Receptors, neurotransmitters and drug responses

TY - JOUR

T1 - Receptors, neurotransmitters and drug responses

AU - Snyder, Solomon H

PY - 1979

Y1 - 1979

N2 - Abnormalities in sensitivity to endogenous hormones and neurotransmitters as well as to exogenous drugs pervade clinical medicine. Idiosyncratic responsers to medication are well known, but their causes are rarely ascertained. Although chronic decreases in sensitivity to drugs accompany classic forms of drug addiction, underlying mechanisms are unknown. Acute tolerance, also known as tachyphylaxis or desensitization, is fundamental to synaptic transmission and has many clinical manifestations, such as the decreased responsiveness of an asthmatic person to epinephrine after multiple administrations. Supersensitivity to endogenous or exogenous agents also has clinical relevance. Examples include the apparent supersensitivity to circulating catecholamines in hyperthyroidism and after abrupt discontinuation of propranolol therapy. Altered sensitivity to a drug or hormone can stem from a variety of causes. Decreased sensitivity can result from reduced drug absorption, increased elimination of the drug, decreased passage to its target organ, homeostatic mechanisms that compensate for the drug's effect and finally specific changes at the cellular site of action of the drug. The last category, receptor-related phenomena, will be the major focus of this review. Both 'metabolic' and 'receptor' changes play a part in altered sensitivity to some drugs. For instance, tolerance to barbiturates and to ethanol derive, in part, from increased metabolism of these substances with chronic use. However, with identical brain levels, the tolerant animals will be less responsive to alcohol and barbiturates than naive animals. Development of antibodies to insulin or parathyroid hormone provides a unique example of metabolic tolerance. Alterations in insulin receptors account for some forms of insulin resistance. Persons who chronically ingest thyroid hormone gradually become tolerant to its effects because of homeostatic feedback mechanisms involving the pituitary and thyroid glands. In contrast to these reasonably well-worked-out examples, the bases of tolerance at the cellular sites of drug action have proved more resistant to analysis. Changes in drug sensitivity may be separated roughly into chronic and acute types. The tolerance and physical dependence associated with addiction to psychoactive drugs is usually thought of as a form of chronic decrease in sensitivity. Although there is considerable dispute about the duration of exposure required for typical addictive alterations, these changes are usually assumed to require days or weeks to take place. By contrast, acute tolerance or desensitization occurs in seconds to hours. Desensitization to humoral substances such as biogenic amines can be demonstrated in isolated-organ baths with a few successive exposures. Desensitization to neurotransmitters has been demonstrated at most synapses in the central and peripheral nervous system and might be a major normal regulatory mechanism. For instance, during stress, the effects of massive release of epinephrine from the adrenal gland might be attenuated by reduced responses of desensitized adrenergic receptors. Desensitization to circulating histamine could explain the paucity of fatal or almost fatal anaphylactic reactions despite the ubiquity of severe allergy and exposure to offending antigens. What might underlie altered sensitivity at cellular sites of drug action? Because of differences in their properties and apparent regulation, this review will consider chronic and acute changes separately.

AB - Abnormalities in sensitivity to endogenous hormones and neurotransmitters as well as to exogenous drugs pervade clinical medicine. Idiosyncratic responsers to medication are well known, but their causes are rarely ascertained. Although chronic decreases in sensitivity to drugs accompany classic forms of drug addiction, underlying mechanisms are unknown. Acute tolerance, also known as tachyphylaxis or desensitization, is fundamental to synaptic transmission and has many clinical manifestations, such as the decreased responsiveness of an asthmatic person to epinephrine after multiple administrations. Supersensitivity to endogenous or exogenous agents also has clinical relevance. Examples include the apparent supersensitivity to circulating catecholamines in hyperthyroidism and after abrupt discontinuation of propranolol therapy. Altered sensitivity to a drug or hormone can stem from a variety of causes. Decreased sensitivity can result from reduced drug absorption, increased elimination of the drug, decreased passage to its target organ, homeostatic mechanisms that compensate for the drug's effect and finally specific changes at the cellular site of action of the drug. The last category, receptor-related phenomena, will be the major focus of this review. Both 'metabolic' and 'receptor' changes play a part in altered sensitivity to some drugs. For instance, tolerance to barbiturates and to ethanol derive, in part, from increased metabolism of these substances with chronic use. However, with identical brain levels, the tolerant animals will be less responsive to alcohol and barbiturates than naive animals. Development of antibodies to insulin or parathyroid hormone provides a unique example of metabolic tolerance. Alterations in insulin receptors account for some forms of insulin resistance. Persons who chronically ingest thyroid hormone gradually become tolerant to its effects because of homeostatic feedback mechanisms involving the pituitary and thyroid glands. In contrast to these reasonably well-worked-out examples, the bases of tolerance at the cellular sites of drug action have proved more resistant to analysis. Changes in drug sensitivity may be separated roughly into chronic and acute types. The tolerance and physical dependence associated with addiction to psychoactive drugs is usually thought of as a form of chronic decrease in sensitivity. Although there is considerable dispute about the duration of exposure required for typical addictive alterations, these changes are usually assumed to require days or weeks to take place. By contrast, acute tolerance or desensitization occurs in seconds to hours. Desensitization to humoral substances such as biogenic amines can be demonstrated in isolated-organ baths with a few successive exposures. Desensitization to neurotransmitters has been demonstrated at most synapses in the central and peripheral nervous system and might be a major normal regulatory mechanism. For instance, during stress, the effects of massive release of epinephrine from the adrenal gland might be attenuated by reduced responses of desensitized adrenergic receptors. Desensitization to circulating histamine could explain the paucity of fatal or almost fatal anaphylactic reactions despite the ubiquity of severe allergy and exposure to offending antigens. What might underlie altered sensitivity at cellular sites of drug action? Because of differences in their properties and apparent regulation, this review will consider chronic and acute changes separately.

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M3 - Article

C2 - 32488

AN - SCOPUS:0018771841

VL - 300

SP - 465

EP - 472

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 9

ER -