Antagonists

An antagonist is a type of ligand or drug that avoids or dampens a biological reaction. Upon binding to the receptor, it does not activate.

Rather it tends to block the particular receptor. Sometimes, they are also referred to as blockers such as alpha-blockers or beta-blockers.

In this article, we will discuss different types of antagonists and the mechanisms of how they work.  We will also discuss specific antagonists in detail that have special importance in neurology.

Types

Antagonists can be classified into different categories depending on the mechanism they use to antagonize a particular biological response. They can also be classified de[ending on the type of receptor.

Here, we will discuss different types of antagonists depending upon their mechanism of action.

Chemical Antagonists

It is a type of antagonist that binds to a drug or ligand and renders it ineffective. A chemical antagonist does so by causing certain chemical changes in the ligand it binds.

The antagonist binds to the agonist and forms an inactive complex that cannot perform any function.

For example, protamine sulfate is a positively charged drug. When it is given IV, it binds to heparin; a negatively charged drug, forming an inactive complex. As a result, heparin cannot perform its function.

Physiological Antagonist

It is a type of antagonist that binds to a separate receptor and counters the effect of the agonist. Two drugs would be said physiological antagonists of one another, if they bind to two different receptors and produce opposite effects.

For example, insulin and glucagon are physiological antagonists of one another. Both of them bind to two different receptors, but the effects produced by each of them are opposite to each other. Insulin decreases blood glucose levels while glucagon increases it.

Pharmacological Antagonist

Pharmacological antagonist binds to the same receptor as the agonist does. It occupies the binding site of the receptor and prevents the binding of agonist to the receptor. In this way, it prevents the activation of the receptor. These include receptor blockers such as alpha-blockers, beta-blockers, etc.

Depending on the fact that whether their effect can be countered or not, pharmacological antagonists are further divided into two types:

Reversible or competitive antagonist

It is a type of pharmacological antagonist whose effect can be countered by increasing the concentration of agonist.

For example, prazosin is a reversible antagonist of alpha-1 receptors.

Irreversible or non-competitive antagonist

It is a type of pharmacological antagonist whose effects cannot be countered by increasing the concentration of agonist.

For example, phenoxybenzamine is an irreversible antagonist of alpha-receptors.

Allosteric Antagonist

It is a type of antagonist that binds to the receptors but on a different as compared to the binding site of the real agonist. Binding of allosteric antagonist induces changes in the receptor.

This type of antagonist can prevent the activation of receptor even after binding of the agonist. They can also change shape of the binding site in such a way that it no longer binds to the agonist.

Physical  antagonist

It is a type of antagonist that is based on the physical property of the drug. It can bind to the agonist and prevent its action.

For example, when charcoal is used in case of poison ingestion, such as alkaloid poisons; it acts as a physical antagonist. It has the ability to absorb the poison. In this way, it prevents the poison from entering the bloodstream, thus countering it.

Inverse agonists

Although sounds more like an agonist, an inverse agonist is a special type of antagonist. An inverse agonist binds to the same receptor as the agonist does. However, instead of increasing the activity of the receptor, an inverse agonist decreases it.

Inverse agonist works only when the receptor has some intrinsic activity. In that case, the binding of an agonist increases the intrinsic activity of the receptor whereas binding of an inverse agonist decreases it.

GABAA receptors have intrinsic activity. Agonists of GABAA receptors include muscimol, whereas certain beta-carbolines act as inverse agonists of GABAA receptors. 

Antagonist important in CNS

In this section, we will discuss some antagonists that have particular importance in the central nervous system.

Dopamine Antagonist

Dopamine antagonists block the action of dopamine. They have profound importance in several antipsychotic diseases such as schizophrenia, bipolar disorder, and psychosis. They are also used in non-psychotic illnesses such as orthostatic hypotension, vomiting, and nausea.

Dopamine antagonists can be classified into two types;

D1 blockers

They block the D1-like receptors. They include D1 and D5 receptors. These are the stimulatory receptors coupled with Gs proteins.

They are present in substantia nigra, and the direct pathway of the basal ganglia. They are peripherally present in the renal artery, mesenteric artery and splenic artery.

D2 blockers

They block the D2 like receptors that include D2, D3, and D4 receptors. These are the inhibitory receptors coupled to Gi proteins.

They are present in presynaptic and postsynaptic neurons, striatum, substantia nigra, indirect pathway of basal ganglia. Peripherally, they are present in kidneys, adrenal cortex, and arteries.

Most of the dopamine antagonists are non-specific. They can block both D1-like and D2-like receptors.

Uses

Dopamine antagonists are also known as typical antipsychotic drugs. They are used in different psychotic conditions such as:

  • Schizophrenia
  • Mania
  • Bipolar disorder
  • Severe psychosis

They are also used in different non-psychotic diseases such as

  • Vomiting
  • Nausea
  • Hyperkinetic disorders
  • Hypertension

Drugs

Dopamine antagonists include drugs such as haloperidol, chlorpromazine, fluphenazine, etc.

Serotonin Antagonist

As the name indicates, they block the activation of serotonin receptors. Serotonin antagonists have profound application in a number of psychiatric diseases such as depression, anxiety, insomnia, etc.

Different types of serotonin receptors are present in the body. However, with respect to the brain, 5HT2 are the most important.

The 5HT2 receptors are widely distributed in the cortex, basal ganglia, the limbic system, and other areas of the brain. They are G-protein coupled receptors that are coupled to Gq proteins. These are the stimulatory receptors. They are associated with increased neuronal activity in the brain.

Uses

These drugs are called novel or atypical antipsychotic drugs. Like dopamine antagonists, they are used in conditions like;

  • Schizophrenia
  • Mania
  • Bipolar disorder
  • Severe psychosis

These drugs have less severe side effects as compared to dopamine antagonists.

Drugs

Serotonin 5HT2 receptor antagonists include clozapine, olanzapine, risperidone, apiprazole etc.

Antagonists important in ANS

In this section, we will discuss antagonists that are important in the autonomic nervous system.

Muscarinic Antagonists

The muscarinic receptor antagonists bind to acetylcholine receptors and prevent their activation. As acetylcholine is the main neurotransmitter of the parasympathetic system, these antagonists can successfully block the entire parasympathetic activation.

There are three types of muscarinic receptors;

  1. M1 receptors, excitatory receptors present in brain
  2. M2 receptors, inhibitory receptors present in heart
  3. M3 receptors, excitatory receptors present inn smooth muscles, glands, eyes, etc.

All these receptors are G-protein coupled receptors. M1 and M3 are Gq-coupled while M2 are Gi-coupled receptors.

All the muscarinic antagonists are non-specific in nature and block all types of receptors.

Uses

Muscarinic antagonists find a number of uses. These include the following;

  • Management of AChE inhibitors overdose
  • Ophthalmology (dilation of pupil)
  • Asthma and COPD
  • Motion sickness
  • Overreactive bladder
  • Anti-spasmodic
  • Antidiarrheal

Drugs

The drugs in this category include atropine, benztropine, ipratropium, scopolamine, etc.

Nicotinic Receptor Antagonists

These antagonists block the activation of nicotinic receptors present in ganglia and skeletal muscle. Thus, they are further classified into two types;

Ganglionic blockers

These antagonists block the nicotinic receptors present in ganglia. Thus, they are able to block sympathetic as well as parasympathetic firing. It is because the ganglia of both these system have nicotinic receptors.

They reduce the predominant autonomic tone. In the case of arterioles, venules and sweat glands, they block the sympathetic tone; while in other organs, they block the parasympathetic tone.

Two important ganglionic blockers include hexamethonium and mecamylamine.

Neuromuscular blocking drugs

They block the nicotinic receptors present at neuromuscular junction. They are used as skeletal muscle relaxants. These include tubocurarine, atracurium, etc.

Alpha Receptor Antagonists

These drugs block the activation of alpha receptors.

They are further classified depending on the type of alpha receptors they block.

Alpha-1 blockers

They block the alpha-1 receptors present in arteries, venules, eyes, bladder, etc. these include prazosin, tamsulosin, etc.

These drugs are used in:

  • Hypertension
  • Urinary retention
  • Dilation of eye
  • Cardiovascular disorders

Alpha-2 blockers

They block the alpha-2 receptors present in the presynaptic nerve terminal. These include drugs like methyl-dopa and clonidine.

They are used in hypertension, especially for the management of hypertension in pregnancy.

Beta Receptor Antagonists

They block the beta-2 receptors. They are of two types;

  1. Cardiocelective, they block only beta-1 receptors present in the heart.
  2. Non-cardioselective, they are non-selective block both beta-1 and beta 2 receptors.

These drugs include esmolol, atenolol, propranolol, etc.

They are used in angina, myocardial infarction, cardiac failure, asthma etc.

Conclusion/Summary

An antagonist is a drug or ligand that tends to stop or impede a biological reaction. They produce effects opposite to that of the agonist.

They are of different types depending on their mechanism of action.

These  include;

  • Physical antagonists
  • Chemical antagonists
  • Physiological antagonists
  • Pharmacological antagonists
  • Allosteric antagonists

An inverse agonist is a special type of antagonist that decreases the intrinsic activity of a receptor.

Antagonist find important applications in the CNS as well as the ANS.

The important CNS antagonists include dopamine antagonists and serotonin antagonists.

The important ANS antagonists include muscarinic antagonists, nicotinic antagonists, alpha-blockers and beta-blockers.

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