Beta blockers

Lecture on beta blockers their classification, therapeutic uses, adverse effects , contraindications.

1. Beta blockers

2. Catecholamines produce their action by direct combination with receptors located on cell membrane Outcome of this drug receptor combination is either ↑ or ↓ in tissue activity Ahlquist 1948 Alpha & beta receptors

3. Interfere synthesis Induce Depletion Reduce release Block Receptors 1 2 3 4  - methyl para -tyrosine ( metyrosine ) Reserpine , Tetrabenazine Guanethidine, Bretylium  - and  - adrenergic receptor blocking drugs

4. Adrenoceptor Blockers (Antagonists) (peripheral) D-blockers  -blockers  -blockers  1 -blockers  2 -blockers  1 -blockers  2 -blockers  3 -blockers Peripheral D-blockers are not clinically significant  1A  1D  1B

5. History of beta blockers Dichloro-isoproterenol 1958 first beta blocker Pronethalol first pure beta blocker propranolol 1962 All beta blockers are competitive antagonists

6. Classification of Beta blockers Non selective Propranolol Pindolol Sotalol Timolol  + β Blocker Labetolol Carvedilol Cardio Selective ( β 1 ) Atenolol Acebutolol Betaxolol Bisoprolol Esmolol Metoprolol Nebivolol

7. Without intrinsic sympathomimetic action: Propranolol Timolol Sotalol With intrinsic sympathomimetic action: Pindolol Acebutolol With membrane stabilizing action: Propranolol , oxprenolol , acebutolol

8. Propranolol Non selective beta blocker also an inverse agonist

9. Pharmacological actions Effects of  blockade No marked effect on normal heart in subject at rest In presence of ↑ sympathetic tone ↓ automaticity and prevents rise in HR ↓ Myocardial contractility, cardiac output and stroke work Slows AV conduction ↓ myocardial oxygen requirement & improves exercise tolerance

10. Heart

11. Blood vessels: Reduce BP ↓ COP ↓ renin levels ↓ central sympathetic outflow ↓ NA release from sympathetic terminal Respiratory tract:

12. CNS: Subtle behavioral changes Forgetfulness, nightmares , ↑ dreaming Supresses anxiety in short term stressful situation Local anaesthetic :

13. Metabolic: blocks lipolysis & subsequent ↑ FFA ↑ TG, ↑ LDL/HDL ratio Inhibit glycogenolysis in heart, muscle, liver No effect on normal BGL but ↓ carbohydrate tolerance by ↓ insulin release Skeletal muscle: Inhibit tremors Decrease exercise capacity Eye : ↓ secretion of aqueous humor Uterus : relaxation of uterus in response to selective  2 agonistis blocked

14. To summarize the pharmacological actions

15. Heart Respiratory CNS Local anaesthetic Metabolic Skeletal muscle Eye Uterus

16. Important actions Membrane stabilizing action: Propranolol , oxprenolol , acebutolol Intrinsic sympathomimetic action: Pindolol , acebutolol

17. Significance of intrinsic sympathomimetic action Less bradycardia & depression of contractility Less likely withdrawl symptoms Lipid profile less worsened Not effective in migraine prophylaxis Not suitable for secondary prophylaxis of MI

18. Cardioselectivity : Metoprolol , acebutolol , atenolol,bisoprolol More potent Beta 1 blockade than beta2

19. Cardioselective  blockers Advantages Lower chances for bronchoconstriction Less interference with carbohydrate metabolism and lipid profile ↓ incidence of cold extremities ↓ precipitation of raynauds disease Less impairment of exercise tolerance Disadvantage Ineffective in essential tremors

20. Pharmacokinetics of propranolol Well absorbed , low bioavailability, high first pass metabolism in liver Lipophilic Metabolism dependent on hepatic blood flow Chronic use of propranolol ↓ es hepatic blood flow Bioavailability and t1/2 ↑ ed by 30 % on repeated administration Food decreases first pass metabolism Saturable metabolism at higher doses Metabolites have blocking action 90% protein bound Dose oral = 10 mg BD to 160 mg QID

21. Uses of betablockers Cardiac : Hypertension Angina pectoris Myocardial infarction Cardiac arrhythmias CCF Hypertrophic obstructive cardiomyopathy Dissecting aortic aneurysm Non cardiac: Pheochromocytoma Thyrotoxicosis Migraine prophylaxis Anxiety Essential tremors Glaucoma Portal hypertension

22. Lipid insoluble beta blockers Atenolol , sotalol , bisoprolol , acebutolol Less central effects Incompletely absorbed orally but do not undergo first pass metabolism, excreted mostly unchanged in urine Longer acting 6-20 hrs Effective in narrow dose range Propranolol is the most lipid soluble beta blocker

23. Drug interactions Digitalis & verapamil : depression of SA & AV node conduction Insulin / oral antidiabetic Delays recovery from hypoglycemia Warning signs supressed – Tachycardia, tremors Some cases increased BP Inhibits insulin release Alpha agonists in cold remedies: Marked ↑ BP NSAIDS : attenuate antihypertensive action Cimetidine: Lidocaine : propranolol retards metabolism

24. Adverse effects & contraindications 1 . Can accenuate myocardial insufficiency & precipitate CHF by blocking sympathetic support to heart in CVS stress 2. Bradycardia 3. COPD, Bronchial asthma 4. Exacerbates variant, prinzmetal angina 5. Impairment of carbohydrate tolerance in prediabetics 6. Increase TG & LDL/HDL ratio 7. Rebound hypertension, angina on withdrawl

25. Adverse effects & contraindication 8. Contraindicated in partial & complete heart block – arrest may occur 9. Tiredness , decreased exercise capacity 10. Cold hands & feet – worsening of PVD due to blockade of vasodilator Beta 2 11. Adverse events not due to beta blockade: GIT upset, lack of drive, night mares, forgetfulness, rarely hallucination , sexual distress

26. Doses of beta blockers Drug Dose in mg Propranolol 80 – 240 mg 6-12 hrly Metoprolol 100 – 200 mg BD Atenolol 25 – 100 mg daily Timolol 10 – 60 mg daily Pindolol 10 – 45 mg 6 hrly Labetolol 200 – 600 mg BD Bisoprolol 5 – 10 mg OD

27. Salient features Sotalol: Non selective, lower lipid solubility, class 3 antiarrhythmic Timolol: Topical preferred in glaucoma Betaxolol, carteolol, levobunolol (Local acting) Pindolol: Non selective, intrinsic sympathomimetic action Metoprolol: Cardioselective , less first pass metabolism

28. Salient features Atenolol: Cardioselective Low lipid solubility No significant first pass metabolism Longer DOA 6-9 Hrs No deleterious effect on lipid profile Effective in narrow dose range Most commonly used beta blocker for angina & hypertension

29. Salient features Acebutolol : Cardioselective Partial agonist & membrane stabilising action Bisoprolol : OD administration in angina , hypertension, CHF Esmolol : Ultrashortacting Celiprolol , nebivolol : vasodilatory release nitric oxide

30. Uses of betablockers Cardiac : Hypertension Angina pectoris Myocardial infarction Cardiac arrhythmias CCF Hypertrophic obstructive cardiomyopathy Dissecting aortic aneurysm Non cardiac: Pheochromocytoma Thyrotoxicosis Migraine prophylaxis Anxiety Essential tremors Glaucoma Portal hypertension

31. Hypertension: First line drugs Absence of postural hypotension Low adverse events Once daily dose Low cost Cardioprotective potential Angina pectoris: Decrease work load and Oxygen requirement by heart Favourable redistribution of blood

32. Myocardial infarction: Catecholamines released during MI More useful if ongoing pain, tachycardia, hypertension , ventricular rhythm instability Secondary prophylaxis; Prevent reinfarction Prevent sudden ventricular fibrillation Myocardial salvage during evolution of MI: Limit infarct size by decreasing oxygen consumption Marginal tissue which is partly ischemic may survive May prevent arrhythmias VF

33. Cardiac arrhythmias Supress tachycardias & extrasystoles mediated by adrenergic system Control ventricular rate in Atrial fibrillation & flutter Esmolol alternative drug for paroxysmal supraventricular tachycardia Dissecting aortic aneurysm: Decrease contractile force & aortic pulsation Hypertrophic obstructive cardiomyopathy Decrease LV outflow obstruction

34. Congestive cardiac failure: Negative ionotropic effect? Worsen ventricular function 1970 waagstein & associates found improved exercise tolerance & improvement in several measures of ventricular function. Immediately after starting beta blockers Decrease in systolic function as reflected by decrease in ejection fraction however continued treatment over 2-4 months systolic function gradually improves This is due to prevention of adverse effects of NA on myocardium that are mediated by beta adrenergic receptors

35. Thyrotoxicosis: Migraine prophylaxis: Anxiety: Pheochromocytoma: Essential tremor: Glaucoma Portal hypertension:

36. Alpha + beta blocker Labetolol : 5 times more potent for beta receptors Has weak beta 2 agonist action also Decrease blood pressure by 3 mechanisms Orally effective but extensive first pass metabolism Uses: hypertension, pheochromocytoma , clonidine withdrawl , Side effects : postural hypotension, failure of ejaculation, other side effects of alpha & beta blockers

37. Carvedilol :  1, β 1, β 2 blocker Vasodilation : alpha 1 + calcium channel blockade Antioxidant property Use: Hypertension Cardioprotective in congestive heart failure Oral bioavailabilty – 30% T1/2 = 6-8 Hrs