PHARMACOTHERAPY (Greek phar-makon a medicine, medicine + thera-peia treatment) — treatment of the patient (diseases) with pharmaceuticals. In traditional understanding F. — one of the main methods of conservative treatment (see Therapy). Modern F. represents quickly developing direction of clinical medicine developing evidence-based system of the principles of use of pharmaceuticals for the purpose of elimination
or interruption or delay of a course of a disease influence of these funds for its reason or the leading links of a pathogeny and also for the purpose of elimination of the most burdensome or predictively its adverse manifestations. Etiotropic treatment of a row inf. diseases and suppression of growth of tumors drugs, the therapeutic effect to-rykh is caused by their action not on an organism of the patient, and on a disease-producing factor (microbes, parasites) or on a tumor cell, it is accepted to call chemotherapy (see), and the drugs used at the same time — chemotherapeutic means (see). However on means and ways of implementation the chemotherapy can be considered as rather independent direction F., as antimicrobic, antiparasitic drugs and cyto-statics carry to certain classes of pharmaceuticals (see), and tactics of use of these drugs is developed, as well as for other pharmaceuticals, taking into account their interaction with a macroorganism (features of distribution in an organism, metabolism, allocation, toxicity etc.). Do not refer use to pharmacotherapy pharmakol. drugs for prevention of diseases, and also as supportive applications at not medicinal methods of treatment (e.g., administration of anesthetics at operations) and conducting diagnostic testings (e.g., administration of cholinolytics for achievement of hypotonia of a duodenum at rentgenol. research).
The use of pharmaceuticals which began since emergence of medicine (see) and continuing throughout almost all its history (up to 20 century), had no scientific justifications, it had empirical character or proceeded from the mystical false doctrines dominating during the different historical periods about the nature of diseases and the effect of drugs. Premises to formation of scientific bases F. appeared only in 19 century in connection with emergence of experimental pharmacology (see), and also thanks to achievements of microbiology (see) and chemistry, to-rye steel a basis of origin of chemotherapy, and development of the functional direction in a wedge, researches that was promoted considerably by the ideas and S. P. Botkin and I. P. Pavlov's works. In 20 century scientific and technical progress qualitatively changed development of medical sciences, including pharmacology, defined creation unknown in terms of the scope of and production new pharmakol. drugs, various on an action spectrum and expressiveness of influence on various functions of an organism, and also on dynamics patol. processes. In the same time the wedge, disciplines were enriched with a powerful arsenal of technical means of functional and laboratory diagnosis that provided a possibility of objective assessment and control of effect of medicines in a wedge, conditions.
At this stage to progress F. development of clinical pharmacology (see Pharmacology clinical), one of prominent founders a cut in the USSR in 50 promoted — the 60th there was B. E. In otchat, representing it not only as new discipline, but also as «a method of thinking of the doctor who is carrying out pharmacotherapy». B. E. Votchal, being a pioneer in creation of a number of functional and diagnostic techniques, purposefully used them for objectification of effect and comparative assessment of therapeutic action pharmakol. drugs.
Scientific principles modern F. form on the basis of data of pharmacology on interaction of pharmaceuticals with an organism, first of all about their pharmacodynamics (see) and pharmacokinetics (see), features to-rykh at the sick person are studied by a wedge, pharmacology (see Pharmacology clinical), these various medical sciences opening patol. physiology and biochemical (biophysical) essence of the processes making a pathogeny of a disease, and also given a wedge, the disciplines studying reflection of these processes on symptoms of a disease, the loudspeaker to-rykh there can be criterion a wedge, evaluation tests and degrees reached pharmakol. effect.
Tactics of use of medicine is proved by data on the mechanism of its action, bioavailability (absorption), distribution in fabrics and elimination from an organism.
At limited number of the applied pharmaceuticals pharmakol. the effect is nonspecific result of physical or chemical properties of drug (e.g., an osmotic diuresis at use of a mannitol, elimination of acidosis administration of sodium bicarbonate), direct chemical interaction of medicine with any substance (e.g., binding by chelates of excess of copper at hepatocerebral dystrophy) or inclusions of a part of chemical structure of drug in a biomolecule (e.g., 'synthesis a methylhole-drenalina at introduction to an organism of Methyldopa). For the vast majority of pharmaceuticals the nature pharmakol. effect is considered within the receptor theory assuming more or less selective interaction of a molecule of drug with biomolecules (most often with enzymes on biol. membranes) which are carrying out specific function in a metabolism or regulation of a certain duration (see Receptors, cellular receptors). The probability of interaction of subjects big, than is higher concentration of medicine in the environment of interaction than it with receptors. Concentration, edges provides pharmakol. the effect sufficient for implementation of therapeutic action, sootvetst
vut therapeutic concentration. If demanded pharmakol. the effect assumes change of exchange processes or functions within one body (a brain, heart, kidneys etc.) due to interaction with receptors in environments of the same body, this body can be considered as a target lekarstvennog actions.
Concentration of medicine in a zone of its reaction with substrate depends on a dose of drug and on its bioavailability at the chosen way of introduction to an organism, i.e. from ability to get through various barriers — a wall went on ways to the scene of action. - kish. a path (for enteral dosage forms), circulatory capillaries, interstitial environments, membranes of cells, etc. Its also general distribution in an organism and removal depends on features of transport of drug.
Transport of pharmaceuticals through various barriers can be passive (on a gradient of concentration of substance) and active (with energy consumption on transfer of molecules of medicine through membranes). The majority of the fat-soluble pharmaceuticals which are easily getting into a lipidic layer of cellular membranes, nonelectrolytes and not ionized molecules of acids and the bases is passively transported. Extent of ionization of the last depends on pH of the environment therefore transport from a stomach in blood of alkaloids is facilitated at low, and acids (salicylates, barbiturates, etc.) at high acidity of the environment in a stomach. Active transport in most cases depends on a gradient of concentration of substance a little and is carried out in one direction.
Distribution of medicine in an organism is defined by permeability for it gistogematichesky barriers and the so-called volume of distribution (see Pharmacokinetics). For drugs, to-rye almost completely communicate proteins of plasma (digitoxin, Butadionum, etc.), the volume of distribution is almost equal to the volume of plasma, and only a small part of total quantity of the administered drug comes to fabrics. At the combined use of the pharmaceuticals competing for communication with proteins of plasma replacement from this communication of one drug by another and transition of molecules of the released medicine to fabrics is possible that can be the cause of increase pharmakol. effect and toxic action.
The main place of metabolism of pharmaceuticals are cells of a liver, and allocation is carried out by hl. obr. kidneys (by filtering in balls and active excretion an epithelium of tubules) and through went. - kish. path.
In cells of a liver pharmaceuticals are exposed to enzymic oxidation R-450 cytochrome (with the participation of NAD-N, NADF-N, NADF • N - tsitokhrom - with - reductases, etc.) generally in the form of a hydroxylation, or to recovery, hydrolysis and other metabolic transformations. Many of these metabolites form in the subsequent almost deprived biol. activities pair connections with glucuronic, sulfuric and acetic to-tami, glycine, quickly removed kidneys.
Maintenance of steady concentration of medicine in zones of its interaction with receptors (usually interconnected with its concentration in a blood plasma) is provided with administration of drug in an organism with the same speed with what its elimination is carried out. In a crust, time the pharmaceuticals inducing activity of mikrosomny enzymes of a liver and accelerating thereby own metabolism (meprobamate, diazepam, etc.) and metabolism of other pharmaceuticals (phenobarbital, Noxyronum, progesterone, etc.), and also suppressors of metabolism are known (etaperazin, levomycetinum, PASK, etc.). Their combined use with other drugs can change the speed of elimination of the last. Elimination of pharmaceuticals is slowed down at diseases of a liver and kidneys.
Identical doses of pharmaceuticals often cause in different individuals different in degree, and sometimes and on quality, pharmakol. effects that emphasizes a role of reactivity of an organism in formation of these effects. For the characteristic of reactions of an organism to medicine use such concepts as sensitivity to medicine, edges it is characterized by the threshold doses of drug causing initial reactions, and also stability, or resistance to medicine — considerable decrease or absence pharmakol. effect during the use of the most admissible dose.
For development F. its improvement concerning certain nosological forms is characteristic (e.g., antirheumatic F.) 7 patol. processes (F. inflammations, dystrophies etc.), and also syndromes (e.g., antishock, antiedematous F.), what corresponds to the direction to treat diseases, but not the specific patient. It found reflection in pharmakol. classifications of pharmaceuticals (see), in particular on their nosological orientation (e.g., antituberculous remedies), to pathogenetic, anti-syndromic or symptomatic action (e.g., antiinflammatory, protivoparkinsoni-chesky, antibechics), including also designation of a number of medicinal groups on clinically to the most significant them pharmakol. to effect (e.g., cardiotonic means, diuretics, expectorants etc.). Such direction of development F. has certain advantages, first of all in connection with a possibility of the generalized formulation of its urgent tasks and uses for their solution of pilot models of pathology. It does not exclude, however, need of development of bases of individualization F. at its practical implementation at the specific patient.
Philosophy and elements of tactics of pharmacotherapy. Majority of the principles F. matches the principles of therapy in general; the principles of safety (treatment shall not be more dangerous, than a disease), rationality, controllability and individualization concern to the main of them.
Safety requirement of treatment is especially urgent for modern F., edges it is carried out highly active, quite often ggolipotentny-m concerning various functions of an organism by drugs with not always predictable remote effects of their use. Therefore to first-priority of the questions arising at purpose of treatment, Laurence (D. R. Laurence, 1973) the question of the need to interfere medicine with the course of a disease carries. After establishment of such need prescription of medicine is possible if the probability of its therapeutic effect surpasses probability of undesirable effects of its use.
Reasonable doubts in safety of use of any medicine (see. Side effects of pharmaceuticals) define the strategic principle of treatment, to-ry it is possible to formulate as the principle minimalizatsin pharmacotherapy. He assumes restriction of volume F. in the general complex of treatment of the patient only with that quantity and such duration of use of pharmaceuticals, without to-rykh treatment or it is impossible (insufficiently effectively), or demands use more «dangerous», than pharmacotherapy, methods of treatment. Ensuring this principle is promoted by the correct assessment of opportunities at least of partial replacement F. by such not medicinal methods of treatment as a balneoterapiya (see), a climatotherapy (see), psychotherapy (see), reflexotherapy (see), physical therapy (see) etc.
The principle of rationality assumes that optimum ratio of efficiency and safety F., thanks to Krom the greatest possible therapeutic effect of pharmaceuticals at the smallest risk of their undesirable actions is provided. The principle of rationality is the cornerstone of creation of tactics F. in specific a wedge, situations, the analysis the cut allows to prove the choice of the most adequate to this situation of medicine (a combination of pharmaceuticals), a dosage form, a dose and ways of administration of drug to an organism, and also the forecast of duration F. Posledny is defined taking into account not only estimated course of disease, but also the expected dynamics pharmakol. effect and a possibility of formation various videv medicinal dependence (see). At indications to the combined use of several pharmaceuticals the principle of rationality assumes medical assessment of the comparative importance of these indications for the purpose of restriction of number of the appointed drugs (the principle of economical pharmacotherapy). So, a possibility of causal treatment or purpose of the means interrupting a pathogeny of the basic patol. process (inflammation, allergic reaction etc.) can exclude or minimize in some cases need of use of the symptomatic means or pharmaceuticals operating on minor links of a pathogeny.
T. shall be controlled. This principle provides the continuous-flow medical analysis and assessment as expected, and unexpected results of use of medicine that allows to korrigirovat timely the chosen tactics of treatment by variations of a dose and ways of administration of medicine, replacement of the ineffective and caused side effects drug with another etc. Ensuring this principle is based on use of objective criteria and methods of evaluation test and degree of therapeutic effect, and also early identification of undesirable and side effects of pharmaceuticals. According to this principle it is necessary to avoid uses of drugs, effect to-rykh it is impossible to estimate at the expected terms due to the lack of clear criteria of its achievement.
Principle of individualization F. let's carry out for the present not in all cases therefore intensive development of scientific premises to his statement — one of key features of modern approach to medicinal treatment. The accounting of individual distinctions in operation of pharmaceuticals depending on a condition of the patient and features of a pathogeny of a disease gives, according to B. E. V an otchal (1965), the basis for fight against the biggest shortcoming F. — template. It is promoted also by disclosure of the patterns defining variability of pharmacokinetics of medicine depending on genetic features of individuals (see the Pharmacogenetics), age of the patient, and also from a form of pathology and from specific conditions of use of medicine (a phase patol. process, interference on biotransformation of the combined drugs etc.). All this provides an active position of the doctor, edge, according to K. M. Lakin (see t. 15, additional materials) and Yu. F. Krylova (1981), «consists in ability to manage destiny of medicinal substance in an organism». Practical implementation of the principle of individualization characterizes the highest step of possession of method F., it is defined by width a wedge, thinking, a high level of all-therapeutic qualification of the doctor and depends also on completeness and the validity of information about interaction of medicine with an organism of the patient.
According to the stated principles basic elements of tactics rational F. at the specific patient include definition of indications to F., choice of medicine, ways and ways of its introduction, definition of a dose, choice of criteria and control facilities F., justification of its cancellation.
The II rendering to pharmako-t e r an ii also also define proceeding from knowledge of the general principles of treatment of this form of pathology which the doctor considers according to the established diagnosis (see) diseases and possible complications, assessment of its forecast (see), extent of disturbance of vegetative functions, existence of the displays of a disease bringing to the patient of suffering. T. it is not shown if the disease is not burdensome for the patient and the predicted its outcome does not depend on use of pharmaceuticals and also when not medicinal ways of treatment are not less successful, being safe, or have advantages or are even inevitable (e.g., need of the emergency surgery).
In the presence of indications to F. the last is concretized by the purposes, achievement to-rykh is supposed to be provided with use of medicine proceeding from knowledge of its pharmacodynamics. Also possible contraindications to F are estimated., among to-rykh at this stage .monut to be an ambiguity of the diagnosis (e.g., contraindications to use of anesthetics at an acute abdomen) and incompatibility of medicinal and not medicinal ways of treatment, napr, defibrillations (see) concerning arrhythmia of heart after preliminary use of cardiac glycosides (see). Sometimes the ambiguity of the diagnosis, on the contrary, can be the indication to F. for diagnosis of ex juvantibus. In some cases indications to use of pharmaceuticals are defined by results of trial treatment (see, e.g., Strofantinovaya test).
Sources of mistakes in assessment of indications to F. there can be an insufficient knowledge of the doctor of the comparative therapeutic value of different methods of treatment, the incorrect forecast, but is especially frequent — inaccuracy and incompleteness of the diagnosis of a disease. So, e.g., rather high frequency of unreasonable use of streptocides and antibiotics at viral respiratory diseases is caused by mistakes directed by the etiological diagnosis.
In the course of scoping F. indications to complex pharmacotherapy, i.e. use of pharmaceuticals of different purpose, and to use of combinations of pharmaceuticals for achievement of one of the purposes F are proved. Indications to complex F. .monut to be existence at the patient of two and more different patol. processes (in connection with complications or the accompanying diseases), each of to-rykh demands medicinal treatment (e.g., development of a thromboembolism of pulmonary arteries in the patient with a circulatory unefficiency against the background of active rheumatism), or the features of disease demanding simultaneous carrying out both etiological, and pathogenetic or (and) symptomatic F.
Tselyyu of a combination of pharmaceuticals can be strengthening of therapeutic effect (at insufficient efficiency of one drug) or increase in its probability (at the incomplete etiological or pathogenetic diagnosis at the seriously ill patient), a dose decline of the toxic or possessing undesirable actions drug, and also neutralization of undesirable effect of the main medicine. Strengthening of therapeutic effect, as well as dose decline of medicine, is reached by a combination of synergists of exponential or additive action, the means which are mutually supplementing a range pharmakol. actions, and also a combination of the main medicine with the means raising it pharmakol. effect. The combination of Reserpinum and a gidralazin for obtaining hypotensive effect are rational, e.g.; drugs of potassium with glucose and insulin for elimination of Hypaque of a ligistiya (see Gipokaliye mi I) etc. Neutralization of undesirable effect of the main drug is reached by a combination it with antagonists on undesirable effect or, with the means compensating the caused disturbances. For this purpose combine, e.g., nitroglycerine with menthol (antagonism on influence on cerebral vessels at a possible synergism on an antianginal-noma to effect), saluretics about potassium - saving diuretics and drugs of potassium etc.
Mistakes at selection of combinations of pharmaceuticals and their combinations within complex F. are most often caused by insufficient knowledge of the doctor of incompatibility of pharmaceuticals (see) that especially often happens at purpose of medicinal «cocktails» for intravenous infusions and at selection of combinations for neutralization of undesirable effects of medicine without a possibility of decrease in their therapeutic action (as, e.g., at purpose of alkalis for elimination of side effects of salicylates).
The choice of pharmaceuticals or their combination belongs to the most responsible and difficult elements F. It includes comparison of features of action, pharmacokinetics, toxicity and other PROPERTIES SAME the 110th to purpose of drugs with features of a pathogeny of a disease and its manifestations at this patient (taking into account his general condition, existence of associated diseases, Ur-gentnosti of a situation), and also compatibility of pharmaceuticals in need of their combination and other data both on medicine, and on the patient. So, at indications to purpose of cardiac glycosides concerning insufficiency of a myocardium the doctor cannot consider equivalent for the choice such drugs as Korglykonum, strophanthin, Isolanidum, digoxin, digitoxin only because the target cardiotonic effect is equally achievable use of any of them (in equivalent doses). E.g., for prolonged use from the listed drugs cannot be chosen entered only intravenously (Korglykonum, strophanthin), and from applied inside the most adequate are elected for given a wedge, situations. In the presence at the patient of insufficiency of the aortal valve Isolanidum has advantages, to-ry at identical cardiotonic effect to a lesser extent urezhat pulse, than digoxin and digitoksinony the Last drugs have advantages at a takhisistolichesky form of a ciliary arrhythmia since they more oppress atrioventricular conductivity. The accompanying renal failure interferes with the choice of digoxin (drug is removed generally with urine), and a disease of a liver — digitoxin (drug is generally metabolized). At simultaneous use of pharmaceuticals, to-rye belkakhm of plasma communicate (e.g., streptocides) consider competitive ability to such communication at one glycosides (e.g., digitoxin contacts proteins of plasma for 97%) and its absence at others (e.g., at strophanthin). In urgent-ache situations one of important criteria of the choice of this or that medicine is the speed of approach of effect, the maximum to-rogo at intravenous administration of drugs is reached after introduction of Korglykonum in 30 min. (the beginning of action in 5 min.), strophanthin — in 40 — 60 min. (the beginning of action in 5 — 10 min.), and digoxin only through 1 1/2 — 3 hours.
In selection process of pharmaceuticals the principle of «economical pharmacotherapy» is implemented, whenever possible. So, at patients with the raised ABP and coronary heart disease, the shown stenocardia and disturbance of a heart rhythm, instead of the combined use hypotensive (see Hypotenum
zivny means), anti-quinsy
ny (see. Anti-anginal means) and antiarrhytmic (see. Against about arhythmic means) means in some cases it is enough to use only one medicine from group | 3 adrenoblockers (see. Adrenolytic means) for achievement of all required effects (hypotensive, antianginal-ny, antiarrhytmic).
The more experience also is higher qualification of the doctor, the is more successful usually there is a choice of means F., however quite often arising need for use of drugs at even incomplete diagnosis (e.g., in the absence of data on the causative agent of already established acute pneumonia) objectively reduces probability of the choice of medicine, optimum for this case, to completion of inspection of the patient. Therefore the final choice of drug sometimes is by force carried out in the course of treatment, and that it was not only an accidental consequence of «tests and mistakes», the doctor is obliged to analyze the possible reasons of inefficiency of earlier appointed pharmaceuticals for logical justification of the choice new. So, e.g., total absence of effect of use of erythromycin for the patient with an acute pneumonia (if it is not caused by a low dose or decrease in bioavailability of drug) defines the choice of an antibiotic with other action spectrum * and makes illogical the choice of penicillin (less probable effect owing to a similar action spectrum).
Choice of ways and ways of administration of medicines. Distinguish enteral (oral and rectal) and parenteral ways of administration of medicines: bezinjektsionny (sublingual, in the form of inhalations, drawing on skin and mucous membranes) and injection (subcutaneously, intramusculary, intravenously, vnutriarteri-alno), including injections in a cavity (subarakhnoidalno, vnutriplevral-but, in a cavity of joints, etc.). At the same time ways of introduction can differ. So, intravenously the drug can be administered through an aspirating needle and through a catheter, introduction can be bystry (a bolus.) slow jet and slow drop etc.
At the choice of a way and way of introduction degree of urgency of the necessary help, a condition of the systems of an organism providing a biodostuinost of medicine (a stomach and intestines for enteral dosage forms, peripheric circulation for the drugs administered subcutaneously, etc.), and also features of a disease are considered that defines advantages of any dosage forms and ways of introduction of drugs, including need of creation of especially high concentration of drug for blood or for the local center patol. process. The combination of ways of administration of medicine (e.g., intravenous and endobronchial administration of an antibiotic is in some cases reasonable at acute abscess of a lung).
At use of pharmaceuticals inside the ratio of their reception sovre-meny meal, edges, depending on character is of great importance, can significantly influence effect and «destiny» of drug in an organism, changing pH of the environment in a stomach and absorption of drugs, participating in cultivation of drug and interacting with it up to an inactivation. So, e.g., at reception of griseofulvin together with greasy food absorbability of drug increases, at reception of tetracycline with the milk and other products containing Sa ++ or ampicillin with acid fruit juice bioavailability of these antibiotics, etc. decreases. It is reasonable to accept the majority of drugs of resorptive action between meals (in 60 — 30 min. prior to food) if conditions of more rational ratio with a rhythm and character of food are specially not stipulated. Just before food, in time or right after food use, e.g., the drugs intended for participation in digestion (a gastric juice, enzymes of a pancreas, etc.).
Definition of a drug dose is made taking into account a way of its introduction. At the same time distinctions in a dose can be very essential. So, e.g., the daily dose of sodium salt of benzylpenicillin at int-ralyumbalny introduction by the patient with purulent meningitis (2000 — 5000 PIECES) is much less, than at intravenous and intramuscular administration of drug (to 50 000 000 PIECES and more).
Defining an individual dose of drug, proceed from idea of its average dose, i.e. the dose providing therapeutic concentration of medicine in an organism at the chosen way of introduction at most of patients (at the so-called average patient); the individual dose is defined as a deviation from average, necessary for a specific case. Need for reduction of a dose arises in connection with age features or pathology of system of elimination of medicine, at a hypoproteinemia, hypersensitivity or restriction of number of receptors in target organs (e.g., for cardiac glycosides at myocarditis), at individual hypersensitivity of the patient to this or similar but to action medicinal sredstvakhm that is often observed, e.g., in relation to caffeine, derivatives benzdiazepi-on etc. Higher, than average, doses are necessary at decrease in bioavailability of medicine, low sensitivity to it of the patient, and also at simultaneous use of drugs with competitive properties or accelerating metabolism or removal of this drug. The individual drug dose can significantly differ from average, specified in in reference books; e.g., the individual dose of atropine causing dryness in a mouth fluctuates at different persons from 2 to 100 drops of 0,1% of solution. If it exceeds the approved highest dose (see Doses), the doctor is obliged to prove strictly need and a possibility of such exceeding. In the course of use of pharmaceuticals their dose korrigirutsya on observed effect and can change in process of change of a condition of sick and total amount of pharmacotherapy.
Doses are defined with purpose and depending on duration of effect of the entered medicine one-time, daily, and sometimes and course. During the definition of a single dose criterion of its adequacy is the required therapeutic effect in the expected periods of validity of medicine after its single introduction. In some cases the amount of drug for one-time use corresponds to a part of the known daily dose distributed on slightly one-time. For providing a continuity of effect of drugs of short action (several hours) their daily dose is calculated from duration of action of the single dose defining intervals between administrations of medicine within a day. Doses of pharmaceuticals, kumuliruyushchy in an organism or giving cumulation of effect (see Cumulation), can be various in an initiation of treatment (the initial doses sating doses) and on its extent (maintenance doses). Various schemes of initial dosing providing the different speed of approach of effect depending on rates of saturation are developed for such pharmaceuticals (e.g., schemes of bystry, average and slow rate of a digitalization are developed for kumuliruyushchy cardiac glycosides of a foxglove). The supporting daily dose is established in such cases after achievement of therapeutic effect, proceeding from amount of the medicine which is saved up by this time in an organism and coefficient of daily elimination of drug (see Pharmacokinetics). The course dose in most cases is defined by dynamics patol. process under the influence of F. and dynamics of efficiency of the used drug. Decrease in effect in process of their use as a result of a tachyphylaxis (see), accelerations of metabolism owing to induction of enzymes of a liver, antibody formation to medicine and for other reasons is characteristic of a number of pharmaceuticals. For the pharmaceuticals having high toxicity or capable to cause medicinal dependence (see), the course dose has the regulated restrictions on absolute amount of the used drug or on the admissible duration of its use.
The choice of criteria and control facilities of the effect of drugs is necessary both for assessment of therapeutic effect, and for identification of their undesirable actions. As criteria can be chosen dynamics of subjective feelings of the patient (e.g., pains, an itch, thirst, appetite, «quality» of a dream etc.) and dynamics of objective symptoms of a disease. As subjective feelings of the patient have multifactorial conditionality and also aggravations are very changeable regardless of drug intake, not to mention a possibility of dissimulation (see) (see), objective criteria it is more preferable. Their search is desirable also in case of use of pharmaceuticals, the effect to-rykh is estimated preferential subjectively (e.g., analgetics, antidepressants). Sledut to consider, in particular, that disappearance of some symptom of a disease is followed, as a rule, by expansion of range of functionality of the patient; it can be revealed by certain objective tests (e.g., increase in volume of movements of the affected joint after reception of an analgetic, change of behavior and intellectual working capacity after use of antidepressant etc.).
Only those changes in a condition of the patient are chosen criteria of effect or undesirable action, to-rye can be put in reasonable communication using medicine. So, e.g., a convincing indicator of anticoagulating effect of heparin is lengthening of a blood clotting time.
The comparative value of clinical, tool and laboratory methods of a research as means of objective control of pharmacotherapy is defined by degree of specificity of the changes revealed with their help for effect of this drug. The methods allowing to characterize quantitatively controlled changes, but only on condition of not their smaller specificity have advantages. So, e.g., control of saturation by digoxin on dynamics a wedge, displays of heart failure and qualitative changes of an ECG is more adequate and better promotes detection of digitalis intoxication, than on dynamics of concentration of drug in blood, edges is expressed by quantitative parameters, but does not reflect effect of digoxin on a myocardium.
Mistakes at assessment of effects of medicine are most often connected with the insufficient accounting of that circumstance that identification of the changes expected from its action in itself does not prove a causal relationship of these changes with pharmakol. effect of this drug. To the loudspeaker of an observed sign also such reasons as the psychotherapeutic effect similar to effect of placebo can cause (see), adjacent effect of other means applied at the same time (e.g., disappearance of extrasystoles at action anti-quinsy of l of the ny, but not antiarrhytmic drug used at the same time), and also the recovery of the broken functions which is not connected with treatment or regress patol. process owing to the begun recovery or remission of a disease or the termination of influence of pathogenic factors and emergence of conditions for turning on of compensatory mechanisms (e.g., decrease in an exercise stress after hospitalization of the patient). The correct assessment of communication of signs of improvement in a condition of the patient with effect of medicines allows to revaluate timely indications to separate means, to cancel unnecessary (e.g., at sufficiency of adjacent effect) or to replace with more effective.
Justification of cancellation and cancellation of pharmaceuticals conclude F. or its some stage. Continuation F. after recovery of the patient contraindicated. In the course of complex F. need of cancellation of a certain medicine or their combination is proved by achievement of the goal F., what is usually connected or with end patol. process (for means of etiotropic and pathogenetic treatment), or with recovery or compensation of any function, disturbance a cut was defined by indications to purpose of this drug. Besides, can be justification of cancellation of medicine in the course of therapy: a) the decrease or disappearance of therapeutic effect caused by features pharmakol. effects of drug or formation during a disease of irreversible changes in target organs; b) dominance at some stage of therapy of contraindications over indications to medicine on dynamics patol. process or in connection with increase on time of risk of dangerous effects of use of drug; a special case of such justification of cancellation is end of a course for drugs with the regulated course dose or duration of use; c) the manifestation of toxic or side effect of medicine excluding a possibility of replacement of drug (e.g., digitalis intoxication is an absolute contraindication to use of all cardiac glycosides).
Cancellation of medicine is absolutely contraindicated if it is the only means of maintenance of the vital functions — breath, blood circulation, a metabolism. A contraindication to drug withdrawal maybe the decompensation of the functions providing adaptation of the patient to the environment assumed in connection with its cancellation.
At nek-ry diseases, and also inborn and acquired patol. states there is a need for the so-called supporting pharmacotherapy for a long time, sometimes for life. It takes place in cases when medicine is applied as means replaceable F. (e.g., insulin at a diabetes mellitus), during the formation of medicinal and dependent option of disease with threat of a lethal outcome owing to drug withdrawal (e.g., glucocorticoids at the hormonal and dependent course of bronchial asthma), and also at correction of the steady functional disturbances significantly influencing adaptation of the patient to the surrounded environment and the forecast of a disease (e.g., lifelong use of cardiac glycosides for patients with hron. heart failure at heart disease).
At indications and lack of contraindications to cancellation of medicine the doctor defines necessary rate of cancellation taking into account that the changes in an organism caused by drug can gain pathogenic value in case of its single-step cancellation (a so-called withdrawal). Most it belongs to the pharmaceuticals operating at the level of systems of regulation with structures of a feed-back (see. Functional systems), first of all to hormones and means of mediator action. So, e.g., at cancellation development of adrenal insufficiency is long the applied glucocorticoids perhaps (because of a lack of adrenocorticotropic hormone); sudden cancellation of a clonidine at patients with an idiopathic hypertensia happens the reason of heavy hypertensive crises etc. Optional versions of cancellation include: a) the termination of administration of medicine that is possible for the vast majority of drugs in case of their short-term use; b) cancellation by gradual decrease in a daily dose in the terms necessary for regress of the functional changes accompanying pharmakol. to effect (e.g., hypersensitivity of adrenoceptors in connection with use of sympatholytics) or for recovery of the function which was suppressed with medicine (e.g., the secretion of adrenocorticotropic hormone which was suppressed with introduction of glucocorticoids); c) cancellation «under cover» another pharmakol. the drug interfering development of undesirable effects of cancellation (e.g., cancellation of glucocorticoids against the background of the use of an etimizol or other means stimulating function of bark of adrenal glands). Each of the listed options is chosen taking into account the forecast of a so-called withdrawal on the basis of specific data on a pharmacodynamics of drug and a functional condition of the systems participating in manifestations pharmakol. effect.
Features of pharmacotherapy at children and elderly people. To the middle of 20 century of feature F. were studied generally at children, and only in the 60th within a developmental pharmacology (see) the geriatric direction was allocated that was promoted by development of gerontology (see) and geriatrics (see).
The pharmacotherapy at children differs in more difficult approach to definition of its tactics since on the nature of interaction with the majority of pharmaceuticals the organism of the child approaches a vzroslokhch to an organism only by 12 — 14 years. Distinctions in a condition of the systems reacting with medicine and defining its transport, metabolism and removal during the different periods of post-natal development of the child are so essential that excludes any standardization in tactics F. children without degree have development of these systems for this age period.
Most of all features of interaction of an organism with medicine are expressed at newborns and babies. For bioavailability of drugs in enteral dosage forms during these periods the richness of circulatory and lymphatic vascularization of a stomach and intestines, low gastric acidity (is 3 — 4 times lower, than at adults), high-permeability of a time of an intestinal wall for large molecules has essential value. In general these features facilitate passive transport of pharmaceuticals, especially alkaloids (Reserpinum, caffeine, etc.) while bioavailability of the drugs demanding active transport at babies is reduced (tetracycline, Riboflavinum, Retinolum are worse soaked up, e.g.). The amount of albumine in plasma of newborns and babies is reduced, many pharmaceuticals communicate proteins less strongly, than at adults, and are easier forced out by natural metabolites, napr, bilirubin. It creates at a toviya for the raised desorption (release from communication with protein) of the pharmaceuticals connected by proteins (digoxin, streptocides, etc.) and increase in free fraction of drug in blood with the corresponding increase of action up to toxic that it is especially important to consider at a hyperbilirubinemia of newborns and at the combined use of the pharmaceuticals competitively connected by proteins of plasma. Nek-ry drugs of subjects are more slowly removed from blood, than the child is younger. So, the elimination half-life from blood of diazepam at premature newborns is twice longer, than at full-term, and is 4 times longer, than at children of 4 — 8 years.
Distribution of pharmaceuticals in an organism of the child happens on the same patterns that at the adult, but penetration of the majority them in various, including a brain, at newborns and babies is higher than orga-Ghana, than at children of advanced age because of incomplete development of gistogematiche-sky barriers (see. Barrier functions). By it it is caused, in particular, the increased receipt in a brain of various fat-soluble pharmaceuticals, including a number of sleeping pill, the oppressing action to-rykh on a brain of newborns is more expressed, than at adults; at the same time many of these pharmaceuticals are to a lesser extent occluded by tissue of a brain since at newborns it contains less lipids. Features of kinetics of water-soluble pharmaceuticals are defined also by the large volume of extracellular water in an organism of newborns and babies, and also high rate of exchange of extracellular water (almost by 4 times to higher, than at adults) that promotes more bystry removal of drugs.
The metabolic inactivation of pharmaceuticals at children is limited in connection with the smaller mass of a parenchyma of a liver, low activity of oxidizing enzymes and systems of a detoxication by formation of conjugates with glucuronic to - that, completing the formation only by 12 years. Newborns have an activity of R-450 cytochrome in 1kh/2 time, and than conjugates cytochrome - with - reductases are 21/2 times lower, than at adults, efficiency of a detoxication of pharmaceuticals in the first days after the birth of the child is reduced in connection with low activity hepatic at ri dindifosfat (UDF) of a glyukuronoziltransferaza. At newborns also qualitative differences in the biotransformations of a number of pharmaceuticals (e.g., aminazine, diazepam, Promedolum) which are characterized by formation of the metabolites which are not found in children of advanced age and in adults are established. It complicates generalization of features of metabolism of pharmaceuticals at children for recommendations about pharmacotherapy since the abundance of exceptions of the determined consistent patterns demands knowledge of features of biotransformation of separate drugs. It is known, e.g., that at newborns and babies metabolism of pyramidon, quarrystone of a dion, diazepam, levomycetinum, morphine and some other drugs is considerably slowed down. Enough obos-novannykhm it is necessary to consider situation, according to Krom at children the speed of the metabolism of pharmaceuticals which is coming to the end with formation of conjugates with a chamois to - that, significantly does not differ from that at adults, and for the pharmaceuticals inactivated as a result of formation of conjugates with glucuronic to - that, metabolism of subjects more slowly, than the age of the child is less.
Removal of medicine kidneys at newborns and children of the first year of life in general is slowed down as because of lower, than at adults, glomerular filtering (on release of creatinine — approximately twice) and smaller permeability of a basal membrane of renal balls, and owing to incomplete development of the fermental systems providing excretion in tubules of kidneys of medicine and their metabolites. Nek-ry drugs, napr, penicillin, at children at the age of 2 — 3 months are removed with the same speed, as at adults.
At the choice of medicine, except features of its pharmacokinetics at children, consider also features of its pharmacodynamics, to-rye depend on the level of development of the systems defining implementation pharmakol. effect at this age of the child. So, e.g., hypotensive action of ganglioblokator (see Ganglioblo-kiruyushchy means) at children of the first two years of life is shown poorly, at babies the hypertensive effect of ephedrine at the expressed influence on the ABP of a phenylephine hydrochloride is weakened, etc. The therapeutic importance expected pharmakol. effect correlate to risk of undesirable effects of drug, the probability and character to-rykh are not identical at children of different age and at adults. So, e.g., in comparison with children of advanced age at children of the first 3 months of life the probability of development of hemolysis and a methemoglobinemia owing to use of nitrofurans, Vikasolum and other drugs is much higher that it is caused by high content in their blood of fetalis hemoglobin (see). The probability of toxic effect of drugs in equivalent (per unit mass bodies) doses at newborns and babies for nek-ry pharmaceuticals is lower (adrenaline, strychnine), for others — above (morphine, levomycetinum, tetracycline, etc.)*. Taking into account undesirable effects of medicines of I. V. Markov and
V. I. Kalinichev (1980) allocate: groups of drugs, use to-rykh at newborns no more dangerously, than in other age groups (penicillin, macroleads, nystatin, caffeine, phenobarbital, etc.); the pharmaceuticals applied with care (atropine, aminazine, pyramidon, cordial glycosides, an Euphyllinum, gentamycin, lincomycin); the means contraindicated to the newborn (levomycetinum, tetracycline, Kanamycinum, Monomycinum, nalidixic to - that, streptocides, salicylates, morphine and morfinopodobny analgetics).
Definition of a dose of drug at children cannot be limited to search of criteria of equivalence to a dose of the adult (on the body weight, a body surface, etc.) since metabolism and removal of pharmaceuticals at children can qualitatively differ from those at adults. Average doses of drugs define from a wedge, experience of their use in different age groups of children. On the basis of such experience determine the general consistent patterns of dosing in mass units (grams, milligrams), the volume (drops, milliliters), activity on 1 kg of weight or 1 sq.m of a body surface or for 1 month or 1 year of life of the child for separate pharmaceuticals (anaprilin, an Euphyllinum, etc.), and in more difficult expression — in milligrams on 1 kg of weight for the separate age periods (taking into account age changes of systems of metabolism of drugs and reactivity of an organism of the child).
The choice of criteria of effect and control facilities of medicinal action at children in all age groups is limited by generally objective signs of dynamics patol. process, a syndrome or a symptom since subjective criteria (dynamics of complaints of the patient) are much less valuable, than at adults, and at children of the first year of life cannot be received at all. Also use of the objective tools of control demanding active participation of the patient in a research is limited (a certain pose, any delay or strengthening of breath, etc.). All this creates difficulties for providing controlled F., especially at children of early age. Respectively value continuous a wedge, overseeing by the slightest deviations in a condition of various functions and behavior of the child against the background of use of medicine, especially in its expected terms pharmakol increases. actionI.
Cancellation of pharmaceuticals at children is made on the same justifications, as at adults.
The pharmacotherapy gains features in process of changes from persons of advanced and senile age, to-rye undergo during the aging of an organism a metabolism, functions of barrier fabrics, systems of metabolism and removal of drugs, and also sensitivity to pharmaceuticals of various bodies and reactivity of an organism in general. Insufficient care in the choice and dosing of pharmaceuticals for patients of advanced age is, apparently, one of the reasons of side effects of drugs, to-rye at persons 70 years, according to different researchers are more senior, are observed by 3 — 7 times more often than patients have 20 — 30 years.
Bioavailability of the drugs applied enterally at advanced age decreases because of decrease in secretory, motor and vsasyvatelny function went. - kish. path. Distribution of drugs is influenced by decrease in water content, characteristic of persons of advanced and senile age, in an organism and amounts of albumine in blood, a degrowth of most bodies, numbers of the functioning blood vessels and narrowing of their gleam, change of permeability of gistogematichesky barriers (see. Barrier functions). The mass of a parenchyma of a liver at persons is more senior than 70 years is reduced, anti-toxic function of a liver is reduced, activity of oxidizing enzymes is weakened. Delay of metabolism of pharmaceuticals, in particular that is connected with it, the inactivation to-rykh comes to the end with sulfating. Also the speed of removal of pharmaceuticals by kidneys in connection with weakening of volatile excretion through an epithelium of tubules, reduction of number of the functioning nephrons (at persons 70 years become more senior than them 30 — 50% less), decrease in efficiency of a renal plazmotok and glomerular filtration rate is reduced.
Tactics F. at persons of advanced and senile age shall provide: restriction of the choice of pharmaceuticals with low-toxic; purpose of higher doses at initial use of drugs in enteral dosage forms; a dose decline of the drugs (especially at parenteral administration) emitted by kidneys or in a slowed-up way metaboliziruyemy in a liver. And doses of the nek-ry pharmaceuticals (neuroleptics, cardiotonic means, diuretics, etc.) recommended to persons of advanced and senile age for initial use average 1/2 doses of the adult of middle age. However these provisions extend not to all pharmaceuticals (e.g., vitamins, many antibiotics and streptocides can be applied in usual doses) and therefore for development of rational tactics of pharmacotherapy it is necessary to consider an originality pharmakol. effects, a cut at persons of advanced and senile age is defined by changes of sensitivity to certain pharmaceuticals and even qualitative changes of reactions to separate drugs.
At persons of advanced and senile age natural features of reactions to the pharmaceuticals operating on c are established. N of page that connect, in particular, with increase in process of aging of an organism of dystrophic changes in neurons, with reduction of number of nervous cells and the number of axons, and also with decrease in functional activity of c. N of page. It is shown that for manifestation of exciting action on c. the N of page of Phenaminum, strychnine, ephedrine at elderly people are necessary high doses of these drugs, than at middle-aged persons. To pharmaceuticals, the oppressing c. the N of page, in particular to barbiturates and other hypnagogues, neuroleptics of different groups, including Reserpinum, to narcotic analgetics, a nek-eye to derivatives of benzdiazepine (chlordiazepoxide), etc., is marked out, on the contrary, hypersensitivity. Straight line pharmakol. the effect (see the Pharmacodynamics) these drugs is reached by smaller doses and quite often combined with the expressed manifestations of undesirable action (respiratory depression, a muscular relaxation, excitement of the emetic center), use of these pharmaceuticals in the doses which are therapeutic for middle-aged persons often leads to intoxication. Thus, it is necessary to observe extra care at use for elderly people even of low-toxic hypnotic drugs and sedatives (poisonings with Noxyronum, bromides are described, e.g.), especially neuroleptics.
More often than in other age groups, elderly people have a need for use of cardiotonic, hypotensive and diuretic means. Wedge, observations indicate hypersensitivity of a myocardium of people of this age group to toxic action of cordial glycosides that few kumuliruyushchy drugs make preferable the choice, slow rates of an initial digitalization and demands more frequent control of adequacy of the picked-up dose. At the choice of antihypertensives consider the increased danger of falloff of the ABP and an orthostatic collapse at use of ganglioblokator, sympatholytics, uses of the pharmaceuticals reducing cordial emission and also means, to-rye, perhaps, it is undesirable influence c. N of page (Reserpinum, gidrala-zin). Under the influence of saluretics elderly people can have more expressed losses of potassium (per unit of volume of a diuresis) at the worst, than at middle-aged persons, portability of these losses and ability to recovery of electrolytic balance; at the same time hypersensitivity to action of antagonists of Aldosteronum is quite often noted owing to what they can be applied in smaller doses.
There are bases to consider that to increase in efficiency and decrease in undesirable effects F. at persons of advanced and senile age simultaneous use of vitamin complexes, in particular vitamins of Vkh promotes, to Wb, B15.
Features of pharmacotherapy of v of pregnant women and nursing mothers. Prevention of undesirable influences on a fruit and on the baby of the pharmaceuticals getting through a placenta or allocated with milk of mother take the central place in tactics F. at pregnant women and nursing mothers. Catastrophic effects of use in the late fifties the pregnant women of a thalidomide (see) expressed in the birth of thousands of children with heavy inborn malformations stimulated researches of teratogenic activity and properties of pharmaceuticals, other, dangerous to a fruit, in nek-ry foreign countries, knowledge to-rykh is the main condition of tactics F. at pregnant women. However and without influences of medicine on a fruit (e.g., at treatment of the pregnant woman according to vital indications) F. has the features caused by reorganization of a metabolism in an organism of the pregnant woman and participation of a placenta and fruit in kinetics of the used drugs. Therefore features of tactics F. at pregnant women it is necessary to consider as without taking into account, and taking into account influence of medicine on a fruit.
Features of pharmacotherapy at pregnant women without taking note of medicinal about means of N and a fruit. Features F. in the second trimester of pregnancy are connected with the progressing increase of level of all triple hormones of a hypophysis and the secondary change of a metabolism and water caused by hormonal activity of so-called fetoplacental unit (the developing fruit and a placenta); to the third trimester in connection with growth and fetation, in addition, noticeable participation of a fruit in distribution of the pharmaceuticals getting through a placenta is observed.
Increase in secretion of thyritropic hormone leads to relative hyperfunction of a thyroid gland at pregnant women with increase in standard metabolism for 15 — 20% and acceleration of metabolism of substances that is promoted by also considerable gain of secretion of somatotropic hormone; at the same time also metabolism of pharmaceuticals increases. Plastic processes in this connection uvelichivav the need of an organism for protein, vitamins, microelements etsyatsya amplify. The progressing growth of secretion of adrenocorticotropic hormone and hormonal activity of a placenta cause substantial increase of contents in an organism of pregnant women of steroid hormones — a cortisone, estrogen, progesterone, mineralokortikoid. As a result of it tolerance to glucose decreases, in an organism sodium is late and the amount of both cellular, and extracellular water increases that changes distribution of water-soluble pharmaceuticals. The body weight, mass of the circulating blood increases, the ABP raises, the minute volume of blood circulation and a renal blood stream increases, also release of medicines accelerates. Despite substantial increase in blood of pregnant women of level of glucocorticoids, Cushing's syndrome (see Cushing a syndrome), as a rule, does not develop that is caused by binding by their protein of plasma — transcortinum, products to-rogo in proportion increase. However development of this syndrome is possible at use of the pharmaceuticals which are forcing out cortisol from communication with protein (e.g., Butadionum).
In process of growth of a fruit at pregnant women vnutribryush-ny pressure increases that reduces absorbability in intestines and bioavailability of the pharmaceuticals entered rektalno; the blood stream with switching of its essential part to a placenta is redistributed that increases intake of medicines in a fruit.
Thus, changes in an organism of the woman during pregnancy since its second trimester increase its exogenous chemical substances resistance, including to pharmaceuticals, due to their cultivation in the bigger mass of aqueous mediums of an organism that leads to decrease in concentration of drugs in blood and in liquid of fabrics, their distributions in the bigger body weight of the pregnant woman and in addition in fabrics of a fruit (decrease in concentration in target organs), accelerations of metabolism and removal of pharmaceuticals (reduction of the period pharmakol. activity or toxic action). Respectively during the carrying out F. at pregnant women without taking note of pharmaceuticals on a fruit preference should be given to the means applied parenterally (the period of achievement of therapeutic concentration in blood is reduced); it is necessary to raise doses of the majority of drugs (at least in proportion to growth of body weight) and to reduce intervals between their repeated introductions maintaining therapeutic concentration. These features do not extend to carrying out F. at pregnant women with toxicoses (see Toxicoses of pregnant women).
Features of pharmacotherapy at pregnant women taking into account influence of pharmaceuticals of N of an ii of l about. A placental barrier, being permeable in different degree for the vast majority of pharmaceuticals, interferes with transition from blood of the pregnant woman to a fruit of corpuscles, large molecules and molecular complexes. Getting to blood and fabrics of a fruit, drug can cause: a) pharmakol. effect; b) embriotoksichesky action; c) disturbance of fetation; d) teratogenic action.
Pharmakol. the effect in an organism of a fruit depending on a dose of drug can significantly differ from observed at the pregnant woman. So, appointment of indirect action as the pregnant woman of anticoagulants in doses, to-rye cause in it moderate decrease in a prothrombin, can cause multiple hemorrhages in fabrics of a fruit. Quantitative and qualitative features pharmakol. effect in an organism of a fruit are defined by imperfect development of its systems interacting with pharmaceuticals, features of their distribution in fabrics (e.g., in a brain of a fruit of a phenylephine hydrochloride collects 3 times more, than at the pregnant woman), metabolism and removal.
Embriotoksichesky action is most inherent in the pharmaceuticals inactivated by their metabolism since enzymatic activity of microsomes of a liver at a fruit low. Are explained by imperfect metabolism high toxicity for a fruit of levomycetinum, morphine, barbiturates of short action (hexobarbital, thiopental) at smaller toxicity of barbiturates of long action (bars-bits of l, phenobarbital), to-rye are brought out of an organism in not changed look. A peculiar form of unusual effect of the medicines which are forcing out the bilirubin (so-called jaundice of brain kernels) connected with protein is observed at a fruit at appointment to pregnant women is long or in high doses of the pharmaceuticals connected by proteins of plasma (streptocides, diazepam, a hydrocortisone, etc.) that is caused by weakness of a blood-brain barrier at a fruit and fragile communication of bilirubin with protein of plasma.
The mediated influence of pharmaceuticals on fetation has the different forms. E.g., treat them: disturbances of breath of a fruit owing to decrease in a placental blood-groove or an anoxemia, to-rye can take place at use by pregnant women of the adrenomi-metik causing a vasospasm, the means connecting hemoglobin (nitrates), the drugs provoking an exacerbation of bronchial asthma at the pregnant woman (acetilsalicylic to - that, etc.); vitamin deficiency of group B at use of antibiotics, diuretics, purgatives; deficit of calcium at use of tetracycline; a syndrome of a hypercorticoidism (see Adrenal glands) due to replacement of cortisol by the drugs connected by proteins of plasma.
Teratogenic effect of medicines is most shown in so-called critical periods of an embryogenesis — the period of implantation (the first week after conception), the period of placentation (9 — the 12th week) and especially in pe.riod an organogenesis on 3 —-y to week of pregnancy (see the Teratogenesis). From the second trimester of pregnancy the probability of teratogenic effect of medicines decreases, but completely is not excluded since thin processes of a functional differentiation of fabrics of a fruit continue. Believe that teratogenic action is more inherent in the drugs capable to join in a metabolism of a fruit in connection with similarity of their chemical structure to natural metabolites (e.g., teratogenic activity of a thalidomide connect with similarity it with Riboflavinum). In experiments on animals of anomaly of fetation causes a large number of pharmaceuticals, but at the same time also specific differences are established that reduces the value of experimental data for the forecast of teratogenic influence of separate drugs at the person. From the means influencing c. N of page, teratogenic activity is found, except a thalidomide, in derivatives of a fenotiazin, to-rye cause various anomalies of development in animals and a fokomeliya in the person (see Malformations), Reserpinum, meprobamate, chlordiazepoxide; high teratogenic activity of nek-ry vitamin drugs, in particular Retinolum (splitting of the sky at 100% of animals, an anencephalia — at 50%, the microphthalmia, lack of a crystalline lens), nicotinic to - you, and also bin-zilpenitsillina (a syndactylia at 45% of animals are possible), adrenocorticotropic hormone, a cortisone, cytostatic means is experimentally established.
Thus, taking into account influence of pharmaceuticals on a fruit any F. in the first trimester of pregnancy has relative contraindications in connection with data on teratogenic activity of drugs, incomplete in a crust, time. During the subsequent periods of pregnancy there are contraindications to drugs with embrio-toxic action and breaking normal fetation, and also to the pharmaceuticals influencing patrimonial activity. T. it is carried out during this period only according to serious indications, including developing of diseases, to-rye in itself break the course of pregnancy and fetation.
Most often need for use of pharmaceuticals for pregnant women arises
in connection with inf. diseases, and also with the phlebothromboses which are quite often complicating the course of pregnancy, arterial hypertension, hypostases. At the choice of drugs in these cases consider their comparative danger to a fruit during this period of pregnancy.
From antibacterial agents in the first trimester of pregnancy of advantage have the ampicillin which does not have teratogenic activity, Oxacillinum which is badly getting through a placental barrier, a combination of these drugs (ampioks) and also cephalosporins (see), however in high doses these drugs, as well as streptocides, can cause emergence in a fruit of «jaundice of brain kernels». Rather badly erythromycin gets through a placental barrier (concentration in plasma of a fruit 5 times less, than in plasma mothers). In the first trimester of pregnancy streptocides of the prolonged action since they have teratogenic activity are contraindicated. During the entire periods of pregnancy it is necessary to exclude use of tetracycline and levomycetinum possessing the expressed embriotoksichesky action.
From anticoagulants heparin is preferable, to-ry does not pass through a placental barrier and therefore it is harmless to a fruit. Indirect anticoagulants are contraindicated not only because of danger of hemorrhages at a fruit, their use in the first trimester of pregnancy threatens also with anomalies of development.
Antihypertensives and diuretics often apply at toxicosis of the second half of pregnancy when teratogenic action is improbable. Introduction of Methyldopa is more preferable, is more rare — ismeli-on, at hypertensive crises — apressine (40 — 100 mg intravenously) and hypothiazid (150 — 200 mg in/in) in the form of single injections (it is necessary to remember that prolonged use of hypothiazid causes development in a fruit of a hyperglycemia, hyperbilirubinemia, thrombocytopenia). Reserpinum, biotransformation to-rogo it is slowed down even at the newborn, in a daily dose for the pregnant woman more than 0,5 mg can cause hypersecretion in a nose and bronchial tubes of a fruit and thereof obstruction of respiratory tracts. Uses of ganglioblokator avoid because of threat of mekoniyevy impassability at a fruit.
From diuretic means furosemide has teratogenic activity, but in the second half of pregnancy its use is practically not limited. During the use of hypothiazid at pregnant women with a preeclampsia consider a possibility of increase at the same time in level uric to - you in blood.
Features of pharmacotherapy at nursing mothers come down to decrease in danger of undesirable effect of the drugs accepted by mother on the baby. Get during the feeding to an organism of the child and the drugs used for washing of nipples, in particular solutions boric to - you can have toxic effect (kumulirut in tissues of the child, lead to a metabolic acidosis and damage of kidneys) and lead acetate (threat of lead intoxication with development of encephalopathy). The women applying such solutions shall wash carefully before feeding of the child nipples water.
Release of different medicines mammary gland variously; concentration nek-ry of them in breast milk (e.g., tioura-tsit) can be several times bigger, than in a blood plasma of mother that can cause and pharmakol. effects, and toxic action on an organism of the child. Even the small amount of pharmaceuticals getting into breast milk is not always safe as concerning toxic action (because of imperfection of metabolism of pharmaceuticals in an organism of the baby), and owing to a possible sensitization of an organism of the child with formation of a medicinal allergy (see). Are contraindicated to nursing mothers of salt of lithium, thiouracil, nalidixic to - that, amantadin, drugs of gold, radioactive drugs of calcium, iodine. Than the age of the baby is less, especially treatment of mother Tubazidum (breaks digestion of vitamin of Wb), levomycetinum (toxic action), tetracyclines (disturbance of development in the child of teeth, a skeleton) is contraindicated; with care streptocides, salicylates shall be applied. In need of use by the nursing mother of these drugs it is long or in high doses it is reasonable to transfer the child to artificial feeding.
Problems and tendencies of development of modern pharmacotherapy. At all stages of development and in a crust, time the main problems F. there are an increase in its efficiency and safety of treatment pharmaceuticals.
Decisive contribution to increase in efficiency F. brought achievements of pharmacology, thanking the Crimea for the last 30 years in practice F. new classes of highly effective pharmaceuticals, including neuroleptics, antidepressants, small tranquilizers, hormonal drugs, means of mediator action, new classes of hypotensive, anti-anginal, antiarrhytmic means, etc. are implemented. Thanks to it the current and the forecast of an idiopathic hypertensia, coronary heart disease, a diabetes mellitus and other diseases of endocrine system, mental diseases, kollagenoz, etc. significantly changed. At the same time high pharmakol. activity of modern pharmaceuticals considerably increased risk of dangerous effects of their unreasonable or uncontrolled use. Frequency of side effects of pharmaceuticals increased (see) and the related heavy outcomes, there were lekarstvennozavisimy forms of a course of diseases, changes of reactivity and immunoresistance of an organism are noted, danger of adverse influence of a number of drugs on reproduction of posterity came to light.
In the created conditions became obvious lag in development of the general principles F., and also insufficiency of information for the forecast of the efficiency and undesirable effects of medicinal treatment received at a research of effect of medicines by traditional methods of experimental pharmacology. It defined the main tendencies of development F. at the present stage: communication of a research of the main problems F. with development a wedge, pharmacology (see Pharmacology clinical) and the decision them is preferential in the direction of improvement of tactics F. on the basis of generalization a wedge, experience of use of pharmaceuticals taking into account this developing directions in pharmakol. researches — biopharmacy (see), patol. pharmacology (studying of the changes of medicinal action determined by pathological process), a developmental pharmacology, a pharmacogenetics (see) etc.
Especially the importance is attached to those elements of tactics F., to-rye are directed to the prevention and decrease in danger of side effects of drugs. In an essential measure it is connected with development and practical implementation of the general principles F., in particular requirements to justification of indications to use of pharmaceuticals. Development of bases of forecasting of undesirable effect of drug in specific a wedge, situations belongs to perspective problems of this direction that would improve tactics of its choice as it is realized, e.g., in the developed recommendations on F. at pregnancy taking into account embriotoksichesky effect and teratogenic activity of drugs.
Remains urgent also fight against a polypragmasy, prevalence a cut in all countries is connected with the lag of programs of training of doctors taking place from the progressing qualitative change F. in the conditions of «pharmacological explosion». In a crust, time in the program of training of medical students in the USSR courses a wedge, pharmacology with fundamentals of pharmacotherapy, and are entered into the unified programs of improvement of doctors — thematic cycles of improvement on clinical pharmacology. The improvement of medical recommendations to the patient on use of the appointed pharmaceuticals (especially in out-patient practice) directed to decrease in probability of mistakes in dosing and monitoring effect of the used drugs is of great importance. Important addition in modern tactics F. allocation of criteria and development of methods of early diagnosis and elimination of side effects of pharmaceuticals is that is the most real for drugs, toxic and side effects to-rykh give in to systematization. Can be examples of expediency of such approach already available experience of early diagnosis and treatment of digitalis intoxication, and also attempt of use of inductors of mikrosomny enzymes of a liver for acceleration of elimination of kumuliruyushchy pharmaceuticals at their excess effect or toxic action.
In increase in efficiency F. along with traditional development of the schemes of rational treatment of a separate disease (including the choice, dosing, a combination, the sequence of use and cancellation of drugs) the increasing value get improvement of the general tactics of use of pharmaceuticals on the basis of the multilateral accounting of the factors influencing interaction of an organism with drugs and also improvement of control facilities F., what creates premises to individualization of medicinal treatment. In this respect further studying of genetically caused distinctions in interaction of an organism and medicine is represented perspective. Practical value already got allocation among sick so-called slow and bystry «acetylizers», for to-rykh essential distinction in therapeutic, and also toxic doses of pharmaceuticals, meta-boliziruyemykh N-atsetiltransfera-zoy is established (an isoniazid, nek-ry streptocides, apressine, novokainamid, etc.). Researches of the last years showed also that effect of medicines can in an essential measure change depending on its coincidence on time to certain periods of biological rhythms (see) — daily allowances, an eye-lonedelnykh, okolomesyachny, seasonal, etc. (see also St. Biological rhythms, t. 5, additional materials). The interrelation of effect of medicine with biorhythms is studied within a recent trend — a hronofarmakologiya and is established for many steroid and nonsteroid hormones, nek-ry anticoagulants and others pharmakol. means, and also tsitostatik. To increase in efficiency F. the accounting of new data on compatibility of pharmaceuticals with ingredients of food (for enteral dosage forms), wider use of combinations of pharmaceuticals of exponential action, rationalization of ways of administration of drugs promotes (e.g., by catheterization of cavities, regional arteries, etc.). The important place in improvement of tactics F. it is allocated for development and deployment of available methods of objective control of effect of medicines directly in the course of F., what allows to estimate adequacy of the choice of drug, its single dose, to define necessary intervals between repeated introductions, to estimate expediency of a combination with synergists, to track dynamics of effect throughout treatment etc.
Characteristic of the present stage of development F. the tendency to justification and use of the differentiated approaches in definition of tactics is F. depending on features of formation and display of pathology, deterkhminiro-bathrooms individual qualities of the personality and an organism of the patient. To approach practicians F. to a formula «treat the patient, but not a disease» escalating opportunities a wedge, estimates of features of an organism of the patient, its reactivity, a functional condition practically of all bodies and systems on the basis of achievements a wedge, geneticists (see the Geneticist of the person) objectively promote, to allergology (see), immunology (see), widespread introduction in a wedge, practice of inspection of the patient (see) continuously improved methods of functional diagnosis (see), laboratory diagnosis (see), pharmakol. tests. Important value has also creation and modern production at the same time several pharmakol. drugs, same on purpose, but differing on pharmacokinetics, a range pharmakol. effects etc. that allows to carry out the choice of drug, the most adequate to features. courses of a disease and to a condition of functions of various systems at the diseased.
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