Gs and Gi produce stimulation and inhibition of the enzyme adenylate cyclase

respectively, whilst Gq interacts with phospholipase C.

H. Zhong, K.P. Minneman European Journal of Pharmacology 375 (1999) 261-276

Sympatholytic Drugs

Wording

Adrenoceptor Blocker
Adrenergic Antagonist
Subgroups in Sympathoplegic drugs
Alpha Blocker, Alpha Antagonist
Beta Blocker, Beta Antagonist

Objectives
1. Describe the effects of E and NE in the
presence and in the absence of Alpha
Blocker.
2. Compare the effects among Beta Blockers
3. Compare the pharmacokinetics among
Beta Blockers
4. Describe the clinical applications and
toxicity of typical Alpha- and Beta
Blockers.

Outline
I. Concepts
II. Alpha-Blocking Drugs
A. Classification
B. Pharmacokinetics
C. Mechanism of Action
D. Effects

Outline
II. Alpha-Blocking Drugs (contd)
E. Clinical Uses
F. Adverse Effects
III. Beta-Blocking Drugs
A. Classification and Mechanisms
B. Effects and Clinical Uses
C. Adverse Effects

I. Concepts
Classification is based on receptor
selectivity.
These drugs differ markedly in their
effects and clinical applications.

II. Alpha-Blocking Drugs

A. Classification
based on: selective affinity for alpha
receptors, reversibility
1. Irreversible, long-acting alpha
blockers
2. Reversible, short-acting alpha
blockers
3. Alpha1-selective blockers
4. Alpha2-selective blockers

A. Classification
1. Irreversible alpha blockers :
Phenoxybenzamine
slightly a 1 -selective, long-acting
2. Reversible alpha blockers: Phentolamine
(nonselective), tolazoline (slightly a 2 selective)
3. a 1 blockers: Prazosin, Doxazosin, Terazosin
4. a 2 blockers: Yohimbine, rauwolscine
used primarily in researches

B. Pharmacokinetics
All active orally as well as parenterally
Phenoxybenzamine: short t1/2 but long
duration-48 hr (covalent bond)
Phentolamine, tolazoline: parenteral,
duration 20-40 min by parenteral route
Prazosin: oral, duration 8-10 hr

C. Mechanism of Action
Phenoxybenzamine: binds
covalently--irreversible (insurmount
able) blockade (slightly a 1 -selective)
Other agents: competitive
antagonists--the effects can be overc
ome by increased concn of agonist

Chemical
sympathectomy
Hypertensive
Episodes
- decreases vascular
resistance
- lowers BP
- smooth
muscle relaxation in
the bladder
Used to treat
hypertensive episodes
of
Pheochromocytoma

D. Effects of Alpha Blockers

1. Nonselective alpha blockers
block alpha-mediated sympathetic
responses and exogenous sympathomi
metics
Most important effects: CVS effects
vasodilation --reduce arterial and
venous pressure (a 1 )
no significant direct cardiac effects

D. Effects of Alpha Blockers

1. Nonselective alpha blockers (cont)
Cause reflex tachycardia (due to decreased
MAP)
Tachycardia may be exaggerated because a 2
receptors are also blocked.
e.g. phenoxybenzamine, phentolamine, tolazoline

Selective a1 blockers cause less reflex tachycardia than

Phenoxybenzamine and Phentolamine

D. Effects of Alpha Blockers

2. Selective a 1 blockers
The same effects as nonselective alpha
blockers
But cause much less tachycardia than
nonselective blocker
e.g. Prazosin, Doxazosin, Terazosin

Epinephrine Reversal
occur when alpha blockers are given before Epi
---> Epi produce the opposite effects : decreased
BP resulting from b 2 effect
(a 1 ,a 2, b 1 ,b 2 )

Antagonistic effect of alpha blocker

on pretreatment with alpha agonist

E. Clinical Uses
1. Nonselective alpha-blockers
Presurgery of pheochromocytoma: phenoxybenzamine
During surgery: phentolamine (sometimes)
Carcinoid tumor: phenoxybenzamine (5-HT blocking)
Mastocytosis: phenoxybenzamine (H1 antihistamine)
Accidental local infiltration of alpha agonist: phentolamine
Overdose of sympathomimetics (amphetamine, cocaine,
phenylpropranolamine)
Raynaud s phenomenon, erectile dysfunction
(phentolamine)

Disorders of the Autonomic Nervous System:

Raynauds Disease

Raynauds disease characterized by constriction of blood vessels

Provoked by exposure to cold or by emotional stress

Disorders of the
Autonomic Nervous
System:
Hypertension
Hypertension high
blood pressure
Can result from
overactive
sympathetic
vasoconstriction

E. Clinical Uses
2. Selective a 1 -blockers
Prazosin and others
Essential Hypertension
Urinary hesitancy
Prevention of urinary retention in
benign prostatic hyperplasia (BPH)

F. Adverse effects of Alpha

blockers
Orthostatic hypotension (venodilatation)
Reflex tachycardia (nonselective > selective)
First dose hypotension (take before going to
bed)
Nausea/vomiting
Caution in patients with coronary artery
disease (CAD or CHD): angina

Receptor Type

a1

a2

Selective Agonist

Phenylephrine
Oxymetazoline

Clonidine
Clenbuterol

Selective Antagonist Doxazosin

Prazosin

Yohimbine
Idazoxan

Agonist Potency
Order

A=NA>>ISO

A=NA>>ISO

Second Messengers
and Effectors

PLC activation via

Gp/q causes inc.
[Ca2+]i

dec. cAMP via Gi/o

causes dec. [Ca2+]i

Physiological Effect Smooth muscle

contraction

Inhibition of
transmitter release
Hypotension,
anaesthesia,
Vasoconstriction

QUESTIONS

1. An adrenergic receptor blocker

which is more effective in the
management of benign prostate
hypertrophy:
a) Tamsulosin
b) Phenoxybenzamine
c) Doxazosin
d) Phentolamine
e) Terazosin

2. A non selective adrenergic

receptor blocking agent:
a) Phenoxybenzamine
b) Prazosin
c) Doxazosin
d) Tamsulosin
e) Terazosin

3. A drug useful in the treatment of a

patient with a slightly enlarged
prostate
and
suffering
from
hypertension:
a) Prazosin
b) Labetalol
c) Phentolamine
d) Propranolol
e) Isoproterenol

4. The reversal of the hypertensive

effect of epinephrine (adrenaline) is
produced by the blockade of:
1 receptors
2 receptors
1 receptors
2 receptors
e) M1 receptors

Practice Questions
Blockade of which receptors is responsible for
the therapeutic and adverse effects of
adrenergic receptor agonists?
Therapeutic: a1, b1
Adverse: a2, b2

 Which type of drugs causes

sympathectomy? Give an example?
Non-Competitive a blocker
phenoxybenzamine

chemical

III. Beta-Blocking Drugs

A. Classification and Mechanisms
All are competitive antagonists
Propranolol is prototype
Classification is based on
Beta subtypes selectivity
Partial agonist activity
Lipid solubility
Local anesthetic action

A. Classification and Mechanisms

1. Receptor selectivity
b 1 -selective: metoprolol, atenolol
b 2 -selective: butoxamine (research
only)
Nonselective: propranolol
Combined beta- and alpha-blocking:
labetalol

A. Classification and
Mechanisms
2. Partial agonist activity
Intrinsic sympathomimetic
activity, ISA
eg, pindolol, acebutolol
may be useful in patients
with asthma

A. Classification and
Mechanisms
3. Local anesthetic activity (membranestabilizing activity):
disadvantage when used topically in
the eye
timolol: no this activity
4. Lipid solubility
responsible for CNS adverse effects:
propranolol

Pharmacokinetics of
Beta blockers
For systemic effects, developed for
chronic oral use
Esmolol: short-acting--only used
parenterally
Nadolol: longest-acting
Atenolol, acebutolol are less lipidsoluble

B. Effects and Clinical Uses

Predict from beta blockade
decreased HR, force of contraction
decreased A-V conduction
slow firing rate of SA node
Cardiovascular and ophthalmic
applications are extremly important

 1-antagonist _____
1-antagonists --------

B. Clinical Uses
CVS: hypertension, angina pectoris,
arrhythmia prophylaxis after MI, supr
aventricular tachycardias, hypertrophi
c cardiomyopathy, congestive heart fai
lure*
Glaucoma: reduce aqueous humor
secretion (timolol)

B. Clinical Uses
Migraine: propranolol
Thyroid storm, thyrotoxicosis:
propranolol
Famillial tremor, other types of
tremor, stage fright : propranol
ol

C. Adverse effects
CVS: bradycardia, A-V blockade,
congestive heart failure
Patients with airway disease:
asthmatic attack
Mask sign of hypoglycemia in diabetic
patients: tachycardia, tremor, anxiety
CNS effects: sedation, fatigue, sleep
alterations

Drug List
Alpha-blockers
Nonselective:
phenoxybenzamine*,
phentolamine*
a 1 -selective: prazosin*,
terazosin, doxazosin
a 2 -selective: yohimbine

Drug List
Beta-blockers
Nonselective: propranolol*, timolol,
nadolol
Combined a - and b - blocking:
carvedilol, labetalol
b 1 -selective: metoprolol, atenolol
b 2 -selective: butoxamine

1- Contract vascular
smooth muscle, iris,
bladder sphincter
muscle
2-Inhibits NE
release

2- Relaxes
bronchial,
uterine, and
vascular
smooth
muscle

2-mediates platelet
aggregation;decrease insulin
secretion; decreases secretion
of aqueous humor
2-inhibits platelet aggregation;
promotes glycogenolysis

Receptor
Type

b1

b2

b3

b4

Selective
Agonist

Dobutamine
xamoterol

Salbutamol
salmeterol

BRL 37344

none

Selective
Antagonists

Atenolol
metoprolol

Butoxamine

SR59230A

Bupranolol

Agonist
Potency
Order

ISO>A=NA

ISO>A>>NA

ISO=NA>A

Second
Messengers
and Effectors

Inc cAMP via

Gs

Inc cAMP via

Gs

Inc cAMP via

Gs

Inc cAMP via

Gs

Physiological
Effect

Inc heart rate

and force

Vasodilatation
and bronchodilation

Lipolysis and
thermogenesis

Inc heart rate

and force

SUMMARY

1. A non selective receptor

antagonist:
a) Timolol
b) Acebutalol
c) Atenolol
d) Esmolol
e) Metoprolol

2. A receptor antagonist which also

acts as a partial agonist:
a) Pindolol
b) Propranolol
c) Esmolol
d) Timolol
e) Metoprolol

3. Propranolol is contraindicated in
one of the following diseases:
a) Hypertension
b) Tachycardia
c) Hyperthyroidism
d) Angina pectoris
e) Bronchial asthma

4. Propranolol produces its

antihypertensive action by:
a) Vasodilatation
b) Ganglionic blockade
c) Decreased cardiac output
d) A diuretic action
e) Blockade of 1 receptors

The End