Phase III Comm. I September 2013 Antiprotozoal Drugs Phase III Comm. I September 2013

Antiprotozoal Drugs Protozoan Diseases Amebiasis (Entamoeba histolytica) Giardiasis (Giardia lambia) Leishmaniasis (Leishmania species) Malaria (Plasmodium species) Pneumocystisis Pneumonia (Pneumocystisis carinii ) Toxoplasmosis (Toxoplasma gondii) Trichomoniasis (Trichomonas vaginalis)

Treatment of Malaria More than 200 million people worldwide have malaria More than 1 million people die every year from malaria. It occurs in tropical and sub-tropical areas especially in Asia, Africa, central and south America. It occurs in south and south-east Anatolia in Turkey

Treatment of Malaria Four species of plasmodium cause human malaria: Plasmodium falciparum, P vivax, P malariae, and P ovale. P falciparum is responsible for nearly all serious complications and deaths. Drug resistance is an important therapeutic problem, most notably with P falciparum.

Treatment of Malaria PARASITE LIFE CYCLE An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Merezoides divide in the erythrocite and rupture the cell (hemolysis). They are disseminated into blood as blood schizonts. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease. Some merezoides in the erythrocytes develop into male and female gametocytes. Gametocytes in the erythrocytes are taken up by mosquitoes, where they develop into infective sporozoites (Sexual stage).

Treatment of Malaria In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a latent hepatic stage, the hypnozoite, is not eradicated by most drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is required to cure these infections.

Treatment of Malaria Drugs that eliminate developing or latent liver forms are called tissue schizonticides; those that act on erythrocytic parasites are blood schizonticides; and those that kill sexual stages and prevent transmission to mosquitoes are gametocides.

Treatment of Malaria Tissue schizonticides: Blood schizonticides: Primaquine Blood schizonticides: Chloroquine Amodiaquine Mefloquine Quinine Quinidine Halofantrine Lumefantrine Gametocides:

Chloroquine the drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s. but its utility against P falciparum has been seriously compromised by drug resistance. It remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites. a highly effective blood schizonticide. moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum. Chloroquine is not active against liver stage parasites.

Chloroquine Adverse Effects usually very well tolerated, even with prolonged use. Pruritus is common. Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Rare reactions include; hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and electrocardiographic changes (QRS widening, T wave abnormalities).

Primaquine the drug of choice for the eradication of latent liver forms of P vivax and P ovale. active against hepatic stages of all human malaria parasites. It is the only available agent active against the latent hypnozoite stages of P vivax and P ovale. Primaquine is also gametocidal against the four human malaria species. activity against erythrocytic stage parasites is too weak to play an important role. generally well tolerated. infrequently causes nausea, epigastric pain, abdominal cramps, and headache More serious but rare adverse effects include leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects. Patients should be tested for G6PD deficiency before primaquine is prescribed. should be avoided in patients with a history of granulocytopenia or methemoglobinemia

Quinine and Quinidine Quinine is a rapidly acting, highly effective blood schizonticide against the four species of human malaria parasites. The drug is gametocidal against P vivax and P ovale but not P falciparum. It is not active against liver stage parasites. Quinine dihydrochloride or quinidine gluconate is the treatment of choice for severe falciparum malaria (due to its side effects not prefered for the other therapies in malaria) Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a group of symptoms termed cinchonism. Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria.

Treatment of malaria. Clinical Setting Drug Therapy Alternative Drugs Chloroquine-sensitive P falciparum and P malariae infections Chloroquine phosphate, 1 g, followed by 500 mg at 6, 24, and 48 hours   or- Chloroquine phosphate, 1 g at 0 and 24 hours, then 0.5 g at 48 hours P vivax and P ovale infections Chloroquine (as above), then (if G6PD normal) primaquine, 26.3 mg daily for 14 days

plus one of the following- Treatment of malaria. Clinical Setting Drug Therapy Alternative Drugs Uncomplicated infections with chloroquine-resistant P falciparum Quinine sulfate, 650 mg 3 times daily for 3-7 days Malarone, 4 tablets (total of 1 g atovaquone, 400 mg proguanil) daily for 3 days plus one of the following- or-   Doxycycline, 100 mg twice daily for 7 days Mefloquine, 15 mg/kg once or 750 mg, then 500 mg in 6-8 hours Clindamycin, 600 mg twice daily for 7 days Artesunate or artemether, single daily doses of 4 mg/kg on day 0, 2 mg/kg on days 2 and 3, 1 mg/kg on days 4-7 Fansidar, three tablets once Coartem (coartemether 20 mg, lumefantrine 120 mg), 4 tablets twice daily for 3 days Severe or complicated infections with P falciparum Quinidine gluconate, 10 mg/kg IV over 1-2 hours, then 0.02 mg/kg IV/min Artesunate,3 2.4 mg/kg IV or IM, then 1.2 mg/kg every 12 hours for 1 day, then every day 15 mg/kg IV over 4 hours, then 7.5 mg/kg IV over 4 hours every 8 hours Artemether, 3.2 mg/kg IM, then 1.6 mg/kg/d IM

Major antimalarial drugs. Class Use Chloroquine 4-Aminoquinoline Treatment and chemoprophylaxis of infection with sensitive parasites Amodiaquine1 Treatment of infection with some chloroquine-resistant P falciparum strains Quinine Quinoline methanol Oral treatment of infections with chloroquine-resistant P falciparum Quinidine Intravenous therapy of severe infections with P falciparum Mefloquine Chemoprophylaxis and treatment of infections with P falciparum Primaquine 8-Aminoquinoline Radical cure and terminal prophylaxis of infections with P vivax and P ovale Sulfadoxine-pyrimethamine (Fansidar) Folate antagonist combination Treatment of infections with some chloroquine-resistant P falciparum Atovaquone-proguanil (Malarone) Quinone-folate antagonist combination Treatment and chemoprophylaxis of P falciparum infection Chlorproguanil-dapsone Treatment of multidrug-resistant P falciparum in Africa Proguanil1 Folate antagonist Chemoprophylaxis (with chloroquine) Doxycycline Tetracycline Treatment (with quinine) of infections with P falciparum; chemoprophylaxis Halofantrine1 Phenanthrene methanol Lumefantrine1 Amyl alcohol Treatment of P falciparum malaria in fixed combination with artemether (Coartem) Artemisinins1 Sesquiterpene lactone endoperoxides Treatment of infection with multidrug-resistant P falciparum 1Not available in the USA.

Amebiasis Is the infection with Entamoeba histolytica. Asymptomatic intestinal infection Mild to moderate colitis Dysentery (severe intestinal colitis) Liver abcess

Amebiasis Asymptomatic intestinal infection Diloxanide furoate is the drog of choice. 500 mg 3 tid., for 10 days. Eradicates carriage in about 80 -90 %. Mild to moderate colitis and dysantery Metronidazole is the drug of choice. Oral 750 mg tid., for 10 days. or IV 500 mg every 6 hours. Plus, Diloxanide furoate or Tetracyclin or Erythromycin

Amebiasis Liver Abcess and other exrtaintestinal infections Metronidazole is the drug of choice. Oral 750 mg tid., for 10 days. or IV 500 mg every 6 hours.

Metronidazole Good oral absorption Good tissue distribution including intracellular compartment Half life is 7,5 hours Excreted by urine Specifically reduced in protozoans and converted into toxic reactive reduction products. Side effects; nausia, headache, dry mouth, mettalic taste. Contrindicated in pregnancy.

Metronidazole Drug of choice in; E histolytica infections (luminal amebicide should be added i.e. diloxanide furoate, iodoquinol, or paromomycin) Giardiasis Trichomoniasis

Organism or Clinical Setting Treatment of other protozoal infections. Organism or Clinical Setting Drugs of Choice1 Alternative Drugs Giardia lamblia Metronidazole, 250 mg 3 times daily for 5 days Furazolidone, 100 mg 4 times daily for 7 days   or- Tinidazole, 2 g once Albendazole, 400 mg daily for 5 days Pneumocystis jiroveci, P carinii4 Trimethoprim-sulfamethoxazole, 15-20 mg trimethoprim component/kg/d IV, or two double-strength tablets every 8 hours for 21 days Pentamidine Trimethoprim-dapsone Clindamycin plus primaquine Atovaquone Toxoplasma gondii Acute, congenital, immunocompromised Pyrimethamine plus clindamycin plus folinic acid Pyrimethamine plus sulfadiazine plus folinic acid Pregnancy Spiramycin, 3 g daily until delivery Trichomonas vaginalis Metronidazole, 2 g once or 250 mg 3 times daily for 7 days