From the Guidelines
Hydroxychloroquine works through several mechanisms of action in the body, primarily functioning as a weak base that accumulates in acidic cellular compartments like lysosomes, raising their pH and interfering with protein degradation and cellular function, thereby disrupting antigen processing in immune cells and reducing inflammation, as supported by recent studies 1. The mechanisms of action of hydroxychloroquine (HCQ) are multifaceted and involve various pathways.
- It primarily functions as a weak base that accumulates in acidic cellular compartments like lysosomes, raising their pH and interfering with protein degradation and cellular function.
- This disrupts antigen processing in immune cells, reducing inflammation.
- Hydroxychloroquine also inhibits Toll-like receptor signaling, particularly TLR7 and TLR9, which decreases the production of pro-inflammatory cytokines like TNF-α, IL-1, and IL-6, as noted in studies 1.
- Additionally, it interferes with the interaction between DNA/RNA and their sensors, reducing immune activation.
- The drug blocks phospholipase A2 and stabilizes lysosomal membranes, further reducing inflammatory responses.
- In malaria, hydroxychloroquine concentrates in the parasite's food vacuole, preventing the detoxification of heme and causing parasite death. These multiple mechanisms explain its effectiveness in autoimmune diseases like lupus and rheumatoid arthritis, where it modulates immune responses without completely suppressing the immune system, as well as its historical use as an antimalarial agent, as discussed in guidelines 1. The use of HCQ has been recommended for all patients with SLE, with evidence for multiple beneficial effects, including reducing the risk of flares and improving quality of life, while minimizing drug side-effects, as stated in recent guidelines 1. However, concerns for retinal toxicity with long-term HCQ therapy have led to the use of more sensitive screening techniques, with a prevalence of retinal abnormalities exceeding 10% after 20 years of continuous use, emphasizing the importance of monitoring and collaboration between healthcare providers 1. Overall, the mechanisms of action of hydroxychloroquine are complex and involve multiple pathways, making it a valuable drug for the treatment of various diseases, including autoimmune diseases and malaria, while requiring careful monitoring and management to minimize potential risks, as supported by recent studies and guidelines 1.
From the FDA Drug Label
- 1 Mechanism of Action Malaria Hydroxychloroquine is a 4-aminoquinoline antimalarial [see Microbiology (12. 4)] and antirheumatic agent. Rheumatoid Arthritis, Systemic Lupus Erythematosus and Chronic Discoid Lupus Erythematosus The mechanisms underlying the anti-inflammatory and immunomodulatory effects of hydroxychloroquine sulfate in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus and systemic lupus erythematosus are not fully known.
The mechanisms of action of Hydroxychloroquine (HCQ) are:
- As a 4-aminoquinoline antimalarial for the treatment of malaria
- The mechanisms underlying the anti-inflammatory and immunomodulatory effects of HCQ for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and chronic discoid lupus erythematosus are not fully known 2
From the Research
Mechanisms of Action of Hydroxychloroquine (HCQ)
The mechanisms of action of HCQ are multifaceted and involve several cellular pathways. Some of the key mechanisms include:
- Disruption of lysosomal and endosomal pH 3
- Inhibition of protein secretion/expression 3
- Inhibition of antigen presentation 3, 4
- Decrease of proinflammatory cytokines 3, 5, 6
- Inhibition of autophagy 3, 5, 6
- Induction of apoptosis 3
- Inhibition of ion channels activation 3
- Alteration of endolysosomal functions, including autophagy and endosomal Toll-like receptor activation 5
- Influence on calcium signalling 5
- Protection against cytokine-mediated cartilage resorption 6
- Antioxidant activity, including leucocyte generation of reactive oxygen species (ROS) 6
Effects on the Immune System
HCQ's effects on the immune system are significant, with the drug altering several aspects of immune function, including:
- Reduction of pro-inflammatory cytokine production and release 3, 5
- Inhibition of MHC Class II expression and antigen presentation 6, 4
- Control of toll-like receptor-9 activation 6
- Modulation of T and B cell activity, although the exact mechanisms are less clear 6
Therapeutic Applications
HCQ has been used to treat various diseases, including: