ADRENERGIC ANTAGONISTS

ADRENERGIC ANTAGONISTS
SYMPATHOLYTICS (or) ADRENERGIC RECEPTOR BLOCKING AGENTS
Adrenergic antagonists are drugs that reduce the delivery of catecholamines to the adrenergic receptors by disrupting catecholamine synthesis, storage or release. They abolish the response to stimulation of sympathetic nerves.
These agents competitively antagonize the effect of the catecholamines at α and β adrenergic receptors.

CLASSIFICATION
I. α – Adrenergic blocking agents
1. Imidazolines – Tolazoline, Phentolamine
2. Beta Halo Alkylamines – Phenoxy benzamine, Dibenamine
3. Quinazolines – Prazosin, Terazosin, Doxazosin
4. Ergot Alkaloids – Ergotamine, Ergosin, Ergocrystin, Ergocriptine.
5. Miscellaneous – Yohimbin, Methy sergide
II. β – Adrenergic blocking agents
1. Aryl ethanolamines – Isoproterenol, pronethalol, Dichloro isoproterenol
2. Aryloxy propanolamines – Propranolol, Practalol, Metaprolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol.
III. Both α and β – Adrenergic blocking agents
Labetalol, Carvedilol.

I. α – Adrenergic blocking agents

Synthesis

Quinazoline Derivatives
Ergot alkaloids

II. β – Adrenergic blocking agents

These drugs block the effects of Endogeneous and exogeneous catecholamines. These drugs slow the heart rate and decrease the force of contraction. They competitively inhibit β – Adrenergic receptors. These are also used in the treatment of hypertension, arrhythmiasis, coronary artery disease and open angle glaucoma.

Practolol
Synthesis of Acebutolol

Other Beta blockers

III. Both α and β – Adrenergic blocking agents
Carvedilol

SAR for Beta blockers

1. The O-CH2 group between aromatic ring and the ethylamino side chain is responsible for the antagonistic property.
2. Replacement of catechol hydroxyl group with chlorine or phenyl ring retains the beta blocking activity.
3. N,N- di substitution decrease beta blocking activity. Activity is maintained when phenylethyl, hydroxyl phenyl ethyl or methoxy phenyl ethyl groups are added to amine as a part of molecule.
4. The two carbon side chain is essential for the activity.
5. Nitrogen atom should be of secondary amine for optimum beta blocking activity.
6. The carbon side chain having hydroxyl group must be S- configuration for optimum affinity to beta receptor.(Ex- Levobunolol, Timolol)
7. The aryloxy propanolamines are more potent than aryl ethanolamines.
8. Replacement of ethereal oxygen in aryloxy propanolamines with S, CH2 or N-CH3 is decreased the beta blocking activity.
9. The most effective substituents at amino group is isopropyl and tertiary butyl group.
10. The aromatic portion of the molecules could be varied with good activity.
11. Converting the aromatic portion to phenanthrene or anthracene decrease the activity.
12. Cyclic alkyl substituents are better than corresponding open chain substituents at nitrogen atom of amine.
13. Alpha methyl group at side chain decrease activity.

Mechanism of action

1. These drugs competitively inhibit the adrenergic receptors.


2. Beta antagonists are invariably employed in the treatment of essential hypertension and cause an effective decrease in BP by exerting direct effect on heart and blood vessels, minimizing sympathetic outflow from CNS and affecting the rennin-angiotensin- aldosterone system.


3. Some drugs like propranolol precipitate an asthmatic attack by antagonizing beta-2 receptors in bronchial smooth muscle and give rise to sudden contraction of bronchial smooth muscle.