14 Adrenergic Agonists & Antagonists

Question 1

Neurotransmitter

Answer 1

Norepinephrine - released by post-ganglionic sympathetic fibers at end-organ tissues (except eccrine sweat glands and some blood vessels)

ACh - released by preganglionic sympathetic and all parasympathetic fibers

Neurotransmitter released by exocytosis

NE primarily terminated by reuptake into postganglionic nerve ending but also by diffusion and metabolism (monoamine oxidase [MAO] and catechol-O-methyltransferase [COMT])

Question 2

Types of adrenergic receptors

Answer 2

Alpha: a1 & a2

Beta: B1, B2, & B3

Dopaminergic: D1 & D2

Question 3

a1 Receptors

Answer 3

Post-synaptic adrenoreceptors

Location: smooth muscle in eye, lung, blood vessels, uterus, gut, GU system

Activation leads to increase in intracellular Ca2+, leading to smooth muscle contraction

Effect:

• Smooth muscle: mydriasis, bronchoconstriction, vasoconstriction, uterine contraction, GI/GU sphincter construction
• Inhibit insulin secretion and lipolysis
• Myocardium: positive inotropic
• Vasoconstriction increases peripheral vascular resistance, left ventricular after load, & arterial blood pressure

Question 4

a2 Receptors

Answer 4

Pre-synpatic receptor

Activation inhibits adenylate cyclase activity, decrease entry of Ca2+ into neuronal terminal, which limits subsequent exocytosis of storage vesicles containing NorEpi

Create negative feedback loop that inhibits further NorEpi release from neuron

CNS a2 receptors cause sedation, reduce sympathetic outflow, leads to peripheral vasodilation and lowered BP

Question 5

B1 Receptors

Answer 5

Catecholamine (Epi & NorEpi) equipotent on B1

Most importantly located on postsynaptic membranes of heart

Receptor stimulation activates adenylate cyclase, converts ATP to cAMP, initiates kinase phosphorylation cascade

Positive chronotropic, dromotropic, and inotropic effect

Question 6

B2 Receptors

Answer 6

B2: Epi significantly more potent than NorEpi

Primarily post-synaptic in smooth muscle and gland cells

Same mechanism as B1 (adenylate cyclase activation)

Stimulation relaxes smooth muscle - resulting in bronchodilation, vasodilation, relaxation of uterus (tocolysis), bladder, and gut

Stimulates glycogenolysis, lipolysis, gluconeogenesis, and insulin release

Activates Na-K pump, drives K intracellular (can induce hypokalemia and dysrhythmias)

Question 7

B3 Receptors

Answer 7

Found in gallbladder and brain adipose

Unknown physiology, thought to have effect on lipolysis and thermogenesis in brown fat

Question 8

Dopaminergic Receptors

Answer 8

D1 & D2

D1 - mediate vasodilation in kidney, intestine, and heart

D2 - antiemetic action of droperidol

Question 9

Adrenergic Agonists

Answer 9

Direct or indirect agonists

Direct - bind to receptor

Indirect - increase endogenous neurotransmitter activity (increased release or decreased reuptake)

Catecholamines - adrenergic agonists with 3,4-dihydroxybenzene structure - short acting due to metabolism by MAO or COMT

Naturally occurring catecholamine: Epi, NorEpi, DA

Question 10

Phenylephrine

Answer 10

Non-catecholamine with predominantly a1 activity

peripheral vasoconstriction with concomitant rise in systemic vascular resistance and arterial BP

Reflex tachycardia (vagus mediated) can reduce cardiac output

Dosing:

• IV bolus 50-100 mcg (0.5-1 mcg/kg); lasts ~ 15 min
• Infusion: 100 mcg/ml at rate 0.25-1 mcg/kg/min

Tachyphylaxis can occur with infusion

Question 11

Clonidine

Answer 11

a2 agonist (a2:a1 affinity 200:1)

Anti-hypertensive, negative chronotropic, & sedative effects

Oral (3-5 mcg/kg), IM (2 mcg/kg), IV (1-3 mcg/kg), transdermal (0.1-0.3 mg/day), intrathecal (75-100 mcg), and epidural (1-2 mcg/kg)

Decreases anesthetic and analgesic requirements (decreases MAC), provides sedation and anxiolysis

Direct effects on spinal cord may be mediated by a2 postsynaptic receptors within dorsal horn

Other possible effects: decreased post-op shivering, inhibition of opioid induced muscle rigidity, attenuation of opioid withdrawal symptoms

Side effects: bradycardia, hypotension, sedation, respiratory depression, dry mouth

Question 12

Dexmedetomidine

Answer 12

Lipophilic (a2:a1 affinity 1600:1)

Higher affinity for a2 than clonidine

Shorter half life (2-3 hr) than clonidine (12-24 h)

Sedative, analgesic, and sympatholytic effects

Intraop: reduces IV and volatile anesthetic requirements

Post-op: reduces concurrent analgesic and sedative requirements

Useful sedating Pts for awake fiberoptic intubation and sedating in PACU/ICU b/c no significant ventilator depression

Dose: loading (1 mcg/kg over 10 min) then 0.2-0.7 mcg/kg/hr

Question 13

Epinephrine

Answer 13

Endogenous catecholamine synthesized in adrenal medulla

Direct stimulation of B1 receptor raises BP, cardiac output, and myocardial O2 demand by increasing contractility and HR

a1 stimulation decreases splanchnic and renal blood flow but increases coronary perfusion pressure by increasing aortic diastolic pressure

Systolic BP rises though B2 mediated vasodilation in skeletal muscle may lower diastolic BP

B2 stimulation also relaxes bronchial smooth muscle

Dosing:

• Emergency situations (arrest, shock): IV 0.05-1 mg
• Anaphylaxis: 100-500 mcg (repeated as necessary)
• Infusion (to improve myocardial contractility or HR): 1 mg in 250 mL (4 mcg/mL) at 2-20 mcg/min

1: 1,000 (1 mg/mL)
1: 10,000 (0.1 mg/mL)
1: 100,000 (10 mcg/mL)
1: 200,000 (5 mcg/mL)
1: 400,000 (2.5 mcg/mL)

Question 14

Ephedrine

Answer 14

Non-catecholamine sympathomimetic

Effects similar to epinephrine: increase BP, HR, contractility, CO & bronchodilator

Longer duration of action

Stimulates CNS (raises MAC)

Vasopressor - temporizing measure cause of hypotension determined/remedied

Not believed to decrease uterine blood flow - preferred for obstetric use

Dose:

• Bolus 2.5-10 mg
• Children (0.1 mg/kg)

Question 15

Norepinephrine

Answer 15

Direct a1 stimulation with B1 but little B2

Intense vasoconstriction of arterial and venous vessels

Increased myocardial contractility from B1 effects with peripheral vasoconstriction –> rise in arterial BP

Increased afterload but reflex bradycardia prevent rise in CO

Extravasation causes tissue necrosis

Bolus: 0.1 mcg/kg
Infusion 2-20 mcg/min (preferred due to short half life)

Question 16

Dopamine

Answer 16

Endogenous nonselective direct and indirect adrenergic and dopaminergic agonist - vary on dose

Low dose (0.5-3 mcg/kg/min) - ‘‘renal dose’’

• Activates DA receptors with vasodilation of renal vasculature and promote diuresis and natriuresis
• No beneficial effect on renal function

Moderate dose (3-10 mcg/kg/min)

• B1 stimulation increases myocardial contractility, HR, systolic BP and CO
• Myocardial O2 demand increases more than supply

High dose (10-20 mcg/kg)

• a1 effects more prominent
• Increase peripheral vascular resistance with fall in renal blood flow

Often used with vasodilator to reduce afterload and further improve CO

Question 17

Isoproterenol

Answer 17

Pure B1 agonist

Myocardial O2 demand increases more than supply - making any pure B1 agonist poor inotropic choice in most situations

Question 18

Dobutamine

Answer 18

Racemic mixture of 2 isomers with affinity for B1 & B2 receptors (but B1 > B2)

Rise in CO due to increased myocardial contractility

Decline in peripheral vascular resistance caused by B2 activation prevents much rise in arterial BP

Left ventricular filling pressure decreases where coronary blood flow increases

Favorable myocardial oxygen balance make it good choice for congestive HF and CAD Pts

Infusion: 2-20 mcg/kg/min

Question 19

Dopexamine

Answer 19

Structural analogue of DA

Less B1 adrenergic and a-adrenergic effect

Rare clinical use

Starting infusion: 0.5 mcg/kg/min

Question 20

Fendolopam

Answer 20

Selective D1 receptor agonist - little/no a or B or D2 agonist activity

Antihypertensive effect but maintaining renal blood flow

Increases renal blood flow, diuresis, and naturiesis - but ability to “protect” kidney is unclear

Starting infusion: 0.1 mcg/kg/min

Question 21

Phentolamine

Answer 21

Competitive (reversible) blockade of a1 and a2

Peripheral vasodilation and decline in arterial BP and reflex tachycardia

Reflex tachycardia made greater by antagonism of presynaptic a2 in heart b/c a2 blockade promotes NorEpi release

Bolus (1-5 mg) or infusion

Prevents tissue necrosis when a-agonist extravasated; 5-10 mg in 10mL NS can be locally infiltrated

Question 22

Labetalol

Answer 22

Mixed a, B1, B2 blockade

Ratio a:B blockade of 1:7 following IV

Reduces peripheral vascular resistance and arterial BP without reflex tachycardia

2.5-10 mg over 10 min then 2x given at 10 min interval

Infusion not recommended due to long half life (>5 h)

Question 23

B blockers

Answer 23

Selective B1 has less inhibitory effect on B2 so would be preferred in Pts with chronic obstructive lung disease

Pts with peripheral vascular disease could potentially have decrease in blood flow if B2 receptors (which dilate arterioles) are blocked

Reduced intraocular pressure in patients with glaucoma

Question 24

Esmolol

Answer 24

Ultrashort acting selective B1 antagonist (inhibits B2 at higher doses)

Reduces HR and to lesser extent BP

Controls ventricular rate for a-fib or a-flutter

Rapid redistribution (~2 min distribution half life) & hydrolysis (by RBC esterases, eliminiation t1/2 ~ 9min)

Bolus: 0.2-0.5 mg/kg

Loading dose 0.5 mg/kg over 1 min with infusion 50-200 mcg/kg/min

Question 25

Metoprolol

Answer 25

Selective B1 antagonist

IV: 2-5 mg q2-5 min

Question 26

Propranolol

Answer 26

Nonselective B antagonist

Lowers arterial BP by several mechanisms - decreased myocardial contractility, lower HR, diminished renin release

CO and myocardial O2 demand reduced

Impedence of ventricular ejection benefical in Pts with obstructive cardiomyopathy

Slows ventricular conduction - helps with SVT

Blocks B-adrenergic effect of thyrotoxicosis and pheochromocytoma

Side effects: bronchospasm (B2 antagonism), congestive HF, bradycardia, AV heart block (B1 antagonism), can worsen myocardial depression of volatiles

Extremely protein bound

Hepatic clearance

Elimination t1/2 (100 min) - very long compared to esmolol

IV dose: 0.5 mg q3-5 min and increasing by 0.5 mg (total dosing rarely exceeding 0.15 mg/kg)

Question 27

Nebivolol

Answer 27

Newer generation B-blocker

High affinity for B1 receptors

Also causes direct vasodilation via stimulatory effect on endothelial nitric oxide synthase

Only oral formulation

Question 28

Carvedilol

Answer 28

Mixed B and a blockade

Used in chronic HF secondary to cardiomyopathy, left ventricular dysfunction following acute MI and hypertension

Question 29

Perioperative B-blocker Therapy

Answer 29

Maintenance of B-blockers in Pts already being treated with them is essential (unless contraindicated for other clinical concerns)

Potential to reduce perioperative cardiovascular complications due to counteraction of catecholamine induced tachycardia and hypertension

Reduced risk of in-hospital death in small group of high risk patients (Revised Cardiac Score 3 or greater)

Should be initiated in Pts undergoing vascular surgery who are at high risk of cardiac events because of findings of myocardial ischemia during perioperative testing

Discontinuation of B blocker therapy for 24-48 hr may trigger withdrawal syndrome characterized by (rebound) hypertension, tachycardia, and angina pectoris