Drug therapy for malaria

Malaria treatment goals

Clinical cure, radical cure, and prophylaxis

Clinical cure

Elimination of blood-stage parasites

Radical cure

Elimination of blood-stage and liver-stage parasites to prevent relapse

Suppressive prophylaxis

Prevents blood-stage malaria

Causal prophylaxis

Prevents liver-stage malaria

Blood schizonticide

Drug that kills erythrocytic asexual parasites

Tissue schizonticide

Drug that kills hepatic parasites

Group I antimalarials

Blood schizonticides

Group II antimalarials

Blood and primary liver schizonticides

Group III antimalarials

Tissue schizonticide

Group I drugs

Chloroquine, Quinine, Artemisinin derivatives, Fansidar, Tetracyclines, Clindamycin

Group II drugs

Proguanil and Atovaquone

Group III drug

Primaquine

Only tissue schizonticide

Primaquine

Only drug active against dormant hypnozoites

Primaquine

Drug active against primary liver forms

Primaquine

Drug active against primary liver forms

Proguanil

Drug active against primary liver forms

Atovaquone

Drug active against blood schizonts

Chloroquine

Drug active against blood schizonts

Quinine

Drug active against blood schizonts

Artemisinin derivatives

Drug active against blood schizonts

Fansidar

Drug active against blood schizonts

Tetracyclines

Drug active against blood schizonts

Proguanil

Drug active against blood schizonts

Atovaquone

Drug active against latent liver forms

Primaquine

Drug inactive against latent liver forms

Chloroquine

Drug inactive against latent liver forms

Quinine

Drug inactive against latent liver forms

Artemisinin derivatives

Drug inactive against latent liver forms

Fansidar

Drug inactive against latent liver forms

Proguanil

Drug inactive against latent liver forms

Atovaquone

Dormant liver stage of malaria

Hypnozoite

Malaria species with hypnozoites

P. vivax

Malaria species with hypnozoites

P. ovale

Malaria species without hypnozoites

P. falciparum

Malaria species without hypnozoites

P. malariae

Chloroquine drug class

4-aminoquinoline

Chloroquine pharmacological action

Rapid blood schizonticide

Chloroquine mechanism

Inhibits haem polymerization into haemozoin

Haemozoin

Non-toxic storage form of haem

Effect of chloroquine

Accumulation of toxic free haem

Site of chloroquine action

Parasite food vacuole

Chloroquine activity against liver forms

None

Chloroquine activity against hypnozoites

None

Reason chloroquine cannot prevent relapse

Does not kill hypnozoites

Reason chloroquine can cure sensitive falciparum

Falciparum has no hypnozoites

Major pharmacokinetic feature of chloroquine

Large volume of distribution

Reason chloroquine requires loading dose

Extensive tissue binding

Reason chloroquine persists for years

Extensive tissue storage

Clinical use of chloroquine

Clinical cure of vivax malaria

Clinical use of chloroquine

Clinical cure of ovale malaria

Clinical use of chloroquine

Treatment of chloroquine-sensitive falciparum malaria

Prophylactic use of chloroquine

Suppressive prophylaxis in sensitive areas

Non-malarial use of chloroquine

Rheumatoid arthritis

Non-malarial use of chloroquine

Amoebic liver abscess

Most common adverse effect of chloroquine

Gastrointestinal upset

Serious IV adverse effect of chloroquine

Hypotension

Serious IV adverse effect of chloroquine

Arrhythmia

Serious IV adverse effect of chloroquine

Convulsions

Serious IV adverse effect of chloroquine

Coma

Long-term adverse effect of chloroquine

Retinopathy

Visual adverse effect of chloroquine

Retinal toxicity

Mechanism of chloroquine resistance

Reduced drug accumulation in parasite food vacuole

Cause of chloroquine resistance

Mutation of parasite transporter proteins

Quinine pharmacological action

Rapid blood schizonticide

Quinine mechanism

Inhibits haem polymerization

Quinine activity against liver forms

None

Major indication for quinine

Severe falciparum malaria

Major indication for quinine

Cerebral malaria

Major indication for quinine

Chloroquine-resistant falciparum malaria

Classic quinine toxicity

Cinchonism

Symptoms of cinchonism

Tinnitus, deafness, headache, blurred vision, vertigo

Reason quinine causes hypoglycaemia

Stimulates insulin secretion

Cardiovascular adverse effect of quinine

Hypotension

Cardiac adverse effect of quinine

Cardiotoxicity

Rare adverse effect of quinine

Blackwater fever

Blackwater fever

Massive haemolysis with haemoglobinuria

Source of artemisinin

Artemisia annua

Artemisinin derivatives

Artesunate, Artemether, Dihydroartemisinin

Artemisinin mechanism

Generates free radicals within parasite

Artemisinin pharmacological action

Rapid blood schizonticide

Potency of artemisinin

10-100 times greater than older antimalarials

Reason artemisinin is not used alone

High recrudescence

Second reason artemisinin is not used alone

Rapid resistance develops

ACT

Artemisinin Combination Therapy

Example of ACT

Artemether-Lumefantrine

Example of ACT

Artesunate-Mefloquine

First-line treatment for uncomplicated falciparum malaria

ACT

Treatment for multidrug-resistant falciparum malaria

ACT

Major advantage of ACT

Reduces resistance

Major advantage of ACT

Higher cure rate

Common adverse effect of artemisinin

Generally well tolerated

Fansidar components

Sulfadoxine and Pyrimethamine

Sulfadoxine target

Dihydropteroate synthase

Pyrimethamine target

Dihydrofolate reductase

Fansidar mechanism

Sequential inhibition of folate synthesis

Fansidar pharmacological action

Slow blood schizonticide

Fansidar activity against liver forms

None

Clinical use of Fansidar

Combination treatment of resistant falciparum malaria