β - adrenoceptor antagonists

β - adreneptor antagonists act on β 1 & β 2 or both &

antagonize the effects

Some β –blockers- also possess membrane

stabilizing action – (Local anesthetic action) .

β -blockers - selectivity based on β 1 or β 2

receptors.
 I. Non – selective (β1 + β2) blockers

a. Without intrinsic sympathomimetic activity

- Propranolol, - Timolol, - Sotalol

b. With intrinsic sympathomimetic activity

- Pindolol, - Oxyprenolol

c. With additional α-blocking property.

- Labetalol, - carvediol, - Bucindolol, - Medroxalol
II. Cardio selective - β1 blockers

Atenolol, - Metoprolol, - Acebutolol,

Bisoprolol, - Esmolol, - Betaxolol,

Celiprolol, - Nabivolol
 Propranolol

Prototype, Non selective, β – antagonist

Decreases H.R., F.C., conduction velocity & C.O.

Work load of heart – reduced

Myocardial O2 demand is also reduced.

 Propranolol

 Automaticity of heart suppressed - due

inhibition of latent pacemakers by β1 blocker.

 Product of H.R. & aortic pressure decreases

 Leads to fall in B.P.

 Propranolol

Total coronary flow reduced - blockade of dilator β2

receptors.

Sub epicardial region – only restricted due to this

effect

While the sub endocardial area-which is the site of

ischemia in angina patients, is not affected.

Improvement of O2 supply & exercise tolerance is

increased- angina patients
 Propranolol

 Causes direct depressant & membrane stabilizing

action

- Quinidine like action on myocardium with higher

doses.

 But contributes little anti arrhythmic action at

therapeutic dosage.
 Propranolol

Cardiac effects can be overcome by isoprenaline [β-

agonist ] competitive blocker at β 1 receptor.

Cannot counteract cardiac stimulant action –

myocardial contractility of digoxin, Ca++,
Thoephylline & glucagon.
Propranolol blocks vasodilatation & fall in B.P
evoked by Isoprenaline.

Enhances the rise in B.P. caused by Adr – There is

re-verersal of vasomotor reversal that is seen
after β-blockers.

No direct effect on blood vessels

There is little change in B.P.

On prolonged usage of propranolol - BP
falls in hypertensive patients

Total peripheral resistance (TPR) is

increased initially - blockade of β2 receptors

With continued treatment- resistance

vessels adapted to reduced C.O. finally total
peripheral resistance decreases.

Both systolic & diastolic BP fall.

Through cardiac β1 receptor blockade is main
mechanism of antihypertensive action,
other mechanisms contribute to this effect
are :-

1. Decreases release of renin - reduces

Angiotensin II & aldosterone

β 1 – receptors blockade in J.G cells.

2) Decreases central sympathetic outflow.
Chronically reduces C.O.

3) Blockade of facilitatory effect of

presynaptic β2 receptors on NA
release, +ve feedback mechanism
affected.
 Respiratory effects:

Non-selective β -blocker [propranolol] - severe

bronchoconstriction [ blockade of β2 receptors of
bronchial smooth muscles.]
 Metabolic effects
 β-receptors activates hormone-sensitive
lipase in fat cells, - release free fatty acids.

 Propranolol alter FFAs release - reduce HDL

level & increase LDL cholesterol &
triglycerides.
CAs promote glycogenolysis & mobilize glucose in
hypoglycemia in Type I & II D.M.

Propranolol inhibits glycogenolysis in heart, skeletal

muscles & liver which occurs due to release of adrenaline
during hypoglycemia.

insulin action is delayed

Prolonged propranolol therapy - release carbohydrate

tolerance by decreasing insulin release.
 CNS effects

 Produces sedation, lethargy &

disturbances in sleep after long term
therapy.
Propranolol suppresses anxiety in short
term stressful situation.

i.e Anxiety prior to interview. [due to

peripheral rather than central action].

Propranolol in high doses produces

antipsychotic effects, but cardiac side
effects limit its use.
 Skeletal muscle:
 Propranolol inhibits adrenergically provoked
tremors.

 This is a peripheral action - directly on muscle

fibres through β2 receptors .

 β2 blocker reduces exercise capacity - increase in

blood flow to exercising muscles as well as
restricting fuel to working muscles by limiting
glycogenolysis & lipolysis.
 Local Anaesthetic effect

 Propranolol is as potent a local

anaesthetic as lidocaine,

 Not used clinically - irritant properly.

 Ocular effects:

Decreases - aqueous humor &, reduces

IOP in glaucomatous patients

Propranolol is less potent local

anaesthetic action on
cornea .undesirable
 Other effects

(i) Prevents platelet aggregation & promotes

fibrinolysis.
Used in MI

(ii) Reduces portal vein pressure in patients with

cirrhosis,
Used in Oesophageal variceal bleeding.
 Pharmacokinetics:

Propranolol – completely absorbed orally

Has low bioavailability

Extensively metabolized by liver

- undergoes first pass metabolism.

Highly lipid soluble, - crosses BBB.

Plasma half-life t ½ - short (4-6 hrs)

Exists in 2 isomeric forms.

l-Propranolol is 80-100 times more

potent than d-propranolol in blocking β-
adrenoceptor.
D-form of Propranolol exhibits more
Quinidine like action
[membrane stabilizing effects
compared to L-form].

Commercial preparations are racemic

Long acting sustained release

preparations are available
Adverse effects
&
Contraindications
of
β - Blockers
Bronchoconstriction :

Little significance in normal person.

Bronchoconstriction can aggravate life threatening

situation in patients with bronchial asthma,
bronchitis, emphysema & COPD.

Contraindicated in respiratory disorders

Cardioselective β1 blockers preferred.

Cardiac failure:

Sympathetic drive - required to support the heart to

maintain C.O. in patients with C.C.F

β-blockers block this support & may aggravate

heart failure.

A-V nodal depression can lead to A-V nodal

dissociation & may precipitate heart block.
 β-blockers are contraindicated in C.C.F.

 Even though, β1 blockers are beneficial in C.C.F in

patients with mild to moderate heart failure. They
are used in C.C.F.
Hypoglycaemia:

Release of glucose through glycogenolysis is a

sympathetic response to hypoglycaemia.

This is a safety device that warns the patients

of diabetes to eat sugar by producing
symptoms like tachycardia, cold sweating &
Tremors.
 β-blockers mask these symptoms of hypoglycemia
& delay recovery from hypoglycemia.
β-blockers are contraindicated in NIDDM &
IDDM.

Bradycardia
β-blockers lower HR to 55 beats per min. This can
lead to life threatening brady arrhythmias & heart
block.
Cold Extremities

Cold extremities can occur due to blockade of

β2-receptor mediated vasodilatation in the
extremities.

C/I in Raynaud’s disease

Rebound Hypertension & Anginal attacks after

sudden withdrawal
After chronic therapy with β-blockers, there
is up-regulation in the number of β-
adrenoceptors.

β-adrenoceptors show hyper responsiveness

to even small release of CAs.

There should be gradual withdrawal of

therapy instead of sudden stoppage of the
drug.
Adverse lipid profile : increase in TG, LDL,
decrease HDL

SK.M: Fatigue, due to reduced C.O. & poor

muscle perfusion

CNS : Depression, hallucination, sleep

disturbances, bad dreams.

Male patients may complain of sexual

dysfunction
Drug Interactions

1. Due to Pharmacokinetic reasons:

 Al++ salts, cholestyramine & colestipol

decrease absorption of β-blockers.

 Enzyme inducers – Phenytoin, Rifampin &

smoking decrease its plasma concentration.
 Cimetidine & Hydralazine may increase its
bioavailability.

 β-blockers impair the clearance of lignocaine -

increase its bioavailability.
2. Due to pharmacodynamic reasons :
Digitalis & verapamil - depression of SA node
& AV conduction & - cardiac arrest

Indomethacin & Aspirin (other NSAID) oppose

the antihypertensive effects
 Timolol
Non-selective β-blocker

Orally administered – absorbed from G.I.T

moderate first pass metabolism.
Crosses BBB

Uses & side - effects similar to Propranolol

Main use :
Wide angle glaucoma as drops to decrease
I.O.P.
0.25 % & 5 % twice a day.
 Timolol

Reduces formation of aqueous humor by

blocking β2 receptors present in ciliary
epithelium.

Devoid of membrane stabilizing activity

systemic side effects :e.g.

Bronchoconstriction, Bradycardia &
Hypotension

Topical side effects – Dryness of Eye

Advantages of β-blocker: Timolol

No change in pupil size or

accommodation

No diminution of vision in dim light &

in patients with cataract

Convenient dosage schedule of twice a

day

No fluctuations in IOP.
Betaxolol : Selective β1 blocker

Available as eye drops - glaucoma 0.25 %

& 0.5 % topically twice daily

Oral formulations used for hypertension

& angina

Less potent that Timolol

 Betaxolol : Selective β1 blocker

β2 blocking actions are less than Timolol

More selective β1 blocking actions

Negligible bronchoconstriction, safer than

Timolol

Side effects : Transient stinging & burning

in eye.
Betaxolol : Selective β1 blocker
Once daily alternative to Timolol

0.25 % to 0.5 % topically once a day

Offers longer duration of action

Ocular & systemic side effects are similar

to Timolol
Carvedilol
β-blocker with intrinsic sympathomimetic activity

Facilitates ocular perfusion & retinal blood flow

Reduces formation of aqueous humor

Protects the optic nerve from damage from

glaucoma

Better tolerated than Betaxolol or Timlol

Administered 1 % solution topically
 Cardio selective β1 receptors Blockers
Low doses- Block β1 receptors
High doses - can block β2 receptors also.

Advantages:
Metoprolol / Atenolol
Safer in asthmatics compared to Propranolol

Safer in diabetes, - less inhibition of

glycogenolysis, during hypoglycaemia.
 Cardio selective β1 receptors Blockers

Release of glucose from liver is controlled by

β2 receptors.

However, tachycardia in response to

hypoglycaemia is not blocked (β1 blockade).

Safer in patients with PVD [No β2 receptors

blockade].
Have less deleterious effects on lipid profile.
 Cardio selective β1 receptors Blockers

 Safely given during pregnancy in PIH.

 Least chances of CNS side effects with water

soluble Cardioselective β1 blocker like Atenolol.

 Less liable to impair exercise capacity.

 Ineffective in suppressing essential tremors.

 Tremors occurs due to β2 action on muscle

fibers.
 Atenolol

 Cardioselective β1 – blocker

 Low lipid solubility

 Does not cross BBB

 Incompletely absorbed orally

 First pass metabolism is not significant

 Offers long duration of action [once in a day]

 Atenolol

 Less likely to produce CNS side effects.

 No deleterious effects on lipid profile.

 Regresses left ventricular hypertrophy,

besides its cardio vascular actions

 Used in HT & angina

 Available as Tabs 25, 50, 100 mg.

 Metoprolol
Prototype cardioselective β1 blocker.

Potency to block cardiac stimulation is

similar to propranolol.

Nearly 50 times higher dose is required to

block isoprenaline – induced vasodilatation.
 Metoprolol
Preferred in diabetics receiving insulin or
OHD.
Does not allow to develop cold extremities

Completely absorbed from G.I.T

Bioavailability is less due to first pass
metabolism

90 % or more is ultimately metabolized

before excretion
 Metoprolol
There are slow & fast hydroxylators of
metoprolol
Slow hydroxylators may require a lower
dose.
Plasma Half-life : 4 hrs.
Extended release preparations are available.
Used in HT, Angina, M.I.
I.V. inj. 5-15 mg has been used in M.I.

Tabs : 25, 50, 100 mg

Inj : 5 mg/ml
 Mixed α+ β Antagonists
Labetalol
Acts as a competitive antagonists at both
α1 & β adrenoceptors

Exhibits optical isomerism.

Has 4 dia stereomers, each displays

different relative pharmacological activity.
 Labetalol
The racemic mixture exhibits :
Selective blockade of α1 receptors
Blockade of β1 receptors
Blockade of β2 receptors
Partial agonist activity (ISA) at β2 receptors
Inhibition of neuronal uptake of NA
 Labetalol
Labetalol may have direct vasodilating
capacity.

α1 & β1 blocking actions contribute to the fall

in B.P.

Intrinsic sympathomimetic activity (ISA) at β2

receptors may contribute to peripheral
vasodilatation & bronchodilatation.
H.R. remains unaffected
 Labetalol
Side effects :
Postural Hypotension, Hepatotoxicity

Orally effective – undergoes first pass

metabolism, - Bioavailability – less (30 %)

Plasma Hlaf-life : 4 to 5 hrs.

 Labetalol
Uses :
HT in elderly patients
Pheochromocytoma
For controlling rebound HT
after colonidine withdrawal

Tabs :
 Dose: 50 mg BD, 100-200 TDS,
 I.V. inj. 20-40 mg.
 Carvediol
β1 + β2 + α1 adrenoceptors blocker

β1 & β2 blocking effects are more prominent

than α 1 blocking effects.
 Has antioxidant property.
 Inhibits free radicals – induced lipid

peroxidation
 also inhibits vascular smooth muscle
mitogenesis – independent of α or β
adrenoceptor blockade.
 Carvediol

These effects are cardioprotective in

patients with C.C.F.

Oral bioavailability : 30 %
Mainly metabolized &
A t ½ of 2-8 hrs.

Tabs: 3.125, 6.25, 12.5, 25 mg

 Carvediol
 C.C.F: Start with 3.125 mg BD for 2 weeks,
if well tolerated gradually increase to max.
of 25 mg BD.

 HT/Angina : 6.25 mg BD initially titrate to

Max. at 25 mg BD.
Therapeutic uses of β blockers

Coronary artery disease

Hypertension
Arrhythmias
Congestive heart failure
Hypertrophic
obstructive
cardiomyopathy
Pheochromocytoma
Therapeutic uses of β blockers

 Hyperthyroidism.
 Migraine -prophylaxis
 Essential tremor
 Anxiety – stage fright
 Glaucoma (topical)
 Beta-Blockers - Adverse Effects
Cardiac (mechanical; electrical)

Vascular (decreased perfusion)

Pulmonary (bronchocostriction)

Metabolic (diabetes mellitus)

CentralNervous System (depression,

nightmares, etc.)

Withdrawal Syndrome