Codeine metabolism

Yue Q, Sawe K. Interindividual and interethnic differences in codeine metabolism. In Kalow W, ed. Pharmacogenetics of Drug Metabolism. New York Pergamon Press, 1992 721-727. 

Williams DG, Patel A, Howard RF (2001) Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth 86(3) 413—421... 

Codeine (metabolized to 30-60 pg Oral 3-4 Cough, diarrhea, moderate pain As morphine lack of effect in poor... 

Huffman DH and Ferguson RL (1975) Acute codeine overdose Correspondence between clinical course and codeine metabolism. Johns Hopkins Medical Journal 136 136-183. 

Fig. 2. Codeine metabolism. Roughly 90% of a codeine dose is metabolized to inactive compounds by CYP3A4. The other 10% of a codeine dose is metabolized to the active component morphine via CYP2D6. Alt are eventually excreted by the kidneys. Blue, inactive compounds red, active metabolites.

Ammon S, Marx C, Behrens C, Hofmann U, Miirdter T, Griese E-U, Mikus G. Diclofenac does not interact with codeine metabolism in vivo a study in healthy volunteers. BMC Clin Pharmacol (2002) 2, 2. 

The interaction appears to be well established. Prescribers should be aware that smokers may require a greater amount of opioids postoperati vely than non-smokers. In contrast, codeine metabolism does not appear to be affected to a clinically important extent by smoking. 

Cytochrome P450 2D6 Extremely high activity in about 2% of Caucasian populations and completely deficient activity in about 7%. Inefficiency in ultrarapid metabolizers and extremely heavy effects in poor metabolizers for more than 50 drugs. A few drugs requiring bioactivation by CYP have low efficacy in poor metabolizers (example codein is activated to morphine via CYP2D6). 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

Cramps and other reactions from excess codeine effect in 2D6 "ultrarapid metabolizers"... 

Wilcox, R.A. and Owen, H. (2000) Variable cytochrome P450 2D6 expression and metabolism of codeine and other opioid prodrugs implications for the Australian anaesthetist. Anaesthesia and Intensive Care, 28 (6), 611-619. 

Gasche, Y., Daali, Y., Fathi, M., Chiappe, A., Cottini, S., Dayer, P. and Desmeules, J. (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. New England Journal of Medicine, 351 (27), 2827-2831. 

Alkaloids such as boldine, codeine, narceine and morphine are active factors in their receptors. Boldine has morphine-like properties and is active on opioid receptors. It may be used to treat stomach disorders and as metabolic stimulant. As it is similar to morphine, boldine can also be considered in the possible development of treatments for narcotic dependence. Codeine also binds to opiate receptors, and specifically functions to reduce bronchial secretions. Codeine can also be used as a cough suppressant when acting on the centre of the medulla oblongata and as a sedative agent. 

The most important other opium alkaloid is codeine. In contrast to morphine, codeine has a high oral-parenteral potency ratio due to less first-pass metabolism. Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide. Approximately 10% is demethylated to morphine. The analgesic effect of codeine is due to the formation of these metabolites as codeine itself has a very low affinity for opioid receptors. The half-life of codeine in plasma is 2 hours. 

Like morphine, codeine is a naturally occurring opioid found in the poppy plant. Codeine is indicated for the treatment of mild to moderate pain and for its antitussive effects. It is widely used as an opioid antitussive because at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect It is one of the most commonly used opioids in combination with nonopioids for the relief of pain. The administration of 30 mg of codeine in combination with aspirin is equivalent in analgesic effect to the administration of 65 mg of codeine. The combination of the drugs has the advantage of reducing the... 

Pharmacokinetics Variably absorbed from the GI tract. Protein binding low. Metabolized in liver. Primarily excreted in urine as morphineglucuronide con j ugates and unchanged drug—morphine, codeine, papaverine, etc. Unknown if removed by hemodialysis. Half-life 2-3 hr. 

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