Opiates and centrally active analgesics
The opiates include the analogues of morphine, such as codeine, ethylmorphine and diamorphine, as well as the synthetic opiates methadone, pethidine, dextropropoxyphene and the highly potent fentanyl derivatives. Depending on their structural features, the metabolism of opiates can vary widely.
The morphine analogues are metabolised by O-dealkylation or de-esterification and conjugation with glucuronic acid. Thus, diamorphine (heroin) is hydrolysed rapidly in the body to 6-acetylmorphine, which is further and more slowly hydrolysed to morphine. The morphine so formed is excreted largely as the 3- and the 6-glucuronides together with some free morphine. Codeine and ethylmorphine are conjugated and metabolised by O-dealkylation to morphine. Morphine is also metabolised to a minor extent by N-demethylation to normorphine (Fig. 1). Oxycodone is subject to demethylation and conjugation (Fig. 2). Methadone, dextropropoxyphene and pethidine are largely dealkylated. In the case of methadone a cyclisation product known as 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrroli dine (EDDP) is formed (Fig. 3), as well as 2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolidine (EMDP).
The non-opioid centrally active analgesic tramadol is metabolised to N- and O-demethylated products followed by sulfation and glucuronidation of the phenol. The N-desmethyl metabolite (known as M1) is active pharmacologically (Fig. 4).
Figure 1 Metabolic pathways of morphine analogues.
Figure 2 Oxycodone metabolism.
Figure 3 Methadone metabolism.
Figure 4 Tramadol metabolism.
