HuBio 543
September 26, 2007
Neil M. Nathanson
K-536A, HSB
3-9457
nathanso@u.washington.edu
Adrenergic Agonists &Other Sympathomimetics
CLASSES OF SYMPATHOMIMETICS
Direct-acting
Albuterol
Dobutamine
Dopamine
Epinephrine
Fendolopam
Isoproterenol
Norepinephrine
Phenylephrine
Ritodrine
Salmeterol
Terbutaline
Mixed-acting
Ephedrine
Indirect-acting
Amphetamine
Tyramine
Reminder: Subtypes of Adrenergic Receptors
a: EPI > NOR >>ISO
ß: ISO > EPI > NE
a1: contraction of smooth muscle (incl. VSM)
a2: presynaptic receptors ( decrease NE release)
ß1: in heart and juxtaglomerular cells
(and some fat cells)
ß2: relaxation of smooth muscle
ß3: some fat cells
NOTE ON ß2: (1) mediate relaxation of skeletal muscle vasculature
(2) P’cologically administered NE is not effective
The Ugly Truth About Epinephrine
EPINEPHRINE: MORE POTENT AT ß2 THAN AT a1
Therefore: you would predict that low doses of EPI
preferentially activate ß2 receptors over a1 receptors
Low doses of EPI: preferentially activate ß2 receptors in
skeletal muscle vasculature: cause vasodilation, leading to
a decrease in total peripheral resistance (TPR)
High doses of EPI: activate both ß2 and a1 receptors:
a1
response predominates, resulting in vasoconstriction, which
causes an increase in total peripheral resistance (TPR)
Effects of Epinephrine on the Cardiovascular System
Drug
Action
Stimulate
ß-AdR
Stimulate
ß2-AdR
(preferentially
over a1-AdR)
Direct
Effect
Increase rate
and force
Vasodilation
TPR
Reflex
Effect
-----
-----
Result
Cardiac
output,
HR,
Systolic
pressure
Diastolic
pressure
Slow IV administration in humans
(10 µg/min)
EPI
(10 µg/min)
ISO
(10 µg/min)
DA
(0.5 µg/min)
100
50
180
120
60
Peripheral
Resistance
BP (mm. Hg) Pulse rate
NE
15 min
15 min
15 min
15 min
Effects of agonists on cardiovascular function
(slow IV administration)
EPI
TPR
BP
HR
NE
ISO
DA
PHEN.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
“In the Corner With the Gladiators: Trying Out the Life
of the Cut Man” by Harry Hurt, III NYT, 8/26/07
Necrosis Following Extravasation of Epinephrine
Effects of Norepinephrine on the Cardiovascular System
Drug
Action
Strongly
stimulate
ß-AdR
Stimulate
a1-AdR
Direct
Effect
(Increase rate
and force)
Vasoconstriction
TPR
Reflex
Effect
HR
Result
Cardiac
output,
HR,
Diastolic
pressure
Systolic
pressure
Slow IV administration in humans
(10 µg/min)
EPI
(10 µg/min)
ISO
(10 µg/min)
DA
(0.5 µg/min)
100
50
180
120
60
Peripheral
Resistance
BP (mm. Hg) Pulse rate
NE
15 min
15 min
15 min
15 min
Effects of agonists on cardiovascular function
(slow IV administration)
EPI
TPR
BP
HR
NE
ISO
DA
PHEN.
Effects of Isoproterenol on the Cardiovascular System
Drug
Action
Stimulate
ß-AdR
Stimulate
ß2-AdR
Direct
Effect
Increase rate
and force
Much vasodilation
TPR
Reflex
Effect
Result
HR,
Force
Cardiac
output,
HR,
Systolic
pressure
-----
Diastolic
pressure
Slow IV administration in humans
(10 µg/min)
EPI
(10 µg/min)
ISO
(10 µg/min)
DA
(0.5 µg/min)
100
50
180
120
60
Peripheral
Resistance
BP (mm. Hg) Pulse rate
NE
15 min
15 min
15 min
15 min
Effects of agonists on cardiovascular function
(slow IV administration)
EPI
TPR
BP
HR
NE
ISO
DA
PHEN.
DOPAMINE
D1 > ß > a1
Can activate: (1) vasodilatory dopamine (D1) receptors
in renal, mesenteric, and coronary
vascular beds
(2) beta receptors in heart (greater effect
on contractile force that rate)
(3) stimulates NE release from nerve
terminals (contributes to cardiac effects)
(4) high doses can activate vascular
a1 receptors
(10 µg/min)
EPI
(10 µg/min)
ISO
(10 µg/min)
DA
(0.5 µg/min)
100
50
180
120
60
Peripheral
Resistance
BP (mm. Hg) Pulse rate
NE
15 min
15 min
15 min
15 min
Effects of agonists on cardiovascular function
(slow IV administration)
EPI
TPR
BP
HR
NE
ISO
DA
PHEN.
Effects of Phenylephrine on the Cardiovascular System
Drug
Action
------(No Effect)
Stimulate
a1-AdR
Direct
Effect
(No Effect)
Vasoconstriction
TPR
Reflex
Effect
Result
HR
HR
Diastolic
pressure
Systolic
pressure
Effects of agonists on cardiovascular function
(slow IV administration)
EPI
TPR
BP
HR
NE
ISO
DA
PHEN.
+ phenylephrine
BP
mm Hg.
200
50
Symp.
Nerve act.
Vagus
Nerve act
100
HR
bpm
40
0 Time (min) 1.0
100
0
Pulse Interval (msec.)
BP, mm Hg.
200
Sec after phenylephrine
30
10
20
1200
1000
800
130
140
110 120
Systolic Pressure (mm Hg.)
ß2- Adrenergic Agonists
Albuterol
Ritodrine
Terbutaline
Salmeterol
100
% reduction of
intraluminal 50
pressure
0
100
% increase
50
in rate
ISO
Tracheal Muscle
ALB
Cardiac
Muscle
(Rate)
0
100 Cardiac
% increase
in force of 50 Muscle
(Force)
contraction
0
ISO
ALB
ISO
0.0001 0.001 0. 01 0. 1
Concentration (µg/ml)
ALB
1
10
Time Course of Bronchodilation Produced
by Albuterol and Salmeterol
SALMETEROL
FEV1
ALBUTEROL
PLACEBO
FIRST DOSE
0
3
SECOND DOSE
6
Time (Hours)
9
12
EFFECTS OF ISOPROTERENOL & ALBUTEROL IN HUMANS
90
ISOPROTERENOL
% Increase Over Basal Value
Pulse Rate
60
FEV1.0
30
10
50
ALBUTEROL
FEV1.0
30
10
Pulse Rate
DOSE (IV)
“ß1- Adrenergic Agonists”
Dobutamine
One isomer is ß1 agonist and a1 agonist
Other isomer is ß1 agonist (and apparently weak a1 antagonist)
Increases contractile force, little effect on heart rate or TPR
Used to increase cardiac output (e.g., CHF)
Why does dobutamine have little effect on HR and TPR?
1. Human atria: 40- 50% ß1; human ventricle: 7085%ß1
2. Little or no ß2- mediated vasodilation, so no reflex
tachycardia
3. a1 agonist activity may also contribute to direct
stimulation of ventricles and lack of vasodilation
Fenoldopam
• Dopamine D1 receptor agonist
• IV administration causes rapid vasodilation
• Used for emergency management of severe
hypertension
IV Administration of Fenoldopam
Patients with Postcardiac Surgery Hypertension
Heart Rate (bpm)
Pressure (mm Hg)
190
Systolic BP
140
90
40
Heart Rate
Diastolic BP
0
100
200
300
Time (minutes)
400
Indirect-acting sympathomimetics
NE
NE
NE
NE
NE
NE
NE
Re-Up
NE
TYRAMINE
AMPHETAMINE
Cocaine blocks vasopressor response to tyramine
and potentiates response to norepinephrine
BP
+ Tyramine
+ Norepinephrine
Pretreat with Cocaine:
BP
+ Tyramine
+ Norepinephrine
Cocaine potentiates sympathetic transmission
(and effects of NE administration)
NE
NE
NE
NE
NE
NE
NE
NE
NE
Re-Up
NE
NE
NE
NE
X
Re-Up
NE
NE uptake blocked by cocaine
Normal uptake of NE
Effects of epinephrine and ephedrine on blood pressure in dog
BP (mm. Hg)
BP (mm. Hg)
160
80
EPINEPHRINE
0
240
160
80
EPHEDRINE
0
EPHEDRI NE TACHYPHYLAXIS IN THE DOG
BP
1 min.
Ephedrine (3 mg/kg) administered, every 10 min