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Pharmacodynamics

Pharmacodynamics is a section of pharmacology that studies mechanisms of action medicines, as well as a combination of effects caused by them.

The interaction of medicines with the body begins with the reaction of its active molecules with receptors. The concept of "receptors" introduced in the experiments on chemotherapy in the early 20th century Paul Erlich and developed Zagley (1905) in experiments with nicotine and coarara. Erlich formulated the main postulate: "SARRARA NON AGUN NIX FIXALA" - "Substances do not act if not fixed."

The receptor is a protein or glycoprotein nature biomacomolecule, which has a high affinity or selectivity with respect to biologically active substances (endogenous nature and synthetic drugs), when interacting with specific biological effects. The structure of the receptors is different, its study is one of the tasks of pharmacodynamics. Localization of receptors can be different:

1. On the surface of cell membranes

2. Plot of the membrane itself

3. Organelles Cells

4. Enzymes of different location

Receptors are evolutionally adapted to respond with strictly defined evolutionary selected ligands.

Ligands - Ego Substances (endogenous and exogenous nature) capable of contacting receptors and cause specific effects. Examples of endogenous ligands can be hormones, mediators, metabolites, neuropeptides (endorphins and enkephalins).

Medicinal substances and ligands interact with receptors and with the help of physical, physicochemical, chemical reactions.

Most medicinal substances form various chemical bonds with receptors. These can be: 1) Vanderwals, 2) hydrogen, 3) ion, 4) covalent bonds (unitiol + arsenic, calcium tetacin + lead, phos + acetylcholinesterase). The most robust link is covalent, the least - Vanderwals.

Typical mechanisms of action of drugs

They are divided into 2 groups: highly insulating and indiscriminate. Highly selection mechanisms of action are associated with the influence of drugs for receptors. Not electoral - not related to receptors. The group of high-sectorate mechanisms of action includes:

1. Mimetic effects or reproduction of natural ligand action.

Drugs due to the similarity of the chemical structure with a natural ligand (mediator or metabolite) interact with receptors and cause the same changes as ligands.

Mimetics are substances that excite receptors. For example, the natural ligand of cholinoreceptors is acetylcholine. The preparation of carbocholine is close to it, which reunited with cholinoreceptors reproduces the effects of acetylcholine. According to sensitivity to cholinoreceptors, carbochalines is called cholinomimetics. Mimetic effects have drugs - agonists. Agonists are drugs directly exciting or increasing receptor function.

2. Lititary effect or competitive blockade of the natural ligand.

The medicinal product is only partially similar to the natural ligand. This is enough to contact the receptor, but it is not enough to cause the necessary conformational changes in it, that is, to initiate it, while the natural metabolite of NE can interact with the receptor itself, if it is engaged in the blocker, and the effect of natural ligand is absent . If the concentration of the ligand is increasing, then it displaces the drug with a competitive type due to the drug receptor.

Examples of lytic effects: adrenois and cholinoblocators, hystamyolics. Litics are substances depressing (inhibitory) receptors. A lithic effect has substances - antagonists. Antagonists are substances that prevent the action of specific agonists, thereby weakening or preventing them. Antagonists are divided into competitive and nonconnect.

3. Alosteric or non-competitive interaction.

In addition to the active center, the receptor has another alto-class center or receptor II of the order, which regulates the speed of enzymatic reactions. The drug is associated with a natural activator or an inhibitor, it causes a change in the structure of the active receptor center, its disclosure or closure. This makes an active center more or less accessible to establishment and as a result, the receptor function is or activated or blocked.

Examples of the Alosteric mechanism of action: Tranquilizers of benzodiazepine structure, amiodarone (cordaron).

4. Activation or suppression of the function inside and extracellular enzymes. Examples: adenylate cyclase activators - glucagon, inhibitors of Mao - Niamid, activators of microsomal enzymes - phenobarbital, zisorin, acetylcholineserase inhibitors - prozerne, galantamine.

5. Changes in the functions of transport systems and permeability of membranes of cells and organelles:

Blockers of slow sauz channels: verapamil, nifedipine, sensit. Arrhythmic drugs, local anasthetics.

6. Violation of the functional structure of macromolecules.

Cyticostatics, sulfonamides.

Indiscriminate typical mechanisms of action.

1. Direct physico-chemical interaction associated with the physicochemical properties of the drug.

Osmotic action of salt laxatives

Neutralization of gastric hydrochloric acid juice (NaHCO3)

Adsorption of poisons activated coal

2. Communication of medicines with low molecular weight components of the body (microelements, ions). Citrate Na, Trilon B - bind excess calcium.

drug Dependence Block Reaction

Types of action of medicines

Pharmacodynamics includes questions about the types of drugs.

1) resorbative action (from the word resorption - suction) is the effect of drugs developing after absorption to blood (that is, a general action on the body). Most medicinal preparations In different dosage forms (solution, tablets, injections are prescribed for the purpose of resorbative action).

2) Local action is the action of the drug at the place of its application.

For example, this is an action: on the skin of ointments, sprinkles, pastes, lotions; On the mucous membranes of the cavity of rinsing, washing, appliqués, preparations with anti-inflammatory, astringent, painkillers, which are used during stomatitis, gingivitis and other diseases of the oral cavity are used.

3) The reflex action is the effect of the drug on the nerve endings, which leads to the appearance of a number of reflexes by some organs and systems. A special role in the implementation of this type of action is played by the reflexogenic zones of the gastrointestinal tract, the upper respiratory tract, Skin, Sino-carotid zone. The reflector action may accompany local and resorbative effects. Examples: Action of ointments containing essential oils.

4) Central action - This is the action of medicines on the central nervous system. Examples: Any preparations acting on the central nervous system - sleeping pills, drugs for anesthesia, sedatives.

5) The electoral action (or selective) is an action on functionally unambiguous receptors of a certain localization in the absence of significant action to other receptors. The consistency: heart glycosides highly insultly affect the heart, beta-1 Adrenobloclars metoprolol and Talinol blocked only beta-1-cards of the heart, do not act in small and medium doses on beta-2-receptors of bronchi and other organs.

6) an indiscriminate effect is unidirectional effect on most organism organs and tissues. For example, antiseptics - salts of heavy metals block (SH) sulfhydryl groups of thiol enzymes of any tissues of the body, their therapeutic and toxic effects are associated with it.

7) Direct effect is an action that has a drug directly to a certain process or body. For example, cardiac glycosides directly affect the heart, have a cardiotonic effect - increase the strength of heart abbreviations.

8) An indirect effect is an indirect effect that occurs in other OPGs and tissues is secondary as an indirect result of direct action. For example: heart glycosides due to direct action increase the strength of heart abbreviations, increase blood pressure, normalize hemodynamics in the kidneys and these indirectly increase diuresis. Thus, the diuretic action of glycosides is an indirect effect.

9) The main action is the main effect of the drug that determines its practical application. For example, Novocaine is its main effect pain relief, and it is widely used for local anesthesia.

10) Side effect is the ability of the drug substance, in addition to the main action, to change the functions of other organs and systems, that the particular patient is most often inexpedient and even harmful. Side effect may be desirable and undesirable. For example, ephedrine expands bronchi and causes tachycardia. In a patient with bronchial asthma, the occurrence of tachycardia is an undesirable effect. But, if it has a concomitant blockade of the excitation of myocardium, the effect of ephedrine on the conductive heart system is a desirable side effect.

11) A reversible action is the action of the drug determined by the strength and duration of communication with the receptor. Feedback is destroyed at different time intervals and the effect of the drug is terminated. For example, reversible acetylcholineserase inhibitors.

12) The irreversible action is the action of the drug for receptors by forming a long and durable covalent bond. Often it entails irreversible changes in the cell, fabric and toxic effect develops. For example, irreversible inhibitors of acetylcholineserase (phosphall).

13) Toxic effects are sharp shifts of the function of organs and systems that go beyond the limits of physiological when prescribed, as a rule, excessive doses of the drug. The manifestation of such actions is considered as a complication of drug therapy.

Reactions caused by long-term intake and cancellation of drugs.

These reactions include:

1. Cumulation

2. Sensitization

3. Getting used

4. Tahofilaxia

5. "Rotim" syndrome

6. Syndrome "Cancellation"

7. Drug addiction.

Cumulation is the accumulation of the medicinal substance and its effects in the body. Cumulation is 2 species: material when the medicinal substance itself accumulates, and the functional when the effect of the drug accumulates. The causes of material cumulation are:

Durable connection and a high percentage of drug communication with blood plasma proteins,

Slow inactivation of the drug

Deposit, for example, in adipose tissue

Slow excrement or reaberence reaberence

The presence of enterogeptic circulation

Pathology of liver and kidney and as a result, disruption of neutralization and drug removal. Examples of material cumulation: Heart Gdikosides, Barbiturates. Sulfadimetoxin, Hinghamin (Degin, Chlorin).

Examples of functional cumulation: ethyl alcohol ("white hotness", psychosis after taking alcohol, which is quickly oxidized to the final products). In the case of cumulation, not only therapeutic but also the toxic effect of the drug is intensified. To prevent the cumulation, reduce the dose of the drug and increase the intervals between the receptions.

Sensitization is an increase in the action of medicinal substances when they are re-administered even in small doses. This reaction of immune (allergic nature) and it can arise to any drugs that are allergens in this case.

Exchange (tolerance) is a decrease in the effect when re-conducting the drug in the same dose. For example, at a constant reception, hypnotic drugs, droplets from a cold, cease to operate.

The basis of this effect lies a number of reasons:

1. Induction of liver microsomal enzymes and accelerated neutralization and reject drugs. Examples: Barbiturates, partly morphine.

2. Reducing the sensitivity of receptors (desensization). Examples: phosphorganic compounds, caffeine, drops from a cold - Galazoline.

3. Autoonybizing, that is, due to the excess of the drug substance with the receptor, not one molecule is associated, and several, the receptor, as it were, becomes "overloaded" (in biochemistry this is the phenomenon of the inhibition of the enzyme substrate). Pharmacological effect The preparation is reduced by the drug.

4. Development of cell stability, for example, to antitumor drugs (combined treatment).

5. Inclusion of compensation mechanisms, which reduces the shift caused by the drug.

The effect of the drug can be restored:

Increasing the dose (this is irrational, since it is impossible to increase it continuously)

Alternate drugs

Take a break

Use combinations of drugs.

KAK The type of addiction arises cross-addiction or tolerance to drugs close biological structure, for example, to nitrates (nitro glycerin, slander, nitrong, nitrosorbit and other drugs of nitrates).

Another type of addiction is tachofilaxia - this is the main form of addiction, developing on the re-administration of the drug in the range of several mi nut to one day.

An example is a tachyphylaxia to ephedrine, adrenaline, norerangen, which, at the first introduction, significantly increase the blood pressure, and when repeated in a few minutes, more weakly. This is due to the fact that the receptors are occupied by the first portion of the medicinal substance, and in the case of ephedrine, which acts through the emission of the mediator from synapse, with a decrease in its concentration in the synaptic end.

The syndrome (phenomenon) of the return - the supercompensation of the process after the cancellation of the drug with a sharp exacerbation compared with the month. An example, an increase in blood pressure to a hyperotensional crisis after the cancellation of the Cloofelin hypotensive preparation (hemiton). To avoid the "return" syndrome, it is necessary to cancel the drug, gradually reducing the dose.

Syndrome "Cancellation" - suppression of physiological functions associated with a sharp cancellation of the drug. For example, when prescribing hormonal drugs, the production of own hormones is suppressed according to the principle of feedback and the abolition of the drug is accompanied by east hormonal failure.

Drug addiction develops with re-admission of medicinal psychotropic drugs. Drug addiction is psychological and physical. By definition of the World Health Organization, mental dependence is "dependence in which the drug causes a sense of satisfaction and mental lifting and which requires a periodic or constant introduction of the drug to test the pleasure or avoid discomfort."

Physical dependence is an "adaptive state that is manifested in intensive physical disorders (abstine syndrome), when the introduction of the appropriate drug is terminated."

Abstinence is a complex of specific mental and physical symptoms characteristic of each type of drugs.

Drug addiction substances are divided into the following groups:

Alcoholic type substances

Barbituratov type substances

Opa type substances (morphine, heroin, codeine)

Cocaine type substances

Penasia type substances

Tina Cannabis (Hashish, Marijuana)

Hallucinogens type substances (ZS, Mescalin)

Substances like essential solvents (toluene, acetone, carbon tetrachloride).

The most difficult drug addiction proceeds when a complete triad is observed: a combination of mental and physical dependence and tolerance (addiction). Such a combination is characteristic of morphine, alcohol and bubnetic dependence. In fenamism, only physical dependence occurs when cocaine and morihuana is used - only mental dependence.

Combined action of drugs (interaction of medicines).

With the simultaneous administration of two or more drugs, mutual strengthening or weakening their effects may occur.

Strengthening of the action of drugs with joint admission is synergism. The weakening of the action of medicines is called antagonism. The interaction of two or several drugs, as a result of which the effects of one of them (or both) are reduced or completely eliminated by antagonism.

Types of drug interaction are divided into groups:

1. Pharmacodynamic

1.1. synergism

Amount

Potentiation

1.2. antagonism

Functional (physiological)

Competitive

Indirect

Physical and chemical

2. Pharmacokinetic

1.1 at suction phase

1.2. At the stage of competition for blood plasma proteins

1.3. At the stage of penetration through fabric barriers

1.4. At the stage of biotransformation

1.5. At the stage of removal

The effect of the amount of (or simple addition) occurs when the substances influenced by the same receptors or having the same mechanisms of action, that is, this substance of one pharmacological group. For example, drugs for anesthesia, ether and halotane (fluorotan) in combination give the effect of the summation, since the mechanisms of their action are close, or analgin and acetylsalicylic acid also cause simple addition - the amount of effects (by the same when the chip of the same mechanism of action).

Carbacholin and acetylcholine act on some cholinoreceptors, therefore cause the summation of effects.

The potency (or enhancing the action of drugs under joint admission) occurs with the combined administration of drugs acting in one direction to different receptors having an unequal mechanism of action, that is, these are substances of different pharmacological groups. For example, the hypotensive effect of clofelin potentiate diuretics, anesthetic effect of morphine - neuroleptics.

These are drugs of a different mechanism of action from different pharmacological groups. The effect of potential is often used for combined pharmacotherapy. Since the strengthening of the joint therapeutic effect reduces the dose of drugs, and the dose reduction leads to a decrease in side effects.

With direct functional antagonism, two drugs act on the same receptors, but in the opposite direction. Example: Pilocardia narrows the pupil, as it excites cholinoreceptor of the circular muscles of the eye, and the muscle is shrinking. Atropine expands the pupil, blocking the same receptors. This is an example of direct functional antagonism (straight, since both substances act on the same receptors, functional, since they act on this physiological function is the opposite).

With direct competitive antagonism, two drugs have a structural similarity, therefore compete for contact with the receptor or for the possibility of participation in any biochemical process. For example, morphine and nipfin are close in the structure to morphine, but it is less than 60 times inhibits the respiratory center. With morphine poisoning, he displaces it from the respiratory center receptors and partially restores breathing. Or: Competitive para-aminobenzoic acid antagonists are sulfonamides due to the proximity of the chemical structure.

Indirect antagonism is the action of two drugs on various structures (receptors) in the opposite direction. For example, Tubokuran relieves convulsions caused by strikhnin, but these drugs act at various levels. Strichnin - on the spinal cord, tubocurarine blocks skeletal muscles n-cholinoreceptors. Physico-chemical antagonism is the physicochemical interaction of two drugs, as a result of which they are inactivated. For example. 1. Physical interaction is the adsorption reaction of poisons on the surface of activated carbon; 2. Chemical interaction is an acid neutralization reaction with an acid and vice versa (with poisoning).

Chemical reactions of complex formation: Unitol interacts with arsenic, heart glycosides, mercury due to free sulfigidrial groups.

The phenomenon of antagonism is widely used in medical practice for the treatment of accesses and removal of side effects of drugs.

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Pharmacotherapy - the effects of medicinal substances - based on the use of combinations of drugs, compositions of their symptomatic action. Drug interaction: physical, chemical, pharmacokinetic, pharmacodynamic.

Depending on the purposes, paths and circumstances of the use of drugs, various types of action can be highlighted in accordance with various criteria.

1. Depending on the localization of the drug, the drug is distinguished:

but) local action - manifests itself at the site of applying the drug. It is often used to treat skin diseases, rotion bullshit, eyes. Local action may have a different character - antimicrobial at local infection, topless, anti-inflammatory, binder, etc. It is important to remember that the main medical characteristic Drugs appointed locally is the concentration of the active substance in it. When using the local drug, it is important to minimize its absorption into blood. For this purpose, adrenaline hydrochloride is added to the solutions of local anesthetics, which, narrowing the vessels and, thereby reducing the absorption into the blood, reduces the negative effect of anesthetic to the body and increases the duration of its action.

b) resorbative action - manifests itself after suction medication in blood and more or less uniform distribution in the body. The main healing characteristic of the medication acting resorbately is the dose.

Dose - This is the amount of medicinal substance introduced into the body for the manifestation of resorbative action. Doses can be one-time, daily, coursework, therapeutic, toxic, etc. Recall that, writing down the recipe,

we always focus on the average therapeutic doses of the drug, which can always be found in reference books.

2. When the medicine enters the body, with it in contact with a large number of cells and tissues that can react differently to this medicine. Depending on the affinity of certain tissues and by the degree of selectivity, the following types of action are distinguished:

but) election action - The medicinal substance acts selectively only on one body or system, without affecting other tissues. This is the ideal case of the action of drugs, which is very rare in practice.

b) preferential action - Specifies several organs or systems, but there is a certain preference to one of the organs or tissues. This is the most common option of drug action. The weak selectivity of drugs underlies their side effects.

in) general carrier action - The medicinal substance acts equally to all organs and systems, to any living cage. Preparations of this action are appointed, as a rule, locally. An example of such actions is

the igniting effect of heavy metals salts, acids.

3. Under the influence of the drug, the function of the organ or tissue may vary in different ways, so the following types of action can be distinguished by the character of the change of function:

but) tonic - The effect of the drug begins against the background of a reduced function, and under the action of the drug it increases, coming to normal level. An example of such actions is the stimulating effect of cholinomimetics under a bowel atony, which often occurs in postoperative period In operations on the abdominal organs.

b) exciting- The action of the medicinal substance begins against the background of a normal function and leads to strengthening the function of this organ or system.

An example is the effect of saline laxatives used often to purify the intestine before the operation on the abdominal organs.

in) sedative (soothing)action - a drug reduces an excessively increased function and leads to its normalization. Often used in neurological and psychiatric practice, there is special group drugs called "sedative means".

d) depressing action - The medicine begins to act against the background of a normal function and leads to a decrease in its activity. For example, sleeping pills weaken the functional activity of the CNS and allow the patient
Faster to fall asleep.
e) paralytic action - The medicine leads to a deep oppression of the function of the organ up to complete termination. An example is the action of drugs for anesthesia, which lead to a temporary paralysis of many CNS departments, except for several vital centers.

4. Depending on the method of the emergence of the pharmacological effect of the drug, they allocate:

but) direct action - The result of the immediate influence of the medication to the one, the body whose function it changes. An example is the action of cardiac glycosides, which, fixing in myocardial cells, influence exchange processes In the heart, which leads to a therapeutic effect in heart failure.

b) indirect action - The drug has an impact on a certain body, resulting in indirectly, indirectly changes the function of another organ. For example, cardiac glycosides, providing direct effect on the heart, indirectly facilitate the respiratory function by removing stagnant phenomena, increase the diuresis due to the intensification of the renal blood circulation, as a result of which shortness of breath, swelling, cyanosis disappear.

in) reflexary action - A drug, acting on certain receptors, launches the reflex changing the function of the organ or system. An example is the action of ammonic alcohol, which trimming states, irritating olfactory receptors, reflexively leads to stimulation of respiratory and vascular centers in the central nervous system and the restoration of consciousness. Mountains accelerate permission inflammatory process In the lungs due to the fact that the essential mustard oils, irritating the skin receptors, launch a system of reflex reactions leading to an increase in blood circulation in the lungs.

5. Depending on the area of \u200b\u200bthe pathological process, which is valid for the drug, the following types of action are distinguished, which are still called drug therapy species:

but) etiotropic therapy - The medicinal substance acts directly on the cause caused by the disease. A typical example is the effect of antimicrobial means infectious diseases. It would seem, the perfect case, but it is not quite so. Quite often, the immediate cause of the disease, having had a relevance, since the processes were launched, the flow of the disease is no longer monitored. For example, after an acute disturbance of the coronary blood circulation, it is necessary not to liquidate its cause (thrombus or an atherosclerotic plaque), how much to normalize metabolic processes in myocardium and restore the pump function of the heart. Therefore, in practical medicine is more often used

b) pathogenetic therapy - The medicinal substance affects the pathogenesis of the disease. This action may be deep enough, leading to curable patient. An example is the action of cardiac glycosides, which do not affect the cause, caused by heart failure (cardiodestrophia), but normalize metabolic processes in the heart in such a way that the symptoms of heart failure gradually disappear. Option pathogenetic therapy is substitution therapy, for example, sugar diabetes Insulin is appointed, which fills the lack of his own hormone.

in) symptomatic therapy - The medicinal substance affects certain symptoms of the disease, often without solving influence on the course of the disease. An example is the antitussive and antipyretic effect, removing the head or dental pain. However, symptomatic therapy may become pathogenetic. For example, the removal of severe pain in extensive injuries or burns warns the development of pain, removal of extremely high arterial pressure Warns the possibility of myocardial infarction or stroke.

6. From a clinical point of view, they allocate:

but) preferred action - The main therapeutic effect on which the doctor is calculated, assigning a certain drug. Unfortunately, simultaneously with him, as a rule, arises

b) side effect - This is an action of a medicine that is manifested simultaneously with the desired effect when it is appointed in therapeutic doses.
It is a consequence of a weak selectivity of drugs. For example, antitumor means It is created so that they are more actively influenced by intensively breeding cells. At the same time, acting on tumor growth, they also affect the intensively breeding sex cells and blood cells, resulting in the blood formation and ripening of genital cells.

7. In the depth of the effect of medication on organs and fabrics allocate:

but) overtime - The function of the organ under the action of the drug is changing temporarily, recovering when the drug is canceled. Most of the drugs act this way.

b) irreversible action - Strong interaction of medication and biological substrate. An example may be the inhibitory effect of phosphorodorganic compounds on the activity of cholinesterase associated with the formation of a very solid complex. As a result, the activity of the enzyme is restored only by the synthesis of new cholinesterase molecules in the liver.

There are local and resorbative effects of medicines. Under the "local" action (the relativity of the term should be emphasized) understand the complex of effects arising at the site of application pharmacological preparation. The sources are local, most ointments, creams, line, local anesthetics, etc.
Under the resorbative understand the effect of the pharmacological substance after its suction and admission to blood. So the most drugs are valid. The resorbative effect is directly due to the effect due to the direct effect of the substance on certain structures of this organ, and the indirect (indirect), when the effect of the medication on this body is mediated through other structures. For example, antihypertensive effect Papaverin is associated with direct action on the vessels, and the clonidine - with the influence of hypothalamic centers vascular regulation. At the same time, magnesium sulfate combines two components in the mechanism of action: the peripheral (mullropic) and the central (inhibits the substituent brain vessels).
Sometimes direct and indirect effects are opposite. For example, caffeine causes tachycardia due to direct stimulating action on the myocytes of the heart and bradycardia due to the central exciting effect on the wandering nerve. The ultimate effect of the drug will depend on the predominance of central or peripheral mechanisms in this patient.
One of the species indirect action is reflex. At the same time, when irritating the pharmacological substance of receptors (reflexogenic zones) in some organs, finite effects are recorded in others associated with the first complex reflex mechanisms. For example, n-cholinomimetics of cytioton, irritating receptors in the field of synolockarotide zone, contributes to the reflex excitation of the respiratory and vascular centers of the oblong brain. In case of irritation of the skin receptors, not only vessels of the skin are expanded with mustache or annoying ointments. internal organs, in particular, bronchi and lungs.
The effect of medicinal substances (LV) can be common (non-specific) or selective (specific). The general action says when the pharmacological agent has a non-specific influence on most organism organs and tissues (for example, anabolic preparations, biogenic stimulants). In the event that the drug has a specific effect on any strictly defined structures in the organs, we must talk about the electoral action. Thus, heart glycosides possess a selective action on the heart muscle, analeptics - to respiratory and vascular centers in the oblong brain. It is clear that this division is very conditional. After all, when they talk about the electoral action, they mean the main therapeutic effect and neglect other, less important effects. Therefore, it was proposed to talk about the preferential action of LV on those or other bodies and structures (Mashkovsky MD).
Sometimes it happens that the prevention of the action is determined by the accumulation of LV in certain bodies, but this is not always the case. For example, cardiac glycosides are accumulated in adrenal glands (more than 90%), practically no action on them, and small quantities, focused in myocardium, determine the therapeutic effect.
There are reversible and irreversible Action of LV. Under the reversible implies such an action when the functions of cells and tissues are restored after a certain time (local anesthetics, sleeping pills, antispasmodics, etc.). If the restoration of the function and structure of tissues does not occur, they are talking about an irreversible action (migrating, antitumor agents, radioactive isotopes, etc.) "It should be remembered that there are irreversible changes arising from the effect of toxic doses of almost all drugs.
The dimensions of the LV molecules vary from individual atoms (lithium ions) to large macromolecules (enzymes). However, most LVs have medium sizes (molecular weight from 100 to 1000 daltons). Among the LV there are all classes of organic compounds - carbohydrates, proteins, lipids, as well as various combinations of inorganic substances. Most LVs are salts or weak acids or bases.
The pharmacological effect is called the change in the function of cells, organs or systems of the body, which occurs under the influence of LV. In most cases, it is the result of the interaction of LV molecules with various receptors. This interaction is called primary pharmacological reaction. This reaction is the beginning of the formation of the general response of the body to the effects of LV, which is called the secondary pharmacological reaction. The whole process from the primary interaction of the LV with the target molecule (receptor) to the implementation of its effect on a holistic organisomic level includes many complex biochemical stages. In addition, the nature of the impact of the LV on the body is determined primarily by a number of factors from the LV itself: physical properties, a chemical structure, a dose of (concentration) of the drug, as well as its dosage form.
However, the primary pharmacological response can be changed in one direction or another due to any characteristics of the body and the external environment, in the conditions in which the action takes place this drug. Thus, the correct idea of \u200b\u200bthe pharmacological action of the drug can be made only with a comprehensive assessment of its interaction with the organism and the environment. We consider the appearance of the concept of "environmental pharmacology" timely appearance.
Pharmacodynamics of LV is largely due to its chemical structure - the presence of functionally active groups, shape and size of molecules.
Substances close to the chemical structure possess usually similar pharmacological properties. For example, various barbituric acid derivatives (barbiturates) cause oppression of the central nervous system and are used as hypnotic and anesthesia. But sometimes the substances similar in structure have fundamentally different pharmacological properties (for example, drugs of male and female sex hormones), and in some cases the same action is inherent in substances of various chemical structures (for example, morphine and commotol).
The identification of the dependence of the drugs from their structure is undoubted value for the targeted synthesis of new drugs. Synthesis of many drugs (for example, narcotic analgesics - commotol, fentanyl) was carried out by imitating (including complications or simplification) of the chemical structure of previously known medicinal substances of plant origin (morphine).
The specific effect of LV primarily depends on the nature and sequence of atoms in the molecule, the presence and position in it functionally active radicals.
Replacing only one atom in a pharmacologically active substance molecule can be accompanied by a significant change in activity. Thus, replacing both methyl groups in a novocainamide molecule on an isopropyl radical leads to a decrease in antiarrhythmic activity, and the replacement of one ethyl group onto a benzene ring significantly increases the antiarrhythmic effect. Dibenzdiazepine analogs of phenothiazine derivatives obtained during the transition from dialkylaminalkyl derivatives of dibenzdiazepine (tricyclic antidepressants) to dialkyl-minoscillee, deprived of antidepressive activity, but acquire antiarrhythmic and anti-anti-biological properties.
In some cases, the pharmacological activity of substances depends not only on the nature and sequence of atoms, but also on their spatial location in the molecule relative to each other, i.e. From spatial isomerism (stereoisomeria) molecules - optical, geometric and conformational.
For the interaction of pharmacological substances with cell membrane receptors, the spatial correspondence between the functional groups of the substance molecules and the functional groups of the macromolecule of the receptor, i.e. The presence of complementarity. The higher the degree of complementarity, the larger affinity has LV to the appropriate receptors and the greater may be its pharmacological activity and selectivity of action. This fact explains the various activity of stereoisomers of the same substance.
Thus, on the effect on the blood pressure, the left-hander isomer of adrenaline is significantly more active than the releger. These two compounds differ among themselves only by the spatial arrangement of the structural elements of the molecule, which turned out to be a decisive factor for their interaction with adrenoreceptors (Golikov S.N. Idr.).
The pharmacological activity of a number of compounds may not be so connected with the chemical structure. The degree of pharmacological activity of such substances with non-specific action (for example, sleeping pills and anesthesia) depends not so much from their ability to interact with certain receptors, but from the saturation of these cell compartments. Of course, the ability of these substances to saturate one or another part of the cell is due to the presence of appropriate physical properties (for example, hydrophilicity or hydrophobicity, which is quantitatively expressed in the oil / water distribution coefficient), and the latter are determined by the connection structure. However, in this case, pharmacological activity is determined not the sequence of atoms or their spatial location, but to a greater the ratio of hydrophilic and hydrophobic atomic groups.

Preference Nina Germanovna
Associate Professor of the Department of Pharmacology of the Pharmaceutical Faculty of the First MGMU. THEM. Sechenova, K. Farm.n.

The emergence of unwanted adverse reactions when using the drug contributes:

1. Incorrectly selected therapeutic dose, without taking into account the individual characteristics of the patient, its concomitant diseases, age, weight and growth.
2. Overdose of the drug due to violation of the dosing mode, cumulation or disease of the allocation bodies.
3. Long unreasonable treatment.
4. Sharp (sudden) cancellation of the drug, with exacerbation of the main or related disease.
5. Reception of medication without taking into account its interaction with other collaborated drugs.
6. Nutrition, incorrect lifestyle; Drug use, alcohol and smoking.

Main (main) action - this is the pharmacological activity of the drug for which it is used in clinical practice with prophylactic or therapeutic goal With a specific disease. For example, the main effect of clofelin is a hypotensive, for morphine characterized by an anesthetic effect, but-shpa - has antispasmodic effect. In acetylsalicylic acid, depending on the indication for use and dosing, two main actions are anti-inflammatory and anti-aggregative.

Depending on the path of administration and localization of pharmacological effects, other types of pharmacological action of drugs are manifested.

Resorbative action (Lat. Resorbere - absorption, absorption) develops after suction of medication into the blood, its distribution and admission to the body tissue. Drugs after suction are distributed in the tissues of the body and interact with the molecular target (receptor, enzyme, ion channel) or another substrate. As a result of this interaction, pharmacological effect arises / effects. So there are many medicines - " Snow pills"," Opioid and nonopoidal analgesics "," Antihypertensive LS "and others.

Local action It develops with direct contact of the medication with tissues of the body, for example, with leather, mucous membranes, with a wound surface. The local action also includes the reaction of tissues (subcutaneous tissue, muscles, etc.) on the injection of drugs. The local action develops most often when applying annoying, topless, binders, migrating and other drugs. Local action possess antacids - Almagel, Gevisson Forte, Maaloks, which neutralize hydrochloric acid, increase the pH of the stomach and reduce the activity of pepsin. Gastroprotectors - De NOL, VENTER, possessing a chelate action, create a protective film on the surface of the mucous membrane and protect the inner layer of the stomach cavity from aggressive damaging factors.

Many LS depending on the dosage form used (tablets, capsules, dragee, solutions and suspensions for internal application) And the route of administration has a resortive effect, whereas when using the same medicine in another dosage form (ointment, gel, line, eye drops) there is a local action. For example, nonteroidal anti-inflammatory drugs: Diclofenac is produced not only in tablets, a solution for the introduction, which cause a resorbative effect, but also for external use in the form of 1% Dicloran gel, 2% Ortophen ointments or diclofenac, in eye drops 0, 1% Diclo-F solution that provide local anti-inflammatory effect. When applying suppositories under the TN "Oil", "Diclovit" arises both local and resorbative effect. Another drug is "nimesulide" - is produced in the form of tablets (resorbative action) and gel for outdoor use under the TN "NAZ" (local action).

Drugs irritant Develop the effects both at the site of administration and at a distance. These effects are due to reflex reactions and show reflexary action. Sensitive nerve endings (interior) of mucous membranes, leather and subcutaneous formations are excited, pulses according to afferent nerve fibers reach the central nervous system, nerve cells are excited, and then on the efferent nerves, the action applies to the organ / organs or on the entire body. For example, when applying plant radiant, distracting drugs - "mustard pieces", gel "mustard forte" or "pepper plaster" and others. The reflex action can develop at a distance from the site of the initial contact of the medicinal substance with the tissues of the body, with the participation of all the links of the reflex arc. So act with ammonia (ammonia alcohol 10%) when fainting. When inhalation, the sensitive receptors of the nose shell are irritated, the excitation extends through the centripetal nerves and is transmitted to the central nervous system, the vasodent and respiratory centers of the oblong brain are excited. Next, pulses across centrifugal nerves reach light and vessels, ventilation in the lungs increase, the blood pressure increases and consciousness is restored. It should be remembered that large quantities of ammonia solution can cause unwanted reactions - a sharp gentle of heart cuts and a stop of breathing.

Depending on the mechanism of binding actors, active metabolites with receptors or other "targets", the effect of the drug may be direct, indirect (secondary), indirect, selective (selective), preferential or indiscriminate (non-selective).

Direct (primary) action Remote drugs directly affecting receptors. For example: adrenergic means(Adrenaline, salbutamol) directly stimulate adrenoreceptors, anti-adverergic (propranolol, atenolol, doxazosin) block these receptors and prevent the effects of norepinenaline mediator and other catecholamines circulating in the blood. The cholinergic agents (pylocarpine, aceclay) stimulate peripheral M-cholinoreceptors membranes of effector cells and cause the same effects as in the irritation of vegetative cholinergic nerves. Anticholinergic agents (atropine, pyrenspine, buckopan) block M-cholinoreceptors and prevent the interaction with them acetylcholine mediator.

Indirect (secondary)the action occurs when the drug changing the functions of one body affects another body. In patients suffering from heart failure, tissue swelling often arise. Cardiotonic agents, hearty glycosides of ingredients (digoxin, celainide) have primary effects, increasing the power of heart abbreviations and increasing cardiac output. Improving blood circulation in all organs and tissues, cardiac glycosides enhance the dismissal of the kidneys of the fluid from the body, which leads to a decrease in venous stagnation and removal of edema - these effects are secondary.

Indirect (indirect) action Arises as a result of the effects of medication on the "target" through secondary transmitters (messengers), indirectly forming a particular pharmacological effect. For example, a sympatholic "Reserpin" blocks vesicular capture of dopamine and norepinephrine. The admission of dopamine in vesicles (lat. Vesicular - bubble), a morphological element of synaps, filled with a mediator, is reduced. The synthesis of neurotransmitter - norepinephrine and its release from the presynaptic membrane is reduced. In postganglyonary sympathetic nerve endings, the depot of norepinephrine and the transfer of excitation from adrenergic nerves to effector cells is disturbed; There is a persistent decrease in blood pressure. Anticholinesterase products (Neostigmin Methylsulfate, Distigmin Bromide) Inhibit the enzyme acetylcholinesterase, preventing the enzymatic hydrolysis of the acetylcholine mediator. Endogenous acetylcholine is accumulated in cholinergic synapses, which significantly enhances and lengthens the effect of the mediator on muscarino-sensitive (M-), nico-sensitive (ν-) cholinoreceptors.

The effect of a substance that occurs in the place of its application is called local. For example, enveloping agents cover the mucous membrane, preventing the irritation of the endings of afferent nerves. With surface anesthesia, the application of a local anesthetic on the mucous membrane leads to the end of the endings of sensitive nerves only at the site of the preparation. However, truly local action is extremely rare, since substances can either partially absorb, or have a reflex effect.

The effect of substance evaluating after its suction, admission to the overall blood flow and then in tissue is called resorbative. The resorbative effect depends on the routes of administration of medicines and their ability to penetrate the biological barriers.

With local and resorbative action, drugs are either direct or reflex influence. The first is implemented at the site of direct contact of the substance with a cloth. In the reflex effect, the substance affects the exteroils of inter -ceptors and the effect is manifested by a change in the state or the corresponding nerve centers or executive bodies. Thus, the use of mustard pieces in the pathology of respiratory organs reflexively improves their trophy (the essential mustard oil stimulates skin exteroceptors). The drug Lobelin introduced intravenously has an exciting influence on the carotid glider chemoretoles and, reflexively stimulating the respiratory center, increases the volume and frequency of breathing.

The main task of pharmacodynamics is to find out where medicines are acting, causing those or other effects. Thanks to the improvement of methodological techniques, these issues are solved not only on the systemic and organ, but also on cellular, subcelet, molecular and submolecular levels. So, for neurotropic agents, those structures of the nervous system are established, whose synaptic formations have the highest sensitivity to these compounds. For substances affecting metabolism, the localization of enzymes is determined different fabrics, cells and subcelling formations whose activity varies particularly significant. In all cases, we are talking about those biological substrates, "targets", with which the drug substance interacts.

As "targets" for medicines, receptors, ion channels, enzymes, transport systems and genes are served.

The receptors are called the active groups of macromolecules of the substrates, with which the substance interacts. Receptors that ensure the manifestation of substances are called specific.

Principles of action of agonists on processes controlled by receptors. I is a direct impact on the permeability of ion channels (H-cholinoreceptors, gamka receptors); II is an indirect influence (via G-proteins) on the permeability of the ion channels or the activity of enzymes that regulate the formation of secondary transmitters (M-cholinoreceptors, adrenoreceptors); Iii - direct impact on the activity of the effector enzyme tyrosine kinase (insulin receptors, receptors of a number of growth factors); IV - Effect on DNA transcription (steroid hormones, thyroid hormones).

Allocate the following 4 types of receptors

I. Receptors carrying out direct control over the function of ion channels. This type of receptors directly conjugate with ion channels include n-cholinoreceptors, GABA and -receptors, glutamate receptors.

II. Receptors associated with the effector through the system "G-proteins are secondary transmitters" or "G-proteins-ion channels". Such receptors are available for many hormones and mediators (M-cholinoreceptors, adrenoreceptors).

III. Receptors carrying out direct control of the effector enzyme function. They are directly related to tyrosine kinase and regulate the phosphorylation of proteins. According to this principle, insulin receptors are arranged, a number of growth factors.

IV. Receptors controlling DNA transcription. In contrast to the membrane receptors of I-III types, these are intracellular receptors (soluble cytosol or nuclear proteins). Steroid and thyroid hormones interact with such receptors.

A very fruitful was the study of subtypes of receptors (Table II.1) and related effects. Among the first studies of this kind include the synthesis of many β-adrenoblockers, widely used in various diseases of the cardiovascular system. Then appeared Blockers histamine H 2 -receptors - effective means For treatment peptic disease Stomach and duodenum. Subsequently, many other drugs operating on different subtypes of A-adrenoreceptors, dopamine, opioid receptors, etc. were synthesized. These studies played a big role in creating new groups of selectively active medicinal substances that were widely used in medical practice.

Considering the effects of substances for postsynaptic receptors, it should be noted the possibility of alto-model binding of substances as an endogenous (for example, glycine) and an exogenous (for example, anxiolitics of a benzodiazepine series) of origin. Alosteric interaction with the receptor does not cause a "signal". However, the modulation of the main mediator effect, which can both be intensified and weakened. Creating substances of this type opens up new possibilities for regulating the functions of the CNS. The peculiarity of alumofulators of altowork is that they do not directly act on the main media transmission, but only modify it in the desired direction.

An important role for understanding the mechanisms of regulation of the synaptic transmission was played by the opening of the presynaptic receptors (Table II.2). The paths of homotropic auto regulation were studied (the effect of the mediator on the presynaptic receptors of the same nervous end) and heterotropic regulation (presynaptic regulation at the expense of another mediator) of the release of mediators, which allowed to evaluate the features of many substances in a new way. This information also served as the basis for a targeted search for a number of drugs (for example, prazosin).

Table II.1 Examples of some receptors and their subtypes

Receptors	Subtyps
Adenosine receptors	A 1, A 2A, A 2B, A 3
α 1 -adrenoreceptors	α 1a, α 1b, α 1c
α 2 -adrenoreceptors	α 2a, α 2b, α 2c
β-adrenoreceptors	β 1, β 2, β 3
Angiotensin receptors	AT 1, AT 2
Bradykinin receptors	B 1, b 2
GAMK receptors	GABA A, GABA B, GABA C
Histamine receptors	H 1, H 2, H 3, H 4
Dopamic receptors	D 1, d 2, d 3, d 4, d 5
Lakeotrien receptors	LTB 4, LTC 4, Ltd 4
M-cholinoreceptors	M 1, m 2, m 3, m 4
N-cholinoreceptors	Muscular type, neural type
Opioid receptors	µ, δ, κ
Prostanoid receptors	DP, FP, IP, TP, EP 1, EP 2, EP 3
Purine receptors R.	P 2x, p 2y, p 2z, p 2t, p 2u
Receptors exciting amino acids (ionotropic)	NMDA, AMPA, Caenage
Yehipeptide receptors Y.	Y 1, Y 2
Preceptors atrial sodium-ethical peptide	Anpa, Anpb.
Serotonin receptors	5-HT 1 (A-F), 5-HT 2 (A-C), 5-HT 3, 5-HT 4, 5-HT 5 (A-B), 5-HT 6, 5-HT 7
Cholecystokinin receptors	CCK A, CCK B

Table II.2. Examples of the presynaptic regulation of the release of mediators of cholinergic and adrenergic endings

The affinity of the substance to the receptor, leading to the formation of a complex "Substance-receptor" complex, is indicated by the term "affinity". The ability of the substance when interacting with the receptor to stimulate it and cause one or another effect is called internal activity.

Substances that, when interacting with specific receptors, cause changes in them leading to the biological effect, are called agonists (they have internal activity). The stimulating effect of agonist on receptors can lead to activation or inhibition of the cell function. If the agonist, interacting with the receptors, causes the maximum effect, is called a complete agonist. Unlike the latter, partial agonists when interacting with the same receptors do not cause the maximum effect. Substances binding to receptors, but not causing their stimulation, are called antagonists. Internal activity they are missing (equal to 0). Them pharmacological effects Conducted by antagonism with endogenous ligands (mediators, hormones), as well as with exogenous agonist substances.

If they occupy the same receptors with which the agonists interact, then we are talking about competitive antagonistsif there are other sections of macromolecules that are not related to a specific receptor, but interrelated with it, something about non-competitive antagonists. Under the action of the substance as an agonist on one subtype of receptors and as an antagonist - to another, it is denoted by an antagonist agonist. For example, analgesic pentazocine is an antagonist μ- and agonist Δ- and κ-opioid receptors.

Allocate so-called not specific receptors not related functionally specific. These include blood plasma proteins, mucopolysaccharides connective tissue et al., with which substances are binding without causing any effects. Such receptors are sometimes called "silent" or designate as "loss sites" of substances. However, receptors are advisable to call only specific receptors; Non-specific receptors are more correctly denoted as non-specific binding sites.

The interaction "Substance-receptor" is carried out at the expense of intermolecular connections. One of the species of the most durable connection is covalent. It is known for a small number of drugs (α-adrenoblocator phenoxybenzamine, some antoblast substances). A less resistant is a common ion connection, carried out by electrostatic interaction of substances with receptors. The last typical for gangliplockers, strip-like products, acetylcholine. Van der Waals are an important role that constitutes the basis of hydrophobic interactions, as well as hydrogen bonds (Table II.Z).

Table II.3. Types of interaction of substances with receptor

1 Means the interaction of non-polar molecules in the aquatic environment

* 0,7 kcal (3 kJ) per ch 2-group

Depending on the strength of the connection, the substance-receptor is distinguished by a reversible effect (characteristic of most substances) and irreversible (as a rule, in the case of a covalent bond).

If the substance interacts only with functionally unambiguous receptors of a certain localization and does not affect other receptors, the effect of such a substance is considered selective. Thus, some strip-like drugs are pretty selectively blocking the cholinoreceptors of the terminal plates, causing relaxation of skeletal muscles. In doses that provide a myoparalytic effect on other receptors, they affect little.

The basis of the election of action is affinity (affinity) of the substance to the receptor. This is due to the presence of certain functional groups, as well as the general structural organization of the substance, most adequate to interact with this receptor, i.e. their complementarity. Often, the term "selective action" is replaced with a complete basis with a term "predominant action", since the absolute selectivity of the substances practically does not exist.

Assessing the interaction of substances with membrane receptors transmitting a signal from the outer surface of the membrane to the internal, it is necessary to take into account those intermediate links that bind the receptor with the effector. The most important components of this system are G-proteins, a group of enzymes (adenylate cyclase, guanillatesciclase, phospholipase C) and secondary transmitters (CAMF, CGMF, IF 3, DAG, CA 2+). The increase in the formation of secondary transmitters leads to the activation of proteinkins, which provide intracellular phosphorylation of important regulatory proteins and the development of various effects.

Most of the links of this complex cascade can be a point of application of pharmacological substances. However, so far such examples are quite limited. So, in relation to G-proteins, only toxins are known, which are associated with them. The cholera vibrio toxin interacts with G S, and with G i-belt - toxin flop pertussis.

There are separate substances that have a direct impact on enzymes involved in the regulation of biosynthesis of secondary transmitters. Thus, the Diterpen of plant origin Forskolin, used in experimental studies, stimulates adenylate cyclase (direct action). Phosphodiesterase inhibit methylxantins. In both cases, the CAMF concentration inside the cell increases.

One of the important "targets" for the action of substances is ion channels. Progress in this area is largely associated with the development of methods for registering the function of individual ion channels. This stimulated not only fundamental studies on the study of the kinetics of ion processes, but also contributed to the creation of new drugs regulating ionic currents (Table II.4).

Already in the late 50s, it was found that local anesthetics block potential-dependent NA + -Kanals. Many antiarrhythmic agents are also included to the number of blockers NA + -Kanalov. In addition, it was shown that a number of anti-epileptic agents (diphenin, carbamazepine) also block potential-dependent NA + -Kanals and with this, apparently, their anticonvulsant activity is associated.

In the past 30 years, great attention was paid to C C 2+ blocks - channels that violates the occurrence of Ca 2+ ions inside the cells through potential-dependent Ca 2+ - channels. Increased interest in this group of substances is largely due to the fact that SA 2+ ions take part in many physiological processes: muscle contraction, secretory cell activity, neuromuscular transmission, platelet functions, etc.

Many drugs of this group were very effective in the treatment of so common diseases such as angina, heart arrhythmias, arterial hypertension. Wide recognition was obtained by drugs such as Verapamil, Diltiazem, Penigidine and many others.

Table II.4. Means affecting ion channels

Ligands Na + -Kanalov Na + -Kanalov blockers Local anesthetics (Lidocaine, Novocaine) Anticharmal agents (County, Novocainamide, etmsin) Activators Na + -Kanalov Veratridine (alkaloid, hypotensive action)

Ligands CA 2+ - Kanalov CA 2+ Blockers - Channels Antianginal, antiarrhythmic and antihypertensive agents (verapamil, phenygidine, diltiazem) Activators CA 2+ - channels Wow to 8644 (dihydropyridine, cardiotonic and vasoconductive action)

Ligands K + -Kanalov Blockers K + -Kanalov Means facilitating neuromuscular transmission (pymadine) Anti-diabetic agents (Butamide, Glyibenklamide) Activators K + -Kanalov Antihypertensive means (minoxidil, diazoxide)

Attract Ca 2+ activators - channels, such as dihydropyridine derivatives. Such substances can be used as cardiotonics, vasoconstrictor agents, substances that stimulate the release of hormones and mediators, as well as stimulants of the CNS. So far such drugs for medical application No, but the prospects for their creation are quite real.

Of particular interest is the search for blockers and activators of Ca 2+ - channels with a predominant effect on the heart, vessels of different areas (brain, heart, etc.), CNS. There are certain prerequisites for this, since heterogeneous sa 2+ channels.

In recent years, many attention is attracted to substances that regulate the function K + -Kanalov. It is shown that the potassium channels are very diverse in its functional characteristic. On the one hand, this is significantly difficult to pharmacological studies, and on the other, it creates real prerequisites for the search for selectively actants. Known both activators and blockers of potassium channels.

Activators of potassium channels contribute to the opening and output of ions to + from the cell. If this happens in smooth muscles, it develops hyperpolarization of the membrane and muscle tone decreases. Thanks to this mechanism, minoxidil and diazoxide used as hypotensive drugs.

Blockers of potential-dependent potassium channels are of interest as antiarrhythmic drugs. By blocking influence on the potassium channels, seems to have amiodar, ornid, sotalol.

Blockers of ATP-dependent potassium channels in the pancreas increase the secretion of insulin. According to this principle, antidiabetic means of a group of sulfonylurea (chloropropamide, butamide, etc.) are operating.

The stimulating effect of aminopyridines on the CNS and neuromuscular transmission also bind to their blocking effect on the potassium channels.

Thus, the impact on ion channels underlies the action of various drugs.

An important "target" for the action of substances is enzymes. Previously, the possibility of influencing enzymes regulating the formation of secondary transmitters (for example, CAMF) was noted. It has been established that the mechanism of the action of non-steroidal anti-inflammatory means is due to the inhibition of cyclooxygenase and a decrease in prostaglandin biosynthesis. As hypotensive drugs, inhibitors of angiotensin glittering enzyme (captopril, etc.) are used. Anticholinesterase drugs are well known, blocking acetylcholinesterase and stabilizing acetylcholine.

Antoblast Methotrexat (antagonist folic acid) Blocks dihydrofolatide, preventing the formation of tetrahydrofolate necessary for the synthesis of purine nucleotide - thymidilate. Anticheartic preparation acyclovir, turning into aciclovitriphosphate, inhibits viral DNA polymerase.

Another possible "target" for the action of medicines is transport systems for polar molecules, ions, small hydrophilic molecules. These include the so-called transport proteins that carry substances through the cell membrane. They have recognizing areas for endogenous substances that can interact with medicines. Thus, tricyclic antidepressants block the neuronal grip of norepinephrine. The reserpine blocks the deposit of norepinephrine in vesicles. One of the significant achievements is the creation of proton pump inhibitors in the gastric mucosa (omeprazole, etc.), which showed high efficiency With the ulcer of the stomach and duodenal sector, as well as with hyperacid gastritis.

Recently, in connection with the decoding of the human genome, intensive studies are conducted due to the use of as a target. genes. Undoubtedly gene therapy It is one of the most important directions of modern and future pharmacology. The idea of \u200b\u200bsuch therapy is to regulate the functions of genes, the etiopathogenetic role of which is proved. The basic principles of gene therapy are reduced to an increase, decrease or shutting down the expression of genes, as well as to replace the mutant gene.

The solution of these tasks was real due to the possibility of cloning chains with a given sequence of nucleotides. The introduction of such modified chains is aimed at normalizing the synthesis of proteins that determine the pathology, and, accordingly, to restore the disturbed function of cells.

Central problem In the successful development of gene therapy is the delivery of nucleic acids to target cells. Nucleic acids should get from the extracellular plasma spaces, and then, passing through the cell membranes, penetrate the kernel and incorporate in chromosome. As conveyors, or vectors, it is proposed to use some viruses (for example, retroviruses, adenoviruses). At the same time, with the help of genetic engineering, the vectors are deprived of the ability to replicate, i.e. Of these, there are no formation of new virions. Other transport systems are also proposed - DNA complexes with liposomes, proteins, plasmid DNA and other microparticles and microspheres.

Naturally, the incorporated gene should function quite a long time, i.e. Expression of the gene must be resistant.

Potential opportunities for gene therapy Concerning many hereditary diseases. These include immunodeficientifications, some types of liver pathology (including hemophilia), hemoglobinopathy, lung diseases (for example, cystic fibrosis), muscle tissue (muscle dystrophy of Durane), etc.

Studies are unfolded by a wide front to clarify the potential paths of using gene therapy for the treatment of tumor diseases. These capabilities are to block the expression of oncogenic proteins; in the activation of genes capable of suppressing the growth of tumors; in stimulating the formation in tumors of special enzymes that convert the prodrug to toxic only for tumor cell tumor cells; Enhance the stability of cells bone marrow to the oppressive action of antiblastomy agents; increase immunity against cancer cells, etc.

In cases where the need arises to block the expression of certain genes, use the special technology of the so-called antisense (antisensive) oligonucleotides. The latter are relatively short chains of nucleotides (out of 15-25 bases), which are complementary by the zone of nucleic acids, where the target gene is located. As a result of interaction with the antisense oligonucleotide, the expression of this gene is suppressed. This principle of action is of interest in the treatment of viral, tumor and other diseases. The first drug was created from the group of antisense nucleotides - vitrasens (phomivirzene), applied locally with retrieves, caused by cytomegalovirus infection. Preparations of this type appeared for the treatment of myeloid leukemia and other blood diseases. They pass clinical trials.

Currently, the problem of using genes as targets for pharmacological impact is mainly in the stage of fundamental studies. Only single promising substances of this type are undergoing preclinical and initial clinical trials. However, it does not have to doubt that in this age there will be many effective means for gene therapy not only inherited, but also acquired diseases. It will be fundamentally new drugs for the treatment of tumors, viral diseases, immunodeficiency states, bleeding disorders and blood coagulation, atherosclerosis, etc.

Thus, the possibilities for the directional effects of medicines are very diverse.