Beta adrenoceptor agonists

Mechanism of Action of beta adrenoreceptor agonists

1. Beta- adrenoceptor agonists ( β- agonists )

2. Introduction Beta-agonists  are  sympathomimetic drugs  that bind to beta- adrenoceptors located in cardiac  nodal tissue , the conducting system, and contracting myocytes . The heart has both  beta 1  ( β 1 ) and beta 2  ( β 2 ) adrenoceptors , although the predominant receptor type in number and function is β 1 . These receptors normally bind  norepinephrine  that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine  that circulate in the blood. β 1  and β 2   adrenoceptor activation increases heart rate and contractility, which increases cardiac output. Activation of these receptors also increases conduction velocity within the heart as well as the rate of mechanical relaxation ( lusitropy ). These drugs are used to treat acute and refractory heart failure, as well as circulatory shock.

3. Mechanism of action : Heart 1. Beta-agonists bind to beta- adrenoceptors located in cardiac  nodal tissue , the  conducting system , and contracting myocytes . 2. The heart has both β 1  and β 2   adrenoceptors , although the predominant receptor type in number and function is β 1 . These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood. 4. Beta- adrenoceptors are coupled to   Gs- proteins , which activate adenylyl cyclase to form   cAMP   from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L- type calcium channels , which causes increased calcium entry into the cells . 5. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility).

4. Mechanism of action : Heart 6. Gs-protein activation also increases heart rate by opening ion channels responsible for  pacemaker currents  in the sinoatrial node 7. PK-A phosphorylates sites on the sarcoplasmic reticulum , which enhances the release of calcium through the ryanodine receptors ( ryanodine-sensitive , calcium-release channels ) associated with the sarcoplasmic reticulum . This provides more calcium for binding the   troponin -C , which enhances inotropy . 8.  Finally, PK-A can phosphorylate myosin light chains, which may also contribute to the positive inotropic effect of beta- adrenoceptor stimulation. In summary, the cardiac effects of a β-agonist are increased heart rate, contractility, conduction velocity, and relaxation rate

5. Mechanism of action : Blood Vessels 1. Vascular smooth muscle has β 2 -adrenoceptors that have a high binding affinity for circulating epinephrine and a relatively lower affinity to norepinephrine released by sympathetic adrenergic nerves. 2. These receptors, like those in the heart, are coupled to a Gs -protein , which stimulates the formation of  cAMP . Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. 3. The reason for this is that cAMP inhibits  myosin light chain kinase  that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by β 2 -agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).

6. Mechanism of action : Other Tissues Activation of β 2 -adrenoceptors in the lungs causes bronchodilation . β 2 -adrenoceptor activation leads to hepatic glycogenolysis and pancreatic release of glucagon, which increases plasma glucose concentrations. β 1 -adrenoceptor stimulation in the kidneys causes the release of renin , which stimulates the production of  angiotensin II  and the subsequent release of  aldosterone  by the adrenal cortex.

7. Effects and therapeutic Use Beta- Agonists (EFFECTS) Cardiac effects Increase contractility (positive inotropy ) Increase relaxation rate (positive lusitropy ) Increase heart rate (positive chronotropy ) Increase conduction velocity (positive dromotropy ) Vascular effects Smooth muscle relaxation ( vasodilation ) Other actions Bronchodilation Hepatic glycogenolysis Pancreatic release of glucagon Renin release by kidneys THERAPEUTIC USE HEART FAILURE CIRCULATORY SHOCK

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