Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 52. Antiprotozoal Drugs

Antiprotozoal Drugs: Introduction

Diseases caused by protozoans constitute a worldwide health problem. This chapter concerns the drugs used to combat malaria, amebiasis, toxoplasmosis, pneumocystosis, trypanosomiasis, and leishmaniasis.

Drugs for Malaria

Malaria is one of the most common diseases worldwide and a leading cause of death. Plasmodium species that infect humans (P falciparum, P malariae, P ovale, P vivax) undergo a primary developmental stage in the liver and then parasitize erythrocytes. 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. Primary tissue schizonticides (eg, primaquine) kill schizonts in the liver, whereas blood schizonticides (eg, chloroquine, quinine) kill these parasitic forms only in the erythrocyte. Sporonticides(proguanil, pyrimethamine) prevent sporogony and multiplication in the mosquito.

Drugs used for the treatment of malaria are shown in Table 52-1.

TABLE 52-1 Drugs used in the treatment of malaria.

Drug Uses Adverse Effects Chloroquine Prophylaxis and treatment in areas without resistant P falciparum; treatment of P vivax and P ovale malaria GI distress, rash, headache; auditory dysfunction and retinal dysfunction (high dose) Mefloquine Prophylaxis and treatment in areas with resistant P falciparum GI distress, rash, headache; cardiac conduction defects and neurologic symptoms (high dose) Quininea

Treatment of multidrug-resistant malaria Cinchonism, hemolysis in G6PD deficiency, blackwater fever Primaquine Eradication of liver stages of P vivax and P ovale GI distress, methemoglobinemia, hemolysis in G6PD deficiency Antifolates Prophylaxis and treatment of multidrug-resistant P falciparum malaria GI distress, renal dysfunction, hemolysis, folate deficiency Atovaquone-proguanil (Malarone) Prophylaxis and treatment of multidrug-resistant P falciparum malaria GI distress, headache, rash hemolysis, folate deficiency Artesunate, Artemether Treatment of multidrug-resistant malaria GI distress

aIn most cases quinine is used together with doxycycline or clindamycin, or an antifolate. Quinidine gluconate (IV) is used in severe infections or for patients unable to take oral quinine.

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.

Mechanism of Action

Chloroquine accumulates in the food vacuole of plasmodia and prevents polymerization of the hemoglobin breakdown product heme into hemozoin. Intracellular accumulation of heme is toxic to the parasite. Decreased intracellular accumulation via increased activity of membrane "pumps" is a mechanism of resistance to chloroquine and other antimalarial drugs. 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.

Clinical Use

Chloroquine is the drug of choice for acute attacks of nonfalciparum and sensitive falciparum malaria and for chemoprophylaxis, except in regions where P falciparumis resistant. The drug is solely a blood schizonticide. Chloroquine and hydroxychloroquine are also used in autoimmune disorders, including rheumatoid arthritis.

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, and toxic psychosis. Chloroquine may also precipitate porphyria attacks.

Quinine

Classification and Pharmacokinetics

Quinine is rapidly absorbed orally and is metabolized before renal excretion. Intravenous administration of quinine is possible in severe infections.

Mechanism of Action

Quinine 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 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.

Toxicity

Quinine commonly causes cinchonism, symptoms of which include 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.

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.

Clinical 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.

Toxicity

Common adverse effects include gastrointestinal distress, skin rash, headache, and dizziness. At high doses, mefloquine has caused cardiac conduction defects, psychiatric disorders, neurologic symptoms, and seizures.

Primaquine

Classification and Pharmacokinetics

Primaquine is a synthetic 8-aminoquinoline. Absorption is complete after oral administration and is followed by extensive metabolism.

Mechanism of Action

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.

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.

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.

Antifolate Drugs

Classification and Pharmacokinetics

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).

Mechanisms of Action

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.

Clinical Use

The antifols are blood schizonticides that act mainly against P falciparum. Pyrimethamine with sulfadoxine in fixed combination (Fansidar) is used in the treatment of chloroquine-resistant 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

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.

Other Antimalarial Drugs

Doxycycline

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 artusenate. Hematologic toxicity, including agranulocytosis and aplastic anemia, has been associated with the use of amodiaquine.

Atovaquone

This quinine derivative, a component of Malarone (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.

Artesunate, Artemether, Dihydroartemisinin

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 multidrug-resistant strains. An intravenous form of artesunate is available for severe infections. These drugs are not used for chemoprophylaxis because of their short half-lives of 1-3 h. However, they are playing an increasingly important role in the treatment of malaria and are best used in combination with other agents. The artemisinins are the only drugs reliably effective against quinine-resistant strains. Adverse effects are mild, but include nausea, vomiting, and diarrhea. Their safety in pregnancy has not been established.

Drugs for the Prevention of Malaria in Travelers

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. (For updated information check CDC guidelines at http://www.cdc.gov.

Drugs for Amebiasis

Tissue amebicides (chloroquine, emetines, metronidazole, tindidazole) 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. 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 (Table 52-2). The mechanisms of amebicidal action of most drugs in this subclass are unknown.

TABLE 52-2 Drugs used in the treatment of amebiasis.

Disease Form Drug(s) of Choice Alternative Drug(s) Asymptomatic, Intestinal infection Diloxanide furoate Iodoquinol, paramomycin Mild to moderate intestinal infection Metronidazole plus luminal agent (see above) Tinidazole, or tetracycline, or erythromycin plus luminal agent Severe intestinal infection Metronidazole or tinidazole plus luminal agent Tetracycline or emetine or dihydroemetine plus luminal agent Hepatic abscess and other extraintestinal disease Metronidazole or tinidazole plus luminal agent Emetine or dihydroemetine plus choroquine (for liver abscess) plus luminal agent

Adapted, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.

Diloxanide Furoate

This drug is 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. Diloxanide furoate 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.

Emetines

Emetine and dehydroemetine inhibit protein synthesis by blocking ribosomal movement along messenger RNA. 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). The drugs are restricted to use in severe amebiasis when metronidazole cannot be used.

Iodoquinol

Iodoquinol, a halogenated hydroxyquinoline, is an orally active luminal amebicide used as an alternative to diloxanide for mild-to-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.

Metronidazole and Tinidazole

Pharmacokinetics

Metronidazole and tinidazole are effective orally and distributed widely to tissues. The half-life of metronidazole is 6-8 h, and that of tinidazole 12-14 h. Elimination of the drugs requires hepatic metabolism.

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.

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.

Toxicity

Adverse effects of metronidazole include gastrointestinal irritation (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.

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. 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.

Nitazoxanide

This agent has activity against various protozoans (including Entamoeba) and helminths. It is currently approved in the United States for treatment of gastrointestinal infections caused by G lamblia and Cryptosporidium parvum.Nitazoxanide appears to have activity against metronidazole-resistant protozoal strains.

Drugs for Pneumocystosis & Toxoplasmosis

Pentamidine

Mechanism of Action

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.

Clinical Use

Aerosol pentamidine (once monthly) can be used in primary and secondary prophylaxis, 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 (see later discussion).

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.

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/L. 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.

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. (See Chapter 46 for additional information on TMP-SMZ.)

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 Toxoplasmaencephalitis in AIDS, high-dose treatment with pyrimethamine plus sulfadiazine (or clindamycin) plus folinic acid must be maintained for at least 6 wk.

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.

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.

Drugs for Trypanosomiasis

Pentamidine

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 (Table 52-3).

TABLE 52-3 Drugs used in the treatment of other protozoal infections.

Drug Indications Melarsoprol Mucocutaneous forms of trypanosomiasis and the CNS stage (African sleeping sickness) Metronidazole Drug of choice for infections caused by Giardia lamblia and Trichomonas vaginalisNifurtimox Trypanosomiasis caused by T cruzi Pentamidine Hemolymphatic stage of trypanosomiasis and for Pneumocystis jiroveci infections Pyrimethamine plus clindamycin orsulfadiazine plus folinic acid Drug combinations used in treatment of toxoplasmosis Sodium stibogluconate Treatment of leishmaniasis (all stages) Suramin Drug of choice for hemolymphatic stage of trypanosomiasis (T brucei gambiense, T rhodesiense) Trimethoprim-sulfamethoxazole Drug combination of choice in Pneumocystis jiroveci infections

Melarsoprol

This drug is an organic arsenical that inhibits enzyme sulfhydryl groups. Because it enters the CNS, melarsoprol is the drug of choice in African sleeping sickness. However, treatment failures do occur, possibly because of resistance. Melarsoprol is given parenterally because it causes gastrointestinal irritation; it may also cause a reactive encephalopathy that can be fatal.

Nifurtimox

This drug is a nitrofurazone derivative that inhibits the parasite-unique 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. The drug causes severe toxicity, including allergies, gastrointestinal irritation, and CNS effects.

Suramin

This polyanionic compound is a drug of choice for the early hemolymphatic stages of African trypanosomiasis (before CNS involvement). It is also an alternative to ivermectin in the treatment of onchocerciasis (see Chapter 53). Suramin is used parenterally and causes skin rashes, gastrointestinal distress, and neurologic complications.

Eflornithine

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.

Drugs for Leishmaniasis

Leishmania, parasitic protozoa transmitted by flesh-eating flies, cause various diseases ranging from cutaneous or mucocutaneous lesions to splenic and hepatic enlargement with fever. Sodium stibogluconate (pentavalent antimony), the primary drug in all forms of the disease, appears to kill the parasite by inhibition of glycolysis or effects on nucleic acid metabolism. Stibogluconate must be administered parenterally and is potentially cardiotoxic (QT prolongation). Alternative agents include pentamidine or miltefosine (for visceral leishmaniasis), fluconazole or metronidazole (for cutaneous lesions), and amphotericin B (for mucocutaneous leishmaniasis).

Checklist

When you complete this chapter, you should be able to:

Name the major antimalarial drugs. Know which are used for chemoprophylaxis, which are effective in chloroquine resistance, and which are exoerythrocytic schizonticides.

 Identify the characteristic adverse effects of the major antimalarial drugs.

 Describe the clinical uses and adverse effects of metronidazole.

 Be able to identify the intestinal amebicides.

Identify the drugs used for prophylaxis and treatment of pneumocystosis and toxoplasmosis, and know their characteristic toxic effects.

 Identify the major drugs used for trypanosomiasis and leishmaniasis, and know their characteristic toxic effects.



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