Date post: | 14-Jan-2016 |
Category: |
Documents |
Upload: | john-farmer |
View: | 226 times |
Download: | 2 times |
HuBio 543September 26, 2007
Neil M. NathansonK-536A, [email protected] Adrenergic Agonists &Other Sympathomimetics
CLASSES OF SYMPATHOMIMETICS
Direct-acting Indirect-actingMixed-actingAlbuterolDobutamine DopamineEpinephrineFendolopamIsoproterenolNorepinephrinePhenylephrineRitodrineSalmeterolTerbutaline
Ephedrine
AmphetamineTyramine
Reminder: Subtypes of Adrenergic Receptors
: EPI > NOR >>ISOß: ISO > EPI > NE
1: contraction of smooth muscle (incl. VSM)2: presynaptic receptors ( decrease NE release)ß1: in heart and juxtaglomerular cells (and some fat cells)ß2: relaxation of smooth muscle ß3: some fat cellsNOTE ON ß2: (1) mediate relaxation of skeletal muscle vasculature
(2) P’cologically administered NE is not effective
EPINEPHRINE: MORE POTENT AT ß2 THAN AT 1
The Ugly Truth About Epinephrine
Therefore: you would predict that low doses of EPI preferentially activate ß2 receptors over 1 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 1 receptors: 1 response predominates, resulting in vasoconstriction, which causes an increase in total peripheral resistance (TPR)
Effects of Epinephrine on the Cardiovascular System
Drug Direct ReflexAction Effect Effect Result
Stimulateß-AdR
Increase rateand force -----
Cardiac output, HR, Systolic pressure
Stimulateß2-AdR(preferentiallyover 1-AdR)
Vaso-dilation --
---
TPR
Diastolic pressure
NE EPI ISO DA
Pulse rate
BP (mm. Hg)
60
120
180
50
100
Periphe
ral
Resista
nce
15 min15 min15 min
15 min
(10 µg/min) (10 µg/min) (10 µg/min) (0.5 µg/min)
Slow IV administration in humans
NEEPI ISO DA PHEN.
HR
BP
TPR
Effects of agonists on cardiovascular function (slow IV administration)
QuickTime™ and aTIFF (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 Direct ReflexAction Effect Effect Result
Stronglystimulateß-AdR
(Increase rateand force) HR
Cardiac output, HR,
Stimulate1-AdR
Vaso-constriction
TPR
Diastolic pressureSystolic pressure
NE EPI ISO DA
Pulse rate
BP (mm. Hg)
60
120
180
50
100
Periphe
ral
Resista
nce
15 min15 min15 min
15 min
(10 µg/min) (10 µg/min) (10 µg/min) (0.5 µg/min)
Slow IV administration in humans
NEEPI ISO DA PHEN.
HR
BP
TPR
Effects of agonists on cardiovascular function (slow IV administration)
Effects of Isoproterenol on the Cardiovascular System
Drug Direct ReflexAction Effect Effect Result
Stimulateß-AdR
Increase rateand force
Cardiac output, HR, Systolic pressure
Stimulateß2-AdR
Much vaso-dilation --
---
TPR
Diastolic pressure
HR, Force
NE EPI ISO DA
Pulse rate
BP (mm. Hg)
60
120
180
50
100
Periphe
ral
Resista
nce
15 min15 min15 min
15 min
(10 µg/min) (10 µg/min) (10 µg/min) (0.5 µg/min)
Slow IV administration in humans
NEEPI ISO DA PHEN.
HR
BP
TPR
Effects of agonists on cardiovascular function (slow IV administration)
DOPAMINE
D1 > ß > 1
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 1 receptors
NE EPI ISO DAPulse rate
BP (mm. Hg)
60
120
180
50
100
Periphe
ral
Resista
nce
15 min15 min15 min
15 min
(10 µg/min) (10 µg/min) (10 µg/min) (0.5 µg/min)
NEEPI ISO DA PHEN.
HR
BP
TPR
Effects of agonists on cardiovascular function (slow IV administration)
Effects of Phenylephrine on the Cardiovascular System
Drug Direct ReflexAction Effect Effect Result
-------(No Effect)
(No Effect)HR HR
Stimulate1-AdR
Vaso-constriction
TPR
Diastolic pressureSystolic pressure
NEEPI ISO DA PHEN.
HR
BP
TPR
Effects of agonists on cardiovascular function (slow IV administration)
200
50
BPmm Hg.
Symp.Nerve act.
VagusNerve act
HRbpm
100
40 0 1.0Time (min)
+ phenylephrine
200
100
01200
1000
800
BP, mm Hg.
Pulse Interval (msec.)
30
20
10Sec after phenylephrine
120110 130 140
Systolic Pressure (mm Hg.)
ß2- Adrenergic Agonists
AlbuterolRitodrineTerbutalineSalmeterol
100
50
0
% reduction of intraluminal pressure%
increase in rate
% increase in force of contraction
Tracheal Muscle
Cardiac Muscle (Rate)
Cardiac Muscle (Force)
0.0001 0. 10. 01 100.001 1Concentration (µg/ml)
100
50
0
10050
0
ISO
ISO
ISO
ALB
ALB
ALB
SALMETEROL
ALBUTEROL
PLACEBO
FIRST DOSE SECOND DOSE
0 3 6 9 12
FEV1
Time (Hours)
Time Course of Bronchodilation Produced by Albuterol and Salmeterol
90
60
30
% Increase Over Basal
Value
10
50
30
10
ISOPROTERENOL
ALBUTEROL
Pulse Rate
FEV1.0
Pulse Rate
FEV1.0
DOSE (IV)
EFFECTS OF ISOPROTERENOL & ALBUTEROL IN HUMANS
“ß1- Adrenergic Agonists”
One isomer is ß1 agonist and 1 agonistOther isomer is ß1 agonist (and apparently weak 1 antagonist) Increases contractile force, little effect on heart rate or TPRUsed 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: 70- 85%ß1
2. Little or no ß2- mediated vasodilation, so no reflex tachycardia
3. 1 agonist activity may also contribute to direct stimulation of ventricles and lack of vasodilation
Dobutamine
• Dopamine D1 receptor agonist
• IV administration causes rapid vasodilation
• Used for emergency management of severe hypertension
Fenoldopam
400300200100040
90
140
190
IV Administration of Fenoldopam Patients with Postcardiac Surgery Hypertension
Time (minutes)
Pressure (mm Hg)
Heart Rate (bpm)
Diastolic BP
Heart Rate
Systolic BP
NE
NE
NE
Re-Up
NE
Indirect-acting sympathomimetics
NE NENENE
TYRAMINEAMPHETAMINE
+ Tyramine + Norepinephrine
Pretreat with Cocaine:
Cocaine blocks vasopressor response to tyramine and potentiates response to norepinephrine
+ Norepinephrine+ Tyramine
BP
BP
NE
NE
NE
Re-Up
NE
NENE
NE
NE
NE
Re-Up
NE
NE NENENE XNormal uptake of NE
NE uptake blocked by cocaine
Cocaine potentiates sympathetic transmission (and effects of NE
administration)
BP (mm. Hg)
160
80
0
160
80
0
240
EPINEPHRINE
EPHEDRINE
Effects of epinephrine and ephedrine on blood pressure in dog
BP (mm. Hg)
1 min.
EPHEDRINE TACHYPHYLAXIS IN THE DOG
Ephedrine (3 mg/kg) administered, every 10 min
BP