USMLE1 Anti-Malarial Drugs

Malaria is caused by – Plasmodium

•         Plasmodium vivax

•         Plasmodium  falciparum

•         Plasmodium  malariae

•         Plasmodium  ovale

•         Plasmodium knowlesi : Is a zoonosis that causes malaria in macaques but can also infect humans

Clinical note:

•         Cerebral malaria is only caused by Plasmodium falciparum. Falciparum malaria can also cause hepatitis, gastrointestinal symptoms(diarrhoea), glomerulonephritis/acute tubular necrosis and blackwater fever.

•         Plasmodium ovale is the rarest of the four species and is apparently more restricted in distribution. common in the West African countries of Ghana, Liberia, and Nigeria.

•         Plasmodium vivax and ovale are the only ones which have liver parasite dormancy.

•         Plasmodium vivax and ovale only infect reticulocytes whilst falciparum infects erythrocytes of all stages and malariae infects mature erythrocytes. The Duffy blood group is essential for vivax spread as the merozoites of these attach to the Duffy receptor on red blood cells.

•         Plasmodium malariae causes quartan fever (every 72 hours or fourth day) whereas the other species cause tertian fever (every 48 hours or third day).

Anti-malarial drugs:

•         Chloroquine – most common

•         Quinine – if chloroquine resistant

•         Pyrimethamine (or in combination with Sulfonamides)

•         Primaquine – Radical cure

•         Mefloquine

•         Artemisinin (Artemether, Arteether, Artesunate)

•         Halofantrine – New drugs

1. Drugs for the Exo-erythrocytic phase (liver) and  gametocytes :

•         Primaquine

2. Drugs to suppress erythrocytic phase / Schizontocides /

Clinical cure :

•         Chloroquine

•         Quinine

•         Pyrimethamine

•         Mefloquine

•         Artemisinin:  Artemether, Arteether, Artesunate

3. Radical cure : Exoerythrocytic phase (hypnozoites) with the clinical cure thus achieve total eradication of parasite

•         Primaquine + Chloroquine

Chloroquine : 

•         It is rapidly acting erythrocytic schizontocide against all species of plasmodium

•         No effect on exo-erythrocytic phase

•         It is concentrated by intraerythrocytic plasmodium

•         Chloroquine prevents the formation of hemozoin, which in turn leaves heme in an uncrystallised form.

•          The drug can also decrease DNA synthesis in the parasite by disrupting the tertiary structure of NA.

Chloroquine: spectrum of activity:   

•         Chloroquine is active against entameoba histolytica and giardia lamblia

•         It has anti-inflammatory actions and use for rheumatoid arthritis and SLE (discoid lupus)

•         It is used for the treatment of malaria in pregnancy

Pharmacokinetics : Chloroquine

•         Oral absorption is excellent

•         It has high affinity for melanin (retina) and concentrated in liver, spleen, kidney

•         Metabolized by liver and excreted in urine

•         Half life ~ 3-10 days

Uses : Chloroquine

•         Clinical cure and prophylaxis in malaria

•         Extra-intestinal ameobiasis

•         Rheumatoid arthritis, SLE

•         Lepra reactions

Adverse effects : Chloroquine

•         Nausea , vomiting and epigastric pain

•         Parenteral administration -àhypotension and cardiac arrhythmia, convulsions

•         Prolonged treatment ( as in RA) retinal damage, decrease vision

•         Loss of hearing, mental disturbances, rashes

C/I:

•         Psoriasis

•         Porphyria

 Quinine :

•         It is a levo-rotatory alkaloid from cinchona bark ( dextro isomer – Quinidine)

•         It is an erythrocytic schizontocide

•         The action of quinine has not been fully resolved.

Mechanism Of Action:

•         involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme.

•         Toxic  heme accumulates in the parasites, leading to their death

•         It is orally well absorbed

•         It has local irritant action and has  antipyretic action, affects hearing and vision at high dose

•         High intravenous dose can cause hypotension and cardiac depression

Adverse effects

•         Cinchonism (S/A: Quinidine) – ringing in ears, nausea , difficulty in hearing, visual defects

•         Hypersensitivity reactions

•         Hemolysis – can result in hemoglobinuria

•         Embryotoxic

Hypoglycaemia is an important side effect of quinine therapy (causes insulin release) and  Pl. glucose  should be checked every 2 hours.

Primaquine :

•         Primary indication is radical cure of malaria.

•         It is more active against exo-erythrocytic phase of Pl. falciparum and vivax

•         It is highly active against gametocytes and hypnozoites.

Mechanism Of Action:

•         It attacks the sexual forms of the parasite, rendering them incapable of maturation in the mosquito and making it valuable in preventing the spread of malarial infection.

Side Effects:

•         Dose limiting side effect is hemolysis, methemoglobinemia and cyanosis (dose > 60 mg/day)

•         Other adverse effects - abdominal pain and neutropenia

•         Avoided in pregnancy & G6PD deficiency.

Mefloquine

•         It is rapidly acting erythrocytic schizontocide

•         Effective against even chloroquine resistant strains of plasmodium.

Mechanism Of Action:

•         It appears to damage the plasmodia membranes

•         Oral absorption is good

•         Concentrated in liver, lungs and intestine

•         Metabolized in liver and excreted in bile

•         QT interval prolongation (arrhythmia) when given with halofantrine or quinine

•         Mefloquine is C/I in mental illness e.g schizophrenia

Artemisinin derivatives :

           Artemether

           Arteether

           Artesunate

•         It is a potent and rapidly acting blood schizontocide (and produce peroxide – responsible for its action)

•         Obtained from Chinese herb Artemisia  annua

•         No resistance to Pl .falciparum

Adverse effects :

•         ST segment and QT prolongation –conduction defects

Halofantrine/Lumefantrine :

•         halofantrine is never used to prevent malaria and its mode of action is unknown.

•         A crystallographic study have shown that halofantrine binds to hematin, suggesting a possible mechanism of action .

•         It is highly active against Pl. falciparum resistant to chloroquine

Adverse effects:

•         abdominal pain, diarrhoea, vomiting, rash, headache, itching and elevated liver enzymes.

•         It can be associated with cardiotoxicity

•         Cardiac arrhythmias: causes significant QT prolongation

Uses : Halofantrine/Lumefantrine

•         is only used to treat malaria. It is not used to prevent malaria (prophylaxis) because of the risk of toxicity and unreliable absorption.