Antiparasitic

1. Antiparasitic Korir

2. Types of parasites • Protozoans Amoeba Heamoflagellate Flagellates Cilliates • Helminthes Nematodes Trematodes Cestodes

3. Transmission • Faeco oral route • Poor environmental sanitation • Low socio-economic status • Water • Arthropod vector

4. Amoeba • • Luminal Phase Cysts in Faeces – propagation of disease. • • Tissue phase -Ulcer /dysentery -Abcess /Amoeboma -Extra intestinal ,Lung, Spleen, Kidney, Brain

5. Over view • There can be three potential targets for chemotherapy of parasitic diseases: • Unique essential enzymes only found in the parasite • Similar enzymes found in the host and parasite but indispensable only for the parasite • Common biochemical functions found in both the parasite and the host, but with different pharmacological properties

6. Unique Enzymes found in parasites • Enzymes with developed drugs • Trypanothionereductase – KinetoplastidaNifurtimox • Enzyme for dihydropteroate synthesis- Apicomplexa • Pyruvate-ferrodoxinoxireductase – Nitroimidazolepyruvate + CoA + 2 oxidized ferredoxin acetyl-CoA + CO2 + 2 reduced ferredoxin + 2 H+ • Nucleoside phosphotransferase- allopurinolriboside and formycin B

7. potential enzymes for drug development • Pyruvate phosphate Dikinase • Shikimate pathway • Glycoprotein synthesis - trypanasomes

8. Indispensable enzyme • Lanosterol C- 14α Demethylase – leish and tryps. Azole • Purine Phosphoribosyl Transferase –Protozoa- allopurinol. • Purine nucleoside kinase – T. vaginalis, E.histolytic. None • Ornithine decarboxylase- H.A.T, α- Difluoromethylornithine

9. Common indispensable enzyme • Dihyrofolate reductase-thymidylate synthesis bifunction bifunctional enzyme- pyrimethamine • Thiamine transporter – coccidia – Ampurolium • Mitochondrial electron transporter – apicomplexa – 4 hydroquinolines and 2-hydroxy-naphthoquinones • Microtubules – helminth – Benzimidazoles • Nervous synaptic transission- helminths levamisole.

10. Overview of treatment • • Tissue Amoebiasis *Both intestinal & extra intestinal • Nitroimidazoles –Metronidazole - Tinidazole - Secnidazole - Ornidazole • Alkaloids - Emetine -Hydroemetine

11. * Extra intestinal amoebiasis only -Chloroquine • • Luminal amoebiasis -Amide –Diloxanide furoate-8-Hydroxy quinolones –Quinidochlor -Antibiotics - Tetracycline

12. Treatment with tissue amoebicide • SHOULD always be followed by • Luminal amoebicide • to eradicate source of infection

13. Metronidazole • • Prototype drug. • A nitroimidazole • Effective against • Giardia lamblia, anaerobic bacteria, Bacteroides fragilis, Fusobacterium, Clostridium perfringes, Helicobacter pylori, Anaerobic Streptococci

14. Mechanism of Action • Not clearly understood • • Enters micro-organism by diffusion Nitro group reduced DNA damaged Cytotoxicity

15. pharmacokinetics • Oral metronidazole and tinidazole are readily absorbed by simple diffusion. • 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. • Metronidazole and its metabolites are excreted mainly in the urine. • Plasma clearance is decreased in patients with impaired liver function. • Dose adjustment for renal and liver diseases.

16. Clinical uses • Amebiasis – tissue amoebiasis, for luminal combine • Giardiasis –treatment of choice and well tolerated. • Trichomoniasis – 2gm stat. Metronidazole resistant organism can led to drug failures.

17. Adverse Effects • Frequent Anorexia, nausea, METALLIC TASTE, abdominal cramps • Less frequent Headache, glossitis, dry mouth,dizziness, rashes, transient neutropenia • On prolonged administration Peripheral neuropathy, CNS effects • Taking with food lessens G.I.T

18. Caution • Caution in patients with CNS disease. • Anticoagulant effect of coumarin-type anticoagulants. • Phenytoin and phenobarbital may accelerate elimination, while cimetidine may decrease plasma clearance. • Lithium toxicity may occur when the drug is used with metronidazole.( reduced renal clearance) • Avoided in pregnant or nursing women. • With Alcohol- disulfiram like effect.

19. Iodoquinol (diiodohydroxyquin) • Is a halogenated hydroxyquinoline. • It is an effective luminal amebicide. • 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. • It is effective against organisms in the bowel lumen but not against trophozoites in the intestinal wall or extraintestinal tissues.

20. Adverse efffects • Infrequent adverse effects include diarrhea, anorexia, nausea, vomiting • The drug may increase protein-bound serum iodine, leading to a decrease. • Severe neurotoxicity with prolonged use at greater than recommended doses. • Taken with meals to limit G.I.T toxicity. • Caution in- 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

21. Diloxanidefuroate • Diloxanide furoate is a dichloroacetamide derivative.In the gut, it 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. • Highly effective luminal amoebicide but not tissue trophs • Directly kills trophozoites • No systemic antiamoebic activity seen despite absorption • No anti bacterial action • It does not produce serious adverse effects. Flatulence is common, but nausea and abdominal cramps are infrequent and rashes are rare. • Not recommended in pregnancy

22. Emetine • Alkaloid from Cephaelis ipecacuanha • Potent directly acting amoebicide (trophozoites) Does not kill cysts • Cumulative toxicity high –Seldom used • Reserve drug • Luminal amoebicide follows emetine to eradicate cysts • Dihydroemetine =effective but less toxic Preferred over emetine. • Administered SC or IM but never I.V

23. Adverse effects • mild when the drugs are used for 3-5 days. • sterile abscesses may develop. • Diarrhea is common. Others are nausea, vomiting, muscle weakness and discomfort, and minor electrocardiographic changes. • Serious toxicities include cardiac arrhythmias, heart failure, and hypotension. • The drugs should not be used in patients with cardiac or renal disease, in young children, or in pregnancy unless absolutely necessary.

24. Pentamidine • Pentamidine has activity against trypanosomatid protozoans and against P jiroveci, but toxicity is significant. Chemistry & Pharmacokineticsits an aromatic diamidine formulated as an isethionate salt. • Pentamidine is only administered parenterally. • The drug leaves the circulation rapidly, with an initial half-life of about 6 hours, but it is bound avidly by tissues. • accumulates and is eliminated very slowly, with a terminal elimination half-life of about 12 days. • Only trace amounts of pentamidine appear in the central nervous system.

25. Clinical Uses A. PNEUMOCYSTOSIS • prophylaxis against pneumocystosis in 10 and 20 -aerosol . The drug is well-tolerated in this form. • Its efficacy is very good but clearly less than that of daily trimethoprim-sulfamethoxazole. HAT • Its used for early hemolymphatic stage • The drug can also be used with suramin. • Chemoprophylaxis against African trypanosomiasis, with dosing of 4 mg/kg every 3-6 months. • LEISHMANIASISalternative to sodium stibogluconate in the treatment of visceral leishmaniasis. • The dosage is 2-4 mg/kg intramuscularly daily or every other day for up to 15 doses,.

26. Adverse effects • highly toxic drug, with adverse effects noted in about 50% of patients receiving 4 mg/kg/d. • Rapid intravenous administration can lead to severe hypotension, tachycardia, dizziness, and dyspnea, so the drug should be administered slowly (over 2 hours). • Pancreatic toxicity. Hypoglycemia • Reversible renal insufficiency is also common. • Other adverse effects include rash, metallic taste, fever .....

27. Sodium stibogluconate • Pentavalent antimonials, including sodium stibogluconate and meglumine antimonate, are generally considered first-line agents for cutaneous and visceral leishmaniasis. • The drugs are rapidly absorbed after intravenous or intramuscular administration and eliminated in two phases. • Few adverse effects occur initially, but the toxicity of stibogluconate increases over the course of therapy

28. NITAZOXANIDE • Nitazoxanide is a nitrothiazolyl-salicylamide. • It is rapidly absorbed and converted to tizoxanide and tizoxanide conjugates, • which are subsequently excreted in both urine and feces. • The active metabolite, tizoxanide, inhibits the pyruvate:ferredoxin oxidoreductase pathway. • activity against metronidazole-resistant protozoal strains and is well tolerated..The recommended adult dosage is 500 mg twice daily for 3 days.

29. SURAMIN • Suramin is a sulfated naphthylamine that was introduced in the 1920s. • It is the first-line therapy for early hemolymphatic African trypanosomiasis. • It does not enter the central nervous system, • The drug's mechanism of action is unknown. • It is administered intravenously and displays complex pharmacokinetics with very tight protein binding. • It has a short initial half-life but a terminal elimination half-life of about 50 days. • The drug is slowly cleared by renal excretion. • Combination therapy with pentamidine may improve efficacy. • Suramin can also be used for chemoprophylaxis • Adverse effects are common. Immediate reactions andLate reactions .

30. MELARSOPROL • It is a trivalent arsenical. • first-line therapy for advanced central nervous system African trypanosomiasis. • After intravenous administration it is excreted rapidly, but clinically relevant concentrations accumulate in the central nervous system within 4 days. • Melarsoprol is extremely toxic. • The most important toxicity is a reactive encephalopathy

31. EFLORNITHINE • Eflornithine (difluoromethylornithine), • an inhibitor of ornithine decarboxylase, • is the only new drug registered to treat African trypanosomiasis in the last half-century. • It is a second therapy for advanced central nervous system African trypanosomiasis • Is less toxic than melarsoprol but not as widely available. • Eflornithine is administered intravenously, and good central nervous system drug levels are achieved. • Peak plasma levels are reached rapidly, and the elimination half-life is about 3 hours. • Toxicity from eflornithine is significant, but considerably less than that from melarsoprol. • Adverse effects include diarrhea, vomiting, anemia, thrombocytopenia, leukopenia, and seizures. These effects are generally reversible.

32. NIFURTIMOX • A nitrofuran, is the most commonly used drug for American trypanosomiasis . • It is well absorbed after oral administration and eliminated with a plasma half-life of about 3 hours. • Nifurtimox decreases the severity of acute disease and usually eliminates detectable parasites, but it is often ineffective in fully eradicating infection. • Adverse effects are reversible but often lead to cessation of therapy before completion of a standard course.pregnant within 2 months of treatment) because of its teratogenic effects.

33. BENZNIDAZOLEBenznidazole is an orally administered nitroimidazole that appears to have efficacy similar to that of nifurtimox. • Important toxicities include peripheral neuropathy, rash, gastrointestinal symptoms, and myelosuppression. AMPHOTERICINThis important antifungal drug, is an alternative therapy for visceral leishmaniasis, especially in parts of India with high-level resistance to sodium stibogluconate, MILTEFOSINEMiltefosine is an alkylphosphocholine analog that has recently shown efficacy in the treatment of visceral leishmaniasis. • Transient elevations in liver enzymes and nephrotoxicity are also seen. The drug should be avoided in pregnancy