Tuesday, April 19, 2011

Opioid analgesics : pharmacodynamics

Analgesic effect of morphine and other opioid analgesics due to their interaction with opiate receptors of different types, but mainly with the m-receptors. Excitation of peripheral opioid receptors and prevents or reduces the activation of nociceptors and primary afferents algogennymi factors. In the CNS activation of opioid receptors causes a suppression of the transmission of pain signals to the segmental (inhibition of afferent input) and suprasegmentarnom level (disturbance of transmission of pain signals in the nuclei of the thalamus) and also stimulates the endogenous antinociceptive system and, consequently, enhances the inhibitory descending control of afferent pain. In addition, at the level of the limbic system opioids cause inhibition of the structures responsible for the formation of negative emotional reactions to pain, and at the same time - excited structures of the "award" that leads to improved mood until the euphoria.

Sedative and hypnotic effects often accompany the action of morphine and are dose-related. Sleep, which can be easily interrupted by any stimulus, is more common in younger than in older people, the ratio of fast and slow phases of sleep while impaired. However, this effect is very useful (and more pronounced), sleep disturbances caused by pain. Sedation, blurred consciousness may be accompanied by a breach of intellectual activity.

Amnesia at the same time, it is insignificant or absent. Morphine potentiates the effects of other substances depressing the central nervous system - general anesthetics, antipsychotics, tranquilizers, sedatives and alcohol.

Respiratory depression. Under the action of morphine is dose-dependent reduction in the frequency and depth of breathing. In cases of acute poisoning seen initially periodic breathing (Cheyne Stokes respiration), and then complete cessation of breathing, which serves as the primary cause of death in acute poisoning. Along with respiratory depression suppresses the cough reflex. Respiratory effect is due to a direct inhibitory action of morphine on neurons of the respiratory center. This reduces the sensitivity of these neurons to the stimulating effect of increased carbon dioxide levels in the blood (RaSO2) and reflex actions. A variety of external stimuli may some time to stimulate the respiratory center in these conditions. When such stimuli are absent, for example, during sleep, respiratory depression effect of morphine is greatly enhanced.

Respiratory depression is more pronounced in children (especially under age 3 years) and elderly persons in connection with the higher permeability of BBB. The drug crosses the placental barrier and can cause asphyxia in the newborn, so it is not used for labor analgesia. Worse than other morphine transfer patients with chronic obstructive pulmonary disease because the drug enhances bronchial tone. Respiratory effects of morphine potentiate neuroleptics, hypnotics and sedatives, and alcohol. To restore the activity of the respiratory center in acute poisoning with morphine as an antagonist naloxone is expedient to apply.

Rigidity of skeletal muscles caused by the action of morphine at the spinal level, leads, including a decrease in the efficiency of respiratory muscles, which further worsens the pulmonary ventilation. The effect is more pronounced during the rapid intravenous injection of large doses of fentanyl and its derivatives (sufentanil, etc.).

Miosis, evolving under the action of morphine is associated with a stimulating effect on the center of the oculomotor nerve. It is implemented with the participation of cholinergic mechanisms, and therefore hindered not only by naloxone but also by atropine. This is a very important diagnostic feature of poisoning by morphine and other opiates (except promedola), because this effect does not develop tolerance or she develops very slowly, and miosis will occur even in drug addicts, tolerant to high doses of drugs.

Nausea and vomiting associated with the activating influence of morphine on the trigger zone hemoretseptornuyu vomiting center. As already mentioned, these effects are usually quickly develops tolerance and they pass with time or, given the right dose. But sometimes required the appointment of antiemetics in the first 1-2 weeks of treatment.

Tolerance, or addiction, manifested by progressive reduction of the pharmacological effects of opioid analgesics like morphine during prolonged use of the drug. Dose-dependent effect. In the appointment of high-dose tolerance can develop very quickly, especially when administered intravenously, as well as in individuals not suffering from pain, and may dictate the need for increased doses of one to two orders of magnitude. But in patients with chronic pain syndrome, it develops slowly. Degree of expression of tolerance for different effects of morphine varies. Expressed tolerance is formed with respect to analgesia, euphoria, sedation, nausea and vomiting, respiratory depression. Minimum tolerance develops with respect to miosis and constipation.

It should be noted that tolerance to eyforiziruyuschemu and respiratory effects of morphine decreases rapidly within a few days after discontinuation of the drug, while resistance to the emetic effect lasts up to several months. Tolerance to morphine is usually accompanied by the development of cross-tolerance to other opiate agonists (but not antagonists).

Euphoria and dependence, usually arising from the application of morphine symptoms, especially when administered intravenously, are interrelated effects.

Euphoria as a pleasant feeling of bliss, indifference to the environment, disappearance of fear and anxiety creates a desire to repeat the drug, ie, generates psychological dependence, which is the first stage of addiction. At this stage, the discontinuation of the drug leads only to the development of negative emotional experiences. With continued use of morphine is formed by a physical dependence or addiction. Addiction - a model of behavior, form a permanent or recurring desire to seek and receive the drug, which differs compulsive (hardly controllable) character. Dependence is much less formed in patients suffering from pain than in healthy persons using morphine with non-medical purposes. Physical dependence develops in parallel with the formation of tolerance to the drug, and if the patient manifested increased tolerance, it is likely that it is formed and dependence.

Characteristic manifestation of physical dependence is the opiate withdrawal syndrome (withdrawal). It appears that if you can not get another dose of morphine or other narcotic drug in humans develop agitation, restlessness, anxiety, hostility, insomnia, yawning, chills, watery eyes and runny nose, piloeorektsiya ("goose bumps"), muscle pain, mydriasis, vomiting and diarrhea, tachycardia and other symptoms. If necessary, discontinuation of the drug gradually decrease the dose of morphine (eg, at 20% per day) significantly reduces the risk of withdrawal symptoms in a patient [2].

It should be noted that in case of pain caused by inoperable cancer and other terminal conditions, all the fears of dependence must be put aside and provide quality patient analgesia. To avoid problems associated with the development of tolerance in these patients, using WHO-recommended scheme of gradual strengthening of drug analgesia.

To the peripheral effects of morphine is spasmogenic effect. Morphine increases the tone of the smooth muscle of many organs, mainly due to the interaction with peripheral m-opioid receptors. The development effect plays a role and gain (disinhibition) of parasympathetic influences. As a result, increases the tone of the intestines and bowel sphincter, it slows down peristalsis, slows the transit of food and chyme, therefore, increases the absorption of water from it. Often end up developing constipation (constipation). Contributes to the development of constipation and general weakness, low physical activity the patient. If necessary, such patients are prescribed laxatives. Morphine increases the tone of the bile duct and sphincter of Oddi, disrupting flow of bile and pancreatic juice into the intestine. The drug also increases the tone of the ureters and the urinary sphincter, thereby making it difficult urination. Given the spasmogenic action of morphine, the drug is not indicated for the relief of spasmodic pain ("colic"), or used in conjunction with mandatory antispasmodics (papaverine, drotaverine, atropine). An alternative to morphine in spastic pain may serve omnopon containing papaverine in its composition, or promedol with independence myotropic antispasmodic effect.

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