Synthesis Of Morphine

Introduction:
The pharmacokinetics of a drug describes the journey of a drug through the body i.e. its absorption, bioavailability, distribution, metabolism and excretion. Opioids are substances (endogenous or synthetic), which produce ‘opiate-like effects’. Opiates are alkaloids derived from the Papaver somniferum poppy e.g. Morphine, Codeine (a morphine-like agonist) and Methadone (a synthetic analogue of morphine) and are primarily used as analgesics.[1]
Discussion:
Morphine has a 4-ring structure with a tertiary nitrogen (permits anchoring to opioid receptors) and 2 OH groups shown in Figure 1. When the benzene OH group is substituted for a methyl group, you obtain 3-methoxymorphine (codeine) shown in Figure 2.[2] Morphine’s route of administration
Morphine is therefore given intravenously to treat acute severe pain, and orally to treat chronic pain.[4] Morphine has a bioavailability of 40-50% (proportion of administrated morphine available to exert its pharmacological effect). This is low as morphine has extensive first pass metabolism (occurring the fist time the drug passes through the liver). Morphine is not as effective as other opioids e.g. methadone at getting into the brain tissue due to its poor lipid solubility. It is ionised (hydrophilic) at physiological pH, so struggles to traverse the lipid based blood brain barrier. 30-40% of morphine is bound to plasma proteins e.g. albumin and γ-globulin (the latter to a lesser extent), which cannot exit the blood.[5] Morphine has a volume of distribution (volume necessary to contain the total amount of
itself it’s not pharmacologically active but it is metabolised to morphine. As with morphine, codeine ‘s ROA is predominantly oral (cannot be given by injection), and is absorbed primarily in the small intestine. Codeine has a similar volume of distribution to morphine of 3-6L/kg due to its similar chemical structure and lipid solubility. Only 7-25% of codeine is bound to plasma proteins, so a higher proportion is able to access the tissues compared to morphine. Codeine has a higher bioavailability than morphine (90%) as it’s more readily absorbed by mouth.[9] There are 2 isoforms of CYP450 in the liver involved in codeine’s phase 1 metabolism: CYP2D6, activating 5-10% codeine to generate morphine in an O-demethylation reaction and CYP3A4, activating 10% of codeine to an inactive metabolite, norcodeine. The former reaction is comparably slower to the latter, resulting in codeine being deactivated faster than it’s activated. The CYP2D6 enzyme is genetically polymorphic, and 5-10% of the population have decreased CYP2D6 activity and are ‘poor metabolisers’ of codeine (experience diminished analgesic affects). 0.5-2% of the population have multiple functional alleles of CYP2D6 and are ‘ultra-fast metabolisers’. These individuals can experience life-threatening intoxication because morphine is generated so rapidly.[10] Like morphine, codeine (70-80%) undergoes conjugation with glucoronide to form codeine-6-glucoronide in phase 2 metabolism, catalysed by