Download S 06 Adrenoceptor Agonists And Sympathomimetic Drugs

Adrenoceptor Agonists &
Sympathomimetic Drugs
Overview

Adrenergic neurons release norepinephrine as
the primary neurotransmitter

These neurons are found in the CNS and also
in the sympathetic nervous system, where they
serve as links between ganglia and the
effector organs

The adrenergic neurons and receptors, located
either presynaptically on the neuron or
postsynaptically on the effector organ, are the
sites of action of the adrenergic drugs
Sympathatic innervation
of adrenal medulla
Sympathatic
Parasympathatic
Somatic
Ganglionic
transmittion
NN receptor
Adrenal
medulla
NN receptor
NN receptor
Neuroeffector
transmittion
Acetylcholine
Norepinephrine
Effector organ
Effector organ
α or β Adrenergic receptor
M receptor
Neuromuscular junction
NM receptor
Neurotransmission at adrenergic
neurons
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential
H+
DA
NE
NE
Uptake
NE
NE
a1
NE
Effector organ
NE
b
Adrenergic receptors
(adrenoceptors)

All the adrenoceptors
receptors (GPCRs)

There are two main groups of adrenergic receptors, α
and β, with several subtypes

Adrenoceptors were initially identified on the basis of
their responses to the adrenergic agonists
epinephrine, norepinephrine, and isoproterenol
are
G-protein
coupled
α Adrecoceptros
Epinephrine
Norepinephrine
Isoprotenol
β Adrecoceptros
Isoprotenol
High affinity
Epinephrine
Norepinephrine
Low affinity
Adrenergic receptors (adrenoceptors)
Alpha receptors

The α-adrenoceptors are subdivided into
two subgroups, α1 and α2, based on their
affinities for α agonists and blocking drugs

α1 receptors (GPCR-Gq) are present on
the postsynaptic membrane of the effector
organs and mediate many of the classic
involving contraction of smooth muscle
Adrenergic receptors (adrenoceptors)
Alpha receptors

α2 receptors (GPCR-Gi) are located
primarily on presynaptic nerve endings
and function their as autoreceptor

The are located on other cells (e.g β cell
of the pancreas)
Adrenergic receptors (adrenoceptors)
Beta receptors

The β-adrenoceptors can be subdivided into
three major subgroups, β1, β2, and β3, based
on their affinities for adrenergic agonists and
antagonists

β1 Receptors have approximately equal
affinities for epinephrine and norepinephrine,
whereas β2 receptors have a higher affinity for
epinephrine than for norepinephrine

The β-adrenoceptors are coupled via G
proteins in the Gs family to adenylyl cyclase
Adrenergic receptors (adrenoceptors)
Beta receptors

β1 Receptors are found on most notably on the heart,
where they increase heart rate and cardiac
contractility

β2 receptors are found in a variety of bronchial and
vascular smooth muscles, where stimulation triggers
muscle relaxation

β3
Receptors
may
mediate
responses
to
catecholamine at sites with "atypical" pharmacological
characteristics (e.g., adipose tissue)

β3 receptors are expressed in the detrusor muscle of
the bladder and induce its relaxation (e.g.Mirabegron)
Distribution of adrenoceptor subtypes
Type
α1
α2
β1
β2
β3
Tissue
Most vascular smooth muscle
(innervated)
Pupillary dilator muscle
Actions
Pilomotor smooth muscle
Prostate
Heart
Erects hair
Contraction
Increases force of contraction
Postsynaptic CNS neurons
Platelets
Adrenergic and cholinergic nerve
terminals
Some vascular smooth muscle
Fat cells
Probably multiple
Aggregation
Heart, juxtaglomerular cells
Respiratory, uterine, and vascular
smooth muscle
Skeletal muscle
Human liver
Bladder
Fat cells
Contraction
Contraction (dilates pupil)
Inhibits transmitter release
Contraction
Inhibits lipolysis
Increases force and rate of
contraction; increases renin
release
Promotes smooth muscle
relaxation
Promotes potassium uptake
Activates glycogenolysis
Relaxes detrusor muscle
Activates lipolysis
Sympathomimetic Drugs
I.
Direct acting sympathomimetics:
 Act
directly on one or more of the adrenergic
receptors
 These agents may be:
a) Selective: for a specific receptor subtype
(e.g., phenylephrine for α1, terbutaline for
β2)
b) None selective: have no or minimal
selectivity and act on several receptor
types (e.g., epinephrine for α1, α2, β1, β2,
and β3 receptors)
Sympathomimetic Drugs
II.
Indirect acting sympathomimetics:

Increase the availability of norepinephrine or
epinephrine to stimulate adrenergic receptors

This can be accomplished in several ways :
1)
Displacement of stored catecholamines from the
adrenergic nerve ending (amphetamine-like or
“displacers” )
2)
Inhibition of reuptake of catecholamines already
released (e.g. cocaine & tricyclic antidepressants)
From: Adrenoceptor Agonists & Sympathomimetic Drugs
Basic & Clinical Pharmacology, 13e, 2015
Legend:
Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine
target monoamine (norepinephrine, dopamine, and serotonin) transporters with different potencies. A shows the mechanism of
reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is
sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). B and C show the effects of
amphetamine and cocaine on these pathways. See text for details.
Date of download: 3/12/2015
Copyright © 2015 McGraw-Hill Education. All rights reserved.
Sympathomimetic Drugs
III.

Mixed acting sympathomimetics:
Indirectly
induce
the
release
of
norepinephrine from the presynaptic
terminal and directly activate receptors
(e.g. Ephedrine)
Organ System Effects of
Sympathomimetic Drugs

The response of any cell or organ to
sympathomimetics is the density and
proportion of α and β adrenergic receptors

Adrenergically innervated organs and
tissues tend to have a predominance of
one type of receptor: tissues such as the
vasculature to skeletal muscle have both
α1 and β2 receptors, but the β2 receptors
predominate
Organ System Effects of
Sympathomimetic Drugs
a.





Cardiovascular system
Effects of Alpha1-Receptor Activation:
α1 receptor activation constrict skin, mucous
membranes, and splanchnic blood vessels and
causes a rise in peripheral resistance due to
vasoconstriction of most vascular beds
The enhanced arterial resistance usually leads to
a dose-dependent rise in blood pressure
In the presence of normal CV reflexes, the rise in
blood pressure elicits a compensatory reflex
bradycardia
Cardiac output may not diminish in proportion to
this reduction in rate, since increased venous
return may increase stroke volume
Organ System Effects of
Sympathomimetic Drugs
a.
Cardiovascular system

Effects of Beta-Receptor Activation

β1 receptors: direct effects on the heart are
determined largely by β1 receptors. Both the
heart rate (chronotropic effect) and the force of
contraction (inotropic effect) are increased,
resulting in a markedly increased cardiac
output and cardiac oxygen consumption

β2 receptors: activating β2 receptors, leading
to vasodilation in vasculature of skeletal
muscles
Organ System Effects of
Sympathomimetic Drugs
b.
Respiratory system

Activation of β2 receptors in bronchial
smooth muscle leads to bronchodilation
and also inhibits the release of allergy
mediator such as histamines from mast
cells
Organ System Effects of
Sympathomimetic Drugs
c.
The Eye

Activation of α1 receptors mediates
contraction of the radial pupillary dilator
muscle of the iris and results in mydriasis

Activiation of Alpha 2 receptors reduces
intraocular pressure

Activiation of β2 receptors on the ciliary
epithelium facilitate the secretion of aqueous
humor
Organ System Effects of Sympathomimetic
Drugs
Genitourinary tact
 The bladder:
 Stimulation of α1A receptors mediate the
contraction of the trigone and sphincter
 Stimulation of β2 receptors cause the
relaxation of the detrusor muscle
 This can result in hesitancy in urination
and may contribute to retention of urine
in the bladder
d.
Organ System Effects of Sympathomimetic
Drugs
Genitourinary tact
 Uterus
(female): Stimulation of β2
receptors mediate relaxation which may
cause significant uterine relaxation
d.

Genitile (male): α1 receptor activation
mediates the contraction of smooth
muscles in the ductus deferens, seminal
vesicles, and prostate resulting in normal
ejaculation
Organ System Effects of Sympathomimetic
Drugs
e.
Gastrointestinal tract

Activation of both α1 and β2 receptors, located
both on smooth muscles and on neurons of
the enteric nervous system
leads to
relaxation of GIT

Stimulation of α2 receptors decrease muscle
activity indirectly by presynaptically reducing
the release of acetylcholine and may also
decrease salt and water flux into the lumen of
the intestine
Organ System Effects of Sympathomimetic
Drugs
f.
Metabolism
1.
Lipolysis: enhanced by stimulating β3
receptors in adipocytes
2.
Glycogenolysis: β2 receptors in the liver
and muscles
3.
Insulin secretion: is inhibited by α2
receptors activation and is enhanced by
activation of β2 receptors
Organ System Effects of
Sympathomimetic Drugs
h.
Hormones secretion

Renin secretion is stimulated by β1 and
inhibited by α2 receptors
Direct acting adrenergic agonists
Catecholamine
a.
Epinephrine (adrenaline)

It is an agonist at both α and β adrenergic receptors

Respiratory: bronchodilation and inhibiting the
release of allergy mediators such as histamines from
mast cells (β2 action)

Hyperglycemia: because of increased glycogenolysis
in the liver (β2 effect), increased release of glucagon
(β2 effect), and a decreased release of insulin (α2
effect)

Lipolysis: epinephrine initiates lipolysis through its
agonist activity on the β receptors of adipose tissue
Direct acting adrenergic agonists
Catecholamine
a.
Epinephrine (adrenaline)

Cardiovascular effect:

Epinephrine is a very potent cardiac stimulant
(predominantly β1 receptors): cardiac output
increases and myocardial oxygen demand is
increased

Epinephrine causes a decrease in total peripheral
resistance that results from the predominance of
vasodilation in the skeletal muscle vascular bed

Therefore, the cumulative effect is an increase in
systolic blood pressure, coupled with a slight
decrease in diastolic pressure
Direct acting adrenergic agonists
catecholamine
b.
Norepinephrine (noradrenaline)

Activates both α-adrenergic receptor (α1 & α2) and
β1 receptors, but has relatively no effect on β2
receptors

Norepinephrine increases peripheral resistance and
both diastolic and systolic blood pressure

Compensatory baroreflex activation tends to
overcome the direct positive chronotropic effects of
norepinephrine; however, the positive inotropic
effects on the heart are maintained
Direct acting adrenergic agonists
Catecholamine
c.
Isoproterenol (isoprenaline)

Predominantly stimulates both β1- and β2adrenergic receptors. It has little effect on αreceptors

It produces intense stimulation of the heart to
increase its rate and force of contraction,
causing increased cardiac output

It also dilates the arterioles of skeletal muscle
(β2 effect), resulting in decreased peripheral
resistance: these actions lead to a marked
fall in diastolic and mean arterial pressure
Cardiovascular effects of sympathomimetics
Norepinephrine
PULSE RATE
(min)
Isoproterenol
Epinephrine
100
50
BLOOD
PRESSURE
(mm Hg)
180
120
80
PERIPHERAL
RESISTANCE
0
15
0
15
TIME
(min)
0
15
Direct acting adrenergic agonists
Direct acting sympathomimetics
a.
Phenylphrine

It binds primarily to α receptors and
favours α1 receptors over α2 receptors

It has no effect on the heart itself but
rather induces reflex bradycardia when
given parenterally

It is often used topically on the nasal
mucous membranes as a decongestant
and in ophthalmic solutions for mydriasis
Direct acting adrenergic agonists
Direct acting sympathomimetics
b.
Midodrine

Is a selective α1-receptor agonist

Primarily indicated for the treatment of
orthostatic hypotension, typically due to
impaired autonomic nervous system function

The drug may cause hypertension when the
subject is supine. This can be minimized by
avoiding dosing prior to bedtime and elevating
the head of the bed
Direct acting adrenergic agonists
Direct acting sympathomimetics
c.
Oxymetazoline

Is a direct-acting α-adrenoceptor agonists

It is used as topical decongestants (nasal
spray) because of their ability to promote
constriction of the nasal mucosa

When
taken
in
large
doses,
oxymetazoline may cause hypotension,
presumably because of a central
clonidine-like effect (α2A receptors)
Direct acting adrenergic agonists
Direct acting sympathomimetics
d.
Alpha2-selective agonists

Agents:
clonidine,
guanfacine, guanabenz

These agents are used primarily for
the treatment of systemic hypertension
due to their ability to decrease blood
pressure through actions in the CNs
methyldopa,
Direct acting adrenergic agonists
Direct acting sympathomimetics
g.
Beta-selective agonists

β1-selective agents:

Dobutamine: it increases cardiac
output (positive inotropic action) with
little change in heart rate, and it does
not significantly elevate oxygen
demands of the myocardium—a major
advantage
over
other
sympathomimetic drugs
Direct acting adrenergic agonists
Direct acting sympathomimetics
g.
Beta-selective agonists



β2-selective agents:
Albuterol,
pributerol,
terbutaline,
salmeterol and formoterol : used
primarily
as
bronchodilator
the
treatment of asthma
Ritodrine is used clinically to achieve
uterine relaxation in premature labour
(arrest premature labour)
Therapeutic Uses of Sympathomimetic Drugs
a. Cardiovascular applications
1)
Hypotensive emergency to preserve
cerebral and coronary blood flow: direct
acting α agonists such as: norepinephrine,
phenylephrine, and methoxamine is used for short
duration
2)
Chronic orthostatic hypotension: increasing
peripheral resistance is one of the strategies to
treat chronic orthostatic hypotension using
midodrine (α1 agonist Midodrane ) or droxidopa
3)
Emergency treatment of cardiac arrest:
isoproterenol and epinephrine
Therapeutic Uses of Sympathomimetic Drugs
a. Cardiovascular applications
4)
Cardiogenic and septic shock: Dopamine is
the drug of choice b/c it is a β receptor agonists
increase heart rate and force of contraction, α
receptor agonists increase peripheral vascular
resistance, and it enhances perfusion to the
kidney and splanchnic areas (D1 receptors)
5)
Acute heart failure: Dobutamine is a β1
agonists useful in this situation because it
increases cardiac output and, cause relatively little
peripheral vasoconstriction.
It does not
significantly elevate oxygen demands of the
myocardium
Therapeutic Uses of Sympathomimetic Drugs
b. Inducing Local Vasoconstriction

Reduction of local or regional blood flow
through α-receptor activation is desirable
for:
1)
Achieving hemostasis in surgery, for
reducing diffusion of local anesthetics
away from the site of administration:
1:200,000 parts epinephrine
2)
Reducing mucous membrane congestion
(decongestant):
phenylephrine,
xylometazoline, and oxymetazoline (nasal
spray)
Therapeutic Uses of Sympathomimetic Drugs
c. Pulmonary applications

Epinephrine is the primary drug used in the
emergency treatment of bronchoconstriction

Short-acting β2-selective agents (albuterol,
metaproterenol, terbutaline) are used in the
treatment of acute asthmatic bronchoconstriction

Longer-acting β2-selective agonists (salmeterol
and formoterol) are used in combination with
corticosteroids for chronic asthma treatment in
adult

Ultra-long acting β2 agonists (Indacaterol,
olodaterol, and vilanterol) are approved for oncea-day use in COPD
Therapeutic Uses of Sympathomimetic Drugs
d. Anaphylaxis

Epinephrine (IM) is the DOC for the
immediate treatment of anaphylactic
shock

It can relief bronchospasm, mucous
membrane congestion, angioedema, and
severe hypotension associated with
anaphylactic shock, and can inhibit the
release of allergy mediators such as
histamine from mast cells
Therapeutic Uses of Sympathomimetic Drugs
e. Ophthalmic Applications

The α- agonists phenylephrine is an effective
mydriatic agent frequently used to facilitate
examination of the retina and are useful
decongestant for minor allergic hyperemia and
itching of the conjunctival membranes

Sympathomimetics administered as ophthalmic
drops are also useful in localizing the lesion in
Horner's syndrome

Apraclonidine and brimonidine (α2-selective
agonists) that lower intraocular pressure and are
approved for use in glaucoma
Right Horner's syndrome
Therapeutic Uses of Sympathomimetic Drugs
f. Genitourinary Applications

Ritodrine & terbutaline (selective β2
agonist) have been used to suppress
premature labor

β-agonist therapy may have no
significant benefit on perinatal infant
mortality and may increase maternal
morbidity