Antiprotozoal Drugs (PDF)

Antiprotozoal drugs (I) Protozoa are motile, unicellular eukaryotic organisms. Protozoa may be conveniently classified into four main groups based on their mode of locomotion: amoebas, flagellates, and Sporozoa, but the final group comprises ciliates and other organisms of uncertain affiliation, su...

Antiprotozoal drugs (I) Protozoa are motile, unicellular eukaryotic organisms. Protozoa may be conveniently classified into four main groups based on their mode of locomotion: amoebas, flagellates, and Sporozoa, but the final group comprises ciliates and other organisms of uncertain affiliation, such as the Pneumocystis jirovecii MALARIA AND ANTIMALARIAL DRUGS: The parasite's life cycle consists of a sexual cycle, which occurs in the female Anopheles mosquito, and an asexual cycle, which occurs in humans. - An Anopheles 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. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease. - Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, developing into infective sporozoites. 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, a treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant 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 The symptoms of malaria include fever, shivering, pain in the joints, headache, repeated vomiting, generalized convulsions, and coma. Symptoms become apparent only 7–9 days after being bitten by an infected mosquito. By far the most dangerous parasite is P. falciparum The WHO reports that half the world’s population is at risk from malaria and it remains a significant public health problem in more than 100 countries. In 2015, there were an estimated 212 million cases and >400,000 deaths from the disease. More than 90% of these occurred in sub-Saharan Africa, and most of the victim's children 1 Classification of antimalarial drugs: Drug Class Chloroquine 4-Aminoquinoline Amodiaquine Piperaquine Bisquinoline Quinine Quinidine Quinoline methanol Mefloquine Primaquine 8-Aminoquinoline Chloroquine: Since the 1940s, chloroquine has been the drug of choice for treating and chemoprophylaxis of malaria. However, drug resistance has seriously compromised its usefulness against P falciparum. Nevertheless, it remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites. 2 Chloroquine is a synthetic 4-aminoquinoline formulated as a phosphate salt for oral use. It is rapidly and almost completely absorbed from the gastrointestinal tract, reaches maximum plasma concentrations in about 3 hours, and is rapidly distributed to the tissues. It has a very large apparent volume of distribution of 100–1000 L/kg and is slowly released from tissues and metabolized. Chloroquine is principally excreted in the urine with an initial half-life of 3–5 days but a much longer terminal elimination half-life of 1–2 months. chloroquine is a highly effective blood schizonticide. It is also 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. Mechanism of Action: Chloroquine acts by concentrating in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, thus eliciting parasite toxicity due to the buildup of free heme. Clinical Uses: 1. Treatment of non-falciparum and sensitive falciparum malaria. It rapidly terminates fever (in 24–48 hours) and clears parasitemia (in 48–72 hours) Chloroquine does not eliminate dormant liver forms of P vivax and P ovale, and for that reason, primaquine must be added for the radical cure of these species. 2. Chemoprophylaxis Chloroquine is the preferred chemo-prophylactic agent in malarious regions without resistant falciparum malaria. 3. Amebic Liver Abscess: Chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole 4. Rheumatoid arthritis; the metabolite hydroxychloroquine has a disease-modifying effect on rheumatoid arthritis Adverse Effects: Chloroquine is usually very well tolerated, even with prolonged use. Pruritus is common. Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and Dosing after meals may reduce some adverse effects. hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons. The long-term administration of high doses of chloroquine for rheumatologic diseases can result in irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy. Large intramuscular injections or rapid intravenous infusions of chloroquine hydrochloride can result in severe hypotension and respiratory and cardiac arrest. 3 Piperaquine: Piperaquine is a bisquinoline that was used widely to treat chloroquine-resistant falciparum malaria in China in the 1970s through the 1980s, but its use waned after resistance became widespread. Recently, piperaquine has been combined with dihydroartemisinin in co- formulated tablets (Artekin, Duocotexcin) that have shown excellent efficacy and safety for the treatment of falciparum malaria, without apparent drug resistance. Piperaquine has a longer half-life (~ 28 days) leading to a longer period of post-treatment prophylaxis with dihydroartemisinin-piperaquine than with the other leading artemisinin-based combinations Quinine and quinidine: Quinine and quinidine remain first-line therapies for falciparum malaria—especially severe disease. Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. Quinidine, the dextrorotatory stereoisomer of quinine, is as effective as parenteral quinine in the treatment of severe falciparum malaria. After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1–3 hours, and is widely distributed in body tissues. The use of a loading dose in severe malaria allows the achievement of peak levels within a few hours. The pharmacokinetics of quinine varies among populations. Individuals with malaria develop higher plasma levels of the drug than healthy controls, but toxicity is not increased, apparently because of increased protein binding. The half-life of quinine also is longer in those with severe malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter half-life than quinine, mostly as a result of decreased protein binding. Quinine is primarily metabolized in the liver and excreted in the urine. Quinine is a rapid-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. Its mechanism of action is the same as that of chloroquine, but quinine is not so extensively concentrated in the plasmodium as chloroquine, so other mechanisms could also be involved Clinical Uses: 1. Parenteral Treatment of Severe Falciparum Malaria; Quinine can be administered slowly intravenously or, in a dilute solution, intramuscularly, treatment should begin with a loading dose to rapidly achieve effective plasma concentrations. Oral Treatment of Falciparum Malaria 4 2. Quinine sulfate is an appropriate first-line therapy for uncomplicated falciparum malaria. Quinine is commonly used with a second drug (most often doxycycline or, in children, clindamycin) to shorten quinine's duration of use (usually to 3 days) and limit toxicity. Unwanted effects 1. Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a constellation of symptoms termed cinchonism. 2. Hypersensitivity reactions include skin rashes, urticaria, angioedema, and bronchospasm. 3. Hematologic abnormalities include hemolysis (especially with G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia. 4. hypoglycemia through stimulation of insulin release; this is a particular problem in severe infections and in pregnant patients, who have increased insulin sensitivity. 5. Quinine can stimulate uterine contractions, especially in the third trimester. 6. Intravenous infusions of the drugs may cause thrombophlebitis. 7. Severe hypotension can follow too-rapid intravenous infusions of quinine or quinidine. Because of its cardiac toxicity and the relative unpredictability of its pharmacokinetics, intravenous quinidine should be administered with cardiac monitoring. 8. Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria in It appears to be due to a hypersensitivity reaction to the drug, although its pathogenesis is uncertain. Mefloquine: Mefloquine is an effective therapy for many chloroquine-resistant strains of P falciparum and against other species. Although toxicity is a concern, mefloquine is one of the recommended chemo-prophylactic drugs for use in most malaria-endemic regions with chloroquine-resistant strains. Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-dose treatment regimen. The terminal elimination half-life is about 20 days, allowing weekly dosing for chemoprophylaxis. With weekly dosing, steady-state drug levels are reached over several weeks; this interval can be shortened to 4 days by beginning a course with three consecutive daily doses of 250 mg, although this is not standard practice. Mefloquine and acid metabolites of the drug are slowly excreted, mainly in the feces. The drug can be detected in the blood for months after the completion of therapy. 5 Mefloquine has strong blood schizonticide activity against P falciparum and P vivax, but it is not active against hepatic stages or gametocytes. The mechanism of action of mefloquine is unknown. Clinical Uses: 1. Chemo-prophylaxis: Mefloquine is effective in prophylaxis against most strains of P falciparum and probably all other human malarial species. 2. Treatment: Mefloquine is effective in treating most falciparum malaria. The drug is not appropriate for treating individuals with severe or complicated malaria, since quinine, quinidine, and artemisinin are more rapidly active since drug resistance is less likely with those agents. The combination of artesunate plus mefloquine showed excellent antimalarial efficacy. Adverse Effects: - Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. - Neuropsychiatric toxicities: giddiness, confusion, dysphoria and insomnia seizures and psychosis, - Leukocytosis, thrombocytopenia, and aminotransferase elevations have - Mefloquine can also alter cardiac conduction, and arrhythmias and bradycardia have been reported - Mefloquine is contraindicated in pregnant women or in those liable to become pregnant within 3 months of stopping the drug, because of its long half-life and uncertainty about its teratogenic potential. Primaquine: Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P ovale and can also be used for chemoprophylaxis against all malarial species. Etaquine and tafenoquine are more active and slowly metabolized analogs of primaquine. Primaquine phosphate is a synthetic 8-aminoquinoline The drug is well absorbed orally, reaching peak plasma levels in 1–2 hours. The plasma half-life is 3–8 hours. Primaquine is widely distributed to the tissues, but only a small amount is bound there. It is rapidly metabolized and excreted in the urine. Its three major metabolites appear to have less antimalarial activity but more potential for inducing hemolysis than the parent compound. Primaquine is active against the hepatic stages of all human malaria parasites. It is the only available agent active against the dormant hypnozoite stages of P vivax and P ovale. Primaquine is also gametocidal against the four human malaria species. 6 Primaquine acts against erythrocytic stage parasites, but this activity is too weak to play an important role. The mechanism of antimalarial action is unknown. Clinical Uses: 1. Radical Cure of Acute Vivax and Ovale Malaria (14-day course of primaquine is given). 2. Terminal Prophylaxis of Vivax and Ovale Malaria 3. Chemoprophylaxis of Malaria 4. Gametocidal Action A single dose of primaquine (45 mg base) can be used as a control measure to render P falciparum gametocytes noninfective to mosquitoes. This therapy is of no clinical benefit to the patient but will disrupt transmission. 5. Pneumocystis jiroveci Infection: The combination of clindamycin and primaquine is an alternative regimen in the treatment of pneumocystosis, particularly mild to moderate disease. Adverse Effects: Primaquine in recommended doses is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common with higher dosages and when the drug is taken on an empty stomach. More serious but rare adverse effects are leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. especially in persons with G6PD deficiency or other hereditary metabolic defects. Atovaquone: Atovaquone, a hydroxynaphthoquinone was initially developed as an antimalarial agent, for the treatment of mild to moderate P jiroveci pneumonia. The drug is only administered orally. Its bioavailability is low and erratic, but absorption is increased by fatty food. The drug is heavily protein-bound and has a half-life of 2–3 days. Most of the drug is eliminated unchanged in the feces. Atovaquone acts against plasmodia by disrupting mitochondrial electron transport. It is active against tissue and erythrocytic schizonts. Malarone, a fixed combination of atovaquone (250 mg) and proguanil (100 mg), is highly effective for both the treatment and chemoprophylaxis of falciparum malaria, 7 Malarone must be taken daily. It has an advantage over mefloquine and doxycycline in requiring shorter periods of treatment before and after the period at risk for malaria transmission. Halofantrine & Lumefantrine: Halofantrine hydrochloride, a phenanthrene-methanol, is effective against erythrocytic (but not other) stages of all four human malaria species. Oral absorption is variable and is enhanced with food. Because of toxicity concerns, it should not be taken with meals. Plasma levels peak 16 hours after dosing, and the half-life is about 4 days. Excretion is mainly in the feces. The mechanism of action of halofantrine is unknown. Halofantrine (three 500-mg doses at 6-hour intervals, repeated in 1 week for nonimmune individuals) is rapidly effective against most strains of P falciparum, but its use is limited by irregular absorption and cardiac toxicity. It should not be used for chemoprophylaxis. Halofantrine is generally well tolerated. The most common adverse effects are abdominal pain, diarrhea, vomiting, cough, rash, headache, pruritus, and elevated liver enzymes. Of greater concern, the drug alters cardiac conduction, with dose-related prolongation of QT and PR intervals. Lumefantrine, an aryl alcohol related to halofantrine, is available only as a fixed-dose combination with artemether (Coartem), which is now the first-line therapy for uncomplicated falciparum malaria in many countries in Africa. The half-life of lumefantrine, when used in combination, is 4.5 hours. Drug levels may be altered by interactions with other drugs, including those that affect CYP3A4 metabolism Coartem should be administered with fatty food to maximize antimalarial efficacy. Coartem is highly effective in the treatment of falciparum malaria when administered twice daily for 3 days. Coartem can cause minor prolongation of the QT interval, but this appears to be clinically insignificant. The most commonly reported adverse events in drug trials have been gastrointestinal disturbances, headache, dizziness, rash, and pruritus. 8 Inhibitors of Folate Synthesis: Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, in the treatment and prevention of malaria. - Pyrimethamine is a 2,4-diaminopyrimidine related to trimethoprim. - Fansidar, a fixed combination of the sulfonamide sulfadoxine (500 mg per tablet) and pyrimethamine (25 mg per tablet),. - Proguanil is a biguanide derivative. Pyrimethamine reaches peak plasma levels 2–6 hours after an oral dose, is bound to plasma proteins, and has an elimination half-life of about 3.5 days. Pyrimethamine is extensively metabolized before excretion Proguanil reaches peak plasma levels about 5 hours after an oral dose and has an elimination half-life of about 16 hours. Proguanil is a prodrug; only its triazine metabolite, cycloguanil, is active. Therefore, proguanil must be administered daily for chemoprophylaxis, whereas pyrimethamine can be given once a week. Fansidar is well absorbed. Its components display peak plasma levels within 2–8 hours and are excreted mainly by the kidneys. The average half-life of sulfadoxine is about 170 hours. Mechanism of Action Pyrimethamine and proguanil selectively inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for the synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase. combinations of inhibitors of these two enzymes provide synergistic activity. Clinical Uses: 1. Chemoprophylaxis in combination regimens. 2. Intermittent Preventive Therapy: A new strategy for malaria control is intermittent preventive therapy, in which high-risk patients receive intermittent treatment for malaria, regardless of their infection status treatment of 3. Chloroquine-Resistant Falciparum Malaria 4. Toxoplasmosis: Pyrimethamine, in combination with sulfadiazine, is a first-line therapy in the treatment of toxoplasmosis, including acute infection, congenital infection, and disease in immunocompromised patients. 4. Pneumocystosis: Pneumocystis jiroveci infection 9 Artemisinin & Its Derivatives: Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide, the active component of herbal medicine that has been used as an antipyretic in China for over 2000 years. Artemisinin is insoluble and can only be used orally. Analogs have been synthesized to increase solubility and improve antimalarial efficacy. The most important of these analogs are: - artesunate (water-soluble; useful for oral, intravenous, intramuscular, and rectal administration), - artemether (lipid-soluble; useful for oral, intramuscular, and rectal administration), and - dihydroartemisinin (water-soluble; useful for oral administration). Artemisinin and its analogs are rapidly absorbed, with peak plasma levels occurring in 1–2 hours and half-lives of 1–3 hours after oral administration. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite dihydroartemisinin. Artemisinin monotherapy for the treatment of uncomplicated malaria is now strongly discouraged. Rather, co-formulated artemisinin-based combination therapies are recommended to improve efficacy and prevent the selection of artemisinin-resistant parasites. Artemisinin and its analogs are very rapidly acting blood schizonticides against all human malaria parasites. Artemisinins do not affect hepatic stages. The antimalarial activity of artemisinins may result from: - the production of free radicals that follow the iron-catalyzed cleavage of the artemisinin endoperoxide bridge in the parasite food vacuole - or from inhibition of a parasite calcium ATPase. Artemisinin resistance is not yet an important problem, but P falciparum isolates with diminished in vitro susceptibility to artemether have recently been described. WHO Recommendations for the Treatment of Falciparum Malaria. Regimen Artemether-lumefantrine (Coartem, Riamet) Artesunate-amodiaquine (ASAQ, Arsucam) Artesunate-mefloquine Artesunate-sulfadoxine-pyrimethamine Amodiaquine-sulfadoxine-pyrimethamine 10 Antibiotics: Several antibiotics in addition to the folate antagonists and sulfonamides are modestly active antimalarials. The antibiotics that are bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like organelle, the apicoplast. None of the antibiotics should be used as single agents in the treatment of malaria because their action is much slower than that of standard antimalarials. Tetracycline and doxycycline are active against erythrocytic schizonts of all human malaria parasites. They are not active against liver stages. Doxycycline is used in the treatment of falciparum malaria in conjunction with quinine, allowing a shorter and better-tolerated course of that drug. Doxycycline is also used to complete treatment courses after initial treatment of severe malaria with intravenous quinine, quinidine, or artesunate. In all of these cases, a 1-week treatment course of doxycycline is carried out. Doxycycline has also become a standard chemoprophylactic drug, especially for use in areas of Southeast Asia with high rates of resistance to other antimalarials, including mefloquine. Doxycycline's adverse effects include gastrointestinal symptoms, candidal vaginitis, and photosensitivity. Clindamycin is slowly active against erythrocytic schizonts and can be used after treatment courses of quinine, quinidine, or artesunate in those for whom doxycycline is not recommended, such as children and pregnant women. Azithromycin also has antimalarial activity and is now under study as an alternative chemoprophylactic drug. Antimalarial activity of fluoroquinolones has been demonstrated, but efficacy for the therapy or chemoprophylaxis of malaria has been suboptimal. Antibiotics also are active against other protozoans. Tetracycline and erythromycin are alternative therapies for the treatment of intestinal amebiasis. Clindamycin, in combination with other agents, is effective therapy for toxoplasmosis, pneumocystosis, and babesiosis. 11 Spiramycin is a macrolide antibiotic that is used to treat primary toxoplasmosis acquired during pregnancy. Treatment lowers the risk of the development of congenital toxoplasmosis. 12