| amebicides classes | Tissue amebicides (chloroquine, emetines, metronidazole, tinidazole) act on organisms in the bowel wall and the liver;
luminal amebicides (diloxanide furoate, iodoquinol, paromomycin) act only in the lumen of the bowel. The choice of a drug depends on the form of amebiasis.
mixed have both action however luminal dose is too low for action |
| drug of choice amebiosis | For asymptomatic disease, diloxanide furoate is the first choice. For mild-to-severe intestinal infection, metronidazole or tinidazole is used with a luminal agent, and this regimen is recommended in amebic hepatic abscess and other extraintestinal disease |
| Diloxanide Furoate | commonly used as the sole agent for the treatment of asymptomatic amebiasis and is also useful in mild intestinal disease when used with other drugs. It is converted in the gut to the diloxanide freebase form, which is the active amebicide. Toxic effects are mild and are usually restricted to gastrointestinal symptoms. |
| enmetines and dehydroemetine | Emetine and dehydroemetine inhibit protein synthesis by blocking ribosomal movement along messenger RNA and blocking chain elongation. These drugs are used parenterally (subcutaneously or intramuscularly) as backup drugs for treatment of severe intestinal or hepatic amebiasis together with a luminal agent in hospitalized patients. The drugs may cause severe toxicity, including gastrointestinal distress, muscle weakness, and cardiovascular dysfunction (arrhythmias and congestive heart failure), neuromuscular weakness, dizziness, rashes. The drugs are restricted to use in severe amebiasis when metronidazole cannot be used.Intramuscular injection is the preferred route. Emetine is concentrated in the liver, where it persists for a month after a single dose. It is slowly metabolized and excreted, and it can accumulate. Its half-life in plasma is 5 days. The use of these ipecac alkaloids is limited by their toxicities (dehydroemetine is less toxic than emetine), and close clinical observation is necessary when these drugs are administered. They should not be taken for more than 5 days. |
| iodoquinol | Iodoquinol, a halogenated hydroxyquinoline, is an orally active luminal amebicide used as an alternative to diloxanide for mildto-severe intestinal infections. Adverse gastrointestinal effects are common but usually mild, especially when taken with meals.Systemic absorption after high doses may lead to thyroid enlargement, skin reactions due to iodine toxicity and possibly neurotoxic effects, including peripheral neuropathy and visual dysfunction. It is a halogenated 8-hydroxy quinolone, is amebicidal against E. histolytica and is effective against the luminal trophozoite and cyst forms. Side effects from iodoquinol include rash, diarrhea, and dose-related peripheral neuropathy, including a rare optic neuritis. Long-term use of this drug should be avoided. |
| Metronidazole and Tinidazole pharmacokinetics | Metronidazole and tinidazole are effective orally and distributed widely to tissues. The half-life of metronidazole is 6–8h, and that of tinidazole 12–14 h. Elimination of the drugs requires hepatic metabolism. For the treatment of amebiasis, metronidazole is usually administered with a luminal amebicide, such as iodoquinol or paromomycin. This combination provides cure rates of greater than 90 percent. Metronidazole distributes well throughout body tissues and fluids. Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk, and cerebrospinal fluid (CSF). Metabolism of the drug depends on hepatic oxidation of the metronidazole side chain by mixed-function oxidase, followed by glucuronylation. Therefore, concomitant treatment with inducers of this enzymatic system, such as phenobarbital, enhances the rate of metabolism. Conversely, those drugs that inhibit this system, such as cimetidine, prolong the plasma half-life of metronidazole. The drug accumulates in patients with severe hepatic disease. The parent drug and its metabolites are excreted in the urine. |
| Metronidazole and Tinidazole mechanism of action | 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. Some anaerobic protozoal parasites (including amebas) possess ferrodoxin-like, low-redox-potential, electron-transport proteins that participate in metabolic electron removal reactions. The nitro group of metronidazole is able to serve as an electron acceptor, forming reduced cytotoxic compounds that bind to proteins and DNA, resulting in cell death. |
| Metronidazole and Tinidazole clinical use | 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. The duration of treatment required with metronidazole is longer than with tinidazole. Metronidazole is the drug of choice for trichomoniasis: tinidazole may be effective against some metronidazole-resistant organisms. 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. Metronidazole a nitroimidazole, is the mixed amebicide of choice for treating amebic infections and kills the E. histolytica trophozoites. [Note: Metronidazole also finds extensive use in the treatment of infections caused by anaerobic cocci, and anaerobic gramnegative bacilli (for example, Bacteroides species). Metronidazole is the drug of choice for the treatment of pseudomembranous colitis caused by the anaerobic, gram-positive bacillus Clostridium difficile and is also effective in the treatment of brain abscesses caused by these organisms.] |
| Metronidazole and Tinidazole toxicity | Adverse effects of metronidazole include gastrointestinal irritation epigastric distress, and abdominal cramps (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. Safety of metronidazole and tinidazole in pregnancy and in nursing mothers has not been established. An unpleasant, metallic taste is commonly experienced with metronidazole. Other effects include oral moniliasis (yeast infection of the mouth) and, rarely, neurotoxicologic problems, such as dizziness, vertigo, and numbness or paresthesias in the peripheral nervous system. [Note: The latter are reasons for discontinuing metronidazole.]Resistance to metronidazole is not a therapeutic problem, although strains of trichomonads resistant to the drug have been reported. |
| Paromomycin | This drug is an aminoglycoside antibiotic used as a luminal amebicide and may be superior to diloxanide in asymptomatic infection. Paromomycin may also have some efficacy against cryptosporidiosis in the AIDS patient and in leishmaniasis. Systemic absorption in renal insufficiency may lead to headaches, dizziness, rashes, and arthralgia. Tetracyclines (eg, doxycycline) are sometimes used with a luminal amebicide in mild intestinal disease. is only effective against the intestinal (luminal) forms of E. histolytica and tapeworm, because it is not significantly absorbed from the gastrointestinal tract. It is an alternative agent for cryptosporidiosis. Paramomycin is directly amebicidal and also exerts its antiamebic actions by reducing the population of intestinal flora. Its direct amebicidal action is probably due to the effects it has on cell membranes, causing leakage. Very little of the drug is absorbed on oral ingestion, but that which is absorbed is excreted in urine. Gastrointestinal distress and diarrhea are the principal adverse effects. |
| Nitazoxanide | This agent has activity against various protozoans (including Entamoeba) and helminths. It is currently approved |
| amebiasis | Amebiasis (also called amebic dysentery) is an infection of the intestinal tract caused by Entamoeba histolytica. The disease can be acute or chronic, with patients showing varying degrees of illness, from no symptoms to mild diarrhea to fulminating dysentery. The diagnosis is established by isolating E. histolytica from fresh feces. Therapy is aimed not only at the acutely ill patient but also at those who are asymptomatic carriers, because dormant E. histolytica may cause future infections in the carrier and be a potential source of infection for others. |
| Life cycle of Entamoeba histolytica | Entamoeba histolytica exists in two forms: cysts that can survive outside the body and labile but invasive trophozoites that do not persist outside the body. Cysts, ingested through feces-contaminated food or water, pass into the lumen of the intestine, where the trophozoites are liberated. The trophozoites multiply, and they either invade and ulcerate the mucosa of the large intestine or simply feed on intestinal bacteria. [Note: One strategy for treating luminal amebiasis is to add antibiotics, such as tetracycline, to the treatment regimen, resulting in a reduction in intestinal flora, the ameba’s major food source.] The trophozoites within the intestine are slowly carried toward the rectum, where they return to the cyst form and are excreted in fece Large numbers of trophozoites within the colon wall can also lead to systemic invasion. |
| chloroquine | Chloroquine is used in combination with metronidazole and diloxanide furoate to treat and prevent amebic liver abscesses. It eliminates trophozoites in liver abscesses, but it is not useful in treating luminal amebiasis. Chloroquine is also effective in the treatment of malaria. |
| liver cycles of malaria | 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. |
| types schizonticides | Primary tissue schizonticides (eg, primaquine) kill schizonts in the liver, whereas blood schizonticides (eg, chloroquine, artemisinins, quinine) kill these forms only in the erythrocyte. Sporonticides (proguanil, pyrimethamine) prevent sporogony and multiplication in the mosquito. |
| chloroquine classification and pharmacokinetics | Chloroquine is a 4-aminoquinoline derivative. 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. Chloroquine is rapidly and completely absorbed following oral administration. Usually, 4 days of therapy suffice to cure the disease. The drug has a very large volume of distribution and concentrates in erythrocytes, liver, spleen, kidney, lung, melanin-containing tissues, and leukocytes. It persists in erythrocytes The drug also penetrates the central nervous system (CNS) and traverses the placenta. Chloroquine is dealkylated by the hepatic mixed-function oxidase system, but some metabolic products retain antimalarial activity. Both parent drug and metabolites are excreted predominantly in urine.The excretion rate is enhanced with acidified urine. |
| chloroquine moa | Resistance in P falciparum can also result from decreased intravacuolar accumulation of chloroquine via a transporter encoded by the pfcrt (P falciparum chloroquine-resistance transporter) gene. After traversing the erythrocytic and plasmodial membranes, chloroquine (a diprotic weak base) is concentrated in the organism’s acidic food vacuole, primarily by ion trapping. It is in the food vacuole that the parasite digests the host cell’s hemoglobin to obtain essential amino acids. However, this process also releases large amounts of soluble heme (ferriprotoporphyrin IX), which is toxic to the parasite. To protect itself, the parasite ordinarily polymerizes the heme to hemozoin (a pigment), which is sequestered in the parasite’s food vacuole. Chloroquine specifically binds to heme, preventing its polymerization to hemozoin. The increased pH and the accumulation of heme result in oxidative damage to the membranes, leading to lysis of both the parasite and the red blood cell. The binding to heme and prevention of its polymerization appear to be a crucial step in the drug’s antiplasmodial activity, which may represent a unifying mechanism for such diverse compounds as chloroquine, quinidine, and mefloquine. |
| chloroquine clinical use | The drug is solely a blood schizonticide. Chloroquine and hydroxychloroquine are also used in autoimmune disorders, including rheumatoid arthritis. it is the drug of choice in the treatment of erythrocytic P. falciparum malaria, except in resistant strains. Chloroquine is less eff ective against P. vivax malaria. It is highly specific for the asexual form of plasmodia. Chloroquine is also effective in the treatment of extraintestinal amebiasis. [Note: The antiinflammatory action of chloroquine explains its occasional use in rheumatoid arthritis and discoid lupus erythematosus.] |
| chloroquine toxicity | At low doses, chloroquine causes gastrointestinal irritation, skin rash, and headaches. High doses may cause severe skin lesions, peripheral neuropathies, myocardial depression, retinal damage, auditory impairment,pruritis and toxic psychosis.Discoloration of the nail beds and mucous membranes may be seen on chronic administration. Chloroquine should be used cautiously in patients with hepatic dysfunction or severe gastrointestinal problems and in patients with neurologic or blood disorders. Chloroquine can cause electrocardiographic (ECG) changes, because it has a quinidine-like effect. It may also exacerbate dermatitis produced by gold or phenylbutazone therapy. [Note: Patients with psoriasis or porphyria should not be treated with chloroquine, because an acute attack may be provoked.] |
| chloroquine resistance | Chloroquine-resistant P. falciparum exhibit multigenic alterations that confer a high level of resistance. [Note: When a chloroquine-resistant organism is encountered, therapy usually consists of an orally administered combination of quinine, pyrimethamine, and a sulfonamide such as sulfadoxine.] |
| Artesunate, Artemether, Dihydroartemisinin moa and use | These artemisinin derivatives are metabolized in the food vacuole of the parasite forming toxic free radicals. Artemisinins are blood schizonticides active against P falciparum, including multidrugresistant strains. An intravenous form of artesunate is available for severe infections. However, they are now considered the first choice for chloroquine-resistant malaria in most countries. They are best used in combination with other agents. The artemisinins are the only drugs reliably effective against quinine-resistant strains. Artemisinin is derived from the qinghaosu plant, which has been used in Chinese medicine for more than 2 millennia in the treatment of fevers and malaria. Its antimalarial action involves the production of free radicals within the plasmodium food vacuole, following cleavage of the drug’s endoperoxide bridge by heme iron in parasitized erythrocytes. It is also believed to covalently bind to and damage specific malarial proteins. |
| artmemesins pharmacokinetics and adverse effects | Oral, rectal, and intravenous (IV) preparations are available, but the short half-lives preclude their use in chemoprophylaxis. They are metabolized in the liver and are excreted primarily in bile. nausea vomiting diarrhoea. Extremely high doses may cause neurotoxicity and prolongation of the QT interval. These drugs are not used alone for chemoprophylaxis because of their short half-lives of 1–3 h. |
| quinine Classification and pharmacokinetics | Quinine is rapidly absorbed orally and is metabolized before renal excretion. Intravenous administration of quinine is possible in severe infections.interferes with heme polymerization, resulting in death of the erythrocytic form of the plasmodial parasite. Alkalinization of urine decreases its excretion.Quinine absorption is retarded when the drug is taken with aluminum-containing antacids. |
| quinine mechanism | —Quinine complexes with doublestranded DNA to prevent strand separation, resulting in block of DNA replication and transcription to RNA. Quinine is solely a blood schizonticide. |
| quinine clinical use | The main use of quinine is in P falciparum infections resistant to chloroquine in patients who can tolerate oral treatment. Quinine is commonly used with doxycycline or clindamycin to shorten the duration of therapy and limit toxicity. Quinidine, the dextrorotatory stereoisomer of quinine, is used intravenously in the treatment of severe or complicated falciparum malaria. To delay emergence of resistance, quinine should not be used routinely for prophylaxis. |
| quinine toxicity | Quinine commonly causes cinchonism (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 (G6PD)-deficient patients. Blackwater fever (intravascular hemolysis) is a rare and sometimes fatal complication in quinine-sensitized persons. Quinine is contraindicated in pregnancy.Drug interactions include potentiation of neuromuscular-blocking agents and elevation of digoxin levels if taken concurrently with quinine. |
| mefloquine classification and pharmacokinetics | Mefloquine is a synthetic 4-quinoline derivative. Because of local irritation, mefloquine can only be given orally, although it is subject to variable absorption. Its mechanism of action is not known. |
| mefloquine use | Mefloquine is a first-line drug (taken weekly) given for prophylaxis in all geographical areas with chloroquine resistance and an alternative drug to quinine in acute attacks and uncomplicated infections resulting from P falciparum. Resistance to mefloquine has emerged in regions of Southeast Asia. |
| mefloquine adverse effects | Common adverse effects include gastrointestinal distress, skin rash, headache, and dizziness. At high doses, mefloquine has caused cardiac conduction defects, psychiatric disorders, and neurologic effects, including seizures. |
| Primaquine Classification and pharmacokinetics | Primaquine is a synthetic 8-aminoquinoline. Absorption is complete after oral administration and is followed by extensive metabolism. Primaquine is well absorbed on oral administration and is not concentrated in tissues. It is rapidly oxidized to many compounds, primarily the deaminated drug. Which compound possesses the schizontocidal activity has not been established. Metabolites appear in urine |
| primaquine moa | Primaquine forms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants. The drug is a tissue schizonticide and also limits malaria transmission by acting as a gametocide. which may remain in the liver in the exoerythrocytic form after the erythrocytic form of the disease is eliminated.] The sexual (gametocytic) forms of all four plasmodia are destroyed in the plasma or are prevented from maturing later in the mosquito, thereby interrupting transmission of the disease. [Note: Primaquine is not eff ective against the erythrocytic stage of malaria and, therefore, is often used in conjunction with a blood schizonticide, such as chloroquine, quinine, mefl oquine, or pyrimethamine.] |
| primaquine clinical use | Primaquine eradicates liver stages of P vivax and P ovale and should be used in conjunction with a blood schizonticide. Although not active alone in acute attacks of vivax and ovale malaria, a 14-d course of primaquine is standard after treatment with chloroquine, and the drug is also an alternative (daily) for primary prevention.eradicates primary exoerythrocytic forms of P. falciparum and P. vivax and the secondary exoerythrocytic forms of recurring malarias (P. vivax and P. ovale). Primaquine is the only agent that can lead to radical cures of the P. vivax |
| primaquine toxicity | 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. Other toxic manifestations observed after large doses of the drug include abdominal discomfort, especially when administered in combination with chloroquine (which may affect patient compliance), and occasional methemoglobinemia. Granulocytopenia and agranulocytosis are rarely seen, except in patients with lupus or arthritis, because both conditions are aggravated by the drug. All Plasmodium species may develop resistance to primaquine. |
| Classification and pharmacokinetics antifolate drugs | The antifolate group includes pyrimethamine, proguanil, sulfadoxine, and dapsone. All these drugs are absorbed orally and are excreted in the urine, partly in unchanged form. Proguanil has a shorter half-life (12–16 h) than other drugs in this subclass (half-life >100 h). |
| mechanism of action antifolate drugs | Sulfonamides act as antimetabolites of PABA and block folic acid synthesis in certain protozoans by inhibiting dihydropteroate synthase. Proguanil (chloroguanide) is bioactivated to cycloguanil. Pyrimethamine and cycloguanil 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 (see Figure 46-1). |
| clinical use antifols | The antifols are blood schizonticides that act mainly against P falciparum. Pyrimethamine with sulfadoxine in fixed combination (Fansidar) is used in the treatment of chloroquineresistant 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 and is also protective against mefloquine-resistant falciparum strains. |
| toxicity of antifolate drugs | The toxic effects of sulfonamides include skin rashes, gastrointestinal distress, hemolysis, kidney damage, and drug interactions caused by competition for plasma protein binding sites. Pyrimethamine may cause folic acid deficiency when used in high doses. |
| doxyclcline | This tetracycline is chemoprophylactic (taken daily) for travelers to geographical areas with multidrug-resistant P falciparum. |
| Amodiaquine | This drug has been widely used to treat malaria in many countries because of its low cost and, in some geographical areas, effectiveness against chloroquine-resistant strains of P falciparum. It is also used in fixed combination with artesunate. Hematologic toxicity, including agranulocytosis and aplastic anemia, has been associated with the use of amodiaquine. |
| Atovaquone | This quinine derivative, a component of Malarone (with proguanil), appears to disrupt mitochondrial electron transport in protozoa. Malarone is effective for both chemoprophylaxis (taken daily) and treatment of falciparum malaria. Abdominal pain and gastrointestinal effects occur at the higher doses needed for treatment. Atovaquone is an alternative treatment for P jiroveci infection. |
| Halofantrine | Although its mechanism of action is unknown, this drug is active against erythrocytic (but not other) stages of all 4 human malaria species, including chloroquine-resistant falciparum. Halofantrine is not used for chemoprophylaxis because of its potential for quinidine-like cardiotoxicity (QT prolongation) and embryotoxicity. Lumefantrine, a related drug with minimal cardiotoxicity, is now used in fixed combination with artemether (Coartem) for uncomplicated falciparum malaria in many countries. |
| drugs used before visiting | 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. Primaquine (daily for 14 d) is recommended for terminal prophylaxis of P vivax and P ovale infections and is an alternative in primary prevention. |
| plasmodium types | Plasmodium falciparum is the most dangerous species, causing an acute, rapidly fulminating disease that is characterized by persistent high fever, orthostatic hypotension, and massive erythrocytosis (an abnormal elevation in the number of red blood cells accompanied by swollen, reddish limbs). P. falciparum infection can lead to capillary obstruction and death if treatment is not instituted promptly. Plasmodium vivax causes a milder form of the disease. Plasmodium malariae is common to many tropical regions, but Plasmodium ovale is rarely encountered. Resistance acquired by the mosquito to insecticides, and by the parasite to drugs, has led to new therapeutic challenges, particularly in the treatment of P. falciparum. |
| life cycle of malarial parasite | When an infected mosquito bites, it injects Plasmodium sporozoites into the bloodstream. The sporozoites migrate through the blood to the liver, where they form cyst-like structures containing thousands of merozoites. [Note: Diagnosis depends on laboratory identification of the parasites in red blood cells of peripheral blood smears.]Upon release, each merozoite invades a red blood cell, becoming a trophozoite and using hemoglobin as a nutrient. The trophozoites multiply and become merozoites. Eventually, the infected cell ruptures, releasing heme and merozoites that can enter other erythrocytes. [Note: Alternatively, released merozoites can become gametocytes, which are picked up by mosquitoes from the blood they ingest. The cycle thus begins again, with the gametocytes becoming sporozoites in the insect.] The eff ectiveness of drug treatment is related to the particular species of infecting plasmodium and the stage of its life cycle that is targeted. |
| mefloquine | appears to be promising as an eff ective single agent for suppressing and curing infections caused by multidrugresistant forms of P. falciparum. Its exact mechanism of action remains to be determined, but, like quinine, it can apparently damage the parasite’s membrane. Resistant strains have been identified. |
| mefloquine pharmacokinetics and adverse effects | absorbed well after oral administration and concentrates in the liver and lung. It has a long half-life (17 days) because of its concentration in various tissues and its continuous circulation through the enterohepatic and enterogastric systems. The drug undergoes extensive metabolism. Its major excretory route is through the feces. Adverse reactions at high doses range from nausea, vomiting, and dizziness to disorientation, hallucinations, and depression. ECG abnormalities and cardiac arrest are possible if mefloquine is taken concurrently with quinine or quinidine. |
| pyrimethamine | The antifolate agent pyrimethamine is frequently employed to effect a radical cure as a blood schizonticide. It also acts as a strong sporonticide in the mosquito’s gut when the mosquito ingests it with the blood of the human host. Pyrimethamine inhibits plasmodial dihydrofolate reductase3 at much lower concentrations than those needed to inhibit the mammalian enzyme. The inhibition deprives the protozoan of tetrahydrofolate, a cofactor required in the de novo biosynthesis of purines and pyrimidines and in the interconversions of certain amino acids. Pyrimethamine alone is effective against P. falciparum. In combination with a sulfonamide, it is also used against P. malariae and Toxoplasma gondii. If megaloblastic anemia occurs with pyrimethamine treatment, it may be reversed with leucovorin. |
| trypanosomiasis | In African sleeping sickness, the causative organisms, T. brucei gambiense and T. brucei rhodiense, initially live and grow in the blood. The parasite invades the CNS, causing an inflammation of the brain and spinal cord that produces the characteristic lethargy and, eventually, continuous sleep. Chagas disease (American sleeping sickness) is caused by T. cruzi and occurs in South America. |
| Melarsoprol moa | Melarsoprol is a derivative of mersalyl oxide, a trivalent arsenical. Its use is limited to the treatment of trypanosomal infections (usually in the late stage with CNS involvement), and it is lethal to these parasites.The drug reacts with sulfhydryl groups of various substances, including enzymes in both the organism and host. The parasite’s enzymes may be more sensitive than those of the host. There is evidence that mammalian cells may be less permeable to the drug and are protected from its toxic effects. Trypanosomal resistance may also be due to decreased permeability of the drug. |
| needle problem drug | Melarsoprol usually is slowly administered intravenously through a fine needle, even though it is absorbed from the gastrointestinal tract. Because it is very irritating, care should be taken not to infiltrate surrounding tissue. Adequate trypanocidal concentrations appear in the CSF, whereas pentamidine does not penetrate the CSF. Melarsoprol is, therefore, the agent of choice in the treatment of T. brucei rhodesiense, which rapidly invades the CNS, as well as for meningoencephalitis caused by T. brucei gambiense. The host readily oxidizes melarsoprol to a relatively nontoxic, pentavalent arsenic compound. The drug has a very short half-life and is rapidly excreted in urine Melarsoprol is given parenterally because it causes gastrointestinal irritation; it may also cause a reactive encephalopathy that can be fatal. |
| advere effects melarsoprol | CNS toxicities are the most serious side effects of melarsoprol treatment. Encephalopathy may appear soon after the first course of treatment but usually subsides. In rare cases, however, it may be fatal. Hypersensitivity reactions may also occur, and fever may follow injection. Gastrointestinal disturbances, such as severe vomiting and abdominal pain, can be minimized if the patient is in the fasting state during drug administration and for several hours thereafter. Melarsoprol is contraindicated in patients with influenza. Hemolytic anemia has been seen in patients with glucose-6-phosphate dehydrogenase deficiency. |
| Pentamidine isethionate | Pentamidine is commonly used in the hemolymphatic stages of disease caused by Trypanosoma gambiense and T rhodesiense. Because it does not cross the blood-brain barrier, pentamidine is not used in later stages of trypanosomiasis. Other clinical uses include pneumocystosis and treatment of the kala azar form of leishmaniasis |
| Pentamidine isethionate use | It is active against a variety of protozoal infections, including many trypanosomes such as T. brucei gambiense, for which pentamidine is used to treat and prevent the organism’s hematologic stage. However, some trypanosomes, including T. cruzi, are resistant. Pentamidine is also effective in the treatment of systemic blastomycosis (caused by the fungus Blastomyces dermatitidis) and in treating infections caused by Pneumocystis jiroveci (formerly called Pneumocystis carinii, the name now used to refer to the organism in animals). [Note: It is now considered to be a fungus, but it is not susceptible to antifungal drugs. Trimethoprim-sulfamethoxazole is preferred in the treatment of P. jiroveci infections. However, pentamidine is an alternative in treating patients with pneumonia caused by P. jiroveci who have failed to respond to trimethoprim-sulfamethoxazole. The drug is also used in treating P. jiroveci–infected individuals who are allergic to sulfonamides. Because of the increased incidence of pneumonia caused by this organism in immunocompromised patients, such as those infected with human immunodeficiency virus, pentamidine has assumed an important place in chemotherapy.] Pentamidine is also an alternative drug to stibogluconate in the treatment of leishmaniasis. |
| pentamide moa | T. brucei concentrates pentamidine by an energydependent, high-affi nity uptake system. [Note: Resistance is associated with inability to concentrate the drug.] Although its mechanism of action has not been defined, evidence exists that the drug binds to the parasite’s DNA and interferes with its synthesis of RNA, DNA, phospholipid, and protein. |
| pharmacokinetics pentamide | Fresh solutions of pentamidine are administered intramuscularly or as an aerosol [Note: The IV route is avoided because of severe adverse reactions, such as a sharp fall in blood pressure and tachycardia.] The drug is concentrated and stored in the liver and kidney for a long period of time. Because it does not enter the CSF, it is ineffective against the meningoencephalitic stage of trypanosomiasis. The drug is not metabolized, and it is excreted very slowly into the urine. Its half-life in the plasma is about 5 days. |
| adverse effects pentamide | Serious renal dysfunction may occur, which reverses on discontinuation of the drug. Other adverse reactions are hypotension, dizziness, rash, and toxicity to β cells of the pancreas. |
| Nifurtimox | has found use only in the treatment of acute T. cruzi infections (Chagas disease), although treatment of the chronic stage of such infections has led to variable results. [Note: Nifurtimox is suppressive, not curative.] Being a nitroaromatic compound, nifurtimox undergoes reduction and eventually generates intracellular oxygen radicals, such as superoxide radicals and hydrogen peroxide These highly reactive radicals are toxic to T. cruzi, which lacks catalase.[Note: Mammalian cells are partially protected from such substances by the presence of enzymes, such as catalase, glutathione peroxidase, and superoxide dismutase.This drug is a nitrofurazone derivative that inhibits the parasiteunique enzyme trypanothione reductase. Nifurtimox is the drug of choice in American trypanosomiasis, an alternative agent in African forms of the disease, and has also been effective in mucocutaneous leishmaniasis. |
| nifurtimox pharmacokinetics | Nifurtimox is administered orally and is rapidly absorbed and metabolized to unidentified products that are excreted in the urine. |
| nifurtimox adverse effects | Adverse effects are common following chronic administration, particularly among the elderly. Major toxicities include immediate hypersensitivity reactions such as anaphylaxis; delayed hypersensitivity reactions, such as dermatitis and icterus; and gastrointestinal problems, cns effects that may be severe enough to cause weight loss. Peripheral neuropathy is relatively common, and disturbances in the CNS may also occur. In addition, cell-mediated immune reactions may be suppressed. |
| suramin | This polyanionic compound is a drug of choice for the early hemolymphatic stages of African trypanosomiasis (before CNS involvement). It is very reactive and inhibits many enzymes, among them those involved in energy metabolism (for example, glycerol phosphate dehydrogenase), which appears to be the mechanism most closely correlated with trypanocidal activity. The drug must be injected intravenously. It binds to plasma proteins and remains in the plasma for a long time, accumulating in the liver and in the proximal tubular cells of the kidney. The severity of the adverse reactions demands that the patient be carefully followed, especially if he or she is debilitated.It is also an alternative to ivermectin in the treatment of onchocerciasis Suramin is used parenterally |
| suramin adverse effects | Although infrequent, adverse reactions include nausea and vomiting (which cause further debilitation of the patient); shock and loss of consciousness; acute urticaria; and neurologic problems, including paresthesia, photophobia, palpebral edema (edema of the eyelids), and hyperesthesia of the hands and feet. Albuminuria tends to be common, but when cylindruria (the presence of renal casts in the urine) and hematuria occur, treatment should cease causes skin rashes, gastrointestinal distress, and neurologic complications. |
| benznidazole | Benznidazole is a nitroimidazole derivative that inhibits protein and RNA synthesis in T. cruzi cells. It is an alternative choice for treatment of acute and indeterminate phases of Chagas disease, but therapy with benznidazole does not off er any signifi cant efficacy or toxicity advantages over that with nifurtimox. However, benznidazole is recommended as prophylaxis for preventing infections caused by T. cruzi among hematopoietic stem cell transplant recipients because treatment in potential donors is not always effective |
| eflorthine | This agent, a suicide substrate of ornithine decarboxylase, is effective in some forms of African trypanosomiasis. It is available for both oral and intravenous use and penetrates into the CNS. It causes gastrointestinal irritation and hematotoxicity; seizures have occurred in overdose. |
| TMP-SMZ clinical use | TMP-SMZ is the first choice in prophylaxis and treatment of pneumocystis pneumonia (PCP). Prophylaxis in AIDS patients is recommended when the CD4 count drops below 200 cells/μL. Oral treatment with the double-strength formulation 3 times weekly is usually effective. The same regimen of TMP-SMZ is prophylactic against toxoplasmosis and infections caused by Isospora belli. For treatment of active PCP, daily oral or intravenous administration of TMP-SMZ is required. |
| TMP-SMZ toxicity | Adverse effects from TMP-SMZ occur in up to 50% of AIDS patients. Toxicity includes gastrointestinal distress, rash, fever, neutropenia, and thrombocytopenia. These effects may be serious enough to warrant discontinuance of TMP-SMZ and substitution of alternative drugs. |
| pentamidine moa | Pentamidine’s mechanism of action is unknown but may involve inhibition of glycolysis or interference with nucleic acid metabolism of protozoans and fungi. Preferential accumulation of the drug by susceptible parasites may account for its selective toxicity. |
| pentamidine clinical use | Aerosol pentamidine (once monthly) can be used in primary and secondary prophylaxis of P jiroveci pneumonia, 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. Pentamidine is also used in trypanosomiasis. |
| pentamidine toxicity | 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. |
| Antifols: Pyrimethamine and Sulfonamides clinical use | Combination of pyrimethamine with sulfadiazine has synergistic activity against Toxoplasma gondii through the sequential blockade of 2 steps in folic acid synthesis. Pyrimethamine plus clindamycin (or sulfadiazine) is a regimen of choice for prophylaxis against and treatment of toxoplasmosis. For treatment of active toxoplasmosis, the drug combination is given daily for 3–4 wk, with folinic acid to offset hematologic toxicity. For Toxoplasma encephalitis in AIDS, high-dose treatment with pyrimethamine plus sulfadiazine (or clindamycin) plus folinic acid must be maintained for at least 6 wk. |
| Antifols: Pyrimethamine and Sulfonamides toxicity | 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. |
| Atovaquone Mechanism and pharmacokinetics | Atovaquone inhibits mitochondrial electron transport and probably folate metabolism. Used orally, it is poorly absorbed and should be given with food to maximize bioavailability. Most of the drug is eliminated in the feces in unchanged form. |
| atovaquone Clinical use and toxicity | Atovaquone is approved for use in mild to moderate pneumocystis pneumonia. It is less effective than TMP-SMZ or pentamidine but is better tolerated. As noted, it is also used in combination with proguanil (as Malarone) for chemoprophylaxis and treatment of chloroquine-resistant 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. |
| Miscellaneous Agents | Other alternative drug regimens for the treatment of pneumocystis pneumonia include trimethoprim plus dapsone, primaquine plus clindamycin, and trimetrexate plus leucovorin |
| toxoplasma gondii | One of the most common infections in humans is caused by the protozoan Toxoplasma gondii, which is transmitted to humans when they consume raw or inadequately cooked infected meat. An infected pregnant woman can transmit the organism to her fetus. Cats are the only animals that shed oocysts, which can infect other animals as well as humans. . |
| agents for toxoplasma gondii | The treatment of choice for this condition is a combination of sulfadiazine and pyrimethamine Leucovorin is commonly administered to protect against folate deficiency. Other inhibitors of folate biosynthesis, such as trimethoprim and sulfamethoxazole, are without therapeutic efficacy in toxoplasmosis. [Note: At the first appearance of a rash, pyrimethamine should be discontinued, because hypersensitivity to this drug can be severe.] |
| types leshmaniasis | There are three types of leishmaniasis: cutaneous, mucocutaneous, and visceral. [Note: In the visceral type (liver and spleen), the parasite is in the bloodstream and can cause very serious problems.] Leishmaniasis is transmitted from animals to humans (and between humans) by the bite of infected sandflies. The diagnosis is established by demonstrating the parasite in biopsy material and skin lesions. |
| life cycle leshmaniasis | The sandfly transfers the flagellated promastigote form of the protozoa, which is rapidly phagocytized by macrophages. In the macrophage, the promastigotes rapidly change to nonfl agellated amastigotes and multiply, killing the cell. The newly released amastigotes are again phagocytized, and the cycle continues. |
| sodium stibogluconate | Pentavalent antimonials, such as sodium stibogluconate, are the conventional therapy used in the treatment of leishmaniasis. Sodium stibogluconate is not eff ective in vitro. Therefore, it has been proposed that reduction to the trivalent antimonial compound is essential for activity. The exact mechanism of action has not been determined. Evidence for inhibition of glycolysis in the parasite at the phosphofructokinase reaction has been found or effects on nucleic acid metabolism. also thought. Because it is not absorbed on oral administration, sodium stibogluconate must be administered parenterally, and it is distributed in the extravascular compartment. Metabolism is minimal, and the drug is excreted in urine |
| adverse effects sodium stibogluconate | Adverse effects include pain at the injection site, gastro intestinal upsets, and cardiac arrhythmias. Renal and hepatic function should be monitored periodically Stibogluconate must be administered parenterally and is potentially cardiotoxic (QT prolongation). |
| alternative drugs for leishmania | Allopurinol has also been reported to be efective (it is converted to a toxic metabolite by the amastigote form of the organism). with pentamidine and amphotericin B as back up agents Alternative agents include pentamidine, paromomycin, or miltefosine (for visceral leishmaniasis), fluconazole or metronidazole (for cutaneous lesions), and amphotericin B (for mucocutaneous leishmaniasis) |
| giardia lambia | Giardia lamblia is the most commonly diagnosed intestinal parasite in the
United States. It has only two life-cycle stages: the binucleate trophozoite with four flagellae and the drug-resistant, four-nucleate cyst Ingestion, usually from contaminated drinking water, leads to infection. The trophozoites exist in the small intestine and divide by binary fission. Occasionally, cysts are formed that pass out in stools. Although some infections are asymptomatic, severe diarrhea can occur, which can be very serious in immune-suppressed patients. |
| drugs for giardia lambia | The treatment of choice is metronidazole for 5 days. One alternative agent is tinidazole, which is equally effective as metronidazole in the treatment of giardiasis but with a much shorter course of therapy (2 grams given once). Nitazoxanide, a nitrothiazole derivative structurally similar to aspirin, was recently approved for the treatment of giardiasis. Nitazoxanide is also equally efficacious as metronidazole and, in comparison, has a two-day-shorter course of therapy. |
