Beta Receptor BlockersDr Ritu Budania

First Year ResidentD Department of Pharmacology

G.M.C Nagpur

Overview• Introduction• Classification• Pharmacological actions• Pharmacokinetics• Therapeutic uses• Adverse effects & Contraindications• Recent advances• Summary

IntroductionSympathetic Nervous System- Fight, Fear , Flight

Beta receptors

β -1 β -2 β - 3

Beta Receptor Blockers

Classification: First Generation ( non-selective)• Propranolol• Timolol• Sotalol• Pindolol• Nadolol

Second generation (Beta 1 selective)• Metoprolol• Atenolol• Acebutolol• Bisoprolol• Esmolol

Third Generation ( additional alpha blocking/ vasodilator property)

• Labetalol• Carvedilol• Celiprolol• Nebivolol

Pharmacological Actions:1. Heart: Sympathetic Stimulation Beta -1 receptors on myocardium

Myocardial contractilityHeart RateCardiac output Cardiac work Oxygen consumption

Beta Blockers

• Increase refractory period • A-V conduction is delayed• Decreases automaticity

2.Blood vessels

Vasoconstriction Vasodilatation

Alpha -1 receptors Beta -2 receptors

With continued treatment, resistance vessels gradually adapt to chronically reduced cardiac output so that t.p.r. decreases ,BP falls

Total peripheral resistance (t.p r.) is increasedinitially (due to blockade of β mediatedvasodilatation)

Cardiac output is reduced

Little change in BP

β blockers

Other mechanisms for Anti- hypertensive action:(i) Reduced NA release from sympathetic terminalsdue to blockade of pre- synaptic β receptor

mediated facilitation of the release process.

(ii) Decreased renin release from kidney

(iii) Decrease in Central sympathetic outflow

3.Respiratory tract• Beta -2 receptors bronchi bronchodilation• Beta blockers broncho constriction• Asthmatics - severe attack may be precipitated

Contraindicated in Asthma

4.Metabolic Effects: Hypoglycemia

Adrenaline

β- 2 receptors in liver

glycogenolysis

Masks sympathetic manifestations of hypoglycemia Plasma triglyceride levels increase LDL/HDL ratio is increased

Propranolol

5.Eye

Ciliary epithelium – β -2 receptors -increases aqueous secretion Their blockade reduces Aqueous secretionReduces Intra- ocular pressure

Pharmacokinetics

• Well absorbed after oral administration• Propranolol- extensive first-pass metabolism-

low oral bioavailability• Chronic use of propranolol - itself decreases

hepatic blood flow- bioavailability of propranolol is increased

• Longest acting- Nadolol- 14-24 hrs

• Shortest- Esmolol Ultra short acting blocker inactivated by esterases in blood plasma t1/2 < 10 min Rapid onset, short lasting effect Intravenous in emergency

Lipid insoluble( Atenolol, Sotalol)

• Less CNS side effects• Less first pass metabolism• Long t ½- 6- 20 hrs

Drugs with partial agonistic activity

• intrinsic sympathomimetic action • Pindolol, Acebutolol

1. Less Bradycardia preferred in those prone to severe bradycardia

2. Withdrawal is less likely to exacerbate hypertension or angina

3. Plasma lipid profile is not worsened

Advantages of Cardio selective Beta blockers over non -selective blockers:

1. safer in asthmatics2. safer in diabetics3 .Peripheral vascular disease 4. less deleterious effect on lipid profile5. Less liable to impair exercise capacity

Therapeutic uses

Cardiovascular uses Non-cardiovascular uses

Cardiovascular Uses

1.Hypertension:

• Past- recommended as first-line therapy• Present status - benefits have been

overshadowed by their side-effect profile

•sexual dysfunction •fatigue• depression • metabolic abnormalities

Consider Beta blocker if:

intolerance or contraindication to ACE inhibitors/angiotensin II receptor antagonists

With increased sympathetic drive- HTN with tachycardia Tense young patientPost MI

• Atenolol 25–100 mg • Metoprolol 25–100 mg • Propranolol 40–160 mg • Labetalol 200–800 mg • Carvedilol 12.5–50 mg

• Combined with Calcium channel blockers- check reflex tachycardia

Atenolol -Most commonly used - Selective β-1 blocker - Low lipid solubility. -Does not cross BBB- CNS ADR are less -Longer duration of action, OD dosing

Metoprolol-Cardioselective Beta 1 blocker-Can be used in Diabetics with HTN, CHF

Hypertensive Emergency:

Systolic BP >180 mm of Hg Diastolic BP > 120 mm of Hg

Treatment:1.Sodium nitroprusside- DOC2.Glyceryl trinitrate3. Esmolol 0.25-0.5 mg/kg IV over 1 min, then 0.05-0.1 mg/kg/min

IV for 4 min4.Labetalol

Labetolol

• 3rd generation• Alpha -1 blocker• β -1 blocker• Partial agonist β -2 (Vasodilation,Bronchodilation)

Uses: • Hypertensive emergencies• Pheochromocytoma• Pregnancy induced hypertension

2.Congestive Heart Failure: Heart Failure Decreased Cardiac output Sympathetic activation

Beta-1 receptors

Myocardium

myocyte hypertrophy, myocyte apoptosis detrimental remodelling

JG cells kidney Renin release

β blocker in CHF -proper patient selection : mild to moderate (NYHA class II, III ) cases of

dilated cardiomyopathy with systolic dysfunction

No place in decompensated patients. Stopped during an episode of acute heart

failure Starting dose -very low -then titrated

upward

Drug Initial dose Maximum dose

Carvedilol 3.125 mg BD 25-50 mg BD

Bisoprolol 1.25 mg QID 10 mg QID

Metoprolol 12.5–25 mg QID 200 mg QID

Carvedilol

• Alpha 1, β1, β2 blocker• Anti oxidant property• Inhibits free radical induced lipid

peroxidation, vascular smooth muscle mitogenesis

• Use: cardioprotective in CHF Hypertension

3. Angina Pectoris

Beta blockers Decrease cardiac work load Decrease myocardial oxygen demand

Angina of effort (Classical Angina)

Combined with nitrates for chronic prophylaxis

Cardioselective- Metoprolol 25- 100 mg Atenolol 25- 100 mg

Abrupt withdrawal- precipitate Angina / MI- up regulation of beta receptors

Contraindicated in Prinzmetals angina

4.Myocardial Infarctiona. Myocardial salvage during evolution of MI

β blockers-(i) limit infarct size by reducing oxygen consumption, prevents re-

infarction(ii) prevent arrhythmias including ventricular fibrillation

• Not given if- - Heart rate < 60/min - Systolic BP < 90 mm Hg - PR interval > 0.24 sec - LVF

• Within 4-6 hrs Metoprolol- 5 mg i.v every 5 mins – 3 doses• Metoprolol 25–50 mg orally every 6 h

b. Secondary prophylaxis of MI : Decrease subsequent mortality by 20%.(i) By preventing re-infarction(ii) By preventing sudden ventricular fibrillation at the second attack of MI

• β- 1 selective antagonist –Atenolol , Carvedilol • Atleast for 2 years

5. Cardiac Arrhythmias

SA node - Decrease slope of phase - 4 depolarisation

Decrease automacity in SA node, purkinje fibres

Prolong ERP of AV node – impedes A-V conduction

Esmolol

Intravenous It has been used to terminate: Paroxysmal supraventricular tachycardia episodic atrial fibrillation or flutterAdrenergically mediated arrhythmia

Pheochromocytomaarrhythmia during anaesthesiaintra operative, post operative hypertension in early treatment of myocardial infarction

Sotalol

• Additional K channel blocking • Class III anti-arrhythmic

Acebutolol- 20- 40mgPropranolol - 40 – 80 mg

6.Dissecting aortic aneurysm

• Intravenous Propranolol, Metoprolol- maintain heart rate of approximately 60 beats/min

7.Hypertrophic obstructive cardiomyopathy

Subaortic region is hypertrophic Forceful contraction of this region under

sympathetic stimulation (exercise, emotion) increases outflow resistance

8. Mitral valve prolapse

Non- cardiovascular uses

1.Hyperthyroidism

• Thyroxine Up regulation of β-1 receptors in myocardium Tachycardia, palpitations • T 4 T 3

β blockers given -

(i) with carbimazole or radioiodine(ii) with iodide preoperatively(iii) Thyroid storm (thyrotoxic crisis): emergency

Propranolol- 1-2 mg slow i.v. 40-80 mg orally

2.Glaucoma

• Decrease aqueous secretion• chronic simple (wide angle) glaucoma

Advantages of topical β- blockers over Miotics

No change in pupil size myopia headachefluctuations in i.o.t

convenient OD / BD dosing

Timolol • Non-selective• Action is smooth , well sustained • Effect on i.o.t. persists for 2-3 weeks following

discontinuation

• Dose – O.25% drops BD

Levobunolol- Long duration, OD

Side effects

• Redness and dryness of eye • Allergic blepharoconjunctivitis • Corneal hypoesthesia• Systemic side effects- threatening

bronchospasm- asthmatics, bradycardia

Betaxolol

• β- 1 selective blocker• Systemic side effects less• Protective effect in retinal neurones -

reducing Na/Ca influx. • O.5 % 1 drop BD

3. Pheochromocytoma:• Adrenal gland tumour Excess catecholamines hypertension, tachycardia• First alpha blocker is given then Beta blocker otherwise dangerous rise in BP can occur

4. Migraine • Prophylaxis • severe migraine • Propranolol - most effective drug - reduces frequency, severity of attacks- in 70% patients - Effect seen in 4 weeks -Dose- 40 mg BD to 160 mg BD • Others- timolol, metoprolol,atenolol

5.Anxiety

- Stage fright, Nervousness, panic - Propranolol- 10- 20 mg BD

6. Alcohol Withdrawal

7.Oesophageal variceal bleeding and portal hypertension

-Nadolol + isosorbide mononitrate

Contraindications1. Asthma, COPD2. Prinzmetals angina 3. Bradycardia Heart Block Acute decompensated heart failure4. Peripheral Vascular disease

Adverse Effects

1 . Adverse Lipid profile-total TG and LDL- cholesterol increase HDL- cholesterol falls. Cardioselective β blockers - little/no

deleterious effect on blood lipids

2.Fatigue and reduced exercise capacity

3.CNS side effects sleep disturbance, bad dreams, sexual dysfunction

4.Hypoglycemia -Masks sympathetic symptoms of hypoglycemia

5.Rebound Hypertension -Chronic therapy up regulation of Beta receptors -sudden withdrawal rebound hypertension -Gradually tapered and Withdrawn

6. Miscellaneous: Labetalol- postural hypotension, Hepatoxicity

Beta blocker Overdose

• Glucagon - specific antidote -positive inotropic action on the heart • Cardiac pacing • If bronchospasm occurs- Ipratopium• Other antidotes –Salbutamol and Isoprenaline

Celiprolol • Selective β1 blocker • Weak β2 agonistic activity • Nitric oxide release ,vasodilatation• No deleterious effects on lipid profile • Safe in asthmatics• Hypertension, Angina• Dose:200mg OD -400mg OD

Nebivolol• highly selective β1 blocker• Nitric oxide release, vasodilatation• Use: Hypertension• Dose - 2.5 mg OD

Newer uses:

• Post traumatic stress disorder

• Agoraphobia

Uses under study:• Propranolol -for orbital , periorbital hemangiomas in infants• Breast cancer• Pindolol- depression

New β blockers:

• Nipradilol (nonselective β-receptor and selective α1-receptor blocking properties, glaucoma)

• Dilevalol ( stereoisomer of Labetalol)- HTN

• Bopindolol

• Butoxamine -Selective β 2 blocker

- Experimental drug

Summary

• Therapeutically important class of drugs

To summarise:• Heart failure- Carvedilol• Hypertension- Atenolol• Emergency - Esmolol• Migraine - Propranolol• Glaucoma - Timolol

References

1.T. Westfall, D. Westfall, Adrenergic agonists & antagonists, Goodman & Gilman’s The Pharmacological basis of Therapeutics, 12 th edition, 2006, Pg 237-296

2.HL, KK Sharma. Principles of Pharmacology. 2nd ed. Pg 185- 190

3.K. D. Tripathi, Adrenergic and Antiadrenergic drugs, Essentials of Medical Pharmacology,6th edition, 2008, Pg 134-148

4.Longo, Fausi, Kasper. Harrisons principles of Internal Medicine, 18TH ed.

5.NICE clinical guideline 127.Developed by the Newcastle Guideline Development and Research Unit and updated by the National Clinical Guideline Centre and the British Hypertension Society. Hypertension Clinical management of primary hypertension in adult

6.Kenji Inoue,Kei Noguchi, Masato Wakakura,Goji Tomita .Effect of five years of treatment with nipradilol eye drops in patients with normal tension glaucoma

7.Lalonde RL, Tenero DM, Kazierad .Dilevalol: an overview of its clinical pharmacology and therapeutic use in hypertension