colchicine

Historical:

*used by ancient Greeks, so along with the opiates, is probably the earliest recorded medication still in current use

6th C AD, Alexander of Tralles proposed use of colchicine for joint pain
1763, specifically described in the Dx & Rx of gout
1820: 1st isolated
recent uses include: familial Mediterranean fever, primary biliary cirrhosis & Behcet's syndrome
the large-scale COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low Dose Colchicine Trial 2) showed a 32% reduction in major adverse cardiovascular events or need for urgent revascularization making it likely it will be added to the secondary prevention guidelines for heart disease

alkaloid f. Colchicum autumnale (autumn crocus or meadow saffron) used for arthritis since 6thC. isol.1820;
A unique anti-inflammatory effective only in gout ? acting mainly as an anti-mitotic agent & thus also used in research on cell division & function;
binds to the intracellular protein tubulin, preventing its alpha & beta forms polymerising to form microtubules, thereby disrupting the microtubular network causing:
- impaired protein assembly in the Golgi apparatus
- decreased endocytosis & exocytosis
- altered cell shape
- depressed cellular motility
- arrest of mitosis - usually in metaphase
reduces CRP levels

lipid soluble alkaloid
well absorbed orally
extensive 1st pass metabolism ⇒ oral bioavailability 40%
peak plasma levels 30-120min
short plasma half-life of 20-90min due to intracellular tissue binding (Vd = 2.1L/kg)
elimination:
- renal 30-40%
- hepatic with eneterohepatic recycling

While colchicine is effective for treating acute gout it has a slow onset of action, with limited effectiveness if treatment is delayed and a narrow therapeutic index ¹⁾

Colchicine should not be used unless non-steroidal anti-inflammatories are contraindicated, or have been used and found to lack analgesic efficacy or to have unacceptable side effects in the individual
The elderly may be more susceptible to cumulative toxicity with colchicine, and due to age-related renal function impairment, other treatments such as corticosteroids should be considered.
If colchicine is used in the elderly lower doses should be given and a maximum cumulative dose of 3mg over four days should be observed
Reduce dose in those with moderate renal impairment - do NOT use in those with severe renal impairment.
Maximum dose in healthy adults in the first 24 hours is 2.5mg and the total dose given in an acute attack should not exceed 6mg over four days.
regime 1 for otherwise healthy adults over 50kg:
- 1mg initially, then 0.5mg every six hours until pain relief is obtained.
regime 2 for otherwise healthy adults over 50kg:
- 0.5mg bd for 3 days.
NB. used to be given until no pain or GIT effects (4-10mg) BUT 7-8mg may be lethal !

In moderate doses well tolerated;
Most common are GIT effects due to effect on rapidly prolif. epith. cells, esp. in jejunum → N/V/D/abdo. pain which are the earliest effects of OD;
Thus, give 1-2hrly doses & stop if GIT effects, but these may worsen as lag effect of several hrs b/n dose & GIT effect!

elderly, cardiac/hepatic/renal/GIT disease; PH poor tolerance to it;
potentially fatal colchicine toxicity from hepatic/renal disease or drug interactions with CYP3A4 inhibitors such as:
- clarithromycin (eg. used as part of triple therapy for Helicobacter eradication in peptic ulcer Mx)

¹⁾