Adrenoreceptors

Adrenoreceptors or Adrenergic receptors are

membrane bound G-protein coupled
receptors which function primarily by
increasing or decreasing the intracellular
production of second messenger cAMP/IP3
DAG.
Classification and Location
of adrenoreceptor
There are main two types of adrenoreceptors α & β. In this
classification there again two types of α & three types of
β-receptors.

Subtypes of α receptors are α1 & α2 while subtypes of β

receptors are β1, β2, β3,. α1 is located in vein pupil bladder

sphincter, pilometor & α2 in arterioles, CNS, kidney &

platelets.

β1 receptors are those in the myocardium and kidney, β2

are those in the smooth muscles & most other sites like
 Beta Blockers

Introduction

All beta adrenoceptors blocking agents are

synthetic compounds and competitively
inhibit the action of adrenergic agonist on
beta receptors.

Beta blockers are competitive inhibitor of the

effect of catecholamine at beta adrenergic
 CLASSIFICATION

Division 1 (NON-CARDIOSELECTIVE)
Group1 - Agents with both MSA & ISA
i.e. Alprenolol and
Oxprenolol
Group2 - Agents with MSA but no ISA
i.e. Propranolol
Group3 - Agents with out MSA but with
ISA i.e. Pindolol
Group4 - Agents without both MSA and
ISA i.e. Sotalol and Timolol
Division 2 (CARDIOSELECTIVE)
Group1 - Agents with both MSA & ISA i.e.
Acebutolol
Group 2- Agents with MSA but no ISA agents
(NOT AVAILABLE)
Group 3- Agents without MSA but with ISA
(NOT AVAILABLE)
Group 4- Agents without both MSA and ISA
i.e. Atenolol & Metoprolol
Division 3 (Beta + Alpha blockers)
Group1 - Nonselective β-blockers i.e.
Propranolol, Nadolol, Pindolol,
Oxprenolol, Sotalol, Timolol,
Alprenolol, Penbutolol
Group2 - Cardioselective P-blockers
i.e.Metoprolol, Atenolol, Acebutolol,
Betaxolol, Esmolol, Celiprolol,
Tolamolol
Group 3- β +α Blockers i.e. Labetalol,
Carvedilol
Group4 - Agents with direct vasodilator
 MECHANISM OF ACTION

Beta blockers combines reversibly with these

receptors to block the response to the sympathetic
nerve stimulation. Beta adrenergic blocking agents
competitively antagonizes the effect of
catecholeamine at β adrenergic receptors. Beta
adrenoceptors are located predominantly in heart (β1)

In arteries and arterioles of skeletal muscles (β2) and

in addition bronchi (β2) where there stimulation

induces cardiac excitation, peripheral vasodilatation &

Blockade of cardiac (β1) receptors reduces heart rate,
mayocardial contractility and cardiac output. The
artioventricular conduction time is slowed and
automaticity is suppressed. Due to this blood pressure
falls. Studies shows that cardiac output falls by 15-
20%. Renin release is reduced by 60%. It is believed
that partly Propranolol exert its antihypertensive
effect by inhibiting the secretion of renin from
juxtaglomerular apparatus of kidney by inducing β
receptor blockade. The peripheral β2 blockade allows α
adrenergic mediated vasoconstriction to be opposed
and peripheral vascular resistance increases initially.
Blockade of non-cardiac β2 receptors increases airway

resistance inhibit catecholamine induced glycogeno

lysis and lipolysis & inhibit the vasodilating effect of
catecholamine on peripheral circulation. These non-
cardiac action are responsible for some of adverse
effect of beta blockers like bronchospasm and
hypoglycemia. [Pg. – 212]
 Pharmacology of Propranolol and
other drugs
Propranolol is the most extensively investigated β
blockers. It was introduces in therapeutics in 1964. It
is considered to be prototype drug. Quantitatively all
β blockers produces similar effects but quantitative
differences exist depending upon intrinsic
sympathomimetic activity and local anaesthetic
action (membrane stabilizing action).
1. Action on cardiovascular system

Stimulation of cardiac β1 receptors leads to increase in

rate and force of contraction of heart, prior

administration can completely block this action of β
agonist and clinical effects are bradicardia, decreased
myocardial contractility, and reduced stroke volume,
decreased automaticity, increased exercise tolerance
with reduced oxygen consumption. ECG shows slow
AV conduction characterized by increased PR
intervals.
2. Action on blood vessels

Stimulation of β2 receptors causes dilatation of skeletal

blood vessels, which is counteracted by Propranolol. It

has no direct effect on other blood vessels. Since
there is decrease in cardiac output simultaneously
with skeletal vasoconstriction. There is a very little
acute change in B.P. as a result of these opposite
action. When Propranolol is given to a normal
individual in therapeutic doses there is a no change in
blood pressure, but in patient of hypertension it lowers
the blood pressure.
3. Action on respiratory system
Stimulation β2 receptors evokes relaxation of smooth
muscles of bronchi, which is blocked by Propranolol.
The increase in resistance of air way is more marked
in patients of bronchial asthma, chronic bronchitis and
in other form of respiratory insufficiency than in
normal individual and Propranolol may precipitate an
acute attack of bronchial asthma in asthmatics.

4. Action on eye
There is a reduction in intraocular pressure which may
be due to decrease formation of aqueous humour.
Timolol is a β blocker with MSA used in Glaucoma.
5. Action on C.N.S.

Inhibition of central β2 adrenoceptor mediated

sympathetic stimulation by Propranolol contributes to

its hypotensive effects over and above its direct
effect on cardiac outputs. Due to central action it also
produces sedation, lethargy, depression, and
disturbances of sleep.

6. Action on skeletal muscles

Propranolol antagonizes the adrenaline induced

tremor due to its peripheral action on β2 receptors on
7. Uterus

Relaxation of uterus in response to selective β2

agonist is blocked by Propranolol. However normal

uterine activity is not significantly affected.

 
8. Local anaesthetic

Propranolol is a potent local anaesthetic as a

Lidocaine but it not clinically used for this purpose
because of its irritant properties.
 Pharmacokinetics

A. Absorption

Most of drugs in this class are well absorbed after

oral administration, peak concentration occurs
within 1-3 hrs after ingestion. Hydrophilic β
blockers like Atenolol, Nadolol, Sotalol are not as
readily absorbed from gut as lipophilic agents like
Propranolol, Metoprolol, Oxprenolol. Propranolol is
almost completely absorbed from gut.
B. Bioavailability
Beta blockers undergoes extensive hepatic (first pass)
metabolism. Its bioavailability is relatively low. The
proportion of drug reaching the systemic circulation
increases as the dose is increased.
C. Distribution and clearance
The β antagonist are rapidly distributed and have
large volume of distribution. Propranolol and
Penbutolol are quite lipophilic and readily crosses the
blood brain barrier. Most β antagonists have half life in
the range of 2-5 hrs. Propranolol and Metoprolol are
extensively metabolized in liver with little unchanged
drug apperaring in urine. Atenolot, Celiprolol &
 Clinical uses
1. Hypertension

2. Angina Pectoris
3. Cardiac arrhythmias
4. For Myocardial Infarction
5. Pheochromocytoma

6. Migraine
7. Hyperthyroidism

8. Parkinson's disease &. Essential

Tremors
9. Glaucoma
10.Anxiety
11. Hypertrophic Cardiomyopathy

12. Essential tremors

 DRUG INTERACTIONS
1. Additive depression of sinus node and A-V
conduction with digitalis and
verapamil cardiac arrest can occur.
However, Propranolol can be used safely with
Nifedippine.
2. Propranolol delays recovery from hypoglycemia
due to insulin and oral
antidiabitics. Warning signs of
hypoglycemia mediated through sympathetic
stimulation (tachycardia,
tremor) are suppressed. In some cases B.P.
raises due to unopposed α action of released
adrenaline.
3. Phenylephrine, epheridine and other α agonists
present in cold remedies can
 5. Cimetidine inhibits Propranolol metabolism.
However, the dose range of propranolol is
wide and this may not be
clinically significant.
6. Propranolol reduces lidnocaine metabolism by
reducing hepatic blood flow.
7. Propranolol increases bioavailability of
chlorpromazine by decreasing
its first pass metabolism.
8. β- blockers furthur adds to the anti hypertensive
effect of Captopril but overall
response is less than additive.
9. The bronchodilating and cardio stimulating action
of sympathomimetics are
antagonized. [Pg. – 127]
 Contraindication
Beta blockers are contraindicated in sinus
bradycardia, greater than 1st degree heart block.
Congestive heart failure, cardiogenic shock overt
cardiac failure and hypersensitivity to β blockers.

Propranolol, Nadolol, Timplol and Pindolol are

contraindicated in the patient with bronchial asthma
or severe chronic obstructive pulmonary disease.
Beta blockers are contraindicated in the management
ofmyocardial infarction patient with heart rate below
45 beats per minute's heart block greater than 1st
degree systolic B.P. less than 100mmHg or moderate
 Adverse reaction and
Precautions
1. Gastromtestinaldisturbances:

(anorexia, nausea, vomiting, diarrhea, abdominal

pain) are the most common adverse effects
reported. Other less frequently reported adverse
effects are: (in descending order) cold extremities
and exacerbation of Raynaud's phenomenon;
congestive heart failure; sleep disturbances including
vivid dreams; dizziness, fatigue and bronchospasm.
Reported adverse effects, according to organ
systems are recorded below.
2. Cardiovascular:
Congestive heart failure; secondary effects of
decreased cardiac output which could include:
syncope, vertigo, lightheadedness, decreased renal
perfusion and rarely, postural hypotension;
intensification of AV block and hypotension; severe
bradycardia; claudication and cold extremities,
Raynaud's phenomenon; dyspnea; palpitations;
precordial pain.

3. CNS
Dizziness, lethargy, weakness, drowsiness,
headache, insomnia, fatigue, anorexia, anxiety,
mental depression, poor concentration, reversible
amnesia and catatonia, vivid dreams with or without
4. Respiratory
Propranolol induces bronchoconstriction and may
provoke asthmatic attack. If severe bronchospasm
develops, β2 agonist (terbutaline) and aminophylline
should be administered.  

5. Metabolic
Propranolol impairs the sympathetically medicated
rebound response to hypoglycemia and may mask
some hypoglycemic symptoms like tachycardia in a
patient on insulin therapy. Although Propranolol can be
given safely to most diabetics, it may prolong the
duration of hypoglycemia in a patient on insulin. Beta
blockers are reported to reduce HDL, Cholesterol and
6. Neurologic
Fatigue and lethargy are common central side
effects. Vivid dreams or nightmares with or with out
insomnia occurs frequently. Depression and memory
loss are not uncommon, hallucination; psychotic
reactions have also been reported.

 7. Pregnancy & Lactation

Propranolol crosses the placenta and may cause
bradycardia, hypotension and hypoglycemia in
neonates bom to mothers on a Propranolol therapy. It
is also excreted in breast milk.
8. Miscellaneous
Propranolol may cause sexual dysfunction
(impotence) or decrease libido, fever, rash,
myopathy, alopecia. Thrombocytopenia and
agranulocytosis may occur rarely. Propranolol mask
the sign and symptoms ofhyperthyroidism.
Indomethacin antagonizes the antihypertensive
activity of Propranolol. [Pg. – 214, 127]
 BETA BLOCKERS
CHEMICAL NAME BRAND NAME (S)
ATENOLOL TENORMIN, *TENORETIC
BETAXOLOL KERLONE
BISOPROLOL ZEBETA, *ZIAC
CARTEOLOL CARTROL
CARVEDILOL** COREG
ESMOLOL BREVIBLOC (Only available for intravenous use)
LABETOLOL*** NORMODYNE, TRANDATE
METOPROLOL LOPRESSOR, *LOPRESSOR HCT, TOPROL
NADOLOL CORGARD, *CORZIDE
PENBUTOLOL LEVATOL
PINDOLOL VISKEN
PROPRANOLOL INDERAL, *INDERIDE, INNOPRAN
TIMOLOL BLOCADREN, *TIMOLIDE, TIMOPTIC (eye drops)

*These are a combination of the beta blocker with a diuretic for

the control of blood pressure.
**This is also an alpha blocker and a free radical scavenger. It has
been specifically developed as treatment for heart failure.
This is a combined alpha and beta blocker and also dilates
arteries.
 Newer drugs and combination

1. Atenolol + Amiodipme
Beta blockers + calcium channel blockers, anti
hypertensive

  Action : Atenolol is a cardioselective p blocker

which reduces heart rate and blood pressure.
Amiodipine, a dihydropyridine which is a calcium
channel blockers causes peripheral
vasodilatation, reduces peripheral resistance and after
load. There is a no reflex tachycardia. Amiodipine
dilates the coronary vessel in normal and ischemic
areas and blunts the vasoconstrictor stimuli. Pulse
pressure product is reduced and exercise tolerance
 Indication & Dosage

Oral: Hypertension, Adult: (Atenolol 50 mg +

Amiodipine as a besylate 5mg) one tablet OD.
 
Safety alerts

  Contraindication: Hypotension, sinus bradycardia

2nd and 3rd degree block, cardiogenic shock, CCF,
poor LV functions, hypersensitivity to either
component, pregnancy.
Special precaution:

Excessive fall of blood pressure may occur in elderly

patients, should be used with caution in a patient
with thyrotoxicosis, CCF, Vasospastic angina,
 Interaction:

No significant interaction for Amiodipine have been

reported. Additive anti hypertensive effects with
other antihypertensive may occur.
 

Adverse reaction: Headache, hypotension

dizziness, breathlessness, fatigue, muscle cramp,
bradycardia, drowsiness, chest pain and
impotence rarely.
 

Preparation : Arnlong A (Amiodipine 5 mg +

Atenolol 50 mg tablet)
2.Metoprolol + Hvdrochlorthiazide
Category: Beta blocker + Diuretic
 

Action: Metoprolol is a cardio selective beta

blocker causing reduction in heart rate, cardiac
output and B.P. Hydrochlorthiazide increases renal
excretion of sodium and chloride. Thus reduces
cardiac load. The two drugs exert a additive
effect in hypertension.

Indication and Dosage:

Oral: Hypertension: Adult: Metoprolol (tartarate)

100 mg + Hydrochlorthiazide 12.5 mg 1-2 tablets
daily
Safety alerts

Contraindication: 2nd or 3rd degree AV blocks,

sinus bradycardia, cardiogenic shock, CCF, anuria,
hypersensitivity, bronchial asthma.
 

Special Precautions: Renal or hepatic impairment,

diabetes, hyperlipidemia, LVH, and ventricular
ectopics.

Interaction : Risk of arrhythmias with digitalis, alter

response to quinidine, amiodarone and possibly other
antiarrythmics. Glycemic controls may be altered in
diabetic patients. Hydrochlorthiazide may increases
nephrotoxicity of aminoglycosides and lithium
Adverse reaction: Fluid and electrolyte imbalance,
dizziness, headache, tiredness, depression,
bradycardia, cold extremities, Raynaud's
phenomenon, bronchospasm, hypokalemia, oedema.
Absorption and bioavailability of both Metoprolol and
hydrochlorthiazide are increased when taken with
food.

Brand: BetaIoc-H