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Chapter 10
Adrenoceptor-Activating ＆
Other Sympathomimetic
Cao Yongxiao 曹永孝
Department of Pharmacology
[email protected];029-82655140
http://pharmacology.xjtu.edu.cn
1
The Mode ＆Spectrum of Action of
Sympathomimetic
Drugs
Drugs of indirect
action are
dependent on the
Sympathomimetics
Drugs
of indirect
action
release
of
aredependent
grouped on
bythe
are
catecholamines.
action of
mode.
release
catecholamines.
They have two
They
have either of two
mechanisms:
different
mechanisms:
(1)
displacement
of store
Some of these drugs
(1)catecholamines
displacement offrom
store
act by direct mode, ie,
catecholamines
from
the
the
adrenergic
nerve
they activate
adrenergic
ending nerve ending.
adrenoceptors.
(2) inhibition of reuptake of
catecholamines.
Basic Pharmacology of Sympathomimetics
Phenylethylamine is the parent compound from
which sympathomimetic drugs are derived.
This compound consists of a benzene ring with an
ethylamine side chain.
Substitutions
may
be
made
(1)
on
the
terminal
amino
group,
The modification of phenylethylamine changes the
(2) on
the benzene
(3) for
on the
α or β-carbons.
affinity
of thering,
drugs
receptors,
the intrinsic
Substitution by
-OH group
at the 3 and 4 positions yield
ability
and pharmacokinetics.
catecholamines.
Table 10-1
Relative selectivity of adrenoceptor agonists
Relative Receptor Affinities
Alpha agonists
Phenylephrine, methoxamine
Clonidine, methylnorepineprine
Mixed alpha and beta agonists
Norepinephrine
Epinephirine
Beta agonists
Dobutamine1
Isoproterenol
Terbutaline, metaproterenol,
albuterol, ritodrine
Dopamine agonists
Dopamine
Fenoldopam
α1﹥α2 ﹥﹥﹥﹥﹥β
α2 ﹥ α1﹥﹥﹥﹥﹥ β
α1=α2； β1﹥﹥β2
Receptor Types
α1=α2；β1=β2
Alpha
β1﹥β2﹥﹥﹥﹥α
Beta
Dopamine
β1=β2﹥﹥﹥﹥α
β2﹥﹥ β1﹥﹥﹥﹥α
D1=D2﹥﹥β﹥﹥α
D1﹥﹥ D2
Receptor Selectivity
Selectivity means that a drugs may preferentially
bind to one subgroup.
Cardiovascular System
A. Blood Vessels
Adrenoceptors regulate vascular tone.
Catecholamines are important in controlling
peripheral vascular resistance and venous
capacitance.
Alpha receptors increase arterial resistance,
whereas β2 receptors relax smooth muscle.
There are differences in receptor
types in the various vascular beds.
The skin vessels have predominantly αreceptors
and constrict in the presence epinephrine and
norepinephrine,
as do the splanchnic vessels.
Vessels in skeletal muscle have both αand
βreceptors, which mediate constriction or
dilatation, respectively.
D1 receptors
promote vasodilation of renal, splanchnic, coronary,
cerebral, and other resistance vessels.
Its activation in the renal vasculature may play a
major role in the natriuresis induced by dopamine.
B. Heart
The heart are determined largely
by β1 receptors.
β-receptor activation increase
calcium influx in cardiac cells.
Pacemaker activity, both normal and abnormal, is
increased.
Conduction velocity in the atrio-ventricular node is
increased. Intrinsic contractility is increased, and
relaxation is accelerated.
As a result, the cardiac
twitch response is
increased in tension
but abbreviated in duration.
In the intact heart, intraventricular pressure
rises and falls more rapidly, and ejection time
is decreased.
Blood Pressure
The effects of sympathomimetic drugs on BP is
based on their effects on the heart, the peripheral
vascular resistance, and the venous return.
Phenylephrine, aαagonist, increases peripheral
resistance and venous capacitance and rises the BP.
The rise in BP increases baroreceptor-mediated
vagal tone with slowing of the heart rate.
BP response to αand βreceptor agonist is different.
βreceptor
Stimulation of βreceptor in the
heart increases cardiac output.
Activation of β2 receptor
dilates vascular beds and decreases
peripheral resistance.
The net effects is to increase systolic
BP and to decrease diastolic BP.
Eye
Phenylephrine activates
αreceptors in radial muscle
of the iris, causes mydriasis.
αagonists increase the aqueous humor from glaucoma,
being a leading cause of blindness.
β stimulants relax the ciliary muscle, and decrease
accommodation.
Adrenergic drugs may protect neuron cells in the retina.
Respiratory Tract
Bronchial smooth muscle contains β2
receptors that cause bronchodilation.
The blood vessels of the respiratory
tract mucosa contains αreceptors;
The decongestant action of
adrenoceptor stimulants is clinically
useful.
snuffle
Gastrointestinal Tract
Beta receptors locate on the smooth
muscle cells and mediate relaxation.
Alpha stimulants, α2-selective agonists, decrease muscle
activity by presynaptically reducing the release of ACh
within the enteric nervous system. Alpha 2 receptors may
also decrease slat and water flux into the lumen of the
intestine.
Specific Sympathomimetic Drugs
Catecholamines
Epinephrine is a potent vasoconstrictor (α) and cardiac
stimulant(β1). It can rise systolic BP by positive inotropic
and chronotropic actions on the heart.
Epinephrine activates β2 receptors, leading to vasodilation.
Consequently, total peripheral resistance and diastolic BP
may fall.
Vasodilation in skeletal muscle increases blood flow during exercise.
Epinephrine (E)
Increase heart rate,
inotropy (β1) and output
Vasoconstriction in
systemic arteries (α)
The overall
response
Vasodilation
in muscle
at
low
(β2);
Atconcentrations
low concentrations,
epinephrine increases cardiac
output with a small change in mean BP.
Vasoconstriction at high
At high concentrations,
epinephrine increases BP
concentrations
(α)
because vasoconstriction of α-receptors offsets the
β2-receptor mediated vasodilation.
Norepinephrine (NE)
NE and epinephrine have similar effects on β1 and
αreceptors, but has relatively little effect on β2 receptors.
NE increase peripheral resistance and both diastolic and
systolic BP.
Compensatory vagal reflexes tend to overcome the direct
positive chronotropic effects; however, the positive
inotropic effects on the heart are maintained.
Norepinephrine (NE)
Increase heart rate
(transiently) and
increased inotropy (β1)
directly.
The overall response
is
Vasoconstriction
in
Increase
of cardiac
systemic
artery
and output and systemic vascular
resistance,
which results in an elevation in BP.
vein
(α)
Heart rate, although initially stimulated by NE,
decreases due to activation of baroreceptor and
vagal-mediated slowing of the heart rate
Isoproterenol
A very potent β-receptor agonist.
It activates β1 and causes positive
chronotropic and inotropic actions;
leading to a marked increase in
cardiac output and an increase in
systolic BP.
It activates β2, results in vasodilation, which associate
with a fall in diastolic and mean arterial pressure.
Dopamine (DA)
DA activates D1 receptors in
vascular beds, leading to
vasodilation and peripheral
resistance decrease.
The effect on renal blood flow
is of clinical value.
DA activates β1 in the heart.
At higher rate of infusion, DA activates vascular α receptor,
leading to vasoconstriction, including in the renal vessel,
which may mimic the actions of epinephrine.
Fenoldopam
is a D1 receptor agonist that selectively
leads to periopheral vasodilation in some
vascular beds.
The primary indication is for treatment of
severe hypertension.
Other Sympathomimetics
They have pharmacokinetic features or relative
selectivity for specific receptors.
Phenylephrine is a relatively pure α agonist.
Because it is not a catechol derivative, it is not
inactivated by COMT and has a much longer
duration of action than the catecholamines.
It is an effective mydriatic and decongestant and
can be used to raise the blood pressure.
Ephedrine
Ephedrine occurs in plants and has been used in
China for over 2000 years.
Ephedrine can activate both αand βreceptors
Because ephedrine is a noncatechol, it has high
bioavailability and a long duration of action –
hours rather than minutes.
Clinical application
Conditions in which blood flow or pressure is to be
enhanced
Sympathomimetic drugs are used in hypotensive
emergency on short duration
αagonist such as norepinephrine, phenylephrine,
methoxamine and ephedrine have been used for
chronic hypotension.
Shock
is a complex acute cardiovascular syndrome that results in
a critical reduction in perfusion of vital tissues, and
usually associated with hypotension, oliguria.
The major mechanisms are hypovolemia, cardiac
insufficiency, and altered vascular resistance.
Sympathomimetic drugs have been used in the treatment
of all forms of shock.
Cardiogenic Shock
usually due to decrease of cardiac output.
In low to moderate doses,
positive inotropic agents such as dopamine or dobutamine
may increase cardiac output and, compared with
norepinephrine, cause relative little peripheral
vasoconstriction.
Isoproterenol increases heart rate and work more than
either dopamine or dobutamine.
Anaphylaxis
Anaphylactic shock affects both the cardiovascular and
respiratory systems.
The syndrome includes bronchospasm, cardiac output
decrease, angioedema, and hypotension.
Epinephrine is the first choice drug for anaphylactic shock .
β1
β2
α
cardiac output
systolic BP
bronchiolar relaxes
vasoconstriction
diatolic BP
Capillary permeability
angioedema
Conditions in Which Blood Flow is to be Reduced
Epinephrine is usually applied topically in nasal
packs or in a gingival string.
Combining αagonists with local anesthetics
greatly prolongs the duration of infiltration nerve
block.
The total doses of anesthetic can be reduced.
Epinephrine is the favored agent for this
applicant.
Cardiac Applications
Isoproterenol and epinephrine have been utilized in
the management of complete heart block and
cardiac arrest.
Heart failure may respond to the positive inotropic
effects of drugs such as dobutamine.
Pulmonary Applications
The most important use is in the therapy of
bronchial asthma.
Nonspecific drugs, βagents, and β2- specific
agents are all available for this indication.
β2-specific drugs have less adverse effects.
Toxicity of Sympathomimetic Drugs
The adverse effects of adrenoceptor agonist are
primarily extensions of their pharmacologic effects
in the cardiovascular and central nervous systems.
Adverse cardiovascular effects include marked
elevations in BP that cause increased cardiac work,
which may precipitate cardiac ischemia and failure.