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Anti-malarial Drugs. Dr Chetna Desai Professor and Head Department of Pharmacology G.M.E.R.S. Medical College, Ahmedabad. Antimalarial drugs. Malaria is caused by four species of protozoa: Plasmodium malariae. P. falciparum. P. vivax. P. ovale (rare)
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Anti-malarial Drugs Dr Chetna Desai Professor and Head Department of Pharmacology G.M.E.R.S. Medical College, Ahmedabad
Antimalarial drugs • Malaria is caused by four species of protozoa: • Plasmodium malariae. • P. falciparum. • P. vivax. • P. ovale (rare) • The plasmodium transmitted to human by the bite of an infected female anopheles mosquito.
Malaria transmission life cycle: • Sporozoites tissue schizonts (in liver) merozoites infect RBC (blood schizonts) rupture of RBC (clinical attack) new crops of merozoites • Sexual form: some merozoites differentiate into male & female gametocytes ingested by a mosquito where they form Sporozoites human
P. malariae & p. falciparum have one cycle of liver invasion and end by the 4th week i.e. no relapse occurs. • P.ovale & p. vivax have dormant stages (hypnozoites) in the liver. These hypnozoites may rupture months or years later causing relapse of the attacks.
Choice of antimalarial drug • Efficacy and half-life • • Acceptability and adherence to treatment formulations) • • Effectiveness • • Adverse effects • • Drug interactions and contraindications • • Use in special groups, e.g. pregnant women, infants • • Capacity of health system to implement policy • • Cost-effectiveness, affordability of various regimens • • Reported resistance and/or cross-resistance
Blood Schizonticides Chloroquine (4- aminoquinoline derivative) Mechanism of action: • Inhibits synthesis of DNA and RNA in the plasmodium. • Increases pH of the vacuoles in the parasite, so prevent its utilization of erythrocyte hemoglobin. Uses: • Acute attack
Other uses: • Amebic liver abscess (as chloroquine is concentrated in the liver). • Anti-inflammatory in autoimmune diseases e.g. rheumatoid arthritis A/E: GIAE rash, headache, peripheral neuritis, cardiac depressant, retinal damage(X use > 5 years without regular ophthalmic examination), toxic psychosis.
Quinine: Mechanism of action: • Inhibits DNA strand separation, transcription and protein synthesis. Uses: • CQ resistant P. falciparum (orally). • Cerebral malaria (i.v infusion until patient can take the drug orally). A/E: • Cinchonism i.e. headache, dizziness, & tinnitus. • Inhibits cardiac conductivity • hemolysis in G-6-P D and black water fever (intravascular hemolysis).
Qinghaosu (Artemisinin) • Chinese herbal medicine used as antipyretic. • Blood schizonticide against all types of malaria including CQR PF • Unknown mechanism of action. Uses: • P. falciparum cerebral malaria (oral & parenteral). • Not used for prophylaxis • Used in pregnancy – only in 2nd & 3rd trimesters
Antifolates (sulfonamides & sulfones): Synergistic blockade of folic acid synthesis • Sulfonamide inhibits dihydropteroate synthetase, inhibits folic acid synthesis. • Pyrimethamine and proguanil inhibit dihydrofolate reductase, so inhibit tetrahydrofolate (folinic acid synthesis).
Fansidar • Combination of sulfadoxine and pyrimethamine. • It is used in CQ R PF. A.E: • Sulfonamide: rashes, renal damage, hemolysis & GIAE, SJ syndrome. • Pyrimethamine: FA deficiency, agranulocytosis Disadvantages: slow blood schizonticide activity, drug resistance & numerous serious adverse effects. C/I:pregnant & nursing women, G-6-PD, renal impairment & children under 2 months of age.
Primaquine • Tissue schizonticide. • It has a cellular oxidant activity and possibly interferes with mitochondrial function. • Gametocide, so inhibits transmission of infection by mosquito. Uses: • Eradication of liver stages (hypnozoites) of P.vivax & P.ovale, after standard chloroquine therapy to prevent relapse. A/E:GIT upset, pruritus, headache, methemoglobinemia, hemolysis especially in G-6-PD.
Doxycycline • Tetracycline derivative • Longer half life • Reliable absorption • Better safety profile in renal insufficiency • Use: • Drug resistant P Falciparum along with quinine • Prophylaxis
Adverse Effects: • GIAE • Oesophageal ulceration • Take sufficient water • X Pregnancy and lactation, Children upto 8 years
Clindamycin • Lincosamide antibiotic • Inhibits protein synthesis • 90% is absorbed by GIT • Use: CQ RPF • Safe in pregnancy and children • Lesser risk of resistance • A/E: ANVD • Pseudomembranous colitis • Hypersensitivity reactions • BM depression • Hepatic damage