Morphine elimination processes

A patient is being treated with morphine by intravenous infusion. The steady state plasma concentration of the drug is to be maintained at 0.04 fig cm 3. Calculate the rate of infusion necessary assuming a first order elimination process (for morphine Vd is 4.0 dm3 and tU2 is 2.5 hours). 

One of the most popular approaches to the laboratory scale synthesis of ethers is the addition of alkoxides and phenoxides to a suitable substrate such as an alkyl bromide. This reaction is known as the Williamson ether synthesis. For primary substrates, this approach tended to work quite well, and a host of ethers have been prepared using this method. The chemistry is less straightforward when secondary or tertiary alkyl halides were used due to competing elimination processes. As a representative example, the successful synthesis of an alkyl aryl ether is shown in Example 2.2 [14]. The reaction was carried out in acetone using allyl bromide and a functionalized phenol as the substrates and potassium carbonate as the base. While many bases have been used in Williamson ether syntheses, a mild base was critical for this work since it was needed to deprotonate the phenol without deprotonating the alkyne. This was critical for the success of the chemistry as the alkyne was needed for later steps in the reaction. In related work, potassium carbonate promoted the synthesis of photo-activatable fluorescein derivatives through a Williamson ether synthesis (Scheme 2.11) [15]. It also promoted the synthesis of a morphine precursor as well (Example 2.3) [16]. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Heroin is rapidly hydrolyzed in vivo to 6-monoacetylmorphine (257) and thence to morphine (1) (see also p. 26). N-Demethylation and O-demethyla-tion are significant metabolic routes in animals, with the former oxidative process leading to normorphine (258) from 1, and norcodeine (259) from 2, which may in turn be eliminated as their 3- and 6-glucuronides, respectively. 

It has been noted that those morphine derivatives in which the nitrogen is allylic (compounds) can be degraded to dihydromethines by reduction of their methiodides with sodium in liquid ammonia (397), and the important observation has been made that a useful alternative to the Hofmann degradation consists in the decomposition of tertiary amine oxides, especially in those cases in which the Hofmann elimination results in loss of the side chain. It will also be noted that double bonds are not isomerized in this process (398) ... 

Some examples of intermolecular addition of carbon-centred radicals, followed by -elimination of tin or sulfur radicals were provided in Schemes 4.38-4.43 and this strategy is effective in intramolecular processes. Thus, in a synthesis of the antitumor agent CC-1065, the aryl radical generated from the bromide 66 underwent cyclization and subsequent p-ehmination to give the indoline 67 (4.59). An advantage of this type of elimination procedure is that it provides a new alkene in a defined position that is suitable for further elaboration. The p-elimination of a sulfur radical has found other applications, such as in syntheses of the alkaloid morphine and the neuroexcitatory amino-acid kainic acid. ... 

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