Adrenergic Pharmacology

NE/Epi Receptor classes

Class Signaling Effects Agonists
Alpha Gq receptor  ↑vascular smooth m. contraction, Phenylephrine >
1 Phospholipase C  PIP2 ↑pupillary dilator m. contraction methoxamine
from lipids  ↑IP3 and (myadrisis), ↑intestinal and
DAG  ↑calcium and bladder spinchter m. contraction
Protein Kinase C
Alpha Gi receptor inhibition of ↓ sympathetic outflow, ↓ insulin Clonidine > alpha-methyl-
2 adenylyl cylase  ↓cAMP release NE > NE > oxymetazoline
 ↓Protein Kinase A
Beta 1 Gs receptor  adenylyl ↑ heart rate, ↑ contractility, ↑ Isoproterenol (ISO) > E >
cyclase  ↑cAMP  insulin release ,↑ lipolysis NE >>> PE
Beta 2 ↑Protein Kinase A Vasodilation, bronchodilation, ↑ ISO > E >>>>NE >>>>
heart rate, ↑ contractility, ↑ PE
insulin release ,↑ lipolysis, ↓
uterine tone
Dopamine Receptor classes
Class Signaling Location of receptors Effects
D1 family (D5 subtype) Increase cAMP Smooth muscle cells Vasodilation,
of vessels, CNS natruieresis, diuresis
D2 family (D3, D4) Inhibit cAMP, blocks SS ganglia, SS nerve Hypotension,
calcium channels, opens terminals, CNS bradycardia,
potassium channels vasodilation
Effects of Dopamine
1. Releases NE from adrenergic neurons (indirectly acting sympathomimetic)
2. Interacts with alpha and beta adrenergic receptors (prefers beta receptors)
3. Interacts with specific dopamine receptors
High dose of dopamine  increased HR, contraction, and cardiac output
Synthesis of catecholamines
Tyrosine  L-DOPA  Dopamine  NE  Epi (underlined reactions occur in vesicles)
1. Tyrosine hydroxylase: rate limiting enzyme. NE synthesis is closely regulated by activation of
TH by (1), phosphorylation and (2), increased TH synthesis in chronically activated neuron
2. Dopamine beta hydroxylase: vesicular enzyme converts dopamine to NE. enzyme is released
with NE into presynaptic nerve terminals
3. PNMT: present mainly in chromafin cells of adrenal gland. Activated by corticosteroids.
Storage of catecholamines
• NE and dopamine are stored in vesicles by the VMAT vesicular pump (requiring Mg2+ and ATP)
o VMAT1: periphery
o VMAT2: CNS
• Within the vesicles, NE is found with : ATP, DBH, chromogranins, calcium,
Release
Depolarization  influx of calcium  exocytosis of vesicles that were once docked to the membrane
Presynaptic modulation: presynaptic nerve membrane has alpha 2 receptors that function to
decrease cAMP or inhibit calcium entry  decrease NE release
Fate of NT after release
1. Diffusion: some NE diffuses to lymphatic/caps  liver  metabolized by MAO and COMT
2. Extraneuronal uptake: some taken up by postsynaptic neuron  metabolized by COMT 
diffuses out to liver  metabolized finally by MAO
3. **NE transporter: recycles the NT by taking it up into the original cell. Higher affinity for NE>
EPI.
Metabolic degradation: MAO is found in nerve terminals and liver, COMT is found in effector cells
and liver. Most usual pathway of degradation: NE first metabolized by COMT, followed by MAO in liver
Adrenergic Responses of Organs
Organ Recept Response
or
Heart Beta 1 A. Heart rate increase (positive chronotropic effect): activation of SA
node pacemaker cells  more rapid diastolic depolarization 
increased frequency of Aps
B. Cardiac force of contraction increased (positive inotropic effect):
increased calcium influx with each AP
C. Conduction velocity increased from SA to AV node (positive
domotropic effect)
D. Refractory period of AV node decreased
E. Arrhythmias possible: more common with NE/Epi than ISO b/c ISO
does not act on alpha receptors and doesn’t increased BP. NE/Epi
also increase BP by binding alpha 1 receptors
F. Cardiac efficiency decrease due to increased oxygen debt
Kidney Alpha 1 Vasoconstriction with E and NE. Slight vasodilation with ISO
Skeletal Alpha 1 NE: vasoconstriction
muscle Beta 2 Epi: vasodilation at lower dose, vasoconstriction at higher dose. This is
b/c Epi prefers beta receptors to alpha receptors
ISO: vasodilation
Liver Alpha 1 Low Epi: some vasodilation
mostly Hgiher dose Epi/NE: vasoconstriction
Coronaries Beta 2 Vasodilation: makes sense b/c the heart needs more oxygen for it’s
increased pumping!
*vasodilation also occurs due to action of adenosine (breakdown
product of ATP)  vasodilation
Pulmonary Alpha Some vasocontriction with NE/Epi
mostly
Overall blood Low dose EPI: systolic ↑ (beta 1), diastolic ↓(prefer beta 2), no change
pressure in MAP. Cardiac output ↑, TPR is ↓

NE or high dose EPI: systolic ↑, diastolic ↑ (alpha 1), MAP ↑, same

cardiac output or slightly ↓, TPR ↑

ISO: some increase in systolic, diastolic ↓, MAP ↓, cardiac output can

decrease as vasodilation ↑, TPR ↓
Bronchial Beta 2 Bronchodilation
smooth m.
Iris radial m. Alpha 1 Muslce contraction  mydriasis
GI tract Alpha 1 Relaxation of smooth muscle.
Beta 2
Bladder Beta 2 Beta 2: located on detrussor m  relaxation
Alpha 1 Alpha 1: located on trigone area  contraction
Uterus Alpha 1 NE stimulates contraction
Beta 2 Epi gives biphasic results
*specific for beta 2  relaxation (delay premature labor)
Spleen Alpha 1 Contraction  blood expultion
mostly
Vas deferens Alpha 1 Contraction  expel contents
and seminal
vesicles
Metabolic Hyperglycemia, hyperlactemia, increased in free FA
effects
CNS effects EPI/NE do NOT cross BBB well. However, associated with restlessness,
anxiety, involved in mood, sleep-wake cycle, motivation, pain
Adrenergic Drugs
Class Name MOA Clinical uses
Indirectly Tyramine* Taken up by the NET  causes Found in food. ADRs when patient
acting release of NE from synaptic on MAO  ↑adrenergic responses
adrenergic vesicles. Oxidized by MAO.
drugs
Amphetamin Taken up by the NET  causes Narcolepsy, ADHD
e, release of NE from synaptic
Ephedrine vesicles. Binds MAO but is not SEs: restlessness, tremor,
metabolized by MAO (prevents suppressed appetite. Chronic use
NE oxidation by MAO). can lead to tachyphylaxis:
*penetrate the BBB tolerance for autonomic effects of
NE due to depletion of NE storage

Metamphetamine: crystal meth

Antihyperten Alpha methyl Inhibits tyrosine hydrolyase Historical use: treatment of
sive drugs tyrosine (inhibiting the formation of L- pheochromocytoma
DOPA) SE: renal damage due to
crystallization in tubules
Resperine Blocks NE carrier of synaptic Long-lasting effects (>1 week)
vesicles  accumulation of NE SEs: unbalanced PS activity  ↑ of
in cystosol  MAO breakdown ACh effects, severe depression
of NE Natural: Indian plant Snakeroot
*also deplets 5-HT and
histamine
Guanethidine Drug taken up by NET  blocks Was used for essential HTN
exocytosis of NE  eventually, SE: postural hypotension
NE storage is also decreased
Clonidine Specific agonist of alpha 2 Treatment of essential HTN
receptors  reduced SS outflow
to blood vessels  lower BP SEs: sudden withdrawal 
*acts on both alpha 2 adenergic hypertensive crisis from overactive
and imidazoline receptors SS system
Methyldopa Enters CNS  converted to
alpha-metyl NE  high affinity
to alpha 2 receptors  lower SS
outflow  lowers BP
*only active on alpha 2
adenergic receptors
Antidepressa TCAs Inhibition of NET SEs: tremor, insomnia, orthostatic
nts hypertension, dry mouth
(also inhibit 5-HT inhibitor, (anticholinergic effects)
muscarinic receptors,
histaminergic receptors, alpha
1)
Abusive Cocaine 1. Blocks NET
drugs 2. Blocks conduction of nerve
impulses (local anesthetic)
Antiasthemat EPI, ISO Beta 2 receptor agonists - Treatment of asthma and chronic
ic agents bronchodilation bronchitis. ISO no longer used to SE
of cardiac stimulation
Orciprenaline More specific beta 2 receptor Asthma
, salbutamol, agonists
terbutalin,
salmeterol
Adjunct to EPI, PE Bind alpha 2 receptors 
local vasoconstriction  keeps drug
anesthestics in area where needed
Other Dubutamine Beta 1 agonist  improves Heart failure management
cardiac output

Adrenergic Receptor Blocking Agents

1. Alpha Blockers
Effects: BP ↓ due to ↓ TPR. This may lead to reflex tachycardia and increased cardiac output.
Drug MOA Effects/clinical use
Phenoxybenza Noncompetitive, irreversible Long duration of action (12-24 hrs)
mine inhibitor of alpha receptors SEs: blocks 5-HT, ACh, and histamine
receptors
Clinical use: pheochromocytoma, severe HTN,
Raynaud’s syndrome
Phentolamine Competitive, reversible Use: HTN, pheochromocytoma, HTN crisis after
antagonist withdrawal of clonidine or tyramine+MAO
inhibitors
Prazosin Antagonist of alpha 1 Lowers BP, reduces preload and afterload
receptors Use: congestive heart failure
Doxazosin Antagonist of alpha 1 Increase in half-life and duration of action over
receptors prozosin
Tamsulosin Antagonist of alpha 1A Benign prostate hyperplasia
receptors on prostate gland

2. Beta Blockers
• Commonly used to treat: HTN, angina, irregular heart rythms, prevention of secondary MI,
migraine, tremors, alcohol withdrawal, anxiety, glaucoma
• Prototype drug: propranolol
o Effects: only exerts profound effects when the SS control is elevated  decreased
HR/CO, increase TPR, ↓ renin secretion, ↓ effects of hyperthyroidism, ↓ intraocular
pressure in glaucoma by decreasing aqueous humor volume, ↓ anxiety
o Contraindications:
 Asthmatic patients
 Can worsen heart failure, Raynaud’s syndrome, DM
 Should never be used with calcium channel blockers  can lead to AV block
 Must be tapered! Quick withdrawal can cause MI
Non-selective Beta- Propranolo, carteolol, levobunolol, nadolol, pindolol, timolol, penbutolol
blockers
Selective for beta 1 Acebutolol, atenolol, betaxolol, esmolol, metoprolol
New beta 1 blocker Bystolic

3. Alpha and beta blockers

Labetelol Blocks beta:alpha receptors competitively in a 3:1 Lower TPR without a major
(oral), 7:1 (IV) ratio change in cardiac output
Little action of presynaptic alpha 2 receptors
Blocks NET Use: primary HTN, HTN with
Good membrane stabilizing action angina, postoperative
management of pts with
pheocromocytoma