General Classification and Use of Adrenergic Agents

Intended
learning outcomes

By the end of the lecture student will be able to

• General classification of adrenergic agents

• Propose the specific uses for the various classes of
adrenergic agents

Sympathomimetic
agents-Classification

• Adrenergic agents are divided into three classes:

I. Direct-acting adrenergic agonists

II. Indirect-acting adrenergic agonists

III. Dual-acting adrenergic agonists

I.
Direct-acting adrenergic agonists

• They bind to and activate α1, α2, β1, and β2 receptors

• Naturally occurring molecules, which bind to these
receptors include NE (a neurotransmitter which binds to α1, α2, and β1
receptors), Epinephrine (a hormone produced in and secreted from the adrenal
medulla, which binds to α1, α2, β1, and β2 receptors, it is a nonselective
adrenergic agonists), and Dopamine (also a neurotransmitter, which binds to α1,
α2, and β1receptors).

Examples of drugs:
xylometazoline, phenylephrine, methoxamine.

II.
Indirect-acting adrenergic agonists

• They produce NE-like actions by stimulating NE release and
preventing its reuptake and produces activation.

Example:
Tyramine.

III.
Dual-acting adrenergic agonists

• These agents act as direct and indirect adrenergic
agonists (hence, dual-acting).

• They bind to adrenergic receptors and stimulate NE release

Examples:
Ephedrine, Amphetamine, Mephenteramine.

Classifications
Based on Therapeutic Uses

• Adrenergic drugs
used for raising blood pressure (vaso-constrictors): Noradrenaline,
Metaraminol

• Drugs used for
their ionotropic action on the heart: Dopamine, Dobutamine, Xamoterol

• Drugs used as
central stimulants: Amphetamine (Benzedrine)

• Drugs used as smooth
muscle relaxants:  Adrenaline
(epinephrine), Isoprenaline, Isoxsuprine

• Selective β2
stimulant: Salbutamol

• Drugs used in
allergic reactions: Adrenaline, Ephedrine

• Drugs used as local
vaso-constrictors:  Adrenaline,
Phenylephrine, Naphazoline

• Drugs used for
suppressing the appetite: Fenfl uramine, Phenteramine, Amphetamine

Classification
Based on Chemical Structures

I. Catecholamines

Compounds with hydroxyl (–OH) substitution in the third and
fourth position of the benzene ring are termed as catecholamines.

II. Noncatecholamines

• Those compounds that lack the hydroxyl at third and fourth
position of the benzene ring are noncatecholamines.

• They release noradrenaline or dopamine from the
sympathetic neurons.

• This indirect action produces effects mainly resembling
those of externally administered noradrenaline.

Examples:

Sympathomimetic
agents: Drug profile

Noradrenaline

Synonym:
Norepinephrine, Nephridine

• These are the drugs which directly acts to adrenergic
receptors and stimulates sympathetic action

Chemical Structure

Properties: It is
a white or brownish-white, crystalline powder, slightly soluble in ethanol and
soluble in water. It differs from adrenaline only by lacking the methyl
substitution on the amino ethanol.

• L-isomer is pharmacologically active.

Medicinal uses:

• Noradrenaline is a potent agonist for α1 receptors and has
relative actions on β2 receptors.

• It is used as a vasoconstrictor in some local anaesthetic
solutions for dental use.

Adrenaline

Synonym:
Epinephrine

• Adrenaline is a catecholamine and belongs to the family of
biogenic amines

Chemical Structure

Properties:

• It is a white or creamy white, sphaero-crystalline powder.
It dissolves in solutions of mineral acids, potassium hydroxide, and of sodium
hydroxide, but sparingly soluble in water, insoluble in ethanol and ether.

Medicinal Uses:

• It is used as a sympathomimetic, broncholytic, and
antiasthmatic.

• It is used to prevent bleeding during surgery or in case
of inner organ bleeding. Because adrenaline leads to constriction of blood
vessel, it is administered in combination with local anaesthetics. In this
combination, anaesthetics have long-lasting effect and can be administered in
smaller doses.

• It is used in the treatment of heart block or circulatory
collapse and open-angle glaucoma.

Phenylephrine

Chemical Structure

1-(3-hydroxyphenyl)-2-methylaminoethanol

• Phenylephrine differs from adrenaline only by lacking the
4-OH group on the benzene ring

Synthesis of
Phenylephrine:

Phenylephrine is prepared by condensation of
3-chloroacetylphenol with methylamine followed by catalytic reduction.

Properties:
Phenylephrine is available as hydrochloride salt. It is white, odorless, bitter
taste, crystalline powder. It is soluble in water, alcohol, and glycerol. It
should be stored in airtight container to protect from light because it is
decomposed by light.

Medicinal Uses.

• Phenylephrine is a selective α1-receptor agonist

• Oral absorption is not reliable and so it is given
parenterally or topically as eye or nasal drops

• Phenylephrine predominantly acts on peripheral arterioles
results in  a  rise 
in  systolic  and 
diastolic  pressures  accompanied 
by  a marked reflex bradycardia

• Phenylephrine is used as a nasal decongestant, mydriatric
and as a vasopressor agent

Dopamine

Synonyms: Domin,
Dopacard

Chemical Structure

Properties: It is
a white or almost white crystalline powder, soluble in alcohol, sparingly
solublein acetone and methylene chloride, but freely soluble in water. It is
used in the treatment of shock.

Medicinal uses:

• It works by improving the pumping strength of the heart
and improves blood flow to the kidneys

• Dopamine injection (Intropin) is used to treat certain
conditions that occur when you are in shock, which may be caused by heart
attack, trauma, surgery, heart failure, kidney failure, and other serious
medical conditions

Methyldopa:

• The L-isomer of alpha-methyldopa, is levo-3-(3,4-dihydroxyphenyl)-2-methylalanine

• Methyldopa is a white to yellowish white, odorless fine
powder, and is soluble in water.

Chemical Structure

• It is an α 2 adrenergic receptor agonist acts centrally by
decreasing the sympathetic outflow which in turn lowers blood pressure

Medicinal uses:

• To treat hypertension in combination with diuretics

• To treat pregnancy-induced hypertension

Clonidine:

Chemical Structure

N-(2,6-dichlorophenyl)-4,5-dihydro-1H- imidazol-2-amine

• Clonidine, an imidazoline-derivative hypotensive agent is
a centrally- acting α2-adrenergic agonist thereby reducing sympathetic outflow
and noradrenaline release

• It crosses the blood-brain barrier and acts in the
hypothalamus to induce a decrease in blood pressure.

Medicinal uses:

• In moderate to severe hypertension

• For withdrawal therapy of alcohol opioids

• To diagnose pheochromocytoma (is a neuroendocrine tumor of
the medulla of the adrenal glands)

Dobutamine:

Synonyms:
Cardiject, Dotamin, Kardia

Dobutamine is a synthetic catecholamine derivative

Chemical Structure

• Dobutamine is a racemic mixture of two enantiomeric forms

• The (+) isomer has potent β-agonistic actions.

• The (–) isomer has potent α1-agonistic and poor
β-agonistic actions

Properties: It is
a white or almost white crystalline powder, sparingly soluble in water and
alcohol, and soluble in methanol.

Medicinal uses:

• Dobutamine is used in patients of heart failure associated
with myocardial infarction, open heart surgery and cardiomyopathy

Isoproterenol:

Synonym:
Isoprenaline, Isoprim, Isosol, Neo-Epinin

• It is a non-selective β adrenoreceptor agonist that is the
isopropylamine analog of epinephrine (adrenaline)

It is a synthetic Isopropyl analogue of adrenaline

Chemical Structure

Properties: It is
a white or almost white crystalline powder, freely soluble in water, sparingly
soluble in alcohol, practically insoluble in methylene chloride.

Medicinal uses:

• Its primary use is in the treatment of bronchial asthma

• It is used as an antiarrhythmic agent and

• The treatment of shock to increase heart rate

• used as a bronchodilator.

Terbutaline:

 • An ethanolamine
derivative, is a β2 adrenergic receptor agonist

Chemical Structure

N-tert-butyl-N-[2-(3,5-dihydroxyphenyl)-2-hydroxymethyl] amine

Properties:

• Terbutaline is a white, odorless, bitter taste crystalline
powder. It is soluble in water, slightly soluble in alcohol and practically
insoluble in ether and chloroform. It should be protected from tight

• Available as its sulphate salt

Medicinal Uses:

• used to prevent and treat wheezing, shortness of breath,
and chest tightness caused by asthma, chronic bronchitis

Salbutamol:

Synonym:
Albuterol, Asthalin, Salbid

Chemical Structure

• A short-acting beta-2 adrenergic agonist that is primarily
used as a bronchodilator agent to treat ASTHMA

Properties: It is
a white or almost white crystalline powder, sparingly soluble in water, but
freely soluble in ethanol.

Medicinal uses:

• It has strong β2 adrenergic activity

• It is useful in the treatment of acute myocardial
infarction, severe left ventricular failure

• It has been used to arrest premature labour and is
effective in ocular hypotension by topical application

• It is used only as a bronchodilator and is the drug of
choice in the treatment of bronchial asthma

Salbutamol Synthesis:

Bitolterol:

Chemical Structure

[4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(4-methylbenzoyl)oxyphenyl]4-methylbenzoate

• Bitolterol is the di-4-toluate ester of (+-)-N-tert-butyl
noradrenaline (colterol).

• A pro-drug for colterol, a beta2-adrenergic receptor
agonist, bitolterol is used as its methanesulfonate salt for relief of bronchospasm
in conditions such as asthma, chronic bronchitis and emphysema

• It has a role as a bronchodilator agent, an anti-asthmatic
drug, a beta-adrenergic agonist and a prodrug.

• It is a member of ethanolamines, a carboxylic ester, a
diester, a secondary amino compound and a secondary alcohol.

Naphazoline
(Ocucel Eye Dropa):

Chemical Structure

• Naphazoline is an imidazole derivative and a direct-acting
sympathomimetic amine with vasoconstrictive activity.

• Upon ocular administration, naphazoline exerts its effect
by acting on alpha-adrenergic receptors in the arterioles of the conjunctiva to
produce   vasoconstriction,   resulting   in  
decreased   conjunctival congestion
and diminished itching, irritation and redness

• It is used topically as nasal decongestant

Oxymetazoline:

• Imidazole derivative

Chemical Structure

6-tert-butyl-3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-
2,4-dimethylphenol;hydrochloride

• A direct acting sympathomimetic used as a vasoconstrictor
to relieve nasal congestion

• An imidazole derivative with a direct acting
sympathomimetic property

• It binds to and activates alpha-2 adrenergic receptors and
congestion

Medicinal uses:

• This medication is used for temporary relief of congestion
in the nose caused by various conditions including the common cold, sinusitis,
hay fever, and allergies.

•   It works by
narrowing the blood vessels in the nose area, reducing swelling

Xylometazoline
(Synonym: Otrivin, Otrinoz, Decon)

•   Imidazole
derivative/ an alkylbenzene.

Chemical Structure

2-(4-tert-butyl)2, 6-dimethylbenzyl)-2-imidazoline.

• A nasal vasoconstricting decongestant drug which acts by
binding to the same receptors as adrenaline.

• It is applied as a spray or as drops into the nose to ease
inflammation and congestion of the nasal passageways.

• It binds alpha-adrenergic receptors to activate the
adrenal system which   causes   systemic  
vasoconstriction,   thereby   easing  
nasal congestion.

Medicinal uses:

Xylometazoline nasal (for use in the nose) is used to treat
stuffy nose caused by allergies, sinus irritation, or the common cold

Summary

• Adrenergic drugs are also called sympatho-mimetic drugs.

• They work out by stimulating the sympathetic nervous
system

• They act directly or indirectly or by mixed actions

• Drug profile of some direct acting sympatho-mimetic drugs