β-Adrenergic Stimulants and

Blockers

Presenter- Dr. Suresh PradhanModerator- Dr. Upendra Krishna Regmi

β1 receptor action

β2 receptor action

β3-receptors• are found in the gallbladder and brain adipose

tissue• role in gallbladder physiology is unknown• they are thought to play a role in lipolysis and

thermogenesis in brown fat

D1 receptor action

• β1 β2 D1 Receptors are Gs coupled

• Increase adenylyl cyclase---increased cAMP

• most of the adrenergic drugs are derivatives of β-phenylethylamine• substitutions on the benzene ring or on the

ethylamine side chains produce a variety of compounds with varying abilities to differentiate between α and β receptors and to penetrate the CNS

• Two important structural features of these drugs are

1) the number and location of OH substitutions on the benzene ring and 2) the nature of the substituent on the amino nitrogen

• Adrenergic Drugs can be:A. CatecholaminesB. Non-catecholaminesC. Substitutions on the amine nitrogen

A. Catecholamines• Sympathomimetic amines that contain the 3,4

dihydroxybenzene group are called catecholamines.• Includes epinephrine, norepinephrine, isoproterenol,

and dopamine

Substitutions at the R1, R2, and R3 sites affect

activity and selectivity

some important catecholaminescatechol is shown for reference

These compounds share the following properties:

1. High potency: Catecholamines (with –OH groups in the 3 and 4 positions on the benzene ring) show the highest potency in directly activating α or β receptors

2. Rapid inactivation: metabolized by COMT post-synaptically and by

MAO intra-neuronally, as well as by COMT and MAO in the gut wall, and by MAO in the liver

so , they have only a brief period of action when given parenterally, and they are inactivated when administered orally

3. Poor penetration into the CNS: are polar and, therefore, do not readily penetrate

into the CNS nevertheless, most catecholamines have some

clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS

B. Non-catecholamines• compounds lacking the catechol hydroxyl groups have

longer half-lives, because they are not inactivated by COMT• include phenylephrine, ephedrine, and amphetamine

• are poor substrates for MAO and, thus, show a prolonged duration of action• increased lipid solubility of many of the non-

catecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS

examples of non-catecholamine sympathomimetic drugsthe isopropyl group is highlighted in color

C. Substitutions on the amine nitrogen• the nature of the substituent on the amine nitrogen is

important in determining β selectivity of the adrenergic agonist• epinephrine, with a –CH3 substituent on the amine

nitrogen, is more potent at β receptors than norepinephrine, which has an unsubstituted amine• isoproterenol, which has an isopropyl substituent –CH

(CH3)2 on the amine nitrogen is a strong β agonist with little α activity

Mechanism of action of adrenergic agonists

1. Direct-acting agonists:· act directly on α or β receptors, producing effects

similar to those that occur following stimulation of sympathetic nerves or release of epinephrine from the adrenal medulla

· Examples: epinephrine, norepinephrine, isoproterenol, and phenylephrine

2. Indirect-acting agonists:· may block the reuptake of norepinephrine or cause

the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron.

· norepinephrine then traverses the synapse and binds to α or β receptors

· Examples: cocaine and amphetamines

3. Mixed-action agonists: · Includes Ephedrine and its

stereoisomer, pseudoephedrine

· stimulate adrenoceptors directly and release norepinephrine from the adrenergic neuron

Epinephrine• prototype drug among the sympathomimetics• Its natural functions on release from the adrenal

medulla include regulation of (a) myocardial contractility,(b) heart rate,(c) vascular and bronchial smooth muscle tone,(d) glandular secretions, and (e) metabolic processes such as glycogenolysis and lipolysis

• the most potent activator of alpha-adrenergic receptors• two to ten times more active than norepinephrine

and more than 100 times more potent than isoproterenol• Epinephrine interacts with both α and β receptors• At low doses, β effects (vasodilation) on the

vascular system predominate, whereas at high doses, α effects (vasoconstriction) are the strongest• Epinephrine also activates beta 1 and beta 2

receptors

• oral administration is not effective because it is rapidly metabolized in the gastrointestinal mucosa and liver• administered SC or IV• absorption after SC injection is slow because of local

epinephrine-induced vasoconstriction• is poorly lipid soluble, preventing its ready entrance

into the CNS and accounting for the lack of cerebral effects

Effects• Cardiovascular• result from epinephrine-induced stimulation of

alpha- and beta-adrenergic receptors• Small doses of epinephrine (1 to 2µg/minute IV)

stimulate principally beta2 receptors in peripheral vasculature• Stimulation of beta receptors occurs at intermediate

doses (4 µg/minute IV)

• large doses of epinephrine (10 to 20 µg/minute IV) stimulate both alpha- and beta-adrenergic receptors with the effects of alpha stimulation predominating in most vascular beds, including the cutaneous and renal circulations• A single rapid injection of epinephrine, 2 to 8 µg IV,

produces transient cardiac stimulation lasting 1 to 5 minutes, usually without an overshoot of systemic blood pressure or heart rate

Drug Dependent effects of Epinephrine

Effect of Low-dose Epinephrineon Heart Rate and Blood Pressure

Effect of medium-dose Epinephrineon Heart Rate and Blood Pressure

Effect of high-dose Epinephrineon Heart Rate and Blood Pressure, is similar to action of norepinephrine

• Airway Smooth Muscle/Respiratory• causes powerful bronchodilation by acting directly

on bronchial smooth muscle (β2 action)• also inhibits/decreases release of vasoactive and

allergy mediators such as histamines from mast cells

• Metabolic Effects• has the most significant effects of all the

catecholamines on metabolism• Beta receptor stimulation due to epinephrine

increases liver glycogenolysis and adipose tissue lipolysis• Alpha receptor stimulation inhibits release of

insulin

• Infusions of epinephrine usually increase plasmaconcentrations of cholesterol, phospholipids, and LDL• Release of epinephrine and resulting glycogenolysis

and inhibition of insulin secretion is the most likely explanation for the hyperglycemia that commonly occurs during the perioperative period

• Electrolytes• activation of the sodium-potassium pump in skeletal

muscles, leading to a transfer of potassium ions into cells• epinephrine-induced hypokalemia could contribute

to cardiac dysrhythmias that occasionally accompany stimulation of the sympathetic nervous system

• Ocular Effects• contraction of the radial muscles of the iris,

producing mydriasis• contraction of the orbital muscles produces an

appearance of exophthalmus• adrenergic receptors responsible for these ocular

effects are probably alpha receptors because norepinephrine is less potent than epinephrine and isoproterenol has practically no ocular effects

• Gastrointestinal and Genitourinary Effects• relaxation of gastrointestinal smooth muscle• activation of beta-adrenergic receptors relaxes the

detrusor muscle of the bladder, whereas activation of alpha-adrenergic receptors contracts the trigone and sphincter muscles

• Coagulation• is accelerated by epinephrine, presumably due to

increased activity of factor V• a hypercoagulable state present during the

intraoperative and postoperative period may reflect stress-associated release of epinephrine• increases the total leukocyte count but at the same

time causes eosinopenia

Pharmacokinetics• has a rapid onset but a brief duration of

action (due to rapid degradation)• preferred route is intramuscular (anterior

thigh) due to rapid absorption• in emergency situations, epinephrine is

given intravenously for the most rapid onset of action• may also be given subcutaneously, by

endotracheal tube, and by inhalation • rapidly metabolized by MAO and COMT,

and the metabolites metanephrine and vanillylmandelic acid are excreted in urine

Adverse effects• can produce adverse CNS effects that include anxiety,

fear, tension, headache, and tremor• can trigger cardiac arrhythmias, particularly if the

patient is receiving digoxin• can also induce pulmonary edema

• may have enhanced cardiovascular actions in patients with hyperthyroidism, and the dose must be reduced in these individuals• inhalation anesthetics also sensitize the heart to the

effects of epinephrine, which may lead to tachycardia• increases the release of endogenous stores of glucose

Clinical Uses• Clinical uses of epinephrine include

treatment of life-threatening allergic reactions administration during cardiopulmonary resuscitation

as the single most important therapeutic drug continuous infusion to increase myocardial

contractility addition to local anesthetic solutions to decrease

systemic absorption and prolong the duration of action of the anesthetic

Usual Adult Dose for Shock

• IV:• 2 to 10 mcg/min (1 mg in 250 mL of D5W or 4

mcg/mL)• May be increased as necessary to establish an

adequate heart rate and blood pressure• rarely doses as high as 20 mcg/min are required

• Endotracheal: 1 mg (10 mL of 1:10,000) once, followed by 5 quick insufflations• Intracardiac: 0.3 to 0.5 mg (3 to 5 mL of 1:10,000) by

direct injection into the left ventricular chamber once

Usual Adult Dose for Asystole

• IV:• 0.5 to 1 mg (5 to 10 mL of 1:10,000) once• may be repeated every 3 to 5 minutes as necessary• if there is inadequate response to 1 mg, then high dose

therapy (2 to 5 mg) every 3 to 5 minutes, escalating 1, 3, then 5 mg every 3 minutes, or 0.1 mg/kg every 3 to 5 minutes, has been used

• Endotracheal: 1 mg (10 mL of 1:10,000) once, followed by 5 quick insufflations• Intracardiac: 0.3 to 0.5 mg (3 to 5 mL of 1:10,000) by

direct injection into the left ventricular chamber once

Usual Adult Dose for Electromechanical Dissociation• IV: • 0.5 to 1 mg (5 to 10 mL of 1:10,000) once• may be repeated every 3 to 5 minutes as necessary• if there is inadequate response to 1 mg, then high

dose therapy (2 to 5 mg) every 3 to 5 minutes, escalating 1, 3, then 5 mg every 3 minutes, or 0.1 mg/kg every 3 to 5 minutes, has been used

• Endotracheal: 1 mg (10 mL of 1:10,000) once, followed by 5 quick insufflations• Intracardiac: 0.3 to 0.5 mg (3 to 5 mL of 1:10,000) by direct

injection into the left ventricular chamber once

Usual Adult Dose for AV Heart Block

• IV:• 0.5 to 1 mg (5 to 10 mL of 1:10,000) once• may be repeated every 3 to 5 minutes as necessary• if there is inadequate response to 1 mg, then high

dose therapy (2 to 5 mg) every 3 to 5 minutes, escalating 1, 3, then 5 mg every 3 minutes, or 0.1 mg/kg every 3 to 5 minutes, has been used

Usual Adult Dose for Asthma - Acute• Subcutaneous:• 0.1 to 0.5 mg (0.1 to 0.5 mL of 1:1000 solution)• may be repeated every 20 minutes to once every 4 hours

as needed• IM:• 0.1 to 0.5 mg (0.1 to 0.5 mL of 1:1000 solution)• May be repeated every 20 minutes to once every 4 hours

as needed• Inhalation aerosol:• 160 to 220 mcg (1 inhalation) once• additional inhalation may be used after at least one

minute• it is recommend that subsequent doses not be

administered for at least three hours

• Nebulized:• 1 to 3 inhalations (8 to 10 drops of a 1% 1:100 solution)

once• if relief does not occur within 5 minutes, the dose may

be repeated once• it is recommended that subsequent doses not be

repeated more often than every 3 hours• Intermittent positive pressure breathing:• 0.3 mg (0.03 mL of a 1:100 solution) once• the least amount of tolerated inhalations required to

provide relief is the recommended dose• most patients respond within 15 minutes• this dose may be repeated once every 3 to 4 hours as

needed

Usual Adult Dose for COPD- Acute

• Subcutaneous:• 0.3 mg (0.3 mL of 1:1000) every 20 minutes for up

to 3 doses• may be repeated once every 2 hours as needed

• IM• Inhalation aerosol• Nebulized• Intermittent positive pressure breathing

Usual Adult Dose for Allergic Reaction

• Subcutaneous:• 0.1 to 0.5 mg (0.1 to 0.5 mL of 1:1000 solution)• may be repeated every 20 minutes to once every 4

hours as needed• IM: • 0.1 to 0.5 mg (0.1 to 0.5 mL of 1:1000 solution)• May be repeated every 10 to 15 minutes

• IV:• 0.1 to 0.25 mg (1 to 2.5 mL of a 1:10,000 solution)

once slowly and cautiously over 5 to 10 minutes• the dose may be repeated every 5 to 15 minutes as

needed and tolerated• in some cases of severe anaphylaxis, an intravenous

infusion of epinephrine (1 mg in 250 mL of D5W, or 4 mcg/mL) can be started to run at 1 to 4 mcg/min (15 to 60 mL/hour)

Usual Adult Dose for Pupillary Dilation

• Induction and Maintenance of Mydriasis during Intraocular Surgery• Use the irrigating solution as needed for the

surgical procedure• Dilute 1 mL of epinephrine 1 mg/mL (1:1000) in

100 mL to 1000 mL of an ophthalmic irrigation fluid to a concentration of 1:100,000 to 1:1,000,000 (10 mcg/mL to 1 mcg/mL)• Do not use if solution is colored, cloudy or contains

particulate matter.

• Renal Dose Adjustments• no dosage adjustments are recommended for

patients with renal dysfunction.• Liver Dose Adjustments• it is recommended that multiple doses or dose

increments be given cautiously to patients with liver dysfunction

Norepinephrine• endogenous neurotransmitter released from

postganglionic sympathetic nerve endings• approximately equal in potency to epinephrine for

stimulation of beta 1 receptors, but unlike epinephrine, norepinephrine has little agonist effect at beta 2 receptors

• a potent alpha-agonist that produces intense arterial and venous vasoconstriction in all vascular beds and lacks bronchodilating effects on airway smooth muscle• hyperglycemia is unlikely to occur

Effects• Cardiovascular• causes a rise in peripheral

resistance due to intense vasoconstriction of most vascular beds, including the vasculature of skeletal muscles, liver, kidneys, and skin

• decreases venous return to the heart and increases systolic, diastolic, and mean arterial pressure

• decreased venous return to the heart combined with baroreceptor-mediated reflex decreases in heart rate tend to decrease cardiac output despite beta 1 effects of norepinephrine

• extravasation during infusion can produce severe local vasoconstriction and possible necrosis

Pharmacokinetics• is given IV for rapid onset of action• duration of action is 1 to 2 minutes, following the

end of the infusion• it is rapidly metabolized by MAO and COMT• inactive metabolites are excreted in the urine

Adverse effects• are similar to epinephrine• in addition, norepinephrine is a potent vasoconstrictor

and may cause blanching and sloughing of skin along an injected vein• if extravasation of drug from the vessel into tissues

surrounding the injection site occurs, it can cause tissue necrosis• impaired circulation from norepinephrine may be

treated with the α receptor antagonist phentolamine

Therapeutic uses• used to treat shock, because it increases vascular

resistance and, therefore, increases blood pressure

Dopamine• is the immediate metabolic precursor of norepinephrine• regulates cardiac, vascular, and endocrine function• is an important neurotransmitter in the CNS and

peripheral nervous system• occurs naturally in the CNS in the basal ganglia, where it

functions as a neurotransmitter, as well as in the adrenal medulla

• the pharmacology of dopamine is complex• differentially stimulates a variety of dopaminergic

and adrenergic receptors• at higher doses, it causes vasoconstriction by

activating α 1 receptors, whereas at lower doses, it stimulates β1 cardiac receptors

• Dopamine receptors are located post-synaptically and when activated • elicit vasodilation (renal, mesenteric, coronary,

cerebral vessels) and• inhibition of sodium-potassium adenosine

triphosphate• activation of these receptors is mediated by

adenylate cyclase

• Dopamine 2 receptors are principally presynaptic and inhibit adenylate cyclase activity and release of norepinephrine• Nausea and vomiting produced by dopamine reflect

stimulation of dopamine 2 receptors• Dopamine receptors - associated with the neural

mechanism for "reward " that is associated with cocaine and alcohol dependence

• rapid metabolism of dopamine mandates its use as a continuous infusion (1 to 2µg/kg/minute) to maintain therapeutic plasma concentrations• dopamine should be dissolved in 5% glucose in

water for IV administration• extravasation of dopamine produces intense local

vasoconstriction, which may be treated with local infiltration of phentolamine

• Dopamine is not effective orally and does not cross the blood-brain barrier in sufficient amounts to cause CNS effects• immediate precursor of dopamine, L-dopa, is

absorbed from the gastrointestinal tract and readily crosses the blood-brain barrier• Hyperglycemia that is commonly present in patients

receiving a continuous infusion of dopamine is likely to reflect drug-induced inhibition of insulin secretion

Actions• Cardiovascular:• Depending on the dose, dopamine stimulates

different receptors• dopamine 1 receptors (0. 5 to 3µg/kg/ minute IV) in

the renal vasculature to produce renal vasodilation• beta 1 receptors (3 to 10µg/kg/ minute IV) in the

heart- having both positive inotropic and chronotropic effects• Alpha 1 receptors (> 10µg/kg/ minute IV) in the

peripheral vasculature resulting in vasoconstriction

• Renal and visceral: • dilates renal and splanchnic

arterioles by activating dopaminergic receptors, thereby increasing blood flow to the kidneys and other viscera• these receptors are not affected

by α- or β-blocking drugs• so, dopamine is clinically useful

in the treatment of shock, in which significant increases in sympathetic activity might compromise renal function

• Ventilation Effects• Infusion of dopamine interferes with the ventilatory

response to arterial hypoxemia, reflecting the role of dopamine as an inhibitory neurotransmitter at the carotid bodies• result is-unexpected depression of ventilation in

patients who are being treated with dopamine to increase myocardial contractility• arterial blood gases have been observed to deteriorate

during infusion of dopamine

• Intraocular Pressure• continuous infusions of dopamine to critically ill

patients are associated with increases in intraocular pressure• this may create a risk in patients with preexisting

glaucoma especially if they are sedated and mechanically ventilated

Therapeutic Uses• the drug of choice for cardiogenic and septic shock• unique among the catecholamines in being able to

simultaneously increase (a)myocardial contractility(b) renal blood flow(c) glomerular filtration rate(d) excretion of sodium(e) urine output

• is given by continuous infusion• It raises blood pressure by stimulating the • β1 receptors on the heart to increase cardiac output • α1 receptors on blood vessels to increase total

peripheral resistance• in addition, it enhances perfusion to the kidney and

splanchnic areas

Adverse effects• produces the same effects as sympathetic

stimulation• is rapidly metabolized by MAO or COMT, and its

adverse effects (nausea, hypertension, and arrhythmias) are, therefore, short-lived

SYNTHETIC CATECHOLAMINES

• two clinically useful synthetic catecholamines are• isoproterenol• dobutamine

Isoproterenol• most potent activator of all the sympathomimetics at

beta 1 and beta 2 receptors• nonselectivity is one of its drawbacks and the reason

why it is rarely used therapeutically• two to three times more potent than epinephrine and at

least 100 times more active than norepinephrine• in clinical doses, isoproterenol is devoid of alpha-agonist

effects

• metabolism-in the liver by COMT is rapid, necessitating a continuous infusion to maintain therapeutic plasma concentrations• uptake of isoproterenol into postganglionic

sympathetic nerve endings is minimal

Effects• intense stimulation of the heart, increasing heart rate,

contractility, and cardiac output• dilates the arterioles of skeletal muscle (β2 effect),

resulting in decreased peripheral resistance• because of its cardiac stimulatory action, it may

increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressures• is a potent bronchodilator (β2 effect)

Clinical Uses• continuous infusion of isoproterenol, 1 to 5 µg/min

is effective in increasing the heart rate in adults in the presence of heart block• provide sustained increases in heart rate before insertion of

a temporary or permanent cardiac pacemaker in the treatment of bradydysrhythmias• the use of isoproterenol as an inotropic drug has decreased

with the availability of dobutamineand phosphodiesterase inhibitors• the use of isoproterenol as a bronchodilator has been

supplanted by availability of specific beta 2 agonists

Dobutamine• synthetic catecholamine that acts as a selective

beta 1 adrenergic agonist• rapid metabolism of dobutamine dictates its

administration as a continuous infusion at 2 to 10µg/kg/minute to maintain therapeutic plasma concentrations• like dopamine, dobutamine should be dissolved in

5% glucose in water for infusion to avoid inactivation of the catecholamine that may occur in an alkaline solution

Clinical Use and Effects• produces potent beta-adrenergic agonist

effects at does < 5µg/kg/minute• dobutamine increases myocardial contractility (beta 1

receptors) • is used to improve cardiac output in patients with

congestive heart failure, particularly if heart rate and systemic vascular resistance are increased• High doses of dobutamine (> 10µg/kg/minute) may

predispose the patient to tachycardia and cardiac dysrhythmias

• increases cardiac output and does not significantly elevate oxygen demands of the myocardium, a major advantage over other sympathomimetic drugs• should be used with caution in atrial fibrillation,

because it increases AV conduction

Summary of the therapeutic uses of adrenergic agonists

BETA-ADRENERGIC RECEPTOR

ANTAGONISTS

• bind selectively to beta-adrenergic receptors and interfere with the ability of catecholamines or other sympathomimetics to provoke beta responses• are competitive antagonists• Nonselective β-blockers act at both β1 and β2 receptors,

whereas cardio-selective β antagonists primarily block β1 receptors• drug-induced beta-adrenergic blockade prevents the

effects of catecholamines and sympathomimetics on the heart and smooth muscles of the airways and blood vessels

• Beta-antagonist therapy should be continued throughout the perioperative period to • maintain desirable drug effects• avoid the risk of sympathetic nervous system

hyperactivity associated with abrupt discontinuation of these drugs

• are derivatives of the beta agonist drug isoproterenol• Substituents on the benzene ring determine whether

the drug acts on beta adrenergic receptors as an antagonist or agonist

Metoprolol• selective beta 1-adrenergic receptor antagonist that

prevents inotropic and chronotropic responses tobeta-adrenergic stimulation• selectivity is dose related, and large doses of

metoprolol are likely to become nonselective, exerting antagonist effects at beta 2 receptors as well as beta 1 receptors

• readily absorbed from the gastro-intestinal tract, but this is offset by substantial hepatic first-pass metabolism such that only about 40% of the drug reaches the systemic circulation

• protein binding is low; it is estimated to account for about 10% of the drug

• elimination half-time of metoprolol is 3 to 4 hours

Esmolol• rapid-onset and short-acting selective beta 1-

adrenergic receptor antagonist that is administered only IV• typical initial dose-0.5 mg/kg IV over about 60 seconds• the full therapeutic effect is evident within 5 minutes• action ceases within 10 to 30 minutes after administration

is discontinued• these characteristics make esmolol a useful drug for

preventing or treating adverse systemic blood pressure and heart rate increases that occur intraoperatively in response to noxious stimulation, as during tracheal intubation

• commercial preparation of esmolol is buffered to pH 4.5 to 5.5, which may be one of the factors responsible for pain on injection• elimination half-time is about 9 minutes• undergoes rapid hydrolysis in the blood by plasma

esterases• Poor lipid solubility limits transfer of esmolol in to the

CNS or across the placenta

Side Effects• side effects of beta-adrenergic antagonists are similar for all

available drugs, although the magnitude may differ depending on their selectivity and the presence or absence of intrinsic sympatho-mimetic activity• exert their most prominent pharmacologic

effects as well as side effects on the cardiovascular system• alter airway resistance, carbohydrate and lipid metabo- lism,

and the distribution of extracellular ions• gastro-intestinal side effects include nausea, vomiting,

and diarrhea

Contraindications• preexisting atrioventricular heart block or cardiac failure• nonselective beta-adrenergic antagonists or high doses

of selective beta adrenergic antagonists are not recommended for administration to patients with chronic obstructive airway disease• in patients with diabetes mellitus, there is the risk that

beta-adrenergic blockade may mask the signs of hyperglycemia and thus delay its clinical recognition

Clinical uses of beta-adrenergicblockers

• Treatment of essential hypertension• Management of angina pectoris• Treatment of acute coronary syndrome• Peri operative beta-adrenergic receptor blockade• Treatment of intraoperative myocardial ischemia

• Suppression of cardiac dysrhythmias• Management of congestive heart failure• Prevention of excessive sympathetic nervous

system activity• Preoperative preparation of hyperthyroid patients• Treatment of migraine headache

Labetalol• is a unique parenteral and oral antihypertensive

drug that exhibits selective alpha 1 and nonselective beta 1 and beta2 adrenergic antagonist effects• presynaptic alpha 2 receptors are spared by labetalol

such that released norepinephrine can continue to inhibit further release of catecholamines

• Metabolism of labetalol is • by conjugation of glucuronic acid• 5% of the drug recovered unchanged in urine

• The elimination half-time is 5 to 8 hours and is prolonged in the presence of liver disease and unchanged by renal dysfunction

• labetalol lowers systemic blood pressure by decreasing systemic vascular resistance (alpha 1 blockade), whereas reflex tachycardia triggered by vasodilation is attenuated by simultaneous beta blockade• Cardiac output remains unchanged• in addition to producing vasodilation by alpha1

blockade, labetalol may cause vasodilation thatis mediated by beta2-adrenergic agonist activity• maximum systemic blood pressure-lowering effect of an

IV dose of labetalol (0.1 to 0.5 mg/kg) ispresent in 5 to 10 minutes

Clinical Uses• safe and effective treatment for hypertensive

emergencies• effective in the treatment of angina pectoris• Labetalol, 0.1 to 0.5 mg/ kg IV, can be administered to

anesthetized patients to attenuate increases in heart rate and blood pressure that are presumed to result from abrupt increases in the level of surgical stimulation

Side Effects• orthostatic hypotension is the most common side

effect of labetalol therapy.• bronchospasm is possible in susceptible patients• other adverse effects associated with beta

adrenergic antagonists (congestive heart failure, bradycardia, heart block) are a potential risk of labetalol therapy, but the Iikely incidence and severity is substantially decreased

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