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HuBio 543 September 26, 2007

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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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slide1

HuBio 543September 26, 2007

Neil M. Nathanson

K-536A, HSB

3-9457

[email protected]

Adrenergic Agonists &Other Sympathomimetics

slide2

CLASSES OF SYMPATHOMIMETICS

Indirect-acting

Direct-acting

Mixed-acting

Amphetamine

Tyramine

Albuterol

Dobutamine

Dopamine

Epinephrine

Fendolopam

Isoproterenol

Norepinephrine

Phenylephrine

Ritodrine

Salmeterol

Terbutaline

Ephedrine

slide3

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

slide4

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)

slide5

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

slide6

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

slide7

NE

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)

slide8

“In the Corner With the Gladiators: Trying Out the Life of the Cut Man” by Harry Hurt, III NYT, 8/26/07

slide10

Effects of Norepinephrine on the Cardiovascular System

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

slide11

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

slide12

NE

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)

slide13

Effects of Isoproterenol on the Cardiovascular System

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

slide14

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

slide15

NE

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)

slide16

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

slide18

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

slide19

NE

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)

slide20

Effects of Phenylephrine on the Cardiovascular System

Drug Direct Reflex

Action Effect Effect Result

(No Effect)

-------

(No Effect)

HR

HR

Diastolic pressure

Stimulate

a1-AdR

Vaso-

constriction

Systolic pressure

TPR

slide21

NE

EPI

ISO

DA

PHEN.

TPR

BP

HR

Effects of agonists on cardiovascular function

(slow IV administration)

slide22

+ phenylephrine

200

BP

mm Hg.

50

Symp.

Nerve act.

Vagus

Nerve act

100

HR

bpm

40

0

1.0

Time (min)

slide23

Sec after phenylephrine

30

10

20

200

BP, mm Hg.

100

0

1200

Pulse Interval (msec.)

1000

800

130

140

120

110

Systolic Pressure (mm Hg.)

slide24

ß2- Adrenergic Agonists

Albuterol

Ritodrine

Terbutaline

Salmeterol

slide25

100

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)

slide26

Time Course of Bronchodilation Produced by Albuterol and Salmeterol

SALMETEROL

FEV1

ALBUTEROL

PLACEBO

FIRST DOSE

SECOND DOSE

12

6

0

3

9

Time (Hours)

slide27

EFFECTS OF ISOPROTERENOL & ALBUTEROL IN HUMANS

ISOPROTERENOL

90

Pulse Rate

60

FEV1.0

30

% Increase Over Basal Value

10

ALBUTEROL

50

FEV1.0

30

Pulse Rate

10

DOSE (IV)

slide28

“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: 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
  • Dopamine D1 receptor agonist
  • IV administration causes rapid vasodilation
  • Used for emergency management of severe hypertension
slide30

0

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)

slide31

NE

NE

NE

NE

NE

NE

NE

Indirect-acting sympathomimetics

NE

Re-Up

TYRAMINE

AMPHETAMINE

slide32

Cocaine blocks vasopressor response to tyramine and potentiates response to norepinephrine

BP

+ Tyramine

+ Norepinephrine

Pretreat with Cocaine:

BP

+ Tyramine

+ Norepinephrine

slide33

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

slide34

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

slide35

EPHEDRINE TACHYPHYLAXIS IN THE DOG

BP

1 min.

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

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