Korir

ProtozoansAmoebaHeamoflagellateFlagellatesCilliates

HelminthesNematodes TrematodesCestodes

Faeco oral route Poor environmental sanitation Low socio-economic status Water Arthropod vector

• Luminal PhaseCysts in Faeces – propagation of disease.

• Tissue phase-Ulcer /dysentery-Abcess /Amoeboma-Extra intestinal ,Lung, Spleen, Kidney, Brain

There can be three potential targets for chemotherapy of parasitic diseases:

1.Unique essential enzymes only found in the parasite

2.Similar enzymes found in the host and parasite but indispensable only for the parasite

3.Common biochemical functions found in both the parasite and the host, but with different pharmacological properties

Enzymes with developed drugsi. Trypanothione reductase –

Kinetoplastida Nifurtimoxii. Enzyme for dihydropteroate synthesis-

Apicomplexaiii.Pyruvate-ferrodoxin oxireductase –

Nitroimidazole pyruvate + CoA + 2 oxidized ferredoxin acetyl-CoA + CO2 + 2 reduced ferredoxin + 2 H+

iv.Nucleoside phosphotransferase- allopurinol riboside and formycin B

i. Pyruvate phosphate Dikinaseii. Shikimate pathwayiii. Glycoprotein synthesis - trypanasomes

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

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.

• Tissue Amoebiasis*Both intestinal & extra intestinal Nitroimidazoles –Metronidazole- Tinidazole- Secnidazole- Ornidazole Alkaloids - Emetine-Hydroemetine

* Extra intestinal amoebiasis only-Chloroquine

• Luminal amoebiasis-Amide–Diloxanide furoate-8-Hydroxy quinolones–Quinidochlor-Antibiotics- Tetracycline

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

• Prototype drug. A nitroimidazole Effective against Giardia lamblia, anaerobic bacteria,

Bacteroides fragilis, Fusobacterium,Clostridium perfringes, Helicobacterpylori, Anaerobic Streptococci

Not clearly understood • Enters micro-organism by diffusion

Nitro group reduced

DNA damaged

Cytotoxicity

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.

Amebiasis – tissue amoebiasis, for luminal combine

Giardiasis –treatment of choice and well tolerated.

Trichomoniasis – 2gm stat. Metronidazole resistant organism can led to drug failures.

FrequentAnorexia, nausea, METALLIC TASTE, abdominal cramps

Less frequentHeadache, glossitis, dry mouth,dizziness, rashes, transient neutropenia

On prolonged administrationPeripheral neuropathy, CNS effects

Taking with food lessens G.I.T

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.

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.

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

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

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

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.

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.

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. LEISHMANIASIS

alternative 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,.

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 .....

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

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.

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 and Late reactions .

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

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.

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.

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