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AUTONOMIC PHARMACOLOGY | ADRENERGIC AGONISTS

Autonomic Pharmacology | Adrenergic Agonists Medical Editor: Ana, Jude

I) ADRENERGIC NEURONS & RECEPTORS
(A) NOREPINEPHRINE
(B) EPINEPHRINE
TYPES OF AGONISTS
II) BETA-ADRENERGIC AGONISTS
(A) BETA-1 AGONISTS
(B) BETA-1+2 AGONIST
(C) BETA-2 AGONIST
(D) BETA-3 AGONIST
OUTLINE
III) ALPHA+BETA AGONIST (D) SUMMARY
(A) NOREPINEPHRINE V) APPENDIX
(B) EPINEPHRINE + DOPAMINE VI) REVIEW QUESTIONS
IV) GRAPHICAL REPRESENTATIONS OF VII) REFERENCES
CVS EFFECTS OF NOREPINEPHRINE,
EPINEPHRINE, & ISOPROTERENOL
(A) NOREPINEPHRINE
(B) EPINEPHRINE
(C) ISOPROTERENOL

I) ADRENERGIC NEURONS & RECEPTORS

(A) NOREPINEPHRINE
(1) Synthesis
Tyrosine enters the neuron through a Na channel
cotransport
Conversion from tyrosine to L-DOPA
L-DOPA gets converted to Dopamine
Dopamine gets converted to Norepinephrine inside
intracellular vesicles
Action potential activates voltage gated Ca++ channels

(2) Receptors

(i) 1 receptor
(iii) 1 receptor
o Works through the Phospholipase C pathway
o Works through stimulation of the Adenylate cyclase
▪ Increases IP3 & DAG
pathway on the cardiac muscle
• Increases intracellular Ca++ in smooth muscle
▪ Increases cAMP
cells
• Increases intracellular Ca++

(i) 2 & 3 receptors

(ii) 2 receptor
o Works through stimulation of the Adenylate cyclase
o Works through the Adenylate cyclase pathway pathway on the cardiac muscle
▪ Inhibits cAMP ▪ Increases cAMP
• Decreases release of neurotransmitters and • Increases intracellular Ca++
hormones

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(3) Metabolism & recycling

(i) COMT

(ii) Reuptake

a. Enter the vesicles to be released into the

synaptic cleft again.
b. Get metabolized by the MAO enzymes
inside the mitochondria and be broken
down into inactive metabolites.

(B) EPINEPHRINE

Epinephrine and norepinephrine are produced by the

adrenal medulla and released after sympathetic stimuli. (i) Difference between NE & EPI

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TYPES OF AGONISTS
1) Direct agonists: Bind directly to the adrenergic receptors
to stimulate its effects.

2) Indirect agonists: Work through increasing NE

accumulation by.
a. Inhibiting the COMT enzymes
b. Inhibiting the NE uptake transporters (NERT)
c. Inhibiting the MAO enzymes
3) Mixed agonists: Bind to adrenergic receptors and
increase NE accumulation.

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II) ADRENERGIC TARGET ORGANS EFFECTS

1 receptor 2 receptor 1 receptor 2 receptor 3 receptor

Cardiac muscle - - +++ + +
Skeletal muscle - - - ++ -
Vascular smooth muscle +++ + - ++ +
Bronchial smooth muscle - - - ++ -
Liver + - - +++ -
Adipose tissue + + + - ++
CNS ++ ++ ++ ++ -
Bladder neck / prostate +++ + - - +++

(A) 1 RECEPTORS (B) 2 RECEPTORS

(i) Smooth muscle contraction (i) Pre-synaptic nerve terminal

o Located on the pre-synaptic nerve terminal

a. Decrease of blood flow

b. Increase of blood pressure

REMEMBER
BP= SVR X Cardiac Output

(ii) Sphincters contraction

i. Urethra
ii. Rectus and anus
(ii) Pancreatic  cells

(iii) Dilator Pupillae contraction

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 (C) 1 RECEPTORS

Located on two areas of the heart and they increase CO (iii) Juxtaglomerular cells
through two different ways

(i) SA and AV node

o Increase conduction
o Vasoconstriction
o Increase ADH

(ii) Cardiac muscle contraction

o Increase contractility

(D) 2 RECEPTORS
(i) Vasodilation
o Vessels supplying the heart and skeletal muscles

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(ii) Bronchial smooth muscle

(iv) Uterus

(iii) Pancreatic  cells

(E) 3 RECEPTORS
(i) Adipose tissue

(ii) Detrusor muscle contraction

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III) ALPHA 1 AGONISTS IV) ALPHA 2 AGONISTS

(1) On arteries → Increase of BP

(A) CLONIDINE

(i) Effects on the CNS

(2) On veins → Increase venous return → Increase BP o Inhibit the release of NE

o Systemic effects

(B) PHENYLEPHRINE

(i) Blood pressure effects

(ii) Effects on the dilator pupilae

(iii) Effect on the nasal cavity vessels

(B) ALPHA-METYLDOPA

Phenylephrine adverse effects: Reflex bradycardia

(C) MIDODRINE
▪ Very good at improving venous return

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 V) BETA-ADRENERGIC AGONISTS
(A) BETA-1 AGONISTS (B) BETA-1+2 AGONIST

Figure 1. Effects of β1 agonists. Figure 2. Effects of β1+2 agonists (i.e. isoproterenol).

Overall effects include: (1) Isoproterenol
o Work on the nodal system (SA, AV nodes) → ↑HR
o Work on contractile cells → ↑contractility → ↑CO Equal affinity for β1 and β2 (β1=β2)

(1) Dobutamine (i) Β1 effects:

Primary β1 agonist ↑HR
Increases HR o Indicated in bradycardia (primary indication)
o Indicated in symptomatic bradycardia ↑contractility → ↑CO
Increases CO to get blood out of heart
o Indicated in acute heart failure or cardiogenic
(ii) Β2 effects:
shock Vasodilates blood vessels → ↓SVR → ↓BP
Adverse effects: o Even though it increases CO, it CANNOT be used in
o Tachycardia/tachyarrhythmias patients with AHF and cardiogenic shock because it
o Exacerbates angina AfraTafreeh.com can ↓BP especially if patients are already hypotensive
▪ Squeezing heart → ↑energy demands; therefore in Relaxes bronchial smooth muscle (bronchodilate)
CAD where ↓oxygen, it can exacerbate angina o Rarely used in asthma
▪ Used in stress test Adverse effects: Tachycardia

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(C) BETA-2 AGONIST (D) BETA-3 AGONIST

Figure 4. Effects of β3 agonists.

(1) Mirabegron
Β3 receptors inhibit the contraction of the detrusor muscle
→ inhibit urination
Indicated for patients with overactive bladder or urinary
urgency

Figure 3. Effects of β2 agonists.

(1) Respiratory Effects
Great bronchodilator
o Good in asthma and COPD

(i) Albuterol
Short-acting β2 agonist (SABA)
Acute treatment in asthma and COPD

(ii) Salmeterol, Formoterol

Long-acting β2 agonist (LABA)
Chronic treatment of COPD and/or asthma

(iii) Terbutaline
Short-acting β2 agonist (48 hrs)
Better used in severe asthma
(2) Uterine Effects
Good for premature labor, as a tocolytic

(i) Terbutaline
Helps in delay of preterm labor
(3) Na-K-ATPase
Increase and stimulates the Na-K-ATPase
o Pumps K into the cell and Na out of the cell

(i) Albuterol
Indicated in hyperkalemia since we want excess K to
shift into the cell
Adverse effect: Drop in K
(4) Other Effects
↑glucose in the blood
o !! Watch out for hyperglycemia
↑afferent and efferent signals to the muscle spindles →
tremors

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 VI) ALPHA+BETA AGONIST

(A) NOREPINEPHRINE (B) EPINEPHRINE + DOPAMINE

Figure 5. Effects of norepinephrine.

⍺>β
o Primarily an ⍺ agonist; β activity at higher doses Figure 6. Effects of epinephrine and dopamine.
o Affects the nodal system at higher doses Epinephrine: β > ⍺
Dopamine: D (dopamine receptor) > β > ⍺
(1) Β1 effects (at higher doses):
(1) B1 effects:
↑↑HR
↑↑contractility → ↑↑CO ↑↑HR → ↑↑CO
o Indicated in bradycardia and for epinephrine, cardiac
(2) A1 effects:
arrest
Constriction of the blood vessels → ↑SVR → ↑DBP (just ↑↑contractility → ↑↑CO
like phenylephrine) o Indicated in AHF and cardiogenic shock
Squeezing more blood into the heart → ↑venous return →
↑preload → ↑SV → ↑CO → ↑SBP AfraTafreeh.com
In the blood vessels, there are ⍺1 and β2 receptors. At
low doses, epinephrine prefers the β2 receptor whereas
Indicated in cases of hypotension (shock, most
commonly in septic shock) at higher doses, it prefers ⍺1 receptors.
o Low doses:
(3) Reflex Bradycardia ▪ ↓⍺1 receptors → ↓SVR → ↓BP
Vasoconstriction → (+) barorceptors → send signals to ▪ ↑β2 receptors → ↓SVR → ↓BP
the CNS → vagus nerve → releases acetylcholine → o High doses:
reflex bradycardia ▪ ↑⍺1 receptors → ↑SVR → ↑BP
o When combined with the mild ↑HR by the β1 ▪ Only at high doses do epinephrine and
receptors → ↓HR overall dopamine have effects on BP
▪ Indicated in hypotension (septic, cardiogenic)
(4) Normalization of CO
(2) B2 effects:
Vasoconstriction → ↑SVR → ↑afterload → ↓SV → ↓CO
o ↓CO brought by the ⍺1 effect is normalized by the Bronchodilation
slight ↑CO by β1 Can be used in asthma, COPD, and anaphylactic shock
(particularly epinephrine)
In clinical settings, Zach has not yet seen a patient o Dopamine CANNOT be used in these conditions as it
who experienced reflex bradycardia or a drop in CO does not have enough β2 agonist activity as
but these things are to consider for the Boards. compared to epinephrine

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VII) GRAPHICAL REPRESENTATIONS OF CVS EFFECTS OF NOREPINEPHRINE, EPINEPHRINE, & ISOPROTERENOL

Comparing the vascular effects of norepinephrine, epinephrine, and isoproterenol
Determines how these agonists affect the following parameters: HR, BP, SVR, CO, MAP, and SVR

(A) NOREPINEPHRINE (B) EPINEPHRINE

Figure 7. Graphical representation of parameters in Figure 8. Graphical representation of parameters in

norepinephrine. epinephrine.

Recall: ⍺ > β Recall: β > ⍺

Table 1. Effects of norepinephrine on CVS parameters. Table 2. Effects of epinephrine on CVS parameters.

REMARKS EFFECT REMARKS

EFFECT
Reflex bradycardia d/t ⍺1 receptor Works in the conduction system through
Deflection points d/t ↑β1 receptors the β1 receptors
↓HR ↑↑HR
Theoretically, it is similar to phenylephrine o No reflex bradycardia because there
are no ⍺1 receptors
↑↑SBP d/t the following:
o ⍺1 receptors on the arteries and veins ↑SBP d/t ↑contractility from β1 receptors
o β1 receptors → ↑CO → ↑SBP
↑↑SBP o SBP is dependent on afterload,
↑↑DBP DBP is dependent upon SVR and blood ↑SBP preload, and contractility
volume (BV) ↓DBP
o ⍺1 receptors increases DBP ↓DBP because of β2 > ⍺1
o β2 causes vasodilation
High SVR d/t ⍺1 receptors o ⍺1 causes vasoconstriction
o ⍺1: squeezes vessels → ↑SVR
↑SVR o There is correlation between SVR and ↓SVR Correlated with DBP
DBP
↑↑CO Due to β1 receptor activity
β1: ↑CO
No effect ⍺1: ↑afterload → ↓CO Because of ↓DBP and ↑PP → evens out
on CO Both of these cancel out → evens out the leading to slight increase in MAP
effect on CO ↑MAP Significant increase IF there is ⍺1
receptor activity in higher doses
Dependent on DBP, which is dependent
on SVR ↑PP Due to ↑SBP and ↓DBP
o ↑↑DBP → ↑↑SVR → ↑↑MAP
↑↑MAP 2 1
𝑀𝐴𝑃 = 3 (𝐷𝐵𝑃) + 3 (𝑆𝐵𝑃)
1
𝑀𝐴𝑃 = 𝐷𝐵𝑃 + 3 (𝑃𝑃)

Pulse pressure is the difference between

SBP and DBP
↑PP Slight increase in PP because both SBP
and DBP increase

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 (C) ISOPROTERENOL (D) SUMMARY
Table 4. Summary of the effects of norepinephrine,
epinephrine, and isoproterenol on CVS parameters.
NE EPI IPT

HR ↓ ↑↑ ↑↑

SBP ↑↑ ↑ ↑↑
DBP ↑↑ ↓ ↓↓

SVR ↑ ↓ ↓↓

CO NE ↑↑ ↑↑

MAP ↑↑ ↑ ↓

PP ↑ ↑ ↑↑
*NE: norepinephrine
*EPI: epinephrine
Figure 9. Graphical representation of CVS parameters in *IPT: isoproterenol
isoproterenol. *NE: no effect

Recall: β1 = β2; no ⍺-receptor activity

Table 3. Effects of isoproterenol on CVS parameters.

EFFECT REMARKS

↑↑HR D/t β1 receptor activity

↑↑SBP d/t ↑↑contractility from β1 receptor
↑↑SBP ↓↓DBP d/t intense vasodilation from β2
↓↓DBP receptor activity → ↓↓SVR
↓↓SVR Due to ↓↓SVR from β2 receptor activity
Dependent upon HR, CO, preload, and
↑↑CO contractility
↑↑contractility + ↑↑HR → ↑↑CO
Dependent on DBP, which is a more
↓MAP important factor
↓↓DBP with ↑PP
↑↑PP D/t ↑↑SBP and ↓↓DBP

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VIII) APPENDIX

(1) ADRENERGIC TARGET ORGANS EFFECTS

1 receptor 2 receptor 1 receptor 2 receptor 3 receptor

Cardiac muscle - - +++ + +
Skeletal muscle - - - ++ -
Vascular smooth muscle +++ + - ++ +
Bronchial smooth muscle - - - ++ -
Liver + - - +++ -
Adipose tissue + + + - ++
CNS ++ ++ ++ ++ -
Bladder neck / prostate +++ + - - +++

ADVERSE
DRUG DRUG EFFECTS INDICATIONS REMARKS
EFFECTS
CLASS

β-adrenergic agonists

Works on the nodal system ↑HR: symptomatic

β1 → ↑HR bradycardia Tachycardia
Dobutamine
agonists Works on contractile cells → ↑CO: AHF or cardiogenic ↑angina
↑contractility → ↑CO shock

CANNOT be used in
β1 = β2
patients with AHF and
β1: ↑HR and ↑CO
cardiogenic shock
β1+2 β2: Bradycardia (primary
Isoproterenol Tachycardia because it can ↓BP
agonists o ↓BP through indication) especially if patients
vasodilation → ↓SVR
are already
o Bronchodilate
hypotensive

Respiratory: bronchodilator Asthma and COPD:

Uterine: tocolytic o Albuterol: acute
Others: treatment
o (+) Na-K-ATPase o Salmeterol, formoterol:
Albuterol (SABA) activity = pumps K into Drop in K →
chronic treatment
β2 Salmeterol, hypokalemia
the cell and Na out of o Terbutaline: acute
agonists Formoterol (LABA) Hyperglycemia
the cell treatment in severe
Terbutaline (SABA) Tremors
o ↑serum glucose asthma
o ↑afferent and efferent Terbutaline: tocolytic; delay
signals to the muscle premature labor
spindles Albuterol: hyperkalemia

β3 (-) contraction of the detrusor Overactive bladder or urinary

Mirabegron
agonists muscle → ↓urination urgency

Combined ⍺ and β agonist

(⍺ > β)
β1: ↑↑HR, ↑↑contractility (=
Hypotension Reflex bradycardia
Norepinephrine ↑↑CO)
Shock (septic, in particular) Normalization of CO
⍺1: ↑DBP through
vasoconstriction, ↑SBP

Only in high doses

do epi and
β > ⍺ (epinephrine) Bradycardia dopamine have BP
⍺+β
D > β > ⍺ (dopamine) Cardiac arrest effects
agonists
β1: ↑↑HR, ↑↑contractility (epinephrine) Dopamine CANNOT
Epinephrine and (=CO) AHF and cardiogenic shock be used in asthma,
Dopamine o Low doses: ↓⍺1 = ↓BP; Asthma, COPD, COPD, and
↑β2 = ↓BP anaphylactic shock anaphylaxis
o High doses: ↑⍺1 = ↑BP (epinephrine) because it does not
β2: bronchodilation Hypotension (high doses) have enough β2
agonist activity vs
epinephrine.

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 IX) REVIEW QUESTIONS
4) Which of the following is correct regarding
adrenergic neurotransmission?
a) Norepinephrine is the major neurotransmitter
released from sympathetic nerve terminals.
b) Norepinephrine is mainly released from the adrenal
glands.
c) TCA and cocaine prevent the release from
norepinephrine from the nerve terminals.
d) Monoamine oxidase (MAO) converts dopamine to
norepinephrine in the nerve terminal.
5) Which of the following adrenergic drugs is used in
the treatment of overactive bladder?
a) Epinephrine
b) Dobutamine
c) Phenylephrine
d) Mirabegron
6) Which of the following classes of adrenergic agents
has utility in the management of hypertension?
a) ⍺1 agonist
b) ⍺2 agonist
c) β1 agonist
d) β3 agonist
7) Which of the following is correct regarding
responses mediated by the adrenergic receptors?
a) Stimulation of alpha1 receptors inc BP
b) Stimulation of sympathetic presynaptic alpha2
receptors inc NE release
c) Stimulation of B2 receptors inc HR (tachycardia)
d) Stimulation of B2 receptors causes
bronchoconstriction
8) An asthma patient was given a non-selective beta-
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agonist to relieve bronchoconstriction. Which
adverse effect would you expect in this patient?
a) Bradycardia
b) Tachycardia
c) Hypotension
d) Worsening bronchoconstriction
9) A 22-year-old male is brought to the ER with
suspected cocaine overdose. Which of the following
symptoms is most likely in this patient?
a) Hypertension
b) Bronchoconstriction
c) Bradycardia
d) Miosis (pupil constriction)

X) REFERENCES

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XI) ANSWERS TO QUESTIONS

QUESTION ANSWER

1) Sarin is a nerve gas that is an organophosphate C. Atropine

cholinesterase inhibitor. Which agent could be used
as an antidote to sarin poisoning? Organophosphate cholinesterase inhibitor are irreversible
a. Pilocarpine drugs.
b. Carbachol
c. Atropine Cholinesterase inhibitors are going to increase ACh in the
d. Physostigmine synapse which can lead to cholinergic crisis.This drug blocks
the effect of ACh at different types of muscarinic receptors.

2) A patient with asthma was prescribed a β2 agonist for B. Ipratropium

acute relief of bronchospasm, but did not respond to
treatment. Which drug is the most likely next option Β2 agonists are supposed to work in the bronchial smooth
for this patient? muscle leading to bronchodilation. If beta-2 agonists do not
a. Benztropine work, other drugs like a muscarinic antagonist against to MR-3
b. Ipratropium can work in bronchodilation. An example would be
c. Oxybutynin ipratropium.
d. Physostigmine

3) A 50-year-old male who is noncompliant with C. Tiotropium

medications was recently diagnosed with COPD. His
physician would like to prescribed an inhaled Ipratropium is for acute relief of bronchoconstriction. For this
anticholinergic that is dosed once or twice daily. case, a longer acting muscarinic antagonist dosed once or
Which drug is most appropriate for this patient? twice daily therefore tiotropium.
a. Atropine
a. Ipratropium
b. Tiotropium
c. Trospium

4) Which is the most effective drug for motion sickness C. Scopolamine

for a person planning to go on a cruise?
a. Atropine Remember that the vestibular function is connected to the
b. Fesoterodine emetic center in the medulla that has a lot of muscarinic
c. Scopolamine receptors. A drug that can block the muscarinic receptors in
d. Tropicamide the emetic center is scopolamine.

5) Which drug is useful in treating sinus bradycardia? A. Atropine

a. Atropine
a. Cisatracurium Sinus bradycardia is usually due to the vagus nerve that
b. Neostigmine releases too much ACh to the AV node leading to slowing
c. Succinylcholine down of heart rate. The best drug to inhibit this is atropine.

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