Drug Receptors & Pharmacodynamics
Therapeutic
and toxic effects of drugs result from their interac-tions with molecules in
the patient. Most drugs act by associating with specific macromolecules in ways
that alter the macromole-cules’ biochemical or biophysical activities. This
idea, more than a century old, is embodied in the term receptor: the component of a cell or organism that interacts with a
drug and initiates the chain of events leading to the drug’s observed effects.
Receptors
have become the central focus of investigation of drug effects and their
mechanisms of action (pharmacodynamics). The receptor concept, extended to
endocrinology, immunology, and molecular biology, has proved essential for
explaining many aspects of biologic regulation. Many drug receptors have been
isolated and characterized in detail, thus opening the way to pre-cise
understanding of the molecular basis of drug action.The receptor concept has
important practical consequences for the development of drugs and for arriving
at therapeutic decisions in clinical practice. These consequences form the
basis for under-standing the actions and clinical uses of drugs described. They
may be briefly summarized as follows:
1. Receptorslargely determine the quantitative
relations between dose or concentration of drug and pharmacologic effects. The receptor’s
affinity for binding a drug determines theconcentration of drug required to
form a significant number of drug-receptor complexes, and the total number of
receptors may limit the maximal effect a drug may produce.
2. Receptors are responsible for selectivity
of drug action. Themolecular
size, shape, and electrical charge of a drug determine whether—and with what
affinity—it will bind to a particular receptor among the vast array of
chemically different binding sites available in a cell, tissue, or patient.
Accordingly, changes in the chemical structure of a drug can dramatically
increase or decrease a new drug’s affinities for different classes of
receptors, with resulting alterations in therapeutic and toxic effects.
3. Receptors mediate the actions of
pharmacologic agonists and antagonists. Some drugs and many natural ligands, suchas
hormones and neurotransmitters, regulate the function of receptor
macromolecules as agonists; this
means that they activate the receptor to signal as a direct result of binding
to it. Some agonists activate a single kind of receptor to produce all their
biologic functions, whereas others selectively promote one receptor function
more than another.
Other drugs act as pharmacologic antagonists; that is, they bind to receptors but do not activate
generation of a signal; con-sequently, they interfere with the ability of an
agonist to activate the receptor. The effect of a so-called “pure” antagonist
on a cell or in a patient depends entirely on its preventing the binding of
agonist molecules and blocking their biologic actions. Other antagonists, in
addition to preventing agonist binding, sup-press the basal signaling
(“constitutive”) activity of receptors. Some of the most useful drugs in
clinical medicine are phar-macologic antagonists.
A 51-year-old man presents to his medical clinic due to dif-ficulty breathing. The patient is afebrile and normotensive, but tachypneic. Auscultation of the chest reveals diffuse wheezes. The physician provisionally makes the diagnosis of bronchial asthma and administers epinephrine by intramus-cular injection, improving the patient’s breathing over several minutes. A normal chest X-ray is subsequently obtained, and the medical history is remarkable only for mild hyperten-sion that was recently treated with propranolol. The physi-cian instructs the patient to discontinue use of propranolol, and changes the patient’s antihypertensive medication to verapamil. Why is the physician correct to discontinue propranolol? Why is verapamil a better choice for managing hypertension in this patient?
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