Propranolol

Isoproterenol
 Name Pot. Beta ISA MSA t1/2 Lipid 1st % % Elim
-1 (h) Sol. Pass Abs. Bioav.
Propranolol 1 ++ 3-4 High Yes >90 30 Hep;
(Inderal) AM
Nadolol 1 10-20 Weak 30 30 Ren
(Blocadren)
Timolol 6 4-5 Mod Little >90 75 Ren
(Blocadren)
Metoprolol 1 ++ 3-4 Mod Yes >90 50 Hep
(Lopressor)
Atenolol 1 ++ 6-9 Weak 50 40 Ren
(Tenormin)
Esmolol 0.02 ++ 9 min Weak NA NA Blood
(Brevibloc) esterases
Pindolol 6 ++ + 3-4 High >90 90 Ren/Hep
(Visken)
Acebutalol 0.3 + + + 3-4 Mod Little 70 40 Ren/Hep
(Sectral) ;AM
Sotalol * 0.3 9-10 Weak 70 60 Ren
(Sotapor)
Labetalol # 0.3 3-6 Mod Yes >90 33 Hep
(Normodyne)
*: Class III antiarrhythmic; #: an alpha-1 blocker also. ISA: intrinsic sympathomimetic activity; MSA: membrane stabilizing
activity. AM: active metabolite. Many other Beta blockers available.
 Properties of Beta-blockers
• Potency
• Membrane stabilizing activity (quinidine-like)
• Structure-activity relationships: L-isomer has
the Beta-blocking action.
• Cardioselectivity (Beta-1 selectivity)
• Intrinsic sympathomimetic activity (partial
agonist activity)
• Lipid solubility – relation to pharmacokinetics
Intrinsic Sympathomimetic Activity
 Intrinsic Sympathomimetic Activity
Rest Exercise
CO Vehicle 5.44 5.27 10.3 10.3
Propranolol 5.15 4.37* 10.5 8.3*
Pindolol 6.12 5.86 11.9 9.8*
HR Vehicle 69 70 107 105
Propranolol 61 54* 105 90*
Pindolol 67 65 105 91*
BP Vehicle 116 115 133 128
Propranolol 95 90* 110 102*
Pindolol 109 111 126 117*
 Beta-Blockers
Pharmacokinetics
• Lipid soluble agents (vs. water soluble) tend
to:
– Be better absorbed
– Have more variable bioavailability
– Be metabolized in liver
– Enter the CNS
– Be more widely distributed
– Have shorter elimination half-lives
 Pharmacological Properties
Propranolol
• Cardiovascular
Blood pressure, heart rate, cardiac output,
peripheral vascular resistance, coronary and organ
blood flows
• Pulmonary
• Central Nervous System
• Metabolic
Beta-Blockers – Cardiovascular Effects
MAP

HR

PVR

SV

CO Pindolol (has ISA)

Propranolol (no ISA)
Effect of Beta-Blockers during Exercise
Heart Rate Stroke Index Cardiac Index

A-V O2 Diff. Arterial Pressure Pulm. Pressure

Propranolol No Propranolol O2 Uptake

Effect of Beta-Blockers during Exercise

+β-Blocker +β-Blocker
Antihypertensive Effect of Beta-Blockers
Mechanisms
1. Decreased cardiac output
2. Inhibition of renin-angiotensin system
3. Decreased central sympathetic outflow
4. Resetting of baroreceptor
5. Others: prejunctional receptors,
prostaglandins, etc.
MAP

HR
PVR

SV

Time (h)

CO
Pindolol
Time (h)
Propranolol
 Pharmacological Properties
Propranolol
• Cardiovascular
Blood pressure, heart rate, cardiac output,
peripheral vascular resistance, coronary and organ
blood flows
• Pulmonary
• Central nervous System
• Metabolic
Effect of Beta-Blockers on Recovery from Hypoglycemia

β-Blocker Insulin

Glucose
(mmol/L)

Control
Atenolol
Propranolol
Beta-Blockers - Adverse Effects
• Cardiac (mechanical; electrical)
• Vascular (decreased perfusion)
• Pulmonary (bronchocostriction)
• Metabolic (diabetes mellitus)
• Central Nervous System (depression,
nightmares, etc.)
• Withdrawal Syndrome
The Withdrawal Syndrome
The Withdrawal Syndrome
 The Withdrawal Syndrome
CD25

Pindolol

Metoprolol

Propranolol
 Beta-Blockers
Therapeutic Uses
• Coronary artery disease • Pheochromocytoma
• Hypertension • Hyperthyroidism
• Arrhythmias • Migraine -prophylaxis
• Congestive heart failure • Essential tremor
• Hypertrophic • Anxiety – stage fright
obstructive • Glaucoma (topical)
cardiomyopathy
• Dissecting aortic
aneurysm
Beta-Blockers in Myocardial Infarction
Beta-Blockers in
Myocardial
Infarction
Beta-Blockers in Heart Failure
Beta-Blockers in Heart Failure
Beta-Blockers in Heart Failure
Cumulative Mortality (%)
in patients with congestive Placebo
heart failure

Metoprolol CR/XL

Risk Reduction = 34%

Beta-Blockers in Heart Failure
 Cardioselective Blockers -
advantages
• In asthma
• In diabetes mellitus
• In peripheral vascular disease
• In hypertension (?)