Propranolol
Isoproterenol
Name
Pot.
Propranolol (Inderal)
1
Nadolol (Blocadren)
Beta -1
ISA
MSA
t1/2 (h)
Lipid Sol.
1st Pass
% Abs.
% Bioav.
Elim
++
3-4
High
Yes
>90
30
Hep; AM
1
10-20
Weak
30
30
Ren
Timolol (Blocadren)
6
4-5
Mod
Little
>90
75
Ren
Metoprolol (Lopressor)
1
++
3-4
Mod
Yes
>90
50
Hep
Atenolol (Tenormin)
1
++
6-9
Weak
50
40
Ren
Esmolol (Brevibloc)
0.02
++
9 min
Weak
NA
NA
Blood esterases
Pindolol (Visken)
6
>90
90
Ren/Hep
Acebutalol (Sectral)
0.3
70
40
Ren/Hep ;AM
Sotalol * (Sotapor)
70
60
Ren
Labetalol # (Normodyne)
>90
33
Hep
++
+
3-4
High
+
+
3-4
Mod
0.3
9-10
Weak
0.3
3-6
Mod
+
Little
Yes
*: 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 CO Vehicle Propranolol
5.44 5.15
5.27 4.37*
Exercise 10.3 10.3 10.5 8.3*
Pindolol HR Vehicle Propranolol
6.12 69 61
5.86 70 54*
11.9 107 105
9.8* 105 90*
Pindolol Vehicle Propranolol Pindolol
67 116 95 109
65 115 90* 111
105 133 110 126
91* 128 102* 117*
BP
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 Time (h)
Pindolol 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 Hypertension Arrhythmias Congestive heart failure Hypertrophic obstructive cardiomyopathy • Dissecting aortic aneurysm
• • • • • •
Pheochromocytoma Hyperthyroidism Migraine -prophylaxis Essential tremor Anxiety – stage fright Glaucoma (topical)
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 heart failure
Placebo
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 (?)