Directly dependent on the dose. Dependence of the effect of drugs on the prescribed dose
The monograph substantiates the position that there are not only treatment methods based on the effect of drugs, but also treatment principles that use the body's response to these effects.
V.V. Korpachev, Doctor of Medical Sciences, Professor, Head of the Department of Pharmacotherapy of Endocrine Diseases, Institute of Endocrinology and Metabolism named after. V.P. Komissarenko AMS of Ukraine
This material is one of the chapters of the book “Fundamental principles of homeopathic pharmacotherapy” (Kyiv, “Chetverta Khvilya”, 2005), the author of which is Doctor of Medical Sciences, Professor Vadim Valerievich Korpachev.
Various fundamental approaches to treatment can significantly expand the capabilities of medicine and make it possible to achieve success where the use of drugs based on generally accepted treatment principles will not be effective enough. The book is intended for doctors, clinical pharmacologists, pharmacists and specialists who are interested in philosophical problems of medicine and pharmacotherapy.
The patterns of manifestation of medicinal properties depending on the dose, as well as on the phase of action, are one of the most important issues in pharmacology, pharmacotherapy, and possibly all of medicine. Knowledge of these patterns can significantly expand the possibilities of treating many diseases, making it more targeted and physiological. The dependence of the strength of a drug on its dose has always attracted the attention of doctors. Even Ibn Sina in the second book of the “Canon” wrote: “If ten people carry a load over a distance of one fars in one day, it does not follow that five people can carry it over any distance, much less over a distance of half-farsakh. It also does not follow from this that half of this burden can be separated so that these five, having received it separately, can carry it... Therefore, not every time the mass of the medicine decreases and its strength decreases, you see that its effect is greater. becomes smaller the same number of times. It is also not at all necessary that the medicine itself should have an effect corresponding to its small magnitude on something that is susceptible to the influence of a large amount of the medicine.”
At the dawn of the development of medicine, it was found that as the dose increases, the strength of the medicine also increases. Now this is known not only to pharmacologists, but also to every clinician. But to what extent does this increase occur? And is there any regularity at all, that is, is an increase in the dose in certain respects accompanied by the same correct increase in the strength of its action, or is everything different?
After conducting a series of studies on the red blood cells of aquarium fish with certain drugs, researcher Jacouffe, back in the last century, derived a law that stated that the increase in the strength of the poison is not proportional to the increase in dose - it goes much faster than the latter. He found that with a doubling of the dose, the strength of action increases not twice, but by 11, 14, 15, 30, 50 times. But when in the laboratory of N.P. Kravkova, his employee A.M. Lagovsky conducted research on an isolated heart with alkaloids, this was not confirmed. In his dissertation for the degree of Doctor of Medicine, “On the dependence of the potency of poisons on the dose,” defended in 1911, he demonstrated that in most cases the potency of the test substance is proportional to its dose.
And yet, later researchers confirmed Jacuff’s findings. It was found that the disproportionality is more pronounced at low doses than at large ones.
It has been empirically established that each drug has a minimum dose, below which it is no longer effective. This minimum dose varies from product to drug. As the dose increases, a simple increase in effect occurs, or toxic effects alternately occur in different organs. For therapeutic purposes, the first action is usually used. There are three types of doses: small, medium and large. Therapeutic doses are followed by toxic and fatal ones, which threaten life or even interrupt it. For many substances, the toxic and lethal doses are much higher than the therapeutic ones, but for some they differ from the latter very slightly. In order to prevent poisoning, therapeutic guidelines and textbooks on pharmacology indicate the highest single and daily doses. The saying of Paracelsus “Everything is poison, and nothing is without poison; just one dose makes the poison invisible” was confirmed in practice. Many poisons have found use in modern medicine when used in non-toxic doses. An example is the poisons of bees and snakes. Even chemical warfare agents can be used for medicinal purposes. The chemical warfare agent mustard gas (dichlorodiethyl sulfide) is known, the toxic properties of which were experienced by the famous chemist N. Zelinsky, who was one of the first to synthesize it. Today, nitrogen mustards are highly effective antitumor drugs.
The pharmacological response varies differently depending on the properties of the drug substance (Fig. 1). If it enhances function in small doses, increasing the dose may cause a reverse effect, which will be a manifestation of its toxic properties. When a pharmacological drug reduces function in low doses, increasing the dose deepens this effect to the point of toxicity.
In 1887, the first part of this pattern was formulated as the Arndt-Schultz rule, according to which “small doses of medicinal substances excite, medium doses enhance, large doses inhibit, and very large doses paralyze the activity of living elements.” This rule does not apply to all medicinal substances. The range of all doses for the same drug is also quite wide. Therefore, many researchers most often studied the patterns of the dose-response indicator in a certain range of doses, most often in the field of therapeutic or toxic.
Three patterns can be distinguished:
- the strength of action increases in proportion to the increase in dose, for example, with fatty anesthetics (chloroform, ether, alcohols);
- an increase in pharmacological activity is observed with a slight increase in the initial threshold concentrations, and a further increase in dose causes only a slight increase in the effect (this pattern, for example, is exhibited by morphine, pilocarpine and histamine);
- As the dose increases, the pharmacological effect initially increases slightly and then becomes stronger.
These patterns are depicted in Figure 2. As can be seen from the curves shown there, the pharmacological response does not always increase in proportion to the dose. In some cases, the effect increases to a greater or lesser extent. The S-shaped curve is most common in studies of toxic and lethal doses, but is rare in the therapeutic dose range. It should be noted that the curves shown in Figure 2 are part of the graph shown in Figure 1.
Soviet pharmacologist A.N. Kudrin proved the existence of a step-like dependence of the pharmacological effect on the dose, when the transition from one reaction value to another sometimes occurs abruptly, and sometimes gradually. This pattern is typical for therapeutic doses.
The effects caused by the administration of toxic doses depend not only on the size of the dose itself or the concentration of the substance, but also on the time of its exposure. Based on the analysis of various relationships between concentration and time, all poisons were divided into two groups: chronoconcentration and concentration. The effect of the latter depends on their concentration and is not determined by the time of action (these are volatile drugs and local anesthetics - cocaine, curare). The toxic effect of chronoconcentration poisons significantly depends on the time of their action. These include substances that affect metabolism and some enzyme systems.
Based on experimental data, it was possible to significantly expand the range of doses used.
There are these types of doses:
- subthreshold – does not cause a physiological effect according to the selected indicator;
- threshold – causing initial manifestations of physiological action according to the recorded indicator;
- therapeutic – the range of doses that cause a therapeutic effect in experimental therapy;
- toxic – causing poisoning (severe disruption of the functions and structure of the body);
- maximum tolerated (tolerant) (DMT) – causing poisoning without fatalities;
- effective (ED) – causing a programmable effect in a certain (specified) percentage of cases;
- LD50 – causing death in 50% of experimental animals;
- LD100 – causing death in 100% of experimental animals.
It is known that the same substances may have no effect on a healthy organism or organ and, on the contrary, exhibit a pronounced physiological effect in relation to the patient. For example, a healthy heart does not react as much to digitalis as a diseased one. Small doses of some hormonal substances have a pronounced effect on a sick body, without showing activity on a healthy one.
This phenomenon can probably be explained based on the teachings of N.E. Vvedensky: under the influence of various external stimuli, a state occurs when biological objects respond to a small stimulus with an increased reaction (paradoxical phase). A similar pattern was observed not only under the action of physical factors, but also with many medicinal substances. The paradoxical phase is also characterized by a significant decrease in the ability to respond to stronger influences. In the mechanism of action of drugs, this phenomenon is also likely to have important practical significance.
At the end of the last century, German pharmacologists G. Nothnagel and M. Rossbach wrote in their “Guide to Pharmacology” (1885) that in a curarized state, in some stages of poisoning, with the slightest touch of the skin, for example, by lightly running a finger over it, by blowing on it mouth, there was a prolonged increase in blood pressure; but the strongest painful interventions in the same places (cauterization with mustard alcohol, concentrated acids, hot iron, etc.) did not have the slightest effect on blood pressure - moreover, occasionally even a decrease in pressure was observed. They also noted that in healthy, unpoisoned animals, neither mild tactile stimulation of the skin nor even the most severe painful interventions affected blood pressure; neither electrical, nor chemical or “caustic” stimulation produced the expected effects.
So, increasing the dose of a drug enhances its pharmacological effect in the range of both therapeutic and toxic doses. If a drug stimulates function, then in the range of toxic doses the opposite effect is observed - inhibition. Against the background of altered reactivity of the body, perverted reactions to the administration of small and large doses of medicinal substances may be observed.
But not only the dose size determines the pharmacological effect. It turned out that the drug exhibits an ambiguous effect - inhibition of function or enhancement of it, it causes a pharmacological reaction, which over time consists of several phases. The concept of the phases of action of drugs was formulated at the beginning of the century, when the effect of muscarine on the isolated heart was studied. After immersing the heart in a muscarine solution, it first stopped in the relaxation phase (diastole), and then began to contract again. After washing in a pure nutrient medium (when the tissue was washed away from the poison), a secondary weakening of cardiac activity was noted. The researchers concluded that the moment the poison is released is also a pharmacologically active phase.
Subsequently, it was proven that a similar reaction is also observed when exposed to other substances (pilocarpine, arecoline, adrenaline) and other isolated organs.
In 1911 N.P. Kravkov wrote that just as when studying the effect of electric current on a nerve one has to take into account the moment of its closing and opening, so when studying the effect of poison it is necessary to take into account not only the moment of its entry into the tissues and their saturation, but also the exit from them . In the laboratory of N.P. Kravkova later found that the substance under study does not always give the same effect in the “entry phase” and in the “exit phase.” For example, veratrine and strychnine constrict the vessels of the isolated rabbit ear in the “entry phase” and dilate in the “exit phase.” Alcohol constricts blood vessels in the “entry phase” and dilates them in the “exit phase.” With unambiguous action in both phases, the effect in the “exit phase” was often significantly higher. In one of his works, Kravkov wrote that when studying the effect of any poison, one should distinguish between the phase of its entry into tissues, the phase of saturation of tissues (or stay in them) and, finally, the phase of exit from them. Note that these results were obtained on isolated organs and, therefore, cannot be completely transferred to the whole organism. At present, it is difficult to answer whether such patterns will appear, for example, when the body is saturated with any pharmacological drug. Kravkov's hypothesis has only historical significance.
To be continued in the next issues.
Drugs can affect the body differently depending on its functional state. As a rule, stimulant-type substances exhibit their effect more strongly when they inhibit the functions of the organ on which they act, and, conversely, inhibitory substances act more strongly against the background of excitement.
The effect of drugs may vary depending on pathological condition body. Some pharmacological substances exhibit their effects only under pathological conditions. Thus, antipyretic substances (for example, acetylsalicylic acid) lower body temperature only if it increases; Cardiac glycosides clearly stimulate cardiac activity only in heart failure.
Pathological conditions of the body can change the effect of drugs: enhance (for example, the effect of barbiturates in liver diseases) or, conversely, weaken (for example, local anesthetic substances in conditions of tissue inflammation reduce their activity).
12. The concept of dose and concentration. Types, expressions and dose designations. Dependence of drug action on dose and concentration. The breadth of therapeutic action of medicinal substances, its significance.
Drug dose is the amount of medication required to provide a therapeutic, prophylactic or diagnostic effect.
Types of doses - therapeutic, prophylactic, diagnostic; minimum, average, maximum; one-time, daily, course; toxic and lethal (in case of drug poisoning).
Drug concentration is the amount of drug per unit volume.
Expression and designation of doses.
The units for measuring drug doses are:
- 1 gram (if the medicine is dosed by weight);
- 1 ml (if dosed by volume);
- Measurement in drops
- ED (if the activity of the drug is established on biological objects)
Dependence of drug action on dose and concentration.
It has been empirically established that each drug has a minimum dose, below which it is no longer effective. This minimum dose varies from product to drug. As the dose increases, a simple increase in effect occurs, or toxic effects alternately occur in different organs. The pharmacological response varies differently depending on the properties of the drug. If it increases function in small doses, increasing the dose may cause the opposite effect, which will be a manifestation of its toxic properties. When a pharmacological drug reduces function in low doses, increasing the dose deepens this effect to the point of toxicity. The effects caused by the administration of toxic doses depend not only on the size of the dose itself or the concentration of the substance, but also on the time of its exposure . Based on the analysis of various relationships between concentration and time, all poisons were divided into two groups: chronoconcentration and concentration. The effect of the latter depends on their concentration and is not determined by the time of action (these are volatile drugs and local anesthetics - cocaine, curare). The toxic effect of chronoconcentration poisons significantly depends on the time of their action. These include substances that affect metabolism and some enzyme systems. Under the influence of various external stimuli, a state occurs when biological objects respond to a small stimulus with an increased reaction (paradoxical phase). increasing the dose of a drug enhances its pharmacological effect in the range of both therapeutic and toxic doses. If a drug stimulates function, then in the range of toxic doses the opposite effect is observed - inhibition. Against the background of altered reactivity of the body, perverted reactions to the administration of small and large doses of medicinal substances may be observed.
The breadth of therapeutic action is the range of doses of a drug from the minimum effective to the minimum toxic dose. This interval can also be considered as the range of acceptable levels of a substance in plasma in which a therapeutic effect is observed. The minimum level of a substance in plasma that provides the required effect is the lower limit of the therapeutic range, and its maximum limit is the level at which toxic effects occur.
13. The concept of pharmacodynamics, pharmacokinetics, pharmacogenetics. Types of action of medicinal substances: local, reflex,
14. resorptive, main and secondary, direct and indirect (mediated), reversible and irreversible, selective (elective), etiotropic.
Pharmacodynamics – changes in the functions of cells, organs, and tissues of the body in response to the administration of a drug. It examines the mechanism, nature and type of action of the drug.
Pharmacokinetics – a set of processes leading to the creation in an organism, tissue, organ, cell, of a drug concentration sufficient to form a complex with a biosubstrate. (Absorption, distribution, transformation, and release of a drug)
Pharmacogenetics - a section of medical genetics and pharmacology that studies the nature of the body’s reactions to drugs depending on hereditary factors.
Local action of the drug. things - the action of a thing that occurs at the place of its application. For example, enveloping materials cover the mucous membrane, preventing irritation of the endings of afferent nerves. With superficial anesthesia, application of an anesthetic to the mucous membrane leads to a block of sensory nerve endings only at the site of application of the drug.
Reflex – substances affect extero- or interoceptors and the effect is manifested by a change in the state of either the corresponding nerve centers or executive organs. (The use of mustard plasters for pathologies of the respiratory organs reflexively improves their trophism)
Resorptive – the action of a substance that develops after its absorption, entry into the general bloodstream and then into the tissues. Depends on the route of administration. Weds and their ability to penetrate biological barriers.
Main action(main) - the effect of the medicine that is expected when using it in this particular case
All other effects are called side effects. Not all side effects are unwanted. For example, diphenhydramine can be used by patients as a sleeping pill, because side effect - depression of the central nervous system, drowsiness.
Direct action - is implemented at the site of direct contact of the substance with the tissue. Its consequence is indirect effects. For example, cardiac glycosides have a direct cardiac stimulating effect. At the same time, they improve hemodynamics in patients with heart failure, reduce congestion in tissues, increase diuresis, etc. These are indirect effects.
Reversible action- disappears after a certain time, which is explained by the dissociation of the drug-substrate complex.
Irreversible action - if such a complex does not dissociate, i.e. It is based on a covalent bond.
Selective action - the substance interacts only with functionally unambiguous receptors of a certain location and does not affect other receptors. It is based on complementarity between the structural organization of the substance and the receptor.
15. Mechanisms of action of drugs: chemical, physical, cytoreceptor, effect on ion channels and biologically active substances, competitive, enzymatic, etc. The concept of agonists and antagonists, agonists-antagonists.
To reproduce the pharmacological effect, the drug must interact with the molecules of the body's cells. The connection of drugs with a biological substrate-ligand can be achieved through chemical, physical, physicochemical interaction.
Special cellular structures that ensure interaction between a drug and the body are called receptors.
Receptors are functionally active macromolecules or their fragments (mainly protein molecules - lipoproteins, glycoproteins, nucleoproteins), which are targets for endogenous ligands (mediators, hormones, other biologically active substances). Receptors that interact with certain drugs are called specific.
Receptors can be located in the cell membrane (membrane receptors), inside the cell - in the cytoplasm or in the nucleus (intracellular receptors). There are 4 known types of receptors, 3 of which are membrane receptors:
receptors directly coupled to enzymes;
receptors directly coupled to ion channels;
receptors that interact with G proteins;
receptors that regulate DNA transcription.
When drug compounds interact with a receptor, numerous effects occur, with biochemical and physiological changes occurring in many organs and systems, which can be represented as typical mechanisms of interaction between drugs and receptors.
The interaction between the substance and the receptor is carried out due to the formation of intermolecular bonds of various types: hydrogen, van der Waals, ionic, less often covalent, which are especially strong. Medicines bound by this type exhibit irreversible effects. An example is acetylsalicylic acid, which irreversibly inhibits platelet cyclooxygenase, which makes it highly effective as an antiplatelet agent, but at the same time it becomes more dangerous regarding the development of gastric bleeding. Other types of intermolecular bonds disintegrate after a certain time, which determines the reversible effect of most drugs.
The drug, having a structure close to the metabolite (mediator), interacts with the receptor, causing its stimulation (simulating the action of the mediator). The drug is called an agonist. The ability of a drug to bind to certain receptors is determined by their structure and is designated by the term “affinity”. The quantitative measure of affinity is the dissociation constant (K0).
A drug that is similar in structure to the metabolite but prevents it from binding to the receptor is called an antagonist. If an antagonist drug binds to the same receptors as endogenous ligands, they are called competitive antagonists; if they bind to other sites on macromolecules that are functionally associated with the receptor, they are called non-competitive antagonists. Medicines (by acting on receptors) can combine the properties of agonists and antagonists. In this case, they are called agonist-antagonists, or synergistic antagonists. An example is the narcotic analgesic pentazoiin, which acts as a δ-agonist and κ-opioid receptors and an antagonist of μ-receptors. If a substance affects only a specific receptor subtype, it exhibits a selective effect. In particular, the antihypertensive drug prazosin selectively blocks α1-adrenergic receptors, in contrast to the α1 and α2-adrenergic blocker phentolamine.
When interacting with the allosteric center of the receptor, drugs cause conformational changes in the structure of the receptor, including activity towards body metabolites - a modulating effect (tranquilizers, benzodiazepine derivatives). The effect of the drug can be realized due to the release of metabolites from bonds with protein or other substrates.
Some drugs increase or inhibit the activity of specific enzymes. For example, galantamine and proserine reduce the activity of cholinesterase, which destroys acetylcholine, and cause effects characteristic of excitation of the parasympathetic nervous system. Monoamine oxidase inhibitors (pyrasidol, nialamide), which prevent the destruction of adrenaline, increase the activity of the sympathetic nervous system. Phenobarbital and ziscorine, by increasing the activity of liver glucoronyltransferase, reduce the level of bilirubin in the blood. Medicines can inhibit the activity of folic acid reductase, kinases, angiotensin-converting enzyme, plasmin, kalikriin, nitric oxide synthetase, etc. and thereby change the biochemical processes dependent on them.
A number of medicinal substances exhibit a physical and chemical effect on cell membranes. The activity of cells of the nervous and muscular systems depends on ion flows that determine the transmembrane electrical potential. Some drugs alter ion transport. This is how antiarrhythmic, anticonvulsant drugs, general anesthesia, and local anesthetics work. A number of drugs from the group of calcium channel blockers (calcium antagonists) are widely used to treat arterial hypertension, coronary heart disease (nifedipine, amlodipine) and cardiac arrhythmias (diltiazem, verapamil).
Blockers of voltage-gated K+ channels - amiodarone, ornid, sotalol - have an effective antiarrhythmic effect. Sulfonylurea derivatives - glibenclamide (manninil), glimepiride samaril block ATP-dependent K+ channels, and therefore stimulate insulin secretion by pancreatic β-cells and are used to treat diabetes mellitus.
Drugs can directly interact with small molecules or ions inside cells and cause direct chemical interactions. For example, ethylenediaminetetraacetic acid (EDTA) strongly binds lead and other heavy metal ions. The principle of direct chemical interaction underlies the use of many antidotes for poisoning by chemical substances. Another example is the neutralization of hydrochloric acid with antacids. Physico-chemical interaction is observed between heparin and its antagonist protamine sulfate, which is based on the difference in the charges of their molecules (negative for heparin and positive for protamine sulfate).
Some drugs are able to be involved in metabolic processes in the body due to the proximity of their structure to the structure of natural metabolites. This effect is exerted by sulfonamide drugs, which are structural analogues of para-aminobenzoic acid. This is the basis for the mechanism of action of some drugs that are used to treat cancer (methotrexate, mercaptopurine, which, respectively, are antagonists of folic acid and purine). The mechanism of action of drugs may be based on nonspecific changes due to their physical or chemical properties. In particular, the diuretic effect of mannitol is due to its ability to increase osmotic pressure in the renal tubules.
16. Types of drug therapy (symptomatic, pathogenetic, replacement, etiotropic, preventive).
Prophylactic use refers to the prevention of certain diseases. For this purpose, disinfectants, chemotherapeutic substances and other desirable symptoms are used
Causal therapy – aimed at eliminating the cause of the disease (antibiotics act on bacteria)
Symptomatic therapy is the elimination of unwanted symptoms (for example, pain), which has a significant impact on the course of the main pathological process. In this regard, and in many cases, symptomatic therapy plays the role of pathogenetic therapy.
Replacement therapy – used for deficiency of natural nutrients. So, with insufficiency of the endocrine glands
17-20 absent
21. Carcinogenic effect. Idiosyncrasy, its differences from allergic reactions, manifestations in dentistry, measures to help and prevention.
Carcinogenicity is the ability of substances to cause the development of malignant tumors. Derivatives of benzene, phenol, tar ointments, and cauterizing agents have a carcinogenic effect. Sex hormones and other stimulators of protein synthesis can promote the growth and metastasis of tumors. Idiosyncrasy can be one of the causes of adverse reactions to substances. Idiosyncrasy is a painful reaction that occurs in some people in response to certain nonspecific (as opposed to allergies) irritants. Idiosyncrasy is based on innate increased reactivity and sensitivity to certain stimuli or a reaction that occurs in the body as a result of repeated weak exposure to certain substances and is not accompanied by the production of antibodies. Idiosyncrasy differs from allergies in that it can develop even after the first contact with a substance. Soon after contact with the irritant, a headache appears, the temperature rises, sometimes mental agitation, disorders of the digestive system (nausea, vomiting, diarrhea), breathing (shortness of breath, runny nose, etc.), swelling of the skin and mucous membranes, and urticaria occur. These phenomena, caused by circulatory disorders, increased vascular permeability, and smooth muscle spasms, usually disappear soon, but sometimes last for several days. The transferred reaction does not create insensitivity to repeated action of the agent.
22. Features of the action of drugs with repeated and prolonged administration: drug dependence, sensitization, addiction, tachyphylaxis, cumulation.
With repeated use of medicinal substances, their effect may change either in the direction of increasing the effect or decreasing it. The increase in the effect of a number of substances is associated with their ability to cumulation. Cumulation can be material and functional. Material cumulation-accumulation of a pharmacological substance in the body. This is typical for long-acting drugs that are slowly released or persistently bind in the body (cardiac glycosides, digitalis). Functional cumulation– in which the effect, not the substance, accumulates (with alcoholism, increasing changes in the functions of the central nervous system lead to the development of delirium tremens. Ethyl alcohol quickly oxidizes and does not linger in the tissues. Only its neurotropic effects are cumulative).
Habituation is a decrease in the effectiveness of substances upon repeated use. It can occur with a decrease in the absorption of the substance, an increase in the rate of its inactivation and an increase in the intensity of its administration. It is possible that addiction to a number of substances is due to a decrease in the sensitivity of receptor formations to them or a decrease in their density in tissues. In case of addiction, to obtain the initial effect, the dose of the drug must be increased or one substance replaced with another.
Tachyphylaxis- a special type of addiction. Addiction develops very quickly, sometimes after the first administration of the substance.
Drug addiction- develops to certain substances upon repeated administration. It is manifested by an irresistible desire to take a substance, usually with the aim of increasing mood, improving well-being, eliminating unpleasant sensations and experiences, including those that arose during the withdrawal of substances that cause drug dependence. Distinguish mental And physical drug addiction. When mental drug dependence stopping the drug only causes emotional discomfort. When taking certain substances (heroin, morphine). This is a more pronounced degree of dependence. Withdrawal of the drug in this case causes a serious condition, which, in addition to sudden mental changes, is manifested by various and often serious somatic disorders associated with disorders of the functions of many body systems, including death.
23. Drug allergies. Differences between the allergic and toxic effects of drugs. Features of allergies in dental patients, ways of prevention and treatment.
Drug allergies are independent of the dose of the substance administered. Medicines act as antigens. There are 4 types of drug allergies.
Type 1. Immediate allergy. This type of hypersensitivity is associated with the involvement of an IgE antibody reaction. This manifests itself as urticaria, vascular edema, rhinitis, bronchospasm, and anaphylactic shock. Such reactions are possible when using penicillins and sulfonamides.
Type 2. In this type of drug allergy, IgG-IgM antibodies, activating the complement system, interact with circulating blood cells and cause their lysis. (for example, methyldopa can cause hemolytic anemia, quinidine - thrombocytopenic purpura.
Type 3. IgG, IgM, IgE antibodies take part in the development of this type. The Antigen-Antibody-compliment complex interacts with the vascular endothelium and damages it. Serum sickness occurs, manifested by urticaria, arthralgia, arthritis, lymphadenopathy, and fever. May cause: penicillins, sulfonamides, iodides.
Type 4. In this case, the reaction is mediated through cellular immune mechanisms, including sensitized T-lymphocytes and macrophages. It occurs when the substance is applied locally and manifests itself as contact dermatitis.
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To quantitatively and qualitatively characterize the effects of medications, concepts such as maximum therapeutic effect, its variability and selectivity are used. The effect of a drug over time can be divided into the latent period, the time of maximum therapeutic effect and its duration. Each stage is determined by certain physicochemical, physiological and biochemical processes in cells and organs.
Thus, the latent period is determined mainly by the route of administration, the rate of absorption and distribution of drugs in organs and tissues, and to a lesser extent - the rate of biotransformation and excretion. The duration of action is mainly due to the characteristics of deposition and the speed of removal of the drug from the body.
A certain dose (or concentration) of a drug causes a pharmacological effect in the body, which is measured quantitatively. The rule of doses is known: small doses stimulate organ functions, medium doses enhance them, large doses depress them, and excessive doses paralyze them.
The effect of drugs depends on their dose. In some cases, there is a direct relationship between dose, concentration and effect. However, in practice, a direct relationship between the concentration of a substance in the serum and the magnitude of the effect is not often observed due to the fact that the therapeutic effect is influenced by many factors from the drugs and the body. Thus, a decrease or increase in blood pressure can be the result not only of the dose, route of administration, pharmacokinetic parameters, mechanism of action, but also a change in cardiac activity, vascular tone, circulating blood volume and nervous regulation, blood pressure level, as well as simultaneous or sequential combinations thereof .
The effect caused by a certain dose of a medicinal substance also depends on: the amount of metabolites formed during the biotransformation process, the proportion of active isomers and the rate of their metabolism in the liver, the reactivity of the corresponding receptors, the nature of the disease, etc. In this regard, the dose-effect curve may be straight, curved up or down, sigmoid type. If you isolate any one component, then the dose-effect curve takes on a certain character with parameters reflecting the strength and maximum effectiveness. In many biological systems, as the dose increases, the effect increases to a certain value (“ceiling”); a further increase in the dose no longer causes an increase in the effect, but often, on the contrary, reduces it. In other cases, a specific dose has an all-or-nothing effect (eg, seizures, anesthesia).
Depending on the characteristics of the dose-effect curve (placement, slope, shape of the curve), one can judge the strength of the drug, pharmacokinetic parameters (absorption, distribution, conversion and output), as well as the affinity of the drug with the receptors. To compare the potency of two or more drugs, the relative potency of their action is used - determining equieffective (equivalent) doses. The nature of the rise in the dose-effect curve characterizes the mechanism of action of the drugs, and the maximum characterizes the internal activity of the drug. Analysis of the dose-effect curves of morphine and butadione shows that morphine has sufficient internal activity to relieve severe and mild pain, while butadione, even in maximum doses, is capable of relieving only pain of moderate severity of neurological origin without identifying toxic manifestations.
Due to the existence of individual differences, pharmacological studies are carried out on large populations of biological objects. Typically, when studying the quantitative relationship “dose → effect → response,” the dose that causes an effect in 50% of representatives of a certain population is determined. This is the average dose that may be effective depending on the effect being tested (DE50). Comparing effective and
The total dose can determine the danger of a given drug using the therapeutic index (THAT.
where Te is the therapeutic index, DL50 is the dose of the substance that causes the death of half of the experimental animals, DE50 is the dose that causes an effect in 50% of cases. These results are obtained in animal experiments and then extrapolated to the patient.
If the dose (concentration) of a drug changes, not only the effect changes, but also the speed at which it is achieved. Thus, the dose determines not only quantitative, but also qualitative changes in the pharmacological effect.
6. DEPENDENCE OF THE PHARMACOTHERAPEUTIC EFFECT ON THE PROPERTIES OF DRUGS AND THE CONDITIONS OF THEIR APPLICATION
6. DEPENDENCE OF THE PHARMACOTHERAPEUTIC EFFECT ON THE PROPERTIES OF DRUGS AND THE CONDITIONS OF THEIR APPLICATION
A) CHEMICAL STRUCTURE, PHYSICAL-CHEMICAL AND PHYSICAL PROPERTIES OF DRUGS
The properties of drugs are largely determined by their chemical structure, the presence of functionally active groups, and the shape and size of their molecules. For effective interaction of a substance with a receptor, a drug structure is necessary that provides
its closest contact with the receptor. The strength of intermolecular bonds depends on the degree of proximity of the substance to the receptor. Thus, it is known that in an ionic bond, the electrostatic forces of attraction of two unlike charges are inversely proportional to the square of the distance between them, and van der Waals forces are inversely proportional to the 6th-7th power of the distance (see Table II.3).
For the interaction of a substance with a receptor, their spatial correspondence is especially important, i.e. complementarity. This is confirmed by differences in the activity of stereoisomers. Thus, in terms of its effect on blood pressure, D(+)-adrenaline is significantly inferior in activity to L(-)-adrenaline. These compounds differ in the spatial arrangement of the structural elements of the molecule, which is crucial for their interaction with adrenergic receptors.
If a substance has several functionally active groups, then the distance between them must be taken into account. So, in the series of bis-quaternary ammonium compounds (CH 3) 3 N + - (CH 2) n - N + (CH 3) 3? 2X - for the ganglion-blocking effect, I = 6 is optimal, and for the block of neuromuscular transmission - n=10 and 18. This indicates a certain distance between the anionic structures of n-cholinergic receptors, with which the ionic bond of quaternary nitrogen atoms occurs. For such compounds, the radicals that “shield” the cationic centers, the size of the positively charged atom and the charge concentration, as well as the structure of the molecule connecting the cationic groups are also of great importance.
Determining the relationship between the chemical structure of substances and their biological activity is one of the most important areas in the creation of new drugs. In addition, comparison of optimal structures for different groups of compounds with the same type of action allows us to gain a certain understanding of the organization of those receptors with which these drugs interact.
Many quantitative and qualitative characteristics of the action of substances also depend on such physicochemical and physical properties as solubility in water, lipids, for powdery compounds - on the degree of their grinding, for volatile substances - on the degree of volatility, etc. The degree of ionization is important. For example, muscle relaxants, structurally related to secondary and tertiary amines, are less ionized and less active than fully ionized quaternary ammonium compounds.
B) DOSES AND CONCENTRATIONS
The effect of drugs is largely determined by their dose. Depending on the dose (concentration), the speed of development of the effect, its severity, duration, and sometimes character change. Typically, with increasing dose (concentration), the latent period decreases and the severity and duration of the effect increase.
A dose is the amount of a substance per dose (usually referred to as a single dose).
It is necessary to be oriented not only to the dose calculated for a single dose (pro dosi), but also in a daily dose (pro die).
The dose is indicated in grams or fractions of a gram. For a more accurate dosage of drugs, calculate their amount per 1 kg of body weight (for example, mg/kg, mcg/kg). In some cases, they prefer to dose substances based on the size of the body surface (per 1 m2).
The minimum doses at which drugs cause the initial biological effect are called threshold, or minimum effective. In practical medicine, average therapeutic doses are most often used, in which the drugs have the necessary pharmacotherapeutic effect in the vast majority of patients. If the effect is not sufficiently pronounced when prescribing them, the dose is increased to the highest therapeutic dose. In addition, toxic doses are distinguished, in which substances cause toxic effects dangerous to the body, and lethal doses (Fig. II.12).
Rice. II.12.Doses, pharmacotherapeutic and adverse effects of drugs (the main, side and toxic effects of morphine are given as an example).
In some cases, the dose of the drug per course of treatment is indicated (course dose). This is especially important when using antimicrobial chemotherapeutic agents.
If there is a need to quickly create a high concentration of a drug in the body, then the first dose (shock) exceeds the subsequent ones.
For substances administered by inhalation (for example, gaseous and volatile anesthetics), their concentration in the inhaled air (indicated as a volume percentage) is of primary importance.
C) REPEATED USE OF MEDICINES
With repeated use of drugs, their effect may change in the direction of either increasing or decreasing effect.
The increase in the effect of a number of substances is associated with their ability to accumulate 1. Under material cumulation They mean the accumulation of a pharmacological substance in the body. This is typical for long-acting drugs that are released slowly or are persistently bound in the body (for example, some cardiac glycosides from the digitalis group). Accumulation of the substance during repeated administration may cause toxic effects. In this regard, such drugs should be dosed taking into account accumulation, gradually reducing the dose or increasing the intervals between doses of the drug.
There are known examples of the so-called functional cumulation, in which the effect “accumulates”, not the substance. Thus, with alcoholism, increasing changes in the function of the central nervous system can lead to the development of delirium tremens. In this case, the substance (ethyl alcohol) quickly oxidizes and does not linger in the tissues. Only its neurotropic effects are summarized. Functional cumulation also occurs with the use of MAO inhibitors.
A decrease in the effectiveness of substances with their repeated use - addiction (tolerance 2) - is observed when using a variety of drugs (analgesics, antihypertensives, laxatives, etc.). It may be associated with a decrease in the absorption of the substance, an increase in the rate of its inactivation and (or) an increase in the intensity of excretion. It is possible that addiction to a number of substances is due to a decrease in the sensitivity of receptor formations to them or a decrease in their density in tissues.
In case of addiction, to obtain the initial effect, the dose of the drug must be increased or one substance replaced with another. With the latter option, it should be taken into account that there is cross-addiction to substances that interact with the same receptors (substrates).
A special type of addiction is tachyphylaxis 3- addiction that occurs very quickly, sometimes after the first administration of a substance. Thus, ephedrine, when repeated at intervals of 10-20 minutes, causes a lesser rise in blood pressure than with the first injection.
To some substances (usually neurotropic), drug dependence develops upon repeated administration (Table II.5). It is manifested by an irresistible desire to take a substance, usually with the aim of increasing mood, improving well-being, eliminating unpleasant experiences and sensations, including those that arise when withdrawing from substances that cause drug dependence. There are mental and physical drug dependence. When mental drug dependence stopping the administration of drugs (for example, cocaine, hallucinogens) causes only emotional
1 From lat. cumulation- increase, accumulation.
2 From lat. tolerance- patience.
3 From Greek tachys- fast, phylaxis- vigilance, security.
Table II.5.Examples of substances that cause drug dependence
discomfort. When taking certain substances (morphine, heroin), it develops physical drug dependence. This is a more pronounced degree of dependence. Withdrawal of the drug in this case causes a serious condition, which, in addition to sudden mental changes, is manifested by various and often serious somatic disorders associated with dysfunction of many body systems, including death. This is the so-called withdrawal syndrome 1, or phenomena of deprivation.
Prevention and treatment of drug addiction are a serious medical and social problem.
D) DRUG INTERACTIONS
In medical practice, several medications are often used simultaneously. At the same time, they can interact with each other, changing the severity and nature of the main effect, its duration, as well as strengthening or weakening side and toxic effects.
Drug interactions can be classified as follows.
I. Pharmacological interaction:
1) based on changes in the pharmacokinetics of drugs;
2) based on changes in the pharmacodynamics of drugs;
3) based on the chemical and physicochemical interaction of drugs in the body’s environments.
II. Pharmaceutical interaction.
Combinations of various drugs are often used to enhance or combine effects useful for medical practice. For example, using some psychotropic drugs together with opioid analgesics can significantly increase the pain-relieving effect of the latter. There are drugs containing antibacterial or antifungal agents with steroidal anti-inflammatory substances, which are also advisable combinations. There are many such examples. However, when combining substances, an unfavorable interaction may occur, which is designated as incompatibility of drugs. Incompatibility is manifested by a weakening, complete loss or change in the nature of the pharmacological
1 From lat. abstinence- abstinence.
therapeutic effect or increased side or toxic effects (the so-called pharmacological incompatibility). This may occur when two or more drugs are used together. For example, incompatibility of drugs can cause bleeding, hypoglycemic coma, seizures, hypertensive crisis, pancytopenia, etc. Incompatibility is also possible during the manufacture and storage of combined drugs (pharmaceutical incompatibility).
Pharmacological interaction
Pharmacological interaction is due to the fact that one substance changes the pharmacokinetics and/or pharmacodynamics of another substance. Pharmacokinetic type of interaction may be associated with impaired absorption, biotransformation, transport, deposition and excretion of one of the substances. Pharmacodynamic type of interaction is the result of direct or indirect interaction of substances at the level of receptors, ion channels, cells, enzymes, organs or physiological systems. In this case, the main effect can change quantitatively (strengthen, weaken) or qualitatively. In addition, it is possible chemical and physicochemical interaction substances when used together.
The pharmacokinetic type of interaction (Table II.6) can appear already at the stage suction substances, which can change for various reasons. Thus, in the digestive tract, it is possible to bind substances with adsorbent agents (activated carbon, white clay) or anion-exchange resins (for example, the lipid-lowering drug cholestyramine), the formation of inactive chelate compounds or complexones (in particular, antibiotics of the tetracycline group interact with iron and calcium ions according to this principle , magnesium). All of these interaction options interfere with the absorption of drugs and, accordingly, reduce their pharmacotherapeutic effects. For the absorption of a number of substances from the digestive tract, the pH of the environment is essential. Thus, by changing the reaction of digestive juices, you can significantly influence the speed and completeness of absorption of weakly acidic and weakly alkaline compounds. It was previously noted that with a decrease in the degree of ionization, the lipophilicity of such substances increases, which facilitates their absorption.
Changes in the peristalsis of the digestive tract also affect the absorption of substances. Thus, an increase in intestinal motility by cholinomimetics reduces the absorption of the cardiac glycoside digoxin, while the anticholinergic blocker atropine, which reduces peristalsis, favors the absorption of digoxin. There are known examples of the interaction of substances at the level of their passage through the intestinal mucosa (for example, barbiturates reduce the absorption of the antifungal agent griseofulvin).
Inhibition of enzyme activity may also affect absorption. Thus, the antiepileptic drug difenin inhibits folate deconjugase and interferes with the absorption of folic acid from foods. As a result, folic acid deficiency develops.
Some substances (almagel, petroleum jelly) form a layer on the surface of the mucous membrane of the digestive tract, which can somewhat complicate the absorption of drugs.
The interaction of substances is possible at the stage of their binding to blood proteins. In this case, one substance can displace another from the complex with blood plasma proteins. Thus, the anti-inflammatory drugs indomethacin and butadione
Table II.6.Examples of pharmacokinetic drug interactions
Group of combined drugs | The result of the interaction of drugs of groups I and II |
||
Effect | mechanism |
||
Almagel | Almagel impedes the absorption of group I substances in the gastrointestinal tract |
||
Indirect anticoagulants (warfarin, neodicoumarin, etc.) | Cholestyramine | Weakening the anticoagulant effect of group I substances | Cholestyramine binds group I substances in the intestinal lumen and reduces their absorption |
Salicylates (acetylsalicylic acid, etc.) | Phenobarbital | Weakening actions salicylates | Phenobarbital enhances the biotransformation of salicylates in the liver |
Opioid analgesics (morphine, etc.) | Non-selective MAO inhibitors | Strengthening and prolonging the effect of group I substances with possible respiratory depression | Non-selective MAO inhibitors inhibit the inactivation of group I substances in the liver |
Synthetic antidiabetic agents (chlorpropamide, etc.) | Butadion | Increased hypoglycemic effect up to coma | Butadione displaces group I substances from their connection with blood plasma proteins, increasing their concentration in the blood |
Salicylates (acetylsalicylic acid) | Antacids facilities, providing systemic action | Some weakening of the effect of salicylates | Antacids reduce the reabsorption of salicylates in the kidneys (in an alkaline environment), increasing their excretion in the urine. The concentration of salicylates in the blood decreases |
release indirect anticoagulants (coumarin group) from the complex with blood plasma proteins. This increases the concentration of the free fraction of anticoagulants and can lead to bleeding. By a similar principle, butadione and salicylates increase the concentration in the blood of the free fraction of hypoglycemic agents (such as chlorpropamide) and can cause hypoglycemic coma.
Some drugs can interact at the level biotransformation substances. There are drugs that increase (induce) the activity of microsomal liver enzymes (phenobarbital, diphenin, griseofulvin, etc.). Against the background of the action of the latter, the biotransformation of many substances occurs more intensely, and this reduces the severity and duration of their effect (as well as the enzyme inducers themselves). However, in clinical conditions this manifests itself quite clearly only when enzyme inducers are used in large doses and for a sufficiently long time.
Drug interactions due to inhibitory effects on microsomal and non-microsomal enzymes are also possible. Thus, a known xanthine oxidase inhibitor is the anti-gout drug allopurinol, which increases the toxicity of the antitumor drug mercaptopurine (increases its inhibitory effect on hematopoiesis). Teturam, at-
changed in the treatment of alcoholism, inhibits aldehyde dehydrogenase and, by disrupting the metabolism of ethyl alcohol, increases its toxic effects.
Removaldrugs may also change significantly when the substances are used in combination. It was previously noted that the reabsorption of weakly acidic and weakly alkaline compounds in the renal tubules depends on the pH values of the primary urine. By changing its reaction, you can increase or decrease the degree of ionization of a substance. The lower the ionization, the higher the lipophilicity of the substance and the more intense its reabsorption in the renal tubules. Naturally, more ionized substances are poorly reabsorbed and are excreted to a greater extent in the urine. Sodium bicarbonate is used to alkalize urine, and ammonium chloride is used to acidify it (there are other drugs with a similar effect). With the combined use of drugs, their secretion in the renal tubules may be impaired. Thus, probenecid inhibits the secretion of penicillins in the renal tubules and thereby prolongs their antibacterial effect.
It should be borne in mind that when substances interact, their pharmacokinetics can change at several stages simultaneously (for example, barbiturates affect the absorption and biotransformation of neodicoumarin).
The pharmacodynamic type of interaction reflects the interaction of substances based on the characteristics of their pharmacodynamics (Table II.7). If the interaction occurs at the receptor level, then it mainly concerns agonists and antagonists of various types of receptors (see above). In this case, one compound can enhance or weaken the effect of another. When synergy 1 the interaction of substances is accompanied by an increase in the final effect.
Table II.7.Examples of pharmacodynamic drug interactions
1 From Greek synergos- acting together.
Continuation of the table.
Drug synergism can be manifested by simple summation or potentiation of effects. The summed (additive 1) effect is observed by simply adding the effects of each of the components (for example, this is how anesthetics interact). If, when two substances are administered, the total effect exceeds (sometimes significantly) the sum of the effects of both substances, this indicates potentiation (for example, antipsychotic drugs potentiate the effect of anesthetic drugs).
Synergism can be direct (if both compounds act on the same substrate) or indirect (if the localization of their action is different).
The ability of one substance to reduce the effect of another to one degree or another is called antagonism. By analogy with synergy, direct
1 From lat. additio- addition.
or indirect antagonism (see above for the nature of interaction at the receptor level).
In addition, there is the so-called synergistic antagonism, in which some effects of the combined substances are enhanced, while others are weakened. Thus, against the background of α-adrenergic blockers, the stimulating effect of adrenaline on vascular α-adrenergic receptors decreases, and on β-adrenergic receptors it becomes more pronounced.
Chemical and physicochemical interaction of substances in the body’s environments is most often used in cases of overdose or acute drug poisoning. Thus, the ability of adsorbents to complicate the absorption of substances from the digestive tract has already been mentioned. In case of an overdose of the anticoagulant heparin, its antidote is prescribed - protamine sulfate, which inactivates heparin due to electrostatic interaction with it. These are examples of physicochemical interactions.
An illustration of a chemical interaction is the formation of complexones. Thus, calcium ions are bound by the disodium salt of ethylenediaminetetraacetic acid (Trilon B; Na 2 EDTA), ions of lead, mercury, cadmium, cobalt, uranium - thetacine-calcium (CaNa 2 EDTA), ions of copper, mercury, lead, iron, calcium - penicillamine .
Thus, the possibilities for pharmacological interaction of substances are very diverse (see Tables II.6 and II.7).
Pharmaceutical interactions
There may be cases of pharmaceutical incompatibility, in which during the manufacturing process of drugs and (or) their storage, as well as when mixing in one syringe, the components of the mixture interact and such changes occur as a result of which the drug becomes unsuitable for practical use. In this case, the pharmacotherapeutic activity previously present in the original components decreases or disappears. In some cases, new, sometimes unfavorable (toxic) properties appear.
Dose- the amount of substance introduced into the body. Usually the drug is prescribed in therapeutic dose, causing healing effect. The therapeutic value doses may vary depending on age, route of administration medicinal substance, the desired therapeutic effect. There are doses prescribed for one dose - one-time, during the day - daily, for a course of treatment - course. The drug can be prescribed per 1 kg of body weight or per 1 square millimeter of body surface. Toxic dose - the amount of a substance that causes poisoning in a child. Lethal dose causes death. Therapeutic index- an indicator of the breadth of safe action of the drug. It is the ratio of the median lethal dose to the median effective dose of the drug (risk/benefit ratio). Concept introduced P. Ehrlich. Drugs with a low therapeutic index (up to 10) should be used with extreme caution; drugs with a high therapeutic index are considered relatively safe.
Dose is the amount of a substance, determined in grams.
Therapeutic: minimal, medium, highest.
Toxic – cause poisoning;
Lethal – cause death;
2. Antihistamines
Histamine was synthesized in 1907, drugs appeared only in 1937, and receptor subtypes were identified in the 1960s.
AK histidine decarboxylase histamine
Accumulation – granules of mast cells, basophils.
It is a natural ligand of histamine H receptors (H 1; H 2; H 3; H 4)
Localization of histamine receptors:
H 1 – bronchi, intestines (contraction), blood vessels (dilation), central nervous system
H 2 – parietal cells of the stomach (increases HCl secretion), central nervous system
H 3 – central nervous system, gastrointestinal tract, cardiovascular system, upper respiratory tract
H 4 – intestines, spleen, thymus, immunoactive cells
Role of histamine: neurotransmitter; regulator of excitation processes, vestibular drug; functions of the cardiovascular system, thermoregulation; the most important mediator of allergic reactions (through H1 receptors).
Effects of histamine upon stimulation of H1 receptors
Vasodilation and decreased blood pressure, tachycardia
Increased capillary permeability - swelling, hyperemia, pain, itching
Increased tone of smooth muscles of internal organs (bronchial spasm), uterus
Histaymna preparations
Histamine hydrochloride– intravenous, local ointment, electrophoresis (for polyarthritis, rheumatism, radiculitis, plexitis).
Histoglobulin– s/c, i/m (+immunoglobulin, sodium thiosulfate) – production of pro/histamine ATs
Betaserc (Betagistin)– orally – a synthetic histamine analogue – for the treatment of dizziness
Acts through H1; H3 – receptors of the inner ear and vestibular nuclei of the brain. On H1 there is a direct agonist effect. the result is improved permeability and microcirculation of the capillaries of the inner ear, blood flow in the basilar artery and stabilization of endolymph pressure in the cochlea and labyrinth. Prescribed for: labyrinthine and vestibular disorders; headache; dizziness; pain and noise in the ears; nausea, vomiting, progressive hearing loss; syndrome and Meniere's disease; in complex therapy of post-traumatic encephalopathy, vertebrobasilar insufficiency, cerebral atherosclerosis.
Antihistamines
H1 receptor blockers
Generation:
Diphenhydramine (Diphenhydramine)
Clemastine (Tavegil)
Chloropyramine (Suprastin)
Promethazine (Diprazine, Pipolfen) – phenothiazine derivatives
Quifenadine (Fencarol)
Mebhydrolin (Diazolin)
Generation:
Lorotadine (Cloretin)
Ebastine (Kestin)
Cetirizine (Zyrtec)
Generation:
Desloratadine (Erius)
Fexofenadine (Telfast)
H 1 - 1st generation blockers:
Mechanism of action:
Competitive antagonist with histamine for H1 receptors
Less affinity for receptors (not able to displace histamine from its connection with the receptor)
Block free receptors
For the relief of acute ALR of mild severity or for prevention
Can also be used in emergency cases, because... can be administered parenterally
Peculiarities:
Penetrate the BBB - sedation, pr/emetic effect (Fenkarol - daytime, increases the activity of diamine oxidase; Diazolin - weak, 24-48 hours effective)
Weak affinity for H1 receptors
Block of receptors for other mediators (M-CR; AR; CP (side effects and use for other indications)
Short acting (excl.Diazolin)
Sodium channel blocker (local anesthetic effect)
Disadvantages, side effects:
Low DB – 40%. High degree of passage through the liver.
Eating impairs absorption
Drowsiness, weakness
Tachycardia, dry mouth, constipation, urinary retention
Exacerbation of glaucoma
Thickening of bronchial secretions
Hypotension
Numbness of the oral mucosa
Habituation (tachyphylaxis)
Potentiating effect (alcohol!)
Indications for use:
Immediate ALR: urticaria, pruritus, angioedema (angioedema)
ALR conjunctivitis
ALR rhinitis
Hay fever
Dermatitis
Use for other indications:
Doxylamine (Donormil) – hypnotic effect
Cyproheptadine (Peritol) – a serotonin receptor blocker for migraines
Hydroxyzine (Atarax) – anxiolytic, tranquilizer for anxiety, fear
Contraindications:
Work that requires increased attention and concentration
Prostatic hyperplasia
Disturbance of urine outflow
Glaucoma
History of ALR for hypertension drugs
Pregnancy and lactation
H1-blockers 2nd generation
Minimal sedation, high affinity for H1 receptors, allosteric interaction, not replaced by histamine
Prolonged action (24 hours)
Do not block M-HR; SR
Less often addictive
DB high – 90%
Flaws:
Cardiotoxicity (block of K channels - cardiac arrhythmia)
Lack of parenteral forms
H2-blockers 3rd generation
Active metabolites of 2nd generation drugs.
They are not metabolized, the pharmaceutical effect does not depend on individual characteristics and food intake.
Greater stability and reproducibility of the effect.
No cardiotoxicity.
Fexofenadine (Telfax)- H 1 blocker + mast cell membrane stabilizer. Prevents the release of histamine and other allergy mediators, orally 2 times a day, contraindicated for children under 12 years of age.
Mast cell membrane stabilizers (inhibiting degranulation)
Inhibits the current of Ca 2+ ions and reduces their concentration in mast cells
Prevents the release of mediators of allergy and inflammation (+ anti-inflammatory effect)
To prevent asthma attacks
For allergic reactions
Mast cell membrane stabilizers:
Sodium cromoglycate (Intal, Cromolyn) – inhalation, eye drops, nasal spray. TE after 1 month, 4-8 times a day, PD – 4 times a day.
Nedocromil sodium (Tyled) + anti-inflammatory and bronchodilator effect. TE - after 1 week, more effective (6-10 times), 4-6 r / day, PD (maintenance dose) - 2 r / day.
Ketotifen (Zaditen) – orally 2 times a day (+ H 1 blocker), combination with β-mimetics is possible. TE - in 1-2 months.
These drugs reduce the need for bronchodilators and glucocorticoids.
Combined drugs:
Intal + Fenoterol = Ditek
Intal + Salbutamol = Intal plus
3. Antisyphilitic in the classroom
