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Download Pharmacology Ch 10 132-142 Adrenergic Pharmacology
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Pharmacology Ch 10 132-142 Adrenergic Pharmacology -Studies agents that act on pathways mediated by endogenous catecholamines norepinephrine, epinephrine, and opamine -sympathetic nervous system is a major source of catecholamine production and release -effects include: increasing rate and force of cardiac contraction, modifying peripheral resistance of arterial system, inhibiting release of insulin, stimulating hepatic release of glucose,, increasing adipocyte release of free fatty acids -Catecholamines are major effectors of sympathetic signaling Catecholamine Synthesis, Storage, and Release – synthesized by modification of TYROSINE primarily at sympathetic nerve endings and at chromaffin cells -epinephrine predominantly synthesized in chromaddin cells of adrenal medulla -sympathetic neurons produce norepinephrine as primary neurotransmitter -tyrosine is transported into neurons via an aromatic AA transporter that used Na gradient to cross the neuronal membrane -FIRST STEP IN SYNTHESIS – oxidation of tyrosine dihydroxyphenylalanine (DOPA) mediated by tyrosine hydroxylase (TH) and is the RATE-LIMITING STEP in catecholamine synthesis -DOPA Dopamine through a nonspecific aromatic AA decarboxylase -Dopamine norepinephrine by dopamine-B-hydroxylase -norepinephrine epinephrine by phenylethanolamine N-methyltransferase (PNMT) in the adrenal medulla -conversion of tyrosine dopamine occurs in cytoplasm; dopamine is transported into synaptic vesicles by an antiporter called vesicular monoamine transporter (VMAT1) -only inside vesicles is dopamine converted to norepinephrine -3 distinct vesicle transporters: VMAT1 is peripheral (adrenal, sympathetic ganglia). VMAT2 is in CNS, VAChT is in cholinergic neurons and motor nerves -these antiporters use proton gradient generated by H+/ATPase in vesicular membrane to concentrate dopamine on the inside -norepinephrine condenses with ATP in vesicle and is secreted with ATP -in adrenal medullary cells, norepinephrine is transported back into cytoplasm were PNMT converts it to epinephrine; after which it goes BACK into vesicles for storage -activation of sympathetic nervous system and catecholamine release is initiated by signals in areas of CNS like limbic system; after which axons synapse with preganglionic neurons in intermediolateral columns of spinal cord and project to sympathetic ganglia -preganglionic neurons use ACETYLCHOLINE as neurotransmitter to activate nicotinic ACh receptors to depolarize membrane and generate postsynaptic potentials in postganglionic neurons -Hexamethonium and mecamylamine block ganglionic nicotinic ACh receptor -arrival of action potential opens voltage gated Ca channels and Ca influx triggers exocytosis of catecholamine-containing vesicles -ziconotide is a drug that treats severe pain -norepinephrine rapidly diffuses away and regulates target tissue responses (smooth muscle tone) by activating adrenergic receptors Reuptake and Metabolism of Catecholamines – effect is terminated by either reuptake of catecholamine into presynaptic neuron, inactivation, or diffusion way from synapse -Reuptake of catecholamine is mediated by a selective catecholamine transporter norepinephrine transporter (NET) or Uptake 1 -90% of norepinephrine is taken up by this process -Uptake 1 is a symporter that uses inward Na gradient to concentrate catecholamines in the cytoplasm of sympathetic nerve endings and limiting postsynaptic response -inside cytoplasm, catecholamines are concentrated again by VMAT -Metabolism of catecholamines requires two enzymes: MAO and catechol-O-methyltransferase (COMT) -MAO is mitochondrial and exists as MAO-A and MAO-B -MAO-A degrades serotonin, norepinephrine, and dopamine -MAO-B degrades dopamine -MAO inhibitors can treat depression Catecholamine Receptors – adrenergic receptors (adrenoceptors) are selective for norepinephrine and epinephrine; and are divided into α1, α2, and β classes and are all G protein-coupled receptors -all classes are subdivided into three subtypes: α1A, α1B, α1D; α2A, α2B, α2C; β1, β2, β3 α1 and α2 Adrenergic Receptors – involves Gq pathway that activates phospholipase C, which cleaves phosphatidylinositol-4,5-bisphosphate to generate IP3 and diacylglycerol (DAG) -downstream targets include L-type Ca channels, K channels, and MAP kinase pathways α1 receptors expressed in vascular smooth muscle, GU smooth muscle, GI smooth muscle, prostate, heart, liver, and other cell types -in vasculature, α1 receptors increase endogenous Ca stores and influx of Ca, leading to activation of calmodulin and muscle contraction increase vascular resistance and increase blood pressure -also causes contraction of GU smooth muscle and can treat benign prostatic hyperplasia α2 receptors activate Gi (inhibitory) which inhibits adenylyl cyclase to decrease cAMP levels, activation of G protein coupled K channels (causing hyperpolarization), and inhibition of membrane Ca channels in neurons -all of these decrease neurotransmitter release from target neurons -α2 receptors are on both presynaptic and postsynaptic neurons -presynaptic α2 function as autoreceptors to inhibit sympathetic transmission -α2 receptors are also on platelets and pancreatic β cells, where they mediate platelet aggregation and inhibit insulin release, respectively -MOST IMPORANT approach to α2 function is to treat hypertension. α2 receptor agonists act at CNS to decrease sympathetic flow to periphery to result in decreased norepinephrine release at sympathetic nerve terminals and decrease vascular smooth muscle contraction β-Adrenergic Receptors – divided into β1, β2, β3 and all activate a stimulatory G protein Gs. Gs activates adenylyl cyclase to increase intracellular cAMP activates protein kinases (PKA) to phosphorylate proteins like ion channels -β1-Adrenergic Receptors are localized in HEART and KIDNEY; in kidney they are on renal juxtaglomerular cells, where receptor activation causes RENIN release -stimulation of cardiac β1 receptors causes increase in force of contraction and heart rate -force of contraction is mediated by increased phosphorylation of Ca channels -heart rate is mediated by rate of phase 4 depolarization of SA node -β2-Adrenergic Receptors – expressed on skeletal and smooth muscle and liver. In smooth muscle, activation stimulates Gs, adenylyl cyclase, cAMP, and PKA phosphorylates myosin light chain kinase to reduce affinity for Ca/Calmodulin leading to relaxation of contractile apparatus -can also relax bronchial smooth muscle by activation of K channels (hyperpolarization) -in hepatocytes, activation of Gs system initiates phosphorylation cascade to activate glycogen phosphorylase and catabolism of glycogen increase plasma glucose -in skeletal muscle, activation of pathways stimulates glycogenolysis and promotes K uptake -β3 Receptors are expressed on ADIPOSE TISSUE and lead to increased lipolysis Regulation of Receptor Response – when agonist binds adrenoceptor, dissociation of G proteins leads to downstream signaling as well as negative feedback mechanism that limits tissue responses. Accumulation of βγ subunits in membrane recruits a G protein receptor kinase to phosphorylate receptor and inactivates it -phosphorylated receptor can bind to β-arrestin that sterically inhibits receptor/G protein interaction to silence receptor; can also down regulate receptor on membrane Epinephrine – agonist at both α and β adrenoceptors; -at LOW concentrations, epinephrine has β1 and β2 effects, and at HIGH concentrations it affects α1 receptors as well -at β1 receptors, epinephrine increases cardiac contractile force and cardiac output increase oxygen consumption and systolic BP -at β2 receptors, epinephrine causes vasodilation to decrease peripheral resistance and decrease diastolic blood pressure; also increases blood flow to skeletal muscle, relaxes bronchial smooth muscle, and increases concentrations of glucose/fatty acids in blood -epinephrine treats ANAPHYLAXIS -epinephrine prolongs effect of local anesthetics Norepinephrine – agonist at α1 and β1 receptors but NO effect at β2 receptors -administration of norepinephrine increases both systolic (β1 effect) and diastolic pressure and total peripheral resistance -treats hypotension in patients with distributive shock due to sepsis Dopamine – cannot cross BBB; dopamine activates many CNS and peripheral receptors -can activate D1 dopaminergic receptors in renal, mesenteric and coronary vascular beds -activate adenylyl cyclase in vascular smooth muscle increase cAMP vasodilation -at high concentrations, dopamine can activate β1 receptors and α1 receptors (vasoconstriction) -used in treatment of shock caused by low cardiac output and accompanied by compromised renal function Inhibitors of Catecholamine Synthesis – limited clinical utility because they inhibit formation of all catecholamines. -α-Methyltyrosine inhibits tyrosine hydroxylase in nerve terminals to stop catecholamine synthesis and used to treat hypertension associated with pheochromocytoma (tumor of enterochromaffin cells that produce norepinephrine and epinephrine) -can cause significant hypotension and sedation Inhibitors of Catecholamine Storage – catecholamines originate from de novo synthesis and recycled transmitter; in short term, an agent to inhibit storage in vesicles can increase net release of catecholamine from synaptic terminal and mimic sympathetic stimulation -over LONG period, agent depletes pool of available catecholamine and inhibits sympathetic activity -Resperine binds to vesicular antiporter VMAT to irreversible inhibit it vesicles lose ability to concentrate and store norepinephrine and dopamine -at low doses, resperine causes neurotransmitter to leak into cytoplasm where it is destroyed by MAO -at high concentrations, leak is high enough to overwhelm MAO in presynaptic neuron and the high concentration of transmitter exits from cytoplasm to synaptic space through NET acting in reverse; efflux has a transient sympathetic effect -because it is irreversible, over time the stores are depleted and could take weeks for new vesicles to form, to reverse the effect of sympathetics -Tyramine is a dietary amine metabolized by MAO in GI and liver; patients taking inihbitors of MAO have tyramine absorbed by gut and taken into sympathetics, where it is transported to synaptic vesicles by VMAT to displace norepinephrine and massive nonvesicular release of norepinephrine from nerve terminal via reversal of NET and can cause hypertension -Octopamine, a metabolite of tyramine can be stored in vesicles long time to replace norepinephrine, can cause hypotension -Guanethidine is activately transported by NET into neurons where it concentrates in transmitter in vesicles and displaces norepinephrine leading to its depletion -inhibits cardiac sympathetic nerves leading to reduced cardiac output and blocks sympathetically mediated vasoconstriction reduced cardiac preload -inhibition of sympathetic responses by guanethidine can lead to symptomatic hypotension following exercise or standing up -Guanadrel – also a false neurotransmitter and treats hypertension, but not a first-line agent -Amphetamine – displaces endogenous catecholamines from storage vesicles, weak inhibitor of MAO, and blocks catecholamine reuptake mediated by NET and DAT -increased alertness, decreased fatigue, depressed appetite, insomnia; treats depression and narcolepsy -Ephedrine, Pseudoephedrine, and phenylpropanolamine –activate adrenergic responses -Methylphenidate – treats ADHD and increases attention Inhibitors of Catecholamine Reuptake – can exert powerful sympathomimetic effect by prolonging time that catecholamine remains in synaptic cleft -cocaine is a potent inhibitor of NET to completely eliminate transport (unlike other uptake inhibitors (imipramine and fluoxetine) -cocaine promotes vasoconstriction due to capacity to inhibit norepinephrine uptake -Tricyclic Antidepressants (TCAs) inhibit NET-mediated reuptake of norepinephrine into presynaptic terminals and allow accumulation of it in synapse to treat depression Inhibitors of Catecholamine Metabolism – Monoamine oxidase inhibitors (MAOIs) prevent secondary deamination of catecholamines transported into presynaptic terminals or taken up into tissues such as liver -in absence of metabolism, more catecholamines accumulate in presynaptic vesicles for release -Most MAOIs are oxidized by MAO to reactive intermediates which irreversibly inhibit MAO -since there are two forms of MAO, MAO-A and MAO-B; there are selective and nonselective agents -pehelzine, iproniazid and tranylcypromine are nonselective MAOIs -clorgyline – selective for MAO-A -Selegiline selective for MAO-B (treats parkinsons) -Brofarmine, Befloxatone, and moclobemide are new reversible inhibitors of MAO-A -MAOIs are used to treat depression -use of MAOIs is contraindicated with SSRIs because it may cause serotonin syndrome characterized by restlessness, tremors, seizures, and coma Receptor Agonists – therapies for hypertension, asthma, ischemic heart disease, heart failure α1-Adrenergic Agonists – increase peripheral vascular resistance and elevate blood pressure -may also cause sinus bradycardia by activating reflex vagal responses by baroreceptors -methoxamine treats shock (α1 agonist) -phenylephrine, oxymetazole, tetrahydrozoline constrict vascular smooth muscle for nasal congestion and ophthalmic hyperemia -oxymetazole is also an agonist for α2 receptors -phenylephrine also treats shock -Clonidine – α2 receptor agonist that lowers blood pressure by acting in brainstem vasomotor centers to suppress sympathetic outflow to periphery; can cause bradycardia due to decreased sympathetic activity Guanabenz and Guanfacine – α2 agonists Dexmedetomidine – α2 receptor agonist that can cause sedation in surgical patients -suppression of sympathetics helps avoid swings in BP in surgical patients and also has analgesic properties α-Methyldopa – precursor to the α2 agonist α-methylnorepinephrine, which is released by adrenergic nerve terminal to act presynaptically as an α2 agonist resulting in decreased sympathetic flow and lowers blood pressure (used in pregnant women) β-Adrenergic Agonistis – stimulation of β1 receptors causes increase in heart rate and force of cardiac muscle contraction -stimulation of β2 receptors causes relaxation of vascular, bronchial, and GI smooth muscle -Isoproterenol is a nonselective β-agonist which lowers peripheral vascular resistance and diastolic blood pressure, while systolic BP remains unchanged or slightly increased -can increase cardiac contractility and heart rate, cardiac output is increased -can also relieve bronchoconstriction in asthma (β2 effect) -Dobutamine – has 2 stereoisomers in racemic mixture. The (-) isomer acts as both α1 agonist and β1 agonist, whereas the (+) isomer is an α1 antagonist and a POTENT β1 agonist -the α1 agonist/antagonist balance out, and so this is a selective β1 agonist with more prominent inotropic effect (cardiac contractility) than chronotropic (heart rate) -can treat severe heart failure -β2 selective agonists treat asthma and are better than epinephrine in that their effects are limited to select tissues; important to limit β1 stimulation so as not to affect the heart -these agents relax bronchial smooth muscle and decrease airway resistance Metapoterenol – β2 selective agonist treats obstructive airway disease + acute bronchospasm Terbutaline and Albuterol are two other agents in this class Salmeterol is a long acting β2 agonist Receptor Antagonists α-Adrenergic Antagonists – block endogenous catecholamines from binding α1 and α2 receptors to cause vasodilation, decreased BP, and decreased peripheral resistance -baroreceptor reflex usually attempts to compensate by increases in HR and cardiac output -Phenoxybenzamine – rarely used in the clinic blocks both α1 and 2 receptors irreversibly -Phentolamine – reversible, nonselective α-adrenoceptor antagonist used in preoperative management of pheochromocytoma -Prazosin – 1000x affinity for α1 receptors than for α2. Results in decreased peripheral vascular resistance and dilation of venous vessels (decreases venous return to heart) -antihypertensive drug, may cause postural hypotension and syncope w/ first dose -Terazosin and doxazosin – longer half-life than prazosin -α1 not often used to treat hypertension because diuretics are more effective -α1 antagonists can treat benign prostatic hyperplasia -α1A receptor is in GU smooth muscle, and Tamsulosin is an antagonist of this receptor Yohimbine – blocks α2-autoreceptors leading to increased release of norepinephrine with subsequent stimulation of cardiac β1 receptors and peripheral vasculature α1 receptors -α2 selective antagonists also cause increased insulin release through blockade of α2 receptors in pancreatic islets (which suppress insulin secretion) -Yohimbine treats erectile dysfunction too β adrenergic Antagonists – block the positive chronotropic and inotropic actions of endogenous catecholamines at β1 receptors to decrease heart rate and myocardial contractility -drugs decrease BP in hypertensive patients but do NOT lower BP in normotensive patients -long term use causes fall in peripheral vascular resistance -nonselective β blockers also block β2 receptors in bronchial smooth muscle and can cause lifethreatening bronchoconstriction in asthma patients -Propanolol, nadolol, and timolol are nonselective β blockers that do NOT block α receptors -treat hypertension and angina, and tolerated in COPD patients -Nadolol is also efficacious in prevention of bleeding from esophageal varices in cirrhosis patients -long half life and renal excretion without hepatic metabolism -penbutolol is another drug in this class -Levobunolol and carteolol are nonselective β blockers indicated in eyedrops for glaucoma treatment -Labetalol and carvedilol block α1, β1, and β2 receptors; -for Labetalol α1 blockade lowers peripheral resistance and β blockade contributes to decrease in blood pressure -Pindolol is a partial β1 and β2 agonist; blocks action of endogenous norepinephrine at β1 receptors and treats hypertension, but also partially stimulates β1 receptors leading to overall decreases in resting heart rate and BP -Acebutolol is a partial agonist at β1 adrenoceptors with no effect at β2 recpetors; treats hypertension -Esmolol, metoprolol, atenolol, and betaxolol are all β1 selective blockers, distinguished by elimination half-lives -esmolol has short half life (3-4 minutes), metoprolol and atenolol have intermediate half lives at (4-9 hours) -Nebivolol – novel β1 selective adrenergic blocker that has property of promoting vasodilation by nitric oxide release from endothelial cells