

Adrenergic Receptor
Blockers

Pharmacology of autonomic nervous system
 
 Adrenergic receptors antagonists block the effects of
sympathetic stimulation and adrenergic agonist
mediated through α and β receptors.
 SELECTIVE α1 BLOCKERS
 Prazosin is a potent and selective α1 adrenergic receptor
blocker.

 SIDE EFFECTS


First-dose phenomenon (mechanism): Within 30-90 minutes of
oral administration of prazosin, severe postural hypotension and
syncopal attacks may be seen with first dose. Therefore, the
initial dose should be small (1mg). It is usually given at bed time
so that the patient remains in bed for several hours and the risk of
syncopal attack is reduced.
1. Terazosin is similar to prazosin, but less potent than prazosin.
It is almost completely absorbed after oral administration and
has a longer duration of action.
SIDE EFFECTS CONTINUED..

2. Doxazosin is the longest acting selective α1 blocker. The
haemodynamic effects, bioavailability and extent of
metabolism are similar to prazosin.
3. Alfuzosin block all subtypes of α1 receptors (α1A , α1B and α1D
). It is orally effective and used in benign prostatic
hyperplasia (BPH).
Tamsulosin is a uroselective α1 - blocker (α1A). At low doses, it
reduces the resistance to flow of urine with little effect on BP. It
is administered orally and preferred α1 blocker for the treatment
of BPH in normotensive patients. It may cause retrograde
ejaculation.
 Therapeutic uses of α blockers

1. Pheocromocytoma: It is a tumor of adrenal medulla
which releases large amount of adrenaline and NA. The
signs and symptoms are sudden and paroxysmal rise in
BP with headache, palpitation and excessive sweating.
The diagnosis of pheocromocytoma is usually made by
estimating the VMA levels in urine (normal VMA: 4-8mg
per 24 hours urine sample), other diagnostic aids are
compound tomography (CT) and magnetic resonance
imaging (MRI) scans.
 Therapeutic uses of α blockers

 The definite treatment for pheochromocytoma is surgery. In
the preoperative period, phenoxybenzamine is used to treat
hypertension. It is non-selective and irreversible α blocker.
Blockade of α1 -receptors causes vasodilation and fall in BP.
β-Blockers (propranolol) are used to control the cardiac
manifestation- tachycardia and arrhythmias due to excessive
catecholamines.
 Β-Blockers should not be given alone in pheochromocytoma
because blockade of vascular β2- receptors cause unopposed
α1 which leads to severe rise in BP due to vasoconstriction.
This may be fatal. Therefore prior administration α-receptor
blocker is must before giving β-blockers.
 
Metyrosine is used as an adjuvant in
pheochromocytoma. It inhibit tyrosine hydroxylase
enzyme and reduce the synthesis of catecholamines.
During surgery, handling of the tumor results in sudden
release of large quantities of catecholamines, which
may cause marked rise in BP, that can be controlled by
i.v. phentolamine. It is non-selective α with rapid onset
of action.
 Therapeutic uses of α blockers

 Cardiac arrthymias : β blockers are mainly used in atrial
arrhythmias such as atrial fibrillation, atrial flutter and
paroxysmal supraventricular tachycardia (PSVT) but
rarely for ventricular arrhythmias.
 Congestive heart failure: Choronic use of β-blockers such
as carvedilol,metoprolol
 Therapeutic uses of α blockers

Hypertensive emergencies:
α- blocker, i.v. phentolamine may be used in following
conditions,because of its rapid onset of action :
 Intraoperatively during surgery of pheochromocytoma to
control hypertensive episodes.
 To control hypertensive crisis due to clonidine withdrawl.
 To control hypertensive crisis due to ‘cheese reaction’.
 Therapeutic uses of α blockers

 Essential hypertension:
Among α-blockers, selective α1 -antagonist and in the treatment of mild-
to-moderate hypertension.They cause less tachycardia and favourable
effects on lipid profile.

 Benign prostatic hyperplasia :

Transurethral resedtion of the prostate is the commonly used method to
relieve the urinary symptoms of BPH, however medical therapy is helpful
in many patients .α1 –blockers are used in BPH, they reduce the resistance
to uninary flow. Prazosin ,doxazosin,terazosin and alfuzosin are particularly
useful in patients who also have hypertension.
 Therapeutic uses of α blockers

Tamsulosin is preferred in BPH in normotensive
patients .
Tissue necrosis:
Phentolamine is infiltrated locally to prevent tissue
necrosis due to extravasation of α1 –agonist.
Male sexual dysfunction:
Phentolamine with papaverine may be used in the
treatment of male sexual dysfunction.
 Selective α2 – Adrenergic
Antagonist

Yohimbine is an alkaloid.It competitively blocks α2-
receptors. It also has 5-HT receptor blocking effect.It is
an aphrodisiac, but is rarely used therapeutically.
 Beta adrenergic Blockers

 beta adrenergic antagonists block the beta receptor
mediated effects of sympathetic stimulation and
adrenergic drugs.
CLASSIFICATION OF β
BLOCKERS

 NON SELECTIVE β
ADRENERGIC BLOCKERS

 Pindolol, acebutalol,labetalol, celiprolol and carteolol
have partial agonist activity (intrinsic
sympathomimetic activity): They stimulate beta
receptors partially in the absence of catecholamines.
 Propranolol, acebutalol , carvedilol , albetalol,
netoprolol,pindolol, have membrane stabilizing
activity (local anesthetic activity) .
 
 Proranolol is the protype drug. β-blockers competitively block
the β-mediated actions of catecholamines and other adrenergic
agonists.
Pharmacological properties of β-blockers


1. Cardiovascular system:
a. Heart: β-blockers depress all the cardiac properties:
• Decrease heart rate(negative chronotropic effect).
• Decrease the force of myocardial contractility
(negative inotropic effect).
• Decrease cardiac output.
• Depress S-A node and A-V nodal activity
 
 Increase refractory period of A-V node.
 Decrease conduction of in atria and A-V node(negative
dromotropic effect)
 Decrease automaticity of ectopic foci.
 Decrease cardiac work and thus reduce O2 requirement of
the myocardium.

only in high doses, some of them have membrane-stabilizing

effect.
 
b. Blood vessels:
Blockade of β2-receptors of the blood vessels initially
may cause rise in PVR due to the unopposed α1 action.
 However continued administration of these drugs leads
to a fall in PVR in patients with hypertension(reduces
both systolic and diastolic BP).
 They also reduce the release of renin from the
juxtaglomerular apparatus due to the blockade of β1-
receptors.
 2. Respiratory system

 Blockade of β2-receptors in bronchial smooth muscle
can produce severe bronchospasm in patients with COPD
and asthma.

 Therefore β-blockers shold be avoided in patients with

asthma and COPD.

 Selective β1=-blockers such as atenolol, metoprolol etc.

are less likely to cause bronchospasm.
3. Skeletal muscle

 On chronic use β2-blockers my cause skeletal muscle
weakness and tiredness due to blockade of β2-receptors of the
skeletal muscle and blood vessels supplying it.

 They also reduce stress-induced tremors.

4. Metabolic effects:

 β-blockers inhibit glycogenolysis and delay recovery from
hypoglycaemia. They also mask the warning signs and
symptoms of hypoglycaemia.

 Therefore β-blockers should be used cautiously in diabetics on

hypoglycaemic agent.

 Chronic use of non-selective β-blockers decreases HDL(high

density lipoprotein) cholesterol and LDL cholesterol ratio
which may increase the risk of coronary-artery disease.
 5. Eye


 B-blcokers on topical administration decrease the IOP by
reducing the secretion of aquous humour.
 Pharmacokinetics

Propranolol is highly lipid soluble and is well
absorbed from GI tract.

However the bioavailability is low because of its extensive

first-pass metabolism.

It is highly bound to plasma proteins; has large volume of

distribution; freely cross BBB, and metabolites are excreted
in urine.
 Adverse effects of b-blockers


 They are mainly an extension of pharmacological actions.

1. CVS: Bradycardia , heart block and may precipitate congestive heart

fertile in patients with low cardiac reserve.

a. Blockade of vascular β2-receptors causes unopposed α-1 action, reduce

further blood supply and may worsen peripheral vascular disease.

b. β-blockers can exacerbate prinzmetal angina(variant angina) due to

unopposed α1 action hence are contraindicated.
Adverse effects of b-blockers

2. Respiratory system: Blockage of β2-receptors in the
bronchial smooth muscle can cause severe
bronchospasm in patients with asthma and
COPD .Hence ,β-blockers are contraindicated in above
condition.
3. CNS: Sleep disturbances ,hallucination ,fatigue and
mental depression.
4. Metabolic : Hypoglycemia is common with non-
selective beta blockers especially in diabetics on
hypoglycemic agents.
Adverse effects of b-blockers

Beta blockers also may mask the warning symptoms of
hypoglycaemia.
5. Muscular weakness and tiredness:
These are due to reduced blood flow to skeletal muscle.
6. Abrupt withdrawal symptoms:
Abrupt withdrawal of β-blockers after chronic use is
dangerous, because they can precipitate angina or frank
myocardial infarction and even sudden death. This is
due to the upregulation ( supersensitivity) of beta
receptors in response to prolonged blokade.
 Drug interactions

1. Propranololverapamil: They produce additive
cardiac depressant effects and may cause CCF,
bradyarrhythmias , heart block or even cardiac
arrest.
2. Propranololliganocaine : Propranolol reduces the
clearances of lignocaine by decreasing hepatic blood
flow.
 
3. Cholestyramine and colestipol β-blockers :
Cholestyramine anfd colestipol are bile acid-binding
resins. They bind to –blockers in the gut and interfere
with the absorption of beta blockers.
4. Insulin / Sulphonylureas blockers: Non- selective β-
bolckers inhibit glycogenolysis and delay the recovery
from hypoglycaemia.
Therapeutic uses of β-blockers:

1. Hypertension: β – blockers are useful for all grades of
hypertension .These drugs are preferred especially in
patients with angina .MI or cardiac arrhythmias .
The advantage of beta blockers are:
 Sodium and water retension is rare.
 Cheaper
 Have long duration of action
 Well tolerated.
Therapeutic uses of β-blockers:

2. Angina prophylaxis and MI : beta blockers reduce
myocardial oxygen demand by decreasing heart rate ,
myocardial contractility and arterial pressure. They
improve exercise tolerance and reduce the frequency of
anginal episodes. Use of beta blockers early in acute
phase of MI may limit infract size. Long term use of
beta blockers may reduce mortality and reinfraction.
Therapeutic uses of β-blockers:

 GLAUCOMA:
β blockers decrease the IOP by reducing the production
of aqueous humor ,used in the treatment of chronic
simple glaucoma.

Timolol , cartelol, levobunolol,betaxolol etc are used

topically in glaucoma.
Therapeutic uses of β-blockers:

Timolol is most frequently used β blocker in glaucoma
because:
1) It lacks local anaesthetic or partial agonist properties.
2) Does not affect the pupil size or accommodation
3) Has longer duration of action
4) It is well tolerated
5) Less expensive

Betaxolol is a selective blocker hence the systemic adverse

effects(cardiovascular and pulmonary) are rare
 
 PROPHYLAXIS OF MIGRANE :
propranolol and metoprolol are effective in reducing
the frequency of migrane headache,the mechanism is
not known.

Meaning of prophylaxis
 PROPRANOLOL ATENOLOL


1. Non selective β blocker 1. Selective β blocker
2.In large doses , has membrane 2.Has no membrane stabilizing
stabilizing effect ( local effect
anaesthesia)
3.Highly lipid soluble , freely 3.Poorly lipid soluble , does not
crosses BBB and produces central hence no central side effects
side effects
4.Has shorter duration of 4. Has longer duration of action
action ,bur propranolol SR
formulation has a duration of 24
hrs.
5.Less potent 5. More potent
 HYPERTHYROIDISM:

The signs and symptoms of hyperthyroidism such as
trachycardia ,palpition , tremor , anxiety ,etc.are reduced due to
blockade of bete receptors.
Propranolol is used in thyroid storm and it inhibits the peripheral
conversion of T4 to T3.

 ESSENTIAL TREMORS:
Oral propranolol may give some benefit in patients---tremors.
 ACUTE ANXIETY:
β Blockers are useful in controlling the symptoms of anxiety such as
palpitation , tachycardia ,tremor , sweating etc.
 
 ALOCHOL WITHDRAWAL:
Proparonolol may produce some benefit in the treatment
of alcohol withdrawal.

 DISSECTING AORTIC ANEURYSM:

β Blockers are useful in the management of diseccting
aortic aneurysm , decrease in cardiac contractility and the
rate of pressure during systole.
β1- SELECTIVE ADRENERGIC
BLOCKERS

ESMOLOL:
 Administered intravenously.
 Has no membrane stabilizing agent.
 Rapidly metabolized by esterase in RBCs.
 Selective β blocker and has shorter duration.
 t/2 is about 10 minutes.

ESMOLOL is used for rapid control of ventricular heart in

supraventricular arrhythimias. It is the second drug of
choice for rapid control of PSVT.
 β BLOCKERS WITH ADDITIONAL
VASODILATION ACTION.

 LABETALOL:
It is a competitive blocker at . It is administered orally
or intravenously . It goes extensive first pass
metabolism after oral administration ,hence its
bioavalability is poor .oral labetolol is useful in the
treatment of essential hypertension and i.v. labetolol
for hypertensive medicine.