PharmacologyTier 1Medical Sciences concept

Antimalarial drug mechanisms and radical cure of relapsing malaria (primaquine, G6PD)

Core concept

The parasite life cycle dictates the drug - no single agent covers every stage

Stage	Site	Drugs active
Sporozoite	Blood -> liver	(Vaccine target)
Hepatic schizont	Liver	Primaquine, tafenoquine, atovaquone-proguanil
Hypnozoite (dormant)	Liver - P. vivax and P. ovale ONLY	Primaquine, tafenoquine - nothing else
Blood schizont	Erythrocyte	Artemisinins, chloroquine, quinine, mefloquine, doxycycline, atovaquone-proguanil
Gametocyte	Blood	Primaquine (single dose, transmission blocking)

Radical cure = kill the blood stage AND the hypnozoite
- A schizonticide alone (e.g. artemether-lumefantrine) clears the parasitaemia and the illness, but relapse follows weeks to months later from surviving hypnozoites
8-aminoquinolines (primaquine, tafenoquine) are the only hypnozoitocidal drugs, and they cause oxidative haemolysis in G6PD deficiency

G6PD must be quantified before primaquine or tafenoquine - qualitative screening is insufficient, particularly in women (X-linked, lyonisation gives intermediate activity)
- Normal (>70%) -> full course
- Intermediate -> weekly primaquine regimen under supervision, or avoid
- Deficient -> do not give tafenoquine; primaquine only with specialist advice
- Also avoid in pregnancy (fetal G6PD status unknown) - use weekly chloroquine prophylaxis until delivery
Tafenoquine - single dose, long half-life (~15 days), convenient but the same G6PD constraint and a longer exposure if haemolysis begins

Mechanisms

Drug	Mechanism
Artemisinins	Endoperoxide bridge cleaved by haem iron -> free radicals; fastest parasite clearance
Chloroquine, quinine, mefloquine	Concentrate in the food vacuole, inhibit haem polymerisation to haemozoin -> toxic free haem
Atovaquone-proguanil	Atovaquone collapses the mitochondrial membrane potential (cytochrome bc1); proguanil inhibits DHFR
Doxycycline, clindamycin	Inhibit the apicoplast ribosome - slow acting
Primaquine/tafenoquine	Oxidative metabolites disrupt parasite mitochondria; the same oxidative stress haemolyses G6PD-deficient red cells

Falciparum is the killer: severe malaria = impaired consciousness, acidosis, hypoglycaemia, parasitaemia >2-10%, AKI, ARDS, shock, DIC
- IV artesunate is first-line for severe malaria in all groups - superior to quinine (SEAQUAMAT, AQUAMAT)
- Delayed post-artesunate haemolysis at 1-3 weeks - check FBC after treatment
Chloroquine resistance is widespread in falciparum; vivax chloroquine resistance is emerging (Indonesia, Papua New Guinea)

Any fever in a returned traveller is malaria until three thick and thin films (or a rapid antigen test) are negative - and vivax can present months to years later
Sequence: treat the blood stage first, then check G6PD, then give radical cure - primaquine is not an emergency
Species identification changes management - falciparum and knowlesi need urgent assessment for severe disease; vivax and ovale need radical cure
Prophylaxis for travellers: doxycycline, atovaquone-proguanil, or mefloquine (neuropsychiatric effects); none prevents vivax relapse
Splenic rupture, hyperreactive malarial splenomegaly and nephrotic syndrome (P. malariae) are the chronic complications

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