Analgesic means, or analgegika (from Greek algos - pain and an - without), the medicines having specific ability to weaken or eliminate feeling of pain call.
Analgetik, but also other substances relating to different pharmacological groups can have analgesic (soothing) effect not only actually. So, the drugs used for an anesthesia (general anesthesia), and some of them in the corresponding concentration and doses can have analgesic effect (for example, trichloroethylene, nitrous oxide) are used especially for an analgesia. Mestnoanesteziruyushchy means on the substance of the action also are analgesic. In the pains connected with spasms of smooth muscles, spasmolytic and cholinolytic means can have soothing effect.
Under analgetichesky (analgesic) properly mean means which dominating effect is the analgesia which is caused resorptive action and not followed in therapeutic doses by switching off of consciousness and the significant disturbance of motive functions.
By the chemical nature, the nature and mechanisms of pharmacological activity the modern analgetik divide into two main groups. A. The narcotic analgetik including morphine and alkaloids (opiates) and synthetic connections, close to it, having opiatopodobny properties (opioids). B. The non-narcotic analgetik including synthetic derivatives of salicylic acid, pyrazyl ketone, aniline and other connections.
The following main features are characteristic of narcotic analgetik.
1. The strong analgesic activity providing a possibility of their use as highly effective sedatives in the different fields of medicine, especially in injuries (operational interventions, wounds, etc.) and in the diseases which are followed by the expressed pain syndrome (malignant new growths, a myocardial infarction, etc.). 2. The special influence on central nervous system of the person which is expressed in development of euphoria and emergence at repeated use of syndromes of mental and physical dependence (drug addiction) that limits a possibility of prolonged use of these drugs.
3. Development of a disease state (abstinence syndrome) in persons with the developed syndrome of physical dependence at deprivation of their analgetichesky drug.
4. Removal of the sharp toxic phenomena caused by them (respiratory depressions, disturbances of warm activity, etc.) and also analgetichesky effect specific antagonists (see Naloxonum).
At repeated use of narcotic analgetik the accustoming (tolerance), i.e. weakening of action when for obtaining analgesic effect more and more high doses of drug are required usually develops.
Action of narcotic analgetik is not limited to soothing effect. In any given degree they drowse, breath and a tussive reflex oppress, raise a tone of intestines and bladder, can make sick, vomiting, a constipation and other by-effects.
Due to the expressed narcogene potential (i.e. ability to cause addiction with a dependence syndrome) and the related significant shifts in activity of central nervous system and other systems of an organism all narcotic analgetik are subject to storage, appointment and release from pharmacies according to special rules.
On expressiveness of analgetichesky action and side effects different drugs of this group differ among themselves that is connected with features of their chemical structure and physical and chemical properties and according to interaction with the receptors involved in implementation of their pharmacological effects.
In recent years a number of earlier applied narcotic analgetik having the expressed narcogene potential (Thecodinum, a hydrocodon the phosphate, Fenadonum, some ready dosage forms containing opium or codeine), is excluded from the nomenclature of medicines.
At the same time a number of new synthetic highly effective narcotic analgetik is created.
On sources of receiving and the chemical building the modern narcotic analgetik are divided into 3 groups: a) natural alkaloids - the morphine and codeine which are contained in somnolent poppy; b) the semi-synthetic connections received by chemical modification of a molecule of morphine (ethyl morphine, etc.); c) the connections formed as a result of full chemical synthesis (Promedolum, fentanyl, pentazocine, nalbufin, butorfanol, tramadol, etc.). The majority of synthetic drugs is received by the principle of modification of a molecule of morphine with preservation of elements of its structure or its simplification. By this way a set of the drugs differing on force and duration of soothing effect, on speed and extent of development of accustoming, addiction and other side effects on ability to slow down physical activity of intestines and to have antidiarrheal effect (see Loperamide), on antibechic effect, etc. is received. Some drugs have on smooth muscles spasmolytic effect (see Promedolum).
By chemical modification of a molecule of morphine also connections, being his pharmacological antagonists are received (see Naloxonum).
The mechanism of action of narcotic analgetik is insufficiently studied.
Neurophysiological researches demonstrate oppression by narcotic analgetika of the thalamic centers of painful sensitivity and blocking of transfer of painful impulses to bark of a great brain. This effect is, most likely, the leader in the physiological mechanism of action of analgetik of this group.
In neurochemical aspect the studying influence of these substances on neuromediator processes of a brain and peripheral bodies is important. There are data on the oppressing effect of morphine on hydrolysis of acetylcholine and its discharge from nerve terminations. It is established that morphine activates serotonin biosynthesis. At the same time the reserpine reducing the contents in a serotonin brain weakens analgesic effect of morphine and its analogs.
In general there are no sufficient data on a role of this neurotransmitter in the mechanism of action of narcotic analgetik. Are contradictory also given about a role of adrenergic processes and the GAMKergicheskiy system. Shifts in the GAMK system under the influence of different opiates and similar to them substances are ambiguous.
Especially the data on existence in a brain and other bodies of specific<опиатных> receptors obtained recently are important for understanding of the mechanism of effect of opiates. Endogenous ligands, i.e. the specific, formed in an organism physiologically active connections contacting these receptors, are neuropeptids - enkephalins and endorphins. Enkephalins are the pentapeptides containing five residues of amino acids. So-called met-enkephalin (methionine-enkephalin) has the building: N-tirozil-glitsil-glitsil-fenilalanil-metionil-ON. Endorphins have a little more complex structure. So, ~ - endorphin (one of the most active endorphins) consists of 31 amino acids. Enkephalins and endorphins, contacting opiate receptors, have analgetichesky effect, and their effect is blocked by specific antagonists of opiates. Linking of morphine with these receptors is provided that a certain part of its molecule has structural and conformational similarity to a part of molecules (tirozinovy rest) of enkephalins and endorphins. Thus, exogenous analgetik morphine (as well as others close to it on structure opiates and opioids) at introduction to an organism interacts with same<местами связывания> (receptors) which are intended for binding of endogenous analgetichesky connections - enkephalins and endorphins.
It is possible that action of exogenous analgetik is connected also with stabilization of endogenous neuropeptids (enkephalins, etc.) by an inactivation of the enzymes destroying enkephalins - enkefalinaz.
Now it is established that endogenous ligands for opiate receptors are not only enkephalins and endorphins, but also other peptides (dinorfinums, etc.). It is shown also that opiate receptors exist in the form of different subpopulations: (mi), (kappa), (delta), (sigma), having various functional importance. Believe that - receptors mediate a supraspinal analgesia, euphoria, respiratory depression and physical dependence; - receptors mediate a spinal analgesia, a miosis, sedation, etc. Different endogenous peptides and narcotic analgetik can mainly contact any given subgroup of receptors that can define features of their pharmacological action.
Different narcotic analgetik differ also on the nature of linking with opiate receptors. Some of them (morphine, Promedolum, fentanyl, etc.) are<чистыми> (polnymn) agonists; contacting receptors, they render physiological (pharmacological) action, characteristic of endogenous ligands. Others are<чистыми> antagonists (see Naloxonum). Contacting receptors, they block action of endogenous ligands and exogenous opiates. The third group includes drugs of the mixed type of action (agonists-antogonisty) which are differently contacting different subgroups of opiate receptors and rendering in this regard by some types of action agonistic effect on others - antagonistic (Nalorfinum, pentazocine, nalbufin, etc.).
Action of narcotic analgetik on peripheral bodies (intestines, etc.) is also connected with interaction with the opiate receptors which are localized in them.
The significant mestnoanesteziruyushchy action at the majority of opiates is not noted. At the same time in recent years it is revealed that they have the strong general anesthetizing effect at epidural and subarakhnondalny introduction. This effect is connected with immediate effect on the neuronalny systems of a spinal cord participating in forming of a painful stream of impulses. This method of administration of opiates began to find the increasing application for stopping of heavy acute and chronic pains recently.
The following main features are characteristic of non-narcotic analgetik.
1. The analgesic activity which is shown at certain types of pain: mainly in neuralgic, muscular, articulate pains, at head and a toothache. In the severe pain connected with injuries, band surgeries, etc. they are almost inefficient.
2. The febrifugal action which is shown at feverish states and the anti-inflammatory action expressed in different degree at different connections of this group.
3. Lack of the oppressing influence on the respiratory and tussive centers.
4. Absence at their use of euphoria and the phenomena of mental and physical dependence.
The main representatives of non-narcotic analgetik are:
a) derivatives of salicylic acid (salicylates) - sodium salicylate, acetylsalicylic acid, Salicylamidum, etc.;
b) pyrazyl ketone derivatives - antipyrine, pyramidon, analgin;
c) paraaminophenol derivatives (or aniline) - acetphenetidiene, paracetamol.
In the mechanism of action of non-narcotic analgetik a part is played by influence on the thalamic centers which leads to slowing down of carrying out painful impulses to bark. On the central action these analgetik differ, however, from narcotic analgetik in a number of features (for example, do not affect ability of central nervous system to summation of subthreshold impulses).
In the mechanism of effect of salicylates an important role is played inhibition of biosynthesis of prostaglandins (see acetylsalicylic acid) and also the stimulating influence on<ось> a hypophysis - adrenal glands, promoting release of corticosteroids. The essential value in operation of non-narcotic analgetik has their influence on a kinin system (antagonism with algeziruyushchy effect of bradykinin, etc.).