Visual definition of an antagonist, where it compared to agonists and reverse agonists.
An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors.
There are five adrenergic receptors, which are divided into two groups.
The first group of receptors are the beta (β) adrenergic receptors.
There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.
Antagonists reduce or block the signals of agonists. They can be drugs, which are added to the body for therapeutic reasons, or endogenous ligands. The α-adrenergic antagonists have different effects from the β-adrenergic antagonists.
Pharmacology
Adrenergic ligands are endogenous proteins that modulate and evoke specific cardiovascular
effects. Adrenergic antagonists reverse the natural cardiovascular
effect, based on the type of adrenoreceptor being blocked. For example,
if the natural activation of the α1-adrenergic receptor leads to vasoconstriction, an α1-adrenergic antagonist will result in vasodilation.
Some adrenergic antagonists, mostly β antagonists, passively diffuse from the gastrointestinal tract. From there, they bind to albumin and α1-acid glycoprotein in the plasma, allowing for a wide spread through the body. From there, the lipophilic antagonists are metabolized in the liver and eliminated with urine while the hydrophilic ones are eliminated unchanged.
Mechanisms of action
There are three different types of antagonists.
Competitive
While only a few α-adrenergic antagonists are competitive, all β-adrenergic antagonists are competitive antagonists. Competitive antagonists are a type of reversible antagonists. A competitive antagonist will attach itself to the same binding site
of the receptor that the agonist will bind to. Even though it is in
activator region, the antagonist will not activate the receptor. This
type of binding is reversible as increasing the concentration of agonist
will outcompete the concentration of antagonist, resulting in receptor
activation.
Adrenergic competitive antagonists are shorter lasting than the
other two types of antagonists. While the antagonists for alpha and beta
receptors are usually different compounds, there has been recent drug
development that effects both types of the adrenoreceptors.
Phentolamine, an adrenergic antagonist
Examples
Two examples of competitive adrenergic antagonists are propranolol and phentolamine. Phentolamine is a competitive and nonselective α-adrenoreceptor antagonist. Propanalol is a β-adreno receptor antagonist.
Non-competitive
While competitive antagonists bind to the agonist or ligand binding site of the receptor reversibly, non-competitive antagonists can either bind to the ligand site or other site called the allosteric site.
A receptor's agonist does not bind to its allosteric binding site. The
binding of a non-competitive antagonist is irreversible. If the
non-competitive antagonist binds to the allosteric site and an agonist
binds to the ligand site, the receptor will remain unactivated.
An example of an adrenergic non competitive antagonists is
phenoxybenzamine. This drug is a non-selective α-adrenergic antagonist,
which means it binds to both alpha receptors.
Uncompetitive
There were few if any adrenergic uncompetitive antagonists.
An uncompetitive antagonist is slightly different from the other two
types of antagonists. The action of an uncompetitive antagonist is
dependent on the receptor's prior activation. This means only after the
agonist binds to the receptor can the antagonist block the receptor's
function.
Examples
Alpha blockers
Beta blockers
- Propranolol
- Nebivilol
- Atenolol
- Oxprenolol
- Metoprolol
- Timolol
- Pindolol
- Nadolol
- Pindolol
- Esmolol
- Acebutolol
- Sotalol
- Talinolol
- Betaxolol
Mixed action
Major effects
Major complications of persistent high blood pressure, which can be attenuated by adrenergic antagonists.
Adrenergic antagonists have inhibitory or opposing effects on the
receptors in the adrenergic system. The adrenergic system modulates the fight-or-flight response. Since this response, which is mostly seen as an increase in blood pressure, is produced by the release of the endogenous adrenergic ligands, administration of an adrenergic antagonist results a decrease in blood pressure, which is controlled by both heart rate and vasculature tone.
Administration of an adrenergic antagonist that specifically targets
the beta receptors, results in this decrease in blood pressure by
slowing or reducing cardiac output.
Medical uses
Adrenergic antagonists are mostly used for cardiovascular disease. The adrenergic antagonists are widely used for lowering blood pressure and relieving hypertension. These antagonists have a been proven to relieve the pain caused by myocardial infarction, and also the infarction size, which correlates with heart rate.
There are few non-cardiovascular uses for adrenergic antagonists. Alpha-adrenergic antagonists are also used for treatment of ureteric stones, pain and panic disorders, withdrawal, and anesthesia.
Limitations
While
these adrenergic antagonists are used for treating cardiovascular
disease, mainly hypertension, they can evoke harmful cardiac events.
Some adrenergic antagonists have a diminished ability to reduce stroke compared to placebo drugs.
Side effects and toxicity
While
adrenergic antagonists have been used for years, there are multiple
issues with using this class of drug. When overused, adrenergic
antagonists can result in bradycardia, hypotension, hyperglycemia and even hypodynamic shock. This is because adrenergic stimulation by agonists results in normal calcium channel
regulation. If these adrenergic receptors are blocked too often, there
will be an excess in calcium channel inhibition, which causes most of
these problems.
