BETA ADRENERGIC

RECEPTOR ANTAGONISTS
Dr Shalini Salwan
 Beta blockers
 Competitive inhibitors of β -adrenergic receptors – inhibit action of
CA & other β agonists.
 Most are pure antagonists – some partial agonists
 Differ in relative affinities for β 1 & β 2 Receptors .
 Selectivity is dose related-diminishes at higher concentration. It is
NOT absolute.
 Also differ in PK

ISA : Intrinsic sympathomimetic activity /partial agonistic activity

MSA: Membrane stabilizing activity/ local anaesthetic activity

CLASSIFICATION

NON SELECTIVE CARDIOSELECTIVE

 Without ISA: Propranolol,  Atenolol

 Metoprolol
Sotalol, Timolol
 Acebutolol
 With ISA: Pindolol
 Bisoprolol
 With additional α  Esmolol
blocking property:  Celiprolol

Labetolol, Carvedilol  Nebivolol

CLASSIFICATION
FIRST GEN SECOND GEN THIRD GEN
(NON SELECTIVE) (β1 SELECTIVE) (ADDITIONAL α
BLOCKING/VASODILAT
OR PROPERTY)

•PROPRANOLOL •METOPROLOL •LABETALOL

•TIMOLOL •ATENOLOL •CARVEDILOL
•SOTALOL •ACEBUTOLOL •CELIPROLOL
•PINDOLOL •BISOPROLOL •NEBIVOLOL
•ESMOLOL •BETAXOLOL
Classification of Beta blockers
Beta blockers: PK
Absorption:
 Most are well absorbed PO.
 Peak conc. 1-3 hrs.
 Propranolol extensive 1st pass metab –low BA.
 Due to variation in first- pass there is great individual
variability in plasma conc.
Distribution & Clearance :
 Rapidly distributed and have large Vd.
 Propranolol & penbutalol lipophilic-cross BBB readily.
 Most have t1/2 of 3-10 hrs. (EXCEPT Esmolol-10 mins) .
PK..
 Propranolol & Metoprolol extensively metab. in
liver mainly by CYP2D6 .
 Poor metabolizers have 3-10 times higher pl. conc.
than extensive metab.
 Atenolol , celiprolol, & pindolol less completely
metab.
 Nadolol excreted unchanged in urine & has longest
t1/2.
 Elimination of propranolol prolonged in liver
disease & CHF or d/t enzyme inhibition
Pharm actions of Beta blockers
 1. On CVS:
Propranolol depresses SAN , AVN & myocardial contraction :
 Pharmacological actions of Beta
blockers..CVS..
- Decrease the expected increase in HR during exercise/stress
- Decreases force of contraction and CO – useful in HT
- Cardiac work & oxygen consumption are decreased d/t β 1 blockade
–useful in angina
- Total coronary flow is reduced.
- Effectively suppress cardiac arrythmias by decreasing automaticity.
Effects on CVS…
 Peripheral Vasoconstriction:
 β blockade opposes β 2 mediated vasodilation. Can acutely lead to
rise in PVR d/t unopposed α- receptor mediated effects. (Re-
reversal of VASOMOTOR REVERSAL)
 Acute effects –Rise in PVR ,CO is reduced(little change in BP).
 Chronic admn leads to fall in PVR in pt of HT.
ANTI-HYPERTENSIVE ACTION
 Resistance vessels adapt to chronically reduced CO.
 Inhibit release of renin from the JGA caused by sympathetic NS.
 Reduced NA release
 Central action reducing sympathetic outflow.
Effects on Respiratory tract
 Bronchoconstriction
 Blockade of β2 receptors in bronchial sm ms – increase in airway
resistance esp in pt of asthma –
 β1 selective antagonists m/b better BUT no available β1 selective
agent can completely avoid action on β2 receptors.
 Hence these drugs are CI in pt of asthma
Metabolic & Endocrine effects
 Disturbance in CHO & lipid metab.
 Propranolol inhibits symp NS stimulation of lipolysis .
 Glycogenolysis in liver inhibited (β2 blockade)
 Propranolol may delay recovery from hypoglycemia in
Type 1 DM and less frequently in Type 2DM.
 Also interfere with counter –regulatory effects of CA
secreted during hypoglycemia- tremor, tachycardia ,
nervousness
 Should be used with caution in pt with diabetes and
frequent hypoglycemia.
 If indicated, β1 antagonists preferred
Metabolic…
 Chronic use causes
↑LDL- C, ↑ Triglycerides
↓ HDL –C
 Unfavourable for heart
 Occur with both selective & non-selective blockers
 But some vasodilating βblockers (carvedilol, carteolol,
celiprolol ) may be devoid of this effect.
 Effects on eye
 β blockers reduce IO pressure d/t decreased aqueous humor
production- useful in glaucoma.
Effects on CNS
Forgetfulness, dreaming and nightmares.
Suppresses anxiety in stressful situations.
Effects on skeletal muscle
 Suppresses tremor

 Reduces exercise capacity

Local Anaesthetic Effect

Membrane stabilizing action
Ocular irritation and corneal anaesthesia.
 Specific agents
CARDIOSELECTIVE β-BLOCKERS
Metoprolol , Atenolol,Acebutalol,Bisoprolol
Safer than propranolol in, DM, PVD , COPD (with MI)
No deleterious effect on lipid profile, exercise capacity
Ineffective in essential tremor. (β2 )
Nebivolol
Third generation selective β1 blocker
Additional vasodilatory axn d/t release of endoth NO
May increase insulin sensitivity
Doesn’t effect lipids and CHO metabolism.
Used in HT and CHF.
Celiprolol
Third generation selective β1 blocker, NO production.
Additional β2 agonist activity: : safe in Asthmatics
Specific agents…
ISA (partial agonist activity)
Pindolol, Acebutolol, Celiprolol

 Less prominent bradycardia.

 No exacerbation of HT, Angina after withdrawal.

 Lipid profile is not worsened.

 Not effective in migraine prophylaxis, MI.

 Celiprolol- has mild β2 agonist activity – Br. Asthma

Specific Agents
MSA (LA)
d/t blockade of Na channels.
Propranolol,acebutalol,oxprenolol.
 Not seen after systemic admn.(low conc)
 Seen after topical adm. : such agents not used in glaucoma e.g
propranolol
Esmolol
 Ultrashort acting β1 antagonist. T1/2=10min

 Rapidly metab. by esterases in RBCs.

 Given by infusion for controlling supraventricular arrhyth. d/t

thyrotoxicosis, perioperative HT & Myo ischemia in critical

conditions.
Sotalol
Nonselective - β blocker with Class III antiarrhythmic act. Used in
ventricular arrhythmias & AF & Afl
Specific agents..
Labetalol
 Racemic mixture of 2pairs of chiral isomers .
 Potent α1 blocker and β1 and β2 blocker and weak β2 agonism.
 Causes less bronchospasm & vasoconstriction than Ppnol
 Used as IV infusion in hypertensive emergencies & PIH,clonidine
withdrawal, cheese reaction and in essential hypertension.
Carvedilol
Nonselective β blocker & α1 blocking capacity.
Extensively metab in liver by CYP 2D6 & CYP2C9. t1/2=7-10 hrs .
Has MSA but no ISA
Produces vasodilation d/t α blocking and calcium channel blocking
property
Has antioxidant & anti-inflammatory effects- useful in trt of CHF, & L V
dysfunction following MI
Therapeutic uses: Cardiovascular
diseases
 Hypertension
 β blockers effective & well tolerated
 MOA: Exact not clear
 ↓ CO ; ↓ Renin sec. ↓ PVR on chronic use & ↓sympathetic outflow
from CNS
β blockers in Hypertension…
 Often used along with diuretic or a vasodilator
 Given once or twice daily despite short t1/2
 Maybe less effective in the elderly Blacks
 Mostly β1 selective agents used eg atenolol, metoprolol

 Ischemic heart disease: Angina pectoris

 β blockers reduce the frequency of anginal episodes & increase
exercise tolerance in pt of angina.
 Not suitable for variant angina
β blockers in Cardiovascular diseases..
Myocardial Infarction : Administ. of β blockers
1. during early phase of MI : Limits infarct size and prevent
arrythmias
2. long term use for secondary prophylaxis may decrease mortality
by 25%.: Prevent re-infarction and sudden ventricular fibrillation.

metoprolol, propranolol most useful

Cardiovascular diseases..
 Cardiac arrhythmias
 Effective in both supraventricular & ventricular arrhythmias
- Increase AV nodal refractory pd.- slow ventricular response in AF &
Afl .
Also reduce ventricular ectopics d/t CA.
Mainly Propranolol
Esmolol: Alternative in PSVT.
Sotalol : antiarryhthmic as well as β blocker
Cardiovascular diseases..
 Heart failure
 Earlier were CI in CHF
 Reduce mortality in pt of compensated mild-moderate HF (class2-3)
on ACE inhibitors & diuretics
 Only 4 agents shown to be effective- BMCN- Bisoprolol, Metoprolol,
Carvedilol,Nebivolol.
 MOA: Prevent excessive effects of CA on heart;
attenuate cardiac remodelling;
sudden arrhythmias,
antioxidant actions.
 Precautions: START LOW & GO SLOW eg Carvedilol 3.125 mg BID
( Normal Anti HT dose 6.25 bid) ; Bisoprolol 1.25 mg OD (N Anti HT
dose 5mg )
0ther Cardiac Indications
 Hypertrophic obstructive cardiomyopathy:
Ppnol is std therapy . High dose -462 mg /d reduces ventricular
arrhythmias
 Mitral stenosis with sinus rhythm: β blockers ↓resting & exercise HR
---allowing longer diastolic filling & improved exercise tolerance.
 Mitral valve prolapse
 Dissecting aortic aneurysms
 Non-cardiovascular uses of β blockers
 Thyrotoxicosis
 Used alongwith antithyroid drugs-
 1. before surgery
 2. in thyroid storm –
 controls symptoms – tachycardia, palpitations, tremor& nervousness
& reduces vascularity of gland .
 Anxiety states
 Ppnol m. commonly used – reduce peripheral s/s –tachy-, tremors .
Useful for orators, musicians with performance anxiety (stage fear) .
 Essential tremors
 Pheochromocytoma: To control tachycardia and arrythmias.(NOT
without α- blocker.)
 Post alcoholic withdrawal synd
Non-cardiovascular uses of β
blockers.. ..
 Glaucoma
 Timolol, carteolol.
 Caution: Systemic s/e can occur
 Migraine Prophylaxis
Ppnol 80-240 mg for prophylaxis – reduces incidence of migraine in
60 % pts .
MOA –vasoconstriction in cranial BV
NOT for attacks once they have occurred
Portal HT: in liver cirhhosis pt- decrease incidence of bleeding
esophageal varices.
 Side effects of β blockers
 Three major mech of side effects of β blockers
-smooth ms spasm-
bronchospasm & cold extremities, worsening of symptoms of PVD or
Reynaud’s phenomenon & claudication
-exaggeration of cardiac pharmacological axn
bradycardia, heart block , excess negative inotropic effect ; may ppt or
exacerbate HF in pt with compensated HF/AMI
-CNS penetration ( related to lipid solubility)
Fatigue, Insomnia, depression, vivid dreams
- Impotence , Metabolic disturbances
- Sudden stopping of is β blockers dangerous –may exacerbate angina &
increase risk of sudden death due to cardiac arrhythmias/MI
 Reason: supersensitivity

 Hence tapering the dose several weeks before stopping

DI
 : Al salts, cholestyramine , colestipol decrease absb.
 Drugs like phenytoin , rifampin increase metabolism.
 Inhibitors like cimetidine , hydralazine increase BA
 PD interactions - β blockers & CCBs esp verapamil & diltiazem =
additive effects on cardiac conducting system –can cause complete
heart blockade.
Contraindications
 ABSOLUTE CI
 Severe asthma or bronchospasm
 Severe bradycardia, high degree heart block, overt LVF, cardiogenic
shock
 Severe PVD, claudication
 Severe depression
 Non-selective agents in T1DM
Selection of a β blocker
 Should depend on PK & PD differences among drugs, cost &
concomitant disease.
 Eg in pt of Diabetes , PVD or Reynaud’s phenomenon - β1
selective antagonists preferred .

Agents with ISA m/b preferred in pts with bradycardia.

Third gen agents may have specific therapeutic advantages.