Vasoactive Peptide Pharmacology Note PDF

Vasoactive peptide Pharmacology-113 3rd year PharmD Dr. Omamah Alfarisi 2024 10/21/2024 Renin-angiotensin system RAS 10/21/2024 Renin-angiotensin system (RAS) RAS participates significantly in the pathophysiology...

Vasoactive peptide Pharmacology-113 3rd year PharmD Dr. Omamah Alfarisi 2024 10/21/2024 Renin-angiotensin system RAS 10/21/2024 Renin-angiotensin system (RAS) RAS participates significantly in the pathophysiology of hypertension, congestive heart failure, myocardia infarction and diabetic nephropathy Components of RAS: Prorenin Renin Angiotensin I (ANGI) Angiotensin II (ANG II) Angiotensin converting enzymes I & II (ACE, ACE II) Angiotensin(1-7) Other.. 10/21/2024 Renin-angiotensin system (RAS) Renin An enzyme synthesized as prorenin, which is activated to form active renin. Location: Synthesized and stored in the juxtaglomerular apparatus of the nephron. Secreted into the renal arterial circulation. Function: Acts as a protease enzyme that converts angiotensinogen to angiotensin I (ANG I). 10/21/2024 Factors controlling the release of renin Intrarenal Baroreceptor pathway: Decrease in blood pressure is sensed mechanically by baroreceptors innervating the afferent arterioles → stimulate renin release Macula densa pathway: Epithelial cells located adjacent to JG cells. Acts as chemoreceptor: when blood pressure or Na, Cl are decreased, stimulates the release of renin Sympathetic nervous system: Hypotension/hypovolemia stimulates sympathetic nervous system (SNS) leading to: Direct SN innervating JG, via β1 adrenergic receptors lead to renin release Indirect activation of α R → activates baroreceptors and macula densa to stimulate renin release from JG 10/21/2024 10/21/2024 Angiotensin Angiotensinogen: Circulating protein substrate of renin. Its concentration is the rate-limiting step for the formation of angiotensin. Renin Angiotensinogen Angiotensin I Formation of Angiotensin II: Angiotensin I is rapidly converted to angiotensin II by angiotensin-converting enzyme (ACE), which removes 2 amino acids. Effects of Angiotensin II: Acts on AT1 and AT2 receptors, inducing different physiological effects. Conversion to Angiotensin (1-7): Angiotensin II can be further converted to angiotensin (1-7) by the enzyme ACE II. Counteraction Effects of Angiotensin (1-7): ANG (1-7) has opposing effects to angiotensin II by acting on the Mas receptor. 10/21/2024 Biosynthesis of angiotensin 10/21/2024  Actions of angiotensin II Blood pressure: ANGII is potent pressor agent (40X > norepinephrine) Due to direct contraction of vascular smooth muscle (especially arteriolar) Stimulates autonomic nervous system, increase the release of epinephrine and Norepinephrine from the adrenal medulla Direct positive inotropic effect on the heart Adrenal cortex & kidney: directly act on the adrenal cortex to stimulate aldosterone synthesis and release At higher concentration, ANGII stimulates glucocorticoid synthesis ANGII acts on the kidney to cause renal vasoconstriction Increase proximal tubular sodium reabsorption Inhibit the release of renin- negative feedback 10/21/2024 Actions of angiotensin II Central nervous system: Acts on the brain baroreceptor reflex to set the threshold at higher pressure Acts on CNS to stimulate drinking and increase secretion of vasopressin and adrenocorticotropic hormone (ACTH) Cell growth: ANGII is mitogenic for VSMCs, cardiac muscle cell, and fibroblasts This contribute to the development of cardiac hypertrophy → increase remodeling and contributes to increase morbidity and mortality Long term increase in preload (Na retention) and increase afterload (arterial BP) contribute to cardiac hypertrophy and remodeling 10/21/2024 Major effects of angiotensin II 10/21/2024 Angiotensin receptors ANGII acts mainly on AT1 and AT2 receptors: Are GPCR located on the plasma membrane of target cells, permitting rapid onset of various action of ANGII ANGII binds with equal affinity to both receptors, but their distribution in tissue varies. AT1 receptors are present in the human vasculature, lung, liver, brain, kidney, adrenal gland, skin, and endometrium. Stimulation of AT1 receptor is responsible for the pressor, retention, and remodeling effects of ANGII AT2 receptors present in all tissue during fetal development but low levels remain after birth Stimulation of AT2 receptor causes vasodilation and counteract the effects of AT1 10/21/2024 10/21/2024 Inhibitors of the RAS Angiotensinogen Renin inhibitors Renin Angiotensin I ACE Bradykinin inhibitors ACE ACE Angiotensin II Inactive ARBs peptides AT1 receptor 10/21/2024