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Antiprotozoal drugs Gábor Pozsgai Pharmacology and Pharmacotherapy University of Pécs 2012 Characteristics of protozoa • single-cell organisms • eukaryotic • selective toxicity is complicated – different metabolic pathways – different amino acid sequences of otherwise similar proteins Characteristics of protozoa • Life cycle includes insect and human hosts – pest control through application of insecticids – treatment of parasites in human hosts with chemotherapeutics Most frequent diseases caused by protozoa • • • • • • • Malaria Amoebiasis Trypanosomiasis Leishmaniasis Toxoplasmosis Trichomoniasis Giardiasis Malaria • The most frequent disease in the world • It is spread by Anopheles mosquitos • It is mostly imported from Africa to western countries Malaria • Attacks of intermittent fever, shivering – erythrocytic phase of the protozoa • Head- and muscle aches • Hemolytic anemia, splenomegaly • It might be fatal within a couple of days Malaria • • • • Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Malaria Plasmodium falciparum • It might cause CNS malaria • Infected red blood cells express PfEMP-1 protein • That binds CD36, ICAM-1, ELAM-1 and chondroitin sulfate • Responsible for decreased elimination of red blood cells in the spleen Malaria Plasmodium falciparum • „Sludging” in blood vessels • Ischemia and bleeding in the brain, lungs and kidneys • Lethal without treatment • More than 20% of patients die despite therapy Malaria P. vivax und P. ovale • They leave hypnozoites in the liver • The disease might get reactivated after months or years • Hypnozoites have to be treated with special medication Antimalarial drugs • Primary tissue schizontocidal effect – pyrimethamine, primaquine, proguanil, atovaquone • Blood schizontocidal effect – chloroquine, quinine, proguanil, atovaquone • Gametocidal effect – pyrimethamine, primaquine • Sporontocidal effect – pyrimethamine • Secondary tissue schizontocidal effect – primaquine Antimalarial drugs • Symptoms might be healed by blood schizontocidal drugs – symptomatic therapy • Hypnozoites in the liver can only be killed by secondary tissue schizontocidal drugs – radical therapy • Sporontocidal and gametocidal drugs inhibit transmission between hosts – prophylactic therapy Metabolic pathways of plasmodia Heme metabolism • Plasmodia cannot synthesize amino acids • They degrade hemoglobin for amino acids • These processes take place in food vacuoles – aspartate proteases (plasmepsine) – cysteine proteases (falcipain) – metalloproteases (falcilysin) Metabolic pathways of plasmodia Heme metabolism • Basic amino acids are released • Toxic ferriprotoporphyrin IX is also produced – damages lysosomal membranes and kills the pathogen – normally it is turned into harmless crystalline hemozoin by heme polymerase Metabolic pathways of plasmodia Electron transport chain • Not involved in ATP synthesis • Important in pyrimidine synthesis and this way in DNA synthesis • Reactivation of dihydroorotate dehydrogenase Inhibitors of heme metabolism: 4-aminoquinoline derivatives Chloroquine • Root or leaves of Dichroa febrifuga • Bark of Cinchona trees • Weak base that accumulates in food vacuoles of plasmodia • Binds ferriprotoporphyrin IX and inhibits detoxification via polymerisation • Effective in rheumatoid arthritis and SLE Inhibitors of heme metabolism: 4-aminoquinoline derivatives Chloroquine • T1/2 5 days • Loading dose is necessary • Accumulates in various tissues – – – – – – lungs liver spleen kidneys leukocytes etc. • It is excreted better in acidic urine Inhibitors of heme metabolism: 4-aminoquinoline derivatives Chloroquine • Ineffective against P. falciparum in Africa, Asia and South-America • It is not accumulated sufficiently in food vacuoles • It is removed from the vacuoles by the PfCRT transporter – normally prefers basic amino acids – plasmodia need another independent mutation to mantain the pH of vacuoles Inhibitors of heme metabolism: 4-aminoquinoline derivatives Chloroquine • Might be used for the treatment of P. vivax, P. ovale, P. malariae and sensitive P. falciparum • Suitable for prophylactic treatment Inhibitors of heme metabolism: 4-aminoquinoline derivatives Chloroquine • Relatively safe in humans – accumulates in infected red blood cells – only high amounts might neutralize mammalian lysosomes Inhibitors of heme metabolism: 4-aminoquinoline derivatives Chloroquine • • • • Itch in individulas of dark complexion Might aggravate psoriasis and porphyria Hair loss, white hair Dizziness, confusion, psychosis, retinopathy, deafness, neuropathy • Vomiting Inhibitors of heme metabolism: 4-aminoquinoline derivatives Chloroquine • Inhibits excitability of the heart • Hypotension, shock • Death (especially in suicide cases and children) • Teratogenic Inhibitors of heme metabolism: 4-aminoquinoline derivatives Mefloquine • • • • • • Unknown mechanism of action Inhibits the formation of hemozoin lumps Can only be administered orally Strong plasma protein binding Accumulation in erythrocytes T1/2 13-33 days Inhibitors of heme metabolism: 4-aminoquinoline derivatives Mefloquine • Therapy of chloroquine-resistant P. falciparum and P. vivax • Prophylactic treatment of sensitive plasmodia Inhibitors of heme metabolism: 4-aminoquinoline derivatives Mefloquine • Bradycardia, QT elongation • Insomnia, nightmares, anxiety, depression, hallucination, psychosis, seizures • Leukocytosis, thrombocytopenia • Elevated liver enzymes • Teratogenic Inhibitors of heme metabolism: Cinchona alkaloids Quinine and quinidine • • • • Quinidine is an enantiomer of quinine Pharmacological effects are similar Inhibition of heme polymerase Binding of the strands of DNA Inhibitors of heme metabolism: Cinchona alkaloids Quinine and quinidine • Therapy of acute malaria • Especially in case of chloroquine-resistant P. falciparum Inhibitors of heme metabolism: Cinchona alkaloids Quinine and quinidine • Cinchonism – tinnitus, headache, nausea, visual disturbances • • • • Respiratory depression Negative cardiac effects Vasodilatation, hypotension Perspiration Inhibitors of heme metabolism: Cinchona alkaloids Quinine and quinidine • • • • Hemolysis, leukopenia, thrombopenia Hepatotoxic Hypoglycemia Smooth muscle contraction – contraindicated in pregnancy – plasmodia released from the spleen might trigger fever attack Inhibitors of heme metabolism: artemisinin and derivatives Artemisinin, artesunate, artemether • • • • Activated by free or heme-bound iron Production of a reactive radical Alkylation of proteins and heme Mechanism of selectivity is not fully understood – heme is necessary for the activation – accumulation in plasmodia Inhibitors of heme metabolism: artemisinin and derivatives Artemisinin, artesunate, artemether • First choice drugs in case of acute malaria in Africa and Southeast-Asia • No resistant strains are known – T1/2 only 1-11 hours – always in combination • Not suitable for prophylaxis Inhibitors of heme metabolism: artemisinin and derivatives Artemisinin, artesunate, artemether • Neurotoxicity, headache, dizziness • Cardiotoxicity, elongated QT interval Inhibitors of the respiratory chain: 8-aminoquinoline derivatives Primaquine • Secondary tissue schizontocidal effect – hypnozoits of P. vivax and P. ovale • No blood schizontocidal effect – not suitable for the treatment of acute disease • An active metabolite inhibits the function of ubiquinone • Other metabolites damage mitochondria of plasmodia oxidatively Inhibitors of the respiratory chain: 8-aminoquinoline derivatives Primaquine • Effective against exoerythrocytic forms of P. falciparum, P. vivax and P. ovale • Gametocidal against all plasmodia Inhibitors of the respiratory chain: 8-aminoquinoline derivatives Primaquine • Leukopenia • Methemoglobinemia, hemolysis – especially in individuals lacking glucose-6phosphate dehydrogenase activity – enzyme activity has to be checked every time before initiation of therapy – might lead to life-threatening hemolysis of the fetus in pregnancy Inhibitors of the respiratory chain: ubiquinone analogues Atovaquone • Inhibition of pyrimidine synthesis • Other metabolic pathways are probably inhibited, too • Hundred fold higher affinity to cytochrome bc1 protein of plasmodia • A single point mutation renders the pathogen resistant Inhibitors of the respiratory chain: ubiquinone analogues Atovaquone • Always in combination with doxycycline or proguanil • Synergistic effects of proguanil and atovaquone – not related to inhibition of folic acid synthesis by proguanil – proguanil might induce uncoupling in plasmodia Inhibitors of the respiratory chain: ubiquinone analogues Atovaquone • Suitable for both treatment and prophylaxis of malaria • Effective against Toxoplasma and P. jirovecii Inhibitors of the respiratory chain: ubiquinone analogues Atovaquone • Lipophilic, poor absorption – better absorption when taken with a fatty meal • Strong plasma protein binding • T1/2 2-4 days Inhibitors of the respiratory chain: ubiquinone analogues Atovaquone • Headache, dyssomnia • Nausea, diarrhoea • Rash Inhibitors of protein synthesis Doxycycline • • • • • Tetracycline antibiotic Inhibition of protein synthesis of apicolpasts Delayed effect Effective against erythrocytic schizonts Unsuitable for monotherapy Inhibitors of protein synthesis Doxycycline • In case of suspected multiresistance it might be combined with quinine • Suitable for prophylaxis of malaria even in case of chloroquine resistance • Not licenced for malaria prophylaxis in some European countries Inhibitors of protein synthesis Clindamycin • Active against erythrocytic schizonts • In pregnancy and for children because they cannot be administered tetracycline antibiotics • After treatment with quinine, quinidine or artesunate Inhibitors of folic acid synthesis Proguanil, pyrimethamine • Inhibitors of protozoal dihydrofolic acid reductase • Only in combination due to fast development of resistance • Delayed effect • Synergistic effects with some other medications – pyrimethamine + sulfadoxine (fansidar) – proguanil + atovaquone (malarone) Inhibitors of folic acid synthesis Proguanil, pyrimethamine • Pyrimethamine is also active against Toxoplasma • Pyrimethamine might be administered once weakly for prophylaxis due to its long half life • Therapy has to be continued for 6 weeks after the journey • Unsuitable for acute treatment Inhibitors of folic acid synthesis Proguanil, pyrimethamine • • • • Abdominal distress, diarrhoea Hematuria Macrocytic anemia Might be prevented by administration of folic acid Table 53-2. Summary of drugs used for treatment and chemoprophylaxis of malariaa Infections Infection with chloroquine-resistant Plasmodium falciparum or with unknown or mixed organisms Typical drug choices for acute attacks Oral quinine plus: proguanil + atovoquone;b or artemether + lumefantrinec Typical drug choices for chemoprophylaxis Short term (weeks): atovoquone + proguanil or doxycycline Long term (months/years): chloroquine + proguanil or atovoquone + proguanil a It must be appreciated that this is only a summary, not a definitive guide to prescription, as the recommended drug combinations vary depending on the patient, the area visited, the overall risk of infection, the presence of resistant forms of the disease and so on. This information is based on current UK recommendations (source: British National Formulary 2008). b Malarone is a proprietary combination of atovoquone and proguanil hydrochloride. c Riamet is a proprietary combination of artemether and lumefantrine. Rang et al: Rang & Dale’s Pharmacology, 7e Copyright © 2011 by Churchill Livingstone, an imprint of Elsevier Ltd. All rights reserved. Amoebiasis • Caused by Entamoeba hystolytica • E. dispar is similar, but it is not a human pathogen • Cysts reach the gastrointestinal tract with contaminated beverages or food • Occurance of invasive disease depends on – – – – the number of ingested cysts the strain of the pathogen intestinal motility presence of bacteria serving as food for the parasite Amoebiasis • Cysts are inactive, but infectious • Excystation and ripening of trophozoites occurs in the intestine • Trophozoites are able to move with pseudopodia and consume bacteria, other protozoa, intestinal cells and erythrocytes Amoebiasis • Trophozoites turn into binuclear, then quadrinuclear cysts excreted with the feces • Trophozoites spread sideways • Trophozoites sometimes penetrate deeper into the colon, perforation might occur • This way the parasite might enter the portal circulation and induce the formation of hepatic abscesses Amoebiasis • Diarrhoea, abdominal cramps, dysentery • Hepatic abscess • Symptoms often occur days or even years after infection • Patients are frequently asymptomatic, but infectious Amoebiasis • E. hystolytica lacks the following enzymes – enzymes of fermentation – enzymes of ative phosphorylation – enzymes of the Krebs cycle – pyruvate dehydrogenase • The parasite depends on the metabolism of glucose to ethanol Amoebiasis • Some enzymes are specific for luminal protozoa and anaerobic bacteria • Pyruvate-ferredoxin oxidoreductase (PFOR) and alcohol dehydrogenase E are of significance • They contain ferredoxin Amoebiasis Metronidazole • Prodrug • Activated by – reduced ferredoxin – specific nitroreductase • Proteins, membranes and DNA are damaged by radicals produced Amoebiasis Metronidazole • Only active against tissue trophozoites • Distributed in the intracellular compartment, bones and adscesses • Inactive against luminal parasites – absorbed in the samll intestine – only small amount reaches the colon • Invasive amoebiasis is first treated with metronidazole, then with drugs that are active against luminal trophozoites Amoebiasis Metronidazole • Resistance – mutated nitroreductase – lowered expression of ferredoxin – decreased PFOR activity – decreased permeability of parasites Amoebiasis Metronidazole • Resistance is rare amongst luminal protozoa – diploid genetic material – no alternative pathways for PFOR – metronidazole is a substrate of P-glycoprotein Amoebiasis Metronidazole • Headache, neuropathy, encephalopathy, seizures, metallic taste • Nausea, abdominal discomfort, pancreatitis • Dark urine • Disulfiram-like effect • Contraindicated in pregnancy Amoebiasis Tinidazole • Similar mechanism of action • Longer half life • Fewer side effects Amoebiasis Emetine, dehydroemetine • Active against tissue trophozoites • Only used if metronidazole is contraindicated due to severe side effects • Dehydroemetine is favoured for its fewer side effects Amoebiasis Emetine, dehydroemetine • Binds 40S ribosome subunits and inhibits eukaryotic protein synthesis • Administered s.c. or i.m. Amoebiasis Emetine, dehydroemetine • Sterile abscesses • Arrhythmia, cardiac failure, hypotension • Hepatotoxic, nephrotoxic, cardiotoxic and damages skeletal muscles • Myopathy, cardiomyopathy • Unsuitable for children and pregnant women Amoebiasis Diiodohydroxyquinoline (iodoquinol) • Luminal amoebicidal effect • Low absorption • Forms complexes with iron that is essential for parasites Amoebiasis Diiodohydroxyquinoline (iodoquinol) • • • • Optic and peripheral neuropathy Enlarged thyroid Nausea, diarrhoea, abdominal discomfort Itch, rash Amoebiasis Diloxanide furoate • • • • Luminal amoebicidal effect Hydrolized into diloxanide and furoate 90% of diloxanide is absorbed Diloxanide remaining in the colon is responsible for the amoebicidal effect Amoebiasis Diloxanide furoate • Nausea, flatulence • Unsuitable for children and pregnant women Amoebiasis Paramomycin • Aminoglycoside antibiotic • Low intestinal absorption • Used only orally – systemic administration would induce severe side effects Toxoplasmosis • • • • The pathogen is Toxoplasma gondii Animal hosts are mammals and birds Transferred by food Disease progression depends on host immunity • The disease is mostly asymptomatic Toxoplasmosis • • • • • Infection often occurs transplacentarily Meningitis, encephalitis Intraocular infection Lymphadenopathy Immunocompetent patients with lymphadenopathy only do not need pharmacotherapy Toxoplasmosis • Pharmacotherapy is required in the following situations: – disease affects organs – chorioretinitis – acute infection during pregnancy – connatal toxoplasmosis in children Toxoplasmosis Pyrimethamine + sulfadiazine • Synergistic inhibition of folic acid synthesis • Folic acid has to be administered to prevent myelosuppression Toxoplasmosis Spiramycin • Macrolide antibiotic • Therapy of children and pregnant women with acute infection • Does not totally prevent fetal infection, but lowers its incidence Trypanosomiasis African trypanosomiasis • Sleeping sickness • Trypanosoma brucei gambiense, T. brucei rhodesiense • Intermediate hosts are tsetse flies • At the site of the bite a primary chancre might occur • From the primary chancre protozoa reach the circulation and lymphatic organs Trypanosomiasis African trypanosomiasis • Generalized lymphadenopathy, fever • Parasites reach the CNS through the circulation • Meningoencephalitis and narcoleptic state are induced • High mortality Trypanosomiasis African trypanosomiasis • West-African sleeping sickness is more dangerous – early CNS involvement – cardiomyopathy – fast disease progression Trypanosomiasis Pentamidine • Treatment of early phase of T. brucei gambiense infection • In combination with suramin • T. brucei rhodesiense might be sensitive, too • Second choice drug for P. jirovecii pneumonia Trypanosomiasis Pentamidine • Positively charged molecule • Transported actively into parasites • Binds negatively charged molecules Trypanosomiasis Pentamidine • Synthesis of DNA, RNA, proteins and phospholipids are inhibited • High affinity to DNA of kinetoplasts • Dihydrofolic acid reductase and topoisomerase II are inhibited, too Trypanosomiasis Pentamidine • • • • • Administered slowly i.v. Might also be given i.m. or inhaled Accumulates in various tissues T1/2 10 days Very slow elimination Trypanosomiasis Pentamidine • Frequent and potentially fatal side effects • Nephrotoxic • Sterile abscess at the site of i.m. administration • Dizziness, headache, nausea, dispnoea, tachycardia – due to histamine release Trypanosomiasis Pentamidine • • • • • Elongated QT interval Pancreatitis Diabetes, hypo- or hyperglycemia Hepatitis Changes of blood counts Trypanosomiasis Suramin • Also known as Germanin • Tretament of early phase of african trypanosomiasis • High electronegativity, poor absorption • Strong plasma protein binding • Administered i.v. Trypanosomiasis Suramin • Interaction with various macromolecules • Inhibition of the following enzymes – glycerolphosphate dehydrogenase – RNA polymerase Trypanosomiasis Suramin • • • • • • • Fatigue, unconciousness Headache, joint aches, ocular irritation Neuropathy Nausea Seizures, shock Nephrotoxic Hemolytic anemia, agranulocytosis Trypanosomiasis Melarsoprol • First choice drug for the treatment of late phase of sleeping sickness • Lipophilic and reaches the CNS • Contains arsenic and only soluble in propylene glycol • Damages plastic bottles Trypanosomiasis Melarsoprol • • • • Inhibits protozoal pyruvate kinase Inhibits the uptake of adenine and adenosine mammalian cells less permeable for the drug Treatment is fatal in 5% of the cases Trypanosomiasis Melarsoprol • Phlebitis • Reactive encephalitis – mortality is over 50% – risk might be lowered by steroid administration • Polyneuropathy – necessitates thiamine administration Trypanosomiasis Tryparsamide • Treatment of T. brucei gambiense infection • Crosses the blood-brain barrier Trypanosomiasis Eflornithine • Treatment of early and late phases of WestAfrican trypanosomiasis • Only slowly degraded by T. brucei gambiense • Faster eliminated by T. brucei rhodesiense and human cells renders these less sensitive to the drug Trypanosomiasis Eflornithine • Selective irreversible inhibitor of ornithine decarboxylase – the enzyme produces putrescine from ornithine – this is the rate limiting step in the synthesis of spermine and spermidine – these are involved in nucleic acid synthesis and regulate protein synthesis of the parasite – inhibited polyamine synthesis Trypanosomiasis Eflornithine • Nausea • Seizures • Hair loss – used in the treatment of hirsutismus • Fever • Anemia, thrombocytopenia, leukopenia Trypanosomiasis American trypanosomiasis • • • • Chagas disease Caused by T. cruzi Intermediate hosts are triatomine bugs Human infection is caused by rubbing the insect feces into bite wounds or naïve conjunctiva Trypanosomiasis American trypanosomiasis • Transplacentar infection might occur and breastmilk might also spread the disease • Site of infection becomes swollen (Romana sign in the ocular area) • Acute phase only occurs in immunocompromised patients – – – – fever, lymphadenopathy, edema diarrhoea, abdominal discomfort seizures enlarged heart Trypanosomiasis American trypanosomiasis • Latent phase might take years • Chronic disease – dilated cardiomyopathy – megaesophagus, megacolon – intestinal occlusion, penetration, peritonitis Trypanosomiasis Nifurtimox • Prodrug • Yields nitroaryl radicals if reduced • These produce superoxide and hydrogen peroxide if oxidized Trypanosomiasis Nifurtimox • Trypanosomes are sensitive because they lack catalase • Mammalian cells contain catalase, superoxide dismutase and glutathione peroxidase • Oral administration • Progression of intestinal and cardiac disease frequently fails to respond to therapy Trypanosomiasis Nifurtimox • • • • Nausea, abdominal discomfort Rash Dyssomnia, agitation, damaged memory Neuropathy, seizures Leishmaniasis Three different presentations of the disease • Kala azar (visceral leishmaniasis) – spleen and liver involvement • Oriental sore (cutaneous leishmaniasis) – skin symptoms – spontaneous improvement • Espundia (mucocutaneous leishmaniasis) – involvement of mucous membranes of the upper airways and gastrointestinal tract Leishmaniasis • • • • Intermediate hosts are sand flies Disease is pread by the saliva of the insect Parasites are taken up by phagocytes Disease progression depends on – the strain of the pathogen – the distribution of infected macrophages – the state of the immune system Leishmaniasis Sodium stibogluconate, meglumine antimonate • Contain antimony • Mechanism of action is not fully understood • Glycolysis and fatty acid oxidation of the parasite might be inhibited • Antimony reacts with sulfhydryl moieties Leishmaniasis Sodium stibogluconate, meglumine antimonate • • • • • • Myelosuppression Disorders of circulation, shock Elongated QT interval Hepatotoxic Pancreatitis Rash Leishmaniasis Amphotericin B • In case of resistance for stibogluconate • Frequent in India Leishmaniasis Paramomycin • Only applied topically due to severe side effects • Except systemic administration in case of visceral leishmaniasis • Ototoxic • Hepatotoxic • No nephrotoxicity has been reported Leishmaniasis Miltefosine • Synthetic ether analogue of phospholipids • Mechanism of action is unknown • Antineoplastic, immunomodulatory and antiprotozoal effects • Administered orally Leishmaniasis Miltefosine • Inhibition of enzymes in the plasma membrane – protein kinase C • Inhibited phosphatidylcholine synthesis • Inhibited PAF production • Inhibited inositol phosphate synthesis Leishmaniasis Miltefosine • • • • Enhanced T cell activation Increased INF-γ release Increased expression of IL-2 receptors Increased expression of MHC molecules Leishmaniasis Miltefosine • • • • Nausea, diarrhoea Hepatotoxic Nephrotoxic Teratogenic Trichomoniasis and giardiasis • Trichomoniasis affects vaginal and urethral mucous membranes • Often asymptomatic, but activated in case of immunosuppression or mixed infection • T. vaginalis is transmitted sexually • Sexual partners of the patient have to be treated, as well Trichomoniasis and giardiasis • Giardiasis is the most frequent protozoal infection in developing countries • Often asymptomatic • Resides in the duodenum • Malabsorption, steatorrhoea and weight loss might occur • Transmitted by feces • Intermediate hosts might be animals or humans Trichomoniasis and giardiasis Metronidazole, nimorazole, tinidazole • Resistance is rare