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