BETA BLOCKERS AND OTHER

SYMPATHOLYTIC AGENTS
 CENTRAL

NERVOU
S
SYSTEM
SOMATIC

PERIPHE SENSO
RAL RY

AUTONO SYMPATHETIC
MIC
MOTOR
PARASYMPATH
ETIC
 AUTONOMIC NERVOUS SYSTEM
(ANS)
Largely independent from direct conscious control
Integrated and controlled at many levels from the
CNS
Sensory inputs modify autonomic output through
reflex arcs

It regulates visceral functions, such as:

Contraction of vasal and visceral smooth muscle
Contractility, automaticity, and conduction
velocity of heart
Exocrine gland secretion
Endocrine gland secretion (pancreas, posterior
pituitary)
Energetic metabolism (liver, muscle)
PARASYMPATHETIC

CHOLINERGIC
SYMPATHETIC

NORADRENERGIC
SYMPATHETIC

DOPAMINERGIC
SYMPATHETIC
MODIFIED
SYMPATHETIC

Katzungetal,BasicandClinicalPharmacology12thedition
 Generally the parasympathetic and the
sympathetic system innervate the same
visceral organs,
but determining opposite effects
REST FIGHT
AND OR
DIGEST FLIGHT

Internal body homeostasis is a dynamic balance

between the two autonomic branches, which
exert a physiological continuous
control of organic functions
SYMPATHETIC TRANSMITTERS:
CATECHOLAMINES (CA)
In some In most In the
kidney sympatheti adrenal
sympatheti c medulla
c postgangli and in
postganglio onic some brain
nic neurons neurons areas

RATE-
LIMITI
NG
STEP

Tyrosine Dopa Dopamine Phenylethanolamine

hydroxylase decarboxylase -hydroxylase N-methyltransferase
 ADRENERGIC RECEPTORS

ALPH ALPHA2 BETA

Gq A1
protein Gi protein Gs protein
coupled coupled coupled

1A 1B 1C 2A 2B 2C 1 2 3

D1like D2
Gs protein like
Gi protein
coupled coupled

D1 D5 D2 D3 D4
Katzungetal,BasicandClinicalPharmacology12 thedition
Katzungetal,BasicandClinicalPharmacology12 thedition
 SYMPATHETIC ACTIVATION
It prepares the body to cope with physiological stressors,
such as exercise, excitement, and danger

Increased activity of those Inhibition of

systems fundamental, in
order to give the body
strength and speed
Heart rate acceleration
Generalized
vasoconstriction
Eye pupils dilation
Sweat secretion
Bronchiolar dilation
Liberation of glucose
and fat
non-essential functions,
such as digestion and
diuresis
Inhibition of salivary
flow
Reduction of
gastrointestinal motility
Increase of visceral
sphincteric tone
Relaxation of bladder
NORADRENERGIC PATHWAYS IN
CNS
NEOCORTEX
THALAMUS

HYPOTHALAMUS

AMYGDALA
HYPPOCAMPUS

LOCUS COERULEUS
CEREBELLUM

SPINAL CORD
NORADRENERGIC PATHWAYS IN
CNS
Regulation of blood pressure
Vasomotor centre within the medulla is involved
in the postural baroreflex

Induction of wakefulness and state of

alertness
Control of mood state
Descending control of pain circuits
Involvement in cognitive processes
Katzungetal,BasicandClinicalPharmacology12thedition
 SYMPATHOLYTIC DRUGS
Block of sympathetic transmission from
the postganglionic fibres to the effector
organs

1. BETA BLOCKERS
Propranolol, Pindolol, Atenolol, Bisoprolol, Labetalol,
Carvedilol
2. ALPHA1 ANTAGONISTS
Prazosin, Doxazosin, Terazosin
3. ALPHA2 AGONISTS
Clonidine, Alpha metildopa, Guanfacine, Guanabenz
4. ADRENERGIC NEURON BLOCKERS
Guanethidine, Guanadrel, Reserpine
5. SYMPATHETIC GANGLION BLOCKERS
Trimetaphan
 SYMPATHOLY
TICS: SITES 3

OF ACTION

2
1

Katzungetal,BasicandClinicalPharmacology12thedition
BETA BLOCKERS
 MILESTONES blocker, is developed
useful beta
the frst clinically
Propranolol,
1964

1954
Isoproterenol
hydrochloride
induces relaxation in
vitro of tracheal tissue
1958 - 1962
James Black recognizes that a
therapeutic strategy against angina
would be to antagonize the beta
adrenergic receptors to which the
stress hormones CA bind, thereby
1847 increasing the workload and oxygen
Nitroglycerin reduces the demand of the heart
pain of angina by dilating the
cardiac blood vessels, thereby
increasing the supply of
 MEDICINE NOBEL PRICE 1988

In recognition of the activity of Sir James

Black,
the Nobel Committee defnes Propranol as

The greatest breackthrough when it

comes to pharmaceuticals against heart
illness since the
discovery of digitalis 200 years ago
CHEMICAL STRUCTURES

Propranolol Metoprolol

Pindolol Timolol

Labetalol Atenolol

Nebivolol

Katzungetal,BasicandClinicalPharmacology12thedition
PHARMACODYNAMIC PROPERTIES

No pharmacological activity
in the absence of sympathetic activation

Non Selective
Blockade of beta1 and beta2 receptors in the presence
of high CA concentrations (competitive antagonism)

Beta1 Selective or Cardio-Selective

Competitive beta1 blockade
Beta1 selectivity decreases or disappears with larger

dose of the drug

PHARMACODYNAMIC PROPERTIES
Some molecules exhibit

Intrinsic Sympathomimetic Activity (ISA)

Properties as partial agonist
Beta block in the presence of high CA
concentrations
Moderate beta activation in the absence of CA

Peripheral Vasodilator Activity

Due to
Alpha1antagonism Carvedilol, Labetalol
Beta2 agonism Celiprolol
Enhancement of nitric oxide release
Lopez-Sendon et al, Eur Heart J. 2004
Contraction Vasoconstricti Bronchoconstri Inhibition
of uterine on of ction of renin
muscle muscular release
arteries

heart rate
conduction

productio BETA velocity of

BLOCKE impulse
n of
cardiac
aqueous RS output
humor
O2
consumption

release glycogenesis
lipolysis of insulin glycogenolys and
is glycogenolysis
ModifiedfromRossiCuomo,MinervaMedica
 PHARMACOKINETICS
Max Min

LIPOPHILIC
GI absorption
IDROPHILIC
Short half-life
Propran hepatic
olol metabolism
drug-protein
Alprenol bond
Oxpreno
ol Nadolol
Transfer into GI absorption
lol Celiprol
CNS Long half-life ol
Metopro hepatic Sotalol
lol metabolism
Atenolo
drug-protein
l
bond
Min Max
Renal elimination
 CARDIOVASCULAR INDICATIONS

Hypertension
Stable and acute coronary artery disease
Heart failure
Cardiac arrhythmias
Hypertrophic cardiomyopathy
 COMPLEX ANTIHYPERTENSIVE
EFFECT
First haemodynamic response
Decrease of cardiac output
Reflex peripheral vasoconstriction

In days, secondary haemodynamic response

Decrease of cardiac output Decrease
Inhibition of renin release of
Presynaptic beta2 block of NA release
blood
pressure
Reduction of central vasomotor activity (lipophilic
molecules)
Cochrane Database Syst Rev. 2012

13 RCTs comparing beta-blockers to placebo (4 trials), diuretics

(5 trials), calcium antagonists (4 trials), and RAS inhibitors (3
trials)

Beta Blockers appear to be

worse than calcium antagonists for total mortality and
cardiovascular events
worse than calcium antagonists and RAS blockers for stroke
equal to calcium antagonists, RAS blockers and diuretics for
 British Medical Journal 2009

Beta-blocker-initiated therapy is

equally as effective as the other major classes

of antihypertensive agents in preventing
coronary outcomes

highly effective in preventing cardiovascular

events in patients with a recent
myocardial infarction and those with heart
 - Class I, Level of evidence A -
All Beta Blockers, similarly to diuretics thiazides,
calcium antagonists, ACE Inhibitors, and angiotensin
receptor blockers, are suitable and recommended for
the initiation and maintenance of antihypertensive
therapy, either as monotherapy or in some
 ANTISCHEMIC AND
ANTIARRHYTMIC PROPERTIES
perfusion
pressure

duration of
diastolic
heart rate
perfusion
contractility
O2 DEMAND vs O2 endocardic
SUPPLY blood flow
A-V conduction
vascular
spontaneous firing of
resistance in non-
ectopic pacemakers
ischaemic areas
systolic blood pressure

ventricular size
 STABLE CORONARY ARTERY
DISEASE (SCAD)
STABLE ANGINA MANAGEMENT

ACEI angiotensin converting enzyme inhibitor; CABG coronary artery bypass

graft; CCB calcium channel blockers; CCS Canadian Cardiovascular Society;
DHP dihydropyridine; PCI percutaneous coronary intervention
 STABLE CORONARY ARTERY
DISEASE
MICROVASCULAR ANGINA
Beta blockers are the frst choice therapy,
particularly in patients with increased adrenergic
activity, e.g. high heart rate at rest or during low-
workload exercise
Calcium antagonists are recommended as second-
line therapy

VASOSPASTIC ANGINA
Calcium antagonists and nitrates should be
considered
Beta blockers must be avoided, as they might
favour spasm by leaving alpha mediated
vasoconstriction unopposed by beta mediated
 ACUTE CORONARY ARTERY
DISEASE
CRITICAL OCCLUSION OF A CORONARY ARTERY,
DUE TO THE RUPTURE/EROSION OF AN ATHEROMATOUS
PLAQUE AND TO THE FOLLOWING THROMBOSIS

NON-ST ELEVATION ST ELEVATION

cardiac enzymesNo cardiac enzymes cardiac enzymes

UA NSTEMI STEMI
Unstable Angina Non ST Segment ST Segment
Elevation Elevation
Myocardial Myocardial
PharmacologicalInfarction
therapy Reperfusion (PCI) or
Infarction
Fibrinolysis
First choice in all the patients First choices
Reperfusion (PCI O CABG) Pharmacological therapy
In medium-high risk patients of
 Eur Heart J. 2012; Eur Heart J.
2015
ACUTE CORONARY ARTERY
DISEASE
Early oral treatment with beta-blockers is
recommended in all NSTEMI patients with ongoing
ischaemic symptoms and should be considered as
ancillary in STEMI patients during hospital

It is recommended to continue chronic beta-blocker

therapy in all the acute CAD patients

Beta blockers are especially recommended in those

patients with heart failure characterized by LVEF
40% after stabilization, to reduce the risk of death,
recurrent myocardial infarction and hospitalization
for heart failure
 OTHER CLINICAL INDICATIONS

Prophylaxis of migraine
Essential tremor
Glaucoma
In hyperthyroidism and anxiety, control of
somatic symptoms, such as tremor,
tachycardia
Infantile hemangioma
Bleeding of oesophageal varices
associated with portal hypertension
 European Federation of Neurological
Societies 2009
MIGRAINE
PREVENTION

Societ Italiana per lo Studio delle

Cefalee 2012
 NEJM2015

A total of 88% of patients who received 3 mg of

propranolol per kilogram per day for 6 months showed
improvement by week 5, versus 5% of
patients who received placebo
ANTICANCER PROPERTIES?
 SIDE EFFECTS
BETA
1 Extreme bradycardia and AV block

Raynauds phenomenon
Worsening of severe peripheral vascular
BETA disease
2 In type-I diabetes, mask of warning
symptoms of hypoglycaemia, such as
tremor and tachycardia
Bronchospasm in asthma/COPD
Reduced capability to exercise
LIPOPHILIC Impotence and loss of libido
MOLECULES
Central effects, such as fatigue,
headache, insomnia and vivid dreams,
ALPHA1 ANTAGONISTS
 PRAZOSIN, DOXAZOSIN,
TERAZOSIN
Prazosin (short-acting)
Doxazosin and Terazosin (long-acting)

Mechanism of action and clinical uses

Hypertension
Decrease of blood pressure
Larger depressor effect with frst dose may cause
orthostatic hypotension
Generally associated to other classes of
antihypertensive drugs

Benign Prostatic Hyperplasia

Relaxing action on prostatic and ureteral smooth muscle
ALPHA2 AGONISTS
 CLONIDINE
High oral bioavailability

Available as tablets, patches,

Imidazoline injections

Mechanism of action and clinical uses

Postsynaptic alpha2 Blood pressure

agonism decrease
Hypertension
Vasomotor centre
Cardiac output
Presynaptic alpha2 decrease
agonism
Peripheral neurons Reduction of
aqueous
Glaucoma
humor
production