hubio 543 september 26, 2007 neil m. nathanson k-536a, hsb 3-9457 nathanso@u.washington.edu...

HuBio 543September 26, 2007

Neil M. NathansonK-536A, HSB3-9457nathanso@u.washington.edu 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