What is the mechanism of action of colchicine?

Colchicine Mechanism of Action

Colchicine exerts its therapeutic effects primarily by binding to tubulin and inhibiting microtubule polymerization, which disrupts multiple cellular processes including neutrophil migration, inflammasome activation, and cytoskeletal-dependent inflammatory signaling. 1

Primary Molecular Mechanism

• Colchicine binds to the tubulin heterodimer and blocks β-tubulin polymerization into microtubules, preventing the assembly of the cytoskeletal framework required for numerous cellular functions 1
• This binding is irreversible and interferes with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes 2, 3
• The drug inhibits tubulin heterodimer recycling by interfering with tubulin cofactors TBCA, TBCB, and TBCE, leading to disruption of the system that controls the critical concentration of free tubulin heterodimers and microtubule dynamics 2

Anti-Inflammatory Effects Through Inflammasome Inhibition

• Colchicine specifically inhibits NLRP3 inflammasome activation, which is the cytosolic multiprotein complex responsible for generating active forms of pro-inflammatory cytokines 3, 4
• By blocking inflammasome assembly, colchicine prevents the activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), two key mediators of inflammatory responses in conditions like familial Mediterranean fever, gout, and cardiovascular disease 1, 4
• The mechanism involves preventing the signal transduction required for complete NLRP3 inflammasome activation 2

Cellular-Level Effects on Inflammatory Cells

Neutrophil Function Disruption

• Colchicine concentrates preferentially in leukocytes, especially neutrophils, where it blocks tubulin polymerization and affects microtubule assembly 4
• The drug prevents neutrophil activation, degranulation, and migration by disrupting cytoskeletal functions necessary for these processes 1
• Neutrophil chemotaxis is inhibited through modulation of the viscoelastic properties of subcellular compartments, making cells less deformable and impairing their ability to migrate through confined spaces during extravasation 5
• Colchicine reduces neutrophil adhesion to endothelial cells and platelets, further limiting inflammatory cell recruitment 6

Effects on Other Cell Types

• Endothelial cell dysfunction and inflammation are inhibited 3
• Smooth muscle cell proliferation and migration are suppressed 3
• Macrophage chemotaxis, migration, and adhesion are reduced 3
• Platelet activation is inhibited 3

Molecular Signaling Pathways

• Colchicine reduces pro-inflammatory cytokine release through multiple mechanisms 3
• The drug inhibits NF-κB signaling, a central pathway in inflammatory gene expression 3
• By disrupting microtubules, colchicine affects any cellular process requiring cytoskeletal changes, including cell mitosis and neutrophil motility 7

Clinical Relevance of Mechanism

• The disruption of microtubule assembly explains colchicine's efficacy in treating gout (by preventing neutrophil-mediated inflammation), familial Mediterranean fever (by blocking inflammasome activation), and pericarditis (by reducing inflammatory cell recruitment) 1, 4
• In cardiovascular disease, colchicine's ability to reduce high-sensitivity C-reactive protein and low-attenuation plaque volume stems from its anti-inflammatory effects on atherosclerotic plaque formation and destabilization 6, 4
• The mechanism also explains why colchicine has a narrow therapeutic index and significant toxicity potential—disruption of microtubule function affects multiple essential cellular processes including cell division, leading to bone marrow suppression and multi-organ dysfunction in overdose 6, 8

Important Mechanistic Considerations

• Colchicine's effects on tubulin are not selective, which explains both its therapeutic benefits and its toxicity profile across multiple organ systems 7
• The drug undergoes enterohepatic recirculation and biliary excretion, contributing to prolonged tissue exposure and explaining why toxicity can develop even after initial dosing 1
• Secondary plasma peaks occur 3-36 hours post-dose due to intestinal secretion/reabsorption and biliary recirculation, maintaining drug effects over extended periods 1