Lecture Notes on Anti-Malarial Drugs

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