Lecture #172: Chemotherapy of Malaria

What causes malaria?

Malaria is caused by Plasmodium protozoan parasites transmitted by female Anopheles mosquitoes.

Which Plasmodium species is the deadliest?

P. falciparum is the most widespread and deadliest malaria parasite.

Which malaria species form hypnozoites?

P. vivax and P. ovale form dormant liver hypnozoites that can cause relapse months or years later.

What is the exoerythrocytic stage?

The liver stage of malaria before parasites invade red blood cells.

What is the erythrocytic stage?

The stage where parasites infect and multiply within red blood cells.

What is schizogony?

Asexual reproduction of malaria parasites producing multiple merozoites.

What are merozoites?

Daughter parasites released from schizonts that invade red blood cells.

What is a hypnozoite?

A dormant liver form of P. vivax and P. ovale that can reactivate later.

What is hemozoin?

A non-toxic crystalline pigment formed when malaria parasites detoxify free heme from hemoglobin digestion.

What is a schizonticide?

A drug that destroys schizont stages of malaria parasites.

What is a gametocide?

A drug that destroys gametocytes and reduces transmission to mosquitoes.

Which stage causes clinical malaria symptoms?

The asexual erythrocytic stage causes clinical malaria.

What are common symptoms of uncomplicated malaria?

Fever, malaise, mild anemia, and splenomegaly.

What are complications of severe falciparum malaria?

Hyperparasitemia, severe anemia, seizures, shock, hypoglycemia, kidney injury, coma, acidosis, and ARDS.

How is malaria diagnosed?

Giemsa-stained thick and thin blood smears demonstrating intraerythrocytic parasites.

What are the goals of malaria therapy?

Prevention in travelers, prevention in high-risk populations, treatment of uncomplicated malaria, and treatment of severe malaria.

Why are combination therapies used for malaria treatment?

To combine rapid parasite killing with prolonged activity and reduce resistance development.

What is ACT?

Artemisinin combination therapy using a short-acting artemisinin plus a long-acting antimalarial.

What is first-line therapy for uncomplicated P. falciparum malaria?

Oral artemisinin combination therapy such as artemether-lumefantrine.

What is first-line therapy for severe malaria?

IV or IM artesunate followed by oral ACT once tolerated.

Which drugs eradicate hypnozoites?

Primaquine and tafenoquine.

Why is G6PD testing required before primaquine or tafenoquine?

These drugs can cause severe hemolytic anemia in G6PD-deficient patients.

Which drugs are commonly used for prophylaxis in chloroquine-resistant areas?

Atovaquone-proguanil, doxycycline, and mefloquine.

Which antimalarial is preferred in chloroquine-sensitive regions?

Chloroquine.

What is chloroquine’s mechanism of action?

It disrupts heme sequestration in parasite food vacuoles causing oxidative damage.

What mutation causes chloroquine resistance?

K76T mutation in the PfCRT transporter gene.

What are major chloroquine adverse effects?

GI upset, pruritus, headache, visual disturbances, QT prolongation, retinopathy, and neuropsychiatric effects.

Which antimalarial is contraindicated in psychiatric disorders?

Mefloquine due to severe neuropsychiatric adverse effects.

What are major mefloquine adverse effects?

Anxiety, depression, psychosis, dizziness, seizures, and ECG changes.

What is the mechanism of atovaquone?

It inhibits the cytochrome bc1 complex causing collapse of parasite mitochondrial membrane potential.

What is proguanil’s active metabolite?

Cycloguanil.

Why should atovaquone-proguanil be taken with fatty food?

Fatty meals improve absorption and reduce GI side effects.

What are common atovaquone-proguanil adverse effects?

Abdominal pain, nausea, vomiting, headache, dizziness, and elevated liver enzymes.

Why is sulfadoxine-pyrimethamine rarely used now?

Widespread resistance limits its use.

What is sulfadoxine’s mechanism?

Inhibits dihydropteroate synthase in folate synthesis.

What is pyrimethamine’s mechanism?

Inhibits dihydrofolate reductase in folate synthesis.

What are serious adverse effects of sulfadoxine-pyrimethamine?

Stevens-Johnson syndrome, toxic epidermal necrolysis, megaloblastic anemia, leukopenia, and thrombocytopenia.

What drug combination contains lumefantrine?

Artemether-lumefantrine (Coartem).

What is lumefantrine’s major toxicity?

QT interval prolongation.

What structural feature is essential for artemisinin activity?

The endoperoxide bridge.

What is the proposed mechanism of artemisinins?

Interaction with heme generates oxidative stress causing parasite damage.

What activity do artemisinins have?

They are rapid-acting blood schizonticides with gametocidal activity.

Where is artemisinin resistance emerging?

Greater Mekong region, Papua New Guinea, South America, and Eastern Africa.

What mutation is associated with artemisinin resistance?

PFk13 propeller domain mutations.

What are common artemisinin adverse effects?

Nausea, vomiting, diarrhea, dizziness, neutropenia, anemia, and transient liver enzyme elevations.

What is blackwater fever?

Massive hemolysis with hemoglobinuria and possible renal failure after artesunate or quinine therapy.

What is quinine used for?

Treatment of chloroquine-resistant malaria as an alternative to ACT.

What drugs are combined with quinine?

Doxycycline, tetracycline, or clindamycin.

What is cinchonism?

Quinine toxicity causing tinnitus, headache, dizziness, nausea, sweating, and visual disturbances.

Why is quinine dangerous in pregnancy?

It can cause recurrent hypoglycemia, especially in pregnant patients.

What is the mechanism of G6PD-related hemolysis?

Lack of NADPH protection causes oxidative injury and RBC destruction.

What are doxycycline and clindamycin used for in malaria?

Slow-acting adjunctive blood schizonticides used with quinine or artesunate.

Why can’t doxycycline be used in young children or pregnancy?

It deposits in developing bones and teeth causing discoloration and growth effects.

Which malaria vaccines are WHO approved?

RTS,S/AS01 (Mosquirix) and R21/Matrix-M.