Pharmacology of Vasoactive Substances PDF

Pharmacology of vasoactive substances Dr. Fatemah Alherz PHS 310 1  Vasoactive substances A vasoactive substance is an endogenous agent or pharmaceutical drug with significant actions on smooth muscles of the blood vessel They inclu...

Pharmacology of vasoactive substances Dr. Fatemah Alherz PHS 310 1  Vasoactive substances A vasoactive substance is an endogenous agent or pharmaceutical drug with significant actions on smooth muscles of the blood vessel They include vasoconstrictors, vasodilators and mixed effects Antagonists of these substances or the enzymes that produce them have useful clinical indications It has the effect of either increasing or decreasing blood pressure and /or heart rate through its vascular activity 2  Vasoconstriction signal transduction pathway Vasoconstriction is potentiated by three signaling pathways: First, activation of G protein-coupled receptors (GPCR) associated with heterotrimeric Gq proteins activates phospholipase C (PLC) to produce IP3 and diacylglycerol (DAG). IP3 stimulates Ca2+ release from intracellular stores. DAG activates protein kinase C, which also promotes contraction through a variety of phosphorylation events. Second, GPCRs coupled to heterotrimeric G12/13 proteins stimulate nucleotide exchange on the small G protein RhoA. RhoA activates Rho-kinase to phosphorylate and inactivate myosin light chain (MLC) phosphatase, thereby maintaining MLC phosphorylation. This pathway provides a mechanism to sustain smooth muscle contraction beyond transient increases in intracellular Ca2+. Third, activation of Gi-coupled receptors inhibits adenylyl cyclase and thereby decreases production of cyclic adenosine monophosphate (cAMP). Reduced cAMP decreases protein kinase A (PKA) activity, thereby relieving inhibition of MLCK. 3 Myosin light chain kinase (MLCK), MHC, myosin heavy chain, myosin light chain (MLC) 4  Vasodilatation signal transduction pathway Vasodilation is potentiated by two signaling pathways: First, Gs-coupled receptors stimulate cAMP formation, PKA activation, MLCK inhibition, and ATP- regulated K+ channel (K+ATP) opening. Second, nitric oxide (NO) activates soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). cGMP-dependent protein kinase phosphorylates various downstream targets, leading to smooth muscle relaxation. 5  Regulators of Vascular smooth muscle Tone 2. Autonomic 4. Local 1. Vascular 3. Humoral Nervous Environmental Endothelium Regulators System Factors 6  1.Vascular Endothelium Endothelial cells release vasoactive mediators including prostacyclin (PGI2) and nitric oxide(NO)(vasodilators) and endothelin (vasoconstrictors) 7  1.Vascular Endothelium 1-Nitric Oxide: NO relaxes smooth muscles by increasing cGMP formation Production of NO is stimulated by agonists such as acetylcholine, histamine, or bradykinin. NO can also directly activate 𝐶𝑎+2 - dependent K+ channels. This parallel signaling pathway contributes to relaxation by hyperpolarizing the smooth muscle cell. 8  1.Vascular Endothelium 2- Prostacyclin (PGI2) Prostacyclin is also a vasodilatory molecule produced in endothelial cells from arachidonic acid in reactions that involve the cyclooxygenase (COX) enzymes. Prostacyclin activates Gs-coupled receptors on the vascular smooth muscle cells, leading to vasodilation. Since the COX enzymes are inhibited by nonsteroidal anti-inflammatory drugs, such drugs should be used with caution in patients with hypertension because they decrease prostacyclin production. https://www.uptodate.com/contents/nsaids-and-acetaminophen-effects-on-blood-pressure-and-hypertension#:~:text=All%20nonsteroidal%20antiinflammatory%20drugs%20(NSAIDs,considerably%20%5B2%2D4%5D. 9  1.Vascular Endothelium 3-Endothelin: A potent and long-acting vasoconstrictor peptide formed in and released from endothelial cells. Endothelin also plays an important role in the lungs, kidneys, and brain Three endothelin peptides (ET-1, ET-2, and ET-3) have been identified in humans. ET-1—the isoform mainly involved in cardiovascular actions—is produced by endothelial cells from endothelin precursors to generate the mature active peptides. ET-1 is the predominant endothelin secreted by the vascular endothelium. It is also produced by neurons and astrocytes in the central nervous system and in endometrial, breast epithelial, and other cells. 10  1.Vascular Endothelium 3-Endothelin: ET-1 is released by endothelial cells in response to mechanical stress and vasoactive agents (e.g., vasopressin, angiotensin II), while its release is inhibited by prostacyclin, NO, and atrial natriuretic peptide. ET-1 binds to two receptor subtypes, ETA and ETB, and both are Gq-coupled receptors. Both subtypes are located on vascular smooth muscle cells and mediate vasoconstriction. Endothelial cells express ETB receptors, when occupied by ET-1, activate eNOS and COX, leading to NO and prostacyclin release. This negative feedback pathway is one mechanism by which endothelial cells assist in modulating vascular tone 11  1.Vascular Endothelium 3-Endothelin: Endothelins , Constrict most vessels, through ↑ IP3, DAG via G protein-coupled ETA and ETB receptors. Endothelins are much more potent than norepinephrine as vasoconstrictors and have a relatively long-lasting effect. The peptides also stimulate the heart, increase natriuretic peptide release, and activate smooth muscle proliferation. The peptides may be involved in some forms of hypertension and other cardiovascular disorders and may play a pathophysiologic role in pulmonary hypertension The first antagonist to become clinically available is bosentan, which is approved for use in pulmonary hypertension 12  2. Autonomic Nervous System The sympathetic nervous system is an important determinant of vascular tone through release of norepinephrine from nerve terminals that end on vascular smooth muscle cells. Sympathetic postganglionic neurons release norepinephrine, which binds to postsynaptic α1- and α2-adrenergic receptors coupled to Gq and Gi, respectively, leading to contraction of the smooth muscle cell. The presynaptic nerve terminal also expresses α2-adrenergic autoreceptors, which inhibit further release of norepinephrine in a negative feedback loop. 13  2. Autonomic Nervous System Sympathetic activation also induces epinephrine release from the adrenal medulla. Epinephrine activates both α- and β2-adrenergic receptors on vascular smooth muscle cells. The β2 receptors activate the Gs signaling pathway, leading to smooth muscle cell relaxation. Thus, the effects of epinephrine on a given vascular bed depend on: 1. The dose of epinephrine: i.e. β2 receptors have a higher affinity for epinephrine and, thus, are activated at lower epinephrine concentrations than α receptors 2. The relative composition of receptors expressed on the target cells. For example, during a “fight or flight” response, blood flow is diverted away from skin and viscera, where α > β2, and toward skeletal muscle, where β2 > α. 14  2. Autonomic Nervous System While most blood vessels lack parasympathetic innervation, acetylcholine does cause vasodilation through M3-muscarinic receptor-mediated NO release from vascular endothelial cells 15  3. Humoral Regulators In addition to the autonomic nervous system, several humoral mediators contribute to the regulation of vascular tone and integrate renal and cardiovascular function. 1. Circulating catecholamines from the adrenal gland (i.e.,epinephrine) 2. Angiotensin II, 3. Natriuretic peptides 4. Bradykinin 5. Calcitonin gene-related peptide (CGRP) 6. Antidiuretic hormone/arginine vasopressin 7. Neuropeptide Y 8. Substance P, neurokinins 9. Vasoactive intestinal peptide (VIP) 16 Angiotensin and Angiotensin Antagonists 1. Angiotensin I is produced from circulating angiotensinogen by renin, an enzyme released from the juxtaglomerular apparatus of the kidney. 2. Angiotensin I is an inactive decapeptide , and is converted into angiotensin II, an active octapeptide , by angiotensin-converting enzyme (ACE). Angiotensin II increases when blood volume decreases. It was found to increase in the blood of hypertensive patients treated with large doses of diuretics 3. angiotensin II stimulates the angiotensin II receptor subtype 1 (AT1 G protein- coupled receptors ) ,↑ IP3, DAG ,constricts arterioles, increases aldosterone secretion and increase intravascular volume 4. Angiotensin II, the active form of the peptide, is rapidly degraded by peptidases (angiotensinases). 17 Aldosterone intravascular volume 18  Angiotensin and Angiotensin Antagonists 2 types of antagonists are available: 1-ACE inhibitors (e.g. captopril, enalapril ) are important agents for the treatment of hypertension and heart failure. 2-Angiotensin receptor blockers (e.g. losartan, valsartan) are orally active nonpeptide inhibitors at the AT1 receptor. -Block of angiotensin's effects by either of these drug types is often accompanied by a compensatory increase in renin and angiotensin I. 3- Aliskiren, a new orally active renin inhibitor, reduces angiotensin I as well as angiotensin II and is approved for use in hypertension. 19 Discuss the differences between ACE inhibitors and AT1-receptor blockers. 20 Bradykinin It is one of the most potent vasodilators known It is rapidly degraded by various peptidases, including ACE It acts through at least two receptors (B1 and B2) and causes the production of (IP3), (DAG), (cAMP), nitric oxide, and prostaglandins in tissues. It dilates arterioles(B2-cAMP, NO), increases capillary permeability, and stimulates sensory nerve endings The peptide is involved in inflammation and causes edema, vasodilation, and pain when released or injected into tissue. Bradykinin induces sensitization of airway sensory nerves, which causes airway smooth muscle to constrict, leading to bronchoconstriction and cough. What could be an adverse effect of ACE inhibitors?? 21  Natriuretic Peptides Natriuretic peptides (atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP]) are synthesized and stored in the cardiac atria of mammals. BNP has also been isolated from brain tissue. They are released from the atria in response to the distention of the chambers. Effects and Clinical Role Natriuretic peptides activate guanylyl cyclase in many tissues ,with ↑ cGMP via Natriuretic peptide receptor-A (NPR-A) They act as vasodilators as well as natriuretic (sodium excretion enhancing) agents Their renal action includes increased glomerular filtration, decreased proximal tubular sodium reabsorption , inhibit renin and aldosterone secretion. Blood levels of BNP have been shown to correlate with the severity of heart failure and can be used as a diagnostic marker. 22 Endogenous Vasoactive substances substance P is a potent vasodilator and a transmitter of sensory pain neurons 23  4. Environmental Factors Arteriolar smooth muscle cells coordinate blood flow into the capillary beds of metabolically active tissues(e.g., heart, brain, lung, kidney) In regions where tissue metabolic demand exceeds supply, increases in H+ (as lactic acid), CO2, K+, and adenosine (from ATP utilization) all lead to vasodilation and increased blood flow. 24  4. Environmental Factors The cerebral circulation is particularly sensitive to fluctuations in pH and CO2, which is why acute hyperventilation (which decreases pH and CO2, leading to vasoconstriction and decreased cerebral blood flow) is one therapy for intracranial hypertension. Increases in extracellular K+ activate inward rectifier K+ channels, thereby causing hyperpolarization of the plasma membrane and inhibiting voltage- gated Ca2+ channel opening. Adenosine activates A2 (Gs-coupled receptors). Systemic vessels also respond to decreased O2 by vasodilation, in contrast to pulmonary vessels that vasoconstrict (i.e., hypoxic vasoconstriction) to preserve ventilation–perfusion matching in the lung. 25 PHARMACOLOGIC CLASSES AND AGENTS 26 PHARMACOLOGIC CLASSES AND AGENTS Vasodilators , that is, drugs that act on vascular smooth muscle and/or on the adjacent vascular endothelium to decrease vascular tone. 27  Ca2+ Channel Blockers Ca2+ channel blockers are among the most prescribed agents for the management of hypertension and angina owing to their effectiveness and ease of use. These agents are primarily arterial vasodilators, having little impact on the venous system. Importantly, Ca2+ channel blockers bind to both vascular smooth muscle cells and cardiac myocytes, which accounts for their effectiveness as positive lusitropic agents (i.e., agents that relax the myocardium) and in the management of certain cardiac arrhythmias. 28  Ca2+ Channel Blockers Mechanism of Action Inhibit the entry of Ca+2 into vascular smooth muscle cells by decreasing activation of L-type Ca2 channels. Additionally, drug-induced dilation of the coronary arteries augments myocardial oxygen supply, helping to alleviate the symptoms of angina in affected patients Three chemical classes of Ca2+ channel blockers are currently in clinical use: Dihydropyridines (e.g. amlodipine) Benzothiazepines (e.g., diltiazem) Non- dihydropyridines Phenylalkylamines (e.g., verapamil) 29 Ca2+ Channel Blockers Dihydropyridine (amlodipine) exhibits much greater arterial vasodilation than non-dihydropyridines while having relatively little impact on cardiac tissue. “due to the preference of dihydropyridines to bind to inactivated channels.” While non-dihydropyridines are more effective in tissue with frequent channel openings (i.e., SA node, AV node, and cardiac myocytes), channel inhibition increases in proportion to heart rate. The negative chronotropic and inotropic effects of non-dihydropyridine agents appear greater for verapamil than diltiazem. 30  K+ Channel Openers Mechanism of action K+ channel openers cause direct arterial vasodilation by opening K+ATP channels in the plasma membrane of vascular smooth muscle cells, leading to membrane hyperpolarization and preventing Ca2+ channel opening While not commonly employed as first-line agents owing to the multiple adverse effects E.g. minoxidil. 31  K+ Channel Openers Adverse effects: headache and flushing, caused by excessive dilation of cerebral and cutaneous arteries, respectively. Peripheral edema, necessitating the use of diuretics. The decrease in arterial pressure often elicits sympathetic activation, reflex tachycardia, and increased myocardial O2 demand. 32  Nitric Oxide Donors Includes: Organic nitrates ,inhaled nitric oxide and nitroprusside. Mechanism of action: Both organic nitrates and nitroprusside cause relaxation via the formation of NO -Organic nitrates do not release NO directly but are chemically or enzymatically reduced -Sodium nitroprusside releases NO spontaneously without enzymatic aid 33  Phosphodiesterase type V (PDE5) inhibitors E.g., Sildenafil. Inhibit phosphodiesterase (PDE). These agents all cause an increase in cGMP, an effect that promotes vascular smooth muscle relaxation. PDE5 inhibitors are most commonly prescribed for erectile dysfunction 34 35  Other vasodilators agents 1. Renin–Angiotensin System Blockers: -ACE inhibitors and AT1 antagonists: all decrease intracellular Ca+2 signaling. The decreased cytosolic Ca+2 results in decreased vascular smooth muscle cell contraction, and, hence, in relaxation. -ACE inhibitors inhibit kininase II (KII), leading to increased levels of bradykinin. 2. Endothelin Receptor Antagonists, Bosentan is a competitive antagonist at ET A and ET B receptors, It is approved for treating pulmonary hypertension. 36  Other vasodilators agents 3. Alpha 1 -Adrenergic Antagonists: norepinephrine stimulates alpha 1-adrenergic receptors on vascular smooth muscle and thereby induces vasoconstriction Alpha - blockers like prazosin 4. Nesiritide is a recombinant form of B-type natriuretic peptide Although the drug lacks positive inotropic action, it is approved for intravenous administration in acute severe heart failure. 37  Systemic hypertension Heart failure Clinical uses of Shock vasoactive Peripheral vascular disease drugs Pulmonary hypertension ( endothelin receptor antagonist) 38 Questions 39