Adrenergic Drugs: Sympathomimetics and Receptors

• Adrenergic drugs (ADD) can be classified as sympathomimetics or sympatholytics
• Sympathomimetics stimulate adrenergic (AD) receptors, increasing sympathetic activity
• Sympatholytics block adrenergic receptors, decreasing sympathetic activity

Adrenergic Receptors

• Adrenergic receptors are divided into alpha (α) and beta (β) receptors
• Alpha receptors are small in size
• Beta receptors are large in size
• For alpha receptors, the affinity order is NE (norepinephrine) > E (epinephrine) > Isoproterenol
• For beta receptors, the affinity oder is Isoproterenol > E > NE
• Alpha receptors are further divided into α1 and α2 subtypes
• Beta receptors are further divided into β1 and β2 subtypes
• Beta 1 receptors primarily act on the heart
• Beta 2 receptors primarily act on the bronchi

Sympathomimetic Drugs (Adrenergic Agonists)

• Direct-acting drugs directly act on α/β adrenergic receptors, examples include albuterol and isoproterenol
• Indirect-acting drugs stimulate the release of norepinephrine (NE), an example is amphetamine
• Mixed-acting drugs have both direct and indirect actions, an example is ephedrine

Structure-Activity Relationship (SAR) of Phenyl Ethanolamine

• This section pertains to the structure-activity relationship (SAR) of phenyl ethanolamine derivatives.
• Modification at different positions of the benzene ring and the nitrogen substituent (R1 and R2) affects adrenergic receptor selectivity and drug metabolism.
• Numbering of the Benzene Ring has the OH at position 1

Benzene Ring Modifications

• Hydroxyl (OH) substitution at position 3 favors action on α1 receptors
• OH at position 4 favors action on β receptors
• OH at positions 3' and 4' leads to non-selective activity and metabolism by COMT (Catechol-O-Methyltransferase)
• OH at positions 2' and 5' favors action on α1 receptors and prevents metabolism by COMT
• OH at positions 3' and 5' favors action on β2 receptors and prevents metabolism by COMT
• Having CH2OH at 3' and OH at 4' favors action on β2 receptors and prevents metabolism by COMT
• No substitution on the benzene ring results in direct and indirect activity

R2 Substitutions

• If R2 is CH3, it increases stability against MAO enzyme and increases selectivity for α-receptors
• If R2 is CH2CH3, it increases stability against MAO enzyme and increases selectivity for β-receptors

R1 Substitutions

• H at R1 favors action on α>β receptors
• CH3 at R1 favors action on α=β receptors
• Isopropyl (CH(CH3)2) at R1 favors action on β>α receptors
• t-butyl (C(CH3)3) at R1 makes the drug more selective for β2 receptors
• Bulky groups at R1, such as those larger than butyl, can result in β2 agonist or α-antagonist activity

Direct Acting Drugs

• Direct acting drugs can act on the α and β receptors

Norepinephrine

• Non-selective (α>β)
• Used to treat acute hypotension
• Has rapid metabolism via MAO and COMT, making it ineffective orally
• Administered intravenously

Epinephrine

• Non-selective (β≥α)
• Not effective orally because it is metabolized by COMT orally
• Taken by injection or inhalation
• Used for hemorrhage, nasal congestion, asthma, and anaphylactic reactions

Phenylephrine

• Selective α1 agonist
• Can be taken orally; resists metabolism by COMT
• Potent vasoconstrictor
• Used for severe hypotension, nasal congestion, and open-angle glaucoma

Etilefrine

• β1 agonist with some α agonist activity
• Cardiac stimulant
• Vasoconstrictor in hypotension

Midodrine

• Prodrug used for orthostatic hypotension and urinary incontinence

Isoproterenol

• Selective β (β1 & β2) agonist
• Not effective orally because it is metabolized by COMT
• Taken by inhalation, I.V., or sublingual tablet
• Used for bronchial asthma (to relieve bronchospasm) and heart block

Metaproterenol

• Resorcinol analogue
• Selective β2 agonist (but less selective than terbutaline)
• Orally active with a long duration of action
• Used in bronchial asthma
• May cause cardiovascular adverse effects

Terbutaline

• Resorcinol analogue
• Selective β2 agonist (more selective than metaproterenol)
• Orally active
• Used in bronchial asthma
• May cause cardiovascular adverse effects

Albuterol (Salbutamol)

• Selective β2 agonist; replacement of meta -OH with -CH2OH
• Contains a benzene ring
• Orally active
• Longer duration of action than Isoproterenol
• Used to treat Bronchial asthma

Pirbuterol

• Selective β2 agonist; replacement of meta -OH with -CH2OH
• Contains a pyridine ring
• Orally active
• Longer duration of action than Isoproterenol
• Used to treat Bronchial asthma

Salmeterol

• Selective β2 agonist
• Long duration of action due to a phenylalkyl group that binds to a hydrophobic pocket at β-2 adrenoceptors, causing slow dissociation (anchoring effect)
• Used in bronchial asthma

Formoterol

• Selective β2 agonist
• Long duration of action
• Rapid onset
• Used in bronchial asthma

Mixed Acting Drugs

Ephedrine

• Acts directly and indirectly
• Used locally as a nasal decongestant
• Used systemically to treat asthma, hay fever, and urticaria

Pseudoephedrine

• Acts indirectly only
• Used as a nasal decongestant

Aryl Imidazoline α1-agonist

• Contains the general skeleton of phenylethylamine
• Used topically as a nasal decongestant and in eye drops

Structure Requirements

For Phenyl Ring (Ar)

• Lipophilic group at the ortho position leads to α1 & α2 agonist activity
• Bulky lipophilic group at the meta or para position leads to selective α1 agonist activity

Examples

• Naphazoline
• Oxymetazoline