14 Adrenergic Agonists & Antagonists Flashcards
Neurotransmitter
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])
Types of adrenergic receptors
Alpha: a1 & a2
Beta: B1, B2, & B3
Dopaminergic: D1 & D2
a1 Receptors
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
a2 Receptors
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
B1 Receptors
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
B2 Receptors
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)
B3 Receptors
Found in gallbladder and brain adipose
Unknown physiology, thought to have effect on lipolysis and thermogenesis in brown fat
Dopaminergic Receptors
D1 & D2
D1 - mediate vasodilation in kidney, intestine, and heart
D2 - antiemetic action of droperidol
Adrenergic Agonists
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
Phenylephrine
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
Clonidine
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
Dexmedetomidine
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
Epinephrine
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)
Ephedrine
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)
Norepinephrine
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)
Dopamine
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
Isoproterenol
Pure B1 agonist
Myocardial O2 demand increases more than supply - making any pure B1 agonist poor inotropic choice in most situations
Dobutamine
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
Dopexamine
Structural analogue of DA
Less B1 adrenergic and a-adrenergic effect
Rare clinical use
Starting infusion: 0.5 mcg/kg/min
Fendolopam
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
Phentolamine
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
Labetalol
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)
B blockers
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
Esmolol
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
Metoprolol
Selective B1 antagonist
IV: 2-5 mg q2-5 min
Propranolol
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)
Nebivolol
Newer generation B-blocker
High affinity for B1 receptors
Also causes direct vasodilation via stimulatory effect on endothelial nitric oxide synthase
Only oral formulation
Carvedilol
Mixed B and a blockade
Used in chronic HF secondary to cardiomyopathy, left ventricular dysfunction following acute MI and hypertension
Perioperative B-blocker Therapy
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
