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Malaria is caused by Plasmodium parasites transmitted through mosquito bites. There are four main species that cause malaria in humans. The life cycle involves the parasite reproducing in the liver and blood of humans and mosquitoes. Symptoms include fever, chills, and flu-like illness. Common antimalarial drugs include chloroquine, amodiaquine, quinine, primaquine, and artemisinins. Chloroquine is often used for treatment and prevention, but resistance has emerged, particularly for P. falciparum.
Malaria is caused by Plasmodium parasites transmitted through mosquito bites. There are four main species that cause malaria in humans. The life cycle involves the parasite reproducing in the liver and blood of humans and mosquitoes. Symptoms include fever, chills, and flu-like illness. Common antimalarial drugs include chloroquine, amodiaquine, quinine, primaquine, and artemisinins. Chloroquine is often used for treatment and prevention, but resistance has emerged, particularly for P. falciparum.
Malaria is caused by Plasmodium parasites transmitted through mosquito bites. There are four main species that cause malaria in humans. The life cycle involves the parasite reproducing in the liver and blood of humans and mosquitoes. Symptoms include fever, chills, and flu-like illness. Common antimalarial drugs include chloroquine, amodiaquine, quinine, primaquine, and artemisinins. Chloroquine is often used for treatment and prevention, but resistance has emerged, particularly for P. falciparum.
It is protozoal disease caused by Plasmodium species, which
are carried by the female anopheles mosquito
Etiology: Four Plasmodium species are responsible for human malaria, P. falciparum, P. vivax, P. ovale P. malariae.
BLOOD AND TISSUE PROTOZOA Antiprotozoal Drugs Epidemiology: There are about 200 million estimated global cases of malaria with a mortality of more than one million. P. falciparum (malignant tertian malaria) and P. malariae (quartan malaria) are the most common species and are found in Asia and Africa. P. vivax (benign tertian malaria) predominates in Latin America, India and Pakistan, whereas, P. ovale (ovale tertian malaria) is almost exclusively found in Africa.
Life cycle of malarial parasite Three stages Schizogony Gametogony Sporogony
The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host. After initial replication in the liver (exoerythrocytic schizogony), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony). Multiplication of the blood stage parasites is responsible for the clinical manifestations of the disease. In the blood, some parasites differentiate into sexual erythrocytic stages (gametocytes). The gametocytes, after ingestion by an Anopheles mosquito during a blood meal, undergo a sporogonic cycle yielding sporozoites.?Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle. Of note, in P. vivax and P. ovale, a dormant stage (hypnozoites) can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later P. falciparum:
It has an erythrocytic cycle of 48 hours in humans
It produces malignant tertian malaria-'tertian' because the fever was believed to recur every third day (actually, it varies), 'malignant' because it is the most severe form of malaria and can be fatal.
The plasmodium induces, on the infected red cell membrane, receptors for the adhesion molecules on vascular endothelial cells. These parasitised red cells then stick to uninfected red cells, forming clusters (rosettes), and also adhere to and pack the vessels of the microcirculation, interfering with tissue blood flow and causing organ dysfunction including renal failure and encephalopathy (cerebral malaria).
It does not have an exoerythrocytic stage, so if the erythrocytic stage is eradicated, relapses do not occur. P. vivax It produces benign tertian malaria-
'Benign' because it is less severe than falciparum malaria and is rarely fatal.
Exoerythrocytic forms may persist for years and cause relapses.
P. ovale which has a 48-hour cycle and an exoerythrocytic stage, is the cause of a rare form of malaria.
P. malariae has a 72-hour cycle, causes quartan malaria and has no exoerythrocytic cycle.
Symptoms: The symptomatology of malaria depends on parasitemia, the presence of the organism in different organs and the parasite burden. The incubation period varies generally between 10-30 days.
The chill and fever follows a cyclic pattern (paroxysm) with the symptomatic period lasting 8-12 hours. This interval is about 34-36 hours in the case of P. vivax and P. ovale (tertian malaria), and 58-60 hours in the case of P. malariae (quartan malaria). Classical tertian paroxysm is rarely seen in P. falciparum: persistent spiking or a daily spasm/convulsion is more usual.
Fever is associated with severe headache, nausea (vomiting) and convulsions. The patient experiences euphoria, and profuse perspiration and the temperature begins to drop. Within a few hours the patient feels exhausted but symptomless and remains symptomatic until the next paroxysm.
Each paroxysm is due to the rupture of infected erythrocytes and release of parasites This organism causes sequestration of capillary vasculature in the brain, gastrointestinal and renal tissues. Chronic malaria results in splenomegaly, hepatomegaly and nephritic syndromes.
Treatment wise Drugs used to treat the acute attack: Blood schizonticidal agents means act on erythroctic form This group of drugs includes quinine and mefloquine, chloroquine, halofantrine, sulfones, pyrimethamine and proguanil, as well as the hydroxynaphthoquinone compound atovaquone.
Drugs that effect a radical cure: Tissue schizonticidal agents Acting on the parasites in the liver Only the 8-aminoquinolines (e.g. primaquine and tafenoquine) have this action. These drugs also destroy gametocytes and thus reduce the spread of infection Drugs used for chemoprophylaxis They block the link between the exoerythrocytic stage and the erythrocytic stage, and thus prevent the development of malarial attacks. chloroquine, mefloquine, proguanil, pyrimethamine, dapsone and doxycycline. They are often used in combinations. Drugs used to prevent transmission Some drugs (e.g. primaquine, proguanil and pyrimethamine) have the additional action of destroying the gametocytes preventing transmission by the mosquito and thus preventing the increase of the human reservoir Structures of the major drugs. CHLOROQUINE
Chemistry
Chloroquine is a synthetic 4-aminoquinoline formulated as the phosphate salt for oral use. Antimalarial Action & Resistance
A. Antimalarial Action: Chloroquine is a highly effective blood schizonticide and remains the principal antimalarial drug in much of the world. I It is also moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P. falciparum.
Chloroquine is not active against liver stage parasites.
B. Mechanism of Action: The mechanism of action remains controversial. Chloroquine probably acts by concentrating in parasite food vacuoles, preventing the polymerization of the hemoglobin breakdown product, heme, into hemozoin and thus eliciting parasite toxicity due to the buildup of free heme.
C. Resistance: Resistance to chloroquine is now very common among strains of P falciparum and uncommon but increasing for P vivax. Resistance appears to result from enhanced efflux of the drug from parasitic vesicles
Pharmacokinetics It is rapidly and almost completely absorbed from the gastrointestinal tract, reaches maximum plasma concentrations in about 3 hours, and is rapidly distributed to the tissues.
The complex pharmacokinetics of chloroquine necessitate the use of a loading dose to rapidly achieve effective serum concentrations . I
It has a very large apparent volume of distribution of 100-1000 L/kg and is slowly released from tissues and metabolized.
Chloroquine is principally excreted in the urine with an initial half-life of 3-5 days but a much longer terminal elimination half-life of 1-2 months.
Clinical Uses
A. Treatment: Chloroquine is the drug of choice for the treatment of nonfalciparum and sensitive falciparum malaria. B. Chemoprophylaxis: Chloroquine is the preferred chemoprophylactic agent in malarious regions without resistant falciparum malaria. Eradication of P vivax and P ovale requires a course of primaquine to clear hepatic stages.
C. Amebic Liver Abscess D. It is also used in rhuematoid arthritis E. Giardiasis, Taeniasis Chloroquine is considered to be safe for use by pregnant women. Adverse Effects: Skin rash, angioneuroticedema, photosensitivity , exfoliated dermatitis Pruritus is common, primarily in Africans. Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Parentral administration produces Convulsion , arrythmia,hypotension, cardiac depression The long-term administration of high doses of chloroquine for rheumatologic diseases can result in irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy etc.
AMODIAQUINE
Amodiaquine is closely related to chloroquine, and it probably shares mechanisms of action and resistance with that drug. Amodiaquine has been widely used to treat malaria in many countries because of its low cost, limited toxicity, and, in some areas, effectiveness against chloroquine- resistant strains of P falciparum.
QUININE & QUINIDINE
Introduction
Quinine and quinidine remain first-line therapies for falciparum malaria specially severe disease though toxicity concerns complicate therapy. Resistance to quinine is uncommon but increasing.
Antimalarial Action & Resistance
A. Antimalarial Action: Quinine is a rapidly acting, highly effective blood schizonticide against the four species of human malaria parasites. The drug is gametocidal against P vivax and P ovale but not P falciparum.
It is not active against liver stage parasites. The mechanism of action of quinine is unknown.
B. Resistance: Increasing in vitro resistance of parasites from a number of areas suggests that quinine resistance will be an increasing problem in the future
Pkinetics: Quinine is well absorbed and is usually administered orally as a 7-day course, but it can also be given by slow intravenous infusion for severe P. falciparum infections and in patients who are vomiting. The half-life of the drug is 10 hours It is metabolised in the liver and the metabolites are excreted in the urine within about 24 hours.
Clinical Uses
A. Parenteral Treatment of Severe Falciparum Malaria: B. Oral Treatment of Falciparum Malaria C. Malarial Chemoprophylaxis
Adverse Effects : Tinnitus, headache, nausea, dizziness, flushing, and hearing visual disturbances, a constellation of symptoms termed cinchonism. Severe hypotension and severe CNS disturbances such as delirium and coma can follow too-rapid intravenous infusions of quinine or quinidine. Electrocardiographic abnormalities (QT prolongation- cardiac dysrhythmias ) are fairly common with intravenous quinidine. Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria. It also produces blood dyscrasias (especially thrombocytopenia) and hypersensitivity It also increase insulin release so can cause hypoglycemia
MEFLOQUINE
Introduction
Mefloquine is effective therapy for many chloroquine-resistant strains of P falciparum and against other species.
Chemistry & Pharmacokinetics
Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. .
Antimalarial Action & Resistance
A. Antimalarial Action: Mefloquine has strong blood schizonticidal activity against P falciparum and P vivax, but it is not active against hepatic stages or gametocytes. The mechanism of action of mefloquine is unknown.
B. Resistance: Sporadic resistance to mefloquine has been reported from many areas. At present, resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance appears to be associated with resistance to quinine and halofantrine but not with resistance to chloroquine.
PKinetics: It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-dose treatment regimen. The terminal elimination half-life is about 20 days, allowing weekly dosing for chemoprophylaxis. With weekly dosing, steady state drug levels are reached over a number of weeks; this interval can be shortened to 4 days by beginning a course with three consecutive daily doses of 250 mg, though this is not standard practice. Mefloquine and acid metabolites of the drug are slowly excreted, mainly in the feces. The drug can be detected in the blood for months after the completion of therapy Clinical Uses A. Chemoprophylaxis B. Treatment: Mefloquine is effective in treating most falciparum malaria, but the drug has not been approved by the FDA for this purpose. The drug is not appropriate for treating individuals with severe or complicated malaria since quinine and quinidine are more rapidly active and drug resistance is less likely with those agents.
PRIMAQUINE , Tafequine, etaquine
Introduction
Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P ovale.
Antimalarial Action & Resistance
A. Antimalarial Action: Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active against the dormant hypnozoite stages of P vivax and P ovale. B. Primaquine acts against erythrocytic stage parasites, but this activity is too weak to play an important role. C. The mechanism of antimalarial action is unknown.
B. Resistance: Some strains of P vivax in New Guinea, Southeast Asia, and perhaps Central and South America are relatively resistant to primaquine. Liver forms of these strains may not be eradicated by a single standard treatment with primaquine and may require repeated therapy with increased doses (eg, 30 mg base daily for 14 days) for radical cure. Pharmacokinetic Primaquine is given orally and is well absorbed. Its metabolism is rapid, and very little drug is present in the body after 10-12 hours. The half-life is 3-6 hours Tafenoquine is broken down much more slowly and therefore has the advantage that it can be given on a weekly basis
Clinical Uses
Therapy (Radical Cure) of Acute Vivax and Ovale Malaria Terminal Prophylaxis of Vivax and Ovale Malaria C. Chemoprophylaxis of Malaria. D. Gametocidal Action E. Pneumocystis carinii Infection.
Adverse Effects : nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common with higher dosages and when the drug is taken on an empty stomach. More serious but rare adverse effects include leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. Standard doses of primaquine may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects.
INHIBITORS OF FOLATE SYNTHESIS
Introduction
Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, for the treatment and prevention of malaria.
Chemistry & Pharmacokinetics
Pyrimethamine is a 2,4-diaminopyrimidine related to trimethoprim Proguanil is a biguanide derivative
Antimalarial Action & Resistance
A. Antimalarial Action: Pyrimethamine and proguanil act slowly against erythrocytic forms of susceptible strains of all four human malaria species..
B Mechanism of Action: Pyrimethamine and proguanil selectively inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase.
C. Resistance: In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less common for P vivax. Resistance is due, at least in part, to mutations in dihydrofolate reductase and dihydropteroate synthase. Because different mutations may mediate resistance to different agents, cross- resistance is not uniformly seen.
Clinical Uses
Chemoprophylaxis: Treatment of Chloroquine-Resistant Falciparum Malaria Presumptive Treatment of Falciparum Malaria Toxoplasmosis Pneumocystosis
HALOFANTRINE -
Halofantrine hydrochloride, a phenanthrene-methanol related to quinine, is effective against erythrocytic stages of all four human malaria species.
It is not active against hepatic stages or gametocytes. Halofantrine is rapidly effective against most chloroquine-resistant strains of P falciparum, but its use is limited by irregular absorption and cardiac toxicity. T1/2: 4-6 hr and metabolite with 1-2 day
In addition, cross-resistance with mefloquine may occur.
ARTEMISININ & ITS DERIVATIVES
Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide , Artemisinin and analogs are very rapidly acting blood schizonticides against all human malaria parasites. Artemisinin has no effect on hepatic stages. Artemisinin-resistant P falciparum has not yet been identified. The antimalarial activity of artemisinin probably results from the production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge in the parasite food vacuole.
ANTIBIOTICS
Tetracycline and doxycycline are active against erythrocytic schizonts of all human malaria parasites. Clindamycin is slowly active against erythrocytic schizonts and can be used in conjunction with quinine or quinidine in those for whom doxycycline is not recommended, such as children and pregnant women. Azithromycin also has antimalarial activity and is now under study as an alternative chemoprophylactic drug.
Antimalarial activity of fluoroquinolones has been demonstrated, but efficacy for the therapy or chemoprophylaxis of malaria has been suboptimal.
Antibiotics also are active against other protozoans.
ATOVAQUONE
Atovaquone, a hydroxynaphthoquinone was initially developed as an antimalarial but has been approved by the FDA for the treatment of mild to moderate P carinii pneumonia.
The drug is only administered orally.
Atovaquone is an alternative therapy for P carinii infection, though its efficacy is lower than that of trimethoprim-sulfamethoxazole.