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 2 nd & 3 rd 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.

Treatment of malaria P. vivax, P. ovale & P. malariae: Chloroquine NB: It is also allowed in pregnancy. P. Falciparum (most cases are CQR):  Quinine 600 mg salt/8h till patient become better and blood is free of parasites (usually in 3-5 days).  Followed by a single dose of fansidar (3 tablets).  In pregnancy 7-day course of quinine alone should be given.

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

Thanks