This article throws light upon the three important things you need to know about receptors. They are:- 1. Spare Receptors 2. Silent Receptors 3. Tachyphylaxis and Desensitization.
Thing # 1. Spare Receptors:
A highly active agonist with a high efficacy can produce a maximal response with a concentration that does not occupy all the receptors. The receptors that remain unoccupied are termed as spare receptors or reserve receptors. They are in no way different from those whose occupation has produced the maximum response.
It has been estimated that highly active agonists may occupy as few as 0.1% of the receptors in concentrations just sufficient to produce a maximal response. The interaction of an agonist with any of these spare receptors can evoke a response, but the maximum effect is produced as soon as the appropriate number of receptors have delivered their stimulus to the effector organ.
Thing # 2. Silent Receptors:
A silent receptor is one to which the agonist may become attached but which is incapable of producing a pharmacological response. They act as adsorbents on the plasma membrane of cell.
This has the effect of reducing the immediate effect of the drug because fewer molecules reach the ‘pharmacological’ receptors in the tissues, but it has a effect of prolonging the action of drug as it gets slowly released from such receptors and are then available for ‘pharmacological’ receptors.
These silent receptors can be readily transformed into pharmacological receptors and back again under the influence of a changing chemical environment. This is one of the hypothesis which seeks to explain the development of physical dependence on drugs and denervation super sensitivity in striated muscles.
Thing # 3. Tachyphylaxis and Desensitization:
Successive applications of the same dose of a powerful agonistic drug, usually produce constant responses, (within the limits of biological variation), provided that modest concentrations are used, the exposure time is not too prolonged, and a sufficiently long rest period is allowed to enable the tissue to recover from the response.
However, with some drugs, the responses gets smaller, even when above conditions are maintained, this phenomenon is known as tachyphylaxis. This suggests that drug blocks or antangonizes its own action. For example nicotine’s action on ganglion cells is to stimulate them initially and then to block them. This effect is attributed to a conformational change to an inactive form of the receptor.
Another type of tachyphylaxis is exhibited by some drugs that act indirectly, that is, drugs that owe their pharmacological activity to the release of an active agent within the tissue which brings about tissue response e.g. Allergens or histamine releasers.
Here, tachyphylaxis occurs because the amount of histamine available for release on subsequent stimulations is exhausted, and also because the receptors become desensitized after exposure to a considerable concentration of histamine.
Desensitization is another term closely related to tachyphylaxis. When small doses to an agonist are given at appropriate intervals, the tissue shows reproducible responses. However, when the tissue is exposed to a high concentration of agonist; the subsequent responses to small doses are depressed, but slowly recovers. This is known as desensitization (Fig. 3.1)
For example cholinoceptors on neuromuscular end plate exhibit such property.
Many a times the terms tachyphylaxis and desensitization are used synonymously.
A drug which can combine with receptors and elicit a positive response from the tissue in which the receptors are located is called an agonist. The tendency of that agonist to combine with a particular kind of receptors is known as affinity, whereas the ability to initiate a observable effect is known as intrinsic activity α or efficacy. These two properties of a drug are considered to be unrelated.
An agonist can activate the receptor because it resembles the endogenous regulatory compound such as neurotransmitters or hormones, and they have greater capacity to resist metabolic degradation, thereby acting for a longer duration than their natural counterparts. Agonists are roughly classified as: full agonists, partial agonists and inverse agonists.
A full agonist is able to elicit the greatest response of which the respective tissue is capable of. This maximal response is defined as that response beyond which no further increase in response is obtained by further increases in agonist concentration.
For a full agonist, the intrinsic activity α is equal to unity or 1 e.g., salbutamol.
A partial agonist is that compound which has high affinity to receptors, but possess a low or moderate intrinsic activity. For a partial agonist the intrinsic activity is less than 1. They have both agonist and antagonist action and hence sometimes referred to as dualist eg., pindolol and oxprenolol. A partial agonist cannot produce a maximal response even at 100% receptor occupancy. (Fig 3.2)
If a partial agonist occupies on functionally significant fraction of the receptors it will antagonize the actions of agonist e.g, Naloxone and Nalorphine. Some substances produce effects that are specifically opposite to those of the agonist. For example, the action of benzodiazepines on the benzodiazepine receptors in the CNS produces sedation, anxiolysis, muscle relaxation and control convulsions.
This is the conventional agonistic activity of benzodiazepines, but recently, a new type of drug has been discovered, β-carbolines, which binds to benzodiazepine receptors and exerts the opposite effect, producing stimulation, anxiety, increased muscle tone and convulsions ; they are known as inverse agonists.
Antagonists are drugs that interact with the receptor or other component of the effector mechanism and inhibit the action of an agonist. They possess a high affinity to the receptor but are devoid of intrinsic pharmacological activity. Antagonists are classified as competitive and non-competitive antagonists.
Competitive antagonism as the name implies, is based on the competition between the antagonist and an agonist for the receptors to which both have affinity. This class of drugs when given in appropriate dosage are capable of reversing or blocking agonistic effects.
Competitive antagonism is completely reversible; an increase in the bio-phasic concentration of the agonist will overcome the effect of the antagonist. For example, atropine, propranolol, diphenhydramine. These antagonists have a great therapeutic value, especially for the purpose of reversing or blocking the effects of agonist over dosage.
A non-competitive antagonist prevents the agonist from producing its effect at a given receptor site. This could result from irreversible interaction of the antagonist either with the same site as the agonist or with different sites, in a manner such that the capacity of the agonist to combine with its receptors or its efficacy is altered.
The essential feature of non-competitive antagonism is that the agonist has no influence upon the degree of antagonism or its reversibility with respect to concentration in the bio-phase (Fig. 3.3).
For example, Phenoxy-benzamine, organophosphorus pesticides
Depending on the site of action, antagonism can be divided into pharmacological, physiological, chemical and physical antagonism. When a drug reduces another’s effect by binding to same receptor species, it is called as pharmacological antagonism. Competitive and non-competitive antagonism are both examples of such type.
When a drug reduces another’s effect by eliciting an opposing response due to activation of a second species of receptors, the reduction is termed physiological antagonism/functional antagonism e.g., on heart, atropine blocks the acetylcholine effect by virtue of pharmacological antagonism whereas adrenaline opposes the acetylcholine effect by virtue of physiological antagonism.
The administration of a second drug for the purpose of changing the structure of the first or nullifying the effect of first drug is known as chemical antagonism e.g., chelators EDTA removes lead, antacids for gastric acidity.
Adsorbents, such as charcoal, bind to the free form of drug or poisons in the gut and remove them. This is known as physical antagonism. Pharmacokinetic antagonism is the situation in which the antagonist effectively reduces the concentration of the active drug at its site of action.
This can happen in various ways like the metabolic degradation of the active drug may be increased or the rate of absorption of the active drug from the GIT may be reduced or the rate of renal excretion may be increased, e.g., phenobarbitone in known to induce hepatic microsomal enzymes, which will increase metabolism rate of other drugs administered concurrently.
Dose Ratio:
The effect of antagonism can be measured in terms of the dose ratio by finding out the equiactive doses of agonist in the presence and in the absence of the competitive antagonist.
Dose ratio = ED50 after antagonist/ED50 before antagonist
The dose-ratio is the factor by which the concentration of agonist must be multiplied to maintain a given response in the presence of antagonist. Higher the dose ratio, more specific is the antagonist. Dose ratio generally increases with the time of exposure, hence it is desirable to adopt a standard time of exposure in very long experiments.
Double Reciprocal Plot of Lineweaver and Burk:
This is another method/procedure for analyzing drug antagonism. In this, the reciprocal of effect is plotted against the reciprocal of the dose (Fig 3.4)
By this procedure, linearization of graph is obtained and the straight line intersects the Y-axis at 1/max-effect. If the plotted straight lines of agonist alone and in presence of antagonist intersect X-axis (negative side) at a single point, the antagonism is of non-competitive nature, whereas if both the straight lines intersect y-axis at a single point, the antagonism is said to be of competitive nature.