Hindu College of PG Courses Submitted by Sirigiri Vijayalakshmi M.Sc (Chemistry)

Malaria Most important parasitic disease of humans, causing hundreds of millions of illnesses and probably over a million deaths each year

Antimalarial drugs Antimalarial drugs are used for the treatment and prevention of malaria infection. Most antimalarial drugs target the erythrocytic stage of malaria infection, which is the phase of infection that causes symptomatic illness. The extent of pre-erythrocytic (hepatic stage) activity for most antimalarial drugs is not well characterized.

Treatment Treatment of the acute blood stage infection is necessary for malaria caused by all malaria species. For infection due to Plasmodium ovale or P. vivax, terminal prophylaxis is required with a drug active against hypnozoites (which can remain dormant in the liver for months -- and occasionally years -- after the initial infection).

4-aminoquinolines Chloroquine: has activity against the blood stages of Plasmodium ovale, P. malariae, and susceptible strains of P. vivax and P. falciparum. Widespread resistance in most malaria- endemic countries has led to decline in its use for the treatment of P. falciparum, although it remains effective for treatment of P. ovale, P. malariae, and, in most regions, P. vivax.

Chloroquine MECHANISM OF ACTION :  Binds to and inhibits DNA and RNA polymerase; interferes with metabolism and hemoglobin utilization by parasites; inhibits prostaglandin effects; chloroquine concentrates within parasite acid vesicles and raises internal pH resulting in inhibition of parasite growth; may involve aggregates of ferriprotoporphyrin IX acting as chloroquine receptors causing membrane damage; may also interfere with nucleoprotein synthesis.

DOSING: ADULTS Malaria, suppression or prophylaxis: Oral: 500 mg/week (300 mg base) on the same day each week; begin 1-2 weeks prior to exposure; continue for 4-6 weeks after leaving endemic area; if suppressive therapy is not begun prior to exposure, double the initial loading dose to 1 g (600 mg base) and administer in 2 divided doses 6 hours apart, followed by the usual dosage regimen. Malaria, acute attack: Oral: 1 g (600 mg base) on day 1, followed by 500 mg (300 mg base) 6 hours later, followed by 500 mg (300 mg base) on days 2 and 3.

Side effects of chloroquine include headaches, dizziness, abdominal discomfort, vomiting, and diarrhea. Chloroquine may also produce pruritus in some patients; this has been noted to occur most frequently in African populations. The pruritus is transient, lasting 48 to 72 hours, and is not responsive to antihistamines.

As clinical curative: Sulfadoxine 1500 mg + pyrimethamine 75 mg (3 tab) single dose Children 9-14 yr 2 tab 4-8 yr 1 tab 1-4 yr ½ tab

ANTIFOLATES Antifolates include sulfonamides, pyrimethamine, proguanil and dapsone. These drugs act synergistically to target enzymes involved in folate synthesis, a pathway required for parasite DNA synthesis

Mechanism of action of antifolates

ANTIMICROBIALS Tetracycline, doxycycline, and clindamycin target prokaryotic protein synthesis. In malaria parasites, these drugs appear to target the apicoplast, an organelle derived from prokaryotic ancestors. They have relatively slow antimalarial activity because they exert their toxic effects in the subsequent cycle of cell division. They are typically paired with fast-acting antimalarials (usually quinine). Doxycycline has a longer half life than tetracycline so is used more commonly. Resistance has not been detected to tetracycline, doxycycline or clindamycin.

ARTEMISININ DERIVATIVES The artemisinins are derived from the leaves of the Chinese sweet wormwood plant, Artemisia annua. They have been used in China for the treatment of malaria for over 2000 years and came to attention outside of China in the 1970s and 1980s.

Treatment Uncomplicated P.falciparum malaria (oral): Mefloquine (Lariam) Proguanil/atovaquone (Malarone) Chloroquine (Aralen) Pyrimethamine/sulfadoxine (Fansidar) Quinine sulfate with antibiotics.