Receptors

Most receptors are protein macromolecules. When the agonist binds to the receptor, the proteins undergo an alteration in conformation which induces changes in systems within the cell that in turn bring about the response to the drug. Different types of effector-response exist. (1) The most swift are the channel-linked receptors, i.e. receptors coupled directly to membrane ion channels; neurotransmitters act on such receptors in the postsynaptic membrane of a nerve or muscle cell and give a response within milliseconds. (2) Another type of response involves receptors bound to the cell membrane and coupled to intracellular effector systems by a G-protein. Catecholamines (the first messenger) activate [3-adreno-ceptors to increase, through a coupled G-protein system, the activity of intracellular adenylate cyclase which raises the rate of formation of cyclic AMP (the second messenger), a modulator of the activity of several enzyme systems that cause the cell to act; the process takes seconds. (3) A third type of membrane-bound receptor is the kinase-linked receptor (so called because a protein kinase is incorporated within the structure), which is involved in the control of cell growth and differentiation, and the release of inflammatory mediators. (4) Within the cell itself, steroid and thyroid hormones act on nuclear receptors which regulate DNA transcription and, thereby, protein synthesis, a process which takes hours.

Radioligand binding studies2 have shown that the receptor numbers do not remain constant but change according to circumstances. When tissues are continuously exposed to an agonist, the number of receptors decreases (down-regulation) and this may be a cause of tachyphylaxis (loss of efficacy with frequently repeated doses), e.g. in asthmatics who use adrenoceptor agonist bronchodilators excessively. Prolonged contact with an antagonist leads to formation of new receptors (up-regidation). Indeed, one explanation for the worsening of angina pectoris or cardiac ventricular arrhythmia in some patients following abrupt withdrawal of a (3-adrenoceptor blocker is that normal concentrations of circulating catecholamines now have access to an increased (up-regulated) population of p-adreno-ceptors (see Chronic pharmacology, p. 119).

Agonists. Drugs that activate receptors do so because they resemble the natural transmitter or hormone, but their value in clinical practice often rests on their greater capacity to resist degradation

2 The extraordinary discrimination of this technique is shown by the calculation that the total p-adrenoceptor protein in a large cow amounts to 1 mg (Maguire ME et al 1977 In: Greengard P, Robison GA (eds) Advances in Cyclic Nucleotide Research. Raven Press, New York: 8:1.)

and so to act for longer than the natural substances (endogenous ligands) they mimic; for this reason bronchodilation produced by salbutamol lasts longer than that induced by adrenaline (epinephrine).

Antagonists (blockers) of receptors are sufficiently similar to the natural agonist to be 'recognised' by the receptor and to occupy it without activating a response, thereby preventing (blocking) the natural agonist from exerting its effect. Drugs that have no activating effect whatever on the receptor are termed pure antagonists. A receptor occupied by a low efficacy agonist is inaccessible to a subsequent dose of a high efficacy agonist, so that, in this specific situation, a low efficacy agonist acts as an antagonist. This can happen with opioids.

Partial agonists. Some drugs, in addition to blocking access of the natural agonist to the receptor, are capable of a low degree of activation, i.e. they have both antagonist and agonist action. Such substances are said to show partial agonist activity (PAA). The (3-adrenoceptor antagonists pindolol and oxprenolol have partial agonist activity (in their case it is often called intrinsic sympathomimetic activity) (ISA), whilst propranolol is devoid of agonist activity, i.e. it is a pure antagonist. A patient may be as extensively '(3-blocked' by propranolol as by pindolol, i.e. exercise tachycardia is abolished, but the resting heart rate is lower on propranolol; such differences can have clinical importance.

Inverse agonists. Some substances produce effects that are specifically opposite to those of the agonist. The agonist action of benzodiazepines on the benzodiazepine receptor in the CNS produces sedation, anxiolysis, muscle relaxation and controls convulsions; substances called (3-carbolines which also bind to this receptor cause stimulation, anxiety, increased muscle tone and convulsions; they are inverse agonists. Both types of drug act by modulating the effects of the neurotransmitter gamma-aminobutyric acid (GABA).

Receptor binding (and vice versa). If the forces that bind drug to receptor are weak (hydrogen bonds, van der Waals bonds, electrostatic bonds), the binding will be easily and rapidly reversible; if the forces involved are strong (covalent bonds), then binding will be effectively irreversible. An antagonist that binds reversibly to a receptor can by definition be displaced from the receptor by mass action (see p. 99) of the agonist (and vice versa). If the concentration of agonist increases sufficiently above that of the antagonist the response is restored. This phenomenon is commonly seen in clinical practice — patients who are taking a p-adrenoceptor blocker, and whose low resting heart rate can be increased by exercise, are showing that they can raise their sympathetic drive to release enough noradrenaline (agonist) to diminish the prevailing degree of receptor blockade. Increasing the dose of p-adrenoceptor blocker will limit or abolish exercise-induced tachycardia, showing that the degree of blockade is enhanced as more drug becomes available to compete with the endogenous transmitter. Since agonist and antagonist compete to occupy the receptor according to the law of mass action, this type of drug action is termed competitive antagonism.

When receptor-mediated responses are studied either in isolated tissues or in intact man, a graph of the logarithm of the dose given (horizontal axis), plotted against the response obtained (vertical axis), commonly gives an S-shaped (sigmoid) curve, the central part of which is a straight line. If the measurements are repeated in the presence of an antagonist, and the curve obtained is parallel to the original but displaced to the right, then antagonism is said to be competitive and the agonist to be surmountable.

Drugs that bind irreversibly to receptors include phenoxybenzamine (to the a-adrenoceptor). Since such a drug cannot be displaced from the receptor, increasing the concentration of agonist does not fully restore the response and antagonism of this type is said to be insurmountable.

The log-dose-response curves for the agonist in the absence of and in the presence of a noncompetitive antagonist are not parallel. Some toxins act in this way, e.g. a-bungarotoxin, a constituent of some snake and spider venoms, binds irreversibly to the acetylcholine receptor and is used as a tool to study it. Restoration of the response after irreversible binding requires elimination of the drug from the body and synthesis of new receptor, and for this reason the effect may persist long after drug administration has ceased. Irreversible agents find little place in clinical practice.

Physiological (functional) antagonism

An action on the same receptor is not the only mechanism by which one drug may oppose the effect of another. Extreme bradycardia following overdose of a (5-adrenoceptor blocker can be relieved by atropine which accelerates the heart by blockade of the parasympathetic branch of the autonomic nervous system, the cholinergic tone of which (vagal tone) operates continuously to slow it. Bronchoconstriction produced by histamine released from mast cells in anaphylactic shock can be counteracted by adrenaline (epinephrine), which relaxes bronchial smooth muscle (p2-adrenoceptor effect) or by theophylline. In both cases, a pharmacological effect is overcome by a second drug which acts by a different physiological mechanism, i.e. there is physiological or functional antagonism.

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