Probenecid and colchicine

Uses

Prophylaxis and treatment of gout flares in adults.

Familial Mediterranean fever (FMF) in adults and children 4 years or older.

Probenecid is a medication used to treat gouty arthritis, tophaceous gout, and hyperuricemia.

For the reduction of serum uric acid concentrations in chronic gouty arthritis and tophaceous gout in patients with frequent disabling gout attacks. Has also been effectively used to promote uric acid excretion in hyperuricemia secondary to the administration of thiazide and related diuretics.

Probenecid and colchicine is also used to associated treatment for these conditions: Behcet's Syndrome, Familial Mediterranean Fever (FMF ), Gout Flares, Pericarditis, Postpericardiotomy SyndromeBacterial Infections, Chronic Gouty Arthritis, Elevated Serum Uric Acid, Gout Chronic, Hyperuricemia, Infection

How Probenecid and colchicine works

The exact mechanism of action of colchicine has not been fully established, however likely occurs via the downstream inhibition of inflammation caused by tubulin disruption. Studies have implied that that colchicine causes disruption of the inflammasome complex that is present in both monocytes and neutrophils, which normally leads to the activation of interleukin-1, an important mediator of inflammation. In addition to the above actions, colchicine acts to interfere with pathways including neutrophil adhesion and recruitment, superoxide production, the RhoA/Rho effector kinase (ROCK) pathway, as well as a type of nuclear factor κΒ (NF-κΒ) pathway, reducing inflammation.

On a molecular level, colchicine can be described as an anti-mitotic drug, blocking the mitotic activity cells in the metaphase part of the cell cycle. Specifically, colchicine binds to tubulin, forming complexes that bind to microtubules. This stops their elongation. At low concentrations, colchicine stops microtubule growth and, at elevated concentrations, colchicine causes the depolymerization of microtubules.

Probenecid inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Probenecid may also reduce plasma binding of urate and inhibit renal secretion of uric acid at subtherapeutic concentrations. The mechanism by which probenecid inhibits renal tubular transport is not known, but the drug may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules.

Dosage

Probenecid and colchicine dosage

Acute gouty arthritis: Articular pain and swelling typically reduced within 12 hours and are usually gone in 24 to 48 hours, an interval of three days between colchicine courses is advised in order to minimize the possibility of cumulative toxicity. The total amount of colchicine needed to control pain and inflammation during an attack usually ranges from 4 to 8 mg. First dose- 1 to 1.2 mg (two 0.6 mg tablets) at a time, then one (0.6 mg) tablet every 2 hours until pain and inflammation aborted.For prophylaxis during intercritical periods: Severe cases may require two or three 0.6 mg tablets daily. For cases involving more than one attack per year, the usual dose is 0.6 mg daily. In patients who have less than one attack per year, the usual dose is 0.6 mg per day, three or four days a week. To reduce the frequency of their severity, colchicine may be administered continuously.For prophylaxis against attacks of gout in patients undergoing surgery: In patients with gout, an attack may be precipitated by even a minor surgical procedure. one 0.6 mg tablet three times daily should be administered for three days before and three days after surgery.

Side Effects

Nausea, vomiting, and abdominal pain. Excessive doses may cause profuse diarrhea.

Toxicity

The oral LD50 of colchicine in mice is 5.87 mg/kg.

Overdose information

Fatal overdoses have been reported in adults and children following the ingestion of colchicine. There are several stages involved in colchicine toxicity. The signs and symptoms generally occur within 24 hours of colchicine ingestion. Gastrointestinal disturbance, including abdominal pain, nausea, vomiting, diarrhea, and volume depletion. Elevated leucocyctes may also be detected during laboratory testing. Dangerous complications may occur during the second stage of a colchicine overdose, is generally during the time frame of 24 to 72 hours after ingestion. Multiorgan failure may occur and death is usually caused by respiratory depression in addition to cardiovascular collapse.

In the case of a colchicine overdose, gastric lavage and supportive measures to prevent shock should be undertaken. Treat symptoms related to the overdose. There is currently no antidote to a colchicine overdose. This drug should be kept out of the reach of children. Colchicine is not well removed by dialysis.

Precaution

Keep Kolchin out of the reach of children.

Interaction

Co-administration with clarithromycin or Cyclosporine have been demonstrated to alter the concentration of Kolchin.

Volume of Distribution

According to the FDA label, the mean apparent volume of distribution in young and healthy patients is calculated to be about 5-8 L/kg. It is known to cross the placenta and to distribute into the breast milk. Colchicine has been found to distribute to various tissues but mainly into the bile, liver, and kidney tissues. Smaller amounts have been detected in the heart, lungs, intestinal tissue, and stomach.

Elimination Route

Colchicine is rapidly absorbed after oral administration from the gastrointestinal tract. During a pharmacokinetic study, a mean Cmax of 2.5 ng/mL was achieved within 1-2 h (range 0.5 to three hours) after an orally administered dose of colchicine. The bioavailability of colchicine is about 45%, according to the FDA label, however, another reference indicates that the bioavailability is highly variable, ranging from 24 to 88%. In a multiple-dose study of colchicine administration at a dose of 1 mg per day, steady-state concentrations were achieved by 8 days following administration.

Half Life

After several doses of 0.6 mg twice daily, the average 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.

6-12 hours

Clearance

The FDA label reports a clearance of and 0.0292 ± 0.0071 to 0.0321 ± 0.0091 mL/min after a single oral dose of one 0.6 mg of colchicine. Patients with end-stage renal impairment showed a 75% lower clearance of colchicine. In a pharmacokinetic study of patients with Familial Mediterranean Fever (FMF), the apparent mean clearance was calculated at 0.726 ± 0.110 L/h/kg.

Elimination Route

In a pharmacokinetic study of healthy research subjects(n=12), 40% to 65% of a 1 mg oral colchicine dose was measured as unchanged drug in the urine. Both enterohepatic recirculation and biliary excretion are routes which are involved with the excretion of colchicine.

Excreted principally in the urine as monoacyl glucuronide and unchanged drug. Alkalinization of urine increases renal probenecid excretion.

Pregnancy & Breastfeeding use

There are no adequate studies of Kolchin in pregnant women.

Nursing mothers: Kolchin is excreted into human milk and may cause adverse effects in the infant.

Contraindication

Patients with renal or hepatic impairment should not be given Colchicine in conjunction with Permeability glycoprotein (P-gp) or strong CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine).

Special Warning

Pediatric Use: The safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with colchicine. Gout is rare in pediatric patients, safety and effectiveness of colchicine in pediatric patients has not been established.

Geriatric Use: Clinical studies with colchicine for treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Acute Overdose

Symptoms: Nausea, anorexia, abdominal pain, vomiting, paralytic ileus, diarrhoea; stomatitis, arthralgia, malaise, hypocalcaemia, fever, rashes; renal damage; hepatomegaly and liver tenderness; extreme vascular damage; leucopenia followed by leukocytosis; bone marrow depression, thrombocytopenia, granulocytopenia, immature leucocytes, pancytopenia, anaemia with anisocytosis, polychromasia, basophilic stippling; muscular weakness; CNS paralysis; mental confusion, delirium, seizures; loss of deep tendon and Achilles tendon reflexes, Babinski's reflex may be elicited; resp depression or CV collapse may result to death.

Management: Symptomatic and supportive treatment. Perform gastric lavage to prevent shock. Maintain circulation, correct fluid and electrolyte imbalance. Consider activated charcoal in patients who ingested more than 0.1 mg/kg w/in 1 hr of presentation. May administer morphine sulfate 10 mg IM to relieve severe abdominal cramps.

Storage Condition

Store between 20-25° C. Protect from light and moisture.

Innovators Monograph

You find simplified version here Probenecid and colchicine