Physiological Basis of Adrenergic Receptors Function

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Chapter: Medicinal Chemistry : Adrenergic Drugs

The important factors in this function are the response of any cell or organ to the sympathomimetic amines due to the density and proportion of α and β-adrenergic receptors, including their subtypes .


PHYSIOLOGICAL BASIS OF ADRENERGIC RECEPTOR FUNCTION

The important factors in this function are the response of any cell or organ to the sympathomimetic amines due to the density and proportion of α and β-adrenergic receptors, including their subtypes (discussed in the section IV, ‘Introduction to ANS’). For example, norepinephrine has relatively little capacity to increase the bronchial airflow, the receptors in the bronchial smooth muscle are largely of β2 subtype. In contrast, isoproterenolol and epinephrine are potent bronchodilators. Cutaneous blood vessels physiologically express almost exclusively α receptors; thus, norepinephrine and epinephrine cause constriction of such vessels, whereas isoproterenolol has little effect. Most of the actions of sympathomimetics are broadly classified into seven types:

  1. Peripheral excitatory action on certain types of smooth muscles (i.e. blood vessels supplying skin, kidney, mucous membrane, and glands).

  2. A peripheral inhibitory action on certain other types of smooth muscles (i.e. gut, bronchial tree, and blood vessels supplying skeletal muscle).

  3. Cardiac excitation leads to increase in the heart rate.

  4. Metabolic action (i.e. glycogenolysis in tissues and muscle, liberation of fatty acids).

  5. Endocrine actions (i.e. increase in release of hormones).

  6. CNS stimulation (i.e. psychomotor stimulation, wakefulness, and respiratory stimulation).

  7. A presynaptic action that results in either inhibition or excitation, physiologically the inhibitory action is more than excitatory motion.

Therapeutically these agents are classified into the following:

  • Pressor agents: Noradrenaline, Ephedrine and Dopamine

  • Cardiac stimulants: Adrenaline, Dobutamine and Isoprenaline

  • Bronchodilators: Isoprenaline, Salbutamol, Terbutaline, Formeterol, etc

  • Nasal decongesents: Phenylephrine, Naphazoline, Pseudoephedrine

  • CNS stimulants: Amphetamine, Methamphetamine, Dexamphetamine, etc


Mechanism of Action of Sympathomimetics

β1 ADRENERGIC RECEPTOR ACTION

The β adrenergic actions mediated through cyclic AMP (cAMP). Adrenaline activates membrane bound enzyme adenylcyclase through regulatory protein Gs. Adenosine-triphosphate (ATP) is broken into cAMP at the inner face. In the heart, proteins such as troponin and phospholamban, are phosphorylated and results in increased interaction with calcium at myofilaments, leading to increased force of contraction.

β2 ADRENERGIC RECEPTOR ACTION

β2 receptors are predominantly found in the respiratory system. The β2 receptor agonist produces bronchodilation by binding with the β2 receptors.

α1 ADRENERGIC RECEPTOR ACTION

Stimulation of α1 adrenergic receptors elicits a primary mode of signal transduction that involves the mobilization of intracellular Ca2+ from endoplasmic stores. This increase in intracellular Ca2+ is thought to result from the activation of phospholipase Cβ isoforms through Gq family of G protein. The hydrolysis of membrane bound polyphosphoinositides through phospholipase C results in generation of diacylglycerol (DAG) and Inositol 1, 4, 5-triposphate (IP3). IP3 stimulates the release of Ca2+ from intracellular stores. In smooth muscles increased intracellular Ca2+ cause contraction, mediated by Ca2+ sensitive protein kinases, that is, calmodulin dependent myosin light chain kinase.

α2 ADRENERGIC RECEPTOR ACTION

α2 adrenergic receptors activate G protein gated K+ channels resulting in hyper-polarization. These α2 receptors are also capable of inhibiting voltage gated Ca2+ channels mediated by G protein and also activates the mitogen activated protein kinase (MAPK). These lead to activation of a variety of tyrosine kinase mediated downstream events, and these inhibit the release of norepinephrine from nerve endings and suppresses the sympathetic outflow to the brain.


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