Morphine clearance

M3G is the predominant metabolite in young children. The total body morphine clearance is 80% of an adult at 6 months of age.23 When the brains of experimental animals are directly injected with M3G, neuroexcitatory and anti-analgesic responses result, although this does not happen after system administration. Nonetheless, small amounts of M3G do cross the blood-brain barrier, and this may account for some reports of neuroexcitatory responses to morphine in humans. Attempts at correlating M3G plasma concentrations or M3G morphine or M3G M6G concentration ratios with the clinical activity of M3G have sometimes been successful, and sometimes not. To date, there are only two published studies describing the effects of injecting M3G directly into humans both studies yielded equivocal results.24... 

Increased glucuronidation may explain the fact that oral contraceptives enhance morphine clearance (352). 

Watson KJR, Ghabrial H, Mashford ML, Harman PJ, Breen KJ, Desmond PV. The oral contraceptive pill increases morphine clearance but does not increase hepatic blood flow. Gastroenterology 1986 90 1779. 

At birth, compounds that rely on glucuronidation for elimination have prolonged half-lives compared to those in adults. Morphine clearance is five times lower in neonates (two to 12 days) than in children aged one to 16 years. Morphine is cleared faster in children over one than in adults [32]. 

Although glucuronidation is thought to be less affected than oxidation in patients with cirrhosis [50], morphine clearance may be reduced and the half-life prolonged [27]. A reduction in first-pass metabolism could increase the bioavailability of oral morphine, but will also reduce the formation of the active (morphine-6-glucuronide) and inactive metabolites. The clinical significance of this is uncertain [50]. 

Morphine is extensively metabolized. Its main metabolite, morphine-3-glucuronide is without analgesic effects, while morphine-6-glucuronide (also called morphine glu-curonide) is supposed to be more potent than morphine. In patients with cirrhosis, morphine clearance may be reduced and the half-life prolonged, and dosages should be reduced (SEDA-22,101). 

Several phase II enzymes may also be expressed as a function of age. Studies of paracetamol (acetaminophen) suggest that sulfation is the major metabolic pathway during the neonatal period and early infancy, changing to glucuronidation over several months (Miller et ai, 1976). The increase in morphine clearance due to glucuronidation is related to postconceptional age (Scott et ai, 1999). 

Opiates can effect serum levels of enzymes and other substances whose homeostatic control depends on clearance through the liver (F8, G12, M15, N4, S19). In one reported case, the aspartate aminotransferase was within normal limits before the administration of codeine, but within 2 hours after the drug, the enzyme activity had risen to two times the normal value by 8 hours to eight times the normal activity, and within 24 hours it had returned to normal (F8). Increases in transaminase to levels 5-85 times the control value have been reported in 6 of 16 patients with disease of the biliary tree following the administration of codeine phosphate (2 grains) (B7, F8). Gross has shown that morphine, codeine, or mepheridine administration produce elevations of serum amylase or lipase (G12). These elevations have been attributed to constriction of the sphincter of Oddi and increased intraductal pressure on the pancreatic duct (G12, N4). 

In retrospect, the reason for this is not all that obscure. Most of the soldiers were in hypo-volaemic shock with low blood pressure, low blood volume, and as part of the shock syndrome, systemic circulation was minimal with intense vasoconstriction - hence the poor therapeutic effect. The repeated doses of morphine were usually given intramuscularly into the buttock or thigh but their clearance into the systemic circulation was minimal until resuscitation occurred and the peripheral circulation was restored. Blood flow to the muscle increased and all the morphine injected became available - all at once. This was the reason for the morphine overdoses and the occasional death. Thereafter it has become standard practice to give morphine in emergency directly into the veins and not into poorly perfused muscles. 

The clearance of morphine and its active metabolite, morphine-6-glucuronide depends on adequate renal function. The elderly are particularly susceptible to accumulation of the drugs, hence respiratory depression and sedation. Morphine, like all opioids, passes through the placenta rapidly and has been associated with prolongation of labor in pregnant women and respiratory depression in the newborn. 

Like morphine, meperidine has an active metabolite, normeperidine, formed by A-demethylation of meperidine. Normeperidine is not analgesic but is a proconvulsant and a hallucinogenic agent. For this reason, meperidine use in patients with renal or fiver insufficiency is contraindicated because of the decreased clearance of the drug and its metabolite. Convulsant activity has been documented in elderly patients given meperidine and in patients using PCA who have decreased renal function. 

Meperidine readily passes the placenta into the fetus. However, respiratory depression in the newborn has not been observed, and meperidine clearance in the newborn is rapid in that it does not rely upon conjugation to glucuronides. Meperidine, unlike morphine, has not been associated with prolongation of labor conversely, it increases uterine contractions. 

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

Methadone is an MOR(OP3, i) receptor agonist with pharmacological properties similar to those of morphine. It is an attractive alternative MOR opioid receptor analgesic, because of its lack of neuroactive metabolites, a clearance that is independent of renal function, good oral systemic availability, a longer half-life with fewer doses needed per day, and extremely low cost. It is mainly metabolized by CYP3A4. 

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