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HuBio 543 September 26, 2007. Neil M. Nathanson K-536A, HSB 3-9457 [email protected] Adrenergic Agonists &Other Sympathomimetics. CLASSES OF SYMPATHOMIMETICS. Indirect-acting. Direct-acting. Mixed-acting. Amphetamine Tyramine. Albuterol Dobutamine Dopamine Epinephrine

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HuBio 543September 26, 2007

Neil M. Nathanson

K-536A, HSB

3-9457

[email protected]

Adrenergic Agonists &Other Sympathomimetics


CLASSES OF SYMPATHOMIMETICS

Indirect-acting

Direct-acting

Mixed-acting

Amphetamine

Tyramine

Albuterol

Dobutamine

Dopamine

Epinephrine

Fendolopam

Isoproterenol

Norepinephrine

Phenylephrine

Ritodrine

Salmeterol

Terbutaline

Ephedrine


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 Direct Reflex

Action Effect Effect Result

Cardiac output, HR, Systolic pressure

Increase rate

and force

Stimulate

ß-AdR

-----

Stimulate

ß2-AdR

(preferentially

over a1-AdR)

Vaso-

dilation

Diastolic pressure

-----

TPR


DA

NE

EPI

ISO

(0.5 µg/min)

(10 µg/min)

(10 µg/min)

(10 µg/min)

100

Pulse rate

50

180

BP (mm. Hg)

120

60

Peripheral Resistance

15 min

15 min

15 min

15 min

Slow IV administration in humans


NE

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)


“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 the Cut Man” by Harry Hurt, III NYT, 8/26/07


Effects of Norepinephrine on the Cardiovascular System the Cut Man” by Harry Hurt, III NYT, 8/26/07

Drug Direct Reflex

Action Effect Effect Result

Cardiac output, HR,

(Increase rate

and force)

Strongly

stimulate

ß-AdR

HR

Diastolic pressure

Stimulate

a1-AdR

Vaso-

constriction

Systolic pressure

TPR


DA the Cut Man” by Harry Hurt, III NYT, 8/26/07

NE

EPI

ISO

(0.5 µg/min)

(10 µg/min)

(10 µg/min)

(10 µg/min)

100

Pulse rate

50

180

BP (mm. Hg)

120

60

Peripheral Resistance

15 min

15 min

15 min

15 min

Slow IV administration in humans


NE the Cut Man” by Harry Hurt, III NYT, 8/26/07

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)


Effects of Isoproterenol on the Cardiovascular System the Cut Man” by Harry Hurt, III NYT, 8/26/07

Drug Direct Reflex

Action Effect Effect Result

Cardiac output, HR, Systolic pressure

HR, Force

Increase rate

and force

Stimulate

ß-AdR

Stimulate

ß2-AdR

Much vaso-

dilation

Diastolic pressure

-----

TPR


DA the Cut Man” by Harry Hurt, III NYT, 8/26/07

NE

EPI

ISO

(0.5 µg/min)

(10 µg/min)

(10 µg/min)

(10 µg/min)

100

Pulse rate

50

180

BP (mm. Hg)

120

60

Peripheral Resistance

15 min

15 min

15 min

15 min

Slow IV administration in humans


NE the Cut Man” by Harry Hurt, III NYT, 8/26/07

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)


DOPAMINE the Cut Man” by Harry Hurt, III NYT, 8/26/07

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


DA the Cut Man” by Harry Hurt, III NYT, 8/26/07

NE

EPI

ISO

(0.5 µg/min)

(10 µg/min)

(10 µg/min)

(10 µg/min)

100

Pulse rate

50

180

BP (mm. Hg)

120

60

Peripheral Resistance

15 min

15 min

15 min

15 min


NE the Cut Man” by Harry Hurt, III NYT, 8/26/07

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)


Effects of Phenylephrine on the Cardiovascular System the Cut Man” by Harry Hurt, III NYT, 8/26/07

Drug Direct Reflex

Action Effect Effect Result

(No Effect)

-------

(No Effect)

HR

HR

Diastolic pressure

Stimulate

a1-AdR

Vaso-

constriction

Systolic pressure

TPR


NE the Cut Man” by Harry Hurt, III NYT, 8/26/07

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)


+ phenylephrine the Cut Man” by Harry Hurt, III NYT, 8/26/07

200

BP

mm Hg.

50

Symp.

Nerve act.

Vagus

Nerve act

100

HR

bpm

40

0

1.0

Time (min)


Sec after phenylephrine the Cut Man” by Harry Hurt, III NYT, 8/26/07

30

10

20

200

BP, mm Hg.

100

0

1200

Pulse Interval (msec.)

1000

800

130

140

120

110

Systolic Pressure (mm Hg.)


ß the Cut Man” by Harry Hurt, III NYT, 8/26/072- Adrenergic Agonists

Albuterol

Ritodrine

Terbutaline

Salmeterol


100 the Cut Man” by Harry Hurt, III NYT, 8/26/07

ISO

Tracheal Muscle

% reduction of intraluminal pressure

50

ALB

0

100

Cardiac Muscle (Rate)

ISO

% increase in rate

ALB

50

0

100

Cardiac Muscle (Force)

% increase in force of contraction

ISO

50

ALB

0

0.0001

0.001

0. 01

0. 1

1

10

Concentration (µg/ml)


Time Course of Bronchodilation Produced by Albuterol and Salmeterol

SALMETEROL

FEV1

ALBUTEROL

PLACEBO

FIRST DOSE

SECOND DOSE

12

6

0

3

9

Time (Hours)


EFFECTS OF ISOPROTERENOL & ALBUTEROL IN HUMANS Salmeterol

ISOPROTERENOL

90

Pulse Rate

60

FEV1.0

30

% Increase Over Basal Value

10

ALBUTEROL

50

FEV1.0

30

Pulse Rate

10

DOSE (IV)


“ß Salmeterol1- 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: 70- 85%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
Fenoldopam Salmeterol

  • Dopamine D1 receptor agonist

  • IV administration causes rapid vasodilation

  • Used for emergency management of severe hypertension


0 Salmeterol

100

200

300

400

IV Administration of Fenoldopam

Patients with Postcardiac Surgery Hypertension

190

Systolic BP

140

Heart Rate (bpm)

Pressure (mm Hg)

90

Heart Rate

Diastolic BP

40

Time (minutes)


NE Salmeterol

NE

NE

NE

NE

NE

NE

Indirect-acting sympathomimetics

NE

Re-Up

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

X

NE

NE

Re-Up

Re-Up

NE

NE

NE

NE

NE

NE

NE uptake blocked by cocaine

Normal uptake of NE


Effects of epinephrine and ephedrine on blood pressure in dog

160

80

BP (mm. Hg)

EPINEPHRINE

0

240

160

BP (mm. Hg)

80

EPHEDRINE

0


EPHEDRINE TACHYPHYLAXIS IN THE DOG dog

BP

1 min.

Ephedrine (3 mg/kg) administered, every 10 min


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