTIC STAGE ALSO : GAMETOCYTES NOT ERYTHROCYTIC SCHIZONTS ORAL ROUTE, RENAL EXCRETION SE : GIT, ANEMIA IN G6PD def pt AGRANULOCYTOSIS IN Pt – LUPUS USE : RADICAL CURE (P. vivax & ovale)

12. 12 Blood schizonticides Chloroquine Mefloquine Pyrimethamine Quinine Artemisinin

13. 13 CHLOROQUINE MECH : Inhibits polymerization to hemozoin FORMS SOL. HEME in food vacuole Leading to oxidative damage to the membranes → lysis of both the parasite and RBC

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15. 15 Most widely used drug DOC : ERYTHROCYTIC FALCI. MALARIA (NON – RESISTANT ) Other uses: It is used also in extra intestinal amebiasis, rheumatoid arthritis, discoid lupus

16. 16 ORAL, PARENTERAL MET : LIVER EXCRETION : RENAL SE : GIT, pruritus Blurring of vision, HEADACHE NAIL BED – DISCOLORATION Prolongs QT-interval cos of its quinidine like effect INTERACTIONS : GOLD compounds, PHENYLBUTAZONE CI : PSORIASIS, PORPHYRIA

17. 17 Quinine & Quinidine Highly effective blood schizonticides No effect on Sporozoites or liver stages of any parasite. MOA: similar to chloroquine Use : reserved for severe infestations and strains resistant to other drugs

18. 18 SE Gastrointestinal Effects: Cinchonism: slight visual disturbances mild tinnitus dizziness headache nausea rapid IV infusion: hypotension, seizures, ventricular fibrillation and prolongation of QT-interval.

19. Drug interactions: Potentiation of neuromuscular blocking agents Elevation of digoxin levels if taken concurrently with quinine Quinine absorption is decreased when drug is taken with aluminum-containing antacids. CI: is fetotoxic 19

20. 20 Mefloquine Mech : unknown Use : Resistant cases of P. falci. SE: nausea, dizziness, hallucinations

21. pharmacokinetics Half life : long (17 days) Well absorbed after oral administration Excretion: feces CI: with quinine and beta- blockers due to development of cardiac arrest 21

22. 22 Blood schizonticide, sporonticide PYRIMETHAMINE MOA:INHIBITS DIHYDRO FOLATE REDUCTASE Pyrimethamine alone: used against P.falciparum IN COMBINATION with sulfonamides : against P.malaria &toxoplasmosis OTHER USE : TOXOPLASMOSIS

23. Other blood schizonticides Artemisinin MOA: production of free radicals within the plasmodium food vacuole Uses: treatment of severe, multidrug-resistant P.falciparum 23

24. Route: oral, rectal and intravenous Metabolism: extensively in the liver Excretion: in bile Adverse effects: nausea, vomiting, diarrhea, neurotoxicity and prolongation of QT-interval 24

25. 25 PROPHYLAXIS CHLOROQUINE SENSITIVE – CHLOROQUINE CHL. RESISTANT – MEFLOQUINE, Artemisinin In pregnancy: chloroquine OR mefloquine

26. 26 AMOEBIASIS Caused by E. histolytica Disease can be acute or chronic with pts showing varying degrees of illness from no symptoms(carriers) to mild diarrhea to fulminant dysentry

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28. Drugs for amebiasis Luminal amebiasis Systemic amebiasis Mixed amebiasis 28

29. Luminal amebiasis 1. Diloxanide furoate CI : CHILDREN, PREG., 2. Paramomycin- aminoglycoside 3. iodoquinol- optic neuritis, rash, diarrhea 29

30. 30 SYSTEMIC AMEBICIDES EMETINE DEHYDRO EMETINE MOA: inhibit elongation step of protein synthesis ROUTE : IM SE : RASHES, PAIN, MUSCULAR WEAKNESS, CARDIOTOXICITY.

31. CHLOROQUINE –combination with metronidazole and diloxanide furoate LIVER ABSCESS 31

32. 32 MIXED(luminal and systemic) METRONIDAZOLE MOA: The nitro grp serves as an electron acceptor forming reduced cytotoxic compds that binds proteins and DNA, resulting in cell death Administered with a luminal amebicide with a cure rate of >90%

33. SE : MC – GIT METALLIC TASTE, ORAL CANDIDIASIS RARE : DIZZINESS, VERTIGO Avoid alcohol – disulfiram like effect Other uses: trichomonia, giardiasis, pseudomembranous colitis 33

34. Metabolized by cyt-P450 system. Inducers of cytP450 increases its rate of metabolism Inhibitors of cytP450 prolongs its half-life Excretion: urine 34

35. 35 TRYPANOSOMIASIS AFRICANSLEEPING SICKNESS -TRYPANOSOMA BRUCEI GAMBIENCE & RODIENSE. Transmitted by bite of TSE TSE FLY AMERICAN SS -CHAGAS TRYPANOSOMA CRUZI

36. African sleeping sickness Trypanosoma brucei gambiense and trypanosoma brucei rhodiense, initially live and grow in the blood but can invade the CNS causing inflammation of the brain and spinal cord that produces the characteristic lethargy and, eventually continuous sleep and death. 36

37. 37 MELARSOPROL ---treatment of trypanosomal infections usually in the late stage with CNS involvement MOA: REACTS WITH THE SULFHYDRYL GROUPS. SLOW IV HIGHLY IRRITATING ENTERS THE CSF QUICKLY DOC—TREPANOSOMAL MENINGOENCEPHALITIS caused by T.brucei rhodesiense which rapidly invades the CNS SE—CNS TOXICITY, HYPERSENSITIVITY, HEMOLYTIC ANEMIA –G 6 PD DEFICIENCY.

38. 38 PENTAMIDINE Effective against T.brucei gambiense for the treatment and prevention of the organism’s hematologic stage. MOA: not known but binds to the parasite’s DNA interfering with the synthesis of DNA, RNA &protein of the parasite. Adverse effect: hypotension, dizziness, rash and toxic to pancreas

39. Other uses: Rx AND PROPHYLAXIS BLASTOMYCOSIS DOC—PCP not responding to TMP-SMX Alternative for treatmnent ofLEISHMANIASIS. 39

40. SURAMIN USED FOR THE PROHYLAXIS OF AFRICAN TRYPANOSOMIASIS MOA: inhibits many enzymes and those involved in energy metabolism (glycerol phosphate dehydrogenase) 40

41. Route: must be IV SE: Vomiting, nausea, shock, loss of consciousness, urticaria and neurologic problems(paresthesia, photophobia, palpebral edema), albuminuria 41

42. NIFURTIMOX FOR acute Rx – CHAGAS MOA: undergoes reduction, generating free radicals which are toxic to T-cruzi SE: hypersensitivity(dermatitis, icterus), GIT disturbances, peripheral neuropathy 42

43. 43 LEISHMANIASIS-CUTANEOUS, MUCOCUTANEOUS,& VISCERAL SODIUM STIBOGLUCONATE (I.V,) INHIBITION OF GLYCOLYSIS --URINE EXCRETION GIARDIASIS —BINUCLEATE WITH 4 FLAGELLA DOC--METRONIDAZOLE CI: PREG,

44. 44 TOXOPLASMOSIS ONE OF THE MOST COMMON INFECTIONS CAUSED BY PROTOZOAN T.GONDI TRANSMITTED BY CONSUMING RAW, UNCOOKED INFECTED MEAT. DOC-PYRIMETHAMINE LEUCOVORIN GIVEN TO PREVENT FOLATE DEFICIENCY