Antiprotozoal Drugs Dr. Kaukab Azim Israa Omer

Be able to recognize the main therapeutic uses of the drugs of each class Be able to indicate the main contraindications of the drugs of each class if any Be able to describe the adverse effects of the drugs of each class Be able to describe the mechanism of action of each drug in each drug group if known Be able to relate the action of drugs with the life cycle of the organism Learning Objectives

Tissue Schizonticides Blood Schizonticides Gametocides insect repellents Insecticides bed nets Therapeutic options

Drugs used for treatment of Malaria

Chloroquine Phosphate Safe and low-cost Rapidly absorbed through oral route Very well tolerated even with prolonged use. Highly effective blood schizonticide Not effective liver stage parasites Moderately gameticidal Does not eliminate hypnozoites of P. vivax and P. ovale

Chloroquine is the drug of choice in the treatment of nonfalciparum and sensitive falciparum malaria

Mechanism of action It accumulates in the food vacuole of plasmodia and prevents polymerization of Hb breakdown products heme into hemozoin. Intracellular accumulation of heme is toxic to parasite

Adverse effects Pruritus is common, primarily in Africans. Uncommon side effects: - Peripheral neuropathy, retinal damage, auditory impairment, myocardial depression and toxic psychosis It can also precipitates porphyria attack Dosing after meals reduces some adverse effects.

Quinine and quinidine First line drugs for severe form of P. falciparum malaria Highly effective blood schizonticide against all four types of plasmodia Gameticidal against P. vivax and P. ovale Not active against liver stage parasites MAO unknown Resistance uncommon

Mechanism of action It 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.

Clinical uses IV quinidine standard therapy for severe P. falciparum malaria e.g. cerebral malaria Administered with cardiac monitoring Oral quinine sulphate + doxycycline (clindamycin in children) first line therapy for chloroquine-resistant uncomplicated falciparum malaria

Clinical uses BABESIOSIS Quinine is first-line therapy, in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial infections

Adverse effects Cinchonism  Tinnitus, visual disturbances, dizziness, nausea, flushing, headache Rapid IV infusion leads to hypotension RBCs hemolysis in G6PD deficient patient, blackwater fever is a rare fatal complication in quinine-sensitized person. Cardiotoxicity  ECG abnormalities with IV quinidine, hence cardiac monitoring

Recommended chemoprophylactic drug for use in most malaria-endemic regions with chloroquine- resistant strains of P. falciparum. Strong blood schizonticide against P falciparum and P vivax but it is not active against hepatic stages or gametocytes. The mechanism of action of mefloquine is unknown. Resistance is uncommon (except Thailand) Mefloquin

Adverse effects (More common with high doses) It can only be given orally because severe local irritation occurs with parenteral use neuropsychiatric toxicities (depression, psychosis, confusion, or seizures – contraindicated if these are already present) nausea, vomiting, diarrhea, abdominal pain, dizziness, headache. altered cardiac conduction, arrhythmias and bradycardia

Primaquin Effective against liver stage of all four species of plasmodia Drug of choice for the eradication of hypnozoites of P vivax and P ovale Gametocidal against all four species of plasmodia Weak blood schizonticidal activity

Mechanism of action It forms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants. The drug is tissue schizonticide and also limits malaria transmission by acting as gametocide.

Clinical uses For malaria – in combination with a blood schizonticide, usually chloroquine The combination of clindamycin and primaquine is an alternative regimen in the treatment of pneumocystosis (Pneumocystis jiroveci )

Adverse effects Generally well tolerated more common with higher dosages and when the drug is taken on an empty stomach Primaquine may cause hemolysis in persons with G6PD deficiency Infrequently causes nausea, abdominal cramps, and headache CI in pregnancy.

Atovaquone MAO? In plasmodia it appears to disrupt mitochondrial electron transport. It is a quinine dervitave Malarone, a combination of atovaquone and proguanil, is highly effective for both the treatment and chemoprophylaxis of falciparum malaria, and it is now approved for both indications in the USA

Clinical uses Malaria – treatment and prophylaxis P jiroveci pneumonia. Mild to moderate cases.

Adverse effects Generally well tolerated. Abdominal pain, nausea, vomiting, diarrhea, headache

Inhibitors of Folate synthesis Pyrimethamine Proguanil Both drugs act against erythrocytic forms of all four human malaria species. Both drugs also have some activity against hepatic forms of P. falciparum. Neither drug is effective against the persistent liver stages of P vivax or P ovale. Neither drug is adequately gametocidal

Clinical Uses MALARIA (uncomplicated cases only) –Fansidar, a combination of sulfadoxine and pyrimethamine TOXOPLASMOSIS PNEUMOCYSTOSIS

Amodiaquine Closely related to chloroquine Probably shares mechanisms of action and resistance It is low cost Important toxicities –agranulocytosis –aplastic anemia –hepatotoxicity World Health Organization lists amodiaquine plus artesunate as a recommended therapy for chloroquine resistant falciparum malaria in poor countries

Artemisinin, artemether, dihydroartemisinin Artemisinin and its derivatives are endoperoxide- containing compounds which represent a promising new class of antimalarial drugs In the presence of intra-parasitic iron, these drugs are converted into free radicals and other electrophilic intermediates which then alkylate specific malaria target proteins. Combinations of available derivatives and other antimalarial agents show promise both as first-l ine agents and in the treatment of severe disease It is not used as chemoprophylaxis because of the short half-life.

Drugs for amebiasis Tissue amebicide (chloroquine, emetine, metronidazole) act on organism in the bowel wall and the liver. Luminal amebicides(diloxinde furoate, idioquinol, paromomycin). For asymptomatic disease, diloxinde is the first choice. For mild to severe intestinal infection and amebic liver abcess metronidazole and tinidazole is used with luminal agent.

Metronidazole or tinidazole (better toxicity profile) drug of choice in the treatment of extra-luminal amebiasis treatment of choice for giardiasis treatment of choice for trichomoniasis Oral metronidazole readily absorbed and permeates all tissues by simple diffusion It undergoes reductive bio-activation of its nitro group by ferrodoxin to form reactive oxygen radical

Adverse effects Nausea, headache, dry mouth, or a metallic taste in the mouth occurs commonly Nausea and vomiting can occur if alcohol is ingested during therapy Taking the drug with meals lessens gastrointestinal irritation Most serious adverse effect includes neutropenia, dizziness and ataxia. Drug interaction includes disulfiram like reaction and potentiation of comarin anticoagulant effect.

Emetine Inhibit protein synthesis by blocking ribosomal movement along messenger RNA. Used as backup drugs for treatment of severe intestinal and liver amebiasis together with luminal agent in hospitalized patients. The drug can cause severe toxicity, including GI upset, muscle weakness, and cardiovascular dysfunction.

Diloxinde furoate Luminal Amebicides Commonly used as the sole agent for the treatment of asymptomatic amebiasis and is also useful in mild intestinal disease when used with other drug It is converted in the gut to diloxinde free base, which is active amebicide Toxic effect are mild restricted to GI symptoms and generally well tolerated

Luminal Amebicides Ninety percent of the drug is retained in the intestine and excreted in the feces. Active against trophozoites. MOA - unknown Active only in large bowel Should be taken with meals to limit GIT toxicity Adverse effects:  diarrhea, nausea, vomiting, abdominal pain, headache and thyroid enlargment. Iodoquinol

Paromomycin It is an aminoglycoside antibiotic used as a luminal agent and may be superior to diloxinde in asymptomatic infection. Not significantly absorbed from the GIT MOA: inhibition of protein synthesis Adverse effects: abdominal pain and diarrhea.

Treatment of leishmaniasis sodium stibogluconate (only injection) For all forms of the disease; cutaneous, mucocutanous and visceral leishmaniasis MAO – inhibtion of glycolsis or effects on nucleic acid metabolism Adverse effects : it is potentially cardiotoxic (QT prolongation). IM injections very painful – lead to sterile abscesses Alternative agents include pentamidine or miltofosine for visceral disease, fluconazole or metronidzole for cutaneous lesions and amphotericinB for mucocutanous disease

Treatment of trypanosomiasis Pentamidine:used to treat the hemolymphatic stage of T.gambiense and T.rhodesiense. The drug can not cross the BBB; so it is not used in the later stage of the disease Melarsoprol: inhibit enzyme sulfhydryl groups, it enter the CNS so it is the treatment of choice for African sleeping sickness. The drug can cause reactive encephalopathy Nifurtimox: drug of choice for American trypanosomiasis

Sumarin : used for early stage of African trypanosomiasis Eflornithine: suicide substrate for ornithine decarboxylase,it is effective in some forms of african tryposomiasis, the drug can penetrate the BBB.

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