Repeated administrations of the same medicinal substance can lead to a quantitative (increase or decrease) and qualitative change in the pharmacological effects.
Among the phenomena observed with repeated administration of drugs, there are cumulation, sensitization, addiction (tolerance) and drug dependence.
Cumulation (from Lat. Cumulatio - increase, accumulation) is the accumulation of a medicinal substance in the body or the effects it causes.
Material cumulation - an increase in the concentration of a drug in the blood and / or tissues after each new administration in comparison with the previous concentration. Drugs that are slowly inactivated and slowly excreted from the body, as well as drugs that firmly bind to blood plasma proteins or are deposited in tissues, for example, some hypnotics from the barbiturate group, digitalis drugs, can accumulate with repeated injections. Material accumulation can cause toxic effects, which must be taken into account when dosing such drugs.
Functional cumulation is an increase in the effect of a drug with repeated injections in the absence of an increase in its concentration in the blood and / or tissues. This type of cumulation occurs with repeated intake of alcohol. With the development of alcoholic psychosis ("delirium tremens") in susceptible persons, delusions and hallucinations develop at a time when ethyl alcohol has already been metabolized and is not detected in the body. Functional cumulation is also characteristic of MAO inhibitors.
Sensitization. Many medicinal substances form complexes with blood plasma proteins, which acquire antigenic properties under certain conditions. This is accompanied by the formation of antibodies and sensitization of the body. Repeated administration of the same medicinal substances causes allergic reactions. Often such reactions occur with repeated injections of penicillins, procaine, water-soluble vitamins, sulfanilamides, etc.
Addiction (tolerance, from Lat. Tolerantia - patience) is a decrease in the pharmacological effect of a drug when it is repeated in the same dose. With the development of addiction, in order to achieve the same effect, it is necessary to increase the dose of drugs. Tolerance develops to both the therapeutic and toxic effects of drugs. For example, with prolonged use of morphine, tolerance arises not only to its analgesic effect, but also to the depressing effect on the respiratory center. So, the main reason for addiction to phenobarbital is considered to be the activation of its metabolism due to the induction of liver enzymes caused by phenobarbital itself. Drug addiction can develop over several days or months.
In the case of the development of addiction, a break is taken in the use of this substance, and if it is necessary to continue treatment, drugs with a similar effect, but from a different chemical group, are prescribed. When replacing one substance with another, regardless of its chemical structure, cross-addiction may occur (if these substances interact with the same receptors or enzymes).
A special case of addiction is tachyphylaxis (from the Greek tachys - fast, phylaxis - protection) - the rapid development of addiction with repeated injections of the drug at short intervals (10-15 minutes). Tachyphylaxis to ephedrine is well known due to depletion of norepinephrine reserves at the endings of synaptic nerve fibers. With each subsequent introduction of ephedrine, the amount of norepinephrine released into the synaptic cleft decreases, and the hypertensive effect of the drug (increased blood pressure) is weakened.
Another special case of addiction is mitridatism - the gradual development of insensitivity to the action of the drug and poisons, which arises during their prolonged use, first in very small, and then in increasing doses. According to ancient Greek legend, King Mithridates thus acquired insensitivity to many poisons.
With repeated administration of certain substances that cause extremely pleasant sensations (euphoria), drug dependence develops in predisposed individuals.
Drug addiction - an urgent need (irresistible urge) to constantly or periodically resume the intake of a certain drug or group of substances. First, the substance is taken to achieve a state of euphoria, well-being and comfort, eliminate painful experiences, test new sensations. However, after a certain time, the need for repeated admission becomes insurmountable, which is aggravated by the withdrawal syndrome: the emergence of a severe condition associated with mental and somatic disorders (dysfunctions of organs and body systems) when the drug is discontinued. This condition is designated by the term "abstinence" (from Latin abstinentia - abstinence).
Distinguish between mental and physical drug dependence. Psychic drug dependence is characterized by a sharp deterioration in mood and emotional discomfort, a feeling of fatigue when deprived of the drug. It occurs with the use of cocaine and other psychostimulants (amphetamine), hallucinogens (lyzergic acid diethylamide, LSD-25), nicotine, Indian hemp (marijuana, hashish, plan, marijuana). Physical drug addiction is characterized not only by emotional discomfort, but also the occurrence of withdrawal syndrome. Physical drug dependence develops to opioids (heroin, morphine), barbiturates, benzodiazepines, alcohol (ethyl alcohol).
Drug dependence is often combined with addiction, while increasing doses of the substance are required to obtain euphoria. The most severe drug dependence occurs in the case of a combination of mental dependence, physical dependence and addiction.
Substance abuse - the use of substances in order to obtain intoxicating effects. Drug addiction is a special case of substance abuse, when a substance referred to the list of substances causing drug dependence (narcotic substances) and subject to control is used as an intoxicating agent. Cancellation Phenomenon. It can be expressed in two (essentially opposite) versions. The first is less common, mainly with prolonged use of hormonal agents and consists in persistent suppression of the function of its own glands and the loss of the corresponding hormones from regulation. This option occurs especially easily and often with tragic consequences when treating with corticosteroids (hydrocortisone, prednisolone, dexametazone). A hormone (or its analogue) introduced from the outside makes the work of its own gland unnecessary, and it undergoes (as an inoperative organ) atrophy, the degree of which is proportional to the duration of treatment. Restoration of the structure and function, for example, of the adrenal glands after a course of cortisone therapy, may require up to six months or more. A sharp withdrawal of the hormone used causes acute corticoid insufficiency with a shock-like syndrome with severe stress, surgical interventions.
Ganglion blockers - These are drugs that selectively block the H-cholinergic receptors in the autonomic ganglia (sympathetic and parasympathetic). In addition, ganglion blockers block the H-cholinergic receptors of the chromaffin cells of the adrenal medulla (reducing the release of catecholamines), as well as the H-cholinergic receptors reflex arousal of respiratory and vasomotor)
Classification: 1. Short-acting: Gigronium (12-20 min.), Arfonad (15-20 min.), Imekhin (4-10 min.); 2. Average duration: Pentamin (1-2 hours), benzohexonium (2-4 hours), Pachikarpin (4-6 hours); 3. Long-term action: Camphonium (6-8 hours), Pyrylene (8-12 hours) - an adverse effect on the central nervous system.
Mechanism of action: Ganglion blockers block sympathetic and parasympathetic ganglia, as well as n-cholinergic receptors of the cells of the adrenal medulla and the carotid glomerulus, they are referred to as antidepolarizing substances.
Pharmacological effects: sedative effect on the central nervous system, dilated pupil, decreased IOP, tachycardia, dilates blood vessels, lowers blood pressure, dilated bronchi, decreased tone of smooth muscles and peristalsis in the gastrointestinal tract, decreased tone of the bladder.
Indications: "Controlled" hypotension, hypertensive crisis, pulmonary and cerebral edema, trophic ulcers, burns, bedsores, open-angle glaucoma, peptic ulcer disease, bronchospasm.
Side effects: 1. Orthostatic collapse; 2.Hypotension; 3.Tachycardia; 4.Reduction of intestinal motility; 5.Photophobia; 6. Atonic constipation.
Contraindications: 1. BP less than 100/60 mm Hg; 2. Atony of the gastrointestinal tract; 3. Atony of the urinary tract; 4. Angle-closure glaucoma; 5.Adenoma of the prostate; 6.Myocardial infarction.
Pyrylene is well absorbed from the gastrointestinal tract, well penetrates the blood-brain barrier, has a stimulating effect on the myometrium. Pentamine - high activity, pronounced selectivity, poorly absorbed in the gastrointestinal tract, so it is advisable to administer it intravenously.
Hyperacidity, increased activity of pepsin and lack of mucin predispose to the development of diseases such as gastric ulcer and duodenal ulcer, erosive gastritis, etc. The main tactic of treatment for such a pathology is a decrease in the secretory activity of the gastric glands and an increase in cytoprotective mechanisms.
Classification:
1) M-anticholinergics: non-selective: atropine, platifilin, metacin.
Selective: pirenzepine, telenzepine
Mechanism of action: block the M-cholinergic receptors of the parasympathetic ganglia of the stomach, reduce the secretion of hydrochloric acid and pepsinogen, have a cytoprotective effect on the gastric mucosa.
2) blockers of H2 - histamine receptors; 1st generation: cimetidine; 2nd generation: ranitidine; 3rd generation: famotidine; 4th generation: nizotidine; 5th generation: roxatidine
Mechanism of action: competitively blocks H2 - histamine receptors of parietal cells of the gastric mucosa
3) proton pump inhibitors: omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole.
Mechanism of action: a proton pump is an enzymatic protein located on the apical membrane of the parietal cells that exchanges hydrogen ions for potassium ions, inhibitors suppress HCI secretion, reduce the total volume of gastric juice and inhibit the release of pepsinogen.
4) prostaglandins, their synthetic derivatives and somatostatin: misoprostol
Mechanism of action: they have an antisecretornone effect by inhibiting adenylate cyclase.
5) antagonists of gastrin receptors;
Indications - gastric ulcer and duodenal ulcer, peptic ulcerative esophagitis, hypergastrinemia, reflux esophagitis, duodenitis, erosive gastritis.
1) Blockers of histamine H2-receptors - histamine antagonists, reduce the secretion of hydrochloric acid, pepsinogen. The volume of gastric juice is reduced. They do not penetrate into the central nervous system. Ranitidine - duration 8-12 hours, side effects - headache, rash, diarrhea. Famotidine is more active than ranitidine, it lasts longer.
2) Proton pump inhibitors - omeprazole - selectively acts on parietal cells, reduces the secretion of hydrochloric acid and pepsinogen, reduces the volume of gastric juice, has gastroprotective activity, and has a long-term effect. Side effects - diarrhea, nausea, intestinal colic, headache.
3) Blockers of cholinergic receptors - block the M1-cholinergic receptors of the parasympathetic ganglia of the stomach. Pirenzepine - does not pass through the BBB, reduces the secretion of hydrochloric acid and pepsinogen. Has gastroprotective activity. Reduces the secretion of the salivary glands.
4) Prostaglandins - have an antisecretory effect by inhibiting adenylate cyclase, do not have gastroprotective activity.
Side effects - diarrhea, nausea, swelling, drowsiness, anorexia, flatulence, abdominal pain, allergy, convulsions, candidiasis
Contraindications - pregnancy, breastfeeding, severe renal failure.
4. Antibiotics of the tetracycline and chloramphenicol group. Classification. Mechanism of action. The nature of the action. Spectrum of action. Indications for use. Side effects. Contraindications Comparative evaluation.
Classification: Tetracyclines: natural (tetracycline) and semi-synthetic (doxycycline, morphocycline, metacyclin). Levomycetin belongs to nitrobenzenes.
Mechanism: inhibit protein synthesis.
Mode of action: bacteriostatic.
Spectrum: wide - gram (+) (-), suppresses aerobic and anaerobic bacteria, actinomycetes, legionella, spirochetes, leptospira, mycoplasma, ureaplasma, reketsia, plasmodia; levomycetin has a bacteriostatic effect on streptococci, gonococci, pneumococci, clostridia, anthrax pathogens, diphtheria, plague, whooping cough, salmonella, shigella, brucella.
Indications: rickettsiosis, chlamydial infections, pneumonia, bronchitis, sinusitis, syphilis, leptospirosis, brucellosis, tularemia, cholera, plague, anthrax, typhoid fever, meningitis caused by Haemophilus influenzae.
Side effects: a decrease in hematopoiesis to agranulocytosis, irritate the gastrointestinal tract, teratogenic (tetracyclines), allergies, dysbiosis, candidiasis.
Contraindications: liver, kidney, blood diseases, pregnancy, children under 8 years old.
Doxycycline and metacyclin last longer (up to 12 hours). All are reserve antibiotics (very toxic).
Tetracyclines are very toxic, therefore they are rarely used in children, especially those for 3-5 years. Levomycetin in children under 3 years of age is used to a limited extent, because toxic effects may occur