1 Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 17 & 18 Adrenergic Agonists & Antagonists

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenergic Agonists  Produce their effects by activating adrenergic receptors  Sympathomimetic  Drugs that turn on sympathetic nervous system (light or flight response)  Broad spectrum of applications  Congestive heart failure  Asthma  Preterm labor 2

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Mechanisms of Adrenergic Receptor Activation  Direct receptor binding  Promotion of norepinephrine (NE) release  Inhibition of NE reuptake  Inhibition of NE inactivation 3

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Overview of the Adrenergic Agonists Cannot be used orally (MAO and COMT) Brief duration of action Cannot cross the blood-brain barrier (polar molecules) Catecholamines Can be given orally Metabolized slowly by MAO; longer half-life More able to cross the blood-brain barrier Noncatecholamines 4

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Receptor specificity Most drugs discussed: Peripherally acting sympathomimetics Direct receptor activation Amphetamine and cocaine: Indirect-acting sympathomimetics 5

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Receptor Specificity Beta2 only Albuterol Beta1 and beta2 Isoproterenol Alpha1 and alpha2 Beta 1 and beta 2 Epinephrine 6

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Adrenergic Receptor Activation  Clinical consequences of alpha 1 activation  Hemostasis  Nasal decongestion  Adjunct to local anesthetic  Elevation of blood pressure  Mydriasis 7

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenergic Receptor Activation (alpha 1 receptor activation) Clinical Consequences  Hemostasis  Nasal decongestion  Adjunct to local anesthesia  Elevation of blood pressure  Mydriasis Therapeutic Applications  Arrests bleeding via vasoconstriction  Mucosal vasoconstriction  Delays absorption of local anesthetic  Vasoconstriction  Dilation of the radial muscle of the iris 8

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Effects of Adrenergic Receptor Activation  Vasoconstriction  Hypertension  Necrosis: Alpha 1 -blocking agent (for example, phentolamine)  Bradycardia 9

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drugs capable of activating alpha 1 receptors  Epinephrine  Norepinephrine  Phenylephrine  Dopamine 10

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Adrenergic alpha 2 Receptor Activation  Clinical consequences of alpha 2 activation  Reduction of sympathetic outflow to the heart and the blood vessels  Relief of severe pain 11

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Adrenergic beta 1 Receptor Activation  Clinical consequences of beta 1 activation  All of the clinically relevant responses to activation of beta 1 receptors result from activating beta 1 receptors in the heart  Activation of renal beta 1 receptors is not associated with either beneficial or adverse effects  Beta 1 receptors can be activated by epinephrine, NE, isoproterenol, dopamine, dobutamine, and ephedrine 12

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Adrenergic beta 1 Receptor Activation  Therapeutic application of beta 1 activation  Shock  Profound hypotension and greatly reduced tissue perfusion  Primary goal of treatment is to maintain blood flow to vital organs  Beta 1 stimulation increases heart rate and force of contraction  Increases cardiac output  Improves tissue perfusion 13

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Adrenergic Receptor Activation  Therapeutic application of beta 1 activation  Heart failure Activation of beta 1 receptors in the heart has a positive inotropic effect (i.e., increases the force of contraction) Drugs that activate these receptors can improve cardiac performance 14

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Adrenergic Receptor Activation  Therapeutic application of beta 1 activation  ​ Atrioventricular (AV) heart block Activation of cardiac beta 1 receptors can enhance impulse conduction through the AV node Beta 1 stimulants can help overcome AV block Drugs are only a temporary form of treatment Long-term management: Pacemaker 15

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Adrenergic Receptor Activation  Therapeutic application of beta 1 activation  ​ Cardiac arrest Activation of cardiac beta 1 receptors can initiate contraction in a heart that has stopped beating Drugs are not the preferred treatment Initial management focuses on cardiopulmonary resuscitation, external pacing, or defibrillation as well as the identification and treatment of the underlying cause Epinephrine 16

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Effects of Adrenergic beta 1 Receptor Activation  Adverse effects of beta 1 activation  Dysrhythmias  Angina pectoris: Because beta 1 agonists increase cardiac oxygen demand by increasing the heart rate and the force of contraction, patients with compromised coronary circulation are at risk of an anginal attack 17

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Clinical Consequences of Beta 2 Activation  Applications of beta 2 activation are limited to the following:  Lungs  Uterus  Beta 2 activating drugs  Epinephrine  Isoproterenol  Albuterol 18

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Application of Beta 2 Activation  Asthma  Activate beta 2 receptors in the lung to promote bronchodilation  Help relieve or prevent asthma attacks  Selective for beta 2 receptors (such as albuterol)  Less selective agents (such as isoproterenol) 19

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Application of Beta 2 Activation  Delay of preterm labor  Activation of beta 2 receptors in the uterus  Relaxes uterine smooth muscle  Used to delay preterm labor 20

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Effects of Beta 2 Activation  Hyperglycemia  Activation of beta 2 receptors in the liver and the skeletal muscles  Breakdown of glycogen into glucose  Beta 2 agonists cause hyperglycemia only in patients with diabetes  In patients with normal pancreatic function, insulin release will maintain blood glucose at an appropriate level 21

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Effects of Beta 2 Activation  Tremor  Tremor is the most common side effect of beta 2 agonists  Tremor generally fades over time and can be minimized by initiating therapy at low doses 22

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Clinical Consequences of Dopamine Receptor Activation  Used to treat shock: Dilation of the renal blood vessels reduces the risk of renal failure  Dopamine dilates the renal vasculature  Enhances cardiac performance by activating beta 1 receptors in the heart 23

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Multiple Receptor Activation: Treatment of Anaphylactic Shock  Pathophysiology of anaphylaxis  Severe allergic response  Hypotension, bronchoconstriction, and edema of the glottis  Treatment  Epinephrine: Treatment of choice for anaphylactic shock 24

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Therapeutic uses  Delays absorption of local anesthetic  Controls superficial bleeding  Elevates blood pressure  Overcomes AV block  Restores cardiac function during arrest  Causes bronchial dilation in patients with asthma  Treatment of choice for anaphylactic shock 25

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Pharmacokinetics  Absorption: Intramuscular (IM), subcutaneous (SQ), and intravenous (IV)  Inactivation: Short half-life  Adverse effects  Hypertensive crisis  Dysrhythmias  Angina pectoris  Necrosis after extravasation  Hyperglycemia 26

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Adverse effects  Hypertensive crisis Vasoconstriction as a result of excessive alpha 1 activation Dramatic increase in blood pressure Cerebral hemorrhage can occur 27

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Adverse effects  Dysrhythmias Excessive activation of beta 1 receptors in the heart can produce dysrhythmias Cautious use in patients with hyperthyroidism: Because of their sensitivity to catecholamines, these patients are at high risk for epinephrine-induced dysrhythmias 28

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Angina pectoris Activation of beta 1 receptors in the heart can increase cardiac work and oxygen demand If the increase in oxygen demand is significant, an anginal attack may ensue Provocation of angina is especially likely in patients with coronary atherosclerosis 29

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Necrosis after extravasation Extravasation: Necrosis Local injection of phentolamine, an alpha-adrenergic antagonist  Hyperglycemia In patients with diabetes, epinephrine can cause hyperglycemia If hyperglycemia develops, dosage adjustments will need to be made for medications used to manage diabetes 30

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Drug interactions  Monoamine oxidase (MAO) inhibitors MAO is one of the enzymes that inactivate epinephrine and other catecholamines The inhibition of MAO will prolong and intensify epinephrine’s effects Patients who are receiving MAO inhibitors should not receive epinephrine 31

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Drug interactions  Tricyclic antidepressants (TCA) TCAs block the uptake of catecholamines into adrenergic neurons Blocking uptake can intensify and prolong epinephrine’s effects Patients receiving a tricyclic antidepressant may require a reduction in epinephrine dosage  General anesthetics  Alpha-adrenergic blocking agents  Beta-adrenergic blocking agents 32

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Drug interactions  General anesthetics Several inhalation anesthetics render the myocardium hypersensitive to activation by beta 1 agonists Potential for tachydysrhythmias 33

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Drug interactions  Alpha-adrenergic blocking agents Drugs that block alpha-adrenergic receptors can prevent alpha-adrenergic receptor activation by epinephrine Alpha blockers (such as phentolamine) can be used to treat toxicity (such as hypertension or local vasoconstriction) caused by excessive epinephrine- induced alpha activation  Beta-adrenergic blocking agents 34

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Drug interactions  Beta-adrenergic blocking agents Drugs that block beta-adrenergic receptors can prevent beta-adrenergic receptor activation by epinephrine Beta-blocking agents (such as metoprolol) can reduce adverse effects (such as dysrhythmias, anginal pain) caused by epinephrine and other beta 1 agonists 35

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Epinephrine  Preparations, dosage, and administration  EpiPen  IV (monitor closely)  IM  SQ  Intracardiac (rarely used; only used during asystole if IV not available)  Intraspinal  Inhalation  Topical 36

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Norepinephrine  Receptor specificity  Alpha 1  Alpha 2  Beta 1  Chemical classification  Catecholamine  Therapeutic uses  Hypotensive states  Cardiac arrest 37

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Norepinephrine  Differs from epinephrine: Does not activate beta 2 receptors  Does not promote hyperglycemia  Cannot be given orally (MAO and COMT)  Necrosis with extravasation  Drug interactions  MAO inhibitors (MAOIs), TCAs, general anesthetics, and adrenergic blocking agents 38

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Isoproterenol  Receptor specificity: Beta 1 and beta 2  Chemical classification: Catecholamine  Therapeutic uses  Cardiovascular AV heart block Cardiac arrest Increase cardiac output during shock 39

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Isoproterenol  Adverse effects  Fewer than those of NE and epinephrine (does not activate alpha-adrenergic receptors)  Tachydysrhythmias and angina pectoris  Hyperglycemia in diabetes patients  Drug interactions  MAOIs, TCAs, and beta-adrenergic blockers  Preparations and administration  IV, IM, and intracardiac injections 40

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Dopamine  Receptor specificity  Low therapeutic dose: Dopamine  Moderate therapeutic dose: Dopamine and beta 1 receptors  Very high dose: Alpha 1 receptors, beta 1 receptors, and dopamine 41

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Dopamine  Therapeutic uses  Shock Increases cardiac output Increases renal perfusion  Heart failure Increases myocardial contractility 42

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Dopamine  Adverse effects  Tachycardia, dysrhythmias, and anginal pain  Necrosis with extravasation  Drug interactions  MAOIs, TCAs, certain general anesthetics, and diuretics  Preparations, dosage, and administration  Preparations: Dispensed in aqueous solutions  Dosage: Must be diluted  Administration: Administered by IV 43

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Dobutamine  Receptor specificity: Beta 1  Chemical classification: Catecholamine  Actions and uses  Congestive heart failure  Adverse effects  Tachycardia  Drug interactions  MAOIs, TCAs, and certain general anesthetics  Preparations, dosage, and administration  Continuous IV infusion 44

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Phenylephrine  Receptor specificity  Alpha 1  Chemical classification  Noncatecholamine  Therapeutic uses  Reduces nasal congestion (locally)  Elevates blood pressure (parenterally)  Dilates pupils (eyedrops)  Local anesthetic (delays absorption) 45

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Albuterol  Receptor specificity: Beta 2  Chemical classification: Noncatecholamine  Therapeutic uses  Asthma (selective for beta 2 )  Adverse effects  Minimal at therapeutic doses  Will activate beta 1 receptors at higher doses  Tremor is most common  Tachycardia 46

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Ephedrine  Receptor specificity: Alpha 1, alpha 2, beta 1, and beta 2  Chemical classification: Noncatecholamine  Ephedrine is referred to as a mixed-acting drug  Direct activation results from the binding of the drug to alpha and beta receptors  Asthma  Shock  Anesthesia-induced hypotension 47

48 Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenergic-Blocking Drugs Adrenergic Antagonists 48

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenergic Antagonists  Cause direct blockade of adrenergic receptors  Drugs that turn off the sympathetic nervous system (fight-or-flight response)  With one exception, all produce reversible (competitive) blockade  Most adrenergic antagonists are more selective than the adrenergic agonists  Two major groups:  Alpha-adrenergic blocking agents  Beta-adrenergic blocking agents 49

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenergic Antagonists  Alpha-adrenergic antagonists I: Therapeutic and adverse response to alpha blockade  Alpha-adrenergic antagonists II: Properties of individual alpha blockers  Beta-adrenergic antagonists I: Therapeutic and adverse responses to beta blockade  Beta-adrenergic antagonists II: Properties of individual beta blockers 50

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Alpha Blockade  Reversal of toxicity from alpha 1 agonists  Overdose of alpha-adrenergic agonist (for example, epinephrine)  Hypertension due to excessive activation of alpha 1 receptors on blood vessels  Reversal: Alpha-blocking agent  Extravasated necrosis: Infiltrate the region with phentolamine (an alpha-adrenergic antagonist)  Blocks vasoconstriction and prevents injury 51

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Alpha Blockade  Essential hypertension  Lower blood pressure by causing vasodilation by blocking alpha 1 receptors on arterioles and veins  In response to venous dilation: Return of blood to the heart decreases Cardiac output decreases Arterial pressure is reduced 52

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Therapeutic Applications of Alpha Blockade  Benign prostatic hyperplasia (BPH)  Symptoms: Dysuria, increased frequency of daytime urination, nocturia, urinary hesitancy, urinary urgency, a sensation of incomplete voiding, and a reduction in the size and force of the urinary stream  Alpha 1 receptors: Reduce the contraction of smooth muscle in the prostatic capsule and the bladder neck (trigone and sphincter) 53

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Effects of Alpha 1 Blockade  Detrimental effects result from the blockade of alpha 1 receptors  Effects from alpha 2 receptors are minor  Orthostatic hypotension  Blockade of alpha receptors on veins  Reduced muscle tone in the venous wall  Upon standing, blood pools in the veins  Return of blood to the heart is reduced  Cardiac output decreased: Blood pressure drops 54

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Effects of Alpha 1 Blockade  Reflex tachycardia  Reflex to increase heart rate via the autonomic nervous system (ANS)  Nasal congestion  Dilates the blood vessels of the nasal mucosa  Inhibition of ejaculation  Alpha 1 activation required for ejaculation  Impotence is reversible; resolves when drug is discontinued  Sodium retention and increased blood volume  Reduced blood pressure promotes renal retention of sodium and water  Usually combined with diuretic when used for hypertension 55

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Alpha-Adrenergic Antagonists II  Prazosin  Terazosin  Doxazosin  Tamsulosin  Alfuzosin  Phentolamine  Phenoxybenzamine 56

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Effects of Alpha 2 Blockade  Most significant adverse effect associated with alpha 2 blockade: Potentiation of reflex tachycardia 57

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Terazosin [Hytrin]  Actions and uses  Selective and competitive antagonist at alpha 1 - adrenergic receptors  Approved for hypertension and BPH  Pharmacokinetics  Peak effects: 1 to 2 hours after oral dosing  Half-life: Prolonged (9 to 12 hours)  Daily dosing  Hepatic metabolism  Excretion in the bile and urine 58

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Terazosin [Hytrin]  Adverse effects  Orthostatic hypotension  Reflex tachycardia  Nasal congestion  Headache  “First-dose” effect 59

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Angina pectoris Beta-adrenergic blockers are a mainstay of antianginal therapy By blocking beta 1 receptors in the heart, these drugs decrease cardiac workload Reduce oxygen demand by bringing it back into balance with oxygen supply Prevention of ischemia and pain 60

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Hypertension Beta blockers were considered drugs of choice for hypertension Recent data indicate that they are less beneficial than previously believed Long-term use: Beta blockers reduce peripheral vascular resistance, which could account for much of their antihypertensive effect 61

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Myocardial infarction (MI) An MI is a region of myocardial necrosis caused by the localized interruption of blood flow to the heart wall Treatment with a beta blocker can reduce pain, infarct size, mortality, and the risk of reinfarction Therapy with a beta blocker must begin soon after an MI has occurred and should be continued for several years 62

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Heart failure Considered standard therapy for heart failure Previously, heart failure was considered an absolute contraindication to the use of a beta blocker  Carvedilol  Bisoprolol  Metoprolol 63

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Hyperthyroidism Associated with an increase in the sensitivity of the heart to catecholamines (for example, norepinephrine, epinephrine) Normal levels of sympathetic activity to the heart can generate tachydysrhythmias and angina pectoris Blockade of cardiac beta 1 receptors suppresses these responses 64

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Migraine prophylaxis When taken prophylactically, beta-adrenergic blocking agents can reduce the frequency and intensity of migraine attacks Not able to abort a migraine headache once it has begun Mechanism by which beta blockers prevent migraine is not known 65

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Stage fright Public speakers and other performers sometimes experience “stage fright” Prominent symptoms are tachycardia, tremors, and sweating brought on by generalized discharge of the sympathetic nervous system Beta blockers help prevent stage fright by preventing beta 1 -mediated tachycardia 66

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Pheochromocytoma Pheochromocytomas secrete large amounts of catecholamines Can cause excessive stimulation of the heart Cardiac stimulation can be prevented by beta 1 blockade 67

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Therapeutic applications of beta blockade  Glaucoma Elevated intraocular pressure with subsequent injury to the optic nerve Specific group of beta blockers are used for the treatment of glaucoma to lower intraocular pressure 68

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Adverse effects of beta blockade  Therapeutic responses to beta blockers are due almost entirely to the blockade of beta 1 receptors  Adverse effects involve both beta 1 and beta 2 blockade  Nonselective beta-adrenergic blocking agents (i.e., drugs that block beta 1 and beta 2 receptors) produce a broader spectrum of adverse effects than do the “cardioselective” beta-adrenergic antagonists (i.e., drugs that block beta 1 receptors only at therapeutic doses) 69

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Adverse effects of beta 1 blockade  Bradycardia The blockade of cardiac beta 1 receptors can produce bradycardia (excessively slow heart rate) The heart rate can be increased with the use of a beta- adrenergic agonist (for example, isoproterenol) and atropine, which is a muscarinic antagonist 70

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Adverse effects of beta 1 blockade  Reduced cardiac output Beta 1 blockade can reduce cardiac output by decreasing the heart rate and the force of myocardial contraction Beta blockers must be used with great caution in patients with heart failure or reduced cardiac reserve Further decrease in cardiac output could result in insufficient tissue perfusion 71

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Adverse effects of beta 1 blockade  Precipitation of heart failure Suppression of cardiac function with a beta blocker can cause heart failure Patients should be informed about the early signs of heart failure (for example, shortness of breath, night coughs, swelling of the extremities) and instructed to notify the prescriber if these occur Although beta blockers can precipitate heart failure, they are also used to treat heart failure 72

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Adverse effects of beta 1 blockade  AV heart block AV heart block is defined as a delay in the conduction of electrical impulses through the AV node The blockade of cardiac beta 1 receptors can suppress AV conduction, so the production of AV block is a potential complication of beta-blocker therapy Beta blockers are contraindicated for patients with preexisting AV block 73

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Adverse effects of beta 1 blockade  Rebound cardiac excitation The long-term use of beta blockers can sensitize the heart to catecholamines If a beta blocker is withdrawn abruptly, anginal pain or ventricular dysrhythmias may develop The risk of rebound excitation can be minimized by withdrawing these drugs gradually (for example, by tapering the dosage over a period of 1 to 2 weeks) 74

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists II: Other Beta-Adrenergic Blockers  Receptor specificity: Selective blockade  Nonselective  Cardioselective  Labetalol and carvedilol: Differ from all of the others in that they block alpha-adrenergic receptors in addition to beta receptors 75

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists II: Other Beta-Adrenergic Blockers  Therapeutic uses  Hypertension  Angina pectoris  Cardiac dysrhythmias  Prophylaxis of migraine headache  Myocardial infarction  Situational anxiety  Heart failure 76

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists I  Adverse effects of beta 2 blockade  Bronchoconstriction The blockade of beta 2 receptors in the lung can cause constriction of the bronchi In patients with asthma, the resulting increase in airway resistance can be life threatening Drugs that block beta 2 receptors are contraindicated for people with asthma These patients should be given an agent that is beta 1 selective (for example, metoprolol) 77

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Beta-Adrenergic Antagonists II: Propranolol  Pharmacologic effects  Blocking cardiac beta 1 receptors: Reduced heart rate, decreased force of ventricular contraction, and suppressed impulse conduction through the AV node  Net effect is a reduction in cardiac output  By blocking renal beta 1 receptors, propranolol can suppress the secretion of renin  Blocking beta 2 receptors  Bronchoconstriction (through beta 2 blockade in the lung)  Vasoconstriction (through beta 2 blockade on certain blood vessels)  Reduced glycogenolysis (through beta 2 blockade in skeletal muscle and liver) 78

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Vasodilation  The third-generation beta blockers – carvedilol, labetalol, and nebivolol – can dilate blood vessels  Two mechanisms are employed:  Carvedilol and labetalol block vascular alpha 1 receptors  Nebivolol promotes the synthesis and release of nitric oxide from the vascular epithelium 79