Lecture 11 Antimalarial Drugs PDF

‫بسم ﷲ الرحمن الرحيم‬ The Antimalarial Agents By Imad Addeen M Taj Addeen Faculty of Pharmacy Overview The term ‘Malaria’ is coined from the Italian phrase mal aria meaning ‘bad air’. Malaria is caused by parasitic protozoa of the genus Plasmodium and is characteri...

‫بسم ﷲ الرحمن الرحيم‬ The Antimalarial Agents By Imad Addeen M Taj Addeen Faculty of Pharmacy Overview The term ‘Malaria’ is coined from the Italian phrase mal aria meaning ‘bad air’. Malaria is caused by parasitic protozoa of the genus Plasmodium and is characterised by fever with rigor, anaemia and splenomegaly. The morbidity due to malaria in Asia and Africa has been greatly underestimated. Currently, it is estimated that nearly half a billion people in the world suffer from malaria, and more than a million die from malaria every year, most of them from the developing countries. Nearly 50% of the cases the world over are caused by Plasmodium falciparum. Life cycle of Plasmodium There are four major types of plasmodia which infect man: P. vivax, P. falciparum, P. ovale, and P. malariae In order to understand the actions of antimalarials, it is necessary to know parasite life cycle. An individual is infected by malarial parasites through the bite of a female Anopheles mosquito. The disease can also be transmitted by transfusion of infected blood and from mother to the fetus across the placenta. The salivary glands of the infected mosquito contain a large number of sporozoites, which are introduced into of the host during mosquito bite. After the entry, the sporozoites develop further through various stages: (1) Pre-erythrocytic stage, (2) Erythrocytic stage and (3) Development of sexual forms. (Figure) Life cycle of Plasmodium Pre-erythrocytic stage In the pre-erythrocytic stage, sporozoites disappear rapidly from the circulation and invade the hepatic cells (Hepatic cycle– Site I). The duration of the pre-erythrocytic stage varies with the species of plasmodium. It is 5–7 days for P. falciparum and 8 days to several months for P. vivax. The host does not develop any symptoms during this phase. At the completion of this phase, the infected reticuloendothelial cell, termed tissue schizont (primary exoerythrocyte form), releases several thousand merozoites into the blood stream. Life cycle of Plasmodium Life cycle of Plasmodium Erythrocytic stage In the erythrocytic stage (Site II), merozoites invade the erythrocytes and undergo further development and multiplication, giving rise to erythrocytic schizonts (asexual erythrocyte forms). The infected RBCs eventually rupture, and release thousands of merozoites into the blood. This periodic release of merozoites is associated with paroxysms of fever with rigor. The merozoites thus released invade fresh erythrocytes, and the cycle of erythrocytic schizogony repeats. Life cycle of Plasmodium Development of sexual forms starts with the differentiation of some of the released merozoites into male (macro) and female (micro) gametocytes (Site III). During a mosquito bite, these forms are sucked in from the blood and mature into gametes in the mosquito gut. The female gamete is fertilized by the motile male gamete to form a zygote. The zygote invades the gut wall of the mosquito to form an oocyst. The mature oocyst contains thousands of sporozoites. After about 1–4 weeks, depending upon the species of plasmodium, the oocyst ruptures releasing free sporozoites which reach the salivary glands of the mosquito and are ready to be injected in the host. Life cycle of Plasmodium The mentioned cycle in case of P. falciparum, terminates at this point. However P. vivax and P. ovale have persistent hepatic cycle due to presence of hypnozoites, also known as latent tissue phase or exoerythrocytic phase. The delayed formation of tissue schizonts from such latent hypnozoites explains the relapses of P. vivax and P. ovale malaria. In case of P. malariae, the relapse may originate from erythrocytic forms remaining in the body for up to 30 years, due to no exoerythrocytic schizogony. Antimalarial Drugs Chemical classification Cinchona alkaloids: Quinine and quinidine Quinoline derivatives: 4-Aminoquinolines: Chloroquine, hydroxychloroquine, amodiaquine and pyronaridine 8-Aminoquinolines: Primaquine, tafenoquine and bulaquine Quinoline methanol: Mefloquine Antimalarial Drugs Chemical classification Phenanthrene methanol: Halofantrine and lumefantrine Antifolates: Biguanides: Proguanil Diaminopyrimidines: Pyrimethamine Sulphonamides: Sulphadoxine Artemisinin compounds: Artesunate, artether and artemether Antimicrobials: Doxycycline, clindamycin and atovaquone Antimalarial Agents Chloroquine A blood schizonticidal agent. It is effective in erythrocytic forms of all four plasmodium species, but it does not have an effect on sporozoites, hypnozoites or gametocytes. Mechanism of Action It inhibits the haem polymerase, the enzyme that polymerizes toxic free heme to haemozoin. In the erythrocyte, malaria parasites feed on hemoglobin, and one of the byproducts of hemoglobin consumption is the highly reactive heme molecule. The parasite polymerizes heme so that it does not cause it harm. Chloroquine and related drugs interfere with heme polymerization, thus unleashing this highly toxic substance within the parasite, killing it. Chloroquine Therapeutic uses Chloroquine is used for the control of acute, recurrent attacks, but it is not radically curative. Chloroquine is effective against all plasmodia (P. falciparum, P. vivax, P. malariae, and P. ovale). For chloroquine-resistant plasmodia, quinine sulfate is used. Pyrimethamine/Sulphadoxine, doxycycline, quinidine, or clindamycin may be used as adjunctive therapy. In prophylaxis, chloroquine is used to suppress erythrocytic forms either before or during exposure; primaquine is added after exposure to treat exoerythrocytic forms. In regions with chloroquine-resistant strains, mefloquine or atovaquone/proguanil is used for prophylaxis. Doxycycline, an antibiotic, is used when multidrug resistance to P. falciparum is prevalent. Chloroquine is also occasionally used in rheumatoid arthritis for anti-inflammatory action and as an alternative with emetine for amebiasis. Chloroquine Resistance to chloroquine Many species of P. falciparum are resistant to chloroquine. Artemisinin analogues are now widely used instead. P. falciparum is now resistant to chloroquine in most parts of the world The resistance appears to be result from enhanced efflux of the drug from parasitic vesicles (genetic mutation). P. vivax resistance is also a growing problem in many parts of the world. Chloroquine Pharmacokinetic It is administered orally, IM or SC in small doses or in slow continuous IV infusion (severe falciparum malaria) Rapid parenteral administration or a single high dose (30 mg/kg) may be fatal It is completely absorbed, extensively distributed throughout the tissue, metabolized in the liver and excreted in urine (70% unchanged) Adverse drug reaction (ADR) Nausea, dizziness and, headache and urticaria (Pruritus is common) Retinopathies and blurring of vision (in large doses). Rarely, hemolysis can develop in glucose-6-phosphate dehydrogenase deficient persons. Antimalarial Agents Quinine Derived from cinchona, it has been used for treatment of fevers since the 16th century It is a blood schizonticidal agent, effective in the erythrocytic forms or on the gametocyte of P. falciparum It acts by the same mechanism of chloroquine but it is not extensively concentrated in plasmodium as does chloroquine Pharmacological action on host include: depressant action on heart, mild oxytocic effect on uterus in pregnancy, slight blocking action on the neuromuscular junction and as a weak antipyretic effect. Quinine Therapeutic uses It is primarily used to treat chloroquine-resistant P. falciparum, often in combination with doxycycline. Adverse drug reaction (ADR) Quinine has a low therapeutic index. This agent produces curare-like effects on the skeletal muscle. Bitter taste, nausea, vomiting and it can cause headache, visual disturbances, dizziness, and tinnitus (cinchonism). Hypoglycemia, which can be fatal, and (rarely) hypotension may also occur. Cardiac dysrhythmias and severe CNS disturbances. Quinine is associated with “blackwater fever” in previously sensitized patients; although rare, black water fever has a fatality rate of 25%due to intravascular coagulation and renal failure. Quinine Pharmacokinetic Quinine is well absorbed and is usually administered orally as a seven days course, but it can also be given by slow intravenous infusion for severe P. falciparum infections and in patient who are vomiting, a loading dose may be required, but rapid IV administration is contraindicated because of the risk of cardiac dysrhythmias. Resistance to quinine Some degree of resistance to quinine is developing because of increase expression of plasmodial drug efflux transporter. Antimalarial Agents Mefloquine Uses: mefloquine is useful for prophylaxis and the treatment of chloroquine-resistant P. falciparum and with chloroquine for prophylaxis against P. vivax and P. ovale. It acts specifically on the erythrocytic stage of infection (a blood schizonticidal compound) For eradication of P. falciparum, it is used with artesunate. For eradication of P. ovale and P. vivax, it is used with primaquine. Pharmacokinetic: mefloquine is given orally and is rapidly absorbed, it has a slow onset of action and a very long plasma half life up to 30 days. Mefloquine ADR and contraindications Mefloquine causes GI disturbances at therapeutic doses. Seizures and severe CNS toxicity e.g. drowsiness and dizziness and other CNS manifestations are also seen. Use of mefloquine is contraindicated in patients with epilepsy or psychiatric disorders, and in patients using drugs that alter cardiac conduction Resistance to mefloquine Resistance has occurred in P. falciparum in some areas by increased expression in the parasite of drug efflux transporter Antimalarial Agents Lumefantrine It is used in combination with artemether. Lumefantrine by the same mechanism of chloroquine. ADR: GIT disturbances and CNS symptoms. Primaquine (8-aminoquinoline) Primaquine does not affect sporozoite and has little action against the erythrocytic stage of the parasite, however it has a gametocidal action It is the most effective antimalarial drug for preventing transmission of the disease in all four species of plasmodia. It is almost used in combination with another drug usually chloroquine Primaquine Uses of primaquine: in combination with chloroquine, primaquine is used specifically to eliminate liver hypnozoites after exposure to P. vivax or P. ovale for terminal prophylaxis and (radical) cure from malaria. It can be also be used for prophylaxis before exposure (casual prophylaxis) when other drugs are ineffective or unavailable. Etaquine and Tafenoquine are more active and slowly metabolite analogues of primaquine. These drugs can affect a radical cure of P.vivax and P. ovale malaria in which the parasite have a dormant stage in the liver Primaquine  Pharmacokinetic: primaquine is given orally and it is well absorbed.  Primaquine is not given parenterally because of severe hypotension.  Blood dyscrasias or arrhythmias may rarely occur.  ADR: GIT symptoms can occur, methaemoglobinaemia with cyanosis and hemolysis in G6PDD (in large doses).  Due to the relative deficiency of glucose-6-phosphate dehydrogenase, use of this agent is not advised during the first trimester of pregnancy.  Resistance: it is rare although evidence of decreased sensitivity of some P. vivax strains has been reported. Antimalarial Agents Drugs affecting folate metabolism The main sulfonamides used in malaria treatment is sulphadoxine, and the only sulfone used is dapsone They are active against erythrocytic form of P. falciparum but are less active against those of P. vivax, they have no activity against sporozoites or hypnozoites form of plasmodia. Pyrimethamine-sulphadoxine (Fansidar) has been extensively used for chloroquine resistant malaria but resistance to this combination has developed in many areas. Pyrimethamine, and its prodrug analogue proguanil, inhibit dihydrofolate reductase of plasmodia at concentrations less than that needed to inhibit the host enzyme. Drugs affecting folate metabolism Proguanil have additional effect on the initial hepatic stage but not the hypnozoite of the P. vivax. Proguanil is a prodrug and it is metabolized in the liver to its active form cycloguanil The mechanism of antimalarial action of proguanil is uncertain. Its metabolite, cycloguanil, selectively inhibits plasmodia dihydrofolate reductase/thymidylate synthetase to inhibit DNA synthesis. Pyrimethamine is used only in combination with either sulfone or sulfonamide-sulphadoxine Pharmacokinetic: both pyrimethamine and proguanil are given orally and are well and slowly absorbed Drugs affecting folate metabolism ADR: pyrimethamine–dapsone (large doses) cause hemolytic anemia, agranulocytosis and eosinophilic alveolitis The pyrimethamine-sulphadoxine combination cause serious skin reactions, blood dyscrasias and allergic alveolitis. In high doses cause megaloblastic anemia and folate deficiency (at high doses). Resistance: resistance occur from single point mutations in the genes encoding the parasite dihydrofolatereductase. Antimalarial Agents Artemesinin and related compounds: Artemesinin is a fast acting blood schizonticidal agent. It is effective in treating the acute attack of malaria, including chloroquine resistant and cerebral malaria. Artesunate (water soluble derivative ) and the synthetic analogues artemether and artether They are concentrated in parasitized red cell. They act through inhibition of parasite calcium dependent ATPase These drugs are without effect on liver hypnozoites Artemesinin and related compounds: Pharmacokinetics Artemesinin can be given orally or IM, artesunate can be given orally. They are rapidly absorbed and widely distributed, converted in the liver into active metabolite dihydro artemesinin The half lives of artemesinin, artesunate and artemether are 4 hours, 45 minutes and 4-11 hours respectively. Resistance Resistance is developing in some countries. ADR Transient heart block, and decrease in blood neutrophile count and brief episode of fever have been reported. Antimalarial Agents Atovaquone Drug used prophylactically to prevent malaria It acts primarily to inhibit parasite mitochondrial electron transport gene possibly by mimicking the natural substrate ubiquinone. Atovaquone is usually used in combination with antifolate drug (proguanil) because they act synergistically. The mechanism underlying this synergism is not known but it is specific for this particular pair of drug, because other antifolate drugs or electron transport inhibitor have no such synergistic effect. When combined with proguanil atovaquone is highly effective and well tolerated. Atovaquone Resistance to atovaquone: Resistance alone is rapid and it result from a single point mutation in the gene cytochrome enzymes. ADR: Include abdominal pain, nausea and vomiting. Potential new antimalarial drugs Several new drugs are currently under test for anti- malarial activity with positive results in animals and preliminary trials in human. One of these is pyronardine has shown encouraging results It is active against P. falciparum and P. vivax and is also active against chloroquine resistant P. falciparum. It is effective orally and has low toxicity, its mechanism of action is unknown. Action of Antimalarial Agents