Toxicology
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A 68-year-old male presents to the emergency department for evaluation of weakness. According to the patient’s daughter, he has been increasingly confused over the past 24 hours and has been vomiting “constantly” for the past 48 hours. The patient appears lethargic, but adds that he has been experiencing severe stomach cramping as well as several episodes of diarrhea. He denies fevers or chills. He has a past medical history of hypertension, for which he takes lisinopril. He denies any other illness. He appears sleepy during the interview, but arouses to answer questions.

Vital signs
BP 90/60 mmHg, Pulse: 118 beats per min, RR 24 breaths per min, temperature 37.7 oral

Chemistry Panel
Na-122, K- 3.0, Cl-96, CO2-16,
BUN-25, Cr-2.2
CBC: Hgb 9.0. Hct: 23.2
WBC: 3.2, PLT: 80K

The patient’s daughter adds that her father has long suffered from severe gout, and was recently restarted on his gout medication colchicine one week prior. He had been taking another medication, but insisted that his doctor restart colchicine as he stated that this was the only medication that ever gave him any measurable relief. When the pain would not subside with the recommended dose, the patient took “a whole handful” of the pills.

Colchicine
Colchicine is derived from two plants from the Lilly family: Colchicum Autumnale (autumn crocus, meadow saffron or naked lady) and Gloriosa Superba- the Glory Lilly. Colchicine concentrations peak during summer months.

The Autumn Crocus contains varying amounts of colchicine by weight.

  • Bulb-0.8%
  • Flowers 0.1%
  • Seeds 0.8%
  • Stem 0.6%

Colchicine has an intriguing ancient history. The Goddess Aphrodite caused Medea, daughter of King Aeetes of Colchis, to fall in love with Jason during his quest for the Golden Fleece. Years later when rejected by Jason, Medea was believed to have poisoned their children with colchicine. The plant was known to be native to her home island.

As a medicine, Colchicine was first used over 2000 years ago for joint pain. Additionally, the Greek surgeon Dioscorides, first documented uses of the meadow saffron in his lengthy pharmacopeia De Materia Medica.

“The Doctrine of Signatures” was a philosophy shared by herbalists from the time of Dioscorides and Galen. This doctrine implied that the physical form of a plant gives a clue as to its healing purposes. It allowed for a tenuous link between colchicum and gouty arthritis by associating the shape of the flower with that of the crippled arthritic hand.

Colchicine was allegedly introduced into the US by Benjamin Franklin, who was known to suffer from severe debilitating attacks of gout. He encountered colchicine while living abroad in Paris and expounded its benefits on his return to the states. Although used for decades, it was not until 1820 when colchicine, the pharmacologically active constituent of the plant, was isolated by the French chemists Pelletier and Caventon.

Gouty Arthritis
Current medical uses of colchicine include gouty arthritis, familial Mediterranean fever, pericarditis, Behcets disease and as a chemotherapeutic agent. Of these, gout is the disease most associated with colchicine. Gout, from the Latin gutta, meaning drop, was used to describe the symptoms because physicians presumed the disease was caused by the dropping of phlegm into the great toe. Gout is a disorder of purine metabolism, and occurs when its final metabolite, uric acid, crystallizes in the form of monosodium urate, precipitating in joints, on tendons, and in the surrounding tissues. Build up of these crystals trigger the inflammatory reaction that leads to a gout attack. Podagra is the most common presentation, heralded by severe inflammation of the great toe.

For centuries gout has been described as one of the most painful afflictions to affect man. “No other pain is more severe than this, not iron screws, nor cords, not the wound of a dagger, nor burning fire.” described by Aretaeus, the Greek physician of the second century. Thomas Sydenham, a 17th Century physician, described the pain as “a violent stretching and tearing of the ligaments - now it is a gnawing pain, like that of a dog.”

Pharmacology
Colchicine itself functions as an inhibitor of microtubule formation and function.
Tubulin is required for mitosis, and therefore colchicine acts as an inhibitor of mitosis or a mitotic poison.
The microtubules are made of tubulin protein subunits, Alpha, beta and gamma. Colchicine binds to the tubulin Beta subunit at the colchicine binding domain. Binding is slow, but irreversible. Colchicine can also bind at another reversible, lower affinity site. Following binding, conformational changes occur in the tubulin structure, which ultimately results in microtubule spindle disassembly, dysfunction and cell death.

Toxicity
The maximum dose of colchicine in an acute attack of gout should be 6mg (10 tablets). Colchicine should be taken at an initial dose of 1.2mg followed by 1 tablet every 2 hours until the gouty pain is relieved, gastrointestinal symptoms develop, or the maximum dose is reached. Originally 0.8mg/kg was presumed uniformly fatal, but this number has been since revised.
In poisoning, a triphasic response is typical:

  • 0-24 hours vomiting, diarrhea, abdominal pain
  • 1-7 days, pancytopenia, sepsis, renal failure, sudden cardiac death
  • Over 7 days, alopecia, myopathy, neuropathy

Gastrointestinal effects are almost universal with colchicine poisoning. Signs of acute toxicity include nausea, vomiting and diarrhea. Poisoning is frequently associated with dysrhythmias and cardiac arrest. Sudden cardiac collapse usually occurs within 24-48 hours post ingestion. This is often attributed to profound hypovolemia and shock, as well as some direct cardiotoxic effects of the drug itself.

Initial leukocytosis progresses to leukopenia and pancytopenia 48-72 hours post ingestion. Recovery of marrow function typically occurs if the patient survives.

Management
Treatment for colchicine poisoning is mainly supportive. Intravenous hydration, vasopressors, and hemodialysis may be required for renal failure. Orogastric lavage is advised in anyone who presents within 1-2 hours of ingestion and is not vomiting. Activated charcoal should be given because of cholchicine’s enterohepatic recirculation.

The use of colchicine Fab fragments has been documented as effective in advanced poisoning cases by Baud et al in 1995. The process is similar to that used in the antidote for Digoxin poisoning. Immune fragments are obtained from goats, previously sensitized to a colchicine derivative. The fragments are then given to humans poisoned with colchicine, which results in the formation of an immune complex. The complex once formed is unable to bind to the target, and therefore remains in circulation for clearance. Although there appears to be promise in this approach, as yet there is a very limited supply of colchicine Fab Fragment available for use.

Clinical Outcome
The patient was noted to be in the early stages of pancytopenia with severe dehydration, as well as acute renal failure. He was transported to the intensive care unit for further supportive care. Multi-dose activated charcoal was administered once patient appeared more alert and there was decreased risk of aspiration. At day 4 of hospitalization, the WBC count and platelets reached a low of 1.2 and 62,000 respectively. Gradually, renal function was noted to improve with a Cr of 1.2 at hospital day 6. He continued to gradually improve, and on day 9 was transferred to a step-down recovery unit. Patient was noted to be most concerned about the loss of his hair as he noted “I didn’t have much to begin with.” He was discharged from the hospital on Day 12, and as last noted, was doing well.


References

  • “History of the Use of Colchicum and related Medicaments in Gout”. Ann Rheum Dis 13 (3): 190–200. Manuchair S. Ebadi (2007).
  • Pharmacodynamic basis of herbal medicine. Pelletier PS, Caventon J. Ann. Chim. Phys. 1820;14:69
  • Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med. 2005;143(7):499–516.
  • .Choi HK, Curhan G. Gout: epidemiology and lifestyle choices. Curr Opin Rheumatol. 2005;17(3):341–345.
  • Healey LA. Port wine and the gout. Arthritis Rheum. 1975;18(Suppl 6):659–662.
  • Hak AE, Choi HK. Lifestyle and gout. Curr Opin Rheumatol. 2008;20(2):179–186.
  • Baud et al (1995) Fab Fragments for cholchicine
 

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