Codeine Research Paper

Codeine (3-methylmorphine) is a weak agonist at opioid receptors (mu, kappa, delta and sigma). The drug is converted to morphine, in the liver by an isoenzyme of CYP450, which is its active component. Opioid receptors are found at presynaptic and postsynaptic clefts and produce various effects when stimulated. The active form of codeine binds to opioid receptors at the pre-synaptic cleft and inhibits the opening of calcium channels, reducing the release of excitatory neurotransmitters such as acetylcholine, noradrenalin, glutamate, seratonin and substance P. When it binds to opioid receptors at the postsynaptic cleft, it stimulates the opening of potassium channels, causing hyperpolarisation of the neuron and hence, inhibits the generation

The bioavailability of codeine is approximately 53% and it has a biological half-life of approximately 3 hours. Codeine is mainly converted to morphine in the liver by an isoenzyme of CYP450, CYP2D6 (uptodate). CYP3A4 and UGT2B7 also contribute to its metabolism, converting codeine to norcodeine and codeine-6-glucuronide respectively. Furthermore, morphine is further metabolised by glucorinidation to active morphine-3-glucuronide and morphine-6-glucuronide. Codeine is eliminated through bile and excreted out of the body through urine and faeces with 10% of the total dose as unchanged drug (rang and dale). The complexity of the pharmacokinectics is explained by environmental, genetic and psychocosial factors that impact on the absorption, distribution, metabolism and excretion of the drug. The metabolic enzymes of codeine, CYP2D6, CYP3A4 and UGT2B7, possess polymorphisms that are influenced by an individual’s genetic makeup. Genetic influences causing higher enzyme concentration and activity increases the concentration of morphine and decreases the half-life of codeine while lower enzyme concentrations reduces the potency of the

The variants of this enzyme can be broadly classified into low activity, normal activity, high activity and multiple-gene copy. Low activity variants are poor metabolisers and are unable to efficiently convert codeine to morphine and hence experience reduced analgesia while multiple-gene copy variants are ultrarapid metabolizers that metabolise codeine more effectively, leading to morphine intoxication (Yvan et al. 2004). While interindividual variability is present for CYP3A4 enzymes, there is little evidence to suggest any functional consequences due to this polymorphism but, variants in UGT2B7 have been proven to cause some altered enzyme