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