Opioid Analgesics

Opioids are subdivided into three large subgroups according to their action on opioid receptors: agonists, mixed agonists-antagonists, and antagonists. Opioid agonists have an affinity for opioid receptors, imitating the activity of endogenous opioid analgesics. Mixed agonists-antagonists can be semisynthetic derivatives of morphine or peptide analogs of endogenous opioids that display agonistic activity at some opioid receptors and antagonistic activity in others. Opioid antagonists bind to opioid receptors but do not activate them. These compounds are not used for analgesia. Their therapeutic value is in relieving side effects that result from either absolute of relative overdoses or intolerance of drugs by patients, and also in treating cases of opioid dependency.

Agonists include natural alkaloids of opium (morphine, codeine, and a large blend of natural alkaloids, pantopon, and omnopon), their analogs (hydrocodon and hydromor-phone, oxycodone, and oxymorphone), derivatives of morphinane (levorphanol), and a number of synthetic compounds: derivatives of phenylpiperidine (meperidine, promedol), 4-anilidopiperidines (fentanyl, sufentanyl, alfentanil), and derivatives of diphenylheptane (methadone, propoxyphene).

The mixture of agonists-antagonists includes derivatives of morphinane (nalorphine, butorphanol), phenanthrene (nalbuphine), derivatives of benzomorphane (pentazocine, dezocine), and derivatives of opipravin (buprenorphine).

At last, naloxone and naltrexone are antagonists.

It is universally accepted that the action of opioids is mediated by specific receptors. It is presumed that several types of opioid receptors exist: f, k, S, and a. A few of these are in turn subdivided into subtypes. It has been found that opioid receptors are seven transmembrane G-protein-coupled receptors that are localized in the membranous part of the synaptosomal head; it has also been found that they are glycoproteins. They are prone to conformational changes in certain situations, which is essential for their selective binding with agonists or antagonists.

Opioids have various chemical structures, and their relative analgesic potential depends on several different factors, including their affinity to specific binding sites on receptors, activity on the receptors themselves, and distinctive pharmacokinetic properties.

Various types of opioid receptors have been postulated solely for explaining the different actions of opioids.

Receptors that cause reactions in the organism that are analogous to the reactions upon introduction of morphine (suppression of respiration, myosis, disorders of the gastrointestinal tract, euphoria) have been named f -receptors. Receptors that cause effects analogous to those caused by ketazocine (analgesia, sedative effects, myosis) have been named K-recep-tors. Analgesic receptors that also cause psychotomimetic reactions (hallucination dyspho-ria, stimulation of respiratory and cardiovascular system, mydriasis) are characteristic of those included in the class of the agonist-antagonists of the type of N-allylnormethazocine named a-receptors. Receptors that react to the action of enkephalins and that cause analgesia and release of growth hormone have been named S-receptors.

Despite the numerous studies that confirm the fact that influence on different receptors causes various effects, their exact nature and role require considerably more study.

The physiological role of the endogenous opioid system is not limited to pain and analgesia. It unambiguously plays a role in the regulation of the endocrine, behavioral, thermoregulating, immunological, and gastrointestinal systems as well as taking part in the development of mechanisms of addiction and dependence on opioids. It is possible that endogenous opioids may be able to react with many other neurotransmitter systems.

The concept that opioids cause analgesia in response to reaction with certain receptors was suggested many years ago; however, until 1973 specific opioid-binding sites had not been identified, as receptors and their distribution had not been specified. The distribution frequency of opioid-binding sites varies significantly in different regions of the CNS; it is especially high in brain structures associated with physiological functions connected to opioid use, which indicates a correlation between the binding site and the effect. Opiate receptors are found outside the CNS, in particular in the vagus and the gastrointestinal tract.

Neurochemical data indicate that opioid receptors in the brain are associated with presy-naptic structures, thus functioning by reducing neurotransmitter secretion.

It is believed that the reaction of agonists with opioid ^-receptors leads to an increase in the flow of potassium ions from the cell, simultaneously making it difficult for calcium ions to flow into the cell, which makes neurons less excitable. «"-Receptor agonists directly inhibit entrance of calcium ions into neurons by simply reducing their flow through voltage-gated calcium channels. These data are supported by facts indicating that heightened calcium ion concentrations weaken the effect of morphine, while reduced levels strengthen the effect. The action of morphine upon appreciation of pain differs from the action of local anesthetics. Local anesthetics reduce and weaken appreciation of pain by hampering transmission of signals from the source of pain. Opioids barely influence the axonal conduction; rather they block interneuronal transmission of pain impulses at different levels of CNS integration.

Endogenous oligopeptides that bind with parts of opioid receptors and act analogous to opioids were observed in the brain and other tissues. The first of these to be isolated and decoded were met- and leu-enkephalin. /¡-Endorphin, a peptide with quite a large molecular mass and with analogous action, was found produced in pituitary gland.

Another peptide called dynorphin was identified later on. Many other various functions including taking part in neurotransmission are ascribed to endogenous opioid peptides; however, their mechanism of opioid action as with nonpeptides is still unclear.

Opioids cause side effects that limits their use. They include respiratory depression, nausea, vomiting, constipation, a heightened level of blood pressure, urine retention, perspiration, and itching; of course, the most dangerous of these is respiratory depression. Opioids cause dependency and addiction.

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