O

+

Potency of agonist or antagonist shown as + and — respectively. 0 = inadequate data available; ± = partial agonist.

Potency of agonist or antagonist shown as + and — respectively. 0 = inadequate data available; ± = partial agonist.

In man, the changes that result from the activation of different receptors have been inferred from clinical observation and from extrapolation from studies on animals. A summary of the interaction of morphine and a number of synthetic opioids on the three main receptor types is shown in Table 15.4.

To add a further complication to the understanding of ways in which the opioids act, it now appears that the mu receptors may be further subdivided into mi and m2 subtypes, the former being high-affinity receptors that mediate supraspinal analgesia, while the latter are of relatively low affinity and are involved in respiratory depression and in the gastrointestinal effects of the agonists.

Certain benzomorphan analgesics related to pentazocine selectively bind to kappa receptors in the spinal cord, thereby producing analgesia. This analgesia is still present in animals that have been made to tolerate the analgesic effects of morphine, suggesting that there is a distinct separation of the functional effects of these receptor subtypes. The kappa agonists produce dysphoria, rather than the euphoria caused by morphine-like drugs, and occasionally such psychomimetic effects as disorientation and depersonalization.

The precise role of the delta receptors in man is uncertain, as specific agonists have not yet been developed which cross the blood-brain barrier. The structures of pentazocine and some other opiates are shown in Figure 15.3.

Mechanism of action

Of all the drugs of abuse which have been investigated, the mechanisms responsible for opioid-induced physical dependence have been the most thoroughly studied. There does not appear to be a significant change in the opioid receptor number following chronic drug administration, but there is evidence of a decrease in the functional activity of these receptors, as shown by a decrease in adenylate cyclase activity. This action is mediated by the inhibitory guanine nucleotide binding regulatory protein (Gi). Following abrupt withdrawal of the opioid, the cyclase activity returns to normal. This may be the explanation for the excessive sympathetic activity associated with the abrupt withdrawal of these drugs, particularly as some opiate receptors are located in the local coeruleus. This relationship between the opioid and adrenergic system in the brain may help to explain why the a2-adrenoceptor agonist clonidine can attenuate some of the symptoms of opiate withdrawal. Nevertheless, the fact that opiates act on at least two different types of opioid receptors in the brain, the mu and delta receptors, which are widely distributed in the central and peripheral nervous systems, means that the pharmacological effects of these drugs and the symptoms seen on withdrawal cannot be entirely ascribed to changes in central noradrenergic transmission.

The mechanism of action of opioids at their receptor sites is complex and incompletely understood. However, they all share a number of characteristics. Thus they all facilitate inhibitory transmission in the brain and gastrointestinal tract, and appear to be located on presynaptic receptor sites, where they function as heteroreceptors. Furthermore, they all appear to be coupled to guanine nucleotide-binding regulatory proteins (G proteins), and thereby regulate the transmembrane signalling systems. In this way, the opioid receptors can regulate adenylate cyclase, the phosphatidyl inositol system, ion channels, and so on. There is evidence that the mu and delta receptors appear to operate via potassium channels and the adenylate cyclase system, while kappa receptors inhibit voltage-dependent calcium channels.

Pharmacological properties

Drugs in this therapeutic group include morphine, heroin, pethidine, methadone, codeine, dihydrocodeine, dextropropoxyphene, pentazocine, phenazocine, levorphanol and buprenorphine. The principal antagonists in clinical use are naloxone and naltrexone (see Figure 15.3).

All agonists in this therapeutic group decrease the sensation of painful stimuli, which is their main clinical application. They tend to subdue dull, persistent pain rather than sharp pain, but this difference is to some extent dose dependent. The major difference between the non-opioid analgesics such as aspirin and the opiates is that the former reduce the perception of peripherally mediated pain, by reducing the synthesis of local hormones that activate the pain fibres, whereas the latter attenuate the affective reaction to pain without affecting the perception of pain. This clearly suggests that the site of action of the opiate analgesics is in the central nervous system.

Euphoria is a common side effect of most opiates after chronic use, and undoubtedly this effect contributes to their dependence-producing

Mcntazocinc
Figure 15.3. Chemical structure of some non-morphine-type opiates.

tendency. This may play an important part in modifying the response of the patient to chronic pain. Many opiates also produce sedation, particularly after acute administration.

The opiates reduce anxiety, possibly through their sedative effects, and induce nausea and vomiting. These effects are more marked after acute administration. The emetic effect is due to their stimulant effects on the chemoreceptor trigger zone in the area postrema on the floor of the fourth ventricle, an effect that has been ascribed to an activation of dopamine receptors. The emetic effect is particularly pronounced in the case of the non-analgesic analogue of morphine, apomorphine, which has been used experimentally in the treatment of parkinsonism and in inducing emesis following a drug overdose.

The opiates cause constipation by inducing spasm of the stomach and intestines, presumably by the stimulation of opioid receptors in the myenteric plexus and reducing the release of acetylcholine. This property can be used therapeutically for the symptomatic relief of diarrhoea. Biliary colic and severe epigastric pain can occur because of the contraction of the sphincter of Oddi and the resulting increase in pressure in the biliary ducts.

One of the serious complications of the use of the opiate analgesics, even at therapeutic doses, is respiratory depression, an effect which is further complicated by the ability of these drugs to decrease the sensitivity of the respiratory centre to carbon dioxide. The administration of oxygen to a patient whose respiration has been depressed by the opiates is therefore counterproductive and may lead to total respiratory paralysis.

Many opiate analgesics are effective cough suppressants (also called anti-tussives), although only codeine and dihydrocodeine are generally used for this purpose. As there is a dissociation between the anti-tussive and analgesic action of the opiates, dextromethorphan and noscapine are now commonly used as cough suppressants because of their efficacy and lack of dependence-producing properties.

Miosis is a characteristic symptom of opiate administration, and while tolerance develops to many of the pharmacological effects of this class of drugs, tolerance to the miotic effects occurs at a much slower rate. Miosis is due to an excitatory action of the autonomic segment of the nucleus of the oculomotor nerve, an effect attributed to the stimulation of the mu receptors. In general, it would appear that the actions of morphine and its analogues on the brain, spinal cord and gastrointestinal tract are due to stimulation of the mu receptors.

Tolerance and dependence

An acute dose of 100-200 mg morphine, or its equivalent, in the nontolerant 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.

Cross-tolerance occurs between all opiates that act primarily via the mu receptors. This is the basis of the methadone substitution therapy which is commonly used to withdraw people who are dependent on heroin or morphine; methadone is used because of its relatively long half-life (about 12 hours) and its ease of administration in an oral form. Cross-tolerance does not occur between the opiates and other classes of dependence-producing drugs such as the barbiturates, alcohol or the amphetamines, which act through different mechanisms.

The sudden reduction in plasma opiate levels, or the administration of an opiate antagonist such as naloxone, leads to withdrawal symptoms. These include restlessness, craving, lacrimation, perspiration, fever, chills, vomiting, joint pain, piloerection and mydriasis. These effects are maximal

2 or 3 days after the abrupt withdrawal of heroin, morphine or related drugs, but are slower in onset and less severe in the case of drugs like methadone which have a longer half-life and whose tissue concentration therefore decreases more slowly.

Endogenous opioids and the pain response

It has long been known that stress can elevate the pain threshold. In rodents this may be quantified by measuring the increase in the pain threshold following prolonged unavoidable foot shock. Under conditions of environmental stress, the pain threshold has also been shown to increase in man. Such effects have been attributed to a rise in opioid peptides in the cerebrospinal fluid (CSF). Conversely, in chronic pain syndromes, the CSF concentration of the endorphins decreases.

While the physiological basis of acupuncture is incompletely understood, it is now apparent that the endogenous opioid systems are activated by such techniques. Furthermore, when acupuncture is simulated in animals there is a decrease in the pain response to noxious peripheral stimuli, which can be reversed by naloxone.

From such studies, it may be concluded that physical stress leads to an activation of endogenous opioid systems, which raises the pain threshold. The euphoriant effect of physical exercise may also be attributed to the effects of these opioids acting on limbic regions of the brain.

The discovery that the opioid peptides cause analgesia and have anti-tussive and antidiarrhoeal effects led to the widespread search for synthetic peptides that could be administered orally but that would not have the dependence-producing effects of morphine and related drugs. Synthetic peptides modelled on the endogenous opioids have been synthesized which have longer half-lives than the endogenous substance and which are resistant to the enkephalinases which rapidly degrade the endogenous opioids. Unfortunately, to date, all of the experimental and clinical studies have been disappointing, as it has been found that morphine-dependent animals show cross-tolerance with all such compounds.

The endogenous opioid peptides have a range of affinities for the different types of opioid receptor. Some met-enkephalin derivatives, for example, show affinity for mu and delta receptors, whereas other peptides, derived from pro-enkephalin, show a preference for the delta sites. All peptides from prodynorphin act predominantly on kappa sites, while beta-endorphin behaves like the enkephalins and shows selectivity for the mu and delta sites.

Perhaps it may be possible to use this diversity and selectivity of action to develop new synthetic opiates that will have therapeutic advantages over morphine and its analogues which, in one form or another, have been used by mankind for nearly 2000 years.

Nicotine as a drug of abuse

Nicotine is an alkaloid derived from the leaves of the Nicotiana species. It originated in South America where it has been smoked by the native population for hundreds of years. It was introduced into Western Europe in the 16th century but shortly after its introduction into Great Britain it was condemned as a habit ''injurious to the lung'' by King James I.

Nicotine has both stimulant and depressant actions on the brain. The stimulant and rewarding action is attributed to the action of the drug on the nicotinic cholinergic receptors that indirectly increase the release of dopamine from the nucleus accumbens reward system; an increase in dopamine release has been detected in this brain region following the administration of the drug to rats. This action is a common property of most drugs of abuse and has already been covered in detail at the beginning of this section. In addition, nicotine indirectly increases the release of endogenous opioids and glucocorticoids which add to the complexity of action of the drug.

Because nicotine provides the reinforcement for the smoking of cigarettes in particular, it is arguably the most influential dependence-producing drug available. The dependence, both psychological and to a lesser extent physical, is extremely durable as exemplified by the failure rate among smokers who try to stop the habit. For example, it has been calculated that although over 80% of smokers wish to stop the habit, only 35% succeed each year. It has been estimated that dependence can occur in individuals who smoke more than 5 cigarettes per day; most smokers consume about 20 cigarettes per day.

Nicotine is readily absorbed through the skin, mucous membranes and lungs but smoking is the preferred route because of the rapid absorption of the drug across the mucosa of the lung leading to an effect on the brain within about 7 seconds. Thus each puff of a cigarette produces a discrete reinforcement and it has been calculated that with an average of 10 puffs per cigarette, 20 cigarettes per day will reinforce the habit 200 times daily. In dependent smokers, there is evidence that the urge to smoke correlates with a low blood nicotine concentration and it has been concluded that those who are dependent smoke not only in order to obtain the reinforcing effect of the drug but also to avoid the symptoms of nicotine withdrawal. The symptoms of nicotine withdrawal include: irritability; impatience; hostility; anxiety; dysphoria; difficulty in concentrating; restlessness; bradycardia, increase in appetite; and weight gain.

Smokers who have been abstinent for several weeks, or those who smoke for the first time, often experience nausea even at low blood nicotine concentrations. This aversive effect is due to the action of the drug on the chemoreceptor trigger zone whereby it indirectly activates the release of dopamine. Apomorphine and related dopamine agonists also cause nausea by activating the dopaminergic system in this brain region.

The nicotine withdrawal syndrome can be alleviated by nicotine replacement therapy. There are several forms of nicotine replacement products which are widely available. These are nicotine gum, transdermally delivered nicotine (nicotine patch) and nasal nicotine spray. Both the nicotine gum and the patch have shown efficacy in increasing short term abstinence rates, reducing the symptoms of nicotine withdrawal and relieving the craving for cigarettes. Nasal nicotine spray appears to be efficacious in sustaining abstinence from smoking and has the advantage over the other nicotine formulations in that the venous pharmacokinetic profile of nicotine administration closely follows that of smoking a cigarette. Unlike the patch or gum, nicotine spray can cause nasal and throat irritation.

Of the more recently introduced methods for smoking cessation, bupropion (an antidepressant with dopaminomimetic properties) has recently been introduced. Clinical trial data, in which the nicotine patch, bupropion at 300 mg, and a combination of the two drugs were compared with placebo treatment, have shown cessation of smoking rates of 36% for the patch, 49% for bupropion and 58% for the combined treatments following 7 weeks of treatment. The placebo response rate was 23%. All subjects received relapse prevention therapy. Thus bupropion appears to be a reasonably safe and effective treatment for nicotine dependence. It is however contraindicated in those subject to epilepsy; its main side effects are dry mouth and insomnia.

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Defeat Drugs and Live Free

Defeat Drugs and Live Free

Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.

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