ADRENERGIC AGONIST

(SYMPATHOMIMETIC AGENT)

Dr. Shrikant Ghodse

Assistant Professor
Prin. K. M. Kundnani College of Pharmacy, Mumbai

SMG/KMKCP Mumbai
 Adrenergic hormones
• Adrenaline is a hormone produced within the adrenal gland in response to stress
that increases heart rate, strengthens the force of the heart’s contraction and
cardiac output, increases blood pressure and opens up the bronchioles in the lungs,
and raises the blood levels of glucose and lipids among other effects.

• The secretion of adrenaline is a part of the human “fight or flight” response, the
acute stress response to fear, perceived threat, or panic.

• An excessive adrenaline level usually is observed in highly emotional and

overaggressive persons.

SMG/KMKCP Mumbai
 Adrenergic hormones
• On the other hand, there are some disorders of the adrenal glands that reduce the
level of epinephrine to below normal, including Addison disease and other forms of
hypoadrenalism.

• Any drug that mimics the functioning of the sympathetic nervous system by affecting
the release or action of epinephrine (adrenaline), norepinephrine (noradrenaline)
and dopamine—hormones that are secreted by the adrenal gland—is considered an
adrenergic drug.

• The term adrenergic literally means “having to do with adrenaline (epinephrine)

and/or noradrenaline (norepinephrine)

SMG/KMKCP Mumbai
EFFERENT AUTONOMIC NERVOUS SYSTEM

SMG/KMKCP Mumbai
BIOSYNTHESIS OF CATECHOLAMINE

SMG/KMKCP Mumbai
METABOLISM OF CATECHOLAMINE

SMG/KMKCP Mumbai
 METABOLISM OF
NOREPINEPHRINE

AD : Aldehyde Dehydrogenase
AR : Aldehyde reductase
(1) (2) COMT : Catechol o methyl transferase
MOA : Monoamine oxidase

(3) (4) (5) (1) (R)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetaldehyde

(2) (R)-1-(4-hydroxy-3-methoxyphenyl)ethane-1,2-diol
(3) (R)-4-(1,2-dihydroxyethyl)benzene-1,2-diol
(4) (R)-2-(3,4-dihydroxyphenyl)-2-hydroxyacetic acid
(5) (R)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetic acid
SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
 ADRENERGIC RECEPTOR

Adrenergic receptor were first subclassified by Ahlquist in 1948 into

alpha and beta adrenoreceptor classes according to their responses to
different adrenergic receptor agonist, principally norepinephrine,
epinephrine and isoproterenol.

Alpha-adrenoceptor descending order of potency

Raymond P. Ahlquist
Epinephrine> Norepinephrine> Isoproterenol

Beta adrenoreceptor descending order of potency

Isoproterenol > Epinephrine > Norepinephrine

SMG/KMKCP Mumbai
 ADRENERGIC RECEPTOR

• Additional small molecule agonist and antagonist have been used to

allow further subclassification of alpha and beta receptor to allow
further subclassification of alpha and beta receptor into alpha-1 and
alpha-2 subtypes and beta-1, beta-2 and beta-3 adrenoreceptors.

• Currently, three types of alpha-1 adrenoreceptor, called α1A , α1B and

α1D are known. (There is no α1Ac was found to be incorrect.)

SMG/KMKCP Mumbai
 CLASSIFICATION OF ADRENERGIC RECEPTOR

Alpha-1
Alpha
Alpha-2
Adrenergic receptor
Beta-1

Beta Beta-2
Molecular cloning has further identified
3 subtypes of α1(α1A, α1B, α1D) and Beta-3
3 subtypes of α2 (α2A, α2B, α2C) receptors. SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
 Structural Activity relationship

β-Phenyl ethanolamine

SMG/KMKCP Mumbai
Structural Activity relationship
Important binding groups on catecholamines

SMG/KMKCP Mumbai
SMG/KMKCP Mumbai
 Structural Activity relationship
The alcohol group: R-enantiomer of
noradrenaline is more active than the S-
enantiomer, indicating that the secondary
alcohol is involved in a hydrogen bonding
interaction.

Compounds lacking the hydroxyl group (e.g.

dopamine) have a greatly reduced interaction.
Some of the activity is retained, indicating that
the alcohol group is important, but not essential;

SMG/KMKCP Mumbai
 Structural Activity relationship

the amine is normally protonated and ionized at physiological pH. This

is important as replacing nitrogen with carbon results in a large drop in
activity.

Activity is also affected by the number of substituents on the nitrogen.

Primary and secondary amines have good adrenergic activity, whereas
tertiary amines and quaternary ammonium salts do not; both phenol
substituents are important.

SMG/KMKCP Mumbai
 Structural Activity relationship

• For example, tyramine , amphetamine and phentermine have little, or

no, affinity for adrenoceptors

SMG/KMKCP Mumbai
 Structural Activity relationship

• alkyl substitution on the side chain linking the aromatic ring to the
amine decreases activity at both α- and β-adrenergic receptors.

• This may be a steric effect which blocks hydrogen bonding to the

alcohol or which prevents the molecule adopting the active
conformation

SMG/KMKCP Mumbai
 CLASSIFICATION OF ADRENERGIC DRUGS
DIRECT ACTING INDIRECT ACTING MIXED ACTING
Non-selective Selective Ephedrine
Tyramine
Adrenaline Alpha (α) Beta (β) Amphetamine Pseudoephedrine
Noradrenaline Hydroxy amphetamine Dopamine
Isoprenaline Methamphetamine Metaraminol
α-1 β-1
(Isoproterenol) Methylphenidate Me phentermine
Phenylephrine Phenylephrine Dobutamine Phenoxybenzamine
Oxymetazoline Methoxamine
Naphazoline
Midodrine β-2
Xylometazoline
Salbutamol
(Albuterol)
α-2
Terbutaline
Clonidine Bitolterol
Apraclonidine Salmeterol
Brimonidine Metaprotocol
Tizanidine Formoterol
Isoxsuprine
Ritodrine
SMG/KMKCP Mumbai
2-arylalkylimidazolines

These agents are used for their vasoconstrictive effects

as nasal and ophthalmic decongestants.

Ortho-lipophilic groups on the phenyl ring are important

for α-activity.

However, meta or para-bulky lipophilic substituents on

the phenyl ring may be important for the α1-selectivity.

SMG/KMKCP Mumbai
 2-arylalkylimidazolines

• They have limited access to the CNS, because they essentially exist in an ionized
form at physiological pH caused by the very basic nature of the imidazoline ring
(pKa 10–11).

• Xylometazoline and oxymetazoline have been used as topical nasal decongestants

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.

• Oxymetazoline also has significant affinity for α2A-receptors.

SMG/KMKCP Mumbai
 Metaraminol is structurally similar to phenylephrine
except that it is a primary instead of a secondary amine.

It possesses a mixed mechanism of with its direct-acting

effects mainly on α-adrenergic receptors.

It is used parenterally as a vasopressor in the treatment and prevention of the acute

hypotensive state occurring with spinal anaesthesia.

It also has been used to treat severe hypotension brought on by other traumas
that induce shock

SMG/KMKCP Mumbai
 Alpha-2 agonist
CLONIDINE
• The o-chlorine groups afford better activity than o-methyl
groups at 2 sites.

• Importantly, clonidine contains a NH bridge (amino

imidazolines) instead of CH2 bridge in 2-arylimidazoline

• The α1:α2 ratio is 300:1

• α2A adrenergic receptor subtype agonist

• Clonidine is easily absorbed. The plasma levels

of clonidine peak within 30 to 60 minutes after its oral
administration, and its plasma half-life is 6 to 13 hours.
SMG/KMKCP Mumbai
 Beta-1 agonist

Dobutamine is a positive inotropic agent administered intravenously for

congestive heart failure.

It resembles DA structurally but possesses a bulky 1-(methyl)- 3-(4-

hydroxyphenyl)propyl group on the amino group

It possesses a center of asymmetry, and both enantiomeric forms are present in

the racemic mixture used clinically.

SMG/KMKCP Mumbai
 Beta-1 agonist

The (-) isomer of dobutamine is a potent α1-agonist, which is capable of causing

marked pressor responses.

In contrast, (+)-dobutamine is a potent α1-antagonist, which can block the effects

of (-)-dobutamine.

Importantly, the effects of these two isomers are mediated via β1-receptors.

Both isomers appear to be full agonists, but the (+) isomer is a more potent β1-
agonist than the (-) isomer

SMG/KMKCP Mumbai
 Beta-2 agonist
Albuterol (Salbutamol)

• A racemic mixture, Albuterol is short-acting and is

relatively selective for beta-2 adrenoceptor sites.

• R-albuterol has a greater affinity than S-albuterol for

the beta-2 receptor, while S-albuterol may have
unwanted pharmacological actions

• It is used to relieve symptoms of asthma and

chronic obstructive pulmonary disease (COPD)
such as coughing, wheezing and feeling breathless

SMG/KMKCP Mumbai
 Beta-2 agonist
Terbutaline is a synthetic sympathomimetic amine
derived from resorcinol.

Terbutaline is structurally different

from epinephrine and isoproterenol in
that terbutaline has a tertiary butyl group on the
nitrogen atom.

This tertiary butyl group apparently increases the duration of action by making the
drug resistant to metabolism by monoamine oxidase and is proposed to underlie
the selectivity of the drug for beta-2 adrenoceptors.

Because of its selectivity for beta-2 adrenoceptors, terbutaline is used

therapeutically to treat reversible airways obstruction which occurs
in asthma and chronic obstructive pulmonary disease.
SMG/KMKCP Mumbai
 Beta-2 agonist
Because it also relaxes uterine smooth muscle and reduces uterine contractility,
terbutaline can also be used to arrest premature labour.

It was the first β2-selective adrenoreceptor agonist in general clinical use.

In 2011, the Food and Drug Administration (FDA) placed a black-boxed warning
on terbutaline stating that terbutaline injections should not be given to pregnant
women nor should be used to prevent preterm labour or for long-term (greater
than 48–72 h) treatment of preterm labour.

Oral terbutaline should not be used at all due to its potential for cardiac toxicity
and death.

SMG/KMKCP Mumbai
 Beta-2 agonist
• Colterol (active metabolite of bitolterol)
differs from ISO by replacing the -directing
N-isopropyl to 2-directing N-tert-butyl
group, which results in the increased 2-
selectivity.

• Bitolterol is a prodrug of colterol

• The presence of two toluic acid esters

make more lipophilic than colterol

• Administered by inhalation for bronchial

asthma and reverse bronchospasm
• Longer duration of action than isoproterenol and is metabolized, after hydrolysis
of the ester, by COMT and conjugation.SMG/KMKCP Mumbai
Mixed acting

SMG/KMKCP Mumbai
 Mixed acting

Propylhexedrine is an analogue of amphetamine in which the aromatic ring has

been replaced with a cyclohexane ring.

This drug produces vasoconstriction and a decongestant effect on the nasal membranes,
but it only about one-half the pressor effect of amphetamine and produces decidedly
fewer effects on the CNS.

Its major use is for a local vasoconstrictive effect on nasal mucosa in the symptomatic
relief of nasal congestion caused by the common cold, allergic rhinitis. or sinusitis.
SMG/KMKCP Mumbai
 Mixed acting
Ephedrine has two asymmetric carbon atoms; thus there are
four optically active forms.

The erythro racemate is called "ephedrine." and the threo

racemate is known 'pseudoephedrine"

Natural ephedrine is D(—) isomer, and it is the most active of

the four isomers as a pressor amine.

This is largely due to the fact that this isomer has the correct
(R) configuration at the carbon atom bearing the hydroxyl
group and the desired (S) configuration at the carbon
bearing the methyl group for optimal direct action at
adrenergic receptors.
SMG/KMKCP Mumbai
 Mixed acting

• (S,S) diastereoisomer of ephedrine.

• It is a naturally occurring alkaloid from the Ephedra species.

• The structural basis for this difference in mechanism is the stereochemistry of

the carbon atom possessing the β-hydroxyl group. In pseudoephedrine. this
carbon atom possesses the (S) configuration, which is the wrong
stereochemistry at this center for a direct-acting effect at adrenergic receptors.

• This agent is found in many over-the-counter nasal decongestant and cold

medications

SMG/KMKCP Mumbai
Synthesis of salbutamol

SMG/KMKCP Mumbai