B blockers

CLASS FOR UNDER GRADUATES

1. BETA BLOCKERS Dr. RENJU.S.RAVI MD

2. Overview Introduction MOA Classification Actions Adverse effects Drug interactions Uses Contraindications Overdose

3. Beta blockers Drugs which inhibit adrenergic response mediated by beta receptors

4. BETA RECEPTORS Receptors Sites actions β 1 Heart JG cells-kidney Posterior pituitary Adipose tissue stimulatory Renin release ADH release lipolysis β 2 Bronchi Blood vessels of skeletal muscle Smooth muscle (Uterus ,intestine , detrusor) Liver, Muscle Adipose tissue Eye Bronchodilation Vasodilatation Relaxation Glycogenolysis Lipolysis Enhanced aqueous secretion β 3 Adipose tissue Lipolysis

5. Professor Raymond P Ahlquist Classified adrenoreceptor s. (1948)

6. HISTORY 1 st β blocker –DICHLORO ISOPROTERENOL-1958 PRONETHALOL---1962 PROPRANOLOL--1963 NEWER β BLOCKERS James Black

7. MOA Ac PKA α GTP ATP cAMP + GDP α βγ

8. Mechanism of action Via GPCR Antagonist binding to receptor No stimulation of G protein No change in cAMP conc No EFFECT

9. Properties Receptor Blockade Nonselective β blockade Selective β 1 blockade Β + α blockade Intrinsic sympathomimetic property-ISA (partial agonistic action) Membrane stabilising action-MSA (Local anaesthetic action-Na channel block)

10. CLASSIFICATION

11. 1 st generation – Non selective With ISA only Penbutolol With MSA only Propranolol With ISA & MSA Pindolol Without ISA &MSA Timolol Nadolol Sotalol

12. 2 nd generation – Selective β 1 agents With MSA only Metoprolol With ISA & MSA Acebutolol Without ISA &MSA Atenolol Bisoprolol Esmolol

13. 3 rd generation Non-selective Selective With ISA Carteolol With ISA Celiprolol With MSA Betaxolol With MSA Carvedilol With MSA & ISA Labetalol

14. β blockers With ISA Penbutolol Carteolol Celiprolol Both Pindolol Acebutolol Labetalol With MSA Propranolol Metoprolol Betaxolol Carvedilol Without ISA & MSA Timolol , Sotalol, Nadolol Atenolol , Bisoprolol, Esmolol

15. Properties of β 1 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

16. 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

17. Actions On CVS Heart Negative Ionotropy Chronotropy Dromotropy Bathmotropy

18. Actions…. On CVS Blood vessel V asoconstriction 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

19. Actions…. On CVS Antihypertensive action Decreased CO Decreased TPR on long term administration Decreased renin release

20. Betablockers with vasodilator property Alpha blockade Labetalol Carvedilol Bucindolol Bevantolol Nipradilol Beta2 agonism Celiprolol Carteolol Bopindolol CCB action Betaxolol Bevantolol Carvedilol K+ Channel opening Tilisolol NO production Celiprolol Carteolol Bopindolol Nipradilol Nebivolol Anti oxidant Carvedilol

21. Actions -CNS Anti anxiety Behaviour changes Forgetfulness Night mares Increased dreaming Non-selective lipid soluble

22. Actions -Metabolic CHO metabolism Hypoglycemia Inhibits muscle glycogenolysis Hypoglycemic unawareness Lipid Increases VLDL(TG) levels Alters HDL/LDL ratio Less with β 1 selective agents

23. Actions - Eye Decrease secretion of aqueous Decrease IOT No effect on pupil size or accommodation Ciliary body

24. Actions- Bronchus Increases airway resistance Less with beta 1 selective agents

25. SKELETAL muscles Decrease exercise capacity By decreasing blood flow Inhibit glycogenolysis and lipolysis.

26. MISCELLANEOUS Antagonise catecholamine induced Tremor Inhibition of mast cell degranulation Prevent platelet aggregation and promote fibrinolysis

27. Water soluble Lipid soluble By Liver By Kidney 100% 80 60 40 20 20 40 60 80 100 % PROPRANOLOL TIMOLOL PINDOLOL BISOPROLOL ACEBUTOLOL ATENOLOL CARVEDILOL NADOLOL METOPROLOL SOTALOL LABETALOL CARTEOLOL PENBUTOLOL Pharmacokinetics

28. Adverse effects - CVS Bradycardia Exacerbation of angina Precipitation of CHF

29. Adverse effects… Increased air way resistance  worsening of bronchial asthma

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

31. Adverse effects… Nightmares Decreased exercise capacity Tiredness Lack of drive

32. Drug interactions Pharmacokinetic Al salts, Cholestyramine Decrease absorption E nzyme inducers Decrease plasma conc . Cimitidine, Hydralazine Increase BA They impair clearance of lidocaine Pharmacodynamic Digoxin CCB (Verapamil) CCB (DHP) NSAIDs Adrenaline & other α agonists

33. 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

34. Hypertension Cardioselective beta blockers Rationale Decrease in HR,CO, myocardial contractility. Decrease renin release Decrease central sympathetic out flow

35. Angina Metoprolol Atenolol Bisoprolol Prophylaxis Treatment Contraindication Variant angina

36. Angina - Rationale Decrease HR & contractility Decrease myocardial oxygen demand Antianginal action

37. MI Prophylaxis Treatmen t Anti anginal action Reduce infarct size Prevents arrhythmia Prevents reinfarction Prevents arrhythmia Metoprolol Esmolol Timolol

38. Arrythmias Propranolol Esmolol Acebutolol Sotalol Decreases AV conduction Inhibits impulses from atria to ventricle  controls ventricular rate Mainly effective in Arrhythmias precipitated by catecholamines Sotalol K+ channel block  class3 anti arrhythmic Esmolol  ultra short acting  supraventricular tachycardia

39. ARRHYTHMIA Control ventricular rate in atrial flutter and fibrillation. Suppress extrasystole and tachycardia especially mediated adrenergically .

40. HOCM ↓ contractility ↓ LV outflow obstruction Improve cardiac output in exercise

41. CHF ONLY in compensated CHF Antagonise sympathetic overactivity on myocardium Prevents myocyte apoptosis ↓ cardiac remodelling Retard progression of CHF Metoprolol Bisoprolol Carvedilol

42. Dissecting aortic aneurysm ↓ cardiac contractility, and aortic pulsation .

43. Non - cardiac uses Pheochromocytoma Used after an α blocker To control tachycardia and arrhythmia Suppress cardiomyopathy due to excess catecholamines Thyrotoxicosis Control sympathetic symptoms Inhibit peripheral conversion of T4 to T3 Preoperative use

44. Migraine prophylaxis Propranolol Nadolol Metoprolol

45. Portal hypertension To Decrease Portal Vein Pressure in Patients with Cirrhosis Decrease variceal bleeding Propranolol

46. Glaucoma Decrease aqueous humour secretion Attenuating neuronal Ca and Na influx  Protection to retinal neurons Inhibit ganglion cell death Timolol Carteolol Betaxolol Levobetaxolol Levobunolol Metipranolol

47. CNS Anxiety Essential tremor Akathisia induced by antipsychotics Alcohol withdrawal

48. 3 rd generation agents Drug MSA ISA Beta blockade Other properties Labetalol + + Non selective α 1 blockade Carvedilol + Non selective α 1 blockade,CCB Antioxidant Bucindolol + Non selective α1 blockade, β 2, β 3 agonism Increases HDL cholesterol Celiprolol + β1 selective β2 agonism NO release Nebivolol β1 selective NO release Inhibits platelet aggregation Bevantolol Nonselective α1 blockade CCB

49. CONTRAINDICATIONS Absolute Severe Bradycardia Pre-existing High Grade Heart Block Overt Untreated Heart Failure Cardiogenic Shock Severe Bronchospasm Severe Depression Active Raynaud’s Phenomenon

50. CONTRAINDICATIONS Relative Prinzmetals Angina Concomitant Use Of :Verapamil/ Diltiazam / Digoxin Mild Asthma Insulin Requiring DM

51. OVERDOSAGE Manifestations  extension of p harmacological properties Hypotension Bradycardia Prolonged Conduction Times Widened QRS Complexes

52. SIGNS AND SYMPTOMS Seizures Depression Hypoglycemia Bronchospasm

53. Treatment Atropine Initially Cardiac Pacemakers Required Large amt of Isoproterenol /  Agonist Glucagon

54. Thank you