Cardiac drug therapy humana press (2015)

Thus, supply and dosage are given first, followed by action and pharma-cokinetics, and then advice as to efficacy and comparison with other drugs, indications, adverse effects, and inter

Contemporary Cardiology Series Editor: Christopher P Cannon

M Gabriel Khan

Cardiac

Drug Therapy

8th Edition

Cardiac Drug Therapy

8th Edition

ISSN 2196-8969 ISSN 2196-8977 (electronic) ISBN 978-1-61779-961-7 ISBN 978-1-61779-962-4 (eBook) DOI 10.1007/978-1-61779-962-4

Springer Totowa Heidelberg New York Dordrecht London

Library of Congress Control Number: 2014952818

© Springer Science+Business Media New York 2015

This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or

in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed Exempted from this legal reservation are brief excerpts

in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer Permissions for use may be obtained through RightsLink at the Copyright Clearance Center Violations are liable to prosecution under the respective Copyright Law

The use of general descriptive names, registered names, trademarks, service marks, etc

in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use

While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made The publisher makes

no warranty, express or implied, with respect to the material contained herein Printed on acid-free paper

Humana Press is a brand of Springer

Springer is part of Springer Science+Business Media ( www.springer.com )

University of Ottawa

The Ottawa Hospital

Ottawa , ON , Canada

evi-of his own recommendations even when these tions are at odds with those of official bodies In such situa-tions the ‘official’ recommendations are also stated but clearly are not preferred.”

And for the fourth edition a cardiologist reviewer states that it is “by far the best handbook on cardiovascular thera-peutics I have ever had the pleasure of reading The informa-tion given in each chapter is up-to-date, accurate, clearly written, eminently readable and well referenced.”

The entire text has been revised and, most importantly, tinues to give practical clinical advice New chapters include:

con-• Endocrine Heart Diseases

• Management of Cardiomyopathies

• Newer Agents

A new feature involves diagnosis

• Because appropriate therapy requires sound diagnosis the short sections on diagnosis given in previous editions have been expanded

Other highlights include:

• Chapter 11 : “Acute Myocardial Infarction ” contains more

than 24 relevant ECG tracings; an echocardiogram depicting Takotsubo syndrome is shown to remind readers that this syndrome mimics acute MI

• Chapter 14 : “Management of Cardiac Arrhythmias” vides more than 24 ECG samples

pro-• Chapter 22 : “Hallmark Clinical Trials ” has been expanded

to accommodate the wealth of practical information derived from recent randomized clinical trials

As in all previous editions, therapeutic strategies and advice are based on a thorough review of the scientific lit-erature, applied logically:

• Scientific documentation regarding which drugs are superior

• Information on which cardiovascular drugs to choose and which agents to avoid in various clinical situations

• Information that assists with the rapid writing of tions To write a prescription accurately, a practitioner needs

prescrip-to know how a drug is supplied and its dosage Thus, supply and dosage are given first, followed by action and pharma-cokinetics, and then advice as to efficacy and comparison with other drugs, indications, adverse effects, and interactions

The text contains practical advice, such as the following:

The life-saving potential of 160–240 mg chewable aspirin is

denied to many individuals who succumb to an acute nary syndrome because of poor dissemination of clinically proven, documented facts The text advises: three ~80 mg

coro-chewable aspirins should be placed in the cap of a

nitrolin-gual spray container to be used before proceeding to an emergency room Clinicians should inform patients that rapidly acting chewable aspirin may prevent a heart attack

or death but that nitroglycerin does not The world faces an

epidemic of heart failure [HF]

Although medical therapy for acute HF has improved dramatically from 1990, unfortunately more than 50 % of patients require readmission within 6 months of discharge Several of these patients are not administered appropriate medications to prevent a recurrence The chapter on heart failure gives practical advice as do other chapters on what drugs are best for a given situation

Notable physicians have stated that the beta-blockers should not be prescribed for primary hypertension because of their ineffectiveness Many investigators have reported in peer-reviewed journals that diuretics and beta-blockers cause diabetes and their use should be restricted for the manage-ment of hypertension Chapter 2 discusses these controver-sies and gives clear answers to clinicians worldwide

The information provided in the eighth edition should serve as a refresher for cardiologists and internists The information should improve the therapeutic skills of interns, medical residents, generalists, and all who care for patients with cardiac problems

I have quoted the published works of several tors These persevering women and men of medicine deserve my respect and my thanks

A special, thank you, to my wife Brigid, who has allowed

me to be a student of the science of Medicine to this day

1 Beta-Blockers: The Cornerstone

of Cardiac Drug Therapy 1

This chapter tells you 1

Beta-Blockers and Cardioprotection 2

Beta-Receptors 6

Mechanism of Action 9

Other Important Clinically Beneficial Mechanisms 10

Beta-Blocker Effect on Calcium Availability 10

Dosage Considerations 11

Pharmacologic Properties and Clinical Implications 14

Cardioselectivity 14

Intrinsic Sympathomimetic Activity 18

Membrane-Stabilizing Activity 19

Effects on Renin 19

Lipid Solubility 20

Plasma Volume 20

Hepatic Metabolism 21

Effects on Blood and Arteries 21

Effect on Serum Potassium 22

Salutary Effects of Beta-Adrenergic Blockade 23

Beta-Blockers Versus Calcium Antagonists

and Oral Nitrates 24

Indications for Beta-Blockers 26

Angina 26

Arrhythmias 26

Acute Myocardial Infarction 29

Elective Percutaneous Coronary Intervention (PCI) 29

Heart Failure 31

Prolonged QT Interval Syndromes 33

Dissecting Aneurysm 33

Mitral Valve Prolapse 34

Mitral Regurgitation and Mitral Stenosis 34

Tetralogy of Fallot 34

Hypertrophic Cardiomyopathy 34

Marfan’s Syndrome 35

Subarachnoid Hemorrhage 36

Perioperative Mortality 36

Neurocardiogenic Syncope (Vasovagal/ Vasodepressor Syncope) 38

Diabetic Patients 39

Chronic Obstructive Pulmonary Disease 39

Noncardiac Indications 41

Advice and Adverse Effects 41

Warnings 41

Side Effects 43

Individual Beta-Blockers 44

Dosage (Further Advice) 47

Action 48

Indications 48

Dosage (Further Advice) 49

Action 50

Indications 50

Dosage (Further Advice) 52

Indications 56

Indications 57

Contraindications 58

Which Beta-Blocker Is Best

for Your Patients? 58

References 61

2 Beta-Blocker Controversies 69

Beta-Blockers Are not a Good Initial Choice for Hypertension: True or False? 69

Beta-Blockers Are not Recommended for Treatment of Elderly Hypertensives: True or False? 73

Beta-Blockers Cause Genuine Diabetes Mellitus: True or False? 74

Do all Beta-Blockers Cause Benign Glucose Intolerance? 78

Beta-Blockers Should not Be Given to Patients During the Early Hours of Acute Mi: True or False? 79

References 80

3 Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers 85

Mechanism of Action 86

ACE Inhibitors Versus Other Vasodilators 93

Clinical Indications 94

Hypertension 94

Heart Failure 97

Acute Myocardial Infarction 100

Renoprotection 101

Coarctation of the Aorta 104

Pulmonary Hypertension 105

Scleroderma Renal Crisis 105

Bartter’s Syndrome 105

ACE Inhibitors/ARBs and Diabetes 105

Contraindications 106

Advice, Adverse Effects, and Interactions 107

Hypotension 107

Renal Failure 107

Hyperkalemia 107

Cough 107

Loss of Taste Sensation 108

Angioedema 108

Rash 109

Proteinuria 109

Neutropenia and Agranulocytosis 109

Mild Dyspnea and/or Wheeze 109

Anaphylactoid Reactions 109

Uncommon Adverse Effects 110

Interactions 110

Individual ACE Inhibitors 110

Pharmacologic Profile and Individual Differences 110

Subtle Differences 110

Hypotension 111

Dosage (Further Advice) 112

Pharmacokinetics 112

Dosage (Further Advice) 113

Pharmacokinetics 114

Dosage (Further Advice) 115

Pharmacokinetics 115

Dosage (Further Advice) 116

Angiotensin II Receptor Blockers 119

Clinical Trials 120

References 124

4 ACE Inhibitor ARB Controversies 129

ACE Inhibitors Versus ARBs: Does the Choice Matter? 129

ACE Inhibitors/ARBs Cause Renoprotection: True or False? 132

ACE Inhibitors Decrease the Incidence of Diabetes: True or False? 134

Combination of ACE Inhibitor and ARB Proven Effective: True or False? 135

References 136

5 Calcium Antagonists

(Calcium Channel Blockers) 139

Mechanism of Action 140

Action 143

Adverse Effects and Interactions for DHPs 144

Action 147

Adverse Effects and Interactions 147

Action 149

Advice, Adverse Effects, and Interactions 150

Dosage (Further Advice) 153

Indications for Calcium Antagonists 153

Hypertension 153

Stable Angina 154

References 158

6 Calcium Antagonist Controversies 161

Calcium Antagonists Cause an Increased Incidence of HF and MI: True or False? 161

Newer Calcium Antagonists Are Better Than Older Agents: True or False? 162

Are Calcium Antagonists Safe for Hypertensives with CAD? 163

INVEST 163

CONVINCE 164

References 166

7 Diuretics 167

Indications 170

Hypertension 170

Heart Failure 171

Thiazides 172

Loop Diuretics 174

Mechanism of Action 174

Dosage (Further Advice) 175

Action and Pharmacokinetics 175

Potassium-Sparing Diuretics 179

Advantages 182

Disadvantages 183

Combination of a Thiazide or Furosemide and Potassium-Sparing Diuretic 185

Other Diuretics 186

Potassium Chloride Supplements 187

Potassium Chloride 190

Salt Substitutes 190

Further Advice 192

Torsemide 192

Aldosterone Antagonists 192

References 195

8 Hypertension 199

Relevant Key Issues 199

Controversies 205

Definitions 206

Isolated Systolic Hypertension in Older Patients 206

Pseudohypertension 207

Home Measurements 208

Nondrug Therapy 208

Which Drugs to Choose 209

Recommendations for Patients Without Coexisting Disease 210

Therapy for Patients with Coexisting Diseases 220

Beta-Blockers 223

Dosage 223

Action of Beta-Blockers 224

Diuretics 227

Action 227

Use Proven in Elderly 229

Chlorthalidone 231

ACE Inhibitors and Angiotensin II Receptor Blockers 234

Adverse Effects and Interactions 236

Contraindications 237

Dosage (Further Advice) 238

ACE Inhibitor-Diuretic Combination 239

Calcium Antagonists 240

Alpha1-Blockers 243

Centrally Acting Drugs 244

Resistant Hypertension 244

Cathetehr-Based Radiofrequency Renal Denervation 246

Hypertensive Crisis 247

Action and Metabolism 250

Advice, Adverse Effects, and Interactions 250

References 253

9 Hypertension Controversies 261

Beta-Blockers Should Not Remain First Choice in the Treatment of Primary Hypertension: True or False? 261

Conclusion 268

Diabetic Risk with Beta-Blockers and Diuretics 269

An Increased Risk: True or False? 269

Hypertensive Agents Increase Heart Failure Risk: True or False? 271

Age and Ethnicity Hold the Key for Drug Choice 272

References 278

10 Angina 283

Salient Clinical Features 283

Pathophysiologic Implications 284

Treatment of Stable Angina 285

Beta-Adrenoceptor Blocking Agents 286

Cardioprotection and Dosage of Beta-Blocker 290

Contraindications to Beta-Blockers 290

Combination of Beta-Blockers

and Calcium Antagonists 292

Nitrates 292

Cutaneous Nitroglycerins 293

Cutaneous Nitrates 295

Indications 298

Aspirin 299

Ranolazine 301

Consider Interventional Therapy 303

Management of Unstable Angina 303

Investigations 303

Medications 304

Statins 306

Variant Angina (Prinzmetal’s) 306

References 307

11 Myocardial Infarction 311

Overview 311

TRIGGERS for ACS 313

DIAGNOSIS 314

Electrocardiographic Features 317

Inferior MI Diagnosis 317

Anterior MI Diagnosis 317

ECG Mimics of Acute Myocardial Infarction 320

Therapy 330

Pain Relief 332

Percutaneous Coronary Intervention 334

Clopidogrel 335

Prasugrel 335

Ticagrelor (BRILINTA; Brilique in UK) 336

Thrombolytic Therapy 339

The incidence of ICH in RCTs was reported as follows 341

Contraindications 341

Streptokinase [Kabikinase, Streptase] 342 Tenecteplase 343 Enoxaparin 343 Fondaparinux 344 Beta-Blockers 345 ACE Inhibitors 348 NITRATES 349 STATINS 350 Management of Complications

of Infarction 350 Arrhythmias 350 Heart Failure 353 Right Ventricular Infarction 354 Cardiogenic Shock 354 Management 355 Early Reperfusion 356 Management of Non-ST-Elevation

Myocardial Infarction 357 Conservative Generally Preferred

[angiogram 24–36 h] 360 Medications on Discharge 360 References 361

12 Heart Failure 369

The Size of the Problem 369 Causes of Heart Failure 372 Basic Cause 372 Diagnosis 376 Pathophysiology 379 Management Guide 381 Vasodilators 382 ACE Inhibitors/Angiotensin II

Receptor Blockers 382 Angiotensin-Receptor Blockers 387 Transcend (2008) 388

Hydralazine 389 Calcium Antagonists 389 Amlodipine 389 Diuretics 389 Indications and Guidelines 389 Aldosterone Antagonists 390 Beta-Blockers 393 Inotropic Agents 399 Digoxin Studies 399 Dosage Considerations 405 Symptoms of Toxicity 409 Beta-Stimulants 412 New Developments 413 Spironolactone 413 Istaroxime 413 Omecamtiv mecarbil 414 SERCA2a 413 Serelaxin 414 Rosuvastatin 415 LCZ696 415 Management of Pulmonary Edema 415 References 417

13 Heart Failure Controversies 423

Are ARBs as Effective as ACE Inhibitor

Therapy for Heart Failure? 423 Management of Heart Failure Preserved

Ejection Fraction 424 Treatment 426 Digoxin Is Not Useful for HFPEF:

True or False? 427

Is CHARM-Preserved a Clear Study

of HFPEF? 427 Does an ACE Inhibitor Combined

with an ARB Improve Outcomes? 428 Heart Failure in Blacks:

Do Differences Exist? 429

Are Statins Recommended

for Patients with Heart Failure? 429 References 430

14 Arrhythmias 433

Classification 434 Diagnosis of Arrhythmias 435 Arrhythmias with Narrow QRS

Complex 437 Arrhythmias with Wide QRS

Complex 437 Management of Supraventricular

Disorders 472 Wolff–Parkinson–White Syndrome 472 Ventricular Arrhythmias 477 Premature Ventricular Contractions:

Benign Arrhythmias 477 Ventricular Tachycardia 478 Fatal Ventricular Arrhythmias 478 Antiarrhythmic Agents 481

Class IA 481 Advice, Adverse Effects, and Interactions 483 Class IB 486 Class IC 488 Class II 490 Class III 492 Adverse Effects 494 References 496

15 Cardiac Arrest 503

“Time Is of the Essence” 503 Two Cardiac Rhythms 505 Basic Life Support 507 Defibrillation 510 Drug Therapy 512 Asystole and Pulseless Idioventricular

Rhythms 514 Isoproterenol Is Contraindicated

in the Treatment of Cardiac Arrest 514 Beta-Blockers 514 References 514

16 Infective Endocarditis 517

Classification and Diagnosis 518 Diagnostic Guidelines 518 Therapy 522

S aureus Endocarditis 523

Prosthetic Valve Endocarditis 525 Native Valve Endocarditis Caused by

Staphylococci 525 Native Valve Endocarditis 525 Prosthetic Valve Endocarditis Caused

by Susceptible S viridans or S bovis

Infections 526 Other Bacteria Causing IE 528 Right-Sided Endocarditis 528 Fungal Endocarditis 530

Heart Failure Complicating Endocarditis 532 Prophylaxis of Bacterial Endocarditis 533 Older Regimen Acceptable to Many 535 References 538

17 Dyslipidemias 541

Diagnosis 541 Fasting or Non-fasting LDL-C? 541 Conversion Formula for mg to mmol 543 Secondary Causes of Dyslipidemias 543 Dietary Therapy 545 Drug Therapy 547 Statins 549 Statins Possess Subtle Differences 550 Advice and Adverse Effects 550 Nicotinic Acid 561 Adverse Effects and Interactions 562 Fibrates 563 HDL Lowering 565 Evacetrapib 565 References 566

18 Endocrine Heart Diseases 571

Acromegaly 571 Management 571 Carcinoid Syndrome 572 Cushing’s Syndrome 573 Diabetes and the Heart 573 Which Cardiovascular Drugs Are Best

ACE Inhibitors/ARBS? 574 Beta-Blockers Underused in Diabetics 574 Aspirin 575 Dyslipidemia in Diabetics 575 Blood Pressure Control 576 Oral Diabetic Agents 577 Metformin 577 Sulfonylurea 578

Thiazolidinediones 579 Acarbose (Glucobay) 579 Dipeptidyl Peptidase-4 (DPP-4)

Inhibitors (Gliptins) 580 Hyperaldosteronism 581 Pheochromocytoma 581 Hyperthyroidism 586 Cardiac Disturbances 586 Hypothyroidism 588 Cardiac Involvement 588 References 588

19 Antiplatelet Agents, Anticoagulants,

Factor Xa Inhibitors, and Thrombin

Inhibitors 593

Antiplatelet Agents 593 Historical Review 597 Actions 599 Aspirin Resistance 601 Indications 602 Platelet Glycoprotein IIb/IIIa

Receptor Blockers 608 Anticoagulants 610 Low-Molecular-Weight Heparin 612 Specific Thrombin Inhibitors 613 Factor Xa Inhibitors 615 References 618

20 Cardiac Drugs During Pregnancy

and Lactation 623

Antihypertensive Agents in Pregnancy 623 Methyldopa 625 Calcium Antagonists 631 ACE Inhibitors 632 Magnesium Sulfate 632 Aspirin 633 Drug Therapy for Heart Failure 634 Diuretics 636

Antiarrhythmics in Pregnancy 636 Adenosine 636 Beta-Adrenergic Blockers 637 Disopyramide 637 Lidocaine 637 Cardiac Drugs During Lactation 638 References 642

21 Drug Interactions 645

Interactions of Cardiovascular Drugs 646 ACE Inhibitors/ARBs 646 Antiarrhythmic Agents 649 Adenosine 649 Amiodarone 649 Disopyramide 651 Flecainide 651 Lidocaine or Lignocaine 651 Mexiletine 652 Phenytoin 652 Propafenone 652 Procainamide 652 Quinidine 653 Antiplatelet Agents/Anticoagulants 653 Beta-Blockers 654 Calcium Antagonists 655 Digoxin 658 Diuretics 658 Nitrates 659 Lipid-Lowering Agents 660 Statins 660 Interactions of Cardiac and Noncardiac

Drugs 660 Antibiotics 660 Antimalarials 663 Anticonvulsants 663 Cyclosporine 663 Lithium 664

Nonsteroidal Anti-inflammatory Drugs 664 Psychotropic Agents 664 Theophylline 665 Thyroxine 665 Cardiac Effects of Noncardiac Drugs 667 Antibiotics 667 Antimalarials 667 Histamine H 1 Antagonists 667 Antidepressants 669 Cancer Chemotherapeutic Agents 670 Other Agents 670 References 673

22 Hallmark Clinical Trials 675

Acute Coronary Syndrome RCTs 676 ATLAS ACS 2–TIMI 51: Rivaroxaban

for ACS 676 Bivalirudin for ACS 677 LMWH and Major Bleeding Advice 681

IV Metoprolol Studies 689

COMMIT/CCS-2: Second Chinese

Cardiac Study (CCS-2) (31) 690 The METOCARD-CNIC 691 Aspirin for Cardiovascular Disease

Prevention 692 Aspirin Pseudoresistance 692Angina RCTs 692PCI Versus Optimal Medical Therapy 692Carvedilol in Postinfarct Patients 694Atrial Fibrillation RCTs 694Lenient Rate Control 694Rate Versus Rhythm Control in

Atrial Fibrillation 695Newer Anticoagulants for Reduction

in Stroke 696RE-LY 2010: Dabigatran Versus

Warfarin in Patients with

Atrial Fibrillation 696

Colchicine for Cardiovascualr Disease 698Colchicine for Stable Coronary

Artery Disease 698Colchicine for pericarditis 699Colchicine for Post-op Atrial

Fibrillation 699Heart Failure RCTs 701COPERNICUS 2001: Carvedilol

in Severe Chronic HF 701Heart Failure Trials 702MERIT-HF 2000: Metoprolol CR/XL

in Chronic Heart Failure 702The Seniors Study: Nebivolol

for Heart Failure 702Aldosterone Antagonist Trials 703ACE Inhibitors and ARB RCTs 704PRoFESS 2008: Telmisartan

to Prevent Recurrent Stroke 707Hypertension Trials 709ALLHAT 2002 709Nebivolol Combined with

Valsartan Study 710Dyslipidemia RCTs 712Early and Late Benefits of High-Dose

Atorvastatin 712Arrhythmia RCTs 718AFFIRM (2002): Rate Versus Rhythm

Control in Atrial Fibrillation 718Beta-Blockers And Diabetes 718GEMINI (2004): Beta-Blockers

for Hypertensive Diabetics 718Clopidogrel 719PCI-Clarity: Clopidogrel Before PCI 719Folic Acid/B6, B12 720HOPE-2: Homocysteine Lowering 720 References 721

23 Management of Cardiomyopathies 729

Hypertrophic Cardiomyopathy 729 Pathophysiology 730 Clinical Diagnosis 731 Therapy 735 Implantable Cardioverter-Defibrillators 738 Risk Factors for Sudden Death

and Guide for ICD Include 738 Dilated Cardiomyopathy 739 Diagnosis 739 Physical Signs 740 Echocardiogram 741 Therapy 741 Restrictive Cardiomyopathy 744 Clinical Features 745 Therapy 748 Peripartum Cardiomyopathy 748 Treatment 749 References 750

24 Newer Agents 755

Apixaban 755 Rivaroxaban 757 Dabigatran 758 Edoxaban 760 Conclusion 760 Omecamtiv Mecarbila 761 Celivarone 761 Dronedarone 762 Nebivolol 763 Prasugrel [Efient IN UK] 763 Ticagrelor [Brilinta; Brilique in UK] 764 Cangrelor 765 Evacetrapib 765 References 766

Index 769

Dr M Gabriel Khan is a cardiologist at the Ottawa Hospital and an Associate Professor of Medicine, at the University of Ottawa Dr Khan graduated MB, BCh, with First-Class Honors at The Queen’s University of Belfast He obtained, by thesis, the Degree of Doctor of Medicine with Honors [QUB]

Gabriel is a clinical Professor who loves teaching and was appointed Staff Physician in charge of a Clinical Teaching Unit at the Ottawa General hospital and is a Fellow of the American College of Cardiology, the American College of Physicians, and the Royal College of Physicians

of London and Canada

He is the author of Encyclopedia of Heart Diseases

(2006), Academic Press/Elsevier; Encyclopedia of Heart Diseases , 2nd ed., Springer, New York Online 2011; Rapid ECG Interpretation , 3rd ed., Humana Press New York 2008;

Cardiac Drug Therapy , 7th ed., Humana Press 2007; On

Call Cardiology , 3rd ed., Elsevier, Philadelphia (2006);

Heart Disease Diagnosis and Therapy , 2nd ed., Humana Press (2006); Cardiac and Pulmonary Management (1993); Medical Diagnosis and Therapy (1994); Heart Attacks, Hypertension and Heart Drugs (1986); and Heart Trouble Encyclopedia (1996)

Dr Khan’s books have been translated into Chinese, Czech, Farsi, French, German, Greek, Italian, Japanese, Polish, Portuguese, Russian, Spanish, and Turkish He has built a reputation as a clinician-teacher and has become an internationally acclaimed cardiologist through his writings Here is an excerpt from the foreword, written by a renowned cardiologist and author, Dr Henry J L Marriott

for the book, Heart Disease Diagnosis and Therapy :

Whenever I read Khan, I am affected as the rustics were by Oliver Goldsmith’s parson:

And still they gaz’d, and still the wonder grew

That one small head could carry all he knew

Khan’s knowledge is truly encyclopedic and, for his fortunate readers, he translates it into easily read prose

His peers have acknowledged the merits of his books by

their reviews of Cardiac Drug Therapy, the Encyclopedia of

Heart Diseases, and Rapid ECG Interpretation

© Springer Science+Business Media New York 2015

M Gabriel Khan, Cardiac Drug Therapy, Contemporary Cardiology,

DOI 10.1007/978-1-61779-962-4_1

Beta-Blockers

The Cornerstone of Cardiac Drug Therapy

THIS CHAPTER TELLS YOU

• Which beta-blocker is best for your patients

The pharmacodynamic reasons why atenolol is a relatively ineffective beta-blocker and why the vast worldwide use of atenolol should be curtailed

• More about the important indication for heart failure (HF), for New York Heart Association (NYHA) class II and III and compensated class IV, and for all with left ventricular (LV) dysfunction regardless of functional class; thus, in class I patients with an ejection fraction (EF) <40 % and in those with myocardial infarction (MI) with HF or LV dys-function without HF, beta-blockers are recommended at the same level as angiotensin-converting enzyme (ACE) inhibi-tors Beta-blockers are the mainstay of therapy for heart failure They decrease total mortality, an effect only modestly provided by ACE inhibitors, and marginally by angiotensin receptor blockers [ARBS] See discussion under ARBs

• Why beta-blockers should be recommended for diabetic patients with hypertension with or without proteinuria and

for diabetic patients with coronary heart disease (CHD) From about 1990 to 2007, most internists proclaimed in editorials and to trainees that these agents were a poor choice in this setting

1

• More recently, their use as initial agents for the treatment of primary hypertension has been criticized, particularly for diabetics with hypertension; do beta-blocking drugs cause diabetes or is the condition observed, simply, benign glu-

cose intolerance in some? (see Chap 2 )

• Why is it incorrect to say that beta-blockers are not able for hypertensive patients over age 70, as many teach-

advis-ers, textbooks, and editorials state

• The results of randomized clinical trials (RCTs) that prove the lifesaving properties of these agents

• All their indications

• Salient points that relate to each beta-blocker and show the subtle and important differences confirming that beta- blockers are not all alike Beta-blockade holds the key, but lipophilic vs hydrophilic features may be important, and brain concentration may enhance cardioprotection

BETA-BLOCKERS AND CARDIOPROTECTION

Sufficient attention has not been paid by the medical fession and researchers regarding the subtle differences that exist amongst the available beta-blocking drugs (Khan

pro-2005 ) The subtle differences in beta-blockers may provide the solution for the apparent lack of protection of some beta- blockers ( Khan and Topol 1996 )

• The common threads for enhanced cardioprotection are beta1, beta2, and lipophilicity that augment brain concentra-tion and may protect from sudden death In the timolol study, there was a 67 % reduction in sudden death (The Norwegian Multicenter Study Group 1981 )

• Timolol is non-cardioselective and lipophilic No other diovascular agent has produced such an outstanding reduc-tion in cardiac sudden deaths, yet the drug is rarely prescribed worldwide

car-• Propranolol, a beta1, beta2 lipophilic drug, caused a 56 % decrease in early morning sudden death from acute myocar-dial infarction [MI]; see later discussion of BHAT ( 1982 ), and Peters et al ( 1989 )

• Atenolol, a non-lipophilic agent, has been the most scribed beta-blocker in the USA and worldwide from 1980

pre-to 2007 with more than 44 million prescriptions in the USA annually The drug is a poorly effective beta-blocker and its use should become obsolete Unfortunately, investigators and trialists not noticing the subtle differences that exist among the beta-blocking drugs have used atenolol in the majority of large RCTs of hypertension conducted from

1980 to the present time (see Beta-Blocker Hypertension Controversy) Lindholm et al ( 2005 ) from a meta-analysis

of hypertension RCTs without regard for beta-blockers’ subtle differences described above reached a conclusion, which was printed on the front cover of the Lancet: “beta- blockers should not remain first choice in the treatment of primary hypertension” (Lindholm et al 2005 ) Atenolol was the beta-blocker used in the majority of RCTs analyzed by Lindholm et al

• A rebuttal stated, “by lumping together all randomized hypertension trials involving beta-blockers, Lars Lindholm and colleagues have arrived at misleading conclusions” ( Cruickshank 2000 ) But rebuttals are observed by few cli-nicians Many notable physicians have endorsed the find-ings of Lindholm and colleagues and the misleading information has been disseminated worldwide

• Lipophilicity allows a high concentration of drug in the brain This appears to block sympathetic discharge in the hypothalamus and elevate central vagal tone to a greater extent than water-soluble, hydrophilic agents (Pitt 1992 ) This may relate to the prevention of sudden cardiac death Highly lipid-soluble, lipophilic beta-blockers—carvedilol, propranolol, nebivolol, timolol, and metoprolol—reach high concentrations in the brain and are metabolized in the liver

• Atenolol, nadolol, and sotalol are lipid insoluble, show poor brain concentration, and are not hepatic metabolized; they are water soluble, are excreted by the kidneys, and have a long half-life Pindolol and timolol are about 50 % metabo-lized and about 50 % excreted by the kidney Importantly, brain :plasma ratios are ~15:1 for propranolol and timolol, 3:1 for metoprolol, and 1:8 for atenolol

• Lipid-soluble beta-blocking agents with high brain concentration block sympathetic discharge in the hypothala-mus better than water-soluble agents (Pitt 1992 ) and they are more effective in the prevention of cardiac deaths Bisoprolol

is 50 % lipophilic and liver metabolized but does not involve the cytochrome P-450 3A4 pathway Nebivolol is highly lipophilic Propranolol and metoprolol have high first-pass liver metabolism Acebutolol is metabolized to an active metabolite diacetolol, which is water soluble and is excreted

by the kidneys Atenolol, nadolol, and sotalol are not olized in the liver First- pass metabolism varies greatly among patients and can alter the dose of drug required, espe-cially with propranolol

metab-• Cigarette smoking interferes with drug metabolism in the liver and reduces the efficacy of propranolol, other hepati-cally metabolized beta-blockers, and calcium antagonists (Deanfield et al 1984 )

Beta-blockers are now recommended and used by ally all cardiologists because they are necessary for the management of acute and chronic ischemic syndromes, manifestations of CHD

Many internists and family physicians, however, remain reluctant to prescribe beta-blockers in many cardiovascular situations including HF, in hypertension in patients aged

>65 years, and in diabetic patients

Fears that beta-blockers influence lipid levels ably are unfounded Beta-blocking drugs do not alter low- density lipoprotein (LDL) levels; they may cause a mild increase in levels of triglycerides and may produce

unfavor-a 1 % to ~ 6 % lowering of high-density lipoprotein lesterol (HDL-C) in fewer than 10 % of patients treated

(3) The alteration in HDL-C levels is of minimal clinical

concern because the effect is so small, if it occurs at all (Frishman 1997 ) The clinical importance of this mild disturbance in lipid levels is of questionable significance and should not submerge the prolongation of life and

other salutary effects obtained with the administration of beta-blocking drugs (Fig 1-1 ).

Since their original discovery by Sir James Black at Imperial Chemical Industries in the UK ( Black et al 1964 ) and the introduction of the prototype, propranolol, for the treatment of hypertension in 1964 by Prichard and Gillam ( 1964), more than 12 beta-blocking drugs have become available

Fig 1-1 Salutary effects of beta-adrenergic blockade

The first edition of Cardiac Drug Therapy in 1984 included a table entitled “Beta-blockers: first-line oral drug treatment in angina pectoris” (Table 1-1 ); this table indi-cated the superiority of beta-blockers over calcium antago-nists and nitrates Calcium antagonists were down rated because they decreased blood flow to subendocardial areas;

in addition, in the condition for which they were developed, coronary artery spasm (CAS), they were not shown to decrease mortality This table has never been altered The 1990s have shown the possible adverse effects and potential dangers of dihydropyridine calcium antagonists Dihydropyridines increase the risk of death in patients with unstable angina; these agents are not approved for use in unstable angina in the absence of beta-blockade

The cardiovascular indications for beta-blockers are given in Table 1-2 and allow the author to proclaim that beta-blockers are the cornerstone of cardiac drug therapy

BETA-RECEPTORS

The beta-receptors are subdivided into

• The beta 1 -receptors, present mainly in the heart, intestine, renin-secreting tissues of the kidney, those parts of the eye responsible for the production of aqueous humor, adipose tissue, and, to a limited degree, bronchial tissue

• The beta 2 -receptors, predominating in bronchial and lar smooth muscle, gastrointestinal tract, the uterus, insulin- secreting tissue of the pancreas, and, to a limited degree, the heart and large coronary arteries Metabolic receptors are usually beta 2 In addition, it should be noted that

(a) None of these tissues contains exclusively one subgroup

of receptors

(b) The beta-receptor population is not static, and beta- blockers appear to increase the number of receptors during long-term therapy The number of cardiac beta 2 -receptors increases after beta 1 -blockade ( Kaumann 1991 )

(c) The population density of receptors decreases with age

The beta-receptors are situated on the cell membrane and are believed to be a part of the adenyl cyclase system An ago-

nist acting on its receptor site activates adenyl cyclase to

pro-duce cyclic adenosine-5′-monophosphate, which is believed to

be the intracellular messenger of beta-stimulation

The heart contains beta 1 - and beta 2 -adrenergic receptors

in the proportion 70:30 Normally, cardiac beta -adrenergic

Table 1-1 Beta-blockers: fi rst-line oral drug treatment

in angina pectoris

Effect on

Beta- blocker

Calcium antagonist

Oral nitrate

death

Proven No No Prevention of pain owing

to CAS

No Yes Variable Prevention of death in

patient with CAS

b Distal to organic obstruction (Weintraub et al 1982 )

CAS, coronary artery spasm; ↓, decrease; ↑, increase; –, no significant change