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.

GABA_A receptors have intrinsic activity. Agonists of GABA_A receptors include muscimol, whereas certain beta-carbolines act as inverse agonists of GABA_A 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 G_s 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 G_i 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 G_q 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 G_q-coupled
while M2 are G_i-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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