Lecture Notes on Four important Anti-Malarial Drugs - Pharmacology

               Malaria disease and Anti-malarial drugs

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Malaria:

- 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

Antimalarial Drugs Overview Table:

Category	Drug Examples	Target Stage	Mechanism of Action	Notable Side Effects	Resistance Issues
4-Aminoquinolines	Chloroquine, Amodiaquine	Blood schizonts	Inhibits heme detoxification (toxic buildup)	Retinopathy, pruritus	Widespread in P. falciparum
8-Aminoquinolines	Primaquine, Tafenoquine	Liver hypnozoites, gametocytes	Produces reactive oxygen species	Hemolysis (G6PD deficiency), GI upset	Resistance rare
Quinoline Methanols	Quinine, Mefloquine	Blood schizonts	Disrupts DNA replication/protein synthesis	Cinchonism, neurotoxicity, hypoglycemia	Mefloquine resistance in SE Asia

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 was initially for malaria; now widely used for autoimmune diseases like lupus (SLE) and rheumatoid arthritis

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) - Quinoline Methanols

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. Primaquine/ Primaquine phosphate (8-Aminoquinolines)

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)

4. Antifolates (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