BETA BLOCKERS

Dr. RENJU.S.RAVI MD

OVERVIEW Introduction MOA Classification Actions Adverse effects Drug interactions Uses Contraindications Overdose

BETA BLOCKERS

Drugs which inhibit adrenergic response mediated by beta receptors

BETA RECEPTORSReceptors Sites actionsβ1 Heart

JG cells-kidneyPosterior pituitaryAdipose tissue

stimulatoryRenin release ADH releaselipolysis

β2 BronchiBlood vessels of skeletal muscleSmooth muscle(Uterus ,intestine , detrusor)Liver, MuscleAdipose tissueEye

BronchodilationVasodilatationRelaxation

GlycogenolysisLipolysisEnhanced aqueous secretion

β3 Adipose tissue Lipolysis

Professor Raymond P Ahlquist

Classified adrenoreceptors. (1948)

HISTORY

1st β blocker –DICHLORO ISOPROTERENOL-1958

PRONETHALOL---1962

PROPRANOLOL--1963

NEWER β BLOCKERS

James Black

MOA

Ac

PKA

α

GTP

ATP cAMP

+GDP

α βγ

MECHANISM OF ACTION Via GPCR

Antagonist binding to receptor

No stimulation of G protein

No change in cAMP conc

No EFFECT

PROPERTIES Receptor Blockade

Nonselective β blockade Selective β1 blockade Β+α blockade

Intrinsic sympathomimetic property-ISA (partial agonistic action) Membrane stabilising action-MSA

(Local anaesthetic action-Na channel block)

CLASSIFICATION

Beta blockers1st generation

ClassicalNon

selective

2nd generation

ClassicalBeta 1

selective

3rd generationNewer

Non selective & beta1 selective + Add. properties

1ST GENERATION – NON SELECTIVE

With ISA only Penbutolol

With MSA only Propranolol With ISA & MSA

Pindolol

Without ISA &MSATimolol

Nadolol Sotalol

2ND GENERATION – SELECTIVE Β1 AGENTS

With MSA only Metoprolol

With ISA & MSA

Acebutolol

Without ISA &MSAAtenolol

Bisoprolol

Esmolol

3RD GENERATION

Non-selective Selective

With ISACarteolol

With ISACeliprolol

With MSABetaxolol

With MSACarvedilol

With MSA & ISALabetalol

Β BLOCKERS

With ISAPenbutololCarteololCeliprolol

BothPindolol

AcebutololLabetalol

With MSAPropranololMetoprolol

BetaxololCarvedilol

Without ISA & MSATimolol, Sotalol, NadololAtenolol, Bisoprolol, Esmolol

PROPERTIES OF Β1 SELECTIVITY

Less broncho constriction Less interference with CHO metabolism less

hypoglycemia preferred in diabetics Less chances of Raynaud's phenomenon Less deleterious effect on blood lipid profile Less impairment of exercise capacity Less effect on tremor

PROPERTIES OF ISA

Less bradycardia Less rebound effect on withdrawal Less deleterious effect on blood lipid

profile Not effective in migraine prophylaxis Not suitable for secondary prophylaxis of

MI

ACTIONS

On CVS Heart

Negative Ionotropy Chronotropy Dromotropy Bathmotropy

ACTIONS….

On CVS Blood vessel

Vasoconstriction in prone individuals Direct

Vasodilatation due to additional properties

Precipitates Reynaud's disease

•α1 blockade•β2 agonism•Ca ++ channel block•K+ channel opening•NO production

ACTIONS….

On CVS Antihypertensive action

Decreased CO Decreased TPR on long term

administration Decreased renin release

BETABLOCKERS WITH VASODILATOR PROPERTY

Alpha blockadeLabetalolCarvedilolBucindololBevantololNipradilol

Beta2 agonismCeliprololCarteololBopindolol

CCB actionBetaxolol BevantololCarvedilol

K+ Channel openingTilisolol

NO productionCeliprololCarteololBopindololNipradilolNebivolol

Anti oxidantCarvedilol

ACTIONS -CNS

Anti anxiety Behaviour changes Forgetfulness Night mares Increased dreaming

Non-selective lipid soluble

ACTIONS -METABOLIC

CHO metabolism Hypoglycemia

Inhibits muscle glycogenolysis Hypoglycemic unawareness

Lipid Increases VLDL(TG) levels Alters HDL/LDL ratio

Less with β 1 selectiveagents

ACTIONS - EYE

Decrease secretion of aqueous

Decrease IOT No effect on pupil size or

accommodation

Ciliary body

ACTIONS- BRONCHUS

Increases airway resistance

Less with beta 1 selectiveagents

SKELETAL MUSCLES

o Decrease exercise capacity By decreasing blood flowInhibit glycogenolysis and

lipolysis.

MISCELLANEOUS

oAntagonise catecholamine induced Tremor Inhibition of mast cell

degranulation oPrevent platelet aggregation and

promote fibrinolysis

Water soluble

Lipid solubleBy LiverBy Kidney

100% 80 60 40 20 0

0 20 40 60 80 100%

PROPRANOLOL TIMOLOL PINDOLOL BISOPROLOL ACEBUTOLOL ATENOLOLCARVEDILOL NADOLOLMETOPROLOL SOTALOLLABETALOL CARTEOLOLPENBUTOLOL

Pharmacokinetics

ADVERSE EFFECTS - CVS

Bradycardia Exacerbation of

angina Precipitation of CHF

ADVERSE EFFECTS…

Increased air way resistance worsening of bronchial asthma

ADVERSE REACTIONS

Impairment of carbohydrate tolerance Alteration of lipid profile Rebound hypertension on withdrawal Cold hands and feet, worsening of PVD

ADVERSE EFFECTS…

Nightmares Decreased exercise capacity

TirednessLack of drive

DRUG INTERACTIONS

PHARMACOKINETIC

• Al salts, CholestyramineDecrease absorption• Enzyme inducersDecrease plasma conc.• Cimitidine, HydralazineIncrease BA• They impair clearance of

lidocaine

PHARMACODYNAMIC

Digoxin CCB (Verapamil) CCB (DHP) NSAIDs Adrenaline & other α

agonists

USES

CARDIOVASCULAR

Hypertension Angina Myocardial infarction Arrhythmia Cardiomyopathy CCF Dissecting aneurysm of

aorta

NON - CARDIOVASCULAR

Thyrotoxicosis Pheochromocytoma Migraine prophylaxis Essential tremor Glaucoma Anxiety Portal hypertension Anti psychotic induced

akathesia

HYPERTENSION

Cardioselective beta blockers Rationale

Decrease in HR,CO, myocardial contractility.

Decrease renin release Decrease central sympathetic

out flow

ANGINA

Metoprolol Atenolol Bisoprolol

ProphylaxisTreatment

Contraindication•Variant angina

ANGINA - RATIONALE

Decrease HR & contractility

Decrease myocardial oxygen demand

Antianginal action

MI

o Prophylaxiso Treatment Anti anginal action

Reduce infarct size Prevents arrhythmia

Prevents reinfarction Prevents arrhythmia

MetoprololEsmololTimolol

ARRYTHMIAS

Propranolol Esmolol Acebutolol Sotalol

Decreases AV conduction

Inhibits impulses from atria to ventricle controls ventricular rate

Mainly effective inArrhythmias precipitated by catecholamines

Sotalol K+ channel block class3 anti arrhythmicEsmolol ultra short acting supraventricular tachycardia

ARRHYTHMIA

Control ventricular rate in atrial flutter and fibrillation.

Suppress extrasystole and tachycardia especially mediated adrenergically .

HOCM

↓ contractility

↓ LV outflow obstruction

Improve cardiac output in exercise

CHF

ONLY in compensated CHF Antagonise sympathetic overactivity

on myocardium

Prevents myocyte apoptosis

↓ cardiac remodelling

Retard progression of CHF Metoprolol BisoprololCarvedilol

DISSECTING AORTIC ANEURYSM

↓ cardiac contractility, and aortic pulsation.

NON - CARDIAC USES

o Pheochromocytoma Used after an α blocker To control tachycardia and arrhythmia Suppress cardiomyopathy due to excess

catecholamineso Thyrotoxicosis

Control sympathetic symptoms Inhibit peripheral conversion of T4 to T3 Preoperative use

MIGRAINE PROPHYLAXIS

Propranolol Nadolol Metoprolol

PORTAL HYPERTENSION

To Decrease Portal Vein Pressure in Patients with Cirrhosis

Decrease variceal bleeding

Propranolol

GLAUCOMA

Decrease aqueous humour secretion

Attenuating neuronal Ca and Na influx Protection to retinal neurons

Inhibit ganglion cell death

TimololCarteololBetaxololLevobetaxololLevobunololMetipranolol

CNS

Anxiety Essential tremor Akathisia induced by

antipsychotics Alcohol withdrawal

3RD GENERATION AGENTSDrug MSA ISA Beta blockade Other properties

Labetalol + + Non selective α1 blockade

Carvedilol + Non selective α1 blockade,CCBAntioxidant

Bucindolol + Non selective α1 blockade,β2,β3 agonismIncreases HDL cholesterol

Celiprolol + β1 selective β2 agonismNO release

Nebivolol β1 selective •NO release•Inhibits platelet aggregation

Bevantolol Nonselective α1 blockadeCCB

CONTRAINDICATIONS

Absolute

1. Severe Bradycardia

2. Pre-existing High Grade Heart Block

3. Overt Untreated Heart Failure

4. Cardiogenic Shock

5. Severe Bronchospasm

6. Severe Depression

7. Active Raynaud’s Phenomenon

CONTRAINDICATIONSRelative

1. Prinzmetals Angina

2. Concomitant Use Of :Verapamil/ Diltiazam/Digoxin

3. Mild Asthma

4. Insulin Requiring DM

OVERDOSAGEManifestations extension of pharmacological properties

Hypotension

Bradycardia

Prolonged Conduction Times

Widened QRS Complexes

SIGNS AND SYMPTOMS

Seizures Depression Hypoglycemia Bronchospasm

TREATMENT

Atropine Initially

Cardiac Pacemakers Required

Large amt of Isoproterenol / Agonist

Glucagon

Thank you