Opiate metabolism

Another application of target metabolomics illustrative of the importance of isomeric/isobaric separation is in the field of pharmacokinetics. Pharmacokinetic studies focus on the absorption and distribution of drugs and their metabolites in biological systems. " A limiting factor in pharmacokinetic research is a requirement of high-throughput screening of isomeric metabolites. IM-MS is a rapid technique where isomeric separations occur within minutes. For example, IM-MS has been used to separate opiate metabolic isomers in less than 1 minute. ... 

Dmgs, such as opiates, may undergo metabolism both in the intestinal wall and in the fiver (first-pass metabolism). The metabolism may be extensive and considerably reduce the amount of dmg reaching the systemic circulation. Alternatively, the metabolite may be metabofically active and contribute significantly to the action of the parent dmg. Some compounds undergo enterohepatic circulation in which they are secreted into the GI tract in the bile and are subsequently reabsorbed. Enterohepatic circulation prolongs the half-life of a dmg. 

Several classes of drugs modulate the firing rates or patterns of midbrain dopamine neurons by direct, monosynaptic, or indirect, polysynaptic, inputs to the cell bodies within the ventral mesencephalon (i.e., nicotine and opiates). In contrast, amphetamine, cocaine, and methylphenidate act at the level of the dopamine terminal interfering with normal processes of transmitter packaging, release, reuptake, and metabolism. 

Cooper OB, Brown TT, Dobs AS Opiate drug use a potential contributor to the endocrine and metabolic complications in human immunodeficiency virus disease. Clin Infect Dis 37(suppl 2) S132—S136, 2003... 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

Kim HS, Iyengar S and Wood P (1986). Opiate actions on mesocortical dopamine metabolism in the rat. Life Sciences, 39, 2033-2036. 

Careful analyses of the pharmacologic properties of 3H-hailucinogen binding sites indicated that they may correspond to 5-HT receptors (in the case of 3H-LSD), sigma opiate receptors (in the case of 3H-PCP), or even GABA receptors (in the case of 3H-muscimol). Such data recall that hallucinogens should interfere markedly with the metabolism of neurotransmitters in the CNS. These hallucinogen-induced alterations of neurotransmitter metabolism and functions are summarized below. 

Findings continue to accumulate in the field of endogenous opiates, as exemplified by two tetrapeptides isolated from mammalian brain and found to have high affinity and selectivity for p-opioid receptors. These tetrapeptides are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). A number of synthetic analogues have been prepared with the view to improve their metabolic stability and, in some cases, to limit their access to peripheral opioid receptors. The three synthetic endomor-phin analogues Tyr-D-Ala-Phe-Phe-NH2 (6.84), Tyr-D-Arg-Phe-Phe-NH2 (6.85), and Tyr-D-Arg-Phe-Ape-NH2 (6.86), to be discussed in the next section, have potent antinociceptive effects in in vivo inflammatory tests but exhibit modest effects in the CNS. However, and despite the presence of a D-amino acid and a protected C-terminus, they remained sensitive to enzymatic hydrolysis [211][212],... 

The metabolism of heroin is of interest in connection with its pharmacological activities. Earlier opiate -receptor binding studies led to the belief that heroin is a prodrug acting through its metabolites 6-acetylmorphine and morphine [95]. However, heroin is now known to activate (5-receptors, whereas morphine activates -receptor and 6-acetylmorphine acts at both receptor types [96]. Thus, the pharmacodynamic profile of heroin results from both direct and metabolite-mediated effects. 

A comparable reaction was seen decades ago in the metabolism of methadone [173 - 175]. This well-known synthetic opiate undergoes A-demeth-ylation as a major metabolic reaction in humans and laboratory animals. The resulting secondary amine (11.168, Fig. 11.21) has never been isolated, as it undergoes practically instantaneous cyclization. The reaction is believed to proceed via the carbinolamine with formation of metabolite 11.169 as the major urinary metabolite in humans. This structurally intriguing basic compound is, in its neutral form, a pyrrolidine with an exocyclic C=C bond,... 

In opiate abuse, smack ( junk, jazz, stuff, China white mostly heroin) is self administered by injection ( mainUning ) so as to avoid first-pass metabolism and to achieve a faster rise in brain concentration. Evidently, psychic effects ( kick, buzz, rush ) are especially intense with this route of administration. The user may also resort to other more unusual routes opium can be smoked, and heroin can be taken as snuff (B). 

Alkaloids such as boldine, codeine, narceine and morphine are active factors in their receptors. Boldine has morphine-like properties and is active on opioid receptors. It may be used to treat stomach disorders and as metabolic stimulant. As it is similar to morphine, boldine can also be considered in the possible development of treatments for narcotic dependence. Codeine also binds to opiate receptors, and specifically functions to reduce bronchial secretions. Codeine can also be used as a cough suppressant when acting on the centre of the medulla oblongata and as a sedative agent. 

There are some clinically important pharmacodynamic drug-drug interactions to be mentioned. Antipsychotics will potentiate the central depressant effects of sedatives and of alcohol. They will also increase the risk of respiratory-depressant effects of opiates. Inducers of drug metabolic enzymes like for example rifampicin and several antiepileptics, may increase the elimination rate of antipsychotic agents and thus decrease their efficacy. 

Mechanism of Action An opioid agonist that binds at opiate receptor sites in central nervous system (CNS). Therapeutic Effect Reduced intensity of pain stimuli incoming from sensory nerve endings, alteringpain perception and emotional response to pain. Pharmacokinetics Rapidly absorbed. Protein binding 40%-50%. Extensively distributed. Metabolized in liver. Excreted in urine. Half-life 11 hr. 

As previously mentioned, the detection period for a drug depends on a number of factors, including the type of opiate, the type of sample, the frequency of drug use, metabolic rate, age, body mass, drug tolerance, and overall health. Generally speaking opium can be detected for 5-7 days after its use. Other opiates such as heroin and codeine have significantly shorter detection periods (Table 10.3). 

To correct metabolic disturbance caused by opiate dependence... 

Since Nirenberg and his collaborators (5,6,11) have reported that in NG108-15 cells, opiates produce an initial inhibition of cyclic AMP synthesis (0 to 30 min), followed by a period in which the cell adjusts and cyclic AMP levels return to normal (lO -30 hrs), and finally a period where cyclic AMP levels are elevated (when the drug is removed or metabolized supposed withdrawal) it was of interest to follow the time-course of the inhibition. 

Finally, the discovery of a CNS receptor that is specific for benzodiazepines has led to some interesting speculation as to the possible existence of some type of endogenous sedative-like agent. The presence of a certain type of receptor to indicate that the body produces an appropriate agonist for that receptor makes sense. For instance, the discovery of opiate receptors initiated the search for endogenous opiate-like substances, which culminated in the discovery of the enkephalins. It has been surmised that certain endogenous steroids such as allopregnanolone (a metabolic byproduct of... 

R.F. Tyndale, K.P. Droll, E.M. Sellers, Genetically Deficient CYP2D6 Metabolism Provides Protection Against Oral Opiate Dependence , Pharmacogenetics, 7, 375 -379 (1997). 

An acute dose of 100-200 mg morphine, or its equivalent, in the non-tolerant adult can lead to respiratory depression, coma and death. In the tolerant individual, single doses or more than 10 times this amount are tolerated and have little visible effect. The development of tolerance to the opiates does not appear to be due to enhanced metabolism (metabolic tolerance) but is probably due to opioid receptor insensitivity (tissue tolerance). The dependent person therefore ultimately requires high doses of the opiate to prevent withdrawal effects. 

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