Treatment of Malaria Four species of Plasmodium are responsible for human malaria: P. vivax, P. malariae, P. ovale, and P. falciparum. Although all may cause severe illness, P falciparum causes most of the serious complications and deaths. The effectiveness of antimalarial agents varies between parasite species and between stages in their life cycles. 1.1. Parasite Life Cycle The mosquito becomes infected by taking human blood that contains parasites in the sexual form. The sporozoites that develop in the mosquito are then inoculated into humans at its next feeding. In the exoerythrocytic stage, the sporozoites multiply in the liver to form tissue schizonts. Then, parasites escape from the liver into the bloodstream as merozoites. The merozoites invade red blood cells, multiply in them to form blood schizonts, and finally rupture the cells, releasing a new crop of merozoites. This cycle may be repeated many times. The gametocytes (the sexual stage) form and are released into the circulation, where they may be taken in by another mosquito. P falciparum and P malariae have only one cycle of liver cell invasion and multiplication, and liver infection ceases spontaneously in less than 4 weeks. Then, multiplication is confined to the red blood cells. So, treatment that eliminates these species from the red blood cells four or more weeks after inoculation of the sporozoites will cure these infections. In P vivax and P ovale infections, sporozoites also induce in hepatic cells the dormant stage (the hypnozoite) that causes subsequent recurrences (relapses) of the infection. Therefore, treatment that eradicates parasites from both the red cells and the liver is required to cure these infections. 1.2. Drug Classification The antimalarial drugs are classified by their selective actions on the parasite’s life cycle. 1) Tissue schizonticides: drugs that eliminate tissue schizonts or hypnozoites in the liver (eg, primaquine). 2) Blood schizonticides: drugs that act on blood schizonts (eg, chloroquine, amodiaquine, proguanil, pyrimethamine, mefloquine, quinine) . 3) Gametocides are drugs that prevent infection in mosquitoes by destroying gametocytes in the blood (eg, primaquine for P falciparum and chloroquine for P vivax, P malariae, and P ovale.). 179 4) Sporonticidal agents are drugs that render gametocytes noninfective in the mosquito (eg, pyrimethamine, proguanil). None of these drugs prevent infection except for pyrimethamine and proguanil which prevent maturation of P falciparum hepatic schizonts. Blood schizonticides do destroy circulating plasmodia. Primaquine destroys the persisting liver hypnozoites of P vivax and P ovale. 1.3. Individual antimalarial drugs 1.3.1. Chloroquine Pharmacokinetics: Chloroquine is a synthetic 4-aminoquinoline. It is rapidly and almost completely absorbed from the gastrointestinal tract, and is rapidly distributed to the tissues. From these sites it is slowly released and metabolized. The drug readily crosses the placenta. Renal excretion is increased by acidification of the urine. Antimalarial Action: Chloroquine is a highly effective blood schizonticide and is most widely used in chemoprophylaxis and in treatment of attacks of vivax, ovale, malariae, or sensitive falciparum malaria. It is moderately effective against gametocytes of P. vivax, P. ovale, and P. malariae, but not against those of P falciparum. Chloroquine is not active against the preerythrocytic plasmodium and does not effect radical cure. The exact mechanism of action has not been known. Selective toxicity for malarial parasites depends on a chloroquine-concentrating mechanism in parasitized cells. Chloroquine’s concentration in normal erythrocytes is 10-20 times that in plasma; in parasitized erythrocytes, its concentration is about 25 times that in normal erythrocytes. Clinical uses: Acute Malaria Attacks (it clears the parasitemia of acute attacks of P vivax, P ovale, and P malariae and of malaria due to nonresistant strains of P falciparum), and chemoprophylaxis (It is the preferred drug for prophylaxis against all forms of malaria except in regions where P falciparum is resistant to 4-aminoquinolines). Adverse Effects: Gastrointestinal symptoms, mild headache, pruritus, anorexia, malaise, blurring of vision, and urticaria are uncommon. A total cumulative dose of 100 g (base) may, contribute to the development of irreversible retinopathy, ototoxicity, and myopathy. Contraindications: It is contraindicated in patients with a history of liver damage, alcoholism, or neurologic or hematologic disorders, psoriasis or porphyria, in whom it may precipitate acute attacks of these diseases. 1.3.2. Primaquine Primaquine phosphate is a synthetic 8-aminoquinoline derivative. After oral administration, the drug is usually well absorbed, completely metabolized, and excreted in the urine. Primaquine is active against the late hepatic stages (hypnozoites and schizonts) of P vivax and P ovale and thus effects radical cure of these infections. Primaquine is also highly active against the primary exoerythrocytic stages of P falciparum. When used in prophylaxis with chloroquine, it protects against P vivax and P ovale. Primaquine is highly gametocidal against the four malaria species. Clinical Uses
Terminal prophylaxis of vivax and ovale malaria.
Radical cure of acute vivax and ovale malaria.
Gametocidal action.
Pneumocystis carinii pneumonia Adverse Effects: Primaquine is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache. Serious adverse effects like leukopenia and agranulocytosis are rare. 1.3.3. Quinine Quinine is rapidly absorbed, reaches peak plasma levels in 1-3 hours, and is widely distributed in body tissues. The elimination half-life of quinine is 7-12 hours in normal persons but 8-21 hours in malaria-infected persons in proportion to the severity of the disease. Bulk of the drug is metabolized in the liver and excreted for the most part in the urine. Excretion is accelerated in acid urine. Quinine is a rapidly acting, highly effective blood schizonticide against the four malaria parasites. The drug is gametocidal for P vivax and P ovale but not very effective against P falciparum gametocytes. The drug’s molecular mechanism is unclear. Clinical Uses
Parenteral Treatment of Severe Falciparum Malaria
Oral Treatment of Falciparum Malaria Resistant to Chloroquine
Prophylaxis 181
Other Uses: Quinine sulfate sometimes relieves night time leg cramps. Adverse Effects: Quinine often causes nausea, vomiting, hypoglycemia. Cinchonism; a less common effect and manifested by headache, nausea, slight visual disturbances, dizziness, and mild tinnitus and may subside as treatment continues. Severe toxicity like fever, skin eruptions, gastrointestinal symptoms, deafness, visual abnormalities, central nervous system effects (syncope, confusion), and quinidine-like effects occurs rarely. 1.3.4. Proguanil and Pyrimethamine Pyrimethamine and proguanil are dihydrofolate reductase inhibitors. They are slowly but adequately absorbed from the gastrointestinal tract. Pyrimethamine and proguanil are slow acting blood schizonticides against susceptible strains of all four malarial species. Proguanil (but not pyrimethamine) has a marked effect on the primary tissue stages of susceptible P falciparum and therefore may have causal prophylactic action. Resistance to pyrimethamine and proguanil is found worldwide for P falciparum and somewhat less ubiquitously for P vivax. Clinical uses
Chemoprophylaxis
Treatment of Chloroquine-Resistant Falciparum Malaria
Toxoplasmosis treatment Adverse Effects: In malaria treatment, pyrimethamine and proguanil are well tolerated. In the high doses pyrimethamine causes megaloblastic anemia, agranulocytosis and thrombocytopenia (leucovorin calcium is given concurrently). 1.3.5. Sulfones and Sulfonamides Sulfonamides and sulfones have blood schizonticidal action against P falciparum by inhibition of dihydrofolic acid synthesis. But, the drugs have weak effects against the blood schizonts of P vivax, and they are not active against the gametocytes or liver stages of P falciparum or P vivax. When a sulfonamide or sulfone is combined with an antifol, synergistic blockade of folic acid synthesis occurs in susceptible plasmodia. Sulfadoxine with pyrimethamine (Fansidar) and dapsone with pyrimethamine (Maloprim) are the most used combination. 1.3.6. Pyrimethamine-Sulfadoxine (Fansidar) Pyrimethamine-Sulfadoxine (Fansidar) is well absorbed. Its components display peak plasma levels within 2-8 hours and are excreted mainly by the kidneys. Average half-lives are about 170 hours for sulfadoxine and 80-110 hours for pyrimethamine. Pyrimethamine-Sulfadoxine is effective against certain strains of falciparum malaria. But, quinine must be given concurrently in treatment of seriously ill patients, because fansidar is only slowly active. It is not effective in the treatment of vivax malaria. Clinical uses
Treatment of Chloroquine-Resistant Falciparum
Presumptive Treatment of Chloroquine-Resistant Falciparum Malaria Adverse Effects: Rare adverse effects to single-dose Fansidar are those associated with sulfonamide allergy, including the hematologic, gastrointestinal, central nervous system, dermatologic, and renal systems. Fansidar is no longer used in prophylaxis because of severe reactions. However, in our situation, it used for prevention of malaria in pregnant women after the first trimester. Contraindications: Fansidar is contraindicated in patients who have had adverse reactions to sulfonamides, in pregnancy at term, in nursing women, or in children less than 2 months of age. Fansidar should be used with caution in those with severe allergic disorders, and bronchial asthma. 1.3.7. Mefloquine Mefloquine is used in prophylaxis and treatment of chloroquine-resistant and multidrug-resistant falciparum malaria. It is also effective in prophylaxis against P. vivax, P. ovale, P. malariae, and P. falciparum. Mefloquine hydrochloride is chemically related to quinine. It can only be given orally because intense local irritation occurs with parenteral use. It is well absorbed. The drug is highly bound to plasma proteins, concentrated in red blood cells, and extensively distributed to the tissues, including the central nervous system. Mefloquine is cleared in the liver. Its acid metabolites are slowly excreted, mainly in the feces. Its elimination half-life, which varies from 13 days to 33 days, tends to be shortened in patients with acute malaria. Mefloquine has blood schizonticidal activity against P falciparum and P vivax. Sporadic and low levels of resistance to mefloquine have been reported from Southeast Asia and Africa. Resistance to the drug can emerge rapidly, and resistant strains have been found in areas where the drug has never been used. Clinical uses: Prophylaxis of Chloroquine-Resistant Strains of P falciparum and Treatment of Chloroquine-Resistant P falciparum Infection Adverse Reactions: The frequency and intensity of reactions are dose-related. In rophylactic doses it causes; gastrointestinal disturbances, headache, dizziness, syncope, and extra systoles and transient neuropsychiatric events (convulsions, depression, and psychoses). In treatment doses; the incidence of neuropsychiatric symptoms (dizziness, headache, visual disturbances, tinnitus, insomnia, restlessness, anxiety, depression, confusion, acute psychosis, or seizures) may increase. Contraindications: A history of epilepsy, psychiatric disorders, arrhythmia, sensitivity to quinine and the first trimester of pregnancy. 1.3.8. Doxycycline Doxycycline is generally effective against multidrug-resistant P falciparum. The drug is also active against the blood stages of the other Plasmodium species but not against the liver stages. In the treatment of acute malaria, it is used in conjunction with quinine. 1.3.9. Halofantrine Halofantrine hydrochloride is an oral schizonticide for all four malarial species. A fatty food increases absorption up to six fold. Thus, the drug should not be given from 1 hour before to 3 hours after a meal. Excretion is mainly in the feces. 1.3.10. Qinghaosu (Artemisinin) These drugs are especially useful in treatment of cerebral falciparum malaria. The drugs produce abdominal pain, diarrhea.
Drugs used in amebiasis Amebiasis is infection by the protozoan parasite Entamoeba histolytica. E histolytica infection may present as a severe intestinal infection (dysentery), a mild to moderate symptomatic intestinal infection, an asymptomatic intestinal infection, ameboma, liver abscess, or other type of extraintestinal infection. The choice of drug depends on the clinical presentation and on the desired site of drug action, ie, in the intestinal lumen or in the tissues. All of the antiamebic drugs act against Entamoeba histolytica trophozoites, but most are not effective against the cyst stage. Antiamebic drugs are classified as tissue amebicides and luminal amebicides. 2.1. Tissue amebicides eliminate organisms primarily in the bowel wall, liver, and other extraintestinal tissues and are not effective against organisms in the bowel lumen. 2.1.1. Metronidazole, and tinidazole are highly effective against amebas in the bowel wall and other tissues. 2.1.2. Emetine and dehydroemetine act on organisms in the bowel wall and other tissues but not on amebas in the bowel lumen. 2.1.3. Chloroquine -Active principally against amebas in the liver. 2.2. Luminal Amebicides act primarily in the bowel lumen. 2.2.1. Diloxanide furoate 2.2.2. Iodo-quinol 2.2.3. Tetracyclines, paromomycin and erythromycin 2.3. Treatment of Amebiasis 2.3.1. Asymptomatic Intestinal Infection: The drugs of choice, diloxanide furoate and iodoquinol. Alternatives are metronidazole plus iodoquinol or diloxanide. 2.3.2. Intestinal Infection: The drugs of choice, metronidazole and a luminal amebicide. 2.3.3. Hepatic Abscess: The treatment of choice is metronidazole. Diloxanide furoate or iodoquinol should also be given to eradicate intestinal infection whether or not organisms are found in the stools. An advantage of metronidazole is its effectiveness against anaerobic bacteria, which are a major cause of bacterial liver abscess. Dehydroemetine and emetine are potentially toxic alternative drugs. 2.3.4. Ameboma or Extraintestinal Forms of Amebiasis: Metronidazole is the drug of choice. Dehydroemetine is an alternative drug; chloroquine cannot be used because it does not reach high enough tissue concentrations to be effective (except in the liver). A simultaneous course of a luminal amebicide should also be given. 2.4. Antiamoebic drugs 2.4.1. Metronidazole Pharmacokinetics : Oral metronidazole is readily absorbed and permeates all tissues including cerebrospinal fluid, breast milk, alveolar bone, liver abscesses, vaginal secretions, and seminal fluid. Intracellular concentrations rapidly approach extracellular levels whether administered orally or intravenously. Protein binding is low. The drug and its metabolites are excreted mainly in the urine. Mechanism of Action: The nitro group of metronidazole is chemically reduced by ferredoxin within sensitive organisms. The reduction products appear to be responsible for killing the organisms by reacting with various intracellular macromolecules. Clinical Uses: Metronidazole is active against amebiasis, urogenital trichomoniasis, giardiasis, anaerobic infections, acute ulcerative gingivitis, cancrum Oris, decubitus ulcers, and bacterial vaginitis and Helicobacter pylori infection. Adverse effects: Nausea, headache, dry mouth, or metallic tastes occur commonly. Rare adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, stomatitis, rash, urethral burning, vertigo, and paresthesias. It has a disulfiram-like effect. 2.4.2. Other Nitroimidazoles Other nitroimidazole derivatives include tinidazole, and ornidazole. They have similar adverse effects Because of its short half-life, metronidazole must be administered every 8 hours; the other drugs can be administered at longer intervals. However, with the exception of tinidazole, the other nitroimidazoles have produced poorer results than metronidazole in the treatment of amebiasis. 2.4.3. Chloroquine Chloroquine reaches high liver concentrations and is highly effective when given with emetine in the treatment and prevention of amebic liver abscess. Chloroquine is not active against luminal organisms. 2.4.4. Dehydroemetine Emetine Emetine and dehydroemetine are administered parenterally. They are stored primarily in the liver, lungs, spleen, and kidneys. They are eliminated slowly via the kidneys.These drugs act only against trophozoites, which they directly eliminate. Clinical Uses: Severe Intestinal Disease (Amebic Dysentery): Parenterally administered emetine and dehydroemetine rapidly alleviate severe intestinal symptoms but are rarely curative even if a full course is given. Adverse Effects: Sterile abscesses, pain, tenderness, and muscle weakness in the area of the injection are frequent. Emetine and dehydroemetine should not be used in patients with cardiac or renal disease, in patients with a history of polyneuritis, or in young children or liver abscess. They should not be used during pregnancy. 2.4.5. Diloxanide Furoate Diloxanide furoate is directly amebicidal, but its mechanism of action is not known. In the 2gut, diloxanide furoate is split into diloxanide and furoic acid; about 90% of the diloxanide is rapidly absorbed and then conjugated to form the glucuronide, which is rapidly excreted in the urine. The unabsorbed diloxanide is the active antiamebic substance. Diloxanide furoate is the drug of choice for asymptomatic infections. For mild intestinal disease, and other forms of amebiasis it is used with another drug. 2.4.6. Iodoquinol Iodoquinol is effective against organisms in the bowel lumen but not against trophozoites in the intestinal wall or extraintestinal tissues. The mechanism of action of iodoquinol against trophozoites is unknown. Iodoquinol is an alternative drug for the treatment of asymptomatic or mild to moderate intestinal amebiasis. Adverse Effects: Reversible severe neurotoxicity (optic atrophy, visual loss, and peripheral neuropathy). Mild and infrequent adverse effects that can occur at the standard dosage include diarrhea, which usually stops after several days, anorexia, nausea and vomiting, gastritis, abdominal discomfort, slight enlargement of the thyroid gland, headache, skin rashes, and perianal itching. 2.4.7. Paromomycin Sulfate Paromomycin is an alternative drug for the treatment of asymptomatic amebiasis. In mild to moderate intestinal disease, it is an alternative luminal drug used concurrently with metronidazole. Paromomycin is both directly and indirectly amebicidal; the indirect effect is caused by its inhibition of bowel bacteria. It can be used only as a luminal amebicide and has no effect in extraintestinal amebic infections. 187 2.4.8. Other Antibiotics The tetracyclines (oxytetracycline) have very weak direct amebicidal action, and useful with a luminal amebicide in the eradication of mild to severe intestinal disease. Erythromycin although less effective can be used in the treatment of luminal amebiasis.
Drugs used in Giardiasis and Trichomoniasis Metronidazole is a drug of choice for gardiasis and trichomoniasis, and the alternate drug is tinidazole.
Treatment of Leishmaniasis Kala-azar, cutaneous, and mucocutaneous leishmaniasis are caused by the genus Leishmania. Treatment of leishmaniasis is difficult because of drug toxicity, the long courses of treatment, treatment failures, and the frequent need for hospitalization. The drug of choice is sodium antimony gluconate (sodium stibogluconate). Alternative drugs are amphotericin B and pentamidine. 4.1. Amphotericin B Amphotericin B is injected slowly intravenously. Patients must be closely monitored in hospital, because adverse effects may be severe.
Treatment of Pneumocystis Carinii Pneumonia, Trypanosomiasis 5.1. Pentamidine Pentamidine is administered parenterally because it is not well absorbed from the gastrointestinal tract. The drug leaves the circulation rapidly and is bound avidly by the tissues, especially the liver, spleen, and kidneys. The drug is excreted slowly and unchanged in the urine. Pentamidine does not cross the blood-brain barrier. Antiparasitic Action: The mechanisms of pentamidine’s antiparasitic action are not well known. The drug may interfere with the synthesis of DNA, RNA, phospholipids, and proteins. Clinical Uses
Leishmaniasis
Trypanosomiasis: In African trypanosomiasis, pentamidine is an alternative in the hemolymphatic stage of the disease to (1) suramin in Trypanosoma brucei gambiense and T b rhodesiense infections or to (2) eflornithine in T b gambiense infection.
Pneumocystosis Adverse Effects: Pain at the injection site is common; infrequently, a sterile abscess develops and ulcerates. Occasional reactions include rash, gastrointestinal symptoms, neutropenia, abnormal liver function tests, serum folate depression, hyperkalemia, and hypocalcemia. Severe hypotension, hypoglycemia, hyperglycemia, hyponatremia, and delayed nephrotoxicity.
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