adrenergic agonists & antagonists

 The sympathetic nervous system (SNS) is
one of the two main divisions of
the autonomic nervous system, the other
being the parasympathetic nervous system.
 The sympathetic nervous system's primary
process is to stimulate the body for fight-or-
flight response.
 It serves to accelerate the heart rate,
constrict blood vessels, and raise blood
pressure.

 Norepinephrine is the primary neurotransmitter.
 Neurotransmission process involves five steps:
synthesis, storage, release, and receptor binding
of norepinephrine, followed by removal of the
neurotransmitter from the synaptic gap

 Adrenoceptors are typically G-protein coupled
receptors.
 In the sympathetic nervous system, two main
families of receptors, designated as alpha and
beta, are classified on the basis of their
responses to adrenergic agonists epinephrine,
norepinephrine and isoproterenol.
 Alpha adrenoceptors: more responsive to
naturally occuring catecholamines, epinephrine
and norepinephrine than synthetic agonist
isoproterenol
 Beta adrenoceptors: show strong response to
isoproterenol with less sensitivity to epinephrine
and norepinephrine

 Dopamine receptors: However one more
family of receptors is also present which
show strong response for dopamine. These
are distinct from alpha & beta receptors.
Adrenergic receptors classification
 Alpha receptors: alpha1 and alpha2
 Beta receptors: beta1, beta2 and beta3
 Dopamine receptors: D1 & D2 (D3, D4, D5)

Receptor sub
type
Type of G-
protein
coupled
receptor
Basic pathway Location
α1 Gq Stimulation of
PLC, formation
of IP3 & DAG
Vascular smooth muscle, eye,
prostate, heart
α2 Gi InhibitIon of
adenylyl
cyclase,
decrese in cAMP
Postsynaptic CNS neurons,
adrenergic & cholinergic
nerve terminals,
β1 Gs Stimulation of
adenylyl
cyclase,
increase in
cAMP
Heart & kidney
β2 Respiratory, uterine &
vascular smooth muscles, liver
β3 Fat cells
D1 Smooth muscle of kidney
D2 Gi InhibitIon of
adenylyl
cyclase,
decrese in cAMP
Nerve endings (modulates
transmitter release)

 A.) Catecholamines They are called
catecholamines because they contain a catechol
group. Epinephrine, norepinephrine,
isoproterenol, and dopamine) are called
catecholamines. These compounds share the
following properties:
1) High potency: show the highest potency in
directly activating α or β receptors.
2) Rapid inactivation: rapidly metabolized by
COMT and MAO, catecholamines have only a
brief period of action.
3) Poor penetration into the CNS:
Catecholamines are polar and, therefore, do
not readily penetrate into the CNS.

 B.) Non-catecholamines: Compounds lacking
the catechol hydroxyl groups have prolonged
duration of action, because they are not
inactivated by COMT and poor substrates for
MAO because MAO is an important route of
detoxification. Increased lipid solubility
permits greater access to the CNS.
 These include phenylephrine, ephedrine, and
amphetamine.

 Direct-acting agonists: These drugs act
directly on α or β receptors, producing effects
similar to those that occur following stimulation
of sympathetic nerves.
 Indirect-acting agonists: These agents, which
include amphetamine, cocaine and tyramine,
may
1) block the uptake of norepinephrine
2) cause the release of norepinephrine from
adrenergic neuron.
3) inhibit the degradation of NE
 Mixed-action agonists: Some agonists, have
the capacity both to stimulate adrenoceptors
directly and to release norepinephrine from the
adrenergic neuron.

A. Epinephrine
 Epinephrine is one of four catecholamines.
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.
Actions:
1. Cardiovascular: The major actions of
epinephrine are on the cardiovascular system.
Epinephrine strengthens the contractility of the
myocardium (positive inotropic: β1 action) and
increases its rate of contraction (positive
chronotropic: β1action). Cardiac output
therefore increases.

2. Respiratory: Epinephrine causes
powerful bronchodilation by
acting directly on bronchial
smooth muscle (β2 action).
3. Hyperglycemia: Epinephrine
has a significant hyperglycemic
effect because of increased
glycogenolysis in the liver (β2
effect), increased release of
glucagon (β2 effect), and a
decreased release of insulin (α2
effect)..
Glycogenolysis
is the
biochemical
breakdown of
glycogen to
glucose

4. Lipolysis: Epinephrine initiates lipolysis
through its agonist activity on the β
receptors of adipose tissue.
 Therapeutic uses:
1. Bronchospasm:Epinephrine is the primary
drug used in the emergency treatment of
any condition of the respiratory tract when
bronchoconstriction has resulted in
diminished respiratory exchange. Thus, in
treatment of acute asthma and
anaphylactic shock, epinephrine is the drug
of choice.

2. Glaucoma: In ophthalmology, a 2%
epinephrine solution may be used topically to
reduce intraocular pressure in open-angle
glaucoma.
3. Anaphylactic shock: Epinephrine is the drug
of choice for the treatment of (Type I)
hypersensitivity reactions.
4. Cardiac arrest: Epinephrine may be used to
restore cardiac rhythm in patients with
cardiac arrest regardless of the cause.

 5. Anesthetics: (very important to dentists)
 Local anesthetic solutions usually contain
1:100,000 parts epinephrine. The effect of
the drug is to greatly increase the duration
of the local anesthesia. It does this by
producing vasoconstriction at the site of
injection, thereby allowing the local
anesthetic to persist at the injection site
before being absorbed into the circulation
and metabolized
 Adverse effects: anxiety, fear,
tension,tremors, cardiac arrythmias etc

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 and β1 adrenergic
receptor is most affected.
 Cardiovascular actions:
Vasoconstriction: Norepinephrine causes a rise
in peripheral resistance due to intense
vasoconstriction of most vascular beds,
including the kidney (α1 effect). Both systolic
and diastolic blood pressures increase.
Norepinephrine causes greater vasoconstriction
than does epinephrine, because it does not
induce compensatory vasodilation via β2
receptors. The weak β2 activity of
norepinephrine also explains why it is not
useful in the treatment of asthma.
Peripheral
resistance is
the resistance of
the arteries to
blood flow. As the
arteries constrict,
the resistance incr
eases and as they
dilate, resistance
decreases.

 Baroreceptor reflex: NE
increases blood pressure by
stimulating the
baroreceptors, that
induces a rise in vagal
activity. This reflex
bradycardia 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.
Baroreceptors are
mechanoreceptors, their
function is to sense
pressure changes by
responding to change in
the tension of the
arterial wall.
The baroreceptor
reflex is one of the
body's homeostatic
mechanisms that helps
to maintain blood
pressure at nearly
constant levels.

 Therapeutic uses: Norepinephrine is used to
treat shock, because it increases vascular
resistance and, therefore, increases blood
pressure. Other actions of norepinephrine
are not considered to be clinically
significant. It is never used for asthma or in
combination with local anesthetics.
 Note: When norepinephrine is used as a drug,
it is sometimes called levarterenol.

 Can activate both alpha and beta adrenoceptors and
also dopaminergic recptors
 Drug of choice for shock (raises blood pressure) and
superior to norepinephrine which diminishes blood
supply to kidneys and may cause renal shutdown
 Adverse effects: nausea, hypertension, arrythmias
Cardiovascular actions Renal and visceral
Exerts stimulatory effect
on the beta1 receptors in
the heart, having both
ionotropic and chronotropic
effects.
Dilates renal and splanchic
arterioles by activating
dopaminergic receptors,
thus increasing blood flow
to kidneys.

 A synthetic, direct acting,
β1 receptor agonist
 Increases cardiac rate and
output with few vascular
effects
 Dobutamine is used to
increase the cardiac output
in congestive heart failure,
as well as for ionotropic
support after cardiac
surgery.

 Direct acting α1 and α2 agonist
 Directly stimulates α receptors
on blood vessels supplying the
nasal mucosa and conjunctiva,
producing vasoconstriction and
decreasing congestion
 Used in many over the counter
nasal spray decongestants, as
well as in opthalmic drops for
the relief of redness of eyes
associated with swimming,
colds and contact lens.

 Direct acting adrenergic drug that binds
primarily to α1 receptors
 This drug is a vasoconstrictor that raises both
systolic and diastolic blood pressure
 Used to treat hypotension in hospitalized or
surgical patients
 Acts as nasal decongestant when applied
topically (replaced pseudoephdrine)
 Effective mydriatic

 α2 agonist that is used
for treatment of
hypertension
 Can also be used to
minimize the symptoms
that accompany
withdrawl from opiates,
tobacco smoking and
benzodiazepines
 Acts centrally on
presynaptic α2
receptors to produce
inhibition of
sympathetic vasomotor
centers, decreasing
sympathetic outflow to
the periphery

 Short acting β2 agonists used
primarily as bronchodilators and
administered by metered dose
inhaler.
 Albuterol (also known as
salbutamol) is the drug of choice
for management of acute asthma
symptoms
 Terbutaline is also used off-label
as uterine relaxant to suppress
premature labour.

 Long acting β agonists that
are β2 selective
 A single dose by MDI device
provides sustained
bronchodilation over 12
hours, compared with less
than 3 hours for albuterol.
 Not recommended as
monotherapy, but are highly
efficacious when combined
with a corticosteroid
 Agents of choice for nocturnal
asthma in symptomatic
patients taking other asthma
medications

 The marked CNS stimulatory action of
amphetamine is often mistaken by drug
abusers as its only action
 But it also increases blood pressure by alpha-
1 agonist action on the vasculature, as well
as beta-1 stimulatory effect on heart.
 It is used for treating hyperactivity in
children, narcolepsy and appetite control
due to its CNS stimulant actions

 Cocaine is unique among local anesthetics in
having ability to block sodium-chloride
dependent norepinephrine transporter
required for cellular uptake of
norepinephrine into the adrenergic neuron,
resulting in enhanced sympathetic activity.
 Like amphetamine, it can increase blood
pressure by α1 agonist action and β
stimulatory effect.
 Cocaine is also used as a drug of abuse

 Plant alkaloids, that are now made synthetically
 mixed-action adrenergic agents (not only release
stored norepinephrine from nerve endings but
also directly stimulate both α and β receptors)
 Ephedrine produces bronchodilation, but it is
less potent than epinephrine or isoproterenol
 Ephedrine enhances contractility and improves
motor function in myasthenia gravis, particularly
when used in conjunction with
anticholinesterases .

 Ephedrine produces a mild
stimulation of the CNS. This
increases alertness, decreases
fatigue, and prevents sleep.
 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
EXTRA INFO:
Ephedra-containing herbal
supplements were banned
by the U.S. Food and Drug
Administration in April
2004 because of life
threatening cardiovascular
reactions. Thus, products
containing
pseudoephedrine have
certain restrictions and
must be kept behind the
sales counter.

 The adrenergic antagonists/adrenergic
blockers/sympatholytics bind to
adrenoceptors but do not trigger the usual
receptor mediated intracellular effects.
 These drugs act by either reversibly or
irreversibly attaching to adrenoceptors, thus
preventing activation by catecholamines.
 Classified by the type of receptor they block:
--α blockers
--β blockers

 Phenoxybenzamine is nonselective, linking covalently
to both α1 and α2 receptors
Actions:
 Cardiovascular effects: By blocking α receptors,
phenoxybenzamine causes decreased peripheral
resistance. The decreased peripheral resistance
provokes a reflex tachycardia. Furthermore, the
ability to block α2 receptors in the heart can
contribute to an increased cardiac output. [Note:
These receptors when blocked will result in more
norepinephrine release, which stimulates β receptors
on the heart to increase cardiac output]. Thus, the
drug has been unsuccessful in maintaining lowered
blood pressure in hypertension and has been
discontinued for this purpose.

 Epinephrine reversal: All α-adrenergic blockers reverse the α-
agonist actions of epinephrine. α-receptor antagonism may
convert a pressor to a depressor. This change in response is
called epinephrine reversal. For example, the vasoconstrictive
action of epinephrine is interrupted, but vasodilation of other
vascular beds caused by stimulation of β receptors is not
blocked. Therefore, the systemic blood pressure decreases in
response to epinephrine given in the presence of
phenoxybenzamine .
 Phenoxybenzamine is used in the treatment of
pheochromocytoma.
 Adverse effects; can cause postural hypotension, nasal
stuffiness, nausea, and vomiting. It can inhibit ejaculation.

 Competitive blocker of α1 & α2 receptors
 Like phenoxybenzamine, it produces postural
hypotension and causes epinephrine reversal.
 Phentolamine-induced reflex cardiac stimulation and
tachycardia are mediated by the baroreceptor reflex
and by blocking the α2 receptors of the cardiac
sympathetic nerves.
 The drug can also trigger arrhythmias and anginal
pain, and it is contraindicated in patients with
coronary artery disease.
 Phentolamine is also used for the short-term
management of pheochromocytoma.
 Phentolamine is now rarely used for the treatment of
impotence (it can be injected intracavernosally to
produce vasodilation of penile arteries.

 Selective competitive blockers of the α1
receptor.
 The first three drugs are useful in the treatment
of hypertension.
 Tamsulosin and alfuzosin are indicated for the
treatment of benign prostatic hypertrophy (also
known as benign prostatic hyperplasia or BPH).
 Cardiovascular effects: All of these agents
decrease peripheral vascular resistance and
lower blood pressure by causing the relaxation of
both arterial and venous smooth muscle.
Tamsulosin has the least effect on blood
pressure. These drugs, cause minimal changes in
cardiac output, renal blood flow, and the
glomerular filtration rate.

 Adverse effects: The first dose of these drugs
produces an exaggerated orthostatic hypotensive
response that can result in syncope (fainting).
This action, termed a “first-dose” effect, may be
minimized by adjusting the first dose to one-
third or one-fourth of the normal dose and by
giving the drug at bedtime
 α1 Blockers may cause dizziness, a lack of
energy, nasal congestion, headache and
drowsiness.
 Male sexual function is not as severely affected
by these drugs as it is by phenoxybenzamine and
phentolamine;

 Selective competitive α2 blocker
 It is found as a component of the bark of the
yohimbe tree and is sometimes used as a sexual
stimulant.
 Yohimbine works at the level of the CNS to
increase sympathetic outflow to the periphery. It
directly blocks α2 receptors

 All the clinically available b-blockers are
competitive antagonists.
 Non-selective b-blockers act at both b1 and
b2 receptors, whereas cardio-selective b-
antagonists primarily block b1 receptors.
 All beta blockers lower blood pressure, but
do not induce postural hypotension, because
α receptors remain functional.

 Prototype b-adrenergic antagonist
 Blocks both b1 and b2 receptors
Actions:
 cardiovascular: diminishes cardiac output,
having both negative ionotropic & chronotropic
effects
 Peripheral vasoconstriction: prevents b2
mediated vasodilation in skeletal muscles, thus
increasing peripheral vascular resistance
 Bronchoconstriction: blocking b2 receptors in the
lungs causes contraction of bronchial smooth
muscles
 Glucose metabolism: decreased glycogenolysis
and decreased glucagon secretion

Therapeutic uses:
 Hypertension
 Angina pectoris
 Myocardial infarction
 Hyperthyroidism
Adverse effects:
 Brochoconstriction
 Arrythmias
 Sexual impairment
 Depression
 fatigue

 Blocks b1 and b2
adrenoceptors
 More potent than
propranolol
 Timolol reduces the
production of aqueous
humor in the eye
 Used topically in the
treatment of open-angle
glaucoma and occasionally
for systemic treatment of
hypertension

Acebutolol, atenolol,
esmolol, metoprolol &
nebivolol:
 These are cardioselective b1-
blockers , lower the blood
pressure in hypertension
 First line agents for treatment
of angina
 Minimize the unwanted
bronchoconstriction (b2 effect)
seen with propranolol

 Acebutolol and pindolol are not pure antagonists;
instead, they have the ability to weakly stimulate
both β1 and β2 receptors and are said to have
intrinsic sympathomimetic activity (ISA).

 stimulate the β receptor to which they are bound,
yet they inhibit stimulation by the more potent
catecholamines. The result of these opposing actions
is a much diminished effect on cardiac rate and
cardiac output compared to that of β-blockers
without ISA.
 Decreased metabolic effects: Blockers with ISA
minimize the disturbances of lipid and carbohydrate
metabolism that are seen with other β-blockers.
 Therapeutic use in hypertension: β-Blockers with
ISA are effective in hypertensive patients with
moderate bradycardia, because a further decrease in
heart rate is less pronounced with these drugs. [Note:
The b blockers with ISA are not used as anti-
arrhythmic or anti-anginal agents due to their partial
agonist effect.]

 Labetalol and carvedilol are reversible β-blockers
with concurrent α1-blocking actions that produce
peripheral vasodilation, thereby reducing blood
pressure. They contrast with the other β-blockers
that produce peripheral vasoconstriction, and they
are therefore useful in treating hypertensive patients
for whom increased peripheral vascular resistance is
undesirable.

 Therapeutic use in hypertension: Labetalol is
useful for treating the elderly or black
hypertensive patient. [Note: In general, black
hypertensive patients are not well controlled
with β-blockers.] Labetalol may be employed as
an alternative to methyldopa in the treatment of
pregnancy induced hypertension.
 Adverse effects: Orthostatic hypotension and
dizziness are associated with α1 blockade.

adrenergic agonists & antagonists

adrenergic agonists & antagonists

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