Post on 07-May-2015
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