Mechanism of Action of Chloroquine

Introduction

Chloroquine is a 4-aminoquinoline antimalarial drug historically used for the treatment and prophylaxis of Plasmodium falciparum, P. vivax, P. malariae, and P. ovale infections. Although resistance limits its use in many regions, chloroquine remains essential for sensitive strains and for autoimmune diseases such as rheumatoid arthritis and lupus.

The Mechanism of Action of Chloroquine is primarily based on inhibition of heme detoxification in Plasmodium, leading to parasite death within red blood cells. It also has immunomodulatory effects, explaining its role in autoimmune disorders.

Mechanism of Action (Step-wise)

1. Accumulation in Parasite Food Vacuole – Primary Mechanism

Chloroquine is a weak base that diffuses into the acidic food vacuole of Plasmodium-infected erythrocytes.

Inside the vacuole:

• It becomes protonated and trapped (ion trapping).
• Concentration increases more than 1000-fold.

2. Inhibition of Heme Polymerase

During hemoglobin digestion, Plasmodium releases toxic free heme (ferriprotoporphyrin IX).

Normally:
Heme → polymerized into hemozoin (non-toxic)

Chloroquine blocks heme polymerase, leading to:

• Accumulation of toxic heme
• Membrane damage
• Parasite death

This is the central antimalarial mechanism.

3. Increased Lysosomal pH

By raising pH inside the parasite vacuole, chloroquine disrupts:

• Proteolytic enzymes
• Hemoglobin degradation
• Parasite metabolism

4. Oxidative Stress

Accumulated heme generates:

• Reactive oxygen species
• Lipid peroxidation
• Oxidative damage

This enhances parasite killing.

5. Immunomodulatory Effects (Non-antimalarial)

Chloroquine inhibits:

• Toll-like receptor (TLR) signaling
• Antigen presentation
• Cytokine production (IL-1, TNF-α)

These actions explain its use in SLE and rheumatoid arthritis.

6. Summary of Mechanism

Pharmacokinetics

• Absorption: Excellent oral absorption
• Distribution: Very large volume; accumulates in tissues (eye, liver)
• Half-life: 1–2 months (extremely long)
• Metabolism: Hepatic
• Excretion: Renal

Clinical Uses

• Treatment of chloroquine-sensitive malaria
• Prophylaxis in chloroquine-sensitive regions
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Amebic liver abscess (adjunct)
• Porphyria cutanea tarda

Adverse Effects

Common

• Nausea
• Headache
• Pruritus

Serious

• Retinopathy (dose-dependent, irreversible)
• QT prolongation
• Hemolysis in G6PD deficiency
• Hypotension (IV form)
• Neuropsychiatric effects (rare)

Chronic toxicity

• Bull’s-eye maculopathy
• Hearing loss
• Cardiomyopathy

Contraindications

• Pre-existing retinal disease
• Severe hepatic impairment
• G6PD deficiency (relative)
• Concomitant QT-prolonging drugs

Comparative Analysis

MCQs

1. Chloroquine kills Plasmodium by inhibiting:
a) Folic acid synthesis
b) DNA polymerase
c) Heme polymerase
d) Mitochondrial respiration
Answer: c) Heme polymerase

2. Accumulation of free heme in malaria causes:
a) Parasite growth
b) Oxidative damage and death
c) Increased hemoglobin digestion
d) Resistance to chloroquine
Answer: b) Oxidative damage and death

3. Chloroquine is concentrated in the parasite because:
a) It binds ribosomes
b) It undergoes ion trapping in acidic vacuoles
c) It inhibits ATPases
d) It binds to DNA
Answer: b) It undergoes ion trapping in acidic vacuoles

4. Long-term chloroquine therapy may cause:
a) Retinopathy
b) Hepatic necrosis
c) Alopecia
d) Nephritis
Answer: a) Retinopathy

5. Chloroquine resistance occurs mainly due to:
a) Enhanced drug metabolism
b) Efflux pumps in Plasmodium
c) Heme polymerase mutation
d) Failure of absorption
Answer: b) Efflux pumps in Plasmodium

FAQs

Q1. Why does chloroquine cause retinopathy?
It accumulates in retinal pigmented epithelium and damages photoreceptors.

Q2. Is chloroquine still used for malaria?
Only in regions where P. falciparum remains chloroquine-sensitive.

Q3. How fast does chloroquine act?
Rapid action—parasitemia decreases within 24–48 hours.

Q4. Why is it effective in autoimmune diseases?
Due to TLR inhibition and suppression of inflammatory cytokines.

Q5. Is chloroquine safe in pregnancy?
Yes—considered safe at therapeutic doses.

References

Goodman & Gilman’s Pharmacological Basis of Therapeutics
https://accesspharmacy.mhmedical.com/book.aspx?bookid=2189

Katzung: Basic and Clinical Pharmacology
https://accessmedicine.mhmedical.com/book.aspx?bookid=2464

Tripathi: Essentials of Medical Pharmacology
https://jaypeebrothers.com/

Harrison’s Principles of Internal Medicine
https://accessmedicine.mhmedical.com/book.aspx?bookid=2129

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