Metabolism of heroin

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. 

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. 

Criteria for the differentiation of heroin use from other forms of opioid exposure based upon hair analysis have been proposed by Moeller et al. Data from over 1000 hair analyses were evaluated, and the following criteria must be met in order to establish heroin use if the morphine concentration <1.0ng/mg, the morphine-to-codeine ratio must be >5 1 if the morphine concentration >1.0 ng/mg, the morphine-to-codeine ratio must be >2 1. In addition, the presence of 6-AM is definitive evidence of heroin exposure, since it can only be derived from metabolism of heroin. 

Figure 3. Main route of metabolism of heroin and its metabolites.

Early studies of the disposition and metabolism of heroin in humans and animals were performed with PC and TLC. Heroin, 6-acetylmorphine, and morphine were separated by normal-phase and reversed-phase chromatographic systems. The analytes were visualized by spraying with iodopla-tinate, Folin-Ciocalteu reagent, or Dragendorff s reagent. 

Heroin (3,6-diacetylmorphine or diamorphine) was originally synthesized from morphine and is regarded as one of the most dangerous dmgs of abuse. The human metabolism of heroin is presented in Fig. 2.4 its main metabohtes are reported in Table 2.1. It is rapidly deacetylated to 6-acetylmorphine, which is further hydrolyzed to morphine in the liver. The first reaction is catalyzed by blood esterases, while the second occurs in the liver (Baselt, 2004). 

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. 

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... 

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,... 

The metabolic scheme of heroin, morphine, and codeine in hair. 

The metabolism of morphine and related opiates has been investigated extensively and reviewed/424 426 It tends to be very rapid after parenteral administration but unpredictable after oral dosage. Scheme 2.26 illustrates the major metabolic pathways for morphine (1), codeine (2), and heroin (256). 

Heroin is rapidly metabolized in humans 22 and other species 451 452 to 6-acetylmorphine and morphine, the active metabolites/100 Compounds lacking a free 3-0 H function bind poorly to opioid receptor preparations, and heroin was no exception. Morphine and 6-acetylmorphine bound well to receptor preparations, and the binding of the latter accounted for all the apparent binding of heroin. In addition to 6-acetylmorphine and morphine, the 3-glucuronide of morphine (261) occurred as a major metabolite of heroin... 

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. 

Release of Naltrexone. Naltrexone is a narcotic antagonist that occupies the same receptors as morphine but produces no euphoric effects. Therefore, a patient on naltrexone therapy experiences no euphoria upon intake of heroin which is rapidly metabolized in the body to morphine. Naltrexone therapy is currently a method of choice in the rehabilitation of opiate dependent individuals because it provides an enforced opiate free life [44]. 

Bencharit, S., Morton, G. L., Xue, Y, Potter, P. M., Redinbo, M. (2003). Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nature Structural... 

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