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HuBio 543 September 27, 2007. Neil M. Nathanson K-536A, HSB 3-9457 [email protected] Adrenergic Antagonists. Alpha- Adrenergic Antagonists. I. Non-selective alpha adrenergic receptor antagonists. A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine*. B. Noncovalent

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HuBio 543September 27, 2007

Neil M. Nathanson

K-536A, HSB

3-9457

[email protected]

Adrenergic Antagonists


Alpha- Adrenergic Antagonists

I. Non-selective alpha adrenergic receptor antagonists

A. Covalent (haloalkylamines)

Dibenamine

Phenoxybenzamine*

B. Noncovalent

Phentolamine*

Tolazoline

II. a1-selective

Doxazosin

Prazosin*

Terazosin

III. a2-selective

Yohimbine*

(* = Drug List)


CH2

N

CH2Cl

CH2

CH

CH2

O

CH3

CH2

CH2

+

N

CH

CH2

O

CH2

CH3

Covalent inactivation of a-receptor by phenoxybenzamine

Phenoxybenzamine

CH2

CH2

N

CH

CH2

O

CH2

CH3

Ethylene iminium ion

Alkylated a-receptor


Phenoxybenzamine
Phenoxybenzamine

  • Administration causes:

    • Postural hypotension

    • Reflex tachycardia

    • Miosis

    • Impaired ejaculation

    • Can act on the CNS (nausea and sedation)


EPINEPHRINE REVERSAL AFTER PHENOXYBENZAMINE

220

BP (mm. Hg)

180

140

EPINEPHRINE

PRETREAT WITH POB:

120

100

BP (mm. Hg)

80

60

EPINEPHRINE


HR

Effect of phenoxybenzamine on responses to EPI and NE

BP

EPI

NE

NE

EPI

POB


Phenoxybenzamine1
Phenoxybenzamine

  • Indications:

    • Treatment of pheochromocytoma

    • Prior to surgery to remove pheochromocytoma


Alpha- Adrenergic Antagonists

I. Non-selective alpha adrenergic receptor antagonists

A. Covalent (haloalkylamines)

Dibenamine

Phenoxybenzamine*

B. Noncovalent

Phentolamine*

Tolazoline

II. a1-selective

Doxazosin

Prazosin*

Terazosin

III. a2-selective

Yohimbine*

(* = Drug List)


Epinephrine reversal by phentolamine

+ phentolamine

15 µg/kg

Blood Pressure

+ Epi

5 µg/kg

+ Epi

5 µg/kg


Comparison of Competitive vs. “Non-equilibrium” Blockade

Pretreat with

Phentolamine

No Pretreatment

Contraction of arterial strips

(a1- receptor)

Pretreat with

Phenoxybenzamine

Concentration of Norepinephrine


Alpha- Adrenergic Antagonists

I. Non-selective alpha adrenergic receptor antagonists

A. Covalent (haloalkylamines)

Dibenamine

Phenoxybenzamine*

B. Noncovalent

Phentolamine*

Tolazoline

II. a1-selective

Doxazosin

Prazosin*

Terazosin

III. a2-selective

Yohimbine*

(* = Drug List)


Prazosin causes epinephrine reversal

Pretreat with

prazosin

Blood Pressure

Epinephrine

Epinephrine


NE

NE

Presynaptic Receptors Inhibit NE Release

NE

ß1-

AdR

NE

X

X

NE

a2-

AdR

NE


NE

NE

NE

NE

Block Presynaptic Receptors: Increase NE Release

NE

Increased HR

NE

ß1-

AdR

NE

NE

a2-

AdR

XX

NE

POB

Presynaptic Receptors Active: Less NE Release

NE

ß1-

AdR

Less Tachycardia

X

X

NE

a2-

AdR

NE


Long-lasting anti-hypertensive effect of prazosin therapy

150

130

Supine

110

Mean Blood ressureP (mm. Hg)

Standing

90

70

50

24

0

18

6

12

Months


Yohimbine blocks a2 - receptors and thus increases NE release


Beta-Adrenergic Antagonists

I. Non-selective ß-blockers

Nadolol*

Propranolol*

Timolol*

Pindolol

Sotalol

II. ß1-Selective Antagonists

III. ß2-Selective Antagonists

Butoxamine*

Atenolol*

Esmolol*

Metoprolol*

Acebutolol

Betaxolol

Practolol

(* = Drug List)


Propranolol blocks responses to isoproterenol

0.5 mg/kg Propranolol

0.2 µg/kg

ISO

0.2 µg/kg

ISO

1 µg/kg

ISO

Cardiac

Force

Arterial

Pressure

Heart

Rate

1 min.


EFFECT OF ANTAGONISTS ON RESPONSES TO ISO

+ propranolol

+ phentolamine

BP

+ ISO

+ ISO

+ ISO


Effect of antagonists on pressor response to NE

+ Propranolol

2 mg/kg

+ Phentolamine

15 mg/kg

240

160

BP (mm. Hg)

80

NE, 2.5 µg/kg

NE, 2.5 µg/kg

NE, 2.5 µg/kg


Both a and ß receptors contribute to

epinephrine action

+ phentolamine

+ propranolol

Blood Pressure

+ Epi

+ Epi

+ Epi


Effect of antagonists on responses to adrenergic agonists

NE

NE +

PHEN

NE +

PRO

Contraction

of VSM

ISO

ISO +

PHEN

ISO +

PROP

Relaxation

of airway SM

NE

Contraction

of heart

NE +

PRO

NE +

PHEN

CONCENTRATION OF AGONIST


Therapeutic uses of beta blockers

Cardiovascular

Angina Pectoris

Arrhythmias

Hypertension

Recurrence of heart attack

CNS

Prophylaxis of migraine

Alleviation of anxiety

Endocrine

Hyperthyroidism

Pheochromocytoma

Other

Glaucoma

Certain types of tremor

Therapeutic Uses of Beta Blockers


Why do blockers have anti hypertensive action
Why do ß blockers have anti-hypertensive action?

Possible reasons:

  • Block ß-receptors in heart decrease cardiac output

  • Decrease renin secretion from kidney

  • Resets baroreceptor sensitivity

  • Acts in CNS to “decrease” sympathetic activity


Propranolol decreases mortality after heart attack

10

8

Placebo

6

Cumulative mortality Rate (%)

4

Propranolol

2

0

6

12

18

24

30

MONTHS


Therapeutic Uses of Beta Blockers

  • Endocrine

    • Hyperthyroidism

    • Pheochromocytoma

  • Other

    • Glaucoma

    • Certain types of tremor

  • Cardiovascular

    • Angina Pectoris

    • Arrhythmias

    • Hypertension

    • Recurrence of heart attack

  • CNS

    • Prophylaxis of migraine

    • Alleviation of anxiety


ADVERSE EFFECTS OF ß-BLOCKERS

MAJOR EFFECTS

OTHER SIDE EFFECTS

Fatigue

Heart Failure

Bronchospasm

Constipation

Heart Block

Diarrhea

Bradycardia

Nightmares

Hypotension

Depression

Hypoglycemia

Paresthesias

Claudication

Skin Rash


Chronic propranolol increases density of ß-AdR in heart

60

40

Cardiac ß-AdR Number

20

Control

Propranolol-treated


Effects of opthalmic administration of timolol

0

Control Patients

% Change in FEV1 From Control

-20

Asthma Patients

-40

0

1

2

3

Time (hours)


Beta-Adrenergic Antagonists

I. Non-selective ß-blockers

Nadolol*

Propranolol*

Timolol*

Pindolol

Sotalol

II. ß1-Selective Antagonists

III. ß2-Selective Antagonists

Butoxamine*

Atenolol*

Esmolol*

Metoprolol*

Acebutolol

Betaxolol

Practolol

(* = Drug List)


Comparison of propranolol vs. practolol

Block of sympa- thetic nerve-stimulated HR increase

PRO

PRACT

PRO

Block of ISO-mediated vasodilation

PRACT

Block of ISO-mediated bronchodilation

PRO

PRACT

.01

1

10

.1

Dose antagonist, mg/kg


Beta-Adrenergic Antagonists

I. Non-selective ß-blockers

Nadolol*

Propranolol*

Timolol*

Pindolol

Sotalol

II. ß1-Selective Antagonists

III. ß2-Selective Antagonists

Butoxamine*

Atenolol*

Esmolol*

Metoprolol*

Acebutolol

Betaxolol

Practolol

(* = Drug List)


Labetalol
Labetalol

  • UGLY- 4 optical isomers, with different selectivities

  • Non-selective ß-blocker PLUS a1-selective antagonist

  • Used for treatment of:

    • Hypertension

    • Pheochromocytoma-associated hypertension

    • Hypertension following abrupt withdrawl of clonidine

  • Carvedilol is another non-selective ß PLUS a1 blocker


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