ACCUSTOMING TO PHARMACEUTICALS — the phenomenon which is shown decrease in effect at repeated impacts on an organism of medicinal substances and poisons. Is a special case obshchebiol. phenomenon of adaptation of organisms to external influences. Accustoming to pharmaceuticals is observed at the person and animals, is reproduced on the isolated bodies and separate cells. At one-celled, in particular at microorganisms, the phenomena of «accustoming» are shown by development of resistance to action of antibiotics and other chemotherapeutic means (see. Medicinal stability of microorganisms ). Accustoming develops to many, but not to all pharmaceuticals and can concern only certain effects of substance. So, phenobarbital in case of long appointment at epilepsy causes drowsiness in the beginning, edges gradually ceases to be shown though the antiepileptic effect of drug at the same time significantly does not change.
Distinguish slowly and quickly developing accustoming to pharmaceuticals. The first is observed at prolonged use of laxative, hypotensive and analgesic means, alcohol, barbiturates, Phenaminum and some other substances. As a result of prolonged use of such substances sensitivity of an organism to them gradually decreases, and former degree effects are reached only at increase in a dose. The decrease in sensitivity of an organism to toxic effect of poisons acquired as a result of their prolonged use in gradually increasing doses is designated the term «mitridatizm». At the same time the organism becomes capable to transfer without essential harm even deadly doses of poison in usual conditions.
Mechanisms of development of slow accustoming to different substances are not identical. E.g., accustoming can be caused by gradual reduction of absorption of substance from went. - kish. a path (white arsenic), increase in intensity of allocation (morphine), increase in speed of an inactivation in a liver (alcohol, barbiturates). Acceleration of an inactivation at repeated uses of phenobarbital, Butamidum, Butadionum and some other drugs is caused by induction of synthesis the NADF-zavisimykh of microsomal enzymes providing biotransformation of these substances in a liver. Accustomings can be the cornerstone also fiziol, compensatory mechanisms. E.g., accustoming to hypotensive effect of clonidine, Methyldopa or Octadinum develops due to reduction of speed of a blood-groove and decrease in filtering in kidneys that conducts to a delay in an organism of sodium, chlorides, waters and thereof to a hypervolemia and increase in cordial emission. In some cases slowly developing accustoming is caused by decrease in sensitivity of cells to substance owing to braking of synthesis of cytoreceptors (see. Receptors ), interacting with this substance, or accelerations of their degradation. Such is the nature of accustoming to Shadrin and other beta-adrenergic agonists, it is long applied as bronchodilators.
Quickly developing accustoming to pharmaceuticals, or tachyphylaxis (see), it is also caused by various reasons. So, to ephedrine the tachyphylaxis arises owing to exhaustion of stocks of free forms of a mediator of noradrenaline released by this drug from the terminations of axons of sympathetic postganglionic neurons. Decrease in efficiency at repeated (in 8 — 16 hours after the first reception) use of Diacarbum depends on exhaustion of alkaline reserves of blood. Also change of properties of cytoreceptors can be the cause of development of a tachyphylaxis. At frequent or long influences of acetylcholine holinoretseptor of skeletal muscles pass into an inactive form, in a cut they cannot interact with acetylcholine. Such phenomenon called by a desensitization of receptors develops at repeated impacts of nicotine, serotonin, catecholamines, a histamine, oxytocin, vasopressin and angiotensin on the corresponding receptors of muscle or nervous cells.
Accustoming to pharmaceuticals is the frequent reason of decrease in efficiency of medicinal therapy. For the purpose of the prevention of its development it is necessary to limit courses of treatment to optimum terms and to do rather long breaks between courses as accustoming is temporary and disappears after the termination of administration of drugs. With the same purpose in process of treatment it is necessary to replace one medicine with another, similar on action. At the same time it is necessary to consider a possibility of cross accustoming to the drugs close on a chemical structure and the mechanism of action. The most effective way of overcoming accustoming — the combined medicinal therapy which is carried out taking into account mechanisms of its development. So, weakening of hypotensive effect of clonidine or Octadinum can be prevented co-administration of the saluretics providing removal of sodium and water and by that interfering development of a hypervolemia. Efficiently preventions of development of resistance of microorganisms to chemotherapeutic means the combined use of drugs of this group with different mechanisms of action is.
Bibliography: Clinical pharmacology, under the editorship of V. V. Zakusov, page 22, M., 1978; P e t to about in V. Lekarstvo, an organism, pharmacological effect, the lane with bolg., Sofia, 1974; Samoylov and I. M. De-sensitization's h and mechanisms of its development, Pharm. and toksikol., t. 34, No. 6, page 736, 1971; Jacobs S. Cuatreca-s a s P. Cell receptors in disease, New Engl. J. Med., y. 297, p. 1383, 1977; Scheler W. Grundlagen der allgemeinen Pharmakologie, Jena, 1969.
I. V. Komissarov.