(20) Adrenergic beta selective agonist

Give me all Adrenergic Agonist

• Catecholamine

  • Archetype Adrenergic Agonists -

    • Norepinephrine (NE)

    • Epinephrine (EPI)

    • Isoproterenol (ISO)

  • Other Catecholamines

    • Dopamine

    • Dobutamine

• β2 Adrenergic Agonists

  • SABA - Short-Acting

  • LABA - Long Acting Agonists

  • ULABA - Ultra-long-acting

• α-Adrenergic and Mixed-Acting Agonists (NEED TO REVIEW)

  • Phenylephrine

  • Ephedrine / Pseudoephedrine

  • Midodrine (prodrug)

  • L-DOPA (discussed in prodrug section)

  • Arylimidazolines

    • Oxymetazoline

    • Xylometazoline

Three Archetype Adrenergic Agonists

Tell me about it

Drug	N-substituent	Receptor preference
Norepinephrine (NE)	H (small)	α + β; α-like effects
Epinephrine (EPI)	CH₃ (methyl)	α + β; slightly β-favored
Isoproterenol (ISO)	Isopropyl (bulky)	β1 + β2; essentially no α

Three Archetype Adrenergic Agonists

Have similar?

• All three contain catechol (two adjacent phenolic OH groups).

Three Archetype Adrenergic Agonists

receptor preference

• α → NE ≥ EPI >> ISO

• β1 → ISO >> EPI ≥ NE

• β2 → ISO >> EPI > NE

Three Archetype Adrenergic Agonists

Draw

• skip brand names for now

Dopamine

Tell me about it

Receptor	Immediate effect → Outcome
β1	↑ Contractility + ↑ HR → ↑ Cardiac output
D1/D2	Renal vasodilation → ↑ Urine formation
α (high dose)	Vasoconstriction → ↑ BP

• use: Heart failure and shock.

Dopamine

Why professor favors dopamine over NE for shock?

• Dopamine → Stimulates heart + Dilates renal vessels → ↑ Cardiac output without as much BP increase as expected.

Pharmacophore & SAR of adrenergic agonist drugs

Structure feature	Effect
Small N-substituent	Activates α and β (NE/EPI)
Bulky N-substituent	↑ β selectivity (ISO)
Catechol	COMT metabolism → Short action
Non-catechol	Avoids COMT → Longer action
Para-OH	↑ β affinity
Long hydrophobic N-chain	Membrane binding → Longer action

What is the structural framework of the adrenergic agonist called?

Phenylethanolamine pharmacophore

Phenylethanolamine pharmacophore

Explain and Draw

• Protonated amine → Interaction with aspartate.

• β-OH and catechol OH → Hydrogen bonding.

• Aromatic ring → Hydrophobic interactions.

EPI vs. NE vs. ISO

BP Effects

• NE: α + β; α-like effects

  • α1 → Vasoconstriction → ↑ Diastolic BP → Baroreflex → → ↑ Vagal/ACh activity → ↓ HR.

  • β1 → ↑ Contractility in isolated tissue.

• EPI: α + β; slightly β-favored

  • β1 → ↑ HR/force → ↑ Systolic BP

  • β2 → Vasodilation → ↓ Diastolic BP

• β1 + β2; essentially no α

  • β1 → ↑ HR/force → ↑ Systolic BP

  • β2 → Vasodilation → ↓ Diastolic BP.

EPI vs. NE vs. ISO

Overall effects

1. Peripheral Resistance

• NE → ↑ (α1 vasoconstriction)

• EPI → ↓ (β2 vasodilation)

• ISO → ↓↓ (strong β2 vasodilation)

2. Overall BP / Mean Arterial Pressure (MAP)

• NE → ↑

• EPI → Approximately unchanged

• ISO → No increase; may ↓

3. Clarify the BP changes

• NE → ↑ Both systolic and diastolic BP

• ISO → Slight ↑ systolic BP, large ↓ diastolic BP

Drug	Systolic (top)	Diastolic (bottom)
NE	↑	↑
ISO	Slight ↑	↓↓

Epinephrine

• Effects: (SAME INFO, MAY SKIP)

  • α + β; slightly β-favored

  • High dose → α activation → Vasoconstriction.

• METABOLISM: (SAME INFO, MAY SKIP)

  • Catechol → COMT/MAO metabolism

    • Rapid metabolism; poor oral bioavailability

• Hydrophilic → Does not cross BBB.

• Use

  • Anaphylaxis (drug of choice): b2

  • glaucoma: a2

  • with local anesthetics to prolong their action: a1

  • Not preferred for routine asthma because of short duration (due to rapid COMT metabolism)

• Important risks/interactions:

  • Digoxin/digitoxin + EPI → Severe arrhythmia risk.

  • Cocaine → Excess adrenergic stimulation.

  • Hyperthyroidism → ↑ Adrenergic sensitivity.

  • Anxiety, tremor, headache; possible pulmonary edema or cerebral hemorrhage.

Norepinephrine

• Use: Shock.

• Interactions: NE + Atropine → Atropine blocks vagal effects → Tachycardia risk.

Isoproterenol

Sses: Heart failure; asthma/COPD.

Dobutamine

structure

Dobutamine

• Effects

  • β1 selective at normal doses.

    • Positive inotropic → ↑ Contractility.

    • No chronotropic increase at normal doses (MAJOR ADVANTAGE)

      • Heart beats harder, not faster

  • High dose → α activation.

• Used in heart failure/shock.

• Risk: Atrial fibrillation → Rapid ventricular response.

β2 Adrenergic Agonists

β2 Adrenergic Agonists

Drug Classification

Class	Duration	Drugs
SABA (Short-acting)	4–8 hours	Terbutaline, Metaproterenol, Albuterol
LABA (Long-acting)	6–12 hours	Salmeterol, Formoterol
ULABA (Ultra-long-acting)	24 hours	Indacaterol, Olodaterol, Vilanterol

ADMIN STUFF:

1. The professor did not mark these with ***:, so I will skip for now memorizing the structures

• Dopamine

• Terbutaline

• Olodaterol

• Vilanterol

2. Memory Trick

SABA- TAMANAH MET AISHWARYA

LABA - SALMAN FUCKBOY

ULABA - I Own Vans

β2 Adrenergic Agonists

General Rules — Apply to These Drugs

Rule	What it means
β2 selective	Bronchodilation → Opens airways
Bulky N-substituent	↑ β selectivity
Para-OH	↑ β-receptor affinity
Non-catechol	Avoids COMT metabolism
Long hydrophobic N-chain	Membrane binding → Longer action

SABA-specific facts:

• Used for short asthma attacks.

• Better oral bioavailability than epinephrine, but inhalation preferred.

• Longer action than EPI because they avoid COMT and undergo slower MAO metabolism.

SABA (Short-acting)

Draw and tell me about structures of - Terbutaline, Metaproterenol, Albuterol

Drug	✏ Structure to recognize	Why it matters
Terbutaline	Resorcinol	Non-catechol → Avoids COMT
Metaproterenol ***	Resorcinol	Non-catechol → Avoids COMT
Albuterol ***	Salicyl alcohol	Non-catechol → Avoids COMT

LABA(Long-acting)

Draw and tell me about the structures of Salmeterol and Formoterol

Salmeterol ***	Long hydrophobic N-chain	Membrane binding → Longer duration
Formoterol ***	methoxy + formamide-related group	Extra receptor interactions → ↑ β2 affinity

ULABA

Draw and tell me about the structures of Indacaterol, Olodaterol, and Vilanterol

Indacaterol ***	Quinoline ring + bulky hydrophobic N-group	Metabolic stability + longer duration
Olodaterol	Benzoxazinone-containing structure	Recognize as ULABA
Vilanterol	Structure shown on PPT slide 26	Recognize as ULABA

β2 Adrenergic Agonists

metabolism

Drug	🔁 Metabolism process	Elimination
Albuterol (SABA)	SULT1A sulfation	urine
Salmeterol (LABA)	CYP3A4 hydroxylation → Glucuronidation	feces
Formoterol (LABA)	O-dealkylation and/or glucuronidation	feces
Indacaterol (ULABA)	CYP3A4 hydroxylation and/or glucuronidation	feces

SKIP FOR NOW (idk if i need to know in this much detail)

β2 Adrenergic Agonists

metabolism - draw