Excretion methadone

ABSORPTION, FATE, AND EXCRETION Methadone is absorbed well from the G1 tract and can be detected in plasma within 30 minutes of oral ingestion it reaches peak concentrations at 4 hours. After therapeutic doses, -90% of methadone is bound to plasma proteins. Peak concentrations in the brain occur within 1-2 hours of subcutaneous or intramuscular administration, which correlates well with the intensity and duration of analgesia. Methadone also is absorbed from the buccal mucosa. 

The answer is b. (Katzungr pp 806—807J Rifampin induces cytochrome P450 enzymes, which causes a significant increase in elimination of drugs, such as oral contraceptives, anticoagulants, ketoconazole, cyclosporine, and chloramphenicol. It also promotes urinary excretion of methadone, which may precipitate withdrawal. 

Large individual variations in the urine excretion of methadone are observed depending on urine volume and pH, the dose and rate of metabolism. Acidification of the urine may increase the urinary output of methadone from 5 to 22%.37 Typically, following a 5-mg oral dose, methadone and EDDP account for 5% of the dose in the 24-h urine. In those individuals on maintenance therapy, methadone may account for 5 to 50% of the dose in the 24-h urine and EDDP may account for 3 to 25% of the dose. (S)- and (R)-methadone and EDDP have been reported in saliva38 and methadone and (S)- and (R)-methadone in human breast mi Ik.39 40... 

Pharmacokinetics Readily absorbed following oral administration, methadone has a longer duration of action than does morphine. It accumulates in tissues, where it remains bound to protein from which it is slowly released. The drug is biotransformed in the liver and excreted in the urine, mainly as inactive metabolites. 

Methadone is a synthetic drug structurally and pharmacologically similar to morphine it acts mainly at the p-receptor. Methadone is largely metabolised to products that are excreted in the urine (t) 8 h). The principal feature of methadone is its duration of action. Analgesia may last for as long as 24 h. If used for chronic pain in palliative care (12-hourly) an opioid of short t) should be provided for breakthrough pain rather than an extra dose of methadone. 

Alkaline diuresis will favor the excretion of weak acids (anions) such as salicylate or phenobarbital. Indeed, the more the drug is ionized, the more it is trapped in the tubular lumen and consequently is not reabsorbed, hence eliminated in the urine. This mechanism can play a role in the treatment of severe intoxications. The reverse being true for weak bases (cations) such as methadone. Acidification of the urine facilitates the reahsorption of weak acids and will re-... 

Methadone is rapidly absorbed after all routes of exposure. When administered orally, methadone is approximately one-half as potent as when given par-enterally. Oral administration results in a delay of the onset, a lowering of the peak, and an increase in the duration of analgesic effect. It is metabolized primarily in the liver where it undergoes N-demethylation. Protein binding is 85%. Urinary excretion of methadone and its metabolites is dose dependent and comprises the major route of excretion only in doses exceeding 55 mg day It is excreted by glomerular... 

Methadone undergoes significant hepatic metabolism by N-demethylation and cycliza-tion to form pyrrolidines and pyrroline (23). Propoxyphene is also hepatically metabolized predominantly by N-demethylation and renally eliminated. The metabolite norpropoxy-phene is cardiotoxic and produces arrhythmias and pulmonary edema that have led to reports of cardiac arrest and death (59). This is especially problematic because of the long half-life of norpropoxyphenethat accumulates with repeated doses of the parent drug. Methadone is excreted in the urine but also in the bile (23). 

Methadone undergoes extensive biotransformation in the liver. The major metabolites, the results of N-demethy-lation and cyclization to form pyrrolidines and pyrroline, are excreted in urine and bile along with small amounts of unchanged drug. The amount of methadone excreted in urine is increased when urine is acidified. The half-life of methadone is approximately 15 to 40 hours. 

CODEINE In contrast to morphine, codeine is -60% as effective orally as parenteraUy as an analgesic and as a respiratory depressant. Codeine analogs such as levorphanol, oxycodone, and methadone have a high ratio of oral-to-parenteral potency. The greater oral efficacy of these drugs reflects lower first-pass metabolism. Once absorbed, codeine is metaboUzed by the liver, and its metabolites are excreted chiefly as inactive forms in the urine. A relatively small fraction (-10%) of administered codeine is O-demethylated to morphine, and free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, its antitussive actions may involve distinct receptors that bind codeine itself. The tj of codeine in plasma is 2-4 hours. 

X V 1 1 IM/SC/PO. Excreted more slowly than morphine (haif-life = 25h). Thus withdrawal symptoms are less intense, but prolonged. Plasma protein binding. Cross dependent with morphine (basis for narcotic detoxification). Tolerance develops readily. Less psychologically addicting than morphine. Detoxification is based on replacing heroin dependence with methadone dependence. Then slowly reducing methadone administration to zero. 

After consumption of methadone, 20-60% is eliminated within the first 24 h, as much as 30% via the gut. Up to 30% of the methadone present in the urine is unchanged. The extent of excretion in the unchanged form increases with the size of the dose and with decreasing pH of the urine. Approximately half of the amount eliminated via the kidneys is broken down to the desmethyl derivative, almost all of which reacts, undergoing ring closure, to form 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Another cyclic demethylation product, 2-ethyl-5-methyl-3,3-diphenyl-l-pyrrolidine (EMDP) accounts for 5-10% of the consumed dose. 

In cases of consumption of low daily doses (< 5 mg) of methadone, the use of immunological methods can lead to uncertainty with regard to patient compliance, as, directly after consumption of these low doses, methadone is excreted almost exclusively in the form of the cyclic metabolites. The two instrumental analytical methods GC/MS and HPLC/DAD also determine these metabolites with high sensitivity. GC/MS detects the principal metabolite EDDP as well as methadone itself, as shown in Fig. 8-39. The sensitivity of this analytical procedure for the determination of methadone and EDDP from blood or urine without derivatization is better than 20 ng/ml, i.e. it even extends to the subtherapeutic range [62]. Table 8-26 shows the important masses found in the... 

Not fully established, but all of these antiepileptics (except larnotrigine and valproate) are recognised enzyme-inducers that can increase the metabolism of other drugs by the liver, thereby hastening their loss from the body. In one study it was found that phenytoin increased the urinary excretion of the main metabolite of methadone. ... 

Rifampicin is a potent enzyme-inducer, which increases the aetivity of the intestinal and liver enzymes concerned with the metabolism of methadone, resulting in a marked decrease in its levels. In 4 patients in the study cited, the urinary excretion of the major metabolite of methadone rose by 150%. Rifabutin has only a small enzyme-indueing effect and therefore the effects are not as great. 

Methadone is eliminated from the body both by liver metabolism and excretion of unchanged methadone in the urine. Above pH 6 the urinary excretion is less important, but with urinary pH below 6 the half-life becomes dependent on both excretion (30%) and metabolism (70%). Methadone is a weak base (pKa 8.4) so that in acidic urine little of the drug is in the un-ionised form and little is reabsorbed by simple passive diffusion. On the other hand, in alkaline solution most of the drug is in the un-ionised form, which is readily reabsorbed by the kidney tubules, and little is lost in the urine. 

Baselt RC, Casarett LJ. Urinary excretion of methadone in maiL CUn PhamuKol Ther (1972) 13,64-70. 

Seven opioid addicts, without chronic alcoholism or liver disease, and who were receiving methadone maintenance treatment (45 to 65 mg daily) had an increase in the urinary excretion of the major pyrrolidine metabolite of methadone (an indicator of increased A-demethylation) when given disulfiram 500 mg daily for 7 days. However, there was no effect on the degree of opioid intoxication, nor were withdrawal symptoms experienced. No special precautions would seem to be necessary if both drugs are given. 

Methadone undergoes hepatic metabolism and renal excretion. Because of its ionized and lipophilic properties, changes in the pH of the urinary tract can 28 be an important determinant in the elimination of methadone. For example, at a urinary pH above 6,... 

Methadone Methadone was first synthesized as a morphine substitute and possesses many of that drag s pharmacological properties. It is mainly excreted in mine in imchanged form (5%-50% of a dose) or is metabolized by A-demethylation with spontaneoirs cycfization of the resirlting metabolite to 2-ethyfidene-l,5-dimethyl-3,3-dipher5flpyrrofidine (EDDP) (3%-25% of a dose). 

A number of reports have recently appeared confirming that reactions of rifampicin with other concurrently administered drugs are not uncommon. Kreek etal. (33 ) reported that narcotic addicts, stabilized on a methadone maintenance programme, who were under treatment for tuberculosis with rifampicin, developed withdrawal symptoms. Withdrawal symptoms were not reported in patients treated with isoniazid or ethambu-tol or both. Plasma methadone concentrations were found to be consistently lower in the subjects receiving rifampicin and a mean 24-hour urinary excretion of pyrroUdine, a major metaboUte of methadone, was con-... 

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