Adrenoceptor

Blocking Drugs
Department of Pharmacology
College of Medicine- University of
Kirkuk
2019-2020
Lecture 2
Adrenoceptor Blocking Drugs
 The adrenergic antagonists (also called adrenergic
blockers or sympatholytics) bind to Adrenoceptor
but do not trigger the usual receptor-mediated
intracellular effects.
 These drugs act by either reversibly or irreversibly
attaching to the adrenoceptors, thus preventing
activation by endogenous catecholamine.
 Like the agonists, the adrenergic antagonists are
classified according to their relative affinities for α or
β receptors in the sympathetic nervous system.
 Numerous adrenergic antagonists have important
roles in clinical medicine, primarily to treat diseases
associated with the cardiovascular system.
 Dopamine antagonist

 Antagonists that block dopamine receptors

are most important in the central
nervous system (CNS).
Alpha--Adrenoceptor Blocking Drugs:
 Drugs that block α adrenoceptors profoundly affect blood
pressure.
 Because normal sympathetic control of the vasculature
occurs in large part through agonist actions on α-adrenergic
receptors, blockade of these receptors reduces the
sympathetic tone of the blood vessels, resulting in
decreased peripheral vascular resistance.
 This induces a reflex tachycardia resulting from the
lowered blood pressure.
 The α-adrenergic blocking agents, phenoxybenzamine and
phentolamine, have limited clinical applications.
Alpha--Adrenoceptor Blocking Drugs:

 The first generation of alpha-blockers were

non-selective, blocking both α1and α2
receptors.
 blockade of alpha-receptor
reduces the sympathetic tone of blood
vessels TPR
 the sympathetic system is activated via
baroreceptors.
 The normal vasoconstrictive α1 effect to maintain blood
pressure is blocked by the drug, and the failure of such
response results in Postural (Orthostatic) hypotension.
 The sympathetic system is further activated to release
more and more transmitters Noradrenaline.

 The excess released transmitter is free to act on Beta-

Adrenoceptors causing an unpleasant tachycardia and
increased Cardiac output.
So for this reason, the non-selective alpha-blockers are
not used ALONE in hypertension.

An α1 -blocker that spares the α1 receptor, so that

negative feedback inhibition of Noradrenaline is
maintained, thus it's more useful in hypertension.
 Examples of Alpha-Blockers:
 Phentolamine,
 Phenoxybenzamine and
 Prazosin

Phentolamine is a potent competitive antagonist at

both α1 and α2 receptors, is a nonselective α-
adrenoceptor blocker.
 Its cardiac stimulation is due to antagonism of presynaptic α2 receptors
(leading to enhanced release of norepinephrine from sympathetic
nerves) and sympathetic activation from baroreflex mechanisms.
 It is given i.v. for brief effect in adrenergic hypertensive crises.
 used for the short-term management of Pheochromocytoma.
 used to treat hypertensive crisis due to abrupt withdrawal of
clonidine and from ingesting tyramine containing foods in patients
taking nonselective monoamine oxidase inhibitors.
 o In addition to α-receptor blocker it has direct
vasodilator and cardiac inotropic actions.
o The dose for hypertensive crisis is 2-5 mg i.v.
repeated as necessary (in minutes to hours).

 Phentolamine also has minor inhibitory effects at

serotonin receptors and agonist effects at muscarinic
and H1 and H2 histamine receptors.

 Phentolamine's principal adverse effects are related

to cardiac stimulation, which may cause severe
tachycardia, arrhythmias, and myocardial ischemia.
 Phenoxybenzamine
 Is an irreversible nonselective α Adrenoceptor blocking
drug whose effects may last 2 days or longer.

α 1 < α2 non-selective)
Actions:
 Cardiovascular effects:
 By blocking α receptors, phenoxybenzamine prevents
vasoconstriction of peripheral blood vessels by endogenous
catecholamine.
 PR provokes a reflex tachycardia.
 block presynaptic inhibitory α2 receptors in the heart can contribute to
an increased cardiac output.
 the drug has been unsuccessful in maintaining
lowered blood pressure in hypertension
 Indigestion and nausea can occur with oral therapy,
which is best given with food.
 Epinephrine reversal: All α-adrenergic blockers
reverse the α-agonist actions of epinephrine. For
example, the vasoconstrictive action of epinephrine is
interrupted
 but vasodilation of other vascular beds caused by
stimulation of β receptors is not blocked.
 Therefore, in the presence of Phenoxybenzamine,
the systemic blood pressure decreases in response
to epinephrine
 Phenoxybenzamine has no effect on the actions of
Isoproterenol, which is a pure β agonist.
:Therapeutic uses
 Phenoxybenzamine is used in the treatment
of pheochromocytoma
 This drug is also useful in the chronic
management of these tumors, particularly
when the catecholamine-secreting cells are
diffuse and, therefore, inoperable.
 Phenoxybenzamine is sometimes effective
in treating Raynaud disease, frostbite, and
acrocyanosis.
 Raynaud disease
(A disease characterized by excessively reduced blood
flow in response to cold or emotional stress, causing
discoloration of the fingers and toes, whiteness, numbness,
or pain in the fingers,
 Frostbite
localized damage is caused to skin
and other tissues due to freezing
:Adverse effects
 Cause postural hypotension, nasal
stuffiness (lacking fresh air or ventilation),
nausea, and vomiting.
 may induce reflex tachycardia, which is
mediated by the Baroreceptor reflex.
 Phenoxybenzamine is contraindicated in
patients with decreased coronary perfusion.
Prazosin, terazosin, doxazosin, tamsulosin,
and alfuzosin

 selective competitive blockers of the α1

receptor. It is highly selective for α1 receptors
and typically 1000-fold less potent at α2
receptors.
 useful in the treatment of hypertension.
 Tamsulosin and alfuzosin indicated for the
treatment of benign prostatic hypertrophy
(BPH).
 inactive metabolite excreted into the urine
except doxazosin, which appear in feces.
:Cardiovascular effects
 All of these agents decrease peripheral vascular resistance and lower
arterial blood pressure by causing the relaxation of both arterial and
venous smooth muscle.
 Tamsulosin has the least effect on blood pressure because it is
less selective for α1B receptors found in the blood vessels and
more selective for α1A receptors in the prostate and bladder.
 Blockade of the α1A receptors decreases tone in the smooth
muscle of the bladder neck and prostate and improves
urine flow.
 These drugs, unlike phenoxybenzamine and phentolamine, cause
minimal changes in CO (By dilating both arteries and veins, these agents
decrease preload and afterload, leading to an increase in cardiac output
and a reduction in pulmonary congestion), RBF, and the GFR.
Therapeutic uses
 the first dose of these drugs produces an
exaggerated orthostatic hypotensive response
that can result in syncope.
 This action, termed a “first-dose” effect, may be
minimized by adjusting the first dose to one-
third or one fourth of the normal dose and by
giving the drug at bedtime.
 These drugs improve lipid profiles and glucose
metabolism in hypertensive patients.
 Prazosin and others are used to treat
congestive heart failure.
 Tamsulosin and alfuzosin used as an alternative
to surgery in patients with symptomatic BPH (has some
selectivity of the α1A receptors found on the smooth
muscle
 This selectivity accounts for tamsulosin relatively
minimal effect on blood pressure.
 Blockade of the α receptors decreases tone in the
smooth muscle of the bladder neck and prostate
and improves urine flow.
 Finasteride and dutasteride inhibit 5α-
reductase, preventing the conversion of testosterone
to dihydrotestosterone.
 These drugs are approved for the treatment of BPH by
reducing prostate volume in selected patients.
Adverse effects
 α1 Blockers such as prazosin and doxazosin may
cause:
 dizziness
 lack of energy
 nasal congestion
 headache
 drowsiness
 orthostatic hypotension
 An additive antihypertensive effect occurs when
prazosin is given with either a diuretic or a β
blocker, thereby necessitating a reduction in its dose.
Adverse effects
 Due to a tendency to retain sodium (Na+)
and fluid prazosin is frequently used along
with a diuretic.
 These drugs do not affect male sexual
function as severely as phenoxybenzamine
and phentolamine.
 By blocking α receptors in the ejaculatory
ducts and impairing smooth muscle
contraction, inhibition of ejaculation and
retrograde ejaculation have been reported.
Adverse effects
 These agents may cause “floppy iris
syndrome,” a condition in which the iris
billows in response to intraoperative eye
surgery.

Some adverse effects commonly observed

with nonselective α-adrenergic blocking
agents:
 Antagonists α2
 Yohimbine: is a selective competitive α2 blocker.
 sometimes used as a sexual stimulant
 Efficacy of yohimbine for the treatment of impotence
has never been clearly demonstrated.
 It was once widely used to improve male erectile
dysfunction but has been superseded by 5-
phosphodiesterase inhibitors like sildenafil.
 Yohimbine works at the level of the CNS to increase
sympathetic outflow to the periphery.
 It directly blocks α2 receptors and has been used to
relieve vasoconstriction associated with Raynaud
disease.
 Type II diabetes: it increases insulin
secretion because α2 receptors inhibit
insulin secretion.

 Yohimbine is contraindicated in CNS and

cardiovascular conditions because it is a CNS
and cardiovascular stimulant
 Beta-Adrenoceptor Blocking Drugs
 All the clinically available β blockers are competitive
antagonists. The effect depend on the amount of
sympathetic tone present e.g. exercise
 Nonselective β blockers act at both β1 and β2
receptors.
 whereas cardioselective β antagonists primarily
block β1 receptors.
 There are no clinically useful β2 antagonists.
 Although all β blockers lower blood pressure,
pressure in
hypertension,
hypertension they do not induce postural
hypotension, because the α adrenoceptors remain
functional.
β blockers are also effective in treating:
Angina,
 Cardiac arrhythmias
Myocardial infarction
Congestive heart failure
 hyperthyroidism
Glaucoma
 serving in the prophylaxis of migraine headaches
β BLOCKERS
 Acebutolol
 Atenolol TENORMIN
 Betaxolol
 Bisoprolol
 Carteolol
 Carvedilol
 Esmolol
 Labetalol
 Metoprolol LOPRESSOR,
 Nadolol
 Nebivolol
 Penbutolol
 Pindolol
 Propranolol INDERAL LA
 Timolol
 Pharmacodynamics of Beta-blockers:
 CVS:
 They have both negative inotropic and negative chronotropic
effects
 Slowed AV conduction with increased PR
 Cardiac output work and O2 consumption are decreased by
blockade of β1 receptors; these effects are useful in treatment
of angina.

 Vascular system:
 β1 -blockade opposes β2 mediated vasodilation. This may
result initially in a rise in TPR .
 With chronic use: TPR returns to pre-treatment (normal) level or
a little below. This reduction in the CO leads to decreased BP.
 β -blockers antagonize the release of Renin
 Respiratory:
 Blockade of beta2 receptors in bronchial smooth muscle may lead
to increase in airway resistance, particularly in patients with air
disease as in asthma.

Eye:
 Several Beta-blockers reduce IOP in glaucoma.
Metabolic and Endocrine:
 Reduced BP leads to decrease renal perfusion, this will lead to an
increase in Na+ retention and plasma volume.
 Beta-antagonists inhibit Lipolysis
 They decrease glycogenolysis
 decrease glucagon secretion.
 Chronic use of Beta-blockers lead to increase VLDL and decrease
HDL
 They enhance hyperkalemia of muscular exercise
 Classification of Beta-Blockers
 A: According to the Pharmacokinetic properties:
 The solubility of beta-blockers varies, some are either
lipid soluble or water soluble, others are intermediate.
1-Lipid Soluble:
 Are extensively metabolized by liver
 Plasma concentration is unpredictable.
 They readily cross cell membranes so they have a high
apparent volume of distribution (aVd).
 They readily enter the CNS.
 Half-life is about 3 hours.
 Examples: Propranolol and Metaprolol.
2- Water Soluble:( low lipid solubility)
 Excreted unchanged by the kidney.
 They're less subjected to hepatic first pass
metabolism.
 They show more predictable plasma
concentration
 less widely distributed and lower penetration of
CNS.
 Longer half-life is around 9 hours,
 Examples: Atenolol and Nadolol
 :B: According to selectivity
1-Non-selective blocker have combine action α1
and β blocking action. These drugs are
optically active. ex: Timolol, Labetalol,
propranolol, Nadolol, Pindolol and Carvedilol.
2-Beta1 selective blockers (they were called
Cardio-Selective Beta Blocker
 These blockers have higher affinity 50-100 times for
beta1 than beta2 receptors
 Examples: Atenolol, Acebutolol, nebivolol and
Metaprolol.
The Clinical Advantages of SelectiveBeta-
Blockers are:
 Diabetics: Beta2 receptors mediate both
(symptoms of hypoglycemia (except
sweating.
 Asthma: less likelihood of causing
bronchoconstriction
 the available beta1 blockers is sufficiently
selective to be safely used in asthma.
 Peripheral Vascular Disease: selective
beta-blockers have less effect on
peripheral vascular beta2 receptors
 c-According to other non-blocking effects:
Most β-blocking drugs are pure antagonists (i.e.
cause no activation of the receptor).
1- partial agonists causing partial
activation of the receptor.
 This is sometimes described as having intrinsic
sympathomimetic activity (ISA). Examples:
Oxprenolol,Pindolol and Acebutolol differ from
pure antagonists in the following:
 They cause less fall in resting heart rate than do the pure
antagonists, and may be less effective in severe angina
pectoris.
 There are also less fall in cardiac output and possibly
fewer patients experience unpleasantly cold extremities.
 They cause minimal disturbance in lipid and
carbohydrate metabolism.
 Abrupt withdrawal may be less likely to lead
to a rebound effect if there is some partial
agonist action, because up regulation of
receptors, may not have occurred
 It is claimed to have increased safety in
patients with airway disease
 Membrane stabilizing action (MSA) -2
:[quinidine-like or local anesthetic]MSA

 It is a prominent effect of several β-blockers.

 This action is the result of typical local
anesthetic blockage of sodium channels.
These drugs are not used topically on the eye
for glaucoma, where local anesthetic of the
cornea would be highly undesirable e.g.
Propranolol and Acebutolol.
 Nadolol has the longest elimination half life.
 Esmolol has the shortest half life (about 10 minutes) so
it's used during emergencies.
It belongs to the β1-selective blockers but now it isn’t
considered as member of this group. It is used in the
emergencies of arrhythmias
• Carvedilol
• Receptor affinity is beta1 = beta2 > alpha1 > alpha2
which means it is non selective β-blocker and also
blocks α1 receptors.
• It has clinical benefits in congestive heart failure.
• Although β-blockers are contra indicated in heart
diseases but carvedilol has some benefits because it is
a combined blocker
Therapeutic uses of β-receptor blocking
agent:-
 A) Cardiovascular uses:
1- Angina pectoris: β Adrenoceptors blockers reduce
the frequency of angina episode and improve
exercise tolerance in many patients with angina.
2- Hypertension: β -blockers given chronically lower
blood pressure in patients with hypertension.
 Reduction in cardiac output
 Lowering of total peripheral resistance,
 Inhibition of rennin release
 CNS effects.
 Labetalol, a competitive α and β antagonist, is effective
so it is useful in emergency of hypertension.
3- Cardiac tachyarrhythmias:
Β-blockers are class II anti-arrhythmic. They
depress automaticity
 increase the AV nodal refractory period
 Sotalol is a non selective β-receptor antagonist
that has marked class III anti arrhythmic effect
reflecting potassium channel blockade. It causes
lengthening the refractory period of the cardiac
cells.
4- Myocardial infarction:
Β-blocker has a cardioprotective effect in:
Early use within 6-12 hours of infarction and for 3-
4 weeks results in the reduction in the infracted
size and protection against cardiac rupture.
 b. Late use between 4 days-4 weeks after onset of infraction and
is continue for at least 2 years. Useful for secondary prevention
from another M.I (myocardial infarction). The mechanism for
these effects may be a blocking of the actions of circulating
catecholamine, which would increase the oxygen demand in an
already ischemic heart muscle. Propranolol also reduces the
incidence of sudden arrhythmic death after myocardial infarction

5- Hypertrophic obstructive cardiomyopathy or (hypertrophic

subaortic stenosis) and Tetralogy of Fallot (TOF): β-blockers
decrease outflow resistance and increase stroke volume.
6-Hepatic portal hypertension & esophageal variceal bleeding:
 β-blockers cause reduction of portal pressure.
7- Aortic dissection & after subarachnoid hemorrhage:
 β-blockers reduce force and speed of systolic ejection
(contractility) and blood pressure.
.1Carvedilol and labetalol also cause α1adrenoceptor blockade
2
Not determined.
3
Not found.
4
Bioavailability is dose-dependent