Application of Colchicine, side effect and Drug interactions

Application of Colchicine, side effect and Drug

interactions

W.A.S.S.Weerakkodi
LUC0000002320302202021
Pharmacognosy

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Application of Colchicine, side effect and Drug interactions

Content

Page No

 Introduction 03
 Indication 04
 Pharmacodynamic 04
 Pharmacokinetic 05
 Side effects 06
 Interaction 07
 References 08

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 Application of Colchicine, side effect and Drug interactions

Introduction
First approved by FDA in 1961.Colchicine is an alkaloid drug derived from a plant belonging to the
Lily family, known as Colchicum autumnale, or ‘’autumn crocus’’.
It Commonly used for management of gout, the condition associated with the painful deposition of
urate crystals in the joints, Other than its use in gout, Colchicine has been approved for managing
exacerbations of familial Mediterranean Fever (FMF),a hereditary autoinflammatory condion.
Colchicine is in a class of medications called anti-gout agents .it work by stopping the natural process
that cause swelling and other symptoms of gout and FMF.
Type
Small molecule
Structure

Weight
Avarage 399.443
Monoisotopic :399.168187529
Chemical formular
C22H25NO6
Synonyms
Colchicin
Colchicina
Colchicine
Colchicinum

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 Application of Colchicine, side effect and Drug interactions

Indication
 Colchicine is used to prevent or treat Gout attack in adults ( gout attacks is sudden
,severe pain in one or more joint caused by abnormally high levels of substance
called uric acid in the blood) The big toe ,knee, or ankle joints are most often
affected.
 Colchicine also use to relive the pain of gout attacks when they occur.
 Also use to treat Familial Mediterranean fever In adult and children 4 years of age
and older (FMF is an inborn condition that cause episode of fever ,pain and swelling
of the stomach area ,lungs and joints.)

Colchicine not a pain reliever and cannot be used to treat pain that is
not caused by gout or FMF.

 Bechcet's syndrome
 Pericarditis
 Post pericardiotomy syndrome

Pharmacodynamic
Colchicine reduce pain resulting from gout & reduces flares of familial Mediterranean fever by
interfering with inflammatory pathways. This drug has a narrow therapeutic index.

Mechenism of action
The exact mechanism of action of colchicine has not been fully established, however likely occurs via
the downstream inhibition of inflammation causes by tubulin disruption. Studies have implied that
colchicine causes disruption of the inflammation complex that is present In both monocytes and
neutrophils. which normally leads to activation of interleukin 01, an important mediator of
inflammation ,in addition to the above actions, colchicine acts to interfere with pathways including
neutrophils adhesion and recruitment ,superoxide production ,the RhoA/Rho effector kinase ( Rock)
pathway ,as well as a type of nuclear factor KB ( NF- KB) pathway ,reducing inflammation.
On a molecular level , cochicine can be described as an anti- mitotic drug - blocking the mitotic
activity cells in the metaphase part of the cell cycle. Specially ,colchicine binds to tubulin forming
complexes that bind to microtubules. This stop their elongation. At low concentration, colchicines
cause depolymerization of microtubules.

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 Application of Colchicine, side effect and Drug interactions

Pharmacokinetic
Absorption
Rapidly absorbed after oral administration from gastrointestinal tract(GI tract). During
pharmacokinetic study, a mean C-max of 2.5 ng/mL was achieved within 1-2 h (range 0.5 to 3hours)
after orally administered dose of colchicine. Bioavailability of colchicine is about 45%, according to
FDA label(Food and Drug Administration), however, another reference indicates that bioavailability
is highly variable, ranging from 24% to 88%. In a multiple-dose study of colchicine administration at
a dose of 1miligram per day, steady-state concentrations were achieved by eight days following
administration.
Volume of distribution
According to the FDA label, the mean apparent volume of distribution in young and healthy
patients is calculated to be about 5-8L/kg. It is known to cross the placenta & to distribute in to brest
milk.
Colchicine has been found to distribute to various tissues but mainly in to bile, liver and kidney
tissues. Smaller amount have been detected in heart, lungs, intestinal tissue and stomach.
Protein binding
The plasma protein binding for colchicine is low to moderate, at 39 ± 5%, and it is mainly bound to
albumin.
Metabolism
Found to be metabolized in the liver and demethylated to major metabolites, which include 2-O-
demethylcolchicine & 3-O-demethylcolchicine, and one minor metabolite, 10-O-demethylcolchicine.
According to in vitro studies, CYP3A4 metabolizes colchicine to 2- and 3-demethylcolchicine.

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 Application of Colchicine, side effect and Drug interactions

Colchicine

2-demethylcolchicine + 3-desmethylcolchicine

Route of elimination
In a pharmacokinetics study of healthy research subjects (n =12), 40% to 65% of a 1 mg oral
colchicine dose was measured as unchanged drug in urine. Both enterohepatic recirculation and
biliary excretion are routes which are involved with the excretion of colchicine.
Half life
After several dose of 0.6mg twice daily. The avarage elimination half life of colchicine ranges from
26.6 to 31.2 hours.
Another reference measures that the elimination half life ranges from 20 to 40 hours
Clearance
The FDA label reports a clearance of & 0.00292±0.0071 to 0.0321±0.0091 ml/min after a single oral
dose of one 0.6 mg of colchicines.
Patients with end-stage renal impairment showed 75% lower clearance of colchicines. In a
pharmacokinetics study of patients with Familial Mediterranean Fever, the apparent mean clearance
was calculated at 0.726±0.110 L /h /Kg.
Side effects
Common side effects

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 Nauseasdfgsdfgsdfg
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 Diarrheasdfgsdfgsdfg
 Stomach crampssdfgsdfgsdfg
Infrequent side effects

 Headache sdfgsdfg
Rare side effects

 A type of blood disorder with a decrease in all types of blood cells called pancytopenia.
 Decrease function of bone marrow .dfgsdfg
 Low blood counts due to bone marrow failure.sdfgsdfg
 A type of blood clotting disorder called disseminated intravascular coagulation.
 Large purple or brown skin blotches. sdfgsdfg
 Decreased blood platelets.sdfgsdfg
 Very low levels of granulocytes, a type of white blood cells.
 Low levels of white blood cells. dsfgsdfg
 A disorder of the peripheral nerves that enable movement called peripheral motor
neuropathy .sdfgsdfg

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 Application of Colchicine, side effect and Drug interactions

 A decrease with shrinking and weaker muscle called myopathy.

 Inflammation of the skin due to an allergy.
 Hives .
 A condition with muscle tissue breakdown called Rhabdomyolysis .
 A skin Rash.
 A type of allergic reaction called called angioedema.
 A high Alanine Transaminase level.
 A high Aspartate transaminase level.
 Low sperm count.
 Hair loss.
 A type of Bumpy skin rash called a maculopapular rash .
 Absence of sperm in semen .
 Peripheral sensory nerve disorder.
 Black, tarry stools.
 Blood in the urine or stools.
 Burning, "crawling", or tingling feeling in the skin.
 Difficulty with breathing when exercising.

Interaction
Colchicine is a substrate of efflux transporter P-glycoprotein and the CYP3A4 metabolizing enzyme.
Fatal drug interactions have been reported when colchicine is administered with clarithromycin, a
dual inhibitor of CYP3A4 and P-glycoprotein. Toxicities have also been reported when colchicine is
administered with inhibitors of CYP3A4 that may not be potent inhibitors of P-glycoprotein (example
grapefruit juice, erythromycin, verapamil), or inhibitors of P-glycoprotein that may not be potent
inhibitors of CYP3A4 (Example - cyclosporine).
Patients having renal or hepatic impairment shouldn’t be given colchicine capsules with drugs that
inhibit both P-glycoprotein & CYP3A4.
Combining this dual inhibitors with colchicine capsules in patients having renal & hepatic
impairment has resulted in life-threatening or fatal colchicine toxicity.
CYP3A4
Concomitant use of colchicine capsules and CYP3A4 inhibitors (example: ketoconazole, grapefruit
juice, verapamil, clarithromycin , erythromycin) should be avoided due to potential for serious and
life-threatening toxicity
If co-administration of colchicine capsules and a CYP3A4 inhibitor is necessary, dose of colchicine
capsules should be adjusted by either reducing daily dose or reducing dose frequency, & the patient
should be monitored carefully for colchicine toxicity.
P-Glycoprotein
The concomitant use of colchicine capsules and inhibitors of P-glycoprotein (example : cyclosporine
clarithromycin, ketoconazole,)should be avoided due to potential for serious and life-threatening
toxicity .
If co-administration of colchicine capsules & P-glycoprotein inhibitor is necessary, dose of colchicine
capsules should be adjusted by either reducing daily dose or reducing dose frequency, & patient
should be monitored carefully for colchicine toxicity .

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 Application of Colchicine, side effect and Drug interactions

HMG-CoA Reductase Inhibitors And Fibrates

Some drugs such as HMG-CoA reductase inhibitors & fibrates may increase risk of myopathy when
combined with colchicine capsules. Complaints of weaknes or muscle pain or could be an indication
to check serum creatinine kinase levels for signs of myopathy.
Drug-Drug Interaction Studies
4 pharmacokinetic studies evaluated the effects of co-administration of voriconazole (200 mg BD),
fluconazole (200 mg QD), cimetidine (800 mg BD), and propafenone (225 mg BID) on systemic levels
of colchicine. Colchicine can be administered with these drugs at tested doses without a need for
dose adjustment. However, these results should not be extrapolated to other co-administered drugs.
Interactions With CYP3A4 And P-glycoprotein Inhibitors
Because colchicine is a substrate for both CYP3A4 metabolizing enzyme & P-glycoprotein efflux
transporter, inhibition of either of these pathways may lead to colchicine related toxicity. Inhibition
of both CYP3A4 & P-glycoprotein by dual inhibitors such as clarithromycin has been reported to
produce life-threatening or fatal colchicine toxicity due to significant increases in systemic colchicine
levels. So, concomitant use of colchicine capsules & inhibitors of CYP3A4 or P-gp should be avoided .
If avoidance isn’t possible, reduced daily dose should be considered & patient should be monitored
closely for colchicine toxicity. Use of colchicine capsules in conjunction with drugs that inhibit both
P-glycoprotein & CYP3A4 is contraindicated in patients having renal or hepatic impairment.
Major Food Interactions
Drinking large amounts of grapefruit juice can increase blood levels of colchicine to dangerous levels.
Therefore avoid consumption of grapefruit or grapefruit juice during treatment with colchicine.
Colchicine disease interactions
There are 7 disease interactions
 bone marrow suppression
 cardiac dysfunction
 DIC
 electrolyte disturbances
 liver disease
 renal dysfunction
 rhabdomyolysis

References:
Dalbeth N, Lauterio TJ, Wolfe HR: Mechanism of action of colchicine in the treatment of gout. Clin
Ther. 2014 Oct 1;36(10):1465-79. doi: 10.1016/j.clinthera.2014.07.017. Epub 2014 Aug 21
Angelidis C, Kotsialou Z, Kossyvakis C, Vrettou AR, Zacharoulis A, Kolokathis F, Kekeris V,
Giannopoulos G: Colchicine Pharmacokinetics and Mechanism of Action. Curr Pharm Des.
2018;24(6):659-663. doi: 10.2174/1381612824666180123110042.
Loue C, Tod M: Reliability and extension of quantitative prediction of CYP3A4-mediated drug
interactions based on clinical data. AAPS J. 2014 Nov;16(6):1309-20. doi: 10.1208/s12248-014-9663-
y. Epub 2014 Oct 2.