With repeated use of drugs, development is possible. Phenomena that occur with repeated administration of drugs

Phenomena arising from the repeated administration of drugs.

Most drugs are used in courses of several days, weeks, months, and sometimes throughout life.

It is necessary to know that with repeated use of drugs, their pharmacological effect may increase due to cumulation.

Cumulation (lat. cumulatio - increase, accumulation) - the accumulation in the body of drug molecules (material cumulation) or their effects (functional cumulation).

Material cumulation is characteristic of lipophilic substances with low hepatic and/or renal clearance and a long half-life. In the clinic, it is necessary to take into account the accumulation of phenobarbital, bromides, digitalis digitalis cardiac glycosides (digitoxin, celanide, digoxin), indirect anticoagulants.

Cumulation has both positive and negative meanings. A positive value is associated with the prolongation of the action of drugs, the possibility of their rare 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 up the dose of the re-introduced drug with its amount remaining from the previous appointment, in order to exclude intoxication, it is necessary to take cumulative agents in a maintenance dose equal to the amount of the substance eliminated per day. Maintenance Dose = Total Therapeutic Dose ´ EC% /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 with alcohol abuse, paralysis of the centers of the medulla oblongata with lead poisoning, which occurs after the elimination of the poison from the body.

Tolerance is a decrease in pharmacological effects with repeated drug use. To obtain a therapeutic effect, an increase in dose is necessary. So, the dose of the tranquilizer sibazon, which has an anti-anxiety effect, is usually 5-10 mg / day, against the background of addiction, it increases to 1000 mg / day. Addiction can occur non-simultaneously to different effects of drugs. With prolonged use of phenobarbital, addiction to the hypnotic effect occurs 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, protection) is a rapid, within a few hours, addiction to drugs. It is most often caused by the depletion of mediator resources in synaptic endings. The indirect adrenomimetic ephedrine displaces norepinephrine from the granules in adrenergic synapses and inhibits its neuronal uptake, resulting in the emptying of the granules with a weakening of the hypertensive effect.

Addiction is characterized by a change in behavior, when normal life is not possible without taking psychotropic drugs that cause euphoria (Greek eu - good, phero - I endure). With addiction, there is an irresistible desire to reuse drugs with a narcotic effect to obtain euphoria, or to reduce the mental or physical discomfort that occurs as a result of drug deprivation.

Euphoria is manifested by a sense of satisfaction, emotional release, hallucinations, increased efficiency and vitality, or a slight sedation, pleasant relaxation, and the disappearance of pain. It is accompanied by the formation of mental dependence - a condition in which the deprivation of a drug causes mental disorders - depression, irritability, aggression, insomnia, fear, prostration. Euphoria and mental dependence are due to the ability of drugs to increase the release of dopamine in the striatum, as well as in the hypothalamus, limbic system and cerebral cortex. The opiate, GABA and serotonergic systems are also involved in the formation of mental dependence.

physical addiction appears as a result of a significant metabolic disorder of 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 include the function of latent synapses and pathways.

With the withdrawal of drugs that cause physical dependence, there is withdrawal syndrome(Latin abstinentia - abstinence) - a symptom complex of mental and autonomic disorders. The clinic of abstinence syndrome is often characterized by the phenomenon of return - there are dysfunctions that are opposite to those caused by the drug. For example, morphine eliminates pain, depresses the respiratory center, on the contrary, when depriving morphine, spontaneous pain in the abdomen, bones, joints, muscles and shortness of breath appear. After taking the drug, the withdrawal syndrome disappears.

The dependence of the action 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 dose administered. The value of the administered dose determines the rate of development of the effect, its severity and duration. Often, the qualitative characteristics of the effect may also depend on the magnitude of the dose (for example, acetylcholine in small doses excites M-cholinergic receptors, in doses 10 times larger, also N-cholinergic receptors, sodium oxybutyrate in small doses has an analgesic and sedative, in medium doses - anticonvulsant and hypnotic, in large doses - anesthetic effect).

The amount of a substance at one time is a single dose, for a day - daily, for a course of treatment - a course.

Indicate the dose in grams or fractions of a gram. For a more accurate dosage of drugs, their number per 1 kg of body weight is calculated (for example, mg / kg; μg / kg). In some cases, it is preferable to dose substances based on the size of the body surface (per 1 m2).

Therapeutic doses

The minimum therapeutic dose is the minimum amount of the drug that causes a therapeutic effect;

Average therapeutic dose - the range of doses in which the drug has the optimal preventive or therapeutic effect in most patients;

The maximum therapeutic dose is the maximum amount of the drug that does not cause a toxic effect.

In addition, allocate toxic doses, in which substances have toxic effects dangerous for the body, and lethal doses.

O lethal doses more often said in experiment. LD is used to quantify the lethal dose. > 0. This is the dose, the introduction of which causes the death of 50% of the experimental animals.

If there is a need to quickly create a high concentration of a 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 to the average therapeutic dose. Breadth of therapeutic action- the range between the average and maximum therapeutic doses.

Repeated administration of the same drug can lead to increased action, reduced action, and the appearance of drug dependence. Strengthening effects can be expressed in 2 forms: in the form of cumulation and in the form of sensitization.

cumulation called the accumulation in the body of a pharmacologically active substance (material cumulation) or the effects caused by it (functional cumulation). Accumulate with repeated injections can be a substance that is slowly excreted or slowly neutralized in the body. The medicinal substance, administered repeatedly, is added to the remaining in the body and therefore the effect may be more pronounced, up to intoxication. An example of material cumulation can be the cumulation of barbiturates, cardiac glycosides, and other substances. For such drugs, it is important to know the rate of excretion and metabolism. An example of functional cumulation can be the accumulation of the effects of alcohol, cytostatics, drugs containing lead, etc.

Sensitization called the phenomenon in which repeated administration of the same drug causes a greater effect than the previous one. A typical example is the action of serotonin, which, upon repeated administration, causes an effect 1.5 times greater than during the first exposure to the smooth muscles of the stomach. The most common drug sensitization is of an allergic nature.

decline the action of drugs can be in the form of addiction.

addiction (tolerance)- the phenomenon of a decrease in the effect with repeated administration of the drug at the same dose. This is a condition when, in order to achieve a certain effect, it is necessary to increase the dose of the drug. At the heart of addiction are several mechanisms: 1. Decreased sensitivity of receptors; 2. Increased drug metabolism due to increased induction of metabolic enzymes; 3. Increase in the deposition of the drug; 4. Acceleration and enhancement of the excretion of the medicinal substance from the body; 5. The involvement of the drug in the normal metabolism of the body, when it becomes, as it were, its integral part. Addiction can be to many drugs, but more often to those that are close in structure to the structural components of the body.

Rapidly developing addiction is denoted by the word tachyphylaxis(tachys - fast, phylaxis - guard) . The most striking example of such a phenomenon may be the action of an indirect adrenomimetic - ephedrine. It causes a rapid depletion of the neurotransmitter in the presynaptic region of the synapse, so there is no effect when it is re-introduced. It is known that with frequent repeated exposure to acetylcholine on the receptors of the striated muscle, it loses sensitivity to this compound. Such a phenomenon is called desensitization.

Repeated administration of certain drugs can also cause drug dependence - predilection, which manifests itself in the form of an irresistible desire to regularly take this substance in order to obtain one or another pleasant sensation and to eliminate negative reactions that occur in a person when the drug is discontinued. mental dependence is characterized by a pathological craving for a state of euphoria (eu - good, handicap - feel), and physical, representing the second phase of addiction, is characterized by significant changes in internal organs, vegetative reactions and the motor sphere - abstinence ("deprivation" syndrome). Addiction to substances such as alcohol, amphetamines, sleeping pills, tranquilizers, morphine, heroin, cocaine, hashish, etc. is accompanied by the phenomenon of resistance (resistance) to them, therefore, to obtain euphoria, ever larger doses of these substances are required. This condition is called drug addiction and will be discussed in more detail in one of the lectures on private pharmacology.

Types of action of drugs. Changing the effect of drugs when they are repeated.

Types of action of drugs:

1. Local action- the action of a substance that occurs at the site of its application (anesthetic - on the mucous membrane)

2. Resorptive (systemic) action- the action of a substance that develops after its absorption, entry into the general bloodstream, and then into the tissues. Depends on the routes of administration of drugs and their ability to penetrate biological barriers.

Both with local and resorptive action, drugs can have either Direct or Reflex effects:

A) direct influence - direct contact with the target organ (adrenaline to the heart).

B) reflex - a change in the function of organs or nerve centers by influencing extero- and interoreceptors (mustard plasters in the pathology of the respiratory organs reflexively improve their trophism)

Changes in the action of drugs when they are re-introduced:

1. Cumulation- an increase in the effect due to the accumulation of drugs in the body:

a) material cumulation - the accumulation of the active substance in the body (cardiac glycosides)

b) functional cumulation - increasing changes in the function of body systems (changes in the function of the central nervous system in chronic alcoholism).

2. Tolerance (addictive) - Decreased response of the body to repeated administration of drugs; in order to restore the response to drugs, it has to be administered in larger and larger doses (diazepam):

A) true tolerance - observed both with enteral and parenteral administration of drugs, does not depend on the degree of its absorption into the bloodstream. It is based on pharmacodynamic mechanisms of addiction:

1) desensitization - a decrease in the sensitivity of the receptor to the drug (b-adrenomimetics with prolonged use lead to phosphorylation of b-adrenergic receptors that are not able to respond to b-adrenergic agonists)

2) Down-regulation - a decrease in the number of receptors for the drug (with repeated administration of narcotic analgesics, the number of opioid receptors decreases and larger and larger doses of the drug are required to cause the desired response). If a drug blocks receptors, then the mechanism of tolerance to it may be associated with up-regulation - an increase in the number of receptors for the drug (b-blockers)

3) the inclusion of compensatory mechanisms of regulation (with repeated injections of antihypertensive drugs, collapse occurs much less frequently than with the first injection due to the adaptation of baroreceptors)

B) relative tolerance (pseudo-tolerance) - develops only with the introduction of drugs inside and is associated with a decrease in the speed and completeness of absorption of the drug

3. Tachyphylaxis- a condition in which frequent drug administration causes the development of tolerance after a few hours, but with fairly rare drug administration, its effect is fully preserved. The development of tolerance is usually associated with the depletion of effector systems.

4. drug addiction- an irresistible desire to receive a substance introduced earlier. Allocate mental (cocaine) and physical (morphine) drug dependence.

5. Hypersensitivity- an allergic or other immunological reaction to drugs with repeated administration.

The dependence of the action of drugs on age, gender and individual characteristics of the organism. The value of circadian rhythms.

A) From age: in children and the elderly, sensitivity to drugs is increased (because in children there is a deficiency of many enzymes, kidney function, increased permeability of the BBB, in old age the absorption of drugs is slowed down, metabolism is less efficient, the rate of excretion of drugs by the kidneys is reduced ):

B) From the floor:

1) antihypertensive drugs - clonidine, b-blockers, diuretics can cause sexual dysfunction in men, but do not affect the reproductive system of women.

2) anabolic steroids cause a greater effect in the body of women than in the body of men.

AT) From the individual characteristics of the body: deficiency or excess of certain enzymes of drug metabolism leads to an increase or decrease in their action (blood pseudocholinesterase deficiency - abnormally prolonged muscle relaxation when using succinylcholine)

G) From daily rhythms: change in the effect of drugs on the body quantitatively and qualitatively depending on the time of day (maximum effect at maximum activity).

Variability and variability of drug action.

Hypo - and hyperreactivity, tolerance and tachyphylaxis, hypersensitivity and idiosyncrasy. Causes of drug action variability and rational therapy strategy.

Variability reflects differences between individuals in response to a given drug.

Reasons for the variability of the action of drugs:

1) a change in the concentration of a substance in the receptor zone - due to differences in the rate of absorption, its distribution, metabolism, elimination

2) variations in the concentration of the endogenous ligand of the receptor - propranolol (β-blocker) slows down heart rate in people with elevated levels of catecholamines in the blood, but does not affect the background heart rate in athletes.

3) changes in the density or function of receptors.

4) change in the reaction components located distal to the receptor.

Rational therapy strategy: appointment and dosage of drugs, taking into account the above reasons for the variability of the action of drugs.

Hyporeactivity- a decrease in the effect of a given dose of drugs compared with the effect that is observed in most patients. Hyperreactivity- an increase in the effect of a given dose of drugs in comparison with the effect that is observed in most patients.

Tolerance, tachyphylaxis, hypersensitivity - see v.38

Idiosyncrasy- a perverted reaction of the body to a given drug, associated with the genetic characteristics of drug metabolism or with individual immunological reactivity, including allergic reactions.

With repeated use, the effect of drugs may increase or decrease. Strengthening the effect of the drug, as a rule, is associated with its cumulation(accumulation).

Cumulation is typical for long-acting drugs that are slowly eliminated from the body, for example, for cardiac glycosides.

The accumulation of drugs with prolonged use can lead to toxic effects. To prevent them, it is necessary to gradually reduce the dose, increase the intervals between doses of drugs or take breaks in treatment.

Tolerance

The effectiveness of some drugs (antihypertensives, analgesics, laxatives, etc.) decreases over time and tolerance (addiction) develops. Tolerance to drugs is:

Relative (develops when the FC of drugs changes, i.e. as a result of a decrease in absorption, an increase in the rate of biotransformation and excretion, as a result of which the concentration of the drug in the blood plasma decreases);

Absolute (not associated with a decrease in the concentration of drugs in the blood plasma, but occurs as a result of a change in its action at the cell level, for example, due to a decrease in the sensitivity of receptors).

Thus, long-term administration of β 2 -agonists to patients with BA may be accompanied by a weakening of their bronchodilating effect, caused by a decrease in the number and sensitivity of β 2 -adrenergic receptors in the bronchi.

Long-term use of nitrates in high doses also leads to a weakening of their antianginal action.

The decrease in the effectiveness of antimicrobial agents is associated with the development of resistance of microorganisms.

With relative tolerance, the dose of the drug must be increased. With absolute tolerance, increasing the dose does not lead to an increase in the effect, therefore, one drug needs to be replaced by another with a different mechanism of action. Rapid tolerance (tachyphylaxis) may develop as early as the second administration of the drug (for example, when using ephedrine).

To prevent the undesirable effects of drugs, it is necessary to take into account the characteristics of the patient's body, if possible, prescribe the drug in low doses, but sufficient to obtain a therapeutic effect, carefully monitor its effect and tolerability.

Efficacy and tolerability Drugs, their dosage and duration of use depend on the characteristics of the pathological process and its dynamics, which are evaluated using objective criteria. The introduction of new instrumental, laboratory and morphological methods, as well as the use of computer technology, has significantly expanded the possibilities for a quantitative assessment of the effect of drugs by a medical worker.

When prescribing drugs, one should have a good idea of ​​what effect it has on a particular disease (etiotropic, pathogenetic, symptomatic), changes in what subjective and objective symptoms, laboratory parameters, functional parameters and in what time frame should be expected, when and what additional studies need to be carried out.

Side effects drugs can be divided into two main groups of adverse reactions:

Type A reactions are observed in all patients with an increase in the dose of the drug. They are due to the redundancy of the ordinary, i.e. known pharmacological action of drugs. The frequency of occurrence and severity of such reactions can be reduced by the correct use of drugs: careful selection of patients and the exclusion of those who are at high risk of developing side effects; appointment at the beginning of treatment of small doses; a gradual increase in a single and daily dose, and for a number of drugs - their gradual cancellation; the use of combinations with other drugs that neutralize the adverse reactions of the selected drug;

Type B reactions are recorded in a small number of patients. They are attributed to the manifestations of the usual pharmacological properties of the drug, caused by unusual (often very dangerous) reactions to drugs in the body of individual patients. The latter can only be predicted with the help of expensive and therefore practically inaccessible special tests (methods) for many patients. This type includes side effects on the drug, due to the genetic characteristics of the patient and his immunological reactions to a particular drug or related substances. The sensitivity of individual groups of patients to drugs is different. Among them, there are individuals with drug intolerance (for example, with idiosyncrasy, i.e. a qualitatively unusual reaction to a drug due to genetic abnormalities), patients with a normal reaction, and individuals with increased resistance to adverse reactions.

In this regard, subject to knowledge of indications and contraindications, side effects of the drug, an accurate diagnosis of the underlying and concomitant diseases, it is possible to prevent the occurrence of type A and, especially, type B side effects, and to identify groups of patients with a high risk of their development:

Young children (especially premature and newborns), elderly patients (it should be borne in mind that the passport age may not correspond to the biological one) and pregnant women;

Patients with damage to organs that carry out biotransformation and excretion of drugs;

Patients with burdened anamnesis;

Patients receiving drugs for a long time;

Patients receiving more than four drugs at the same time.

Defined:

They develop against the background of taking the drug, in time of occurrence they coincide with the development of its action and in nature correspond to the ideas about the side effects of drugs;

Disappear after discontinuation of the drug;

Reappear when it is re-appointed.

Possible:

They develop against the background of taking the drug, in time of occurrence they correspond to the development of its action, and in nature they correspond to ideas about the side effects of drugs;

Disappear after discontinuation of the drug.

Doubtful:

Occur while taking the drug and disappear, despite continued treatment with it;

They occur while taking the drug and disappear after its withdrawal, but the causal relationship of the undesirable effect with the drug is doubtful. Negative Aftereffect Syndrome- the development of a negative phase of the pharmacodynamic effect after the initial positive effect of a single dose of the drug. It develops, for example, after ingestion of an effective dose of long-acting nitroglycerin tablets, 4 hours after the positive action phase. At the same time, during subsequent repeated physical exertion, when there is no longer a therapeutic concentration of the drug in the blood, more pronounced episodes of ischemia occur for a certain time than those preceding the drug. The development of this syndrome is possible with irregular intake of drugs during the day.

Paradoxical effect- exacerbation of those symptoms of the disease, for the elimination of which drugs are prescribed. For example, in a certain proportion of patients, antiarrhythmic drugs can cause an increase in the incidence of rhythm disturbances; some antihypertensive agents may cause a hypertensive reaction; antianginal agents are sometimes able to increase the frequency or severity of episodes of myocardial ischemia.

Other unusual patient reactions to drugs

hyperreactivity- the usual reaction of the patient to the use of an unusually low dose of drugs.

Hypersensitivity- an increased reaction of the patient to the use of the usual dose of the drug.

Hyporeactivity- the usual effect of the drug when taking very large doses.

Immunity- tolerance to the drug, resulting from the formation of antibodies to it.

Methods for assessing the effectiveness and safety of the use of drugs

Sufficiently informative criteria for the effectiveness and safety of the use of drugs with an indication of their time and quality characteristics is one of the important tasks of the CF. Unfortunately, such criteria have not been developed for all drugs, which is due to a number of objective reasons.

There are several groups of criteria currently used in practice.

Laboratory: determination of the concentration of the drug in the blood; clinical examination of blood, urine, etc.; coprogram; determination of biochemical, bacteriological and immunological parameters, etc.

Paraclinical (instrumental): ECG, EchoCG, EEG, radiography, fibrogastroscopy, spirometry, etc.

Clinical: taking into account the dynamics of the patient's condition and adverse reactions to the drug.

The assessment of the above criteria for long-term use of drugs should be carried out before, at the beginning and during treatment. When changing the dosing regimen and using drugs with a small breadth of therapeutic action, such control is essential.

The choice of a drug for rational PT should be based only on knowledge of the clinical and pharmacological characteristics (PD, FC, interactions and adverse effects).

In clinical practice, the treatment of a patient is rarely limited to a single dose of medication. With repeated use of drugs, the pharmacological effect may increase or decrease due to a change in the sensitivity of receptors to them or a change in pharmacokinetics. The increase in a specific pharmacological action with repeated administration of the same drug substance is called cumulation. With material cumulation, the increase in the effect is due to a constant increase in the concentration of the drug in the blood and tissues due to its slow metabolism and excretion. This may be the reason for the appearance of toxic effects with repeated use of therapeutic doses of the drug. The danger of material cumulation increases with impaired liver and kidney function. For example, cardiac glycosides of the digitalis group are used to treat heart failure, which is often accompanied by liver pathology. Under these conditions, the biotransformation of drugs slows down and material cumulation appears: first, an increase in the therapeutic effect, then intoxication. To prevent cumulation, it is necessary to correct doses (reduce) and intervals between doses of the drug (increase).

With functional cumulation, the drug causes hard-to-reversible or irreversible changes in the body, a trace reaction persists, as a result, repeated administration of the drug can enhance these changes. There is an abrupt increase in the effect, although the concentration of the drug in the blood and cells corresponds to the administered dose. An example of this type of cumulation is the effect of ethyl alcohol on alcoholics: the "delirious tremens" syndrome can develop from a "normal" dose of alcohol, dipsomania (irresistible craving for alcohol) is provoked by a small dose of alcohol. Functional cumulation sometimes persists for life.

During the initial contact, the body can become sensitized to drugs, and then their repeated administration will cause allergic reactions (from the Greek allos- other, not specific, Ergon- action), indicating the immunological incompatibility of the patient's body with a certain group of chemicals. It is dangerous to prescribe drugs of this structure to a patient.

With repeated administration of drugs, a decrease in the specific effect can also be observed. A rapidly emerging (and also rapidly disappearing) decrease in the body's sensitivity to a drug may be due to the depletion of the metabolite, the substrate through which it realizes its effect - this phenomenon is called tachyphylaxis (from the Greek tachys-fast, phylaxis-security). It occurs to some vasoconstrictors (eg, ephedrine), respiratory analeptics from the group of N-cholinomimetics (eg, cytiton). The initial effect will be restored when the level of the biosubstrate with which the drug forms a complex returns to normal.

To many drugs (hypnotics, painkillers, laxatives) with repeated use, addiction or tolerance (resistance) develops. In this case, the repeated appointment of therapeutic doses gives less and less effect. The most likely reason is changes in pharmacokinetics: a decrease in absorption, an increase in the rate of biotransformation (enzyme induction) and excretion. To obtain the initial effect, it is necessary to increase the dose.

Long-term use of drugs that act on the central nervous system and cause euphoria (eu - good, handicap- feel). may be accompanied by the development of drug dependence. Withdrawal of the drug leads to a state of abstinence ("withdrawal" syndrome), since upon repeated contact, the addictive drug is likely to be included in the metabolism of the nervous tissue. Distinguish between mental and physical dependence. With mental drug dependence, withdrawal of the drug causes emotional discomfort and the desire to take the drug becomes an end in itself. With physical drug dependence, along with mental changes, there is a violation of the function of various organs and systems. A severe condition (withdrawal) that develops in a patient who does not receive the appropriate drug makes him take the drug no longer in accordance with its true purpose. Moreover, in parallel with drug dependence, addiction (tolerance) often develops, and increasingly large doses of the drug are required to relieve withdrawal symptoms. With an increase in the dose, the subsequent withdrawal syndrome is aggravated, disorders of mental and somatic functions are intensified, chronic poisoning of the body and moral degradation of the personality develop.