Antimalarial drugsAntimalarial drugsMalaria is cause by four species of protozoa:Malaria is cause by four species of protozoa: Plasmodium malariae.Plasmodium malariae. P. falciparum.P. falciparum. P. vivax.P. vivax. P. ovale (rare).P. ovale (rare).The plasmodium transmitted to human by theThe plasmodium transmitted to human by thebite of an infected bite of an infected female anopheles mosquito.female anopheles mosquito.

Malaria transmission life cycleMalaria transmission life cycle::Sporozoites Sporozoites tissue schizonts (in liver) tissue schizonts (in liver) merozoites infect RBC (blood merozoites infect RBC (blood schizonts)schizonts) rupture of RBC (clinical rupture of RBC (clinical attack) attack) new crops of merozoites new crops of merozoites Sexual formSexual form: some merozoites : some merozoites differentiate into male & female differentiate into male & female gametocytes gametocytes ingested by a mosquito ingested by a mosquito where they form where they form SporozoitesSporozoites humanhuman

P. malariae & p. falciparumP. malariae & p. falciparum have have one cycleone cycle of liver invasion and end by the 4th week of liver invasion and end by the 4th week i.e. no relapse occurs.i.e. no relapse occurs.P.ovale & p. vivaxP.ovale & p. vivax have dormant stages have dormant stages ((hypnozoiteshypnozoites) in the liver. These ) in the liver. These hypnozoites may rupture months or years hypnozoites may rupture months or years later causing relapse of the attacks.later causing relapse of the attacks.

Blood SchizonticidesBlood Schizonticides

Chloroquine (4- aminoquinoline derivative)Chloroquine (4- aminoquinoline derivative)Mechanism of actionMechanism of action::

Inhibits synthesis of DNA and RNA in the Inhibits synthesis of DNA and RNA in the plasmodium.plasmodium.Increases pH of the vacules in the parasite, so Increases pH of the vacules in the parasite, so prevent its utilization of erythrocyte hemoglobin.prevent its utilization of erythrocyte hemoglobin.

Uses:Uses:Acute attack 600 mg base (4 tab.) then 300 mg Acute attack 600 mg base (4 tab.) then 300 mg after 6 h. then 150 mg bid for two more days.after 6 h. then 150 mg bid for two more days.Add 100 mg proguanil/ day (2 tab.) in Add 100 mg proguanil/ day (2 tab.) in chloroquine-resistant area.chloroquine-resistant area.

Chemoprophylaxis:Chemoprophylaxis:300 mg base (2 tab.) / week, 300 mg base (2 tab.) / week, one week before entering the endemic one week before entering the endemic area area & 4 weeks after leaving.& 4 weeks after leaving.

Other uses:Other uses:

Amebic liver abscess (as chloroquine is Amebic liver abscess (as chloroquine is concentrated in the liver).concentrated in the liver).

Anti-inflammatory in autoimmune diseases e.g. Anti-inflammatory in autoimmune diseases e.g. rheumatoid arthritis (unknown mechanism).rheumatoid arthritis (unknown mechanism).

A/EA/E: GIT upset, rash, headache, peripheral : GIT upset, rash, headache, peripheral neuritis, cardiac depressant, retinal damage neuritis, cardiac depressant, retinal damage ((don’t use chloroquin> 5 years without regular don’t use chloroquin> 5 years without regular ophthalmic examination),ophthalmic examination), toxic psychosis and toxic psychosis and precipitates porphyria.precipitates porphyria.

QuinineQuinine::Mechanism of actionMechanism of action: :

Inhibits DNA strand separation.Inhibits DNA strand separation.Inhibits transcription and protein synthesis.Inhibits transcription and protein synthesis.

Uses:Uses:Chloroquine-resistant Chloroquine-resistant P. falciparumP. falciparum (orally). (orally).Cerebral malaria (i.v infusion 10 mg/kg over 4 h.). it Cerebral malaria (i.v infusion 10 mg/kg over 4 h.). it could repeated at an intervals of 8-12 h. until patient can could repeated at an intervals of 8-12 h. until patient can take the drug orally.take the drug orally.

A/E:A/E: CinchonismCinchonism i.e. headache, dizziness, & tinnitus. i.e. headache, dizziness, & tinnitus.Inhibits cardiac conductivity, hemolysis in G-6-P D and Inhibits cardiac conductivity, hemolysis in G-6-P D and black water fever (intravascular hemolysis).black water fever (intravascular hemolysis).

Quinidine:Quinidine:It is the dextro-isomer of quinine.It is the dextro-isomer of quinine.It is used when quinine is not available.It is used when quinine is not available.

Mefloquine:Mefloquine:Its mechanism of action is unknown.Its mechanism of action is unknown.

UsesUses: : treatment & prophylaxis of treatment & prophylaxis of chloroquine-resistant chloroquine-resistant P. falciparum.P. falciparum.

A/EA/E: GIT upset, headache, dizziness, syncope, : GIT upset, headache, dizziness, syncope, extrasystoles & seizures.extrasystoles & seizures.

Halofantrine:Halofantrine:Unknown mechanism of action.Unknown mechanism of action.Used Used only by oral routeonly by oral route in P. falciparum in P. falciparum cerebral malaria.cerebral malaria.NoNo parenteral preparation. parenteral preparation.NotNot used for prophylaxis. used for prophylaxis.Not Not used during pregnancy unless benefit used during pregnancy unless benefit outweighs the risk.outweighs the risk.

QinghaosuQinghaosu ( (ArtemisininArtemisinin):): It is a Chinese herbal medicine was used as It is a Chinese herbal medicine was used as antipyreticantipyretic..It is a blood schizonticide against It is a blood schizonticide against all types of malaria all types of malaria including chloroquine-resistant p. falciparum.including chloroquine-resistant p. falciparum.Unknown mechanism of action.Unknown mechanism of action.

Uses:Uses:P. falciparum P. falciparum cerebral malariacerebral malaria (oral & parenteral). (oral & parenteral).NotNot used used prophylactically.prophylactically.NotNot used in used in pregnancypregnancy as it is emberytoxic in rats. as it is emberytoxic in rats.

Antifolates (sulfonamides & sulfones):Antifolates (sulfonamides & sulfones):Synergistic blockade of folic acid synthesisSynergistic blockade of folic acid synthesisSulfonamideSulfonamide inhibits dihydropteroate inhibits dihydropteroate synthetase, so inhibits folic acid synthesis.synthetase, so inhibits folic acid synthesis.Pyrimethamine and proguanilPyrimethamine and proguanil inhibit inhibit dihydrofolate reductase, so inhibit dihydrofolate reductase, so inhibit tetrahydrofolate (folinic acid synthesis). tetrahydrofolate (folinic acid synthesis).

Fansidar:Fansidar:It is a combination of It is a combination of sulfadoxin and pyrimethamine.sulfadoxin and pyrimethamine.It is used in It is used in chloroquine-resistant p. falciparumchloroquine-resistant p. falciparum..Not Not used for used for prophylaxis prophylaxis as it causes as it causes agranulocytosis & agranulocytosis & Stevens-Johnson syndrome.Stevens-Johnson syndrome.

A.E:A.E:SulfonamideSulfonamide: rashes, kidney damage, hemolysis & GIT : rashes, kidney damage, hemolysis & GIT upset.upset.PyrimethaminePyrimethamine: folic acid deficiency, agranulocytosis & : folic acid deficiency, agranulocytosis & Stevens-Johnson syndrome.Stevens-Johnson syndrome.

DisadvantagesDisadvantages:: slow blood schizonticide activity, drug slow blood schizonticide activity, drug resistance & numerous & serious adverse effects.resistance & numerous & serious adverse effects.

C/I:C/I: pregnancy & nursing women, G-6-PD, renal pregnancy & nursing women, G-6-PD, renal impairment & children under 2 months of age.impairment & children under 2 months of age.

Atovaquone:Atovaquone: Unknown mechanism of action.Unknown mechanism of action.Used alone for treatment of pneumocytosis and Used alone for treatment of pneumocytosis and toxoplasmosis in patients with AIDS.toxoplasmosis in patients with AIDS.Atovaquone +Atovaquone + proguanil proguanil (malarone)(malarone) for for treatment & prophylaxistreatment & prophylaxis of chloroquine-resistant of chloroquine-resistant P. falciparumP. falciparum..

A/EA/E: fever, rashes, cough, nausea, vomiting, : fever, rashes, cough, nausea, vomiting, diarrhea, headache & insomnia.diarrhea, headache & insomnia.

Tissue SchizonticideTissue Schizonticide

Primaquine (8- aminoquinoline derivative):Primaquine (8- aminoquinoline derivative):It is a tissue schizonticide. It is a tissue schizonticide. It has a cellular oxidant activity and possibly interferes It has a cellular oxidant activity and possibly interferes with mitochondria function.with mitochondria function.Gametocide, so inhibits infection transmission by Gametocide, so inhibits infection transmission by mosquito.mosquito.

Uses:Uses:Eradication of liver stages (hypnozoites) of Eradication of liver stages (hypnozoites) of P.vivaxP.vivax & & P.P.

ovaleovale, after standard chloroquine therapy to prevent , after standard chloroquine therapy to prevent relapse.relapse.It should not be given if there is risk of reinfection.It should not be given if there is risk of reinfection.

A/E:A/E: GIT upset, pruritis, headache, methemoglobinemia, GIT upset, pruritis, headache, methemoglobinemia, hemolysis especially in G-6-PD.hemolysis especially in G-6-PD.

Treatment of malariaTreatment of malaria

P. vivax, P. ovale & P. malariae:P. vivax, P. ovale & P. malariae: ChloroquineChloroquineNBNB: It is also allowed in pregnancy.: It is also allowed in pregnancy.

P. Falciparum P. Falciparum (most cases are chloroquine-resistant):(most cases are chloroquine-resistant): Quinine 600 mg salt/8hQuinine 600 mg salt/8h till patient become better and till patient become better and blood is free of parasites (usually in 3-5 days). blood is free of parasites (usually in 3-5 days).

Followed by a single dose of Followed by a single dose of fansidar (3 tablets).fansidar (3 tablets). In pregnancy 7-day course of quinine alone should In pregnancy 7-day course of quinine alone should be givenbe given..

Alternative therapyAlternative therapyMefloquine 20 mg base/kg up to a maximum of Mefloquine 20 mg base/kg up to a maximum of 1.5 g in two divided doses 8 hours apart.1.5 g in two divided doses 8 hours apart.Mefloquine is contraindicated in pregnancy.Mefloquine is contraindicated in pregnancy.

Cerebral malaria:Cerebral malaria:Quinine 10 mg/kg i.v infusion over 4 h. could be Quinine 10 mg/kg i.v infusion over 4 h. could be repeated at intervals of 8-12 h. until patient can repeated at intervals of 8-12 h. until patient can take drug orally. take drug orally. Or Or Halofantrine: Halofantrine: orally onlyorally onlyOr Or QinghaosuQinghaosu ( (ArtemisininArtemisinin): ): oral & i.voral & i.v

Chemoprophylaxis of malariaChemoprophylaxis of malaria

Chloroquine-sensitive area:Chloroquine-sensitive area: Chloroquine 150 mg base ( 2 tab/weekChloroquine 150 mg base ( 2 tab/week))

Chloroquine-resistant area:Chloroquine-resistant area: Chloroquine ( 2 tab/week) plus proguanilChloroquine ( 2 tab/week) plus proguanil

100 mg (one or two tab/ day) 100 mg (one or two tab/ day) oror

Mefloquine Mefloquine 250 mg (one tab./ week)250 mg (one tab./ week)