With repeated administration of drugs, their effect can either increase or decrease. The increase in effect is associated with their accumulation in the body or organs. This phenomenon is called cumulation. Material cumulation occurs when a drug is slowly eliminated from the body and accumulates in it in toxic quantities, so the next administration of the drug should be carried out after its significant elimination or destruction.
Functional cumulation, when the effect accumulates, and not the substance, i.e. the next dose of medicine is received when the function of the organ or system has not yet recovered from the first administration. This can happen when some anticholinesterase drug is removed from the body or destroyed, and the amount of cholinesterase has not yet been restored to physiological levels. Then, with repeated administration of the drug, the function of the organs increases beyond the limits of possible physiological fluctuations, i.e., a toxic effect occurs.
The decrease in effect with repeated use of drugs is called addiction, i.e., tolerance to analgesics, laxatives and other drugs occurs. It may be associated with a decrease in the absorption of the substance, an increase in the rate of its inactivation and excretion, a decrease in the sensitivity of receptor formations to the substance, or a decrease in accumulation in the tissue.
One type of addiction is tachyphylaxis - addiction that occurs very quickly, sometimes after a single injection. For example, ephedrine, with frequent repeated administration (after 10-20 minutes), causes a smaller increase in blood pressure than with the first injection.
Some substances (usually neurotropic drugs) develop upon repeated administration. drug addiction. It manifests itself in people as an irresistible desire to repeat
taking a substance, usually with the aim of increasing mood, improving well-being, eliminating unpleasant experiences and sensations that arise when the effect of a previously administered substance ceases.
Idiosyncrasy- increased sensitivity to medicines. This happens after intravenous administration of iodine, bromine, and some antibiotics to small domestic animals, and to cats - phenol-containing substances.
IN practical conditions It is often necessary to administer to animals not one drug, but several at the same time, since one drug often does not provide the desired effect. There are cases when it acts for a short time or has not only a positive effect, but also a side effect, etc. For example, to obtain anesthesia, muscle relaxants are combined with inhaled or non-inhaled narcotic substances, local anesthetics with small doses of muscle relaxants, and a number of other combinations. The combined administration of medicinal substances that provide the osmotic pressure of blood plasma, and therefore replace it (Ringerag-Lock solution), or a digestive aid (artificial Carlsbad salt) has long been used; for angina pectoris, mixtures of cardiac, sedative and antispasmodic drugs (Watchal drops) are often used.
A combination of two or more similarly active substances is called synergy. If they act in the same direction, as a result of which a more pronounced effect is observed than when each of them is prescribed separately, and on the same system, we speak of direct m om s i n e r g i s m e (the effect of plant astringents and bismuth compounds in the intestines or hypnotics and non-inhalation narcotic substances). Indirect (indirect) synergism - when substances act in one direction, but on different systems(pupil dilation with solutions of atropine and adrenaline).
If, when two drugs are administered, the pharmacological effect is higher than expected, then this phenomenon is called bytending(potentiation of the neuroleptic aminazine and the non-inhalation narcotic substance chloral hydrate when used in small doses).
Antagonism- the opposite effect of two or more substances, when one substance eliminates the effect of the other. It can be physical, chemical and physiological (direct and indirect).
Physical antagonism - when one substance introduced into the body creates a physical obstacle to the action of another drug. Thus, a solution of adrenaline, injected subcutaneously or otherwise, constricts blood vessels and thus prevents the absorption of other substances; activated carbon, adsorbing toxic substances in the gastrointestinal tract, prevents their absorption into the blood.
Chemical antagonism - when a drug reacts with another, the result is a substance that has no pharmacological activity. The action of antidotes is based on this. For example, acids are neutralized with alkalis, heavy metal compounds - with a solution of unithiol or calcium tetatsine or other substances.
However, physiological antagonism is most often possible, i.e., the opposite effect on the same physiological systems body. In this case, there is direct and indirect (indirect) antagonism. Spicy antagonism when two substances act oppositely on the same system (synapses, etc.) or organs. For example, atropine solution dilates the pupil, and pilocarpine constricts it, or the first substance relaxes the smooth muscles of the intestines, and the second contracts them. This happens because both substances act in the area of the endings of cholinergic nerves (on the postsynaptic membrane of cholinergic synapses) in diametrically opposite ways, therefore the function of the innervated circular muscle of the iris changes differently. Or, for example, central nervous system stimulants and narcotic substances act differently - some stimulate the central nervous system, others depress it. This circumstance is used in veterinary practice in case of overdose of certain substances.
When two substances cause opposite effects in organ function, acting on different nerve structures or enzymes, then indirect antagonism appears. For example, the pupil narrows after applying carbacholin to the cornea of the eye (acts on cholinergic synapses in the circular muscle of the iris, which leads to its contraction - miosis), and adrenaline (acts in the area of the endings of adrenergic nerve endings, located in the radial muscles of the iris similar to their excitation) causes pupil dilation.
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 cumulation. Under material cumulation They mean the accumulation of a pharmacological substance in the body. This is typical for a long time active drugs, which are slowly released or 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 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.
Decrease in the effectiveness of substances upon their repeated use - addiction (tolerance)) - 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 - addiction, which occurs very quickly, sometimes after the 1st administration of the substance. Thus, ephedrine, when repeated at intervals of 10-20 minutes, causes a lesser rise in blood pressure than with the first injection.
Some substances (usually neurotropic ones) develop drug dependence 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 experiences and sensations, including those that arise when withdrawing from substances that cause drug addiction. There are mental and physical drug dependence. In case mental drug dependence stopping the administration of drugs (eg, cocaine, hallucinogens) only causes emotional 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, manifests itself in a variety of and often serious somatic disorders associated with dysfunction of many body systems up to fatal outcome. This is the so-called withdrawal syndrome, or phenomena of deprivation.
4. Drug interactions. Phenomena that occur when two and/or more drugs are administered together.
Drug interactions
Simultaneous administration of several medicines(polypharmacy) may be associated with the simultaneous treatment of several diseases. However, even when treating one disease, several drugs are often prescribed to increase therapeutic effect
There are pharmaceutical and pharmacological interactions of drugs.
Pharmaceutical interaction is possible when drugs are administered together in one syringe, one drip system. Pharmacological interactions are divided into pharmacokinetic and pharmacodynamic interactions.
Phenomena that occur during repeated administration of drugs.
Most medications are used in courses of several days, weeks, months, and sometimes throughout life.
You need to know that repeated use of drugs may strengthen them. pharmacological effect due to cumulation.
Cumulation (Latin cumulatio - increase, accumulation) - accumulation in the body of drug molecules (material cumulation) or their effects (functional cumulation).
Material accumulation is typical for lipophilic substances with low hepatic and/or renal clearance and long period semi-elimination. In the clinic, it is necessary to take into account the accumulation of phenobarbital, bromides, digitalis cardiac glycosides (digitoxin, celanide, digoxin), and indirect anticoagulants.
Cumulation has both positive and negative meanings. Positive value associated with prolongation of the action of drugs, the possibility of their infrequent use, for example, patients with severe congestive heart failure may not take cardiac glycosides at night. The negative value of cumulation is due to the danger of intoxication as a result of summing the dose of the re-administered drug with its amount retained from the previous prescription; in order to eliminate intoxication, it is necessary to take cumulating agents in a maintenance dose equal to the amount of the substance eliminated per day. Maintenance dose = Full therapeutic dose ´ KEC% /100%
EC – elimination coefficient (percentage of the dose eliminated per day).
Relative material cumulation occurs in diseases of the liver and kidneys, as well as in children and the elderly.
Examples of functional cumulation are chronic alcoholism due to alcohol abuse, paralysis of the centers of the medulla oblongata due to lead poisoning, which occurs after the elimination of poison from the body.
Tolerance is a decrease in pharmacological effects with repeated administration of drugs. To receive therapeutic action dose increase is necessary. Thus, the dose of the tranquilizer sibazon, which has an anti-anxiety effect, is usually 5-10 mg/day, with addiction it increases to 1000 mg/day. Addiction may not occur simultaneously to different drug effects. At long-term use Phenobarbital becomes addictive to the hypnotic effect while maintaining the anticonvulsant effect; therapy with tranquilizers is accompanied by a weakening of the muscle relaxant effect, while the anti-anxiety effect does not change.
Tachyphylaxis (Greek tachys - fast, phylaxis - vigilance, security) is a rapid, within several hours, addiction to drugs. It is most often caused by depletion of transmitter resources in synaptic endings. The indirect adrenergic agonist ephedrine displaces norepinephrine from granules at adrenergic synapses and inhibits its neuronal uptake, resulting in depletion of granules with a weakening of the hypertensive effect.
Addiction is characterized by a change in behavior when normal life activities are not possible without taking psychotropic drugs that cause euphoria (Greek eu - good, phero - I can tolerate). With addiction, there is an irresistible desire to repeatedly use drugs with narcotic effects to obtain euphoria, or to reduce the mental or physical discomfort that arises as a result of drug deprivation.
Euphoria is manifested by a feeling of satisfaction, emotional release, hallucinations, increased performance and vitality or slight calm, pleasant relaxation, disappearance of pain. It is accompanied by the formation mental dependence– a condition in which drug deprivation causes mental disorders-depression, irritability, aggression, insomnia, fear, prostration. Euphoria and psychological dependence are caused by the ability of drugs to increase the release of dopamine in the striatum, as well as in the hypothalamus, limbic system and cortex cerebral hemispheres. The opiate, GABA and serotonergic systems are also involved in the formation of mental dependence.
Physical dependence appears as a result of a significant metabolic disorder in the brain under the influence of drugs. Their effect on the metabolism of neurotransmitters and bioenergetics is especially pronounced. Many drugs stimulate the synthesis of enzymes involved in the inactivation of mediators, increase the release of mediators, lead to the formation of additional receptors, and activate the function of latent synapses and pathways.
When withdrawing from drugs that cause physical dependence, arises withdrawal syndrome (Latin abstinentia - abstinence) - a symptom complex of mental and autonomic disorders. The clinical picture of withdrawal syndrome is often characterized by a rebound phenomenon—functional dysfunctions that are opposite to those caused by the drug are observed. For example, morphine eliminates pain and depresses the respiratory center; on the contrary, when deprived of morphine, spontaneous pain in the abdomen, bones, joints, muscles and shortness of breath appear. After taking the drug, the withdrawal syndrome goes away.
Dependence of the effect of drugs on the dose. The structure of drugs determines the quality of the effect. The quantitative side of the action of drugs is more determined by the administered dose. The size of the administered dose determines the rate of development of the effect, its severity and duration. Often the size of the dose may also depend on quality characteristics effect (for example, acetylcholine in small doses excites M-cholinergic receptors, in doses 10 times larger - also N-cholinergic receptors, sodium hydroxybutyrate in small doses has an analgesic and sedative effect, in medium doses - anticonvulsant and hypnotic, in large doses - an anesthetic action).
The amount of substance per dose is single dose, for a day - daily, for a course of treatment - course.
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 m).
Therapeutic doses
Minimum therapeutic dose – the minimum amount of the drug that causes a therapeutic effect;
The average therapeutic dose is the range of doses in which the drug provides optimal preventive or therapeutic effect in most patients;
Maximum therapeutic dose – maximum quantity a drug that does not cause toxic effects.
In addition, they highlight toxic doses, in which substances have toxic effects dangerous to the body, and lethal doses.
ABOUT lethal doses more often said in experiments. For quantitative characteristics lethal dose LD is used > 0. This is the dose, the administration of which causes the death of 50% of experimental animals.
If there is a need to quickly create a high concentration medicinal substance in the body, then the first dose (shock) exceeds the subsequent ones.
To assess the therapeutic value of a drug in pharmacology and therapy, it is used therapeutic index. This is the ratio of the lethal dose and the average therapeutic dose. Breadth of therapeutic action– the range between the average and maximum therapeutic doses.
Chemistry and pharmacology
Among the phenomena observed during repeated administration of drugs, a distinction is made between cumulation, sensitization, addiction, tolerance and drug dependence. Drugs that are slowly inactivated and slowly eliminated from the body, as well as drugs that strongly bind to blood plasma proteins or are deposited can accumulate with repeated administrations...
The effect of drugs upon repeated administration is sensitization; tolerance, tachyphylaxis; cumulation and its types; drug dependence and its phases. The concept of “withdrawal”, “recoil”, abstinence syndromes. Examples. Medical and social aspects of the fight against drug addiction.
Repeated use of drugs
Repeated administrations of the same drug can lead to quantitative (increase or decrease) and qualitative changes in the pharmacological effect.
Among the phenomena observed during repeated administration of drugs, there are:
Cumulation (from lat. cumulation increase, accumulation) accumulation in the body of a drug or the effects caused by it.
Material cumulation is an increase in the concentration of a drug in the blood and/or tissues after each new administration compared to the previous concentration. Drugs that are slowly inactivated and slowly eliminated from the body, as well as drugs that tightly bind to blood plasma proteins or are deposited in tissues can accumulate during repeated administrations.
Functional cumulation is an increase in the effect of a drug upon repeated administration in the absence of an increase in its concentration in the blood and/or tissues.
Sensitization is the formation of antibodies. Repeated administration of the same drugs causes allergic reactions. Often such reactions occur with repeated administration of penicillins, procaine, water-soluble vitamins, sulfonamides, etc.
Habituation (tolerance, from lat. tolerance patience) reduction in the pharmacological effect of the drug when it is repeated in the same dose. When addiction develops, in order to achieve the same effect, it is necessary to increase the dose of the drug.
Tolerance develops to both the therapeutic and toxic effects of drugs. For example, when long-term use morphine, tolerance occurs not only to its analgesic effect, but also to its inhibitory effect on the respiratory center.
Addiction to drugs that stimulate receptors may be due to a decrease in sensitivity (desensitization) of receptors and/or a decrease in their density. Addiction to some drugs is associated with changes in their pharmacokinetics (decreased absorption, increased rate of metabolism and/or excretion).
A special case of addiction is tachyphylaxis (from the Greek. tachys fast, phylaxis protection) rapid development addiction with repeated administration of the drug at short intervals (1015 min). Tachyphylaxis to ephedrine is well known, caused by depletion of norepinephrine reserves in the endings of sympathetic nerve fibers.
Another special case of addiction is mithridatism, the gradual development of insensitivity to the effects of drugs and poisons, which occurs with prolonged use, first in very small and then in increasing doses. According to ancient Greek legend, King Mithridates thus acquired insensitivity to many poisons.
Drug dependence is an urgent need (irresistible desire) for constant or periodically renewed use of a certain drug or group of substances.
However, after a certain time, the need for repeated use becomes irresistible, which is aggravated by withdrawal syndrome: the occurrence when stopping taking a given substance serious condition associated with mental and somatic disorders (impaired functions of organs and systems of the body). This condition is referred to as “abstinence” (from Lat. abstinentia abstinence).
substance abuse use of substances for the purpose of obtaining an intoxicating effect.
Drug addiction special case substance abuse, when a substance included in the list of substances causing drug dependence is used as an intoxicant ( narcotic substances) and subject to control.
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With prolonged use of the drug, its effect may be weakened or enhanced. A decrease in the pharmacological effectiveness of drugs with repeated doses is referred to as addiction (tolerance (from Latin tolerantia - patience)), and rapid addiction (up to 1 day) is tachyphylaxis (ephedrine). It may be associated with depletion of mediators, a decrease in the number of receptors, or a decrease in their sensitivity. To get the same effect, you need to increase the dose. Addiction is characteristic of many drugs - antipsychotics, laxatives, antihypertensives, etc. It is necessary to take breaks in treatment or change drugs.
A type of addiction is drug dependence (addiction). Drug dependence is a mental, and sometimes even physical, condition characterized by behavioral and other reactions that always include the desire to take a drug in order to avoid the discomfort that occurs without taking it. At each dose, an increase in the dose of the drug is required in order to produce an effect of the same intensity as previously when taking a lower dose. Most often it develops to substances acting on the central nervous system and causing the condition euphoria: unaccountable well-being, increased mood, pleasant sensations ( narcotic analgesics, tranquilizers, sleeping pills and some others) and is characterized by an irresistible desire to re-take drugs. When you stop taking such substances, withdrawal syndrome occurs (from the Latin abstinentia - abstinence) or the phenomenon of deprivation - nausea, vomiting, pain, cramps, tremors, etc. Painful addiction (drug addiction, alcoholism, smoking) is a social and medical problem.
Strengthening the effect upon repeated administration of the drug is cumulation (from the Latin cumulacio - increase, accumulation). It is associated with the accumulation of the drug in the body and an increase in the response. This is due to the fact that some substances (for example, cardiac glycosides) are slowly inactivated in the liver and are slowly eliminated (material cumulation). Taking this into account, we carry out course treatment, gradually reducing the dose. At chronic alcoholism functional cumulation is observed when the effect accumulates, not the substance.
Withdrawal syndrome is a severe, sometimes with a poor prognosis, symptom complex that develops when a drug is suddenly stopped or its dose is sharply reduced after long-term previous therapy. Body tissues become accustomed to high level Drugs and their withdrawal are reacted with a flash adverse reactions(adrenergic blockers, glucocorticoids, etc.).
When several drugs are prescribed simultaneously, the effect may be enhanced or weakened.
Strengthening the pharmacological effect is called synergism (from the Greek synergos - acting together), when medicines act in one direction.
There are additive (from the Latin additio - addition) - summing synergism (P1 + P2 = P1P2) and potentiating (P1 + P2<Р1Р2). Аддитивным синергизмом обладают вещества с одинаковым механизмом действия, а потенцированным - с различными механизмами, что дает наиболее сильный суммарный эффект. Этот синергизм в основном и используется при создании комбинированных ЛС («Беродуал», «Адельфан», «Капозид» и др.) для получения большего терапевтического эффекта, для уменьшения побочного отрицательного действия отдельных ЛС.
The weakening of the effect of substances when used together is called antagonism. (from the Greek antagonisma - struggle, rivalry). There are several types of antagonism, due to differences in the mechanism of action of antagonist substances. For example, functional antagonism depends on changes in organ function in opposite directions (inhibition or excitation). Such antagonism can be direct or indirect. Competitive antagonism occurs between compounds of similar chemical structure for “capturing” the same receptors. Chemical antagonism is caused by a chemical neutralization reaction between substances. Such substances are called antidotes (antidotes). The phenomenon of antagonism is used to help with poisoning.
Drug antagonism is the most common cause of drug incompatibility.
Depending on the nature of the changes that occur when combining medicinal substances, physical, chemical and pharmacological incompatibility are distinguished.
Physical incompatibility is due to insufficient solubility, immiscibility, volatility, adsorption or coagulation of active ingredients, etc. As a result, the pharmacotherapeutic value of the entire combination is lost, the accuracy of the dosage is disrupted, it becomes difficult to take the medication, and the properties and appearance of the dosage form change.
Chemical incompatibility occurs due to a chemical reaction (oxidation, reduction, etc.) between substances. In this case, the therapeutic value of the medicinal compositions is also lost or its effect changes, and the newly formed compounds may turn out to be toxic.
Pharmacological incompatibility occurs when two or more substances are used that change the activity of tissues and organs in opposite directions. In case of pharmacological incompatibility, the combined use of substances results in negative effects. For example, the administration of adrenaline against the background of a number of inhalation anesthetics (fluorotane) causes cardiac arrhythmias. Neuroleptics (aminazine, etc.) sharply enhance the effect of sleeping pills and ethyl alcohol, which can lead to the development of toxic effects. Prescribing MAO inhibitors with adrenergic agonists can cause a hypertensive crisis.
