Introduction to Antagonism in Pharmacology
Antagonism could be defined as an interaction between two or more drugs that have opposite effects on the body. Drug antagonism may block or reduce the effectiveness of one or more of the drugs. In antagonism, there is always a competition for available receptor by two or more drugs or substances. Antagonism may be noncompetitive and have no pharmacological effect of their own, or competitive in that they are capable of reversing or altering an effect already achieved.
Types of Antagonism in Pharmacology
We classified antagonism in Pharmacology into 5 types These are:
- Pharmacologic Antagonism
- Physiological Antagonism
- Chemical Antagonism
- Pharmacokinetic Antagonism
- Allosteric Antagonism
1. Pharmacologic Antagonism
1a. Competitive Antagonism
This is a type of Receptor Antagonism or Antagonism by receptor blockade. Competitive antagonists (also known as surmountable antagonists) reversibly bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists “compete” for the same binding site on the receptor. Once bound, an antagonist will block agonist binding. The level of activity of the receptor will be determined by the relative affinity of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors that the agonist occupies; higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy. In functional assays using competitive antagonists, a parallel rightward shifts of agonistdose–response curves with no alteration of the maximal response is observed.
Examples of Competitive Antagonism
The opiod receptor antagonist, naloxone is an example of a competitive antagonist. The effects of a competitive antagonist may be overcome by increasing the concentration of agonist. Often (though not always) these antagonists possess a very similar chemical structure to that of the agonist.
1b. Non-competitive Antagonism
This is a type of receptor antagonism or Antagonism by receptor blockade – Pharmacologic antagonism. Non-competitive antagonists (sometimes called non-surmountable antagonists) are allosteric antagonists. These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site.
Cyclothiazide has been shown to act as a reversible non-competitive antagonist of mGluR1 receptor. Cyclothiazide was also found to act as a GABAA receptor negative allosteric modulator, potently inhibiting GABAA-mediated currents.
Non-competitive antagonists do not compete with agonists for binding. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds.
No amount of agonist can completely overcome the inhibition once it has been established. In functional assays of non-competitive antagonists, depression of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced. The rightward shift will occur as a result of a receptor reserve and inhibition of the agonist response will only occur when this reserve is depleted.
An antagonist that binds to the active site of a receptor is said to be “non-competitive” if the bond between the active site and the antagonist is irreversible or nearly so. This usage of the term “non-competitive” may not be ideal, however, since the term “irreversible competitive antagonism” may also be used to describe the same phenomenon without the potential for confusion with the second meaning of “non-competitive antagonism” discussed above e.g Phenoxybenzamine, an irreversible blocker of α-adrenoceptors
Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind toa separate allosteric binding site. This type of antagonism produces a kinetic profile in which “the same amount of antagonist blocks higher concentrations of agonist better than lower concentrations of agonist”. Memantine, used in the treatment of Alzheimer’s disease, is an uncompetitive antagonist of the NMDA receptor.
2. Physiological Antagonism
Physiological antagonism describes the behavior of a substance that produces effects counteracting those of another substance using a mechanism that does not involve binding to the same receptor. There are several substances that have antihistaminergic action despite not being Ligands for the histamine receptor.
For instance, epinephrine raises arterial pressure through vasoconstriction mediated by α1-adrenergic receptor activation, in contrast to histamine, which lowers arterial pressure. Thus, despite not being true antihistamines because they do not bind to and block the histamine receptor, epinephrine and other such substances are physiological antagonists to histamine.
Examples of Physiological Antagonism
Histamine and Epinephrine in anaphylactic shock; Glucagon and insulin on blood glucose level.
3. Chemical Antagonism
Chemical antagonism can be non-receptor mediated. A common example of chemical antagonism is the scenario in which one drug can bind to and inactivate an agonist, thus making less of the drug available to produce an effect.
Examples of Chemical Antagonism
Protamine sulphate & Heparin Protamine sulphate is Antidote in Heparin overdosage. 2. Dimercaprol (Chelating agent) & Arsenic: useful in poisoning.
4. Pharmacokinetic Antagonism
This describes the situation in which the antagonist effectively reduces the concentration of the active drug at the site of action. This can occur either by
- increasing the rate of metabolic degradation of the active drug. Example: reduction of anticoagulant effect of warfarin when an agent that accelerates its hepatic metabolism such as phenobarbitone is given.
- Reduction in the rate of the absorption of active drug from the GIT
- Increase in rate of renal excreation
5. Allosteric Antagonism
Allosteric antagonists modulate the affinity and/or efficacy of agonists for receptors. Although the manner in which this modulation can occur can mimic that of simple competitive antagonists, allosteric antagonists possess unique properties that can present seemingly capricious profiles of antagonism.
References
- Drug antagonism. IAHPC Pallipedia Accessed August 8, 2021.
- Drug Antagonism. Science Direct. Accessed August 8, 2021.
- Allosteric modulators. Pubmed. Accessed August 8, 2021