PharmacologyTier 2Medical Sciences concept

Colchicine mechanism of action (tubulin/mitotic spindle inhibition)

Core concept

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dec microtubule assembly

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It is anti-inflammatory, not urate-lowering. It does nothing to the uric acid level.
Also disrupts the mitotic spindle (metaphase arrest)
- -> toxicity concentrates in rapidly dividing tissue
- -> diarrhoea (gut mucosa) and myelosuppression (marrow)
- -> the same mechanism gives both the therapeutic and the toxic effect - the therapeutic index is narrow

Dosing - low dose, always

Acute gout: 1 mg stat, then 0.5 mg one hour later. Maximum 2.5 mg in the first 24 hours, then 0.5 mg bd-tds.
- Low-dose is as effective as high-dose with far less diarrhoea (AGREE trial) - the old "dose to diarrhoea" regimen is obsolete and dangerous
- Do not repeat a course within 3 days
Prophylaxis during urate-lowering initiation: 0.5 mg daily (or alternate days), for 3-6 months
Maximum total dose ~6 mg per course

Pharmacokinetics and interactions - where people die

CYP3A4 and P-glycoprotein substrate, narrow therapeutic index, large volume of distribution (concentrates intracellularly)
*Fatal interactions* - halve or omit the dose
- Clarithromycin, erythromycin (the classic lethal combination)
- Ketoconazole, itraconazole, voriconazole
- Ciclosporin, tacrolimus, verapamil, diltiazem
- HIV protease inhibitors, ritonavir-boosted regimens
- Grapefruit juice
Renal and hepatic impairment: reduce the dose; avoid entirely if CrCl <10 mL/min or in severe hepatic impairment
*NOT dialysable* (large Vd, high protein binding)

Toxicity - a three-phase course

1. 0-24 h: severe GI - vomiting, profuse diarrhoea, abdominal pain, volume loss

2. 1-7 days: multi-organ failure - bone marrow suppression (nadir day 4-7), AKI, ARDS, arrhythmia, rhabdomyolysis, hepatic failure

3. >7 days (if survived): recovery, rebound leucocytosis, alopecia

No antidote. Supportive care only. >0.5 mg/kg ingestion is potentially fatal; >0.8 mg/kg usually fatal.
Chronic toxicity: proximal myopathy + peripheral neuropathy with a raised CK (often misdiagnosed as polymyositis or statin myopathy - check the drug chart and renal function)

Where colchicine is used

Acute gout flare - alternative to NSAIDs/corticosteroids, especially with CKD-limited NSAID use
Prophylaxis when starting allopurinol/febuxostat - urate-lowering initiation precipitates flares
Acute and recurrent pericarditis - 0.5 mg bd (0.5 mg daily if <70 kg) for 3 months acute, 6 months recurrent; halves recurrence (CORP, ICAP, CORP-2)
Familial Mediterranean fever - prevents attacks and prevents AA amyloidosis; lifelong
Behcet disease - mucocutaneous and arthritic manifestations
Chronic coronary disease - 0.5 mg daily reduces cardiovascular events (LoDoCo2, COLCOT); not universally adopted; check current Australian lipid/CVD guidance before prescribing
Calcium pyrophosphate deposition disease

Practical

Always check renal function and the full medication list before prescribing - especially macrolides
Warn about diarrhoea as a stop signal
Avoid in pregnancy for gout; it is continued in FMF where the risk-benefit favours it

Cell-cycle phases and drug-induced cell-cycle arrest (metaphase/M-phase arrest, like vinca alkaloids)
CYP3A4 and P-glycoprotein-mediated drug interactions
Dialysability of drugs in overdose (large Vd -> not dialysable)
Uricosuric and urate-lowering effects of antihypertensive drugs; gout management
Statin-associated myopathy (overlapping presentation and shared risk with CYP3A4 inhibitors)
Autoinflammatory syndromes and IL-1 biology (anakinra, canakinumab)
Acute pericarditis management

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