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
