Antiamebic agent

Antiamebic agent

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  ANTIAMEBIC AGENTS DR. SHILPA SUDHAKARHARAK ASST. PROF., PHARM. CHEM., GES SIR DR. M. S. GOSAVI COLLEGE OF PHARMACEUTICAL EDUCATION AND RESEARCH, NASHIK
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  PARASITIC INFECTIONS • Affecthuge numbers of individuals > 1 billion • Found in developing nations • Cost of health care is the dominant factor • Sometimes can exceed 80% of the population • Reduced incentive for both the study of the diseases and the development of effective therapy • High cost of drug discovery and Lower incidence in affluentWestern countries • Parasitic infections - • Protozoal - amebiasis, giardiasis, babesiosis, Chagas disease, leishmaniasis, malaria, sleeping sickness, toxoplasmosis, trichomoniasis, and pneumocystosis. • Others - include Helminth infections (worms), scabies, lice (pediculosis), chiggers, and bedbugs (Cimicidae family), are also considered to be parasitic infections.
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  PROTOZOAL DISEASES AMEBIASIS Disease ofthe large intestine • caused by Entamoeba histolytica • The disease occurs mainly in the tropics, but it is also seen in temperate climates. Symptoms – • can be without significant symptoms or • can lead to severe, life-threatening dysentery. The organism exists in one of two forms: • the motile trophozoite form or • the dormant cyst form.
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  AMOEBA Trophozoite Form • foundin the intestine or in the wall of the colon • Expelled from the body with the feces Cyst Form • Encased by a chitinous wall that protects the organism from the environment • the organism can be transmitted through contaminated water and foods. • Responsible for transmission of the disease.
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  AMOEBA Host • rendered susceptibleto infection by preexisting conditions viz. Protein malnutrition, Pregnancy, HIV infection, High-carbohydrate intake.
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  PARASITE CYCLE
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  PARASITE CYCLE
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  ENTAMOEBA HISTOLYTICA Invasion ofHost Intestinal form a. Disintegration of cyst wall in small intestine b. Movement of trophozoites into the colon c.Adhesion of trophozoite to cells of the host, which involves a change in composition and production of mucus Extraintestinal form d. Penetration of intestinal lining and entrance into portal circulation e. Invasion of liver tissue
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  DRUGTHERAPY FOR PROTOZOAL INFECTIONS
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  ANTIAMOEBIC DRUGS • Theseare drugs useful in infection caused by the protozoa Entamoeba histolytica. A.Tissue amoebicides • a) For both intestinal and extraintestinal amoebiasis: I. Nitroimidazoles: Metronidazole,Tinidazole, Secnidazole, Ornidazole, Satranidazole II.Alkaloids: Emetine, Dehydroemetine • b) For extra intestinal amoebiasis only: Chloroquine
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  ANTIAMOEBIC DRUGS B. Luminalamoebicides • a) Amide : Diloxanide furoate, Nitazoxanide • b) 8-Hydroxyquinolines: Quiniodochlor (Iodochlorohydroxyquin, Clioquinol), Diiodohydroxyquin (Iodoquinol) • (c) Antibiotics:Tetracyclines
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  NITROIMIDAZOLES
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  METRONIDAZOLE • Flagyl, Metryl,Satric, Dependal, Metrogyl • Initially introduced for the treatment of vaginal infections caused by Trichomonas vaginalis • But is effective against amebiasis, giardiasis, and anaerobic bacterial infections (Clostridium difficile).
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  MOA
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  ACTIVATION OF MTZ
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  FORMATION OF ROSFROM NITROARYL COMPOUNDS
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  ACTION OF ACTIVATEDFORM
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  METABOLISM • Liver metabolism •to two major metabolites: • hydroxylation of the 2- CH3 to 2-CH2OH metronidazole (HM) • its oxidation 2-CH2OH to 2-CH2COOH (metronidazole acetic acid)
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  PHARMACOKINETICS • Dosage forms- IV, oral, rectal, vaginal suppositories. • Bioavailability ~100% orally but • 67% to 82% rectal route • 19% to 56% vaginal route • Not bound to plasma protein • Distribution - uniform throughout the body, including mother’s milk.
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  THERAPEUTIC APPLICATION • Drugof choice for Protozoal infections: • Amebiasis (intestinal and extraintestinal), • Giardiasis, and • Trichomoniasis • gram-positive bacilli Clostridium difficile
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  THERAPEUTIC APPLICATION Combinations • Helicobacterpylori infections common side effects • abdominal distress, • a metallic taste • disulfiram-like effect if taken with alcohol • Reported to be carcinogenic in mice (acetamide metabolite) • Restrained use during the first trimester of pregnancy
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  TINIDAZOLE • Treatment ofamebiasis, giardiasis, and trichomoniasis. • Highly effective against Helicobacter pylori infections (unapproved) • Rapidly and completely orally • Administered with food to reduce GI disturbance
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  TINIDAZOLE Mechanism of action •parallels to metronidazole • Similar metabolic pathway • Mimic the actions of metronidazole, • Effective against some metronidazole resistant protozoa
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  LUMINAL AMOEBICIDES Antiamebic Agents
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  AMIDES Luminal Amoebicides
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  NITAZOXANIDE • NTZ –orphan drug for the treatment of diarrhea in children (age 1 to 11 years) in giardiasis & also in cryptosporidiosis in patients with AIDS. • Cryptosporidiosis is a protozoal infection caused by Cryptosporidium parvum in HIV infections.
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  NTZ MOA • Prodrugmetabolised to the deacetylated drug tizoxanide (TIZ) • TIZ then undergoes a four-electron reduction of the 5-nitro group giving various short-lived intermediates, which can include the hydroxylamine derivative. • These reduced products represent the active forms of NTZ. • NTZ has the same mechanism of action as metronidazole, this does not appear to be the case. • NTZ is thought to inhibit the enzyme pyruvate: ferredoxin oxidoreductase in Trichomonas vaginalis, Entamoeba histolytica, and Clostridium perfringens. • The result of this inhibition is disruption of the bioenergetics of these organisms.
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  NTZ MOA • Unlikemetronidazole and tinidazole, which fragment DNA and are suspected mutagenic agents, NTZ and TIZ do not cause DNA fragmentation and are not considered to be mutagenic. • This might be associated with the higher redox potential found for NTZ, a nitrothiazole, in comparison with very low redox potential found for the nitroimidazoles, such as metronidazole and tinidazole. • Additional metabolites of TIZ include the glucuronide, which shows some biologic activity, and small amounts of an aromatic hydroxylation product.
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  DILOXANIDE • Furamide, oreutamide, is the 2-furoate ester of 2,2-dichloro-4- hydroxy-N-methylacetanilide • Result of discovery that various a,a-dichloroacetamides possessed amebicidal activity in vitro. • Hydrolysis of the amide is required for the amebicidal effect. • Nonpolar esters of diloxanide are more potent than polar ones. • Diloxanide furoate has been used in the treatment of asymptomatic carriers of E. histolytica.
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  DILOXANIDE • Treatment ofasymptomatic amebiasis • Its effectiveness against acute intestinal amebiasis or hepatic abscesses, however, has not been established. • It is ineffective as a single agent for the extraintestinal form of the disease. • Administered orally and is hydrolyzed in the gut to give diloxanide (active drug) • Diloxanide is the only form identified in the bloodstream. • The drug is found in the urine as the glucuronide
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  8-HYDROXYQUINOLINES Luminal amoebicides
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  QUINOPHENOL/ OXINE • Alsoknown as oxyquinoline • It is the parent compound of antiprotozoal oxyquinolines • The antibacterial and antifungal properties of oxine and its derivatives, which are believed to result from the ability to chelate metal ions, are well known. • Aqueous solutions of acid salts of oxine, particularly the sulfate (Chinosol, Quinosol), in concentrations of 1:3,000 to 1:1,000, have been used as topical antiseptics. • The substitution of an iodine atom at the 7-position of 8- hydroxyquinolines yields compounds with broad-spectrum amebicidal properties.
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  IODOQUINOL • 5,7-Diiodo-8-quinolinol, 5,7-diiodo-8-hydroxyquinoline,or diiodohydroxyquin (Yodoxin, Diodoquin, Diquinol) • Recommended for acute and chronic intestinal amebiasis • It is ineffective in extraintestinal disease • High incidence of optic neuropathy has occurred with its use, iodoquinol should not be used routinely for traveler’s diarrhea.
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  EMETINE AND DEHYDROEMETINE •Obtained from extracts of ipecac • They are levorotatory • Exert a direct amebicidal action on various forms of E. histolytica. • They are protoplasmic poisons that inhibit protein synthesis in protozoal and mammalian cells by preventing protein elongation. • Their effect in intestinal amebiasis is solely symptomatic • Cure rate is only 10% to 15%, hence used only in combination Stereochemical variation
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  EMETINE AND DEHYDROEMETINE •The high concentrations in liver and other tissues after i.m. have high effectiveness against hepatic abscesses and other extraintestinal forms of the disease. • Toxic effects limit the usefulness of emetine. • high frequency of GI distress (especially nausea and diarrhea), • cardiovascular effects (hypotension and arrhythmias), and • neuromuscular effects (pain and weakness). • A lower incidence of cardiotoxicity has been associated with the use of dehydroemetine (Mebadin), which is available from the CDC and is also amebicidal.
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  PENTAMIDINE ISETHIONATE • 4,4'-(Pentamethylenedioxy)dibenzamidine diisethionate (NebuPent, Pentam 300) • It is a water-soluble crystalline salt that is stable to light and air. • The principal use of pentamidine is for the treatment of pneumonia caused by the opportunistic pathogenic protozoan P. carinii, a frequent secondary invader associated with AIDS. • The drug may be administered by slow intravenous infusion or by deep intra- muscular injection for PCP. • An aerosol form of pentamidine is used by inhalation for the prevention of PCP in high- risk patients infected with HIV who have a previous history of PCP infection or a low peripheral CD4+ lymphocyte count.
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  PENTAMIDINE ISETHIONATE • Boththe inhalant (aerosol) and parenteral dosage forms of pentamidine isethionate • Adverse reactions : cough & bronchospasm (inhalation) & hypertension & hypoglycemia (injection). • Used for the prophylaxis and treatment of African trypanosomiasis. • It also has some value for treating visceral leishmaniasis. • It rapidly disappears from the plasma after IV injection & is distributed to the tissues, where it is stored for a long period. • Hence can be used as a prophylactic agent.
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  ATOVAQUONE • 3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone (Mepron) •It is a highly lipophilic, water-insoluble analog of ubiquinone , an essential component of the mitochondrial electron transport chain in microorganisms. • The structural similarity between atovaquone and ubiquinone suggests that the former may act as an antimetabolite for the latter and thereby interfere with the function of electron transport enzymes. • Atovaquone was originally developed as an antimalarial drug, but Plasmodium falciparum was found to develop a rapid tolerance to its action. • More recently, the effectiveness of atovaquone against P. carinii was discovered. • Alternative to trimethoprim- sulfamethoxazole (TMP-SMX) for the treatment and prophylaxis of PCP in patients intolerant to this combination. • Atovaquone was also shown to be effective in eradicating T. gondii in preclinical animal studies.
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  EFLORNITHINE • Treatment ofWest African sleeping sickness, caused by Trypanosoma brucei gambiense. • Specifically indicated for the meningoencephalitic stage of the disease. • Is myelosuppressive drug that causes high incidences of anemia, leukopenia, and thrombocytopenia. • Complete blood cell counts must be monitored during the course of therapy. • Causes irreversible inactivation of ornithine decarboxylase • It causes decarboxylation & release of fluoride ion from the inhibitor • It is enzyme- catalyzed activation of the inhibitor
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  EFLORNITHINE • Only the(-) isomer, stereochemically related to L-ornithine, is active. • Eflornithine is supplied as the hydrochloride salt. • It may be administered either intravenously or orally. • Approximately 80% of the unchanged drug is excreted in the urine. • Penetration of eflornithine into the CSF is facilitated by inflammation of the meninges.
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