(22) Adrenergic Antagonists - PART 1: basic pharmacology and propranolol

β-Blockers

Antagonists that block epinephrine (EPI) and norepinephrine (NE).

β-Blockers

Receptors they block

Receptor	When blocked	Result
β1 — Heart	↓ HR, ↓ contraction	↓ BP systolic
β2 — Lungs	↓ Airway relaxation	Bronchoconstriction (asthma/copd risk)
β2 — Blood vessels	α1 still active	Vasoconstriction → Cold extremities
β2 — Metabolism	↓ Glucose mobilization	↑ Hypoglycemia risk (Masks tachycardia)

β-Blocker warnings to memorize:

• Abrupt withdrawal → rebound angina/arrhythmia; taper over 1–2 weeks per lecture.

• Traditional β-blockers can worsen lipids; ISA/mixed agents have less adverse lipid effects.

β-Blockers

Medications - overview

• Propranolol

• Nadolol

• Timolol

Just look at structures and chart in end!

Propranolol

topic overview

1. Classification

2. STRUCTURE — MUST DRAW

3. SAR — Why is it an antagonist?

4. Physiological effects

5. Therapeutic uses

6. Adverse effects

7. Metabolism — STRUCTURE

8. PK

Propranolol

Classification

Competitive, nonselective β1/β2 blocker.

Propranolol

STRUCTURE — MUST DRAW

• Naphthalene = 2 fused benzene rings.

• Ether oxygen (–O–).

• Longer side chain.

• β-OH group.

• Secondary amine.

• N-isopropyl group.

Propranolol

SAR — Why is it an antagonist?

• Longer chain than epinephrine.

• No catechol OH groups → Loses important H-bonds.

• Naphthalene → Hydrophobic interactions.

• Protonated amine + β-OH → Retain receptor binding.

• Bulky N-substituent → β-directed activity.

Propranolol

Physiological effects

Kidneys

Na⁺ + water retention → Compensatory BP increase

• 🚨 Hypoglycemia: β-blockers can mask tachycardia/palpitations, especially concerning for patients taking insulin.

Propranolol

Therapeutic uses

• Stable angina, NOT acute angina.

• Glaucoma → ↓ Aqueous humor.

• Hypertension → ↓ BP.

• Stable angina → ↓ Oxygen demand.

• Arrhythmia/tachycardia → ↓ HR.

• Myocardial infarction → ↓ Cardiac workload.

• Migraine → Prevention.

• Hyperthyroidism → Blocks adrenergic effects.

Propranolol

Adverse effects

• Abrupt discontinuation → Severe arrhythmias.

• High doses → Anesthetic-like effect.

• ↑ Triglycerides, ↓ HDL.

• Sexual dysfunction → ED, decreased libido.

• CNS effects → Anxiety, depression, sleep disturbance (crosses BBB).

Propranolol

Adverse effects: Abrupt discontinuation → Severe arrhythmias.

Why?

Chronic β-blockade → Receptor upregulation → Sudden withdrawal causes excessive EPI/NE stimulation.

SKIP

Propranolol

Metabolism

Notice: Glucuronidation is not shown in this picture. It's the third metabolic pathway on your professor's slide.

Propranolol

PK

• 100% absorbed orally; 25% reaches circulation due to first-pass metabolism.

• 90% protein bound.

• Half-life 3–6 hours.

• S-isomer = 100× more potent than R; metabolized more slowly.

Nadolol

Topics

• Classification

• structure

• Fun Facts

Nadolol

Classification

• Nonselective β1/β2 antagonist.

Nadolol

STRUCTURE — RECOGNIZE

• Two additional OH groups.

• N-tert-butyl group (not isopropyl).

• Partially saturated fused ring system.

• Long β-blocker side chain.

Nadolol

Fun Facts

• Extra OH → More hydrophilic → Less BBB penetration → Fewer CNS effects.

• Added OH groups are NOT epinephrine's catechol OH group

• Longer duration of action.

Timolol

Topic Overview

• Classification

• Structure

• Fun Facts

• Contraindications:

Timolol

Classification

• Nonselective β1/β2 antagonist.

Timolol

STRUCTURE — RECOGNIZE

• Thiadiazole ring → N + S.

• Morpholine ring → N + O.

• Long β-blocker side chain.

• N-tert-butyl substituent.

Timolol

Fun Facts

• More polar than propranolol → Reduced CNS penetration.

• Glaucoma → ↓ Aqueous humor.

• Also treats systemic hypertension.

• No local anesthetic activity noted.

Timolol

Contraindications:

• Severe asthma/COPD.

• 2nd/3rd-degree AV block.

• Cardiogenic shock.

Compare the drugs

	Propranolol	Nadolol	Timolol
Receptors	β1 + β2	β1 + β2	β1 + β2
Key structure	Naphthalene	Extra OH	Thiadiazole + morpholine
Polarity	Lower	Higher	Higher
CNS effects	More	Less	Less
Remember	Draw structure + metabolism don’t stop suddenly, can cause arrhythmia treat chronic angina, not acute	Longer duration	Glaucoma

🧠 More polar = Less BBB penetration = Fewer CNS effects.