Colchicine

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Colchicine

• By Amy London

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What is colchicine?

• (2)-N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-
  oxobenzoa heptalen-7-yl) acetamide
• tricyclic alkaloid
• trimethoxypnenyl ring
• 7 membered ring with an acetomide at the 7
  position
• tropolonic ring

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Stereoisomers of Colchicine

• Colchicine has 4 isomers
• each pair has either R or S configuration
• (-)-(aS,7S)-Colchicine is the natural isomer
  which can interconvert between aR and aS

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Chemical properties of colchicine

• C22H25NO6
• molecular weight is 399.4426
• melting point is 142 degrees Celsius
• water solubility is less than 10/g mL at 21
  degrees Celsius
• pale yellow to greenish crystalline powder
• photosenstive
• slowly hyrdolyzes in acidic solution

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History of colchicine

• First used over 2000 years ago
• derived form preparations of Colchicum autumnale
• First described by Padanius Dioscordes (AD
  54-68), a Greek surgeon, in De Materia Medica
• currently produced locally by Sigma

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Uses of colchicine

• Treatment of gout
• Treatment of Familial Mediterranean Fever
• minimally effective chemotherapy agent
• research use as an antimitotic agent
• new uses being explored
• chronic hepatitis B and cirrhosis
• Sweets syndrome
• pediatric pericarditis
• constipation

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Symptoms of colchicine poisoning

• Nausea
• diarrhea
• pancytopenia
• alopecia
• weakness
• respiratory distress
• potentially fatal

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Colchicine poisoning is divided into 3 phases

• Stage I is the G.I. Phase
• occurs within hours of ingestion
• Stage II is the multi-phase stage
• cardiovascular insufficiency
• respiratory insufficiency
• metabolic effects
• neuromuscular effects
• hematologic effects

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• Stage III is the recovery phase
• occurs 7 to 10 days after ingestion
• marked by alopecia
• rebound leukocytosis

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Mechanisms of Toxicity

• Metabolized in the liver
• facilitated by cytochrome P450
• undergoes deacetylation and hydrolysis
• converted to oxydicolchicine

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Most is recirculated in the liver

• Significant amount absorbed in the digestive
  tract
• peak plasma concentration reached within 30
  minutes to 2 hours
• large V.O.D. ( 3x-4x total body water volume)
  prevents removal by dialysis
• Average elimination half-life is 20 hours

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• Colchicine arrests cells in metaphase
• binds to tubulin
• prevents polymerization into microtubules
• alters nuclear structure
• inhibits intracellular transport
• allows it to be used for cytogenetic diagnostics

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Treatment of colchicine poisoning

• Largely supportive
• aggressive rearly GI decontamination
• use of activated charcoal within 24 hours

• Administraion of fluids
• assisted respiration as needed
• transfusions with red blood cells, vitamin K, and
  fresh plasma
• anti-seizure medication as needed