1 - Tıbbi Farmakoloji Antiprotozoal İlaçlar ( ingilizce ) Sayfa 1/10 Antiprotozoal İlaçlar Diseases caused by protozoans constitute a worldwide health problem. This chapter concerns the drugs used to combat malaria, amebiasis, toxoplasmosis, pneumocystosis. Drugs for Malaria Malaria is one of the most common diseases worldwide and a leading cause of death. Plasmodium species that infect humans (P falciparum, P malariae, P ovale, P vivax) undergo a primary developmental stage in the liver and then parasitize erythrocytes. P falciparum and P malariae have only 1 cycle of liver cell invasion. The other species have a dormant hepatic stage responsible for recurrent infections and relapses. Primary tissue schizonticides (eg, primaquine) kill schizonts in the liver, whereas blood schizonticides (eg, chloroquine, quinine) kill these parasitic forms only in the erythrocyte. Sporonticides (proguanil, pyrimethamine) prevent sporogony and multiplication in the mosquito. Sayfa 2/10 Sayfa 3/10 Chloroquine (Klorokin) The drug is rapidly absorbed when given orally, is widely distributed to tissues, and has an extremely large volume of distribution. Antacids may decrease oral absorption of the drug. Chloroquine is excreted largely unchanged in the urine. Mechanism of Action Chloroquine accumulates in the food vacuole of plasmodia and prevents polymerization of the hemoglobin breakdown product heme into hemozoin. Intracellular accumulation of heme is toxic to the parasite. Chloroquine is the drug of choice for acute attacks of nonfalciparum and sensitive falciparum malaria and for chemoprophylaxis, except in regions where P falciparumis resistant. The drug is solely a blood schizonticide. Chloroquine and hydroxychloroquine are also used in autoimmune disorders, including rheumatoid arthritis. High doses may cause severe skin lesions, peripheral neuropathies, myocardial depression, retinal damage, auditory impairment, and toxic psychosis. Chloroquine may also precipitate porphyria attacks. Quinine (Kinin) Quinine is rapidly absorbed orally and is metabolized before renal excretion. Intravenous administration of quinine is possible in severe infections. Quinine complexes with double-stranded DNA to prevent strand separation, resulting in block of DNA replication and transcription to RNA. Quinine is solely a blood schizonticide. The main use of quinine is in P falciparum infections resistant to chloroquine Quinine is commonly used with doxycycline or clindamycin to shorten the duration of therapy and limit toxicity. Quinidine(Kinidin), the dextrorotatory stereoisomer of quinine, is used intravenously in the treatment of severe or complicated falciparum malaria. Quinine commonly causes cinchonism, symptoms of which include gastrointestinal distress, headache, vertigo, blurred vision, and tinnitus. Severe overdose results in disturbances in cardiac conduction that resemble quinidine toxicity. Hematotoxic effects occur, including hemolysis in glucose-6-phosphate dehydrogenase Sayfa 4/10 (G6PD)-deficient patients. Quinine is contraindicated in pregnancy. Mefloquine (Meflokin) Its mechanism of action is not known. Mefloquine is a first-line drug (taken weekly) given for prophylaxis in all geographical areas with chloroquine resistance At high doses, mefloquine has caused cardiac conduction defects, psychiatric disorders, neurologic symptoms, and seizures. Primaquine Absorption is complete after oral administration and is followed by extensive metabolism. Primaquine forms cellular oxidant products that damage protozoa. The drug is a tissue schizonticide and also limits malaria transmission by acting as a gametocide. Primaquine eradicates liver stages of P vivax and P ovale and should be used in conjunction with a blood schizonticide. Primaquine is usually well tolerated but may cause gastrointestinal distress, pruritus, headaches, and methemoglobinemia. More serious toxicity involves hemolysis in G6PD-deficient patients. Primaquine is contraindicated in pregnancy. Antifolate Drugs The antifolate group includes pyrimethamine (primetamin), proguanil, sulfadoxine (sulfadoksin), and dapsone (dapson). Proguanil has a shorter half-life (12 –16 h) than other drugs in this subclass (half-life >100 h). Sulfonamides act as antimetabolites of PABA and block folic acid synthesis in certain protozoans by inhibiting dihydropteroate synthase. Pyrimethamine and proguanil are selective inhibitors of protozoan dihydrofolate reductases. The combination of pyrimethamine with sulfadoxine has synergistic antimalarial effects through the sequential blockade of 2 steps in folic acid synthesis. The antifols are blood schizonticides that act mainly against P falciparum. Pyrimethamine with sulfadoxine in fixed combination (Fansidar) is used in the treatment of Sayfa 5/10 chloroquine-resistant forms of this species, although the onset of activity is slow. Proguanil with atovaquone in fixed combination (Malarone) can be used (daily) for chemoprophylaxis of chloroquine-resistant malaria Other Antimalarial Drugs Atovaquone (Atovakon) This quinine derivative, a component of Malarone (proguanil), appears to disrupt mitochondrial electron transport in protozoa. Malarone is effective for both chemoprophylaxis (taken daily) and treatment of falciparum malaria. Common adverse effects are rash, cough, nausea, vomiting, diarrhea, fever, and abnormal liver function tests. The drug should be avoided in patients with a history of cardiac conduction defects, psychiatric disorders, or seizures. Atovaquone is an alternative treatment for P jiroveci infection. Doxycycline, Amodiaquine, Halofantrine, Lumefantrine, Artesunate, Artemether, Dihydroartemisinin Drugs for the Prevention of Malaria in Travelers Chloroquine (weekly) remains an appropriate agent for prophylaxis in regions without resistant P falciparum as does mefloquine (weekly) for regions with P falciparum resistance to chloroquine. In areas with multidrug-resistant malaria, the choice is either doxycycline or Malarone (atovaquone plus proguanil); both drugs must be taken daily. For updated information check CDC guidelines at http://www.cdc.gov. Sayfa 6/10 Drugs for Amebiasis The mechanisms of amebicidal action of most drugs in this subclass are unknown. Metronidazole and Tinidazole Metronidazole and tinidazole are effective orally and distributed widely to tissues. Elimination of the drugs requires hepatic metabolism. Metronidazole undergoes a reductive bioactivation of its nitro group by ferredoxin (present in anaerobic parasites) to form reactive cytotoxic products. The mechanism of tinidazole is assumed to be similar. Metronidazole or tinidazole is the drug of choice in severe intestinal wall disease and in hepatic abscess and other extraintestinal amebic disease. Both drugs are used with a luminal amebicide. Metronidazole is the drug of choice for trichomoniasis. Other clinical uses of metronidazole include treatment of giardiasis (tinidazole is equally effective), and infections caused by Gardnerella vaginalis and anaerobic bacteria (B fragilis, C difficile). Metronidazole is also used in combination regimens for gastrointestinal ulcers associated with H pylori. Adverse effects of metronidazole include gastrointestinal irritation (it is best taken with meals), headache, paresthesias, and dark coloration of urine. Tinidazole has a similar adverse effect profile, but may be better tolerated than metronidazole. More serious toxicity includes neutropenia, dizziness, and ataxia. Drug interactions with metronidazole include a disulfiram-like reaction with ethanol and potentiation of coumarin anticoagulant effects. Sayfa 7/10 Drugs for Pneumocystosis TMP-SMZ TMP-SMZ is the first choice in prophylaxis and treatment of pneumocystis pneumonia (PCP). Pentamidine (Pentamidin) Pentamidine's mechanism of action is unknown Aerosol pentamidine (once monthly) can be used in primary and secondary prophylaxis, although oral trimethoprim-sulfamethoxazole (TMP-SMZ) is usually preferred. Daily intravenous or intramuscular administration of the drug for 21 d is needed in the treatment of active pneumocystosis in the HIV-infected patient. Severe adverse effects follow parenteral use, including respiratory stimulation followed by depression, hypotension resulting from peripheral vasodilation, hypoglycemia, anemia, neutropenia, hepatitis, and pancreatitis. Systemic toxicity is minimal when pentamidine is used by inhalation. Atovaquone Drugs for Toxoplasmosis Antifols: Pyrimethamine and Sulfonamides Combination of pyrimethamine with sulfadiazine has synergistic activity against Toxoplasma gondii through the sequential blockade of 2 steps in folic acid synthesis. Pyrimethamine plus sulfadiazine (or clindamycin) is a regimen of choice for prophylaxis against and treatment of toxoplasmosis. High doses of pyrimethamine plus sulfadiazine are associated with gastric irritation, glossitis, neurologic symptoms (headache, insomnia, tremors, seizures), and hematotoxicity (megaloblastic anemia, thrombocytopenia). Antibiotic-associated colitis may occur during treatment with clindamycin. Sayfa 8/10 Antihelmintik İlalar Antihelminthic drugs have diverse chemical structures, mechanisms of action, and properties. Many act against specific parasites, and few are devoid of significant toxicity to host cells. In addition to the direct toxicity of the drugs, reactions to dead and dying parasites may cause serious toxicity in patients. TABLE 53 –1 Drugs for the treatment of helmintic infections. Infecting Organism Drugs of Choice Alternative Drugs Nematodes Ascaris lumbricoides (roundworm) Albendazole or mebendazole or pyrantel pamoate Piperazine Necator americanus & Ancylostoma duodenale (hookworm) Pyrantel pamoate or albendazole or mebendazole Trichuris trichiura (whipworm) Albendazole or mebendazole Pyrantel pamoate Strongyloides stercoralis (threadworm) Ivermectin Albendazole, mebendazole Enterobius vermicularis (pinworm) Mebendazole or pyrantel pamoate Albendazole Trichinella spiralis (trichinosis) Mebendazole (+/ – corticosteroids) Albendazole Cutaneous larva migrans Albendazole or ivermectin Wuchereria bancrofti and Brugia malayi (filariasis) Diethylcarbamazine Ivermectin Onchocerca volvulus (onchocerciasis) Ivermectin Trematodes (flukes) Schistosoma haematobium Praziquantel Metrifonate Schistosoma mansoni Praziquantel Oxamniquine Schistosoma japonicum Praziquantel Paragonimus westermani Praziquantel Fasciola hepatica (sheep liver fluke) Bithional or triclabendazole Fasciolopsis buski (large intestinal fluke) Praziquantel or niclosamide Cestodes (tapeworms) Sayfa 9/10 Taenia saginata (beef tapeworm) Praziquantel or niclosamide Mebendazole Taenia solium (pork tapeworm) Praziquantel or niclosamide Cysticercosis (pork tapeworm larval stage) Albendazole Praziquantel Diphylobothrium latum (fish tapeworm) Praziquantel or niclosamide Echinococcus granulosus (hydatid disease) Albendazole Albendazole (Albendazol) The action of albendazole is thought to involve inhibition of microtubule assembly. Albendazole has few toxic effects during short courses of therapy (1 –3 d). However, a reversible leukopenia, alopecia, and elevation of liver function enzymes can occur with more prolonged use. Long-term animal toxicity studies have described bone marrow suppression and fetal toxicity. The safety of the drug in pregnancy and young children has not been established. Mebendazole (Mebendazol) Mebendazole acts by selectively inhibiting microtubule synthesis and glucose uptake in nematodes. Mebendazole toxicity is usually limited to gastrointestinal irritation, but at high doses agranulocytopenia and alopecia have occurred. The drug is teratogenic in animals and therefore contraindicated in pregnancy. Piperazine (Piperazin) Piperazine paralyzes ascaris by acting as an agonist at GABA receptors. The paralyzed roundworms are expelled live by normal peristalsis. Piperazine should not be used in pregnant patients or those with hepatic or renal dysfunction or seizure disorders. Pyrantel Pamoate (Pirantal Pomad) Pyrantel pamoate stimulates nicotinic receptors present at neuromuscular junctions of nematodes. Contraction of muscles occurs, followed by a depolarization-induced paralysis. Use with caution in patients with hepatic dysfunction. Sayfa 10/10 Niclosamide (Niklozamid) Niclosamide may act by uncoupling oxidative phosphorylation or by activating ATPases. Toxic effects are usually mild but include gastrointestinal distress, headache, rash, and fever. Some of these effects may result from systemic absorption of antigens from disintegrating parasites. Ethanol consumption should be avoided for 24 –48 h Skill Keeper: Antimicrobial Chemotherapy in Pregnancy Mebendazole is widely used for the treatment of nematode infections but is contraindicated in the pregnant patient because of possible embryotoxicity. Think back over the drugs used for the treatment of bacterial, fungal, protozoal, and viral infections. Which drugs are associated with a greater risk compared with benefit in pregnancy? In the United States a drug is designated (by the FDA) as Pregnancy Risk Category X if the risk of its use in pregnancy is judged to be greater than any possible benefit. Such drugs have been established to cause fetal abnormalities or miscarriage in humans. This category includes the antiviral agent ribavirin and the antimalarial drug quinine. Clomiphene, ergots, ethionamide, HMG-CoA reductase inhibitors, isotretinoin, misoprostol, Premarin, and thalidomide are also category X drugs. For drugs in FDA Pregnancy Risk Category D, there is evidence of human risk, but their potential benefit may outweigh such risk. In other words, they are not absolutely contraindicated in pregnancy. These include aminoglycosides (eg, gentamicin) and tetracyclines. Although they are not category D drugs, fluoroquinolones are not approved by the FDA for use in pregnancy