Naloxone metabolism

Personality variables, state of mind at time of withdrawal, and expectations of severity of symptoms all may affect withdrawal severity (Kleber 1981). One study found that merely providing addicts information about the withdrawal syndrome resulted in lower levels of withdrawal symptoms (Green and Gos-sop 1988). Naloxone rapidly induces a severe withdrawal syndrome, which peaks within 30 minutes and then declines rapidly. Until the antagonist is eliminated, only partial suppression of the withdrawal syndrome is possible, and then only by using very high opioid doses, which may cause respiratory depression when naloxone is metabolized. 

Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy. 

Distribution - After parenteral use, naloxone is rapidly distributed in the body. It is metabolized in the liver, primarily by glucuronide conjugation. 

Because of its fast onset (minutes), naloxone (Narcan) administered IV is used most frequently for the reversal of opioid overdose. However, it fails to block some side effects of the opioids that are mediated by the ct-receptor, such as hallucinations. The rapid offset of naloxone makes it necessary to administer the drug repeatedly until the opioid agonist has cleared the system to prevent relapse into overdose. The half-life of naloxone in plasma is 1 hour. It is rapidly metabolized via... 

It is inactive orally because of high first pass metabolism in liver. Metabolised by glucuronidation in liver. The main use of naloxone is in the treatment of acute opioid overdose (acute morphine poisoning). It also precipitates withdrawal syndrome when administered to morphine addicts. The constricted pupils of addicts dilate after administration of naloxone. This has been used as a diagnostic tool for opioid addiction. 

Pharmacokinetic properties Oral naloxone is extensively metabolized in the gut and liver, predominantly by glucuronidation of the phenol function (Berkowitz, 1976). 

Nalorphine and naloxone are also more effective parenterally than orally. Both are first-pass metabolized in the liver very rapidly, largely by glucuronide formation/420 421 The effects of these antagonists are almost immediate upon intravenous administration and last between 1 and 4h. Naltrexone, on the other hand, maintains a good level of oral activity and has a half-life of around 10 h/422 423 ... 

Naloxone (160) was metabolized to the corresponding dihydromorphine in humans and rabbits 421 458 as well as to naloxone-3-glucuronide.(457,458) N-Deallylation 421 456 to nornaloxone also occurred in subjects receiving large oral doses of the drug. 

Naltrexone (162), like naloxone, was more extensively metabolized after oral adminstration than following the parenteral route. Major metabolites in plasma, urine, and feces have been identified 459 by gc/ms as naltrexone-3-glucuronide and conjugated and unconjugated 6/3-hydroxy reduction product (270). The geometry at C-6 had been established during an earlier study. 460 Minor quantities of the C-2 oxidation product, 270, (R = OMe R = OH) and 270 (R = OMe, R = H) were also found. Oxycodone (44) gave the unusual 6/3,7/3-dihydroxy metabolite (271) in rabbits. 

Naloxone and naltrexone (pure antagonists) are not N-dealkylated in the brain although they are metabolized in this manner in the liver. 

Naloxone undergoes extensive hepatic first-pass metabolism through glucuronida-tion. Naltrexone is metabolized to the active metabolite 6-naltrexol, which is less potent but has a prolonged half-life compared to that of the parent drug. 

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