Adrenergic drugs/adrenergic

agonist
Dr. Jahanara laizu
Dept. of Pharmacology
• Sympathetic nervous system is an important
regulator of the activities of organs such as
the heart and peripheral vasculature.
• The effect of sympathetic stimulation are
mediated by release of norepinephrine from
nerve terminal which then activate the
adrenoceptors on post synaptic sites.
 Neurotransmitter
• Def:
• Neurotransmitters are the chemical
substances which transmit impulse
from nerve to nerve and nerve to effect
organs ( heart, lung, liver and blood
vessel).
 Neurotransmitter
• Norepinephrine or noradrenaline is the
neurotransmitter of postganglionic
sympathetic nerve endings, which exerts
its effects on the peripheral tissues.
• Nor-adrenaline is secreted by—

• All postganglionic sympathetic

neurons (except those that go to sweat
glands)
• In addition,
the sympathetic system releases
adrenaline from the adrenal medulla (in
a response to a variety of stimuli such
as stress) which enters the blood
stream producing widespread effects
throughout the body.
• Epinephrine or adrenaline acts as a
hormone.
• Because the enzyme responsible for
the synthesis of adrenaline is not
available in the adrenergic nerve
ending.
• Synthesis of noradrenaline
• Tyrosine is transported into the adrenergic nerve
ending.
• Tyrosine converted to dopa by tyrosine hydroxylase
and

• Dopa is converted to dopamin by dopa decarbxylase.

(which is transported into the vesicle by the vesicular
monoamine transporter).

• Dopamine is converted to norepinephrine by dopamine

beta-hydroxylase.
• In the adrenal medulla and certain
areas of the brain norepinephrine is
further converted to epinephrine.

• Norepinephrine is converted to
epinephrine by phenylethanolamine-N-
methyltransferase enzyme.
• The conversion of tyrosine to dopa, is the
rate limiting step in catecholamine
transmitter synthesis.
• It can be blocked by metyrosine
 Adrenergic receptor
• Adrenergic receptor – 3 types
• Alpha receptor
• Beta receptor
• Dopamine receptor
• All has subtypes----
• Five subtypes of dopamine receptor present.
• D1 like receptor(D1 and D5)
• D2 like receotor(D2, D3 and D4)
 Adrenoceptor
Type Tissue Actions

Alpha1
most vascular smooth musclec contraction
pupillary dilator muscle
contraction (dilates pupil

pilomotor smooth muscle erects hair

prostate contraction
heart increase force of contraction
Types tissue actions
Alpha2

platelets aggregation

adr energic and cholinergic

nerve ending inhibition of transmitter
release

some vascular smooth muscle contraction

fat cells inhibition of lipolysis

• Type tissue actions

Beta 1 heart, kidney increase force of contraction

increases the release of renin

Beta 2 respiratory, uterine

smooth muscle relaxation

skeletal muscle promotes potassium uptake

human liver activates glycogenolysis
• Type tissue actions

beta 3 fat cells activates lipolysis

dopamine 1 smooth muscle dilates renal blood

vessels

dopamine 2 nerve endings modulates transmitter

release
 Catecholamine
• Catecholamines are compounds containing a
catechol moiety/nucleus (benzene ring with
two adjacent hydroxyl groups) and an amine
side chain.

• Natural– adrenaline
• nor-adrenaline
• dopamine
• Synthetic—isoproterenol
• dobutamine
• Catecholamines has –
• Rapid onset of action
• Brief duration of action
• not administered orally
• do not cross the blood brain barrier
• Non- catecholamine --- ephedrine, salmeterol
has
• Compared to catecholamine
• Longer duration of action
• All can be used orally
Catecholamines
• Catecholamines are metabolized by two
enzymes: monoamineoxidase (MAO) and
catechol-O- methyltransferase (COMT).

• MAO causes oxidative deamination of

catecholamines and autocoid 5-
hydroxytryptamine.

• COMT causes rapid methylation of

catecholamines.
• The major metabolites excreted in urine
are VMA and 3-methoxy-4
hydroxyphenylethylene glycol along
with some metanephrine,
normetanephrine.
 Adrenergic drugs

• These are the drugs which act similar

to the adrenaline or of sympathetic
stimulation or the drugs mimic the
action of epinephrine and
norepinephrine.
 classification
• Adrenergic drugs divided into two types
according to the mode of action------

• Direct sympathomimetics/ direct adrenergic

drugs/adrenergic agonist--

They act directly as agonist on alpha and

beta receptors– adrenaline, noradrenaline,
isoprenaline, phenylephrine, methoxamine,
xylometametazoline.
• Directly acting— further divided into two types--
a) Non-selective– drug acts on more than two
receptor
Adrenaline ( acts on all receptor)
nor-adrenaline ( acts on alpha1, alpha2, beta1
receptor )
dopamine ( alpha1, beta1 and dopaminergic
receptor)
• b)Selective– drug which acts on a
single receptor only

Phenylephrine ( alpha1)
Clonidine (alpha2)
dobutamine (beta1)
Salbutamol (beta2)
terbutaline (beta2)
• Indirect sympathomimetics—their actions
are dependent on the release of endogenous
catecholamines.

They act on adrenergic neurons to

release NA and increases concentration or
amount of noradrenaline which then acts on
adrenoceptors — tyramine, amphetamine
• These indirect agents may have two
different mechanisms—
1.Displacement of stored catecholamines
from adrenergic nerve end/ release of
Noradrenaline from nerve endings-
ng /(amphetamine, ephedrine. and
tyramine)
2. Inhibition of reuptake of
catecholamines already released----
cocaine and tricyclic antidepressant)
• Mixed action sympathomimetics– they
act directly as well as indirectly–
ephedrine.
 Adrenergic drugs
• According to the receptors selectivity
or where they act—
• Alpha agonist—
Phenylephrine, methoxymine
Clonidine, methylnorepinephrin
• Mixed alpha and beta agonists
norepinephrine
epinephrine
• Beta agonist
dobutamine
isoproterenol
terbutaline
• Dopamine agonist
dopamine
fenoldopam
• Cardiac stimulants----------
adrenalin
dobutamine
isoprenaline

• Bronchodilators-----------
isoprenaline
salbutamol
salmeterol
terbutaline
formeterol
• Nasal decongestants---
phenylephrine
xylometazolin
oxymetazolin

• CNS stimulants----------
Amphetamine
Methamphetamine
dexamphetamine
• Vasoconstrictors---------
Phenylephrine
Ephedrine
Methoxamine
• Uterine relaxants----------
Ritodrine
salbutamol
 Adrenaline

• Adrenaline is life saving drug and is used for

cardiopulmonary resuscitation.

• Adrenaline is not available for oral administration

• It is given by parenteral routes.
• The liver is the main organ for its degradation.

• COMT and MAO metabolize the majority of the dose

and the metabolites are excreted in the urine.
• In large doses, adrenaline causes
vasoconstriction in the subcutaneous,
mucosal,splanchnic and renal vascular beds by
alpha receptor mediated mechanism.
• The venous tone is increased. Resulting in
increased venous return to the heart.
• At low concentration, it may cause
vasodilation, because beta receptors are more
sensitive to adrenaline than alpha receptors.
• Adrenaline acts on beta receptors in the heart
and causes an increase in the heart rate,
enhancement of cardiac contractility and
increase in conduction velocity.
• Cardiac stimulation increases myocardial
oxygen consumption.
• The systolic blood pressure rises due to
increased cardiac output.
• The diastolic pressure shows little change as
adrenaline produces vasoconstriction only in the
skin and splanchnic area ( alpha1 effect) and
vasodilation in the arteries in muscle (beta2
effect).
• Metabolic effect of adrenaline—
• glycolysis in liver
• Release of glucagon
• Release of insulin
 How adrenoceptor act?
• Alpha receptor—
• Activation of alpha1 receptor initiates a
series of reaction through the G protein
activation of phospholipase C resulting in
the generation of IP3 and DAG. So it
increase the intracellular calcium ions.
• which leads to cellular events such as
vasoconstriction---- increased blood
pressure.
• Activation of alpha2 receptor decreases
production of cAMP leading to an inhibition
of further release of norepinephrine from
the neurons.
• Beta receptor activation
• When circulating neurotransmitter or
adrenergic drugs bind with any three types
of beta receptors it activates adenylyl
cyclase enzyme and therefore increased
concentration of cAMP within the cell
causes cellular changes such as
relaxation of smooth muscle of respiratory
tract-- Brochodilation,
 Indication of adrenaline–

• 1. In anaphylactic shock (it relieves edema and

swelling by causing vasoconstriction, dose 0.5
ml of a 1:1000 solution intramuscularly).

2. Hypotensive states (shock, spinal

anaesthesia, hypotensive drugs, neurogenic
and haemorrhagic shock.
3. cardiac arrest (drowning, electrocaution,
stockes-Adams syndrome and other causes)–
adrenaline may be used to stimulate the heart
4. Partial or complete A-V block
5. congestive heart failure
6. bronchial asthma . (ad – beta2
receptor—bronchodilation– relief of
asthma.)
7. Adrenaline used with local anesthetic agent
(with exception of cocaine) to prolong the
duration of infiltration anesthesia.
8.Topically in the eye to facilitate aqueous
drainage in chronic open angle glaucama.
9. Control of local bleeding –from skin and
mucous membranes eg epistaxis
compresses of Adr 1 in 10000,
phenylephrine/ ephedine 1%.
10. Used as nasal decongestant
• Adverse effect—
• Anxiety
• Restlessness, dizziness
• Cardiac arrythmia
• Cerebral haemorrage
• CNS disturbances
• Pulmonary oedema
• Contraindication–
• Hypertension
• ischemic heart disease
• Arrhythmia
• cerebral haemorrage
• DM
• Hyperthyroidism
•
 Noradrenaline
• Noradrenaline is the neurotransmitter of
the post ganglionic sympathetic neurons.
Its most important action is to produce
wide spread vasoconstriction leading to a
rise in both systolic and diastolic blood
pressure.
• It has alpha1,alpha2, beta1 action but
beta2 action is less.
 Ephedrine
• Is an alkaloid obtained from ephedra
valgaris.
• It is absorbed orally and is long acting
since it is resistant to COMT and MAO.
• Ephedrine is a mixed acting adrenergic
drug.
• Ephedrine causes release of noradrenaline
from storage in nerve terminals and also
produces direct stimulation of alpha and beta
receptors.
• It crosses the blood brain barrier and causes
CNS stimulation.
• Tachyphylaxis occurs with repeated
administration.
• Used as nasal decongestant
• Ephedrine is less suitable and less safe for
use as a brochodilator because it is likely to
cause arrythmia, insomnia, anxiety and
restlessness.
 Amphetamine
• Amphetamine acts indirectly by releasing
noradrenaline in the CNS.
• It produces euphoria, reduces appetite,
abolish fatigue and increases both mental
and physical activity.
• It is no longer used because it causes
dependence (drug addiction).
• Used as CNS stimulant in the treatment
of children with attention deficit
syndrome
• Narcolepsy and for appetite control
 Dopamine
• Dopamine is the immediate precursor of
noradrenaline.

• It is naturally occurring catecholamine

with an important neurotransmitter in the
CNS.
 Dopamine
• Dopamine acts on alpha1, beta1 and
dopamine receptor.
• At higher doses, it can cause
vasoconstriction by activating alpha1
receptors whereas at lower doses it
stimulates beta1 and dopamine
receptors.
• At very high doses, dopamine activates
alpha1 receptors on the vasculature,
resulting in vasoconstriction.

Lower doses– it acts on dopaminergic and

beta receptor
• Dopamine is clinically used in cardiogenic shock
and is given by continuous infusion.
• It raises the blood pressure by-------
stimulating the beta1 receptor of the heart to
increase HR and FOC– increase BP ( also stimulate
alpha1 receptor to increase peripheral ressitance )

It also acts on dopamine receptor– renal

vasodilatation– increased blood flow to the kidney –
enhances or increase glomerular filtration rate
causes Na diuresis.
• In this regard dopamine is superior to
adrenaline because adrenaline causes
vasoconstriction of renal blood vessels and
decrease renal blood flow and may cause
renal shut down.
 Dobutamine
• Dobutamine is similar to dopamine, but has
no effect on the kidney.
• It has a great effect on the contractility than
rate of the heart.

It can be combined with dopamine for the treatment

of cardiogenic shock, septic shock and
cardiomyopathies
 Salbutamol
• Salbutamol is the most widely used beta2
agonist brochodilator.
• It is only used to relieve the acute
symptoms of asthma.
• prolonged use may lead to tachyphylaxis.
• Inhalation 100 to 200 microgram of
salbutamol is the preferred route for an acute
attack of bronchial asthma, because it
provides immediate relief and causes fewer
systemic side effects( tremors and nervous
tension).
• Salbutamol is also used to inhibit premature
labour/ premature contraction of uterus.