Adrenergic
pharmacology
Catecholamine
Synthesis,
Storage, and
Release
• Reuptake of catecholamine into the neuronal
cytoplasm is mediated by a selective catecholamine
transporter ( norepinephrine transporter, or NET)
that is also known as Uptake 1. Approximately 90%
of the released norepinephrine is taken up by this
process (recycled); the remainder is either
metabolized locally or diffuses into the blood. thus,
limiting the postsynaptic response and allowing
neurons to recycle the transmitter for subsequent
release.
• Catecholamine metabolism involves the two
enzymes MAO and catechol-O-methyltransferase
(COMT).
Adrenergic
receptors
(adrenoceptors)
• α receptors(α1, α2)
epinephrine = norepinephrine >>
isoproterenol
• β-Adrenoceptors (β1, β2, and β3)
• is isoproterenol > epinephrine >
norepinephrine
• β1 receptors have approximately
equal affinities for epinephrine
and norepinephrine, whereas β2
receptors have a higher affinity
for epinephrine than for
norepinephrine.
Distribution
of adrenergic
receptors
Adrenergic agonists can be
classified according to
mechanism of action into:
• Direct-acting agonists
• Indirect-acting agonists
cocaine and amphetamine
• Mixed-action agonists
Ephedrine and pseudoephedrine
DIRECT-ACTING
ADRENERGIC
AGONISTS
Epinephrine
Cardiovascular:
• ↑ heart rate and ↑
contractility → cardiac output→
↑ systolic blood pressure. This
effect is mainly caused by Β1
activation in the heart
• Epinephrine constricts arterioles
in the skin, mucous membranes,
and viscera (α effects), and it
dilates vessels going to the liver
and skeletal muscle (β2 effects).
Consequently, total peripheral
resistance(PVR) may actually
fall, explaining the fall in
diastolic pressure that is seen
with epinephrine injection.
Therefore, the cumulative effect
is an increase in systolic blood
pressure, coupled with a slight
• decrease in diastolic pressure
due to ß2 receptor–mediated
vasodilation in the skeletal
muscle vascular bed
DIRECT-ACTING
ADRENERGIC
AGONISTS
Epinephrine
• Respiratory: Epinephrine causes powerful
bronchodilation by acting directly on bronchial
smooth muscle (ß2 action). It also inhibits the
release of allergy mediators such as histamine from
mast cells.
• Hyperglycemia: Epinephrine has a significant
hyperglycemic effect because of increased
glycogenolysis in the liver (ß2 effect), increased
release of glucagon (ß2 effect), and a decreased
release of insulin (α2 effect).
• Lipolysis: Epinephrine initiates lipolysis through
agonist activity on the ß receptors of adipose tissue.
• Epinephrine activates β1 receptors on the kidney to
cause renin release. Renin is an enzyme involved in
the production of angiotensin II, a potent
vasoconstrictor.
DIRECT-ACTING
ADRENERGIC
AGONISTS
Epinephrine
• Therapeutic uses:
A. Anaphylactic shock: Epinephrine is the drug of choice
for the treatment of type I hypersensitivity reactions
(including anaphylaxis) in response to allergens.
B. Cardiac arrest: Epinephrine may be used to restore
cardiac rhythm in patients with cardiac arrest.
C. Local anesthesia: Local anesthetic solutions may
contain low concentrations (for example, 1:100,000
parts) of epinephrine. Epinephrine greatly increases
the duration of local anesthesia by producing
vasoconstriction at the site of injection. Epinephrine
also reduces systemic absorption of the local
anesthetic and promotes local hemostasis.
• Adverse effects:
DIRECT-ACTING
ADRENERGIC
AGONISTS
Epinephrine
• Epinephrine can produce adverse CNS effects that include anxiety,
fear, tension, headache, and tremor.
• It can trigger cardiac arrhythmias, particularly if the patient is
receiving digoxin.
• Epinephrine can also induce pulmonary edema due to increased
afterload caused by vasoconstrictive properties of the drug.
• Patients with hyperthyroidism may have an increased production of
adrenergic receptors in the vasculature, leading to an enhanced
response to epinephrine, and the dose must be reduced in these
individuals.
• Epinephrine increases the release of endogenous stores of glucose.
In diabetic patients, dosages of insulin may have to be increased.
• Nonselective ß-blockers prevent vasodilatory effects of epinephrine
on ß2 receptors, leaving a receptor stimulation unopposed. This may
lead to increased peripheral resistance and increased blood pressure.
DIRECT-ACTING
ADRENERGIC
AGONISTS
Epinephrine
Question for you : can epinephrine be
used in the treatment of asthma?
• Norepinephrine
DIRECT-ACTING
ADRENERGIC
AGONISTS
Norepinephrine
• is an agonist at both α1 and α2
receptors. Norepinephrine also activates
ß1 receptors with similar potency as
epinephrine, but has relatively little
effect on ß2 receptors. Consequently,
norepinephrine increases peripheral
resistance and both diastolic and systolic
blood pressure.
• Compensatory baroreflex activation :
• Norepinephrine increases blood
pressure, and this stimulates the
baroreceptors, inducing a rise in vagal
activity. The increased vagal activity
produces a reflex bradycardia, which is
sufficient to counteract the local actions
of norepinephrine on the heart,
although the reflex compensation does
not affect the positive inotropic effects
of the drug
DIRECT-ACTING
ADRENERGIC
AGONISTS
Norepinephrine
• Therapeutic uses: Norepinephrine is used to treat
shock (for example, septic shock), because it increases
vascular resistance and, therefore, increases blood
pressure. It has no other clinically significant uses.
• Pharmacokinetics: Norepinephrine is given IV for
rapid onset of action. The duration of action is 1 to 2
minutes, following the end of the infusion. It is rapidly
metabolized by MAO and COMT, and inactive
metabolites are excreted in the urine.
• Adverse effects: These are similar to epinephrine. In
addition, norepinephrine is a potent vasoconstrictor
and may cause blanching and sloughing of skin along an
injected vein.
• Question for you : can Norepinephrine be used in
the treatment of asthma?
DIRECT-ACTING
ADRENERGIC
AGONISTS
Isoproterenol
(isoprenaline) )
• Isoproterenol (isoprenaline)
• It is a very potent ß-receptor
agonist and has little effect on a
receptors. The drug has positive
chronotropic and inotropic
actions; because isoproterenol
activates ß receptors almost
exclusively with insignificant
effect on α receptors, it is a
potent
vasodilator.
These
actions lead to a marked
increase in cardiac output
associated with a fall in diastolic
and mean arterial pressure and
a slight increase in systolic
pressure
DIRECT-ACTING
ADRENERGIC
AGONISTS
Dopamine
• Dopamine
• Dopamine is the immediate precursor of norepinephrine.
Dopamine can activate a- and ß-adrenergic receptors. At higher
doses, it causes vasoconstriction by activating α1 receptors,
whereas at lower doses, it stimulates ß1 cardiac receptors. In
addition, D1 and D2 dopaminergic receptors, different from the
a- and ß-adrenergic receptors, occur in the peripheral
mesenteric and renal vascular beds, where binding of dopamine
produces vasodilation.
• Therapeutic uses:
• Dopamine can be used for cardiogenic and septic shock and is
given by continuous infusion. It raises blood pressure by
stimulating the ß1 receptors on the heart to increase cardiac
output and α1 receptors on blood vessels to increase total
peripheral resistance.
• It enhances perfusion to the kidney and splanchnic areas, as
described above. Increased blood flow to the kidney enhances
the glomerular filtration rate and causes diuresis. By contrast,
norepinephrine can diminish blood supply to the kidney and
may reduce renal function.
• Salbutamol, metaproterenol, and terbutaline
DIRECT-ACTING
ADRENERGIC
AGONISTS
• they are short-acting β2 agonists (SABAs) used primarily as
bronchodilators and administered by a metered-dose inhaler .
Salbutamol is the SABA of choice for the management of acute asthma
symptoms.
• terbutaline is used as a uterine relaxant to suppress premature
labor, and use for this indication should not exceed 72 hours.
• One of the most common side effects of these agents is tremor, but
patients tend to develop tolerance to this effect. Other side effects
include restlessness, apprehension, and anxiety. When these drugs are
administered orally, they may cause tachycardia or arrhythmia (due to
β1 receptor activation), especially in patients with underlying cardiac
disease.
• Salmeterol, formoterol, and indacaterol
• They are long-acting ß2 selective agonists (LABAs) used for the
management of respiratory disorders such as asthma and chronic
obstructive pulmonary disease
• INDIRECT-ACTING SYMPATHOMIMETICS
INDIRECTACTING
ADRENERGIC
AGONISTS
• Indirect-acting sympathomimetics can have one of two different
mechanisms . First, they may enter the sympathetic nerve ending and
displace stored catecholamine transmitter. Such drugs have been called
amphetamine-like or “displacers.” Second, they may inhibit the reuptake of
released transmitter by interfering with the action of the norepinephrine
transporter, NET.
• Amphetamine and amphetamine like
• Amphetamine it displaces endogenous catecholamines from storage vesicles
(similar to tyramine). It can enter the CNS, where it has marked stimulant effects on
mood and alertness and a depressant effect on appetite. Amphetamine’s actions are
mediated through the release of norepinephrine and, to some extent, dopamine.
• Amphetamine can cause psychological and physiologic dependence as well as
tolerance. Amphetamine may cause paranoia and hallucinations.
Methamphetamine (“crystal meth”) is a major drug of abuse
• Tyramine
• Tyramine is a dietary amine that is ordinarily metabolized by MAO in the
gastrointestinal tract and liver. In patients taking MAO inhibitors tyramine is
absorbed in the gut, transported through the blood, and taken up by sympathetic
neurons, where it is transported into synaptic vesicles by VMAT. Uptake of tyramine
by the synaptic vesicles causes displacement o vesicular norepinephrine and
nonvesicular release of norepinephrine from the nerve terminal via reversal of NET.
• Catecholamine Reuptake Inhibitors
• Tricyclic Antidepressant, Cocaine, by inhibiting NET
MIXED-ACTING
ADRENERGIC
AGONISTS
• Ephedrine and pseudoephedrine are mixedaction adrenergic agents. They not only enhance
release of stored norepinephrine from nerve
endings but also directly stimulate both a and ß
receptors. Ephedrine and pseudoephedrine are not
catecholamines and are poor substrates for COMT
and MAO. Therefore, these drugs have a long
duration of action. Oral pseudoephedrine is
primarily used to treat nasal and sinus congestion