Beta blockers

Beta blockers are commonly encountered drugs in cardiology with its wide applications...here we learn about its uses and trials

1. Beta blockers : B-blockers in heart failure Ajay Kumar Yadav PGY2, Internal medicine IOM-TUTH , Kathmandu 2074/10/14

2. Beta-receptors Three types of Beta-receptors (β1, β2, β3) β1 receptors : Heart β2 receptors : Vascular and bronchial smooth muscle β3 receptors : Adipocytes

3. Beta-receptor and its effects

4. Generations of beta-blockers Properties Drugs 1 st generation Non-selective No vasodilatation Propranolol , Timolol , Pindolol , Nadolol , Sotalol 2 nd generation β1- selective without vasodilation Atenolol , Bisoprolol , Metoprolol β1 selective with vasodilation Nebivolol , Acebutolol 3 rd generation Non-selective with vasodilation Carvedilol , Bucindolol

5. V asodilation is due to D irect vasodilation via nitric oxide ( carvedilol,nebivolol ) α receptor blockade ( labetalol , carvedilol ) Carvedilol is also antiproliferative , antioxidant and blocks the expression of several genes involved in myocardial damage

6. Classification of Beta blockers Depending on their level of affinity for B-receptors. Selective β- blockers : affinity β-1> β-2 : selectivity lost at higher doses Atenolol Bisoprolol Celiprolol M etoprolol Nebivolol Non-selective β- blockers : affinity β1 = β2- Carvedilol Labetalol P ropranolol Sotalol

7. Classification cont. Lipophilic β-blockers Rapidly and completely absorbed from the GIT M etabolised in the gut wall and in the liver Low bioavailability : 10-30% Short half-lives R eadily pass into CNS : CNS adverse-effects.

8. Classification cont. Hydrophilic β-blockers I ncompletely absorbed from the GIT Excreted unchanged or as active metabolites by the kidney Longer half-lives D o not interact with other liver metabolised drugs

9. Comparative analysis of Beta blockers

10. Mechanism of beta-blockade in heart failure Upregulation of β receptors and improved β adrenergic signaling Reducing the hyperphosphorylation of calcium release channels of sarcoplasmic reticulum and normalizing their function Bradycardia ( ↑ coronary blood flow and decreased myocardial oxygen demand ) Protection from catecholamine myocyte toxicity . Suppression of ventricular arrhythmias . Anti-apoptosi s : β2 receptors, which are relatively increased, are coupled to inhibitory G protein & block apoptosis . Inhibition of RAAS : When added to prior ACE-I or ARB, metoprolol augments RAAS inhibitors

11. Indications

12. CVD Strongly indicated (level A) Systolic heart failure Post MI Ventricular arrhythmias (Post MI) Other indications (level B) Other arrhythmias STEMI, UA/NSTEMI/Chronic stable angina Hypertension Hypertrophic cardiomyopathy Mitral stenosis , MVP Dissecting aortic aneurysm Marfan’s syndrome (aortic root involvement) Neurocardiogenic syncope Fallot’s tetralogy Inherited arrhythmogenic disorders (LQTS, CPVT)

13. Non-cardiac uses Hyperthyrodism Migraine prophylaxis Anxiety disorder Essential tremor Portal HTN ( prevention of variceal bleeding ) Hyperhydrosis Glaucoma

14. Adverse effects CVS CNS Respiratory Metabolic Bradycardia Insomnia Bronchospasm Glucose intolerance Hypotension Nightmares Dyslipidemia ( increases TG level and decreases HDL cholesterol Heart failure Depression Miscellaneous Heart block Hallucinations Fatigue Exacebation of raynauds syndrome Dizziness Erectile dysfunction Decreased concentration Masks symptoms of hypoglycemia

15. A/E cont. CNS A/E are more common with lipopholic drugs A/E a/w Beta-2 receptor antagonist ( bronchospasm,peripheral vasoconstriction, alternation of glucose and lipid metabolism ) are less common with B-1 selective agents Receptor selectivity diminishes at higher doses B-1 blockade at the macula densa inhibits renin release : potentiate ACEI/ARB. Glucagon is used in the t/t of overdose .

16. A/E cont.

17. Cautions and contraindications for β-blockers Cautions Contraindications Mild to moderate airway disease- monitor peak flow prior to and following initiation Severe bronchial asthma or bronchospasm Renal and hepatic disease Prinzmetal’s angina β-blockers may mask early signs of hypoglycaemia Sinus bradycardia <50bpm Sick sinus syndrome including sino-atrial block, second or third degree AV block Worsening control of blood glucose may occur Hypotension- Systolic BP <90mmHg Cardiogenic shock Decompensated HF First degree AV block Severe peripheral arterial disease Use of concomitant medication that may increase risk of bradycardia Psoriasis , GA Phaeochromocytoma - apart from specific use with α-blockers Patients treated with verapamil

18. Drug interactions Class I antiarrhythmic drugs (e.g. Quinidine , flecainide , disopyramide and lidocaine ): Additive cardiac depressive effects and cause marked bradycardia . AV conduction time may be potentiated and the negative inotropic effect increased Class III antiarrhythmic drugs (e.g. amiodarone ): H ypotension , bradycardia , ventricular fibrillation and asystole in a few pts I nhibit the metabolism of β-blockers metabolised by CYP2D6 (e.g. metoprolol )

19. Drug interactions cont. Calcium channel antagonists of verapamil / diltiazem type: S erious and potentially life-threatening bradycardia . Centrally-acting antihypertensives (e.g. clonidine and methyldopa): Sharp and serious rise in blood pressure (rebound hypertension) can occur with sudden withdrawal of clonidine . Insulin and oral anti-diabetic agents: In pts with diabetes using insulin : hhypoglycemic manifestations may be masked Cardioselective β-blockers seem less likely to interact. The blood glucose lowering effect of the sulfonylureas may be reduced by β-blockers

20. Heart failure

21. Abnormality of cardiac structure or function which leads to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolising tissues or can do so only at an elevated filling pressure. Currently the β-blockers licensed for the treatment of HF are bisoprolol , carvedilol and metoprolol . Reduce the risk of disease progression in heart failure, improve symptoms and increase survival. Current guidelines recommend the use of beta blocker in mild, moderate and severe HFrEF <40% in the absence of contraindications or tolerance in combination with ACE inhibitor and diuretics A B-blocker is added at low starting dose that is gradually increased at 2-3 weeks interval until the maintenance level derived from the mortality trias are achieved.

22. Metoprolol First drug to be studied in HF in the MDC trial in 1993 : shown to reduce mortality and the need of transplantation by 34% compared to placebo MERIT-HF trial : Efficacy of metoprolol in moderate HF patients with NYHA class II-IV using a long-acting metoprolol formulation. Stopped early due to a significant decrease in all-cause mortality of 34%. 39% decrease in cardiovascular mortality , 49% decrease in death caused by progressive heart failure and 35% reduction in hospitalisations .

23. Bisoprolol CIBIS I trial One of the early trials to demonstrate the importance of β-blocker therapy in HF. Pts. with moderate HF treated with bisoprolol demonstrated a reduction in mortality and hospitalisation of 20%. CIBIS II trial The trial was stopped early due the significant mortality benefits. The primary end-point showed a reduction of 34% in mortality and there were significantly fewer sudden deaths and all-cause hospital admissions in the bisoprolol group.

24. Carvedilol The US Carvedilol Heart Failure Programme Compared carvedilol to placebo in pts with chronic HF and LVEF <35%. Shown to reduce mortality risk by 65% compared with placebo and 38% reduction in the combined end-point of hospitalisation or death. COPERNICUS trial Compared carvedilol to placebo in severe HF patients with NYHA III – IV. Significant 35% decrease in all-cause mortality and was well tolerated with fewer treatment discontinuations than the placebo group

25. Carvedilol cont. CAPRICORN study Evaluated if the addition of carvedilol to standard management of MI in pts. with LVSD would reduce morbidity and mortality compared to placebo. Decreased the risk of mortality by 23%. COMET study Only study to compare two β-blockers : carvedilol Vs metoprolol , in terms of mortality in patients with chronic HF with reduced LVEF. Carvedilol reduced mortality by 17% compared with metoprolol . The formulation of metoprolol was different to that used in MERIT-HF ( metoprolol tartrate versus slow release metoprolol succinate ) and the target dose used was lower (50mg/12h versus 100mg/12h).

26. Heart failure clinical trials

27. Summary table of meta-analyses in the treatment of heart failure

28. Summary table cont.

29. Summary The use of β-blockers in clinical studies have been shown to reduce mortality and hospital admissions by approximately 34% when included as part of standard HF therapy.

30. Clinical guidelines for the treatment of HF

31. Controversies?

32. B-Blockers and COPD: Inappropriate Avoidance? Pts with COPD are 3 times as likely to have HF and twice as likely to have CAD . BBs are indicated and considered standard of care for many of the cardiovascular conditions that often accompany COPD, including HF, AF, CAD, and HTN. Pharmacologically and physiologically, blocking b2 adrenoceptors could theoretically lead to bronchoconstriction and worsening lung function. Mounting evidence suggests that BBs are generally well-tolerated in patients with COPD and may actually lead to improved survival and paradoxical improvements in bronchial responsiveness . In retrospective and observational analyses, both cardioselective and noncardioselective BBs appear to decrease mortality in COPD patients with and without overt CVD, including those with hypertension, HF, and atherosclerosis. Official Journal of the American Society of Hypertension 2013

33. B-blockers and COPD cont. Pts. with existing CVD and newly diagnosed COPD have a higher mortality rate with BB discontinuation . Contrary to previous beliefs, BBs do not appear to increase the rate of COPD exacerbations or mortality. Meta-analysis of randomized, blinded,controlled trials, cardioselective BBs produced no significant change in FEV1, the incidence of COPD exacerbations, or the treatment response to b2-agonists compared with placebo. GOLD guidelines : The use of BBs in patients with IHD , AF or HF, including those with severe COPD, is warranted as the morbidity and mortality benefits outweigh the potential risk. Official Journal of the American Society of Hypertension 2013

34. GOLD guidelines for use of BBs in CVD and COPD Official Journal of the American Society of Hypertension 2013

35. Beta-Blockers in Acute Heart Failure : Do They Cause Harm? ACCF/AHA guidelines First, only if B-blocker therapy has just been started or its dosage increased can the drug be held responsible for an acute event. However, if the B-blocker is taken at a steady dosage for months, it cannot be held responsible for any acute HF episode, and it would be more effective and logical to focus on the event triggering the acute HF episode (e.g., infection, rhythm disturbance). The B-blockade remains for some time after drug withdrawal : (e.g., bisoprolol has a half-life of 11 h; carvedilol 6 to 10 h) : these first few hours are often the most critical in these pts.

36. After abruptly stopping B-blocker therapy, rebound may be observed after several days (i.e., a paradoxical activation of the SNS). Abrupt discontinuation of B-blockade after long-term treatment can exacerbate angina and may increase the risk of sudden death . When a positive inotropic agent is required (according to guidelines) during acute HF it is usually very early on, at a time when withdrawal of beta-blocker therapy is of no effect. In those pts not receiving an inotropic support, it is not founded to stop or decrease the protective drug, (i.e., B-blocker therapy) because there is indication that this attitude is associated with increased mortality.

37. Take home message Classification Indications A/E and Contraindications B-blockers in HF Controversies

38. Who runs in ur family ?

39. Thank you!!