Heroin metabolism

Any amount of heroin can be potentially toxic, especially when the purity of this illicit drug is not known. Heroin depresses the CNS, thereby producing coma and respiratory depression. Pulmonary edema has been described following heroin overdose. Respiratory arrest may occur. Miosis is often present but may be absent in the presence of hypoxia or mixed drug over doses. With depression of the CNS, there is also a decrease in sympathetic tone and an increase in parasympathetic tone. This yields bradycardia and hypotension. Hypothermia may also occur as a result of peripheral vasodilation. Urine can be screened for heroin metabolic products. Blood heroin levels are not clinically useful. 

In a study on heroin metabolism Elliot et al. separated codeine, morphine, norcodeine, normorphine, 6-0-acetylmorphine, 3-0-acetylmorphine as trimethyl silyl derivatives and heroin on packed columns with SE-30 and QF-1, and assayed the amounts of morphine, 6-0-acetylmorphine and heroin in blood and urine samples, using methyl arachidate as an internal standard. 

During heroin metabolism, the acetyl groups must be cleaved to yield morphine this might simply be hydrolysis or it may be an enzyme-mediated process. Codeine is also demethylated this is known to be an enzyme-mediated process (there are no simple chemical processes that would achieve this under physiological conditions), and some 10 %-15 % of the population are deficient in the enzyme, so codeine is not converted to morphine, and codeine has little analgesic effect for this group. Another 10 % of the population has overactivity of the enzyme, so that the codeine is demethylated very rapidly and effectively, and they must be careful not to consume an overdose, which would be less for them than for someone with more standard enzyme activity. Finally, in order to be excreted effectively in urine, the morphine is converted to a sugar derivative, to ensure water solubility. 

Dole VP, Nyswander MN Heroin addiction a metabolic disease. Arch Intern Med 120 19-24, 1967... 

Shi J, Hui L, Xu Y, et al Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat 19 459 60, 2002 Shinderman M, Maxwell S, Brawand-Arney M, etal Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses. Drug Alcohol Dependence 69 205-211, 2003... 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

The consumption indicator is the metabolic byproduct excreted at the highest rate. It may be a metabolite, as it is the case for cocaine (BE) and heroin (MOR), or the drug itself, as it is the case of amphetamine-like compounds. THC, the most psychoactive cannabinoid of the cannabis herb, is highly metabolized before excretion, thus, the consumption indicator selected (THC-COOH) presents an excretion rate of 0.6%. Despite the fact that OH-THC presents a slightly higher excretion rate (2%), this analyte was not selected to back calculate cannabis use due... 

While there are clear differences in substrate selectivity between the drug metabolizing hydrolytic enzymes, there is also significant overlap, i.e., they will often tend to metabolize the same substrates but at different rates. For example, pseudocholinesterase, hCE-1, and hCE-2 catalyze the hydrolysis of heroin and cocaine. 

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. 

When heroin is administered, it is rapidly converted to 6-monoacetylmorphine and then to morphine in the brain. Heroin is also more lipid soluble, suggesting that its increased potency is due to increased distribution into the brain. The major metabolic pathway for morphine is... 

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). 

Racemic methadone (MET) is administered to heroin addicts as a substitution therapy. However, methadone enantiomers possess different pharmacological effects, and the drug has been demonstrated to be enantioselectively metabolized to its two major metabolites, 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-l-pyrroline (EMDP). Stereoselective separation of MET, EDDP, and EMDP using an alpha-glycoprotein stationary phase and MS-MS detection was proposed by Kelly et al. [34]. Optimal separation conditions were 20 mM acetic acid isopropanol (93 7, pH 7.4), with a flow rate of 0.9mL/min. 

Pharmacokinetics plays a very important role in the manner in which opioids are abused. Morphine and many of its derivatives are slowly and erratically absorbed after oral administration, which makes this route suitable for long-term management of pain but not for producing euphoria. In addition, opioids undergo considerable first-pass metabolism, which accounts for their low potency after oral administration. Heroin is more potent than morphine, although its effects arise primarily from metabolism to morphine. The potency difference is attributed to heroin s greater membrane permeability and resultant increased absorption into the brain. 

Mechanism of Action An opioid agonist-antagonist that binds with opioid receptors in the CNS. Therapeutic Effect Alters the perception of and emotional response to pain blocks the effects of heroin and produces minimal opioid withdrawal symptoms. Pharmacokinetics Rapidly absorbed following IM administration. Protein binding Very high. Metabolized in liver. Primarily excreted in feces minimal excretion in urine. Half-life 2 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). 

The initial metabolism of heroin involves loss of one acetyl group, forming6-monoacetylmorphine, or 6-MAM. If6-MAM is detected in body fluids and tissues, it can only have come from heroin. When 6-MAM is further metabolized, it loses the second acetyl group and forms morphine. At this point, finding morphine, is not helpful in determining whether the individual had used heroin or morphine, or even codeine, since it also is metabolized to morphine. 

The metabolism of cocaine leaves the person with an abnormal letdown, called "crashing". In an attempt to soften this severe depression cocaine is often compounded with heroin called a "speedball". This is common among those who started out as either heroin or cocaine abusers. The comedian John Belushi died from such a mixture. 

Besides being affected by medications and substances that affect the liver s metabolism, methadone itself affects the liver s metabolism of certain substances. A significant number of people who are taking methadone for heroin addiction also are HIV positive and are taking anti-HIV medications such as Desipramine (DMI) and zidovudine (AZT). Through its actions on the liver, methadone decreases the metabolism of these medications. Because of this, certain troublesome side effects of DMI and AZT, including nausea,... 

Methadone began to be used as a treatment for heroin addiction in the 1960s. In 1963, Dr. Vincent Dole, an expert in metabolic disorders, and Dr. Marie Nyswander, a psychiatrist who had worked in the U.S. Public Health facility for heroin addicts in Lexington, Kentucky, began... 

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