HuBio 543September 27, 2007

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

Adrenergic Antagonists

Alpha- Adrenergic Antagonists

A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. 1-selective

Doxazosin Prazosin* Terazosin

I. Non-selective alpha adrenergic receptor antagonists

III. 2-selective Yohimbine* (* = Drug List)

CH2

NO

CH3

CH

CH2

CH2 CH2Cl

CH2

NO

CH3

CH

CH2 CH2

CH2CH2

NO

CH3

CH

CH2 CH2

CH2

+

Ethylene iminium ion Alkylated -receptor

Phenoxybenzamine

Covalent inactivation of -receptor by phenoxybenzamine

Phenoxybenzamine

• Administration causes: – Postural hypotension– Reflex tachycardia– Miosis– Impaired ejaculation– Can act on the CNS (nausea and sedation)

BP (mm. Hg)

60

120

100

80

220

140

180

EPINEPHRINE REVERSAL AFTER PHENOXYBENZAMINE

EPINEPHRINE

PRETREAT WITH POB:

EPINEPHRINEBP (mm. Hg)

BP

HR

POBNE NE EPIEPI

Effect of phenoxybenzamine on responses to EPI and NE

Phenoxybenzamine

• Indications: – Treatment of pheochromocytoma– Prior to surgery to remove pheochromocytoma

Alpha- Adrenergic Antagonists

A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. 1-selective

Doxazosin Prazosin* Terazosin

I. Non-selective alpha adrenergic receptor antagonists

III. 2-selective Yohimbine* (* = Drug List)

+ Epi5 µg/kg

+ phentolamine15 µg/kg

Epinephrine reversal by phentolamine

+ Epi5 µg/kg

Blood Pressure

Contraction of

arterial strips

1- receptor)

Concentration of Norepinephrine

Pretreat withPhentolamine

Pretreat withPhenoxybenzamine

No Pretreatment

Comparison of Competitive vs. “Non-equilibrium” Blockade

Alpha- Adrenergic Antagonists

A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. 1-selective

Doxazosin Prazosin* Terazosin

I. Non-selective alpha adrenergic receptor antagonists

III. 2-selective Yohimbine* (* = Drug List)

Epinephrine

Pretreat withprazosin

Prazosin causes epinephrine reversal

Blood Pressure

Epinephrine

NE

NE

-AdR NE

X

ß-AdR

XNE

Presynaptic Receptors Inhibit NE Release

NE

NE

Block Presynaptic Receptors: Increase NE Release

NE

NE-AdR

Increased HR

ß-AdR

NE

NE

NE

POBXX

NE

NE

NE

NE-AdRNE

Xß-AdRX NE

NE

Presynaptic Receptors Active: Less NE Release

Less Tachycard

ia

110

70

Mean Blood ressureP (mm. Hg)

0 6 12

18 2450

130

150

90

Months

Long-lasting anti-hypertensive effect of prazosin therapy

Supine

Standing

Yohimbine blocks 2 - receptors and thus increases NE release

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Beta-Adrenergic Antagonists

I. Non-selective ß-blockers

II. ß1-Selective AntagonistsAtenolol*Esmolol*Metoprolol*AcebutololBetaxololPractolol

III. ß2-Selective AntagonistsButoxamine*

Nadolol*Propranolol*Timolol*PindololSotalol

(* = Drug List)

1 min.

HeartRate

ArterialPressure

CardiacForce

0.2 µg/kg ISO 0.2 µg/kg

ISO1 µg/kg ISO

0.5 mg/kg Propranolol

Propranolol blocks responses to isoproterenol

+ phentolamine

+ ISO + ISO + ISO

+ propranolol

BP

EFFECT OF ANTAGONISTS ON RESPONSES TO ISO

NE, 2.5 µg/kg

160

80

240

BP (mm. Hg)

+ Propranolol 2 mg/kg+ Phentolamine

15 mg/kg

Effect of antagonists on pressor response to NE

NE, 2.5 µg/kgNE, 2.5 µg/kg

+ Epi

+ phentolamine

Both and ß receptors contribute to epinephrine action

+ Epi

Blood Pressure

+ propranolol

+ Epi

NE

ISO

NE

NE +PRO

NE + PHEN

ISO +PHEN

ISO +PROP

NE + PHEN

NE +PRO

CONCENTRATION OF AGONIST

Contraction of VSM

Relaxation of airway SM

Contraction of heart

Effect of antagonists on responses to adrenergic agonists

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

Why do ß blockers have anti-hypertensive action?

• Block ß-receptors in heart decrease cardiac output

• Decrease renin secretion from kidney

• Resets baroreceptor sensitivity• Acts in CNS to “decrease” sympathetic activity

Possible reasons:

6 1

218

24

30

8

6

4

2

0

10

Cumulative mortality Rate (%)

Placebo

Propranolol

MONTHS

Propranolol decreases mortality after heart attack

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

ADVERSE EFFECTS OF ß-BLOCKERS

MAJOR EFFECTS OTHER SIDE EFFECTS

Heart FailureBronchospasm

Heart Block

Bradycardia

Hypotension

Hypoglycemia

Claudication

Fatigue

Constipation

Diarrhea

Nightmares

Depression

Paresthesias

Skin Rash

20

60

40

Control Propranolol-treated

Cardiac ß-AdR Number

Chronic propranolol increases density of ß-AdR in heart

0 1 2 3

-40

-20

0

% Change in

FEV1 From

Control Control Patients

Asthma Patients

Time (hours)

Effects of opthalmic administration of timolol

Beta-Adrenergic Antagonists

I. Non-selective ß-blockers

II. ß1-Selective AntagonistsAtenolol*Esmolol*Metoprolol*AcebutololBetaxololPractolol

III. ß2-Selective AntagonistsButoxamine*

Nadolol*Propranolol*Timolol*PindololSotalol

(* = Drug List)

.01 .1 1 1

0Dose antagonist, mg/kg

Block of sympa- thetic nerve-stimulated HR increase

Block of ISO-mediated bronchodilation

Block of ISO-mediated vasodilation

PRO PRACT

PRACT

PRACT

PRO

PRO

Comparison of propranolol vs. practolol

Beta-Adrenergic Antagonists

I. Non-selective ß-blockers

II. ß1-Selective AntagonistsAtenolol*Esmolol*Metoprolol*AcebutololBetaxololPractolol

III. ß2-Selective AntagonistsButoxamine*

Nadolol*Propranolol*Timolol*PindololSotalol

(* = Drug List)

Labetalol

• UGLY- 4 optical isomers, with different selectivities

• Non-selective ß-blocker PLUS 1-selective antagonist

• Used for treatment of:– Hypertension– Pheochromocytoma-associated hypertension– Hypertension following abrupt withdrawl of clonidine

• Carvedilol is another non-selective ß PLUS 1 blocker