Adrenergic agonists and antagonists

• thoracoabdominal or thoracolumbar
• - T1-L2-3
• - Fibers originate in the spinal cord along with spinal nerves between T1 & L2-3 and then pass first into the sympathetic chain then to tissues and end organs

• Craniosacral
• Fibers leave the CNS through cranial nerves 3,7,9,10 & also from lowest part of the spinal cord through S2 and S3

• Starts in the cytoplasm of terminal nerve endings then is completed in secretory vesicles
• 1. Tyrosine --> dopa
• 2. Dopa --> dopamine
• 3. Transport of dopamine into vesicles
• 4. Dopamine --> norepinephrine 

*except the adrenal medulla were 80% of norepi --> epi

• 1. Reuptake into the adrenergic nerve endings by active transport. Removes 50-80% of secreted norepi
• 2. Diffusion away from nerve endings into surrounding body fluids and then into the blood (most of remaining norepi is removed this way)
• 3. Breakdown of small amounts by tissue enzymes including MAO (in nerve endings) and COMT (diffusely present in all tissues)

• Postsynaptic
• Smooth muscle throughout body: eye, lung, blood vessels, uterus, gut and GU

Stimulation causes vasoconstriction, bronchoconstriction and HTN

Presynaptic

Stimulation causes negative feedback inhibiting norepi release resulting in vasodilation, hypotension and sedation

• Causes hyper polarization because of potassium influx
• Decreased firing neurons and decreased norepi release mediated by alpha 2 pre-synaptic receptors 
• Up-regulation may occur with long term use so withdrawal will quickly cause HTN

• Alpha 2A: sedation, analgesia and sympatholysis (hypotension)
• Alpha 2B: hypertension and vasoconstriction
• Alpha 2C: startle reflex

Postsynaptic membranes in the heart

Stimulation causes positive chronotropic, dromotropic and inotropic effects

Postsynaptic in smooth muscle and glands

• Stimulation causes bronchodilation, vasodilation, glycogenolysis, lipolysis and insulin release 
• Also activates Na/K pump so K goes INTO the cell and can induce hypokalemia and various arrhythmias

• Parents compound for sympathomimetics!
• Can have substitutions on the...
• 1. Terminal amino group - NH2 group
• 2. Benzene ring
• 3. Alpha or beta carbons

*these substitutions effect the affinity on the various receptors

• Increases size of alkyl substituents which increases beta receptor activity 
• ex: putting methyl group on norepi to make epi enhanced B2 and replacing methyl on epi with isopropyl group to make isoproterenol enhance B activity even more
• The larger the amino substituent group, the less alpha effect

• Max alpha and beta activity
• If -OH group on C3 (especially) or C4 is missing, the potency of the drug is DRAMATICALLY reduced
• Ex: Phenylephrine is much less potent than epi

• Prolongs the duration of action by blocking oxidation by MAO
• Ex: ephedrine has methyl group at alpha carbon - which means it can displace catecholamine from storage sites in nerve endings aka indirect mechanism of action

Direct acting agnostic typically have a eta hydroxyl group such as epi, norepi or isoproterenol

• Prototype
• Released from adrenal medulla
• Most potent alpha activator but also B1 and B2
• 2-10 times more potent than norepi

• Myocardial contractility
• HR
• Vascular and bronchial smooth muscle tone
• Glandular secretions
• Metabolism (lipolysis and glycogenolysis)

• @1-2mcg/min IV: stimulating mainly B2 receptors in peripheral vasculature 
• @ 4mcg/min: beta 1 stimulation
• @10-20mcg/min: both alpha and beta with alpha predomination
• Rapid bolus of 2-8mcg IV causes cardiac stimulation lasting 1-5 minutes

• BP & HR
• Incr SBP but modestly decreased DBP d/t vasodilation so MAP doesn't change much and baroreceptor mediated bradycardia doesn't occur
• Tachycardia - due to accelerated rate of phase 4 depolarization
• Increased likelihood of arrhythmias
• Vasculature: constriction vs dilation depending on location 
• Coronary flow ENHANCED
• Renal perfusion DECREASED
• Skeletal muscle vessels DILATE (B2)

• Released from postganglionic sympathetic neurons
• equal to epi for B1 stimulation but little/no B2
• Potent Alpha agonist - VASOCONSTRICTION
• No Bronchodilation

• INCREASES: SVR, SBP, DBP, MAP
• DECREASES: venous return, HR (baroreceptor), CO
• Metabolic acidosis may result from hypoperfusion 

4-16mcg/min for refractory hypotension

• Immediate precursor for norepinephrine
• NT in central and periph nervous systems
• Stimulates alpha, beta and dopamine receptors 
• UNIQUE: increases contractility, renal blood flow, glomerular filtration, sodium excretion and urine output

• INCREASES: CO, HR, BP, SVR
• Typically used for the increased CO effect
• Increased inotropy is from the endogenous form, so if that's low, you might not see the same increase when giving dopa

• Selective B1 agonist
• - potent B1 at low dose and moderate vasodilation from B2
• - higher doses the L isomer causes A1 stimulation to prevent further vasodilation
• Isomers oppose each other at alpha receptors 
• 2-10mcg/kg/min
• Increases contractility - increases CO

• Indirect and direct acting
• Stimulates alpha and beta receptors directly
• Causes release of norepi (indirect effect)

• Similar to norepi but much less potent
• Mostly direct A1 activity 
• Small indirect via release of norepi
• Minimal beta stimulation

• Epinephrine
• Norepinephrine
• Dopamine

• Catacholamine: dobutamine
• Noncatecholamines: ephedrine and phenylephrine

• Nonselective alpha blocker
• COMPETITIVE ANTAGONIST
• REVERSIBLE BLOCKADE
• Peripheral vasodilation and hypotension with tachycardia because of baroreflex
• Risk for myocardial ischemia and arrhythmias

• ONSET: 2 minutes
• DURATION: 10-15 minutes
• USES: clonidine withdrawal, phew, autonomic hyperreflexia and treatment for sympathomimetic extravasation (locally infiltrate 2.5-5mg/10ml)
• BOLUS: 1-5mg (30-70mcg/kg)

• Nonselective alpha blocker - A1 > A2
• IRREVERSIBLE BLOCKADE - not competitive 
• Action can only be terminated by metabolism
• Only given orally

• ONSET: up to 60 minutes
• DURATION: with repeated doses can be up to 4 days because half time is so long
• - Orthostatic hypotention, and patients can't compensation for hypovolemia/HoTN/decr SVR
• USES: preop to control BP with pheo (blocks intense vasoconstriction to allow for increased intravascular volume and repletion) Raynaud's

• IV USE ONLY
• Rapid onset, short acting
• Beta 1 selective (HR)
• Half time - 9 minutes (rapid hydrolysis by esterases)
• Poor lipid solubility

• 0.5mg/kg IV: comes in 10mg/mL so usually just give 10mg and go up from there
• Indications: transient events - laryngoscopy, ECT

• Selective alpha 1 and nonselective beta 1 and 2 blocker
• *CAREFUL with reactive airways
• Halftime: 5-8 hours
• Max effect after about 5-10minutes 
• 5mg/mL - start low and work up

1/5th to 1/10th

1/4 to 1/3

7:1