Pain-relieving drugs (analgesics)

Title• Pain is associated with many pathological

conditions. They not only cause painful experiences, but also worsen the underlying disease. Generally recognized the leading role of the factor of pain in the etiology and pathogenesis of traumatic shock, which in some cases can cause death. All this shows the great importance for practical medicine painkillers. Pain is perceived by specific receptors, which are called 'nociceptors'. They represent the end of the tree-like branched afferent fibers located in the skin, muscles, joint capsules, periosteum, internal organs, etc. are damaged (nociceptive) stimuli may be mechanical, thermal and chemical effects.

• Pain is often a cause pathological process (e.g., inflammation). Known endogenous substances which, acting on nociceptors, can cause pain (e.g., bradykinin, histamine, serotonin, potassium ions etc.).

• Prostaglandins (for example, group E2) increase the sensitivity of nociceptors to chemical (and thermal) irritation. Pain caused by irritation of pulses propagate along the C and 'Aδ-fibers and come back in the horn of the spinal cord. Here is the first switch from afferent fibers in the neurons of. Hence the excitement extends to the following paths.

• One - ascending afferent tracts. They spend excitement to the upstream departments - the reticular formation, thalamus, hypothalamus, to basal ganglia, the limbic system and the cerebral cortex. The combined interaction of these structures leads to the perception of pain assessment and the relevant behavioral and autonomic responses. The second way - to send pulses to the motor neurons of the spinal cord, which is manifested motor reflex. The third way is through the excitation of neurons in the lateral horn, which is activated as a result of the adrenergic (sympathetic) innervation.

• The functioning of the neurons of spinal cord dorsal horn is regulated by supraspinal antinociceptive system. The last is a complex of structures, it turns descending inhibitory effect on the transmission of pain stimuli in primary afferent neurons of fibers. For example, it is shown that electrical stimulation of the periaqueductal gray or reticular nucleus or microinjection of enkephalins in them causes a reduction in pain sensitivity. Carried downward through the inhibition of serotonergic, noradrenergic, and neurons. It should also consider the presence of a large number of various endogenous peptides including analgesic activity (enkephalins, β-endorphin, dynorphin, etc.), as well as nociceptive properties (e.g., substance P).

• In the brain tissues are formed and many other biologically active substances which may be involved not only as mediators and modulators but nociceptive stimulation. As the last act, and some neurohormones. Peptides with analgesic activity (opioids) interact with a specifical opiate receptors, which are found in most formations accepting part in the conduct and perception of pain. Identified different types of opioid receptors, which differ in their sensitivity to endogenous and synthetic opioids.

• Thus, in the body there is a complex neurohormonal antinociceptive system. In the event of failure (with over-expressed or long-term damaging effects) pain must be repressed with the help of painkillers. Depending on the origin, nature and intensity, and duration of pain use certain painkillers mediaproperties. Analgesics - drugs that selectively inhibit pain sensitivity. They do not turn off the mind and does not inhibit other types of sensitivity. Based on the pharmacodynamics of the drugs, they are divided on narcotic and non-narcotic analgesics power industry.

• Narcotic analgesics and their antagonists Pharmacological effects of narcotic analgesics and their antagonists anta due to the interaction with opioid receptors are found in the central nervous system and in peripheral tissues. Based on the principle of interaction of these substances with opiate receptors, they can be represented by the following groups: Agonists: Morphine Fentanyl Promedol Agonist-antagonists (partial agonists): Pentazosin Nalorfin Antagonists Naloxone

• Narcotic analgesics mainly relate to the first group of substances. However, this can be used as a partial agonist and if they predominate agonist properties (e.g. pentazocine). Narcotic analgesics have a marked inhibitory effect on the central nervous system. It appears analgesic-sky, sleeping pills, antitussive effect. In addition, most of these changes the mood (euphoria occurs) and causes drug dependence (physical and mental). The group of opioids include a number of products derived from plant material as well as synthetically.

• The most widely used in medical practice has received alkaloid morphine. Set it apart from opium, which is frozen PWM latex heads of opium poppy (Papaver somniferum). In opium for medical purposes, shall not be less than 10% of morphine. Total Opium contains more than 20 alkaloids. According to the chemical structure of some opium alkaloids are derivatives phenanthrene, and others - to derivatives of isoquinoline. For phenanthrene derivatives (morphine, codeine, etc.) character thorn in the main inhibitory effect on the central nervous system (analgesic, antitussive), and for a number of isoquinoline alkaloids (papaverine, etc.) - a direct antispasmodic effect on smooth muscle.

• Of opium alkaloids morphine only be considered as a typical representative of narcotic analgesics. The important thing for the analgesic effect of morphine is. Morphine has a fairly pronounced selective analgesic effect. Other types of sensitivity (tactile, temperature sensitivity, hearing, vision) at therapeutic doses, it is not at suppresses. The mechanism of analgesic effect of morphine is not fully elucidated.

• Nevertheless, there is every reason to believe that it is composed of two main components:

• 1) the inhibition of the process interneural transmission of pain impulses in the central part of the afferent paths and

• 2) violation of the subjective-emotional perception of pain assessment and response to it. The mechanism of analgesic effect of morphine due to its interaction with opiate receptors. This is manifested by activation of endogene antinociceptive system and a violation interneural transmission of painful stimuli at different levels of the central nervous system.

• The experiment showed that administration of morphine in some of these nuclei (eg in the periaqueductal gray in the reticular nucleus and giant paragigantokletochnoe) causes analgesia. The importance of top-down system is also proved by the fact that the destruction of a large raphe nucleus significantly reduces the analgesic effect of morphine. Of considerable importance is also a direct inhibitory effect of morphine on spinal neurons. Thus there is a violation of interneural excitation transfer at the posterior horns of the spinal cord.

• Thus, the inhibitory effect of morphine on the transmission of pain impulses in the spinal cord from primary afferent fibers neurons consists of strengthening the descending inhibitory influences and direct inhibitory action on the formation of synaptic spinal cord. These types of activities are located both on the postsynaptic membrane of neurons, and the level of presynaptic terminals. Violation of morphine interneural transmission in the spinal cord reduces the intensity of the impulses coming into the ascending afferent pathways, and reduces motor and autonomic responses.

• Under the influence of morphine is also the oppression of the transmission of pain stimuli in ascending afferent paths of the brain, particularly in the area of the thalamus. At that disrupts the function of associative and not ¬ specific thalamic nuclei and their relationship to the cerebral cortex. One ¬ temporarily blocked the transmission of nerve impulses to the collaterals of specific pathways in the reticular formation of the brain stem. When pain stimulation of the transmission of nerve stimulation on specific ¬ cal afferent pathways under the influence of morphine at therapeutic doses does not change.

• Changing the perception of pain is due, apparently, not only with de ¬ sheniem receipt of pain impulses to the upstream departments, but also with the soothing effects of morphine. The latter, obviously, affects the assessment of pain and its emotional coloring, which is important for motor and autonomic manifestations of pain. The role of mental health for evaluation of pain is very great. Suffice it to note that the positive effect of the "placebo" with some pain reaches 35-40%.

• The calming effect of morphine may be due to its effect on neurons of the cerebral cortex, the activating upward reticular formation of the brain stem, as well as the limbic system and hypothalamus. For example, it is known that morphine inhibits activation reaction cortex (EEG desynchronization suppresses external stimuli), and the reaction limbic system and hypothalamus, thalamus to afferent impulses. Sedation may be accompanied by improvement in mood, feeling ¬ tion of peace of mind, a positive perception of the situation and prospects in life regardless of the actual real. This condition is called euphoria. Especially it is expressed with repeated use of morphine. However, some people celebrated the opposite phenomenon: poor health, negative emotions (disfORHIA).

• At therapeutic doses of morphine causes drowsiness, and when the good environment conducive to the development of sleep. Dream Caused by the Phin, usually superficial and easily interrupted by external stimuli residents. One of the manifestations of the central action of morphine is a decrease in body temperature associated with inhibition of thermoregulation center, located in the hypothalamus. However, a clear hypothermia is observed only at high doses of morphine. However, morphine may have a stimulating effect on certain centers of the hypothalamus. In particular, this leads to higher release of antidiuretic hormone (vasopressin) and reducing diuresis. One of the effects of morphine is decreased appetite.

• Observed with morphine (especially in toxic doses), constriction of the pupils (miosis) also has a central origin and is associated with the excitation of the centers of the oculomotor nerve. The latter is apparently, secondary and results from exposure to morphine overlying parts of the central nervous system. This conclusion is based on the fact that dogs dekortitsirovannyh morphine does not cause miosis. Significant place in the pharmacodynamics of morphine is its effect on the medulla oblongata and the first on the respiratory center. Morphine (from therapeutic doses) inhibits the respiratory center, reducing its excitability to carbon dioxide and reflex actions. First comes a decrease in the frequency of breaths, offset by an increase in their amplitude. At higher doses to sub-toxic respiratory rate is reduced even more, decreases the amplitude of single breaths and minute volume.

• At therapeutic doses of morphine causes drowsiness, and when the good environment conducive to the development of sleep. Dream Caused by the Phin, usually superficial and easily interrupted by external stimuli residents. One of the manifestations of the central action of morphine is a decrease in body temperature associated with inhibition of thermoregulation center, located in the hypothalamus. However, a clear hypothermia is observed only at high doses of morphine. However, morphine may have a stimulating effect on certain centers of the hypothalamus. In particular, this leads to higher release of antidiuretic hormone (vasopressin) and reducing diuresis. One of the effects of morphine is decreased appetite.

• Often there is an abnormal respiratory rate, possibly periodic breathing (at toxic doses of the substance). When morphine poisoning death occurs from paralysis of the respiratory center. Morphine depresses the central units of the cough reflex and has potent antitussive activity. On the vomiting center morphine, as a rule, is depressing. However, in some cases it can cause nausea and vomiting. Attribute this to the stimulating effect of morphine on the chemoreceptors trigger zone (trigger zone), located at the bottom of the IV ventricle and activating center of vomiting.

• Morphine increases the tone and contractile activity of the ureters. It also tones up the sphincter of the bladder, making it difficult mochebtdelenie. Under the influence of morphine, the tone of the bronchial muscles, which may be due to the direct action of miotropnym, and with having mastered ¬ bozhdeniem histamine. Directly on the blood vessels morphine has virtually no effect. In therapy, ¬ vticheskih doses are usually not alter blood pressure levels. At higher concentrations, can cause a small hypotension, which has been attributed to a slight inhibition of the vasomotor center, as well - the release of histamine. Against the background of the action of morphine may develop orthostatic hypotension.

• Another representative of piperidine derivatives - fentanyl (sentonil) - has a very high analgesic activity. According to the experimental data obtained by different methods of investigation, it is superior to morphine activity 100-400 times. A distinctive feature is the short duration of fentanyl caused them pain relief (20-30 min). The effect is 1-3 minutes. Fenty ¬ nile causes marked, but short depression of respiratory center of ¬ (until you stop breathing). To the piperidine derivative is also piritramide (dipidolor). He actively morphine and operates more lasting. The effect comes quickly. Addiction and drug dependency develop to a lesser extent than morphine. Intramuscularly and subcutaneously. Funds are also fenadona group, which includes fenadon (methadone hydrochloride, Amidon) and dextromoramide (Palffy).

• Fentanyl is primarily used in combination with a neuroleptic droperidol (both substances are included in the drug Talamonal; synonym: innovar) for neyroleptanalgesia. Widely used narcotic analgesics for sedation prior to surgery. Administered morphine and under local anesthesia, as it increases the effects of anesthetics.

• In the application of narcotic analgesics (eg, promedola) for labor analgesia should be aware that they cross the placental barrier and cause respiratory depression of the center of the fruit. If, despite precautions, there was a newborn asphyxia, umbilical vein naloxone or nalorphine - antagonist drugs ¬ cal analgesics. When the pain caused by spasms of the bile duct or ureter, as well as in gastric ulcer and duodenal ulcer, intestinal colic shows the use of a promedola and omnopona, since they are smaller than morphine, increase the tone of smooth muscles.

• When toxic effects using antagonists of narcotic analgesics - nalorfin (antorfin) or naloxone (Narcan). According to the chemical structure and pharmacological properties nalorfin, which is a partial agonist, similar to morphine. It has analgesic activity (similar to morphine), several respiratory depression, reduces the heart rate, constricts the pupils. Does not cause constipation. Drug dependence is not produced to it. However, the independent value as an analgesic due nalorfin has significant side effects (depression of the higher nervous activity, action, breach of focusing islands of vision, nausea, vomiting). Applied nalorphine as active antagonist opioids (excluding pentazocine). Nalorfin eliminates the oppression caused by the last center of breath, bradycardia, vomiting, spasms sphynters of the gastrointestinal tract, etc.

• Non-narcotic analgesics Most of the drugs in this group is characterized by three main types of actions: analgesic, anti-inflammatory and antipyretic. In contrast to the narcotic analgesics, they do not have the sedative action and soporific effects, euphoria, addiction and drug dependence in their application does not arise. For non-narcotic include synthetic drugs. Derivatives of salicylic acid (salicylate):

• Acetylsalicylic acid • Methyl salicylate

Pyrazolone derivatives • Amidopyrine • Analginum Phenylbutazone • Aniline derivatives • Phenacetin Paracetamol

• The analgesic effect of narcotic analgesics, apparently mainly consists of peripheral and to a lesser extent from the central effects. The mechanism of analgesic action of non-narcotic analgesics related to their inhibitory effect on prostaglandin synthesis (by inhibiting the enzyme cyclooxygenase). As known, prostaglandins induce hyperalgesia - sensitize nociceptors to mechanical and chemical stimuli. Therefore, inhibition of the synthesis of prostaglandins (PGE2, PGR2a, PGI2) prevents the development of hyperalgesia. The threshold of sensitivity to painful stimuli thus increased.

• A central component in the analgesic effect of non-narcotic analgesics can not be excluded. Its presence is confirmed in Example dryer and paracetamol, in which the peripheral component (antiinflammatory properties), and that the analgesic effect is expressed sufficiently. Apparently, non-narcotic analgesics are only violated conduct pain stimuli in the afferent pathways without affecting the psychological component of pain and its assessment. It is possible that in this case has a value of inhibition of prostaglandin synthesis, which are way in the central nervous system. Distinct sedative effect of these substances is not detected. Non-narcotic analgesics are characterized antipyretic action.

• In the appointment of therapeutic doses of salicylates in violation of the acid-base balance is limited compensated alkalosis, since the kidneys are rapidly released basic compounds (as well as K + and Na +) and the pH to normal. However, the buffering capacity of tissue fluids is lowered. On the cardiovascular system salicylates affect small. Only in high doses to ¬ they have a direct vasodilator effect. Salicylates may affect on the liver, increasing the separation of bile. Separating renal function salicylates generally do not break.

• Appointment of salicylates to reduce body temperature is only suitable for very high temperature, which is called adversely on the state of the body. Side effects associated with the appointment of salicylates appear as dyspeptic symptoms. So, are frequent nausea and vomiting. They are explained in the main central influence of substances (on chemoreceptors trigger zone of the vomiting center) and partly irritated mucosa of the stomach. Due to the violation of prostaglandin synthesis in the gastric mucosa irritation and salicylates cause damage to the mucous membrane of the stomach. There ulceration, hemorrhage. At regular reception acetylsalicylic acid, these phenomena occur in a significant percentage of cases.

• Chronic poisoning (salitsilizm) is usually observed in long use of salicylates and is associated with some of their overdose. In general, symptoms are similar to that noted for acute poisoning, but the severity of its correspondingly less. Furthermore, there may be skin irritation, hemorrhage (due to gipoprotrombinemiey). Treatment of chronic poisoning to cease the administration of salicylates. In the presence of hemorrhage appropriate to prescribe vitamin K1. Basically salitsilizma symptomatic treatment and depends on the specific ¬ governmental manifestations of toxic effects of salicylates.

• Of pyrazolone derivatives widely used in medical practical got amidopirin (aminophenazone, headache tablets), analgin, algokalmin, metapirin) and phenylbutazone (Phenylbutazone, butazolidin). This group is antipyrine (Phenazone), but he rarely be applicable. Pyrazolone derivatives possess analgesic, antiinflammatory and antipyretic properties. The analgesic effect of pain above expressed in amidopirina and dipyrone, anti butadione. Last significantly increases the excretion of uric acid by the kidneys (due to inhibition of its re-absorption), in connection with what has been applied for gout.

• Phenylbutazone is used primarily due to its anti-inflammatory activity in nonspecific infectious arthritis, and acute gout. The adverse effects are observed when using butadiona very often (about 50% of cases). Phenylbutazone can cause dyspepsia ¬ sical disorders (nausea, vomiting, diarrhea, stomach bleeding), swelling (due to increased reabsorption in the renal tubules of sodium and chloride), allergic reactions (skin reactions, arthritis). Severe complications from the blood (agranulocytosis, aplastic anemia), and liver.

• From the gastro-intestinal tract aniline derivatives are absorbed well. The maximum plasma concentration of phenacetin noted ¬ is denoted by 1-2 h, paracetamol is required even less time - 30 minutes - 1 hour in a part of the blood substances (1/4- ⅓) bound to plasma proteins. Approximately 5 hours phenacetin plasma hardly detported, as it is metabolized in the n-acetaminophenol (paracetamoles). Reduction in the plasma by 50% paracetamol is quite rapidly (within 2 hours). Kidneys secrete substances, mainly in the form of conjugates.

• Apply phenacetin and paracetamol as a non-narcotic analgesics for pain of low intensity. Furthermore, they can be used to reduce the temperature of fever. Both drugs were well tolerated. At therapeutic doses does not violate the circulatory, respiratory, liver, blood, oxygen leaf itself-base status, do not irritate the gastric mucosa. With prolonged use, especially in overdose fenatsetina can form small concentrations of methemoglobin and sulfgemoglobina. It is believed that the appointment of paracetamol side effects occur less frequently. The possibility of a negative impact of phenacetine on the kidneys (called "fenacetine jade"). In this regard, individuals with kidney disease should not be given phenacetin. Toxical action of phenacetin may be accompanied by hemolytic anemia

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