Antiprotozoal Drugs

MALARIA

1. Malaria Malaria is the most important of the transmissible parasitic diseases. Over 90 million cases occur each year. DRUG-RESISTANT MALARIA Plasmodium falciparum is now resistant to chloroquine in many parts of the world. Areas of high risk for resistant parasites include Sub-Saharan Africa, Latin America, Oceania, and some parts of South-East Asia.

Hepatic cycle The incubation period of malaria is 10–35 days. Female anopheles mosquitoes require a blood meal for egg production and in the process of feeding they inject salivary fluid containing sporozoites into humans. Hepatic cycle Sporozoites enter liver cells where they develop into schizonts which form large numbers of merozoites which, usually after 5–16 days, are released into the circulation. persisting hepatic forms (hypnozoites)

Erythrocyte cycle Merozoites enter red cells where they develop into schizonts which form more merozoites which are released when the cells burst giving rise to the features of the clinical attack. The merozoites reenter red cells and the cycle is repeated.

Life cycle of malaria parasites Pl. falciparum Pl. malariae Pl. ovale Pl. vivax

▪ A patient with cerebral malaria Light micrograph of a cerebral capillary blocked with malarial parasitized erythrocytes ▪ A patient with cerebral malaria ▪ Morphological changes in erythrocytes

MALARIA Plasmodium species that infect humans: ► P falciparum (only 1 cycle of liver cell invasion) ► P malariae (only 1 cycle of liver cell invasion) ► P ovale ► P vivax

DRUGS FOR MALARIA ► Kill schizonts in the liver Primary tissue schizonticides (primaquine) ► Kill schizonts in the liver Blood schizonticides (chloroquine, quinine) ► Kill parasitic forms only in the erythrocyte Sporonticides (proguanil, pyrimethamine) ► Prevent sporogony and multiplication in the mosquito

CHLOROQUINE ▪ Rapidly absorbed (orally) ▪ Antacids → ↓ absorption of the drug ▪ Excreted largely unchanged in the urine

CHLOROQUINE Mechanism of action: ▪ Accumulates in the food vacuole of plasmodia ▪ Prevents polymerization heme to Hemozoin (Heme → hemoglobin breakdown product) ▪ Intracellular accumulation of heme is toxic to the parasite

CHLOROQUINE Resistance: ▪ Chloroquine → ↓ Intracellular accumulation (via↑activity of membrane "pumps“) ▪ P falciparum → ↓ Intra-vacuolar accumulation of chloroquine via a transporter encoded by the pfcrt gene (P falciparum chloroquine-resistance transporter)

CHLOROQUINE Clinical use Drug of choice for: ► Acute attacks of non-falciparum & sensitive falciparum malaria (Pregnancy) Chemoprophylaxis (except in regions where P falciparum is resistant) Autoimmune disorders (rheumatoid arthritis) ►Chloroquine & hydroxy-chloroquine

CHLOROQUINE Toxicity At low doses: ► Gastrointestinal irritation ► Skin rash ► Headaches

CHLOROQUINE Toxicity High doses: ▪ Severe skin lesions ▪ Peripheral neuropathies ▪ Myocardial depression ▪ Retinal damage (irreversible) Corneal deposits of chloroquine ▪ Auditory impairment ▪ Toxic psychosis ▪ Precipitate porphyria attacks

Quinine as cinchona bark was introduced into Europe from South America in 1633. It was used for all fevers, amongst them malaria. Further advance in the chemotherapy of malaria was delayed until 1880, when Charles Louis Alphonse Laveran, Prof. of Military Medicine in Paris (Nobel prize winner 1907) finally identified the parasites in the blood.

QUININE ► Quinine is rapidly absorbed (orally) Pharmacokinetics: ► Quinine is rapidly absorbed (orally) ► Metabolized before renal excretion ► In severe infections (I.V. administration)

QUININE Mechanism of action: ► Complexes with double-stranded to plasmodial DNA → prevent strand separation → block of DNA replication and transcription to RNA, prevent protein synthesis. Solely a blood schizonticide

QUININE Clinical use ▪ P falciparum infections resistant to chloroquine in patients who can tolerate oral treatment (main use) , Pregnancy ▪ Quinine + Doxycycline or Clindamycin → shorten the duration of therapy & limit toxicity

Quinidine ▪ Dextrorotatory stereoisomer of quinine ▪ I.V. for treatment of severe falciparum malaria (in United States) ▪ The drugs should not be used routinely for prophylaxis (To delay emergence of resistance)

Cinchonism: (commonly) QUININE Toxicity Cinchonism: (commonly) ▪ Gastrointestinal distress ▪ Headache ▪ Vertigo ▪ Blurred vision ▪ Tinnitus

▪ Hematotoxic effects: QUININE Toxicity ▪ Hematotoxic effects: ► Hemolysis (in G6PD-deficient patients) ► Black-water fever (intravascular hemolysis) (rare and fatal in quinine-sensitized persons)

QUININE Toxicity ▪ Severe overdose: ▪ Contraindication: ► Disturbances in cardiac conduction (resemble quinidine toxicity) ▪ Contraindication: ► visual or auditory problems

Wild Quinine

Quinine

Quinine

Quinine Dyhydrochloride Quinine 324 mg Quinine 200 mg

MEFLOQUINE Clinical uses ▪ Prophylaxis: ► In all geographical areas with chloroquine resistance (Pregnancy) ▪ Alternative drug to quinine: ► In acute attacks from P falciparum ▪ Resistance: ► Emerged in regions of South-east Asia

▪ Adverse effects: (Common) MEFLOQUINE Toxicity ▪ Adverse effects: (Common) ► Gastrointestinal distress ► Skin rash ► Headache ► Dizziness

▪ Adverse effects: (high doses) MEFLOQUINE Toxicity ▪ Adverse effects: (high doses) ► Cardiac conduction defects ► Psychiatric disorders ► Neurologic symptoms ► Seizures

▪ Contraindication: MEFLOQUINE patient with a history of epilepsy psychiatric disorders cardiac conduction defects arrhythmia

PRIMAQUINE Mechanism of action Primaquine forms quinoline-quinone metabolites → electron-transferring → cellular oxidants Tissue schizonticide Limits malaria transmission (by acting as a gametocide)

PRIMAQUINE Clinical use Eradicates liver stages of P vivax and P ovale Used in conjunction with a blood schizonticide Not active alone in acute attacks of vivax and ovale malaria A 14-day course of primaquine is standard after treatment with chloroquine

PRIMAQUINE Toxicity Gastrointestinal distress Pruritus Headaches Methemoglobinemia Hemolysis (in G6PD-deficient patients)

PRIMAQUINE Contraindication ▪ In pregnancy (the fetus is relatively G6PD-deficient and thus at risk of hemolysis) ▪ In G6PD-deficient patients ▪ In patients with history of Methemoglobinemia

Primaquine

Antifolate group: (half life> 100 h) ANTI FOLATE DRUGS Antifolate group: (half life> 100 h) ▪ Pyrimethamine ▪ Proguanil (chloroguanide) [half-life (12-16 h)] ▪ Sulfadoxine ▪ Dapsone

ANTI FOLATE DRUGS Mechanisms of action: ▪ Sulfonamides → Anti-metabolites of PABA ▪ Inhibiting dihydropteroate synthase → Block folic acid synthesis in certain protozoans ▪ Proguanil → Bioactivated to cycloguanil ▪ Pyrimethamine & Cycloguanil → Selective inhibitors of protozoan dihydrofolate reductases ▪ Pyrimethamine + Sulfadoxine → Synergistic anti-malarial effects (sequential blockade of 2 steps in folic acid synthesis)

ANTI FOLATE DRUGS Clinical use Blood schizonticides (mainly against P falciparum) Pyrimethamine + Sulfadoxine → Fansidar ▪ Treatment of chloroquine-resistant forms of species ▪ Onset of activity is slow Proguanil + Atovaquone → Malarone ▪ Chemoprophylaxis of chloroquine-resistant malaria (First-line choice ) ▪ Used against mefloquine-resistant falciparum strains

Fansidar Adverse Effects Most patients tolerate pyrimethamine and proguanil well. GI symptoms, skin rashes, and itching are rare. Mouth ulcers and alopecia ( proguanil) Fansidar is no longer recommended for chemoprophylaxis because of uncommon but severe cutaneous reactions, including erythema multiforme Stevens-Johnson syndrome life-threatening skin condition Erythema multiforme is a skin disorder due to an allergic reaction or infection. Symptoms: Fever; General ill feeling; Itching of the skin; Joint aches; Multiple skin lesions: Start quickly and may return; May spread

Stevens–Johnson syndrome

Atovaquone as a component of Malarone (atovaquane+ proguanil ) is recommended for treatment and prevention of malaria. absorption is increased by fatty food an alternative therapy (mefloquine and doxycycline)

Malarone Adverse effects abdominal pain nausea, vomiting diarrhea, headache, and rash Reversible elevations in liver enzymes

OTHER ANTIMALARIAL DRUGS

Doxycycline ▪ Chemoprophylactic for travelers to geographical areas (both chloroquine-and mefloquine-resistant P falciparum)

Amodiaquine ▪ is closely related to chloroquine, widely used to treat malaria in many countries because: ► Low cost ► Effectiveness against chloroquine-resistant strains of P falciparum. (some geographical areas)

Amodiaquine: ▪ Hematological toxicity: ► Agranulocytosis ► Aplastic anemia Hepatotoxicity, have limited its use.

Halofantrine ▪ Mechanism of action is unknown ▪ Active against erythrocytic stages of all 4 human malaria species (including chloroquine-resistant falciparum) ▪ Not used for chemoprophylaxis because: ► Potential cardiotoxicity (QT prolongation) ► Embryotoxicity

Artesunate & Artemether ▪ Artemisinin derivatives ▪ Metabolized in the food vacuole of the parasite → Forming toxic free radicals ▪ Blood schizonticides active against P falciparum (including multi-drug- resistant strains) ▪ Not used for chemoprophylaxis (because of their short half-lives)

Artesunate + Mefloquine Tab 200mg 250mg

DRUGS FOR AMEBIASIS

Amoebiasis Infection occurs when mature cysts of E. histolytica (Entamoeba )are ingested and pass into the colon where they divide into trophozoites. Amoebiasis occurs in two forms: Bowel lumen amoebiasis is asymptomatic and trophozoites (noninfective) and cysts (infective) are passed into the faeces Tissue-invading amoebiasis gives rise to dysentery, hepatic amoebiasis, and liver abscess Dysentery is an intestinal inflammation, especially in the colon, that can lead to severe diarrhea with mucus or blood in the feces

DRUGS FOR AMEBIASIS ▪ Metronidazole ▪ Emetines ▪ Luminal amebicides: Tissue amebicides: (act on organisms in the liver) ▪ Metronidazole ▪ Emetines ▪ Chloroquine ▪ Luminal amebicides: (act only in the lumen of the bowel) ▪ Diloxanide furoate ▪ Iodoquinol ▪ Paromomycin

DRUGS FOR AMEBIASIS ▪ Diloxanide furoate → For asymptomatic disease (first choice) ▪ Metronidazole + diloxanide furoate, iodoquinol, or paromomycin → For mild to severe intestinal infection

Diloxanide furoate It is an effective luminal amebicide 90% of the diloxanide is rapidly absorbed Then conjugated to form the glucuronide, which is promptly excreted in the urine The unabsorbed diloxanide is the active antiamebic substance flatulence, pruritus, and urticaria

IODOQUINOl ▪ Thyroid enlargement ▪ Neurotoxic effects: Alternative drug for mild-to-severe intestinal infections Adverse gastrointestinal effects are common but usually mild Systemic absorption after high doses: ▪ Thyroid enlargement ▪ Neurotoxic effects: ► Peripheral neuropathy ► Visual dysfunction

METRONIDAZOLE Mechanism of action: ▪ Reductive bioactivation of its nitro group by ferredoxin (present in anaerobic parasites) → Form reactive cytotoxic products (DNA damage)

METRONIDAZOLE Clinical use Drug of choice in: ▪ Severe intestinal wall disease ▪ Hepatic abscess • Usually used with a luminal amebicide

METRONIDAZOLE Clinical use Other important clinical uses: ▪ Treatment of trichomoniasis ▪ Giardiasis (DOC) ▪ Infections caused by: ► Gardnerella vaginalis ► Anaerobic bacteria (C difficile) ▪ Used in combination regimens for gastrointestinal ulcers associated with H pylori (C difficile) Clostridium difficile

METRONIDAZOLE Toxicity ► Gastrointestinal irritation ► Headache ► Dark coloration of urine ▪ More serious toxicity: ► Leukopenia ► Dizziness ► Ataxia

METRONIDAZOLE ▪ Drug interactions: ► Disulfiram-like reaction with ethanol ► Potentiation of coumarin anticoagulant effects ▪ Safety of metronidazole in pregnancy and in nursing mothers has not been established Disulfurim is a type of medicine called an aldehyde dehydrogenase inhibitor. If someone taking this medicine drinks alcohol, its reaction quickly causes a severe unpleasantness and it is potentially dangerous. Knowledge of this fact can help to stop people from drinking. Read more: What does Disulfiram reaction mean? | Answerbag http://www.answerbag.com/q_view/985350#ixzz2Fr9Vs64i

Emetine & Dehydroemetine Severe amebiasis requires effective therapy which metronidazole cannot be used. inhibits protein synthesis diarrhea, nausea, and vomiting; muscle weakness Serious toxicities : cardiac arrhythmias, heart failure and hypotension

Paromomycin Paromomycin sulfate is an aminoglycoside (oral ) Therapy of intestinal parasitic infections For the treatment of visceral leishmaniasis Adverse effects: ototoxicity reversible liver enzyme elevations

African trypanosomiasis (sleeping disease) The organisms are transmitted by bites of tsetse flies which inhabit shaded areas along streams and rivers. (Congo) Treatment: Suramin (Pentamidine) is effective during the early stages After neurological manifestations:melarsoprol

Suramin is a sulfated naphthylamine (IV) It is the first-line therapy for early hemolymphatic East African trypanosomiasis because it does not enter the CNS, it is not effective against advanced disease. The drug's mechanism of action is unknown. Suramin can be used for chemoprophylaxis against African trypanosomiasis.

Adverse effects of Suramin Immediate reactions: fatigue, N, V Rarely: seizures, shock, and death Later reactions: fever, rash, headache, paresthesias, neuropathies, renal abnormalities including proteinuria, chronic diarrhea, hemolytic anemia, and agranulocytosis.

Melarsoprol is a trivalent arsenical (IV) first-line therapy for advanced CNS African tryp Immediate adverse effects: fever, vomiting, abdominal pain, and arthralgias. The most important toxicity is a : reactive encephalopathy due to disruption of trypanosomes in the CNS. Common consequences of the encephalopathy include cerebral edema, seizures, coma, and death. Disruption :پاره شدن

Leishmaniasis Visceral leishmaniasis is caused mainly by Leishmania donovani in the Indian subcontinent and East Africa. Treatment: Sodium stibogluconate (DOC) and meglumine antimoniate Pentamidine is an alternative to sodium stibogluconate in the treatment of visceral leishmaniasis

(Muco-) Cutaneous leishmaniasis is caused mainly by Leishmania tropica, L. major, and L. donovani. Treatment: Mild lesions heal spontaneously, antimonials may be injected intralesionally.

Sodium stibogluconate Pentavalent antimonials including sodium stibogluconate (pentostam) and meglumine antimonate: first-line agents for cutaneous and visceral leishmaniasis IM injections can be very painful and lead to sterile abscesses. Electrocardiographic changes : T-wave changes and QT prolongation.) reversible( But continued therapy may lead to dangerous arrhythmias.

Sodium stibogluconate Adverse Effects GI symptoms fever headache Myalgias arthralgias rash

Pentamidine Adverse Effects is a highly toxic drug IV administration can lead to: Severe hypotension Tachycardia Dizziness Dyspnea

Toxoplasmosis T. gondii, an obligate intracellular protozoan, is found worldwide in humans and in many species of animals and birds. The definitive hosts are cats. Humans are infected after ingestion of cysts in raw or under- cooked meat, ingestion of oocysts in food or water contaminated by cats, transplacental transmission of trophozoites or, rarely, direct inoculation of trophozoites via blood transfusion or organ transplantation.

Life cycle of Toxoplasma gondii

Toxoplasmosis Treatments: Pyrimethamine with sulfadiazine for active toxoplasmosis in immunodeficient patients Alternatives include pyrimethamine with Clindamycin folinic acid is used to counteract the inevitable megaloblastic anaemia.

Pneumocystis Treatment: Pneumocystis jiroveci ( carinii) the causative agent of interstitial plasma cell pneumonia, which can also cause extrapulmonary disease in immunocompromised patients (AIDS, etc) . Treatment: Co-trioxazole: i.v./p.o. in high daily doses trimethoprim plus sulfamethoxazole

Adverse Effects of trimethoprim plus sulfamethoxazole N,V, fever, rash, leukopenia, hyponatremia, elevated hepatic enzymes, anemia, and thrombocytopenia. Less common effects include severe skin reactions, mental status changes, pancreatitis, and hypocalcemia. is also the standard chemoprophylactic drug for the prevention of P jiroveci infection .

Giardiasis Treatment: It is a common infection of the human small intestine with the protozoan Giardia lamblia, spread via contaminated food or water, or by direct person-to-person contact. Treatment: Metronidazole

Antimalarial agents ► Mefloquine ► Primaquine ► Quinine ► Anti-folates ► Chloroquine ► Mefloquine ► Primaquine ► Quinine ► Anti-folates ► Others

Drugs for Amebiasis ► Diloxanide ► Emetine ► lodoquinol ► Metronidazole ► Diloxanide ► Emetine ► lodoquinol