(21) Alpha adrenergic agonist and mixed action adrenergic

Alpha adrenergic agonist

Big picture: α1 vs. α2

	α1 agonists	Central α2 agonists
Main effect	Vasoconstriction	↓ Sympathetic flow
Blood pressure	↑ BP, especially diastolic	↓ BP
Heart rate	May cause reflex bradycardia	↓ HR
Uses	Hypotension, decongestants, mydriasis	Hypertension, glaucoma

(SKIP FOR NOW)

SAR — Structural rules

Structural modification	Effect
Remove para-OH	↓ β activity → favors α
Only 1 phenolic OH	Monophenol
Two adjacent ring OH	Catechol → COMT substrate
No catechol	Not COMT substrate
Small/free amine	More susceptible to MAO
Bulky N-substituent	Less MAO metabolism; tends to favor β
Remove side-chain β-OH in arylimidazolines	Favors α
X = CH₂ vs. NH	Distinguishes xylometazoline from clonidine

• Don't confuse para-OH with β-OH. Para-OH is on the aromatic ring; β-OH is on the side chain.

Phenylephrine

Structure — compare with epinephrine

• Monophenol → one phenolic OH.

• Missing para-OH → ↓ β activity → favors α.

• Not COMT substrate → orally bioavailable.

• Binds α1 and α2.

Uses (basically all of a1)

• Hypotension → ↑ diastolic BP.

• Nasal decongestant.

• Mydriasis → dilates pupil.

Ephedrine vs. Pseudoephedrine

	Ephedrine	Pseudoephedrine
Action	Direct α1 + some indirect	Indirect only (lecture)
Stereochemistry	(−) R,S	S,S (slide)
Mechanism	Activates α1	Inhibits NERT
Result	Vasoconstriction	↑ Synaptic NE
Uses	Decongestant, hypotension	Decongestant
COMT	Not substrate	Not substrate
Risks	Insomnia, agitation, anorexia	↑ BP; MI risk

Midodrine — Prodrug

draw

✅ STRUCTURE: Identify methoxy groups, glycine, and what is removed to form the active metabolites.

Midodrine — Prodrug

Why use midodrine instead of norepinephrine?

Norepinephrine:

• Catechol → oxidizes to inactive quinone.

• COMT + MAO substrate → short duration.

• Injection required in lecture comparison.

Midodrine:

• Not catechol → chemically more stable.

• Not COMT/MAO substrate initially.

• Oral prodrug → requires activation.

Midodrine — Prodrug

Bioactivation

• Both active metabolites contribute to α effects.

• Used for orthostatic hypotension.

• 🚨 Last dose at least 4 hours before bed → supine hypertension risk.

L-DOPA / Droxidopa

draw

L-DOPA / Droxidopa

tell me about it

• Amino acid-like structures → zwitterions (NH₃⁺ / COO⁻).

• Transporter-mediated absorption and BBB crossing.

• L-DOPA: Precursor to dopamine → Parkinson's disease.

• Droxidopa: Precursor to norepinephrine → neurogenic orthostatic hypotension.

  • Droxidopa → avoid lying down after dosing; 4 hours before bed.

Arylimidazolines

General structure

• Imidazoline ring.

• Removal of side-chain β-OH → favors α.

• Connecting group X helps determine α1 vs. α2 activity.

X group	Drug	Main effect
CH₂	Xylometazoline	Nasal α1
NH	Clonidine	Central α2

🚨 Professor called this structural difference a “dead giveaway.”

Arylimidazolines

Oxymetazoline vs. Xylometazoline

	Oxymetazoline	Xylometazoline
Structural difference	Has phenolic OH	Lacks phenolic OH
Receptors	α1 + α2	α1 + α2
Nasal effect	α1 vasoconstriction	α1 vasoconstriction
COMT/MAO	Not substrates	Not substrates
Main use	Nasal decongestion	Nasal decongestion

Arylimidazolines

Oxymetazoline - STRUCTURE

Arylimidazolines

Oxymetazoline - Clinical facts

• Oxymetazoline = Afrin.

• Nasal decongestants; lecture also discussed nosebleeds and red eyes.

• Duration ≈ 12 hours.

• 🚨 Use no more than 3–5 days → rebound congestion.

Arylimidazolines

Clonidine - STRUCTURE

Arylimidazolines

Clonidine - TELL ME ABOUT IT

• Guanidine-like group → pKa ≈ 8.

• Dichloro groups → help BBB penetration.

Mechanism

Central α2 activation → ↓ sympathetic flow → ↓ HR and BP.

Uses - α2 agonist

• Hypertension.

• Glaucoma → ↓ aqueous humor → ↓ intraocular pressure.

🚨 Risk: Dichloro groups → help Crosses BBB → drowsiness, bradycardia, central adverse effects.

Apraclonidine vs. Brimonidine

	Apraclonidine	Brimonidine
Compared with clonidine	Added NH₂	Bromine + extra ring
pKa	~9	~7
Log D	~0.01	~0.5
BBB	Poor penetration	Higher penetration potential
Clinical benefit	Less CNS effects	High α2 affinity
Use	Glaucoma	Glaucoma

• Apraclonidine: Added NH₂ → ↑ polarity → ↓ BBB penetration → less drowsiness.

• Brimonidine: Structural changes → approximately 1,000× α2 selectivity vs. β (lecture).

  • Lower ocular dose of brimonidine helps reduce CNS and cardiovascular effects.

Apraclonidine - structure

Brimonidine - structure