Malaria
- Estimated 300-500 million human infection per year throughout the world
- Transmitted to humans through the anopheles mosquitos
- Caused by Plasmodium sps. Four major species are identified namely P falciparum, P vivax, P ovale, P malariae
Clinically Important Anti-Malarial Drugs
Chloroquine
Quinine
Primaquine
Antifolates
Chloroquine (4-Aminoquinololines)
Clinical Indication
- Chloroquine is mostly effective against all four types of malaria (except chloroquine-resistant P falciparum)
- Used in the treatment of acute malaria
- Malaria prophylaxis
- Rheumatoid arthritis or systemic lupus erythematosus
Mechanism of Action
- Chloroquine is effective during intraerythrocyte stage of the parasite
- Chloroquine concentrates into the parasite infected erythrocytes and enters the food vacuole of the parasite by ion-trapping mechanism
- Mechanism of action may include
- intercalation with DNA, inhibition of heme polymerase
- interaction with Ca++-calmodulin mediated mechanism
- inhibit peptide formation and phospholipases leading to parasite death
Absorption, Metabolism and Excretion
- Rapidly absroberd from intesting
- approximately 50% bound to plasma proteins
- about 70% of a dose is excreted unchanged in urine
- half live is 120 hours
Toxicity
- mild heacheche, visual disturbances, gastrointestinal upsets & pruritus are observed during short term therapy
- After prolonged therapy, retinopathy (bulls-eye macula), lichenoid skin eruption, bleaching of hear etc are observed
Drug Interaction
- Chrolorquine and quinine are antagoinistic and should not be used in combination
Quinine (4-aminoquinoline dervatives)
Clinical Indications
- Quinine is the main alkaloid of cinchona bark
- the machanims for anti-malarial activity remains unclear
- drug of choice in the treatment of an acute attack of falciparum malaria where the parasite is known to resistant to chloroquine
- may be given intravenously and then orally when patients improve
- Doxycycline or clindamycine may be used as combination therapy with quinine
Absorption, Metabolism and Excretion
- Quinine is almost completely absorbed in the upper part of the small intestine
- peaks after 1-3 hours of ingestion
- half live is approximately 10 hours
- metabolized in the liver (95%) to inactive hydroxy derivatives
- approximately 5% is excreted in urine as unchanged drug
Toxicity
- Cinochonism
- Abdominal pain and diarrhoea
- Rashes, fever, renal failure, hemolytic anemia, thrombocytopenia etc.
Primaquine
Clinical Indication
- used to eradicate hepatic form of P vivax or P malariae after standard chloroquine therapy
- may be used as prophylactically with chloroquine
Mechanism of action
- inhibits the electron transport chain in mitochondria (structurally similar to coenzyme Q) of parasite
Absorption, Metabolism and Excretion
-Primaquine is rapidly absorped from gastrointestinal tract
- not bound to tissues
- rapidly metabolized and the metabolites may be pharmacologically active as the parent compound
- peaks after 4 - 6 hours after ingestion
- short half life and almost completely eliminated from body by 24 hours
Toxicity
- Primaquine can cause lethal hemolysis in indivdual with glucose-6-phosphate dehyrogenase deficiency
- higher dose or prolong exposure can cause
- gastrointestinal distress nausea
- nausea
- headache
- pruritus
- leukopenia
Antifolates (Pyrimithamine)
- inibit folate biosynthesis at all stage of parasite life cycles
- serve as competitive inhibitor of the malarial dihydrofolate reductiase
- limited use in malaria prophalyxis due to emergence of resistance