beta-blockers in cardiovascular Medicine

1 SUPPLEMENT OF JAPI dEcEMbEr 2009 VOL. 57 7 Introductionbeta- blockers were first developed by Sir James black at the imperial chemical industries in the United Kingdom in 1962. They are considered one of the most important contributions to clinical Medicine and pharmacology in the 20th century, and Sir James black was awarded the Nobel prize in 1988 for advances in h i s r e v i e w b r i e f l y d i s c u s s e s t h e p e r t i n e n t c l i n i c a l pharmacology of beta-blockers followed by their clinical use in cardiovascular are one of the 4 oral medications proven in randomized control trials to decrease cardiovascular morbidity and mor tality. The other three agents being AcE-inhibitors, antiplatelets and statins. This quadruple therapy reduces 6 months mortality by 90% in AcS compared with treatment by none of approximate life-saving potential of these agents have been estimated;2 beta-blockers 33%, Aspirin 23%, AcE inhibitors 20% and Statins 15%.

2 Clinical PharmacologyAlthough more than 100 beta-blockers have been developed, only about 30 are available for clinical Water-soluble beta-blockers (Atenolol, Nadolol) tend to have longer half-lives and are eliminated via the kidney. Lipid-soluble beta-blockers (metoprolol, propranolol) are metabolized mainly in the liver and have shorter of the drugs in the class are well absorbed after oral administration. The biologic half-life of beta-blockers exceeds the plasma half life considerably. ( propranolol, dosage twice a day despite a plasma half-life of 3 hours). clearly, the higher the dose, the longer the biologic effect. Longer acting compounds and preparations are preferred for angina and hypertension (metoprolol XL, atenolol, nadolol, sotalol, inderal LA). esmolol (I/V) has the shortest half life (10 min).Three t ypes of b eta-receptors ( 1, 2, 3) are var iably distributed in tissues5.

3 1 receptors are mainly located in the heart while 2 receptors are found in vascular and bronchial smooth muscle. 3 receptors are located in the adipocytes and heart beta-blockers (metoprolol, atenolol) exhibit greater affinity for 1 versus 2 receptors at usual drug levels6. This selectivity is lost at higher drug doses. Most beta-blockers in clinical use are pure antagonists. A few (acebutalol, pindalol) are partial The relative density of 1 and 2 receptors changes with disease. In heart failure, 1 receptors are ,7 beta-blockers are also grouped in generations (Table 1). Third generation beta-blockers (carvedilol, bucindolol, nebivolol) are non- selective and of vasodilation is direct vasodilation via nitric oxide (car vedilol, nebivolol) and via receptor block ade (labetalol, car vedilol).8 car vedilol is also antiproliferative, antioxidant and blocks the expression of several genes involved in myocardial of Action of beta-blockers10 All beta-blockers occupy the receptor and counter the effects of catecholamines on the cardiovascular tissues.

4 1 receptors are located on the cardiac sarcolema and belong to the G-protein coupled adenyl cyclase system. When catecholamines stimulate the receptor, Gs protein couples the activated receptor to adenyl c yclase and generates cAMP. cAMP, the second messenger, activates protein k inase A (PKA) which phosphor ylates the membrane calcium channel and increases calcium entry into t h e c y to s o l. P K A a l s o i n c re a s e s c a l c i u m re l e a s e f ro m t h e sarcoplasmic reticulum. This calcium loading accounts for the positive inotropic effect. PKA also phosphorylates Troponin I (decreases affinity of myosin head to actin) and phospholamban (increased calcium reuptake by sarcoplasmic reticulum). This accounts for the lusitropic effect. increased If in the sinus node beta-blockers in cardiovascular MedicineAijaz H Mansoor, Upendra Kaul**Executive director, department of cardiology, Escorts Heart Institute and research centre, New delhiAbstractbeta- blockers are among the proven medication in cardiovascular Medicine , reducing both the morbidity as well as the mortality.

5 Most beta-blockers are well-absorbed after oral intake. The third generation beta-blockers (carvedilol, nebivolol) are non-selective and have additional properties of vasodilatation. currently, beta-blockers are employed in a number of cardiovascular conditions. The strongest evidence for their use (evidence level A) is in systolic heart failure, post- myocardial infarction (myocardial protection) and in prevention and treatment of ventricular arrhythmias in post MI patients. In acute myocardial infarction, current recommendation (based on cOMMIT/ccS-2 trial) are to avoid early use of beta blockers in patients with hemodynamic instability or who are at risk of cardiogenic shock. Once stable, beta blockade is strongly recommended in patients of myocardial infarction. beta-blockers are not currently favoured as the first line anti-hypertensive therapy, particularly in the elderly, unless there are specific indications.

6 For patients undergoing non-cardiac surgery, risk stratification should be performed, and beta-blockers prescribed to patients at high cardiac 110 : 3 Generations of beta-blockersPropertiesdrugs1st GenerationNon-selectiveNo vasodilatationPropranolol, Timolol, Pindolol, Nadolol, Sotalol2nd Generation 1-selective without vasodilation 1selective with vasodilationAtenolol, bisoprolol, MetoprololNebivolol, Acebutolol3rd Generation Non-selective with vasodilationcarvedilol, bucindolol8 SUPPLEMENT OF JAPI dEcEMbEr 2009 VOL. 57leads to positive chronotropic effect. Accelerated conduction a c r o s s AV N a n d c o n d u c t i o n t i s s u e c a u s e s t h e p o s i t i v e dromotropic Uses of beta-blockers Indications for use are listed in Table no. 2 Heart failure (HF) beta-blockers are now the cornerstone of systolic heart failure therapy. The mechanisms involved are summarized in Table meta-analyses of beta-blocker trials have conclusively shown that beta-blocker use is associated with a consistent 30% reduction in mortality, 40% reduction in hospitalizations and 38% reduction in sudden death in patients with chronic heart ,12 It was estimated that 26 patients would need to be treated to avoid one Table 4 depicts the trials of beta-blockers in heart use: Patients are stabilized first (no acute or recent deterioration.)

7 No volume overload) and then evidenced-based beta-blockers (carvedilol, metoprolol succinate XL, bisoprolol and nebivolol) are slowly introduced and gradually Myocardial Infarction (MI)beta blockers significantly reduce morbidity and mortality in patients with acute t u d i e s i n t h e Pre - t h ro m b o l y t i c e ra s h owe d a 1 0 - 1 5 % mortality benefit with beta-blockers in acute ,15 and benefits were confirmed in studies performed in the reperfusion era (upto 40% reduction in mortality).16,17beta- blockers reduced the odds of death by 23%.16 retrospec tive analysis of the cAdILLAc trial showed that beta-blockers were also beneficial in patients undergoing primar y In the PcI era however, the large Table 2 : Indications for use of beta-blockers (in cardiovascular Medicine )Strongly indicated(level A)Systolic heart failurePost MIVentricular arrhythmias (Post MI)Other indications(level b)Other arrhythmiasSTEMI, UA/NSTEMI/chronic stable anginaHypertensionHypertrophic cardiomyopathyMitral stenosis, MVPdissecting aortic aneurysmMarfan s syndrome (aortic root involvement)Neurocardiogenic syncopeFallot s tetralogyInherited arrhythmogenic disorders(LQTS, cPVT)Table 310 : Mechanism of beta-blockade in heart failure Upregulation of receptors and improved adrenergic signaling.

8 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-apoptosis. 2 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 inhibitorsTable 4 : Heart failure trialsTrialAgentNF. up periodPr. End PtresultsMdc (1993)MetoprololTartrate38312-18 monthsdeathEF increasecIbIS (1994)bisoprolol vs Placebo34123 monthsdeath20% P= carvedilolHFTrial program (1996)carvedilol10946 monthsdeath65% cIbIS II (1999)bisoprololVs Placebo264716 monthsdeath34% MErIT HF(2000)Metoprolol cr/cL vs Placebo399112 monthsdeath34% bEST(2001)bucindolol vs Placebo27082 yearsdeath10% cOPErNIcUS (2001)carvedilol vs Placebo228910 monthsdeath35% cAPrIcOrN (2001)carvedilol vs yrsdeath or cV hospitalization8% cOMET (2003)carvedilol vs Metoprolol302958 monthsdeath17% SENIOrSNebivolol vs Placebo212821 monthsdeath or cV admission14 % cO M M I T /ccS - 2 1 9 M e to p ro l o l t r i a l fo u n d n o d i f fe re n ce i n mor tality and no difference in the composite end point of death, re-infarction and VF between metoprolol and placebo groups.

9 Mor tality was increased in Patients presenting with hemodynamic recommendations are to avoid early (<24 hr) beta-blocker use in patients with hemodynamic instability, or risk of cardiogenic shock (age > 70 yrs, systolic blood pressure <120 mmHg, heart rate >110 bpm, killip class III on presentation). Early metoprolol can be given in the setting of ongoing ischaemia with tachycardia or Myocardial Protectionbeta-blocker use in Post MI patients reduces c V events by 23% in prospective studies and upto 40% in observational ,20 The benefits are greatest in patients at high risk20 ( a d va n ce d a g e, LV d ys f u n c t i o n , l a rg e a nte r i o r i n f a rc t i o n , complex ventricular ectopy). In fact, the only medications proven to reduce Scd in Post MI patients are beta blockers . 42 patients treated for 2 years prevents 1 death.

10 The number needed to treat to achieve mortality reduction in post MI patients is fewer for beta-blockers when compared with antiplatelets or As noted earlier, early(<24 hr) use is avoided per the cOMMIT/ccS-2 trial. The SAVE trial21 demonstrated that AcE inhibitors and beta-blockers are additive in reducing post MI also confer a survival benefit in patients with cOPd, dM and peripheral vascular ,23 cardio-selective beta blockers (bisoprolol most cardioselective) are tolerated and effective in patients with mild pulmonary disease, although no beta-blocker is completely safe in bronchial of diabetic subgroups in several Post MI beta-blocker trials demonstrate overall benefit of beta blocker use. Similarly, cardio -selec tive beta blockers do not worsen claudication symptoms and in fact improve survival in patients with PAd. 24cur rent recommendations are that beta-blockers must SUPPLEMENT OF JAPI dEcEMbEr 2009 VOL.