Pandazi Ageliki
Assistant Professor
2nd Department of Anaesthesiology,
Attikon Hospital, University of
Athens
�Sympatholytic drugs (antagonists):
Bind to beta-adrenoceptors
Block norepinephrine and
epinephrine binding
Inhibit normal sympathetic effects.
�Minimal effect on resting subjects,
they reduce the effect of
excitement/physical exertion
Type of b-receptors
Site Effects of stimulation
b1
(E=NE)
Heart (predominant, although
there are also b2)
heart rate (SA node)
conduction velocity
myocardial contractility
oxygen consumption
automaticity (AV node and muscle)
Kidney renin release
Adipose tissue Lipolysis
b2
(E > NE)
Skeletal muscle
Skeletal muscle vasculature
Bronchial smooth muscle
Uterus
Liver
Bladder (detrusor muscle)
Intestinal smooth muscle
Pancreas
Tremors
Vasodilatation in skeletal muscle
Bronchodilatation
Uterine relaxation (Pregnant)
Hypokalaemia and hepatic glycogenolysis
Relaxation
Relaxation
Increase insulin secretion
b3 Brown adipose tissue Heat production
b1/b2 Blood 1. Anti inflammatory effect
2. Platelet aggregation
� Catecholamines (1st messenger transmitter)
� Attachment over b-receptor causes b-receptor
stimulation
� Stimulation of G-protein
� Stimulation of adenyl cyclase
� Increase Cyclic AMP (2nd messenger transmitter)
� Stimulation of protein kinase-A
� • Cardiac effects
• Bronchial dilatation
• Skeletal vasodilatation
• Release of glucose and potassium from liver
�Resemblance to
isoproterenol (potent b-
receptor agonist)
�
�Benzene ring with various
substitutions
�Beta-blockers with intrinsic sympathomimetic activity (ISA):
Partial activation of receptor + prevention of catecholamine binding
‘background’ sympathetic activity, normal and enhanced sympathetic activity prevented
(useful in bradycardia)
�Beta-blockers with membrane stabilizing activity (MSA)=
effect similar to the membrane stabilizing activity of sodium channel blockers (Class I
antiarrhythmics, local anaesthetics).
�Beta blockers with α1-Receptor antagonism: additional arterial vasodilation
Name Pot. Beta
-1
ISA MSA t1/2
(h)
Lipid
Sol.
1st
Pass
%
Abs.
%
Bioav.
Elim
Propranolol
(Inderal)
1 ++ 3-4 High Yes >90 30 Hep;
AM
Nadolol
(Blocadren)
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 ++ + 3-4 High >90 90 Ren/Hep
Acebutalol
(Sectral)
0.3 + + + 3-4 Mod Little 70 40 Ren/Hep
;AM
Sotalol *
(Sotapor)
0.3 9-10 Weak 70 60 Ren
Labetalol #
(Normodyne)
0.3 3-6 Mod Yes >90 33 Hep
*: Class III antiarrhythmic; #: an alpha-1 blocker also. ISA: intrinsic sympathomimetic activity; MSA:
membrane stabilizing activity. AM: active metabolite. Many other Beta blockers available.
�1st generation: non-selective, they block
both β1 and β2 adrenoceptors.
�2nd generation: relatively selective for β1
adrenoceptors (dose-related selectivity,
can be lost at higher drug doses)
�3rd generation: also possess vasodilator
actions through blockade of vascular a-
adrenoceptors
1st generation (non-selective)
2nd generation (‘cardioselective’)
3rd generation
carteolol acebutolol Labetalol
carvedilol atenolol
labetalol betaxolol
nadolol bisoprolol
penbutolol esmolol
pindolol metoprolol
propranolol nebivolol
sotalol
timolol
�All the drugs are well absorbed after oral
administration. Peak concentration occurs 1- 3
hours after ingestion.
�Bioavailability after oral administration limited
to varying degrees for most b-blockers (except
betaxolol, penbutol, pindolol and sotalol),
mainly because of hepatic (first-pass)
metabolism. Bioavailability is very low and
increases as the dose is increased
�Oral administration: lower blood
concentrations than intravenous of the same
dose
� Large volumes of distribution
� Most have half-life of 3-10 hours, except:
� Esmolol: half life of 8-10 minutes and
� Nadolol: longest half life of 24 hrs (excerted unchanged in the urine)
� Propranolol, Penbutol: cross blood-brain barrier (lipophilic)
� Propranolol, Metoprolol: hepatic metabolism.
� polymorphism of P450 2D6: interindividual differences of plasma clearance, poor metabolisers 3fold-10fold higher plasma concentrations
� Hepatic failure, diminished hepatic blood flow, hepatic enzyme inhibition prolongs the half life
� Renal failure prolongs the half life of hydrophilic drugs.
� Randomized controlled trials and meta-analyses provide conflicting guidance on the role of b-blockers in reducing perioperative complications.
� Pharmacological properties of -blockers may contribute to heterogeneous trial results:
� The extent of -blocker metabolism by CYP2D6
� The time available to titrate b-blocker dosage preoperatively, and
� variations in b-blocker selectivity for the b-1 receptor may contribute to the heterogeneous results.
� Metoprolol should probably not be used for perioperative
b-blockade when there is insufficient time to titrate its dose.
� Some level of basal sympathetic tone exists on the heart
� Beta-blockers reduce sympathetic influences that normally stimulate:
� Chronotropy (heart rate)
� Inotropy (contractility),
� Dromotropy (electrical conduction) and
� Lusitropy (relaxation).
� Beta-blockers cause decreases in:
� Heart rate, (Slowed SA node)
� Contractility,
� Conduction velocity (Slowed AV conduction with an increased PR interval)
� Relaxation rate.
� Even greater effect when there is elevated sympathetic activity.
� Reduces myocardial O2 demand by reducing
heart rate and force of contraction.
� Longer diastolic filling time increases
coronary perfusion time.
� Reduces peripheral resistance
� Decreases the slope of phase 4 depolarisation
as well as spontaneous firing rate of sinus or
ectopic pacemakers.
� Reduces cardiac output.
� Reduces plasma renin
�β2-adrenoceptors:only a small modulatory role
on basal vascular tone little vascular
effect
�B-blockers: remove a small β2-adrenoceptor
vasodilator influence that is normally opposing
the more dominant alpha-adrenoceptor
mediated vasoconstrictor influence
� Acutely: rise in peripheral vascular resistance
from unopposed α-receptor-mediated effects.
� Chronic use: decrease in peripheral vascular
resistance in patients with hypertension.
Mechanism unknown.
�Impair relaxation of bronchial muscle (mediated by b-2) increase in airway resistance, particularly in asthmatics
�b-1 selective blockers:
� some advantages, but they do not avoid completely interactions with b-2 receptors
�Avoided in patients with asthma
�Better tolerated in patients with COPD
�Decrease nocturnal melatonin release sleep disturbance
�Protect against social anxiety�Lower aqueous humor secretion decrease
intraocular pressure treatment of glaucoma� Increase of VLDL, decrease of HDL and HDL/LDL
(the same for selective, non-selective, less with blockers with ISA)
� Inhibition of glycogenolysis in liver (b2-blockade)impairement of recovery from hypoglycemia:
� Mask tachycardia (sign of hypoglycemia)� Caution in insulin-dependent diabetics (preferred
b1-selective)� Better tolerance in patients with diabetes type II
�Coronary artery disease (angina, myocardial
infarction)
�Hypertension
�Arrhythmias
�Atrial fibrillation
�Essential tremor
�Symptomatic control (tachycardia, tremor)
in anxiety, hyperthyroidism
�Migraine -prophylaxis
�Glaucoma (topical)
�Hypertrophic obstructive cardiomyopathy
�Acute dissecting aortic aneurysm
�Pheochromocytoma,in conjunction with
α-blocker
�Marfan syndrome (treatment with
propranolol slows progression of aortic
dilation and its complications)
�Prevention of variceal bleeding in portal
hypertension
�Possible mitigation of hyperhidrosis
� Respiratory disease : Cardio selective b-blockers are used.
� Cardio vascular disease : In sick sinus syndrome b-blockers are dangerous
� Active peripheral vascular disease : e.g. Raynaud’s - b-blockers are relatively contra-indicated.
� Renal disease : b-blockers may reduce GFR. They are excreted by kidney so in renal failure doses are changed.
� Liver disease : Avoid b-blockers with high first pass metabolism like propranolol.
� Pregnancy : It may depress vitals of foetus
and causes uterine artery vasoconstriction.
Labetolol and Atenolol can be used. Alpha
methyldopa preferred
� Surgical : It is prophylactically used to
prevent anaesthetic tachycardia
� Smokers : b-blockers are less effective in
reducing coronary events.
� Diabetes mellitus : Cardio selective agents
are preferred.
�In asthma
�In diabetes mellitus
�In peripheral vascular disease
The side effects result from excessive blockade of normal sympathetic influences on the heart and include:
� Bradycardia
� Exacerbating heart failure or precipitating heart failure in those with preexisting myocardial dysfunction
� Hypotension
� Hypertension in phaeochromocytoma (due to preexisting a-effect)
� AV nodal block
� Decrease in exercise tolerance (due to decreased cardiac output)
Therefore:
� Contraindicated in patients with sinus bradycardia and partial AV block.
� Considerable care if given in conjunction with cardiac selective calcium-channel blockers (e.g., verapamil) (additive effects in electrical and mechanical depression).
� Beta-blockers in heart failure: at present only carvedilol and metoprolol have been approved by the FDA for this indication.
� CNS : Sedation, sleep disturbances, depression, psychotic reactions, nightmares, impotence, lethargy, headache.
� Bronchospasm
� Rash
� Fever
� Drug allergy
� Hyperkalaemia in diabetics
� Uraemia, Hyperuricaemia
� Decrease HDL/LDL ratio
� Rare side effects : uveitis, sclerosing cholangitis, peritonitis, purpura, agranulocytosis.[
� Abrupt withdrawal syndrome : exacerbation of MI angina, arrhythmias.
� Patients on chronic b-blockers therapy should be tapered of this therapy slowly.
�Bradycardia, heart block,
hypotension and low output
shock.
�Death is more likely with
agents having membrane
stabilizing action
�Bronchoconstriction can be
severe, even fatal.
� Atropine (1-2 mg iv ):eliminates the unopposed
vagal activity . For long lasting bradycardia: TPI
� Glucagon: cardiac inotropic and chronotropic
actions independent of the b-adrenoceptors
(dose 5-10 mg iv, infusion of 1-10 mg/hr)
� No response: iv injection or infusion of a b-
adrenoceptor agonist is used, e.g. isoprenaline (4
mcg/min, increasing at 1-3 min intervals until
the heart rate is 50-70 beats/min)
� Other sympathomimetics : e.g. dobutamine,
dopamine, dopexamine, noradrenaline,
adrenaline
� For bronchoconstriction: salbutamol
�Prototypical agent
�Low and dose-dependent
bioavailability
�Long-acting form: prolonged
absorbion over 24 hours
�No effect at a, muscarinic receptors
�No ISA
�Blocks brain serotonin receptors
(unknown clinical significance)
� B-1 selective, intravenous, ultra-short acting
� Ester linkage : rapid metabolism by red blood cell
esterases to a metabolite with low affinity for b-
receptors
� About 10-minute half-life, suitable for continuous
infusion
� Rapid clinical onset and offset of action
� Ability to titrate the drug to changing circumstances
� Use in specific clinical settings:
� Supraventricular arryhthmias
� Arrhythmias associated with thyrotoxicosis
� Perioperative hypertension
� Myocardial ischemia in acutely ill patients
�Dosage schedules: 25-300 micrograms/kg/min with a loading dose or bolus.
�The most frequently reported adverse effect with esmolol infusion: hypotension.
�Adverse effects due to beta-blockade can be corrected by down-titrating or discontinuing the infusion with complete disappearance of clinical effects in 20-30 minutes.
�Relatively safe in patients with congestive heart failure or chronic obstructive lung disease
�Careful titration and monitoring of the patient
Barbier GH et al. Clinical rationale for the use of an ultra-short acting beta-blocker: esmolol. Int J Clin Pharmacol Ther. 1995
Apr;33(4):212-8
�Racemic mixture:
�(S,S) and (R,S)-isomers: relatively
inactive
�(S,R)-isomer: potent a-blocker (a-1
selective)
�(R,R)-isomer: potent b-blocker
�Hypotension accompanied with less
tachycardia than a-blockers
�Clinical use: hypertension of
pregnancy
� Hoffman BB. Adrenoceptor Antagonist Drugs.
In Katzung B: Basic & Clinical Pharmacology.
10th Edition, 2007.
� Westfall TC, Westfall DP. Adrenergic Agonists
and Antagonists. Section II Goodman &
Gilman’s The Pharmacological Basis of
Therapeutics. 11th Edition. 2006