Lecture Notes on Four important Anti-Malarial Drugs - Pharmacology

               Malaria disease and Anti-malarial drugs

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- Estimated 300-500 million human infections per year throughout the world
- Transmitted to humans through the bite of female Anopheles mosquitoes
- The parasite Plasmodium spp cause infections in humans that is transmitted by the vector (mosquito).

  Four major species are identified namely P falciparum, P vivax, P ovale, P malariae
Clinically Important Anti-Malarial Drugs, Prevention and Treatment of Malaria:

The four most important and widely used drugs for the treatment of malaria:
1.Chloroquine and Hydroxychloroquine
2. Quinine
3. Primaquine 
4. Antifolates

1. Chloroquine (4-Aminoquinololines) and hydroxychloroquine (HCQ)

Clinical Indication
- Chloroquine (CQ) is mostly effective against all four types of malaria (except chloroquine-resistant P falciparum
- Hydroxychloroquine is the analog of a chloroquine, a less toxic metabolite of CQ.
- Used in the treatment of acute malaria
- Malaria prophylaxis
- HCQ for rheumatoid arthritis or systemic lupus erythematosus

Mechanism of Action
- Chloroquine is effective during an intraerythrocytic stage of the parasite.
- The drug concentrates into the parasite-infected erythrocytes and enters the food vacuole of the parasite by an ion-trapping mechanism.

Mechanism of action:
    - 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 absorbed from the intestine 
- approximately 50% bound to plasma proteins 
- about 70% of a dose is excreted unchanged in the urine 
- half live is 120 hours

Toxicity (side effects)
- mild headache, visual disturbances, gastrointestinal upsets & pruritus are observed during short term therapy
- After prolonged therapy, ocular damage, retinopathy (bulls-eye macula), lichenoid skin eruption, bleaching of hearing, etc. may be observed

Drug Interaction
- Chloroquine and quinine are antagonistic and should not be used in combination.

2. Quinine (4-aminoquinoline derivatives/ Quinoline derivative)

Clinical Indications 
Quinine is the main alkaloid of cinchona bark (tree).
- drug of choice in the treatment of an acute attack of falciparum malaria where the parasite is known to be resistant to chloroquine.
- may be given intravenously and then orally when patients start to improve
- Doxycycline or clindamycin may be used as combination therapy with quinine.

Mechanism of action:
- the mechanism for anti-malarial activity remains unclear for 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 an unchanged drug

Toxicity (side effects)
- Quinine may cause Cinchonism (neural, retinal and auditory toxicity)
- Abdominal pain and diarrhea 
- Rashes, fever, renal failure, hemolytic anemia, thrombocytopenia (too low platelet count in blood), etc.

3. PrimaquinePrimaquine phosphate

Clinical Indication:
- used to eradicate hepatic form of P vivax or P malariea infections after standard chloroquine therapy.
- may be used 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 absorbed from the 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 the body by 24 hours

Toxicity (side effects):
- Primaquine have shown to cause lethal hemolysis in individuals with glucose-6-phosphate dehydrogenase deficiency 
- higher dose or prolonged exposure can cause;
  •     gastrointestinal distress nausea
  •     nausea
  •     headache
  •     pruritus (itchy skin)
  •     leukopenia (low WBC- white blood cell)

4Antifolates (Pyrimethamine)

- inhibits folate metabolism at all stages of parasite life cycles

- serves as a competitive inhibitor of the malarial dihydrofolate reductase

- limited use in malaria prophylaxis due to emergence of resistance