Adrenergic Agonist

The adrenergic drugs affect receptors that are

stimulated by norepinephrine or epinephrine.
Some adrenergic drugs act directly on the adrenergic
receptor (adrenoceptor) by activating it and are said to
be sympathomimetic.
Others will block the action of the neurotransmitters at
the receptors (sympatholytics), whereas still other
drugs affect adrenergic function by interrupting the
release of norepinephrine from adrenergic neurons.
Adrenergic neurons release norepinephrine as the primary
neurotransmitter.
These neurons are found in the central nervous system (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.
1. SYNTHESIS OF NOREPINEPHRINE
 Hydroxylation of tyrosine is the rate-limiting step

2. UPTAKE INTO STORAGE VESICLES

 Dopamine enters vesicle & is converted to
norepinephrine
 Norepinephrine is protected from degradation in vesicle
 Transport into vesicle is inhibited by reserpine
3. RELEASE OF NEUROTRANSMITTER
 Influx of calcium causes fusion of vesicle w/ cell
membrane
 Release blocked by guanethidine & bretylium
4. BINDING TO RECEPTOR
 Postsynaptic receptor activated by binding of
neurotransmitter

5. REMOVAL OF NOREPINEPHRINE
 Released norepinephrine is rapidly taken into neuron
 Uptake is inhibited by cocaine & imipramine

6. METABOLISM
 Norepinephrine is methylated by COMT & oxidized by
monoamine oxidase
 ADRENOCEPTORS

α- β-
RECEPTOR RECEPTOR
S S

α1- α2- β1- β2- β3-

receptor receptor receptor receptor receptor
The α-adrenoceptors show a weak response to the
synthetic agonist isoproterenol, but they are
responsive to the naturally occurring
catecholamines epinephrine and norepinephrine.
For α receptors, the rank order of potency is
epinephrine ≥ norepinephrine >> isoproterenol.
The α-adrenoceptors are subdivided into two
subgroups, α1 and α2, based on their affinities for α
agonists and blocking drugs.
For example, the α1 receptors have a higher affinity
for phenylephrine than do the α2 receptors.
β Receptors exhibit a set of responses different from
those of the α receptors.
These are characterized by a strong response to
isoproterenol, with less sensitivity to epinephrine and
norepinephrine.
For β receptors, the rank order of potency is isoproterenol >
epinephrine > norepinephrine.
The β-adrenoceptors can be subdivided into three major
subgroups, β1, β2, and β3, based on their affinities for
adrenergic agonists and antagonists, although several
others have been identified by gene cloning.
β1 Receptors have approximately equal affinities for
epinephrine and norepinephrine, whereas β2 receptors
have a higher affinity for epinephrine than for
norepinephrine.
Most of the adrenergic drugs are derivatives of β-
phenylethylamine.

Two important structural features of these drugs are:

1. the number and location of OH substitutions on the benzene
ring &
2. the nature of the substituent on the amino nitrogen.
 Sympathomimetic amines that contain the 3,4-
dihydroxybenzene group: (such as epinephrine,
norepinephrine, isoproterenol, and dopamine)
are called catecholamines.

These compounds share the following

properties:
1. High
potency
2Rapid inactivation
3. Poor penetration
into the CNS
 Compounds lacking the catechol hydroxyl
groups have longer half-lives, because they
are not inactivated by COMT(catechol methyl
transferase).

These include:
 phenylephrine,
 ephedrine, and
 amphetamine.
Epinephrine is synthesized from tyrosine in the adrenal
medulla and released, along with small quantities of
norepinephrine, into the bloodstream.
Epinephrine interacts with both α and β receptors.
At low doses, β effects (vasodilation) on the vascular
system predominate, whereas at high doses, α effects
(vasoconstriction) are strongest.
CARDIOVASCULAR RESPIRATORY HYPERGLYCEMIA LIPOLYSIS

Epinephrine Epinephrine causes Epinephrine has a Epinephrine initiates

strengthens the powerful significant lipolysis through its
contractility of the bronchodilation by hyperglycemic effect agonist activity on the
β
myocardium (positive acting directly on because of increased receptors of adipose
inotropic: β1 action) bronchial smooth glycogenolysis in the tissue, which upon
and muscle (β2 action). liver (β2 effect), stimulation activate
increases its rate of increased release of adenylyl cyclase to
contraction (positive
chronotropic: β1 action). glucagon (β2 effect), increase cAMP levels.
and a decreased
release
of insulin (α2 effect).
BRONCHOSPASM GLAUCOMA ANAPHYLACTIC CARDIAC ANESTHETIC
SHOCK ARREST S
Epinephrine is the In Epinephrine is Epinephrine may The effect of
primary drug used ophthalmology, the drug of be used to the drug is to
in the emergency a two-percent choice for the restore cardiac greatly
treatment of any epinephrine treatment of rhythm in increase the
condition of the solution may be Type I patients with duration of the
respiratory tract used topically to hypersensitivity cardiac arrest local
when reduce reactions in regardless of the anesthesia.
bronchoconstrictio intraocular response to cause.
n has resulted in pressure in allergens.
diminished open- angle
respiratory glaucoma.
exchange.
CNS
DISTURBANCE

Includes: anxiety, fear, HEMORRHAGE

tension, headache, and
tremor. CARDIAC
ARRYTHMIA
S
PULMONARY
EDEMA
 Because norepinephrine is the neuromediator of
adrenergic nerves, it should theoretically stimulate all
types of adrenergic receptors.
In practice, when the drug is given in therapeutic doses
to humans, the α-adrenergic receptor is most affected.
VASOCONSTRICTION BARORECEPTOR REFLEX EFFECTS OF ATROPINE
PRE-TREATMENT

Norepinephrine causes a rise in In isolated cardiac tissue, If atropine, which blocks the
peripheral resistance due to norepinephrine stimulates transmission of vagal effects,
intense vasoconstriction of cardiac contractility; however, in is given before norepinephrine,
most vascular beds, including vivo, little if any cardiac then norepinephrine stimulation
the stimulation is noted. of the heart is evident as
kidney (α1 effect). tachycardia.
Isoproterenol is a direct-acting synthetic catecholamine
that predominantly stimulates both β1- and β2-
adrenergic receptors.
Its nonselectivity is one of its drawbacks and the reason
why it is rarely used therapeutically.
Its action on α receptors is insignificant.
CARDIOVASCULAR PULMONARY OTHER EFFECTS
Isoproterenol produces Isoproterenol is as active as Other actions on β
intense stimulation of the epinephrine and rapidly receptors, such as
heart to increase its rate alleviates an acute attack increased blood sugar and
and force of contraction, of asthma when taken by increased lipolysis, can be
causing increased cardiac inhalation (which is the demonstrated but are not
output. recommended route). clinically significant.
Dopamine, the immediate metabolic
precursor of norepinephrine, occurs
naturally in the CNS in the basal ganglia,
where it functions as a neurotransmitter,
as well as in the adrenal medulla.
Dopamine can activate α- and β-
adrenergic receptors.
CARDIOVASCULAR RENAL &
VISCERAL
Dopamine exerts a stimulatory effect on Dopamine dilates renal and splanchnic
the β1 receptors of the heart, having both arterioles by activating dopaminergic
inotropic and chronotropic effects. receptors, thus increasing blood flow to
the kidneys and other viscera.
Therefore, dopamine is clinically useful
in the treatment of shock, in which
significant increases in sympathetic
activity might compromise renal
function.
Dobutamine is a synthetic, direct-acting catecholamine
that is a β1-receptor agonist.
One of the stereoisomers has a stimulatory activity.
It increases cardiac rate and output with few vascular
effects.
Dobutamine is used to increase cardiac output in
congestive heart failure as well as for inotropic support
after cardiac surgery.
Oxymetazoline is a direct-acting synthetic adrenergic
agonist that stimulates both α1- and α2-adrenergic
receptors.
It is primarily used locally in the eye or the nose as a
vasoconstrictor.
Oxymetazoline is found in many over-the-counter short-
term nasal spray decongestant products as well as in
ophthalmic drops for the relief of redness of the eyes
associated with swimming, colds, or contact lens.
Phenylephrine is a direct-acting, synthetic adrenergic
drug that binds primarily to α receptors and favors α1
receptors over α2 receptors.
It is not a catechol derivative and, therefore, not a
substrate for COMT.
Phenylephrine is a vasoconstrictor that raises both
systolic
and diastolic blood pressures.
Methoxamine is a direct-acting, synthetic adrenergic
drug that binds primarily to α-receptors, with α1
receptors favored over α2 receptors.
Methoxamine raises blood pressure by stimulating α1
receptors in the arterioles, causing vasoconstriction.
This causes an increase in total peripheral resistance.
Clonidine is an α2 agonist that is used in essential
hypertension to lower blood pressure because of its
action in the CNS.
It can be used to minimize the symptoms that
accompany withdrawal from opiates or
benzodiazepines.
Clonidine acts centrally to produce inhibition of
sympathetic vasomotor centers, decreasing
sympathetic outflow to the periphery.
Metaproterenol, although chemically similar to
isoproterenol, is not a catecholamine, and it is
resistant to methylation by COMT.
Metaproterenol produces dilation of the bronchioles
and improves airway function.
The drug is useful as a bronchodilator in the
treatment of asthma and to reverse bronchospasm.
Albuterol, pirbuterol, and terbutaline are short-
acting β2 agonists used primarily as
bronchodilators and administered by a
metered- dose inhaler.
Salmeterol and formoterol are β2-adrenergic
selective, long-acting bronchodilators.
Salmeterol and formoterol are the agents of choice
for treating nocturnal asthma in symptomatic
patients taking other asthma medications.
The marked central stimulatory action of amphetamine
is often mistaken by drug abusers as its only action.
The CNS stimulant effects of amphetamine and its
derivatives have led to their use for treating
hyperactivity in children, narcolepsy, and appetite
control.
Its use in pregnancy should be avoided because of
adverse
effects on development of the fetus.
Tyramine is not a clinically useful drug, but it is
important because it is found in fermented foods,
such as ripe cheese and Chianti wine.
It is a normal by-product of tyrosine metabolism.
Normally, it is oxidized by MAO in the gastrointestinal
tract, but if the patient is taking MAO inhibitors, it can
precipitate serious vasopressor episodes.
Cocaine is unique among local anesthetics in having
the ability to block the Na+/K+-activated ATPase
(required for cellular uptake of norepinephrine) on the
cell membrane of the adrenergic neuron.
Like amphetamines, it can increase blood pressure by
α- agonist actions and β-stimulatory effects.
Ephedrine, and pseudoephedrine are plant alkaloids,
that are now made synthetically.
These drugs are mixed-action adrenergic agents.
They not only release stored norepinephrine from
nerve endings but also directly stimulate both α and β
receptors.
Thus, a wide variety of adrenergic actions ensue that
are
similar to those of epinephrine, although less potent.
Ephedrine enhances contractility and improves motor
function in myasthenia gravis.
Ephedrine has been used to treat asthma, as a nasal
decongestant (due to its local vasoconstrictor action),
and to raise blood pressure.
Pseudoephedrine is primarily used to treat nasal and
sinus
congestion or congestion of the eustachian tubes.