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 Lippincott®
Illustrated Reviews:
Pharmacology
South Asian Edition

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LIR_FM.indd 2 16/10/18 12:12 PM
 Lippincott®
Illustrated Reviews:
Pharmacology
South Asian Edition

Karen Whalen PharmD, BCPS, FAPhA Editors

Clinical Professor Sangeeta Sharma MD (Pharmacology),
Department of Pharmacotherapy and Translational MBA (Health Care Administration)
Research Professor & Head
College of Pharmacy Department of Neuropsychopharmacology
University of Florida Institute of Human Behaviour & Allied Sciences
Gainesville, Florida (IHBAS)
Delhi

Thirumurthy Velpandian PhD

Professor (Pharmacology)
Ocular Pharmacology & Pharmacy Division
Dr. R.P. Centre for Ophthalmic Sciences
All India Institute of Medical Sciences (AIIMS)
New Delhi

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 Sr Publisher: Dr. Binny Mathur
Commissioning Editor: Gagandeep Kaur
Development Editor: Dr. Sahil Handa
Production Editor: Tamali Deb
Asstt. Manager Manufacturing: Sumit Johry

Copyright © 2019 by Wolters Kluwer Health (India)

10th Floor, Tower C, Building No. 10, Phase – II, DLF Cyber City
Gurgaon, Haryana - 122002

All rights reserved. This product, consisting of the printed book, is protected by copyright. No part of this book may be reproduced in any
form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from
the copyright owner.

The publisher is not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material
contained herein. This publication contains information relating to pharmacology that should not be construed as specific instructions
for individual patients. Manufacturers’ product information and package inserts should be reviewed for current information, including
contraindications, dosages, and precautions. All products/brands/names/processes cited in this book are the properties of their respective
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publication. Application of this information in a particular situation remains the professional responsibility of the practitioner. Readers are
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Please consult full prescribing information before issuing prescription for any product mentioned in the publication.

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South Asian Edition

ISBN: 978-93-88313-20-9

Published by Wolters Kluwer (India) Pvt. Ltd., New Delhi

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For product enquiry, please contact– Marketing Department ([email protected]) or log on to our website
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 Contributing Authors
Katherine Vogel Anderson, PharmD, BCACP Zachary L. Cox, PharmD
Associate Professor Associate Professor
Colleges of Pharmacy and Medicine College of Pharmacy
University of Florida Lipscomb University
Gainesville, Florida Heart Failure Clinical Pharmacist
Vanderbilt University Medical Center
Shawn Anderson, PharmD, BCACP Nashville, Tennessee
Clinical Pharmacy Specialist—Cardiology
NF/SG Veterans Medical Center Stacey Curtis, PharmD
Adjunct Clinical Assistant Professor Clinical Assistant Professor
College of Pharmacy College of Pharmacy
University of Florida University of Florida
Gainesville, Florida Gainesville, Florida
Angela K. Birnbaum, PhD Eric Dietrich, PharmD, BCPS
Professor Clinical Assistant Professor
Department of Experimental and Clinical College of Pharmacy
Pharmacology University of Florida
College of Pharmacy Gainesville, Florida
University of Minnesota
Minneapolis, Minnesota Lori Dupree, PharmD, BCPS
Clinical Assistant Professor
Nancy Borja-Hart, PharmD College of Pharmacy
Associate Professor University of Florida
The University of Tennessee Health Science Center Jacksonville, Florida
College of Pharmacy
Nashville, Tennessee Eric F. Egelund, PharmD, PhD
Clinical Assistant Professor
Lindsey Childs-Kean, PharmD, MPH, BCPS College of Pharmacy
Clinical Assistant Professor University of Florida
College of Pharmacy Jacksonville, Florida
University of Florida
Gainesville, Florida Carinda Feild, PharmD, FCCM
Clinical Associate Professor
Jonathan C. Cho, PharmD, MBA Department of Pharmacotherapy and Translational
Clinical Assistant Professor Research
The University of Texas at Tyler College of Pharmacy
Tyler, Texas University of Florida
St. Petersburg, Florida
Michelle Chung, PharmD
Clinical Pharmacy Specialist—Cardiology Chris Giordano, MD
NF/SG Veterans Medical Center Associate Professor
Gainesville, Florida Department of Anesthesiology
College of Medicine
Jeannine M. Conway, PharmD University of Florida
Associate Professor Gainesville, Florida
College of Pharmacy
University of Minnesota Benjamin Gross, PharmD, MBA
Minneapolis, Minnesota Associate Professor
College of Pharmacy
Kevin Cowart, PharmD, MPH, BCACP Lipscomb University
Assistant Professor Nashville, Tennessee
College of Pharmacy Clinical Pharmacist
University of South Florida Maury Regional Medical Group
Tampa, Florida Columbia, Tennessee

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 vi Contributing Authors

Jennifer Jebrock, PharmD, BCPS Kyle Melin, PharmD, BCPS

Liver and GI Transplant Clinical Pharmacist Assistant Professor
Jackson Memorial Hospital School of Pharmacy
Miami, Florida University of Puerto Rico
San Juan, Puerto Rico
Sandhya Jinesh, BPharm, MS, PharmD, RPh
Chief Pharmacist Shannon Miller, PharmD, BCACP
West Haven Pharmacy Clinical Associate Professor
West Haven, Connecticut College of Pharmacy
University of Florida
Jacqueline Jourjy, PharmD, BCPS Orlando, Florida
Clinical Assistant Professor
College of Pharmacy W. Cary Mobley, BS Pharmacy, PhD
University of Florida Clinical Associate Professor
Orlando, Florida College of Pharmacy
University of Florida
Adonice Khoury, PharmD, BCPS Gainesville, Florida
Clinical Assistant Professor
College of Pharmacy Cynthia Moreau, PharmD, BCACP
University of Florida Assistant Professor
UF Health Shands Hospital College of Pharmacy
Clinical Pharmacy Specialist Nova Southeastern University
Gainesville, Florida Fort Lauderdale, Florida
Jamie Kisgen, PharmD Carol Motycka, PharmD, BCACP
Pharmacotherapy Specialist—Infectious Diseases Clinical Associate Professor
Sarasota Memorial Health Care System College of Pharmacy
Sarasota, Florida University of Florida
Jacksonville, Florida
Kenneth P. Klinker, PharmD
Clinical Associate Professor Joseph Pardo, PharmD, BCPS-AQ ID, AAHIVP
College of Pharmacy Infectious Diseases Clinical Specialist
University of Florida North Florida/South Georgia Veterans Health System
Gainesville, Florida Gainesville, Florida
Kourtney LaPlant, PharmD, BCOP Kristyn Pardo, PharmD, BCPS
Clinical Pharmacy Program Manager—Oncology Ambulatory Care Clinical Specialist
Department of Veterans Affairs Department of Pharmacy
Gainesville, Florida North Florida/South Georgia VA Medical Center
Gainesville, Florida
Robin Moorman Li, PharmD, BCACP, CPE
Clinical Associate Professor Charles A. Peloquin, PharmD
College of Pharmacy Professor
University of Florida College of Pharmacy
Jacksonville, Florida University of Florida
Gainesville, Florida
Brandon Lopez, MD
Clinical Assistant Professor Joanna Peris, PhD
Department of Anesthesiology Associate Professor
College of Medicine College of Pharmacy
University of Florida University of Florida
Gainesville, Florida Gainesville, Florida
Paige May, PharmD, BCOP Rajan Radhakrishnan, BPharm, MSc, PhD
Oncology Pharmacy Specialist Professor of Pharmacology
Malcom Randall VA Medical Center College of Medicine
Clinical Assistant Professor Mohammed Bin Rashid University of Medicine and
University of Florida Health Sciences
Gainesville, Florida Dubai, United Arab Emirates

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 Contributing Authors vii

Jane Revollo, PharmD, BCPS Joseph Spillane, PharmD, DABAT

Kidney/Pancreas Transplant Clinical Pharmacist Courtesy Associate Professor
Jackson Memorial Hospital Department of Emergency Medicine
Miami, Florida College of Medicine
University of Florida
Jose A. Rey, MS, PharmD, BCPP Jacksonville, Florida
Professor
Nova Southeastern University Amy Talana, BS, PharmD
Davie, Florida Instructor
Clinical Psychopharmacologist College of Pharmacy
South Florida State Hospital University of Florida
Pembroke Pines, Florida Gainesville, Florida
Karen Sando, PharmD, BCACP, BC-ADM
Associate Professor Thirumurthy Velpandian, PhD
College of Pharmacy Professor (Pharmacology)
Nova Southeastern University Ocular Pharmacology & Pharmacy Division
Fort Lauderdale, Florida Dr. R.P. Centre for Ophthalmic Sciences
All India Institute of Medical
Sangeeta Sharma, MD (Pharmacology), Sciences (AIIMS),
MBA (Health Care Administration) New Delhi
Professor & Head
Department of Neuropsychopharmacology Veena Venugopalan, PharmD
Institute of Human Behaviour & Allied Sciences Clinical Assistant Professor
(IHBAS), Delhi College of Pharmacy
University of Florida
Elizabeth Sherman, PharmD Gainesville, Florida
Associate Professor
Nova Southeastern University Karen Whalen, PharmD, BCPS, FAPhA
Fort Lauderdale, Florida Clinical Professor
HIV/AIDS Clinical Pharmacy Specialist Assistant Dean for Clinical Education
Division of Infectious Disease Department of Pharmacotherapy and Translational
Memorial Healthcare System Research
Hollywood, Florida College of Pharmacy
University of Florida
Shyamal Sinha
Gainesville, Florida
Assistant Professor
Department of Pharmacology
Emily Jaynes Winograd, PharmD
Grant Govt. Medical College &
Clinical Toxicology/Emergency Medicine Fellow
Sir J.J. Group of Hospitals
Florida/USVI Poison Information
Mumbai, India
Center—Jacksonville
Kaylie Smith, PharmD Jacksonville, Florida
Instructor
College of Pharmacy Marylee V. Worley, PharmD, BCPS
University of Florida Assistant Professor
Gainesville, Florida College of Pharmacy
Nova Southeastern University
Dawn Sollee, PharmD Fort Lauderdale, Florida
Assistant Director
Florida/USVI Poison Information Center—Jacksonville Venkata Yellepeddi, BPharm, PhD
Associate Professor Associate Professor
Department of Emergency Medicine Department of Pediatrics
College of Medicine School of Medicine
University of Florida University of Utah
Jacksonville, Florida Salt Lake City, Utah

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 Reviewers
Dr. Shashikant Bhargava
Senior Resident
All India Institute of Medical Sciences (AIIMS),
New Delhi

Nandita Mehta
Third-year UG Student
Vardhman Mahavir Medical College and
Safdarjung Hospital
New Delhi

Illustration and Graphic Design

Michael Cooper
Cooper Graphic
www.cooper247.com

Claire Hess
hess2 Design
Louisville, Kentucky

viii

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 Contents
Contributing Authors…v Chapter 14: Opioid Analgesics...281
Reviewers…viii Robin Moorman Li
Illustration and Graphic Design…viii Chapter 15: CNS Stimulants...299
Jose A. Rey

UNIT I: Principles of Drug Therapy

UNIT IV: Drugs Affecting the
Chapter 1: General Pharmacology,
Pharmacotherapeutics, Cardiovascular System
and Pharmacokinetics...1 Chapter 16: Antihypertensives...309
Venkata Yellepeddi and Benjamin Gross
Sangeeta Sharma
Chapter 17: Diuretics...331
Chapter 2: Pharmacodynamics...57 Zachary L. Cox
Joanna Peris and Sangeeta Sharma
Chapter 18: Drugs for Heart Failure...347
Shawn Anderson
UNIT II: Drugs Affecting the ­Autonomic Katherine Vogel Anderson
Nervous System Chapter 19: Antiarrhythmics...365
Shawn Anderson and Michelle Chung
Chapter 3: Autonomic Nervous System...103
Rajan Radhakrishnan Chapter 20: Antianginal Drugs...381
Kristyn Pardo
Chapter 4: Cholinergic Agonists...117
Rajan Radhakrishnan Chapter 21: Anticoagulants...391
Katherine Vogel Anderson
Chapter 5: Cholinergic Antagonists...133
and Kaylie Smith
Rajan Radhakrishnan and Carinda Feild
Chapter 22: Drugs for Hyperlipidemia...413
Chapter 6: Adrenergic Agonists...147
Karen Sando and Kevin Cowart
Rajan Radhakrishnan
Chapter 7: Adrenergic Antagonists...167
Rajan Radhakrishnan UNIT V: Drugs Affecting the Endocrine System
and Sandhya Jinesh Chapter 23: Pituitary and Thyroid...427
Shannon Miller and Karen Whalen
UNIT III: Drugs Affecting the Central Chapter 24: Drugs for Diabetes...437
Nervous System Karen Whalen and Cynthia Moreau
Chapter 25: Estrogens and Androgens...457
Chapter 8: Drugs for Neurodegenerative
Karen Whalen
Diseases...181
Jose A. Rey Chapter 26: Adrenal Hormones...471
Shannon Miller and Karen Whalen
Chapter 9: Anxiolytic/Hypnotic Drugs...197
Jose A. Rey Chapter 27: Drugs Affecting Bone Metabolism...481
Karen Whalen
Chapter 10: Antidepressants...213
Jose A. Rey
Chapter 11: Antipsychotics...227 UNIT VI: Chemotherapeutic Drugs
Jose A. Rey Chapter 28: Principles of Antimicrobial
Chapter 12: Drugs for Epilepsy...239 Therapy...489
Jeannine M. Conway and Angela Jamie Kisgen
K. Birnbaum Chapter 29: Cell Wall Inhibitors...505
Chapter 13: Anesthetics...257 Veena Venugopalan and Kenneth Klinker
Brandon Lopez and Chris Giordano

ix

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 x Contents

Chapter 30: Protein Synthesis Inhibitors...521 Chapter 41: Drugs for Disorders of the Respiratory
Jacqueline Jourjy System...719
Chapter 31: Quinolones, Folic Acid Kyle Melin
Antagonists, and Urinary Tract Chapter 42: Gastrointestinal and Antiemetic
Antiseptics...537 Drugs...737
Kenneth P. Klinker and Joseph Pardo Carol Motycka and Adonice Khoury
Chapter 32: Antimycobacterial Drugs...551 Chapter 43: Drugs for Urologic Disorders...763
Charles A. Peloquin and Eric F. Egelund Katherine Vogel Anderson
Chapter 33: Antifungal Drugs...565 and Kaylie Smith
Lindsey Childs-Kean Chapter 44: Drugs for Anemia...773
Chapter 34: Antiviral Drugs...581 Lori Dupree
Elizabeth Sherman Chapter 45: Drugs for Dermatologic
Chapter 35: Anticancer Drugs...601 Disorders...783
Kourtney LaPlant and Paige May Stacey Curtis and Cary Mobley

Chapter 36: Antiprotozoal Drugs...631 Chapter 46: Clinical Toxicology...797

Marylee V. Worley and Jonathan C. Cho Dawn Sollee and Emily Winograd

Chapter 37: Anthelmintic Drugs...653 Chapter 47: Antisnake Venom...811

Jonathan C. Cho and Marylee V. Worley Shyamal R. Sinha and Sangeeta Sharma

Chapter 38: Immunosuppressants...663 Chapter 48: Drugs of Abuse...823

Jennifer Jebrock and Jane Revollo Carol Motycka and Joseph Spillane

Appendix: Drugs and Dosages...835

UNIT VII: Special Topics in Pharmacology Thirumurthy Velpandian
Chapter 39: Histamine and Serotonin...675 Index...I-1
Nancy Hart and Carol Motycka Figure Credits...C-1
Chapter 40: Anti-inflammatory, Antipyretic, and
Analgesic Agents...693
Eric Dietrich, Amy Talana, and
Thirumurthy Velpandian

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 Detailed Contents
Contributing Authors…v II. The Cholinergic Neuron...................... 117
Reviewers…viii III. Cholinergic Receptors
(Cholinoceptors).................................. 120
Illustration and Graphic Design…viii IV. Direct-Acting Cholinergic Agonists...... 121
V. Indirect-Acting Cholinergic
UNIT I: Principles of Drug Therapy................ 1 Agonists: Anticholinesterase
Agents (Reversible)............................. 124
Chapter 1: General Pharmacology, VI. Indirect-Acting Cholinergic Agonists:
Pharmacotherapeutics, Anticholinesterase Agents
(Irreversible)........................................ 126
and Pharmacokinetics ............................ 1
VII. Toxicology of Anticholinesterase
Venkata Yellepeddi and Sangeeta Sharma
Agents................................................ 127
I. General Pharmacology........................... 1
Study Questions................................. 129
II. Overview of Pharmacokinetics.............. 28
III. Routes of Drug Administration.............. 29 Chapter 5: Cholinergic Antagonists......................... 133
IV. Absorption of Drugs............................. 31 Rajan Radhakrishnan and Carinda Feild
V. Drug Distribution................................... 39 I. Overview............................................. 133
VI. Drug Clearance through II. Antimuscarinic Agents........................ 134
Metabolism........................................... 42 III. Ganglionic Blockers............................ 139
VII. Drug Clearance by the Kidney.............. 46 IV. Neuromuscular-Blocking Agents......... 140
VIII. Excretion by Other Routes................... 47 Study Questions................................. 143
IX. Design and Optimization of
Dosage Regimen.................................. 49 Chapter 6: Adrenergic Agonists.............................. 147
Study Questions................................... 53 Rajan Radhakrishnan
I. Overview............................................. 147
Chapter 2: Pharmacodynamics................................. 57 II. The Adrenergic Neuron...................... 148
Joanna Peris and Sangeeta Sharma III. Characteristics of Adrenergic
I. Overview............................................... 57 Agonists............................................. 152
II. Signal Transduction.............................. 57 IV. Direct-Acting Adrenergic Agonists...... 154
III. Dose–Response Relationships............. 61 V. Indirect-Acting Adrenergic Agonists.... 160
IV. Intrinsic Activity..................................... 64 VI. Mixed-Action Adrenergic Agonists...... 161
V. Quantal Dose–Response Study Questions................................. 164
Relationships........................................ 66
VI. Evaluation of Response to Therapy...... 68 Chapter 7: Adrenergic Antagonists......................... 167
VII. Drug–Drug Interactions......................... 78 Rajan Radhakrishnan and Sandhya Jinesh
VIII. Adverse Drug Reactions ...................... 86 I. Overview............................................. 167
Study Questions................................... 98 II. -Adrenergic Blocking Agents............ 167
III. b-Adrenergic Blocking Agents............ 170
IV. Drugs Affecting Neurotransmitter
UNIT II: Drugs Affecting the ­Autonomic Release or Uptake.............................. 175
Nervous System............................. 103 Study Questions................................. 177
Chapter 3: Autonomic Nervous System.................. 103
Rajan Radhakrishnan UNIT III: Drugs Affecting the Central
I. Overview............................................. 103
II. Introduction to the Nervous System.... 103
Nervous System............................ 181
III. Chemical Signaling Between Cells...... 110 Chapter 8: Drugs for Neurodegenerative
IV. Signal Transduction in the
Diseases................................................ 181
Effector Cell........................................ 112
Jose A. Rey
V. Autonomic Dysfunction
I. Overview............................................. 181
(Dysautonomia)................................... 112
II. Neurotransmission in the CNS........... 181
Study Questions................................. 113
III. Synaptic Potentials............................. 182
Chapter 4: Cholinergic Agonists.............................. 117 IV. Neurodegenerative Diseases.............. 183
Rajan Radhakrishnan V. Overview of Parkinson’s Disease........ 183
I. Overview............................................. 117 VI. Drugs Used in Parkinson’s Disease..... 184

xi

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 xii Detailed Contents

VII. Drugs Used in Alzheimer’s Disease..... 191 VI. Intravenous Anesthetics...................... 268
VIII. Drugs Used in Multiple Sclerosis........ 192 VII. Neuromuscular Blockers..................... 271
IX. Drugs Used in Amyotrophic Lateral VIII. Local Anesthetics............................... 273
Sclerosis............................................. 193 IX. Anesthetic Adjuncts............................ 277
Study Questions................................. 194 Study Questions................................. 279
Chapter 9: Anxiolytic/Hypnotic Drugs..................... 197 Chapter 14: Opioid Analgesics.................................. 281
Jose A. Rey Robin Moorman Li
I. Overview............................................. 197 I. Overview............................................. 281
II. Benzodiazepines................................ 197 II. Opioid Receptors............................... 281
III. Benzodiazepine Antagonist................ 203 III. Opioid Agonists.................................. 282
IV. Other Anxiolytic Agents...................... 203 IV. Partial Agonists and Mixed
V. Barbiturates........................................ 205 Agonist–Antagonists........................... 290
VI. Nonbenzodiazepine Hypnotic Agents.... 206 V. Other Analgesics................................ 291
VII. Other Hypnotic Agents....................... 207 VI. Antagonists........................................ 292
Study Questions................................. 210 Study Questions................................. 294
Chapter 10: Antidepressants..................................... 213 Chapter 15: CNS Stimulants..................................... 299
Jose A. Rey Jose A. Rey
I. Overview............................................. 213 I. Overview............................................. 299
II. Mechanism of Antidepressant II. Psychomotor Stimulants..................... 299
Drugs................................................. 213 III. Hallucinogens..................................... 306
III. Selective Serotonin Reuptake Study Questions................................. 306
Inhibitors............................................. 213
IV. Serotonin/Norepinephrine
Reuptake Inhibitors............................. 217 UNIT IV: Drugs Affecting the
V. Atypical Antidepressants.................... 218 Cardiovascular System................. 309
VI. Tricyclic Antidepressants..................... 219
VII. Monoamine Oxidase Inhibitors........... 221 Chapter 16: Antihypertensives.................................. 309
VIII. Serotonin-Dopamine Antagonists....... 222 Benjamin Gross
IX. Treatment of Mania and Bipolar I. Overview............................................. 309
Disorder.............................................. 222 II. Etiology of Hypertension..................... 310
Study Questions................................. 225 III. Mechanisms for Controlling Blood
Pressure............................................. 311
Chapter 11: Antipsychotics....................................... 227
IV. Treatment Strategies........................... 312
Jose A. Rey
V. Diuretics............................................. 316
I. Overview............................................. 227
VI. -Adrenoceptor–Blocking Agents....... 320
II. Schizophrenia..................................... 227
VII. ACE Inhibitors..................................... 321
III. Antipsychotic Drugs........................... 227
VIII. Angiotensin II Receptor Blockers........ 323
Study Questions................................. 236
IX. Renin Inhibitor.................................... 323
Chapter 12: Drugs for Epilepsy................................. 239 X. Calcium Channel Blockers.................. 324
Jeannine M. Conway and XI. -Adrenoceptor–Blocking Agents....... 325
Angela K. Birnbaum XII.  -/-Adrenoceptor–Blocking
I. Overview............................................. 239 Agents................................................ 325
II. Etiology of Seizures............................ 239 XIII. Centrally Acting Adrenergic Drugs...... 325
III. Classification of Seizures.................... 240 XIV. Vasodilators........................................ 326
IV. Drug Selection.................................... 241 XV. Hypertensive Emergency.................... 326
V. Antiseizure Medications...................... 244 XVI. Resistant Hypertension....................... 327
VI. Status Epilepticus............................... 251 XVII. Hypertension in Pregnancy ................ 327
VII. Women’s Health and Epilepsy............ 252 XVIII. Hypertension in Children
Study Questions................................. 254 and Adolescents ............................... 327
XIX. Drug Interactions................................ 327
Chapter 13: Anesthetics............................................ 257 Study Questions................................. 328
Brandon Lopez and Chris Giordano
I. Overview............................................. 257 Chapter 17: Diuretics................................................. 331
II. Patient Factors in Selection Zachary L. Cox
of Anesthesia...................................... 258 I. Overview............................................. 331
III. Levels of Sedation ............................. 259 II. Normal Regulation of Fluid
IV. Stages of General Anesthesia............ 260 and Electrolytes by the Kidneys.......... 331
V. Inhalation Anesthetics......................... 261 III. Thiazides ........................................... 333

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 Detailed Contents xiii

IV. Loop Diuretics.................................... 337 IX. Thrombolytic Drugs............................ 406

V. Potassium-Sparing Diuretics............... 339 X. Drugs Used to Treat Bleeding............ 407
VI. Carbonic Anhydrase Inhibitor.............. 340 Study Questions................................. 409
VII. Osmotic Diuretics............................... 341
Study Questions................................. 344
Chapter 22: Drugs for Hyperlipidemia....................... 413
Karen Sando and Kevin Cowart
Chapter 18: Drugs for Heart Failure.......................... 347 I. Overview............................................. 413
Shawn Anderson II. Treatment Goals................................. 416
Katherine Vogel Anderson III. Drugs for Hyperlipidemia.................... 416
I. Overview............................................. 347 Study Questions................................. 425
II. Physiology of Muscle Contraction...... 348
III. Inhibitors of the Renin–Angiotensin–
Aldosterone System........................... 352 UNIT V: Drugs Affecting the
IV. -Blockers.......................................... 354 Endocrine System.......................... 427
V. Diuretics............................................. 355
VI. Angiotensin Receptor-Neprilysin Chapter 23: Pituitary and Thyroid............................. 427
Inhibitor.............................................. 355 Shannon Miller and Karen Whalen
VII. Hyperpolarization-Activated I. Overview............................................. 427
Cyclic Nucleotide–Gated II. Hypothalamic and Anterior
Channel Blocker................................. 356 Pituitary Hormones............................. 427
VIII. Vaso- and Venodilators....................... 357 III. Hormones of the Posterior Pituitary.... 431
IX. Inotropic Drugs................................... 358 IV. Thyroid Hormones.............................. 432
X. Recombinant B-type Natriuretic Study Questions................................. 435
Peptide............................................... 360 Chapter 24: Drugs for Diabetes................................ 437
XI. Goals of Treatment and Order Karen Whalen and Cynthia Moreau
of Therapy.......................................... 361 I. Overview............................................. 437
Study Questions................................. 363 II. Diabetes Mellitus................................ 437
Chapter 19: Antiarrhythmics...................................... 365 III. Insulin and Insulin Analogs................. 438
Shawn Anderson and Michelle Chung IV. Insulin Preparations and Treatment..... 439
I. Overview............................................. 365 V. Synthetic Amylin Analog..................... 444
II. Introduction to the Arrhythmias.......... 365 VI. Glucagon-Like Peptide
III. Class I Antiarrhythmic Drugs.............. 368 Receptor Agonists.............................. 444
IV. Class II Antiarrhythmic Drugs.............. 371 VII. Oral Hypoglycemic Agents (OHA)....... 445
V. Class III Antiarrhythmic Drugs............. 371 VIII. Management of Diabetes................... 450
VI. Class IV Antiarrhythmic Drugs............ 373 Study Questions................................. 454
VII. Other Antiarrhythmic Drugs................ 373 Chapter 25: Estrogens and Androgens..................... 457
Study Questions................................. 378 Karen Whalen
I. Overview............................................. 457
Chapter 20: Antianginal Drugs.................................. 381
II. Estrogens........................................... 458
Kristyn Pardo
III. Selective Estrogen Receptor
I. Overview............................................. 381
Modulators (SERMs)........................... 460
II. Types of Angina.................................. 381
IV. Progestogens..................................... 462
III. Treatment Strategies........................... 382
V. Contraceptives................................... 463
IV. -Adrenergic Blockers........................ 383
VI. Androgens.......................................... 466
V. Calcium Channel Blockers.................. 384
Study Questions................................. 469
VI. Organic Nitrates................................. 385
VII. Sodium Channel Blocker.................... 386 Chapter 26: Adrenal Hormones................................. 471
Study Questions................................. 387 Shannon Miller and Karen Whalen
I. Overview............................................. 471
Chapter 21: Anticoagulants....................................... 391
II. Corticosteroids................................... 471
Katherine Vogel Anderson and Kaylie Smith
Study Questions................................. 477
I. Overview............................................. 391
II. Thrombus Versus Embolus................. 391 Chapter 27: Drugs Affecting Bone Metabolism........ 481
III. Platelet Response to Vascular Injury... 391 Karen Whalen
IV. Platelet Aggregation Inhibitors............ 394 I. Overview............................................. 481
V. Blood Coagulation.............................. 399 II. Bone Remodeling............................... 481
VI. Parenteral Anticoagulants................... 399 III. Prevention of Osteoporosis................ 481
VII. Vitamin K Antagonists........................ 403 IV. Treatment of Osteoporosis................. 482
VIII. Direct Oral Anticoagulants.................. 404 Study Questions................................. 486

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 xiv Detailed Contents

UNIT VI: Chemotherapeutic Drugs............ 489 III. Drugs for Leprosy............................... 559
Study Questions................................. 561
Chapter 28: Principles of Antimicrobial Therapy...... 489
Chapter 33: Antifungal Drugs.................................... 565
Jamie Kisgen
Lindsey Childs-Kean
I. Overview............................................. 489
I. Overview............................................. 565
II. Selection of Antimicrobial Agents....... 489
II. Drugs for Subcutaneous and
III. Route of Administration...................... 494
Systemic Mycotic Infections............... 565
IV. Determinants of Rational Dosing........ 494
III. Drugs for Cutaneous Mycotic
V. Chemotherapeutic Spectra................. 495
Infections............................................ 573
VI. Combinations of Antimicrobial
IV. Miscellaneous Agents Meant for
Drugs................................................. 496
Topical Use in Fungal Infections......... 576
VII. Drug Resistance................................. 496
Study Questions................................. 577
VIII. General Antibiotic Use Guidelines....... 499
IX. Prophylactic Use of Antibiotics........... 501 Chapter 34: Antiviral Drugs....................................... 581
X. Complications of Antibiotic Therapy..... 501 Elizabeth Sherman
XI. Sites of Antimicrobial Action............... 502 I. Overview............................................. 581
Study Questions................................. 503 II. Treatment of Respiratory Viral
Infections............................................ 581
Chapter 29: Cell Wall Inhibitors................................. 505
III. Treatment of Hepatic Viral
Veena Venugopalan and Kenneth Klinker
Infections............................................ 583
I. Overview............................................. 505
IV. Treatment of Hepatitis B..................... 583
II. Penicillins............................................ 505
V. Treatment of Hepatitis C..................... 585
III. Cephalosporins................................... 510
IV. Other -Lactam Antibiotics................. 512 VI. Treatment of Herpes Virus
V. -Lactamase Inhibitors....................... 513 Infections............................................ 587
VI. Vancomycin........................................ 515 VII. Treatment of HIV Infection.................. 591
VII. Lipoglycopeptides ............................. 515 VIII. NRTIs Used to Treat HIV Infection...... 591
VIII. Daptomycin........................................ 516 IX. NNRTIs Used to Treat HIV Infection..... 592
IX. Fosfomycin......................................... 516 X. Protease Inhibitors Used to Treat
X. Polymyxins......................................... 516 HIV Infection....................................... 593
Study Questions................................. 518 XI. Entry Inhibitors.................................... 595
XII. Integrase Inhibitors............................. 595
Chapter 30: Protein Synthesis Inhibitors ................. 521 XIII. Pharmacokinetic Enhancers................ 596
Jacqueline Jourjy XIV. National AIDS Control Organization
I. Overview............................................. 521 (NACO) Guidelines.............................. 596
II. Tetracyclines....................................... 521 Study Questions................................. 598
III. Glycylcyclines..................................... 524
IV. Aminoglycosides................................. 525 Chapter 35: Anticancer Drugs................................... 601
V. Macrolides and Ketolides................... 527 Kourtney LaPlant and Paige May
VI. Fidaxomicin........................................ 530 I. Overview............................................. 601
VII. Chloramphenicol................................. 531 II. Principles of Cancer
VIII. Clindamycin........................................ 532 Chemotherapy.................................... 601
IX. Quinupristin/Dalfopristin...................... 532 III. Antimetabolites................................... 606
X. Oxazolidinones................................... 533 IV. Antibiotics........................................... 610
Study Questions................................. 534 V. Alkylating Agents................................ 613
VI. Microtubule Inhibitors......................... 616
Chapter 31: Quinolones, Folic Acid Antagonists, VII. Steroid Hormones and
and Urinary Tract Antiseptics................ 537 Their Antagonists................................ 618
Kenneth P. Klinker and Joseph Pardo VIII. Platinum Coordination Complexes...... 621
I. Fluoroquinolones ............................... 537 IX. Topoisomerase Inhibitors.................... 622
II. Folate Antagonists ............................. 542 X. Antibodies.......................................... 623
III. Sulfonamides ..................................... 542 XI. Tyrosine Kinase Inhibitors................... 623
IV. Trimethoprim ..................................... 544 XII. Immunotherapy.................................. 624
V. Cotrimoxazole ................................... 545 XIII. Miscellaneous Agents......................... 624
VI. Urinary Tract Antiseptics/ Study Questions................................. 627
Antimicrobials .................................... 547
Study Questions................................. 548 Chapter 36: Antiprotozoal Drugs............................... 631
Marylee V. Worley and Jonathan C. Cho
Chapter 32: Antimycobacterial Drugs....................... 551 I. Overview............................................. 631
Charles A. Peloquin and Eric F. Egelund II. Chemotherapy for Amebiasis............. 631
I. Overview���������������������������������������������551 III. Chemotherapy for Giardiasis.............. 637
II. Chemotherapy for Tuberculosis.......... 551 IV. Chemotherapy for Malaria.................. 637

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 Detailed Contents xv

V. Chemotherapy for VII. Other Drugs for Rheumatoid

Trypanosomiasis.................................. 645 Arthritis............................................... 712
VI. Chemotherapy for VIII. Drugs Used for the Treatment
Leishmaniasis..................................... 647 of Gout............................................... 712
VII. Chemotherapy for Study Questions................................. 715
Toxoplasmosis.................................... 648
VIII. Chemotherapy for Lymphatic Chapter 41: Drugs for Disorders of the
Filariasis.............................................. 649 Respiratory System............................... 719
Study Questions................................. 651 Kyle Melin
I. Overview............................................. 719
Chapter 37: Anthelmintic Drugs................................ 653 II. Preferred Drugs Used
Jonathan C. Cho and Marylee V. Worley to Treat Asthma.................................. 719
I. Overview............................................. 653 III. Alternative Drugs Used
II. Drugs for the Treatment to Treat Asthma.................................. 725
of Nematodes..................................... 653 IV. Drugs Used to Treat Chronic
III. Drugs for the Treatment Obstructive Pulmonary Disease
of Trematodes.................................... 657 (COPD)............................................... 727
IV. Drugs for the Treatment V. Inhaler Technique................................ 728
of Cestodes........................................ 658 VI. Drugs Used to Treat Allergic Rhinitis.... 729
Study Questions................................. 660 VII. Drugs Used to Treat Cough/
Antitussive agents.............................. 731
Chapter 38: Immunosuppressants............................ 663 Study Questions................................. 733
Jennifer Jebrock and Jane Revollo
I. Overview............................................. 663 Chapter 42: Gastrointestinal and Antiemetic
II. Induction and Rejection Drugs..................................................... 737
Immunosuppressant Medications....... 665 Carol Motycka and Adonice Khoury
III. Maintenance Immunosuppressant I. Overview............................................. 737
Medications........................................ 668 II. Drugs Used to Treat Peptic Ulcer
IV. Therapeutic Drug Monitoring Disease and Gastroesophageal
of Immunosuppressants..................... 672 Reflux Disease.................................... 737
Study Questions................................. 672 III. Drugs Used to Control
Chemotherapy-Induced Nausea
and Vomiting...................................... 742
UNIT VII: Special Topics in IV. Therapeutic Use Of Antiemetic Drugs.... 746
Pharmacology............................. 675 V. Antidiarrheals...................................... 747
VI. Other Antidiarrheal drugs.................... 748
Chapter 39: Histamine and Serotonin....................... 675 VII. Laxatives............................................ 749
Nancy Hart and Carol Motycka VIII. Gastrokinetic Agents.......................... 753
I. Overview............................................. 675 IX. Irritable Bowel Syndrome.................... 754
II. Histamine........................................... 675 X. Drugs Used to Treat Inflammatory
III. H1 Antihistamines............................... 677 Bowel Disease.................................... 755
IV. Histamine H2-Receptor Study Questions................................. 759
Blockers............................................. 680
V. Serotonin............................................ 680 Chapter 43: Drugs for Urologic Disorders................. 763
VI. Drugs Used to Treat Headache Katherine Vogel Anderson and Kaylie Smith
Disorders............................................ 681 I. Overview............................................. 763
VII. Drugs for Obesity............................... 686 II. Drugs Used to Treat Erectile
Study Questions................................. 689 Dysfunction......................................... 763
III. Benign Prostatic Hyperplasia.............. 766
Chapter 40: Anti-inflammatory, Antipyretic, Study Questions................................. 769
and Analgesic Agents............................ 693
Chapter 44: Drugs for Anemia................................... 773
Eric Dietrich, Amy Talana, and
Lori Dupree
Thirumurthy Velpandian
I. Overview............................................. 773
I. Overview............................................. 693
II. Agents Used to Treat Anemias........... 773
II. Prostaglandins.................................... 693
III. Agents Used to Treat Neutropenia..... 778
III. Nonsteroidal Anti-Inflammatory
IV. Agents Used to Treat Sickle
Drugs................................................. 696
Cell Disease........................................ 778
IV. Paracetamol (Acetaminophen)............ 707
Study Questions................................. 779
V. Traditional Disease-Modifying
Antirheumatic Drugs (DMARDS)......... 708 Chapter 45: Drugs for Dermatologic Disorders........ 783
VI. Biologic Disease-Modifying Stacey Curtis and Cary Mobley
Antirheumatic Drugs .......................... 709 I. Overview............................................. 783

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 xvi Detailed Contents

II. Topical Preparations........................... 783 II. Pathophysiology and Clinical

III. Agents for Acne................................. 783 Manifestations.................................... 812
IV. Agents for Superficial Bacterial III. Management of Snakebite.................. 815
Infections............................................ 786 IV. Management of neurotoxic
V. Agents Used for Rosacea.................. 787 (neuroparalytic) envenomation............ 820
VI. Agents for Pigmentation Disorders...... 788 Study Questions................................. 821
VII. Agents for Psoriasis........................... 790
Chapter 48: Drugs of Abuse...................................... 823
VIII. Agents for Alopecia............................ 794
Carol Motycka and Joseph Spillane
Study Questions................................. 795
I. Overview............................................. 823
Chapter 46: Clinical Toxicology.................................797 II. Sympathomimetics............................. 823
Dawn Sollee and Emily Winograd III. Hallucinogens..................................... 826
I. Overview............................................. 797 IV. Ethanol............................................... 828
II. Emergency Treatment of the V. Prescription Drug Abuse..................... 831
Poisoned Patient................................ 797 Study Questions................................. 831
III. Select Pharmaceutical and
Appendix: Drugs and Dosages������������������������������ 835
Occupational Toxicities....................... 802
Thirumurthy Velpandian
IV. Antidotes��������������������������������������������807
Study Questions................................. 807 Index���������������������������������������������������������������������������� I-1
Figure Credits����������������������������������������������������������� C-1
Chapter 47: Antisnake Venom................................... 811
Shyamal R. Sinha and Sangeeta Sharma
I. Overview............................................. 811

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 UNIT I
Principles of Drug Therapy

General Pharmacology,
Pharmacotherapeutics,
and Pharmacokinetics
Venkata Yellepeddi and Sangeeta Sharma 1
I. GENERAL PHARMACOLOGY

The word “pharmacology” is derived from the words pharmakon, which

means “drug” and logus, which means “science.” Pharmacology is the
­science of the study of substances that interact with living systems through
chemical processes, especially by binding to regulatory molecules and
activating or inhibiting normal body processes. These substances may be
chemicals administered to achieve a beneficial therapeutic effect on some
process within the patient.
Pharmacology is the branch of medicine with a unique combination of sev-
eral biomedical sciences—chemistry, biochemistry, physiology, and clin-
ical medicine. Pharmacology is both a basic and an applied science. It
forms the backbone of rational therapeutics. Pharmacology deals with the
knowledge of drugs, their sources, biochemical and physiological effects,
mechanism of action, and therapeutic uses of drug. Pharmacology stud-
ies the effects of drugs and how they exert their effects. For example,
paracetamol can reduce body temperature in case of fever by inhibiting
an enzyme known as cyclooxygenase in CNS, which is responsible for the
synthesis of a number of inflammatory mediators. Penicillin cures certain
bacterial infections by disrupting the synthesis of bacterial cell walls by
inhibiting a key enzyme.
World Health Organization (WHO) in 1966 defined drugs as any substance
or product which is used or intended to be used to modify or explore phys-
iological systems or pathological states for the benefit of the recipient,
either therapeutic or diagnostic benefits.
Drugs are chemical substances which affect living organisms and are used
by the clinician to diagnose, prevent, or cure diseases. So the safe use
of drugs needs sound knowledge of their various aspects such as mech-
anism of action, doses, routes of administration, adverse drug affects,
­toxicity, and drug interactions.

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2 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

The medicinal/organic chemists may create the candidate molecule or com­

pound (also referred to as a new chemical entity [NCE]), and the pharmacol­
ogist test its pharmacological activity in vitro, in animals, and then in human
beings, ultimately leading to the discovery of novel drugs for therapeutic
intervention.
The general pharmacology involves the aspects of sources of drugs, route
of administration of drugs, absorption of drugs and factors affecting them,
their distribution, biotransformation, and excretion. It also involves the
mechanism by which the drug is acting with receptor, toxicity of drug, and
preclinical and clinical evaluation.

A. Branches of pharmacology
Pharmacology comprises two main branches: 1) pharmacokinetics and
2) pharmacodynamics.
1. Pharmacokinetics (what body does to drug): It involves
movement of drug and includes study of absorption, distribu­
tion, metabolism, and excretion of dr gs. The study of what
happens to the drug in the body is ca led pharmacokinetics.
For example, chlorpromazine is absorbed at a faster rate by the
Relationship between pharmaceutics, parenteral route than the oral route; it binds with plasma and
kinetics and dynamics tissue protein and it is metabolized into the liver and is excreted
in 15 to 30 hours.
.
Pharmaceut1cs
)l Disintegration
of drug
2. Pharmacodynamics (what drug does to body): It is a
quantitative study of the biological and therapeutic effect of drug.

l
Bioavailability
For examl)le, curare (a plant extract used by tribals as arrow
poison) is a nond polarizing blocker which rapidly produces mus­
Dosage requirement cle weakness and finally leads to skeletal muscle paralysis.
The relationship between pharmaceutics, pharmacokinetics, pharma­
Pharmacokinetics
Absorption codynamics, and pharmacotherapeutics is depicted in Figure 1.1.
Distribution
Metabolism

l
-.....
Excretion -"
•- •- •- •
B. Other branches
1. Pharmacotherapeutics: It is a branch of medicine which deals
Concentration in plasma
with clinical application of the pharmacokinetic and pharmaco­
dynamic knowledge of the drug, in finding a cure of diseases
Drug- or relief of symptoms. It includes use of drugs in the treatment,
Pharmacodynamics
receptor
-..._interaction ,,
diagnosis, or prevention of a disease or their purposeful use
____ in alteration of physiological functions for the benefit of the
recipient.
Concentration at the site of action 2. Toxicology: It is a science of poisons. Poisons are substances
that are harmful and dangerous or show fatal symptoms in
Pharmacotherapeutics animals and human beings; many drugs in large dose act as
poisons, for example, aspirin in less dose acts as an anticoag­
Drug effect or response ulant by inhibiting thromboxane A2; thus, it is useful for heart
patients but in high dose causes ulceration and can lead to fatal
bleeding.
Figure 1.1 3. Chemotherapy: It is concerned with the effect of drug upon
Relationship between pharmaceutics, microorganisms and parasites, living and multiplying in living
pharmacokinetics, pharmacodynam­ organisms. It is now also useful for the treatment of cancer by
ics, and pharmacotherapeutics. targeting cancerous cells.
 I. General Pharmacology 3

4. Clinical pharmacology: It is a branch of pharmacology dealing with

drugs and their clinical use. It gives useful data about the potency,
usefulness, doses, and toxicity of new drugs for their safe clinical use.
5. Pharmacoepidemiology: It is a study of the effect of the drugs
on population.
6. Pharmacoeconomics: It is a branch of pharmacology which
studies the cost effectiveness of drug treatment and cost of med-
ications, particularly among certain groups such as elderly and
AIDS patients.
7. Pharmacogenetics: It is the study of the genetic variation that
gives rise to differing response to drugs among individuals or
populations. Some patients respond to certain drugs with greater
than usual sensitivity to standard doses. Screening of individuals
for a variety of such differences before prescribing may help in
individualized therapy.
8. Pharmacogenomics: It is the application of genomic technolo-
gies to drug discovery and further characterization of older drugs.
9. Pharmacognosy: It deals with the study of the sources of drugs
derived from plants and animal origin.
10. Pharmacy: It is the art and science of compounding or preparing
suitable dosage forms for administration of drugs in man and ani-
mals and dispensing drugs. It also includes identification, selec-
tion, collection, purification, isolation, standardization, and quality
control of medicinal substances.
11. Clinical pharmacy: It is a health science discipline in which phar-
macists provide patient care that optimizes medication therapy
and promotes health, wellness, and disease prevention.

C. Definitions
1. Pharmacopoeia: It is an official reference containing a selected
list of the established drugs and medicinal preparations with
descriptions of their physical properties and tests for their identity,
purity, and potency. It defines the standards of preparations. A few
famous pharmacopoeia and other reference books are the British
pharmacopoeia (BP), Indian Pharmacopoeia (IP), International
Pharmacopoeia (IP), and Unites States Pharmacopoeia (USP).
2. National formulary: It provides product information on drugs
available to prescribers in respective countries/states/health sys-
tems. For example, National Formulary of India is published by
Government of India, and British National Formulary (BNF) is
jointly published by British Medical Association (BMA) and the
Royal Pharmaceutical Society.
3. Essential medicines: WHO defines Essential Medicines as
those that satisfy the priority healthcare needs of the population.
Essential medicines are intended to be available within the con-
text of functioning health systems at all times and in adequate
amounts, in appropriate dosage forms, with assured quality and
adequate information, and at a price the individual and the com-
munity can afford.
4. Orphan drugs: These are the drugs or vaccines or biological prod-
ucts for diagnosis, prevention, and treatment of a rare disease or

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 4 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

a more common disease (but endemic only in poor countries) for

which the pharmaceutical industry has little interest in develop-
ing and marketing products as they are intended for only a small
Animal source number of patients. For drug companies, it means huge finan-
cial losses as this involves an extremely high cost of bringing a
medicinal product to market which would not be recovered by
the expected sales of the product. For ethical and legal reasons,
clinical studies in children are severely restricted, but a num-
ber of rare diseases affect the very young population. Similarly,
Minerals rare diseases which occur in small patient populations thus are
“orphaned” by the pharmaceutical industry—that is, only a few
approved drug treatment options available are called “orphan dis-
eases.” Rare diseases or orphan diseases are those that manifest
in patient populations representing at the maximum 6% to 8%
of the world population, for example, genetic diseases—infantile
Micro-organisms
spinal muscular atrophy, cystic fibrosis, patent ductus arteriosus
(PDA), lysosomal storage disorders, familial adenomatous polyp-
osis (FAP), and acute intermittent porphyria.
Some of the examples of orphaned drugs are miglustat used for
Type 1 Gaucher disease, iloprost for pulmonary arterial hyperten-
sion in patients with NYHA Class III or IV symptoms, bosanten for
Human being WHO Class II–IV symptoms, pegvisomant used for acromegaly,
and busulfan used for allogeneic hematopoietic progenitor cell
transplantation for chronic myelogenous leukemia. Various coun-
tries have enacted laws in this regard and provide incentives and
support for drug development.

Synthetic
compounds D. Sources of drugs (Figure 1.2)
Drugs are obtained mainly from plants, animals, microbes, and min-
eral sources. Nowadays, a majority of therapeutically used drugs are
produced from synthetic or semisynthetic products. Various sources
are given in the following text.
Genetic
engineering 1. Animal sources: Insulin, heparin, gonadotrophins, thyroid extract,
and antitoxic sera (for example, antisnake venom).
2. Minerals: Liquid paraffin, ferrous sulfate, magnesium sulfate,
magnesium trisilicate, kaolin, etc.
3. Microorganisms—bacteria and fungi: Penicillin, streptomycin,
Hybridoma erythromycin, polymixin B, bacitracin, chloramphenicol, nystatin,
technique griseofulvin. Apart from antibiotics obtained from m
­ icroorganisms,
other products that are also produced by microorganisms include
streptokinase, an enzyme from gram-positive cocci (Streptococcus
pyogenes), and vitamin B12 (cyanocobalamin), produced from
Streptomyces griseus.
4. Human beings: These products are obtained from human beings.
Plant sources For example, immunoglobulins from blood, growth hormone from
the pituitary gland, placental extract from placenta, and chorionic
gonadotropin from the urine of pregnant women.
5. Synthetic compounds: Analgesics, antimicrobials, hypnotics,
anticancer drugs, etc.
Figure 1.2
6. Genetic engineering: Human insulin, growth hormone, etc.
Sources of drugs.
7. Hybridoma technique: Monoclonal antibodies, etc.

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 I. General Pharmacology 5

8. Plant sources: The pharmacologically active components in

vegetable drugs are given in the following text.
a. Alkaloids: These are water-soluble salts of water-insoluble
nitrogenous compounds. Some of the important alkaloids are
as follows:
• Cinchona (Cinchona officinalis): Quinine, etc.
• Rauwolfia serpentina (root): Reserpine.
• Coca (Erythroxylum coca): Cocaine.
• Opium (Papaver somniferum): Morphine group.
• Belladonna (Atropa belladonna): Atropine group.
• Pilocarpus sp.: Pilocarpine.
• Vinca (Vinca rosea): Vincristine, vinblastine.
b. Glycosides: These are ether-like organic structure combined
with sugars. The nonsugar component is called aglycone or
genin. The important glycosides are as follows:
• Digitalis (Digitalis purpurea, Digitalis lanata): Digoxin, etc.
• Senna (Cassia acutifolia): Sennoside, etc.
• Stropanthus (Strophanthus kombe): Stropanthin, etc.
c. Oils:
[1] Fixed oils: These are glycerides of oleic, palmitic, and
stearic acids. Mostly fixed oils are edible and used for
cooking. The fixed oils used as drug are as follows:
• Castor (Ricinus communis): Castor oil.
• Olive (Olea europaea): Olive oil.
• Cocoa butter (Theobroma cacao): Theobroma oil used
as emollient in skin cream and making suppositories.
[2] Volatile oils: These are essential oils which contain the
hydrocarbon terpene. The important volatile oils are as
follows:
• Turpentine oil, from species of pines, used as a
counterirritant.
• Lemon oil (from citrus limon), used as a flavoring
agent.
• Peppermint, cardamom, ginger, and fennel used as
carminative and flavoring agents.
• Eucalyptus oil used for relieving congestion.
• Oil of clove mainly useful in toothache for relieving
pain.
d. Resins: These are oxidized or polymerized volatile oils. The
different types of resins are as follows:
• Oleoresins: A mixture of volatile oils and resins. Male fern
extract used for tapeworm infestation.
• Gum resins: Asafetida, used as carminative and
antispasmodic.
• Oleo gum resin: Myrrh—it has a local stimulant and anti-
septic properties and generally used in mouthwash.
• Balsams: Benzoin, used internally as expectorant and
externally as astringent.
• Balsam Tolu, used as stimulating expectorant.

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 6 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

e. Gums: These are the secretory products of plants. On hydro-

lysis, they yield simple sugar-like polysaccharides. They are
pharmacologically inert substances and mainly employed as
a suspending and emulsifying agent in various pharmaceuti-
cal products. The widely used preparations are gum acacia
and tragacanth.
f. Tannins: These are non-nitrogenous constituents of plant.
Chemically, these are phenolic derivatives and are char-
acterized by their astringent action. Tannins are generally
used in the treatment of diarrhea and burns. The important
plants which contain tannins are Hirda (in combination form
“Triphala”), Amla, Behera, Ashoka bark, Black catechu, etc.

E. Drug nomenclature/naming of drugs

Drug nomenclature is a system of names that puts drugs into classi-
fication, as of anatomic structures, molecular entities, or organisms.
The three broad name classifications of drugs are as follows:
• Chemical/molecular/scientific name
• International nonproprietary/generic/approved name
• Proprietary/brand/trade name
1. Chemical/molecular/scientific name: It depicts the chemical/
molecular structure of the drug and states the structure in terms
of atoms and molecules accompanied by a diagram of the chem-
ical structure. Chemical or scientific names are complex, long,
BRITISH UNITED STATES can be difficult to pronounce, and are useful to a few techni-
­ PPROVED
A ­APPROVED NAMES
cally trained personnel. For example, acetyl-p-amino-phenol
NAME (BAN) (USAN)
is a chemical name for paracetamol. This name is not suitable
Adrenaline Epinephrine
for routine use by medical professionals or common people.
Cinchocaine Dibucaine However, this name is very helpful for the discovery of new
Dexamphetamine Dextroamphetamine compounds.
Ergotametrine Ergonovine 2. International nonproprietary/generic/approved name: The
Glyceryl trinitrate Nitroglycerin
International Nonproprietary Name (INN) is an official generic
and nonproprietary name given to a pharmaceutical drug—that is,
Hyoscine Scopolamine
this is the abbreviated and approved name of the drug. International
Isoprenaline Isoproterenol nonproprietary names provide a unique standard name for each
Lignocaine Lidocaine active ingredient, thus making communication more precise and
Paracetamol Acetaminophen
avoid prescribing errors. Each drug’s INN is unique. Drugs from
the same therapeutic or chemical class are usually given names
Pethidine Meperidine
with the same stem. -sartan for angiotensin blockers (for exam-
Phenobarbitone Phenobarbital ple, losartan), -azepam suffix for benzodiazepines (for example,
Rifampicin Rifampin lorazepam and diazepam), -pril for ACE inhibitors (for example,
Suxamethonium Succinylcholine
captopril), and ase for enzymes (for example, alteplase).

Thiopentone Thiopental
The nature of a drug can be easily identified by studying the suf-
fix. WHO has laid down the general principles in naming a drug
Salbutamol Albuterol
by the nonproprietary name. However, the nonproprietary name
Frusemide Furosemide may sometimes vary from country to country. Usually, the British
Paracetamol Acetaminophen Approved Name (BAN) and the INN coincide, and where the two
(­Europe) differed, the BAN was modified to match the INN with some
exception where the nonproprietary name of some drugs in UK
Figure 1.3 (BAN) and USA (USAN) is different (Figure 1.3).
Different nonproprietary names for the The generic name can be used by anyone and it removes the
same drug by BAN and USAN. confusion of giving several names to the same drug with the

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 I. General Pharmacology 7

same chemical structure regardless of who manufactures them.

A generic drug name is not capitalized, for example, aspirin
and paracetamol.
3. Proprietary/brand/trade name: These are names given to the drug
by the manufacturing and marketing company. The innovator com-
pany can then exclusively market and sell this “brand-name” prod-
uct during the patent protection period. Copyright laws prevent any
other person from using the brand name. On expiry of the patent
life, a branded-name drug product is eligible to be manufactured
and marketed as a “generic drug.” Trade name refers to a particu-
lar company and appears with the sign ® at its upper right corner
which indicates that the name is registered and its production is
restricted to that pharmaceutical company as the sole owner. For
example, bronchodilator drug salbutamol is marketed as Asthalin;
metformin is a generic name whereas Glyciphage is a brand name.
In most cases, one drug could have so many trade/brand names,
for example, paracetamol (acetaminophen) has more than 30 trade
names; some of these are Crocin, Panadol, Calpol, etc.
A generic medicine is a legitimately produced medicine that is an
exact copy of the innovator/originator product (branded medicine)
and performs in exactly the same way. Though brand-name drug
and its generic version must have the same active ingredient,
dosage, strength, usage directions, safety, quality, performance,
and use, it may differ in inactive ingredients, preservatives, color,
shape, taste, and packaging. For example, generic and brand-
name drugs must meet the exact same standards for equivalency
in effectiveness, safety profile, and quality except cost. The differ-
ence in cost between a generic and a brand-name drug is mainly
due to a difference in the development costs as manufacturers
of the generic versions do not incur expenses on developing and
marketing the generic version which is required for a new drug;
thus, the manufacturers can produce the drug at a lower unit cost
and sell it for less. Further, the competition keeps the prices of
generic medicines down.

F. Regulatory oversight
The Drug Regulatory Authority (DRA) oversees the approval and regu-
lation of drugs. To market a prescription drug in any country, the man-
ufacturer needs the approval of the DRA—that is, product licenses
(known formally as Marketing Authorisations) permitting license
holders to market medicinal products for specified indications under
specified conditions. To get that approval, the manufacturer must
demonstrate the drug’s safety and effectiveness according to criteria
specified in law and agency regulations, ensure that its manufacturing
plant passes DRA inspection, and obtain DRA approval for the drug’s
labeling—that is, every license for a medicinal product contains infor-
mation about the approved uses of the drug, including prescribing
information for physicians, for example, dosage forms, packaging,
therapeutic indications, doses, route of administration, contraindica-
tions, precautions for use or special warnings, adverse drug reactions,
drug interactions, and patient brochures.
Almost all countries have established Drug Regulatory Authorities to
assure the safety and effectiveness of Investigational New Drugs (IND)

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 8 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

through the evaluation of clinical pharmacology and biopharmaceu-

tics data in support in the New Drug Application (NDA) and license
application review programs.
Regulatory oversight is necessary to prevent anyone from selling or
freely advertising outrageous claims of benefit and safety includ-
ing products containing cocaine or opioids (for example, morphine).
Progressively stronger laws intended to ensure the effectiveness and
safety of drugs sold in the country are needed. DRA is responsible for
approval of new drugs, and medical devices as well as oversight of
the drugs and medical devices already available in the market. This
includes both prescription drugs and over-the-counter (OTC) drugs
(drugs that do not require a prescription). Also, “dietary supplements”
such as vitamins, amino acids, mineral, and herbal medication, even
though most of these products have significant pharmacologic activity,
are not regulated.
The states also participate in the process of drug regulation primarily
by controlling the licensing of drug manufacturing premises and health
professionals who can write drug prescriptions—that is, physicians,
dentists, podiatrists, and veterinarians. Though nurse p ­ ractitioners,
physician’s assistants, optometrists, and pharmacists can prescribe,
they have limited prescribing authority.

G. The drug development and approval process

The approval process for new drugs, especially drugs that are the
first in a wholly new chemical class, is complex, time consuming, and
expensive (up to $100 to $500 million dollars per new drug). Once a
promising new candidate is identified, it is tested in preclinical stud-
ies (in vitro systems and experimental animals). Drugs that still look
promising after these preclinical studies’ application of investigational
new drugs (IND) are filed with the DRA for testing in clinical trials first
in healthy people (Phase 0 and I) and then in people with the target
disease (Phases II and III). In phase 0, a very low dose of the drug is
tested for the first time on human subjects (10 to 15 subjects). Based
on the pharmacogenetic or pharmacodynamic properties, a deci-
sion on whether to start phase 1 or not is taken. These clinical trials
assess safety and effectiveness in human beings. If the drug appears
promising through three phases of clinical trials, the manufacturer
files application for approval of NDA from DRA to market the drug.
It is important that the manufacturer and the DRA continue postmar-
keting surveillance of new drugs (Phase IV) in real-life patients under
diverse conditions for early detection of risk of toxicity that occurs
rarely enough which escapes detection in the clinical trials setting.
1. Preclinical and clinical phases of drug evaluation: The drug
development path and objectives of various phases of the clini-
cal trials, the number of patients enrolled at each stage, and the
approximate average time for each stage is shown in Figure 1.4.
2. Patent protection and generic drugs: A company usually patents
novel/new chemical entities early in the drug discovery process.
Usually, patents provide 20 years of protection including the time
from the filing of a patent application to NDA marketing approval
which may be 5 years or longer. On expiry of the patent (that is,
20 years after filing application) companies other than the original
patent holder can sell a generic drug, which is an exact copy of

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 I. General Pharmacology 9

In vitro Animal Human Expanded Efficacy Long- P G

studies studies safety safety and term a e
safety safety in t n
“real-life e e
n r
patients” i
t
c
s
Preclinical Phase I Phase II Phase III Phase IV e
x
a
Lead 20–40 20–40 healthy 100–3000 1000–3000 Thousands p
v
compound healthy patients patient patients of diverse i a
identified participants participants patients
r i
Days or Weeks or Several Continuous;
a l
weeks months months or marketing
years approval t a
Drug Efficacy Unexpected Safety and Common Rare adverse i b
discovery selectivity adverse dosing in adverse effects o l
mechanism effects human beings effects detected n e
identified may appear revealed

Average duration in (years)

2 years 4 years 8–9 years 15 years 20 y
IND NDA

Figure 1.4
Drug development path—phases of clinical trials. IND = Investigational new drug; NDA = new
drug application.

a proprietary drug without paying license fees to the original pat- Prescription-only
ent owner. However, a trade name or the drug’s proprietary name medicine controlled
may be legally protected indefinitely. The process for approval by drug
the DRA of a generic drug is much less cumbersome and less
expensive than the process for approval of a new drug. Basically,
generic product manufacturers just need to document that their
drug has the same pharmacokinetic properties as the innovator/
proprietary drug. Generic products usually cost significantly less Prescription-only
medicine
than trade-named products; in some cases, the difference in the
price of the trade-named products can be many folds higher.

H. Classification of drugs
A drug may be classified by the chemical structure of the active Prescription-only
restricted medicine
ingredient or according to its therapeutic use. Each drug can be clas-
sified into one or more drug classes (for example, laxative, analge-
sics, decongestants relaxants, and antihypertensive) or system drugs
affecting the cardiovascular system, gastrointestinal system, and neu-
rological system.
1. Classification of drugs according to prescription (Figure 1.5): Over-the-counter
/home remedies
Another classification system is according to prescription, based
on the drug’s potential for addiction and subsequent abuse. In
India, medicines fall into four categories:
• Prescription-only medicine controlled drug (POM CD): Schedule X
in India Figure 1.5
• Prescription-only medicine (POM): Schedule H in India Drugs according to prescription.

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 10 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

• Prescription-only restricted medicines: Schedule H1 in India

• Over-the-counter or home remedies: Tab. aspirin, paracetamol,
analgesic balms, antacid preparations
The POM CD category is the most strictly controlled of the four,
and the home remedy is the least strictly controlled. POM CD
medicines have the potential for addiction, subsequent abuse,
and causing harm and also have the potential of being obtained
by illegal means. Narcotic and Psychotropic Substances (NDPS)
Act prohibits certain activities in relation to “Controlled Drugs,”
in particular, their manufacture, purchase, transport, supply, and
possession, and/or consume any narcotic drug or psychotropic
substance. These legal controls govern how controlled medicines
may be stored, supplied, and prescribed. Healthcare providers
including nurses must follow standard operating procedures for
procurement, storage, administration, and maintaining record of
Schedule X medicines.
a. Prescription drugs: A prescription drug is a pharmaceu-
tical agent that legally requires a medical prescription from
a healthcare professional to be dispensed or sold only to
consumers possessing a valid prescription. In contrast, over-
the-counter (nonprescription) drugs can be sold directly to a
consumer or obtained without a prescription. In India, though
there is no separate provision for OTC medicines in the Drugs
and Cosmetics Act, the drugs, which have not been included
in any of the Schedules, may be considered nonprescription
or OTC drugs.
In India, Schedule H1 has been a newly introduced category
imposing certain conditions in the dispensing of medicines
in the list, which are somewhat midway between Schedule H
(that stipulates retail dispensing only against a valid prescrip-
tion) and Schedule X (that stipulates prescription in duplicate,
separate license requirement, and meticulous storage and dis-
pensing records). The schedule is primarily intended to control
the rampant misuse through OTC dispensing of higher antibi-
otics, some of the reserved drugs such as second-line antitu-
bercular drugs, and drugs with abuse/misuse potential in India.
b. Over-the-counter/home remedies: These medicines have
the least number of restrictions placed on them and can be
sold in most shops or supermarkets without any interven-
tion from a healthcare professional. These medicines tend
to carry a low risk of harm if they are used according to the
guidelines that accompany them, for example, vitamin sup-
plements and mild analgesics. If they are used in larger than
recommended doses, they can cause damage. However, for
some medicines, such as paracetamol, there is a limit on the
number of tablets that may be purchased at any one time.

I. Pharmacotherapeutics
1. Rational use of medicines:
a. Definition: Patients receive medications appropriate to
their clinical needs, in doses that meet their own individual

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 I. General Pharmacology 11

requirements, for an adequate period of time, and at the low-

est cost to them and their community (WHO, 1985).
Irrational or nonrational use is the use of medicines in a way
that is not in accordance with the rational use of ­medicines
as defined in the preceding text. Irrational use of medicines
lead to ineffective and unsafe treatment, exacerbation or pro-
longation of illness, hospitalization sometimes, distress and
harm to the patient, and higher cost of treatment. A wide vari-
ety of irrational drug uses that arise from prescription prac-
tices adopted by doctors are as follows:
• The use of too many medicines prescribed per patient
(polypharmacy); often, these result in cross-reactions
between different drugs prescribed.
• Inappropriate prescription of antimicrobials, often in inade-
quate dosage, for nonbacterial infections.
• Overprescription of injections when oral formulations
would be more appropriate.
• Failure to prescribe in accordance with clinical guidelines:
Wrong choice of drugs, inadequate dosages, incorrect
frequency of administration of drug, improper duration of
therapy, or failure to observe drug contraindications.
• Underuse of life-extending drugs for illnesses such as
diabetes mellitus, hypertension, heart disease, asthma,
epilepsy, and other chronic illnesses. Usually, these are
­
situations where a small dose of the drug has to be taken
in a fixed low periodicity, lifelong.
• Choice of more expensive drugs when less expensive
drugs would be equally or more effective.
• Prescription of drugs which have no use, only for their
placebo effect or for impressing the patient or for vested
interests in the prescribed drugs.
• Inadequate consulting time and dispensing time along
with poor communication of information regarding drugs
to a patient in a verbal or written form leading to incor-
rect use by patients is of great public health concern too.
Worldwide, more than 50% of all medicines are prescribed,
dispensed, or sold inappropriately, while 50% of patients
fail to take them correctly.
• Inappropriate self-medication of prescription-only medicines.

2. Impact of irrational use of medicines: Massive detrimental

effects:
• Ineffective treatment leading to serious morbidity and ­mortality,
both in infections and in chronic diseases, such as hyperten-
sion, diabetes, epilepsy, and mental disorders. This would
affect those more who are sicker or who are more vulnerable
due to childhood, old age, or other morbidities.
• Iatrogenic diseases: Diseases caused by the choice of ­hazardous
drugs or by the side effects of essential drugs and inessential
drugs. As the number of drugs prescribed increases, the chances
of adverse effects of drugs also increases.

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 12 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

• Inappropriate use and overuse of medicines leading to high

out-of-pocket payments by patients and resulting in significant
patient harm in terms of poor patient outcomes and adverse
drug reactions and needless and avoidable impoverishment of
the patient.
• Inappropriate use and overuse in the public sector facility,
where the government pays the bills, leads to wastage of
meager resources, and a shift of funds away from necessary
expenditures to unnecessary areas.
• Availability of too many not-needed doubtful medicines in the
market leads to lack of consistent supply of needed drugs and
variation of individual prescribing preferences and inconsistent
prescribing, leading to numerous prescribing and dispensing
errors.
• Irrational overuse of medicines can further stimulate inappro-
priate patient demand, further compromising access to med-
icines and attendance rates due to medicine stock-outs and
loss of patient confidence in the health system.
• Increasing antimicrobial resistance: Inappropriate use of anti-
microbials is leading to increased antimicrobial resistance.
Antimicrobial resistance (AMR) is one of the most serious public
health problems globally resulting in prolonged illness and hos-
pitalization, mortality, and higher costs. Use of drugs other than
first-line drugs in such situations may increase costs (sometimes
as high as 100-fold), makes treatment unaffordable for many
governments/health systems, especially in developing countries,
and increase in out-of-pocket expenditure by patients.
Development and spread of antimicrobial resistance is due to:
• overuse, misuse, and irrational use by doctors;
• noncompliance and self-medication by patients; and
• use in animal husbandry, aquaculture, and agriculture.
3. Twelve core interventions to promote rational use of m­ edicines:
• Essential Medicines List and drug formulary based on that list
• Standard Treatment Guidelines
• Drugs and Therapeutics Committees in hospitals. This is
a committee designated to ensure safe and effective use of
medicines in hospital.
• In-service continuing medical and nursing and pharmacy
education
• Rational drug use in undergraduate curricula
• Supervision, monitoring, audits
• Independent prescriber information on medicines
• Public education about medicines and awareness of essential
drug concepts
• Procurement and logistics within the public health system
• Appropriate and enforced regulation
• Sufficient public health and public drug expenditure

J. Drug information sources

The quantity of medical information and medical literature avail-
able is growing at an overwhelming rate. Numerous resources of

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 I. General Pharmacology 13

information on medicines are available which include textbooks, med-

ical journals, reference books, drug compendia, national medicines
lists, essential medicines and treatment guidelines, drug formularies,
drug bulletins, drug information centers, Internet, and the pharma-
ceutical industry. The technology by which this information can be
accessed is also improving exponentially. The introduction of Internet
resources, personal digital assistants (PDAs), and smartphones has
radically changed the methods and technology of the way information
is accessed. It is therefore important to evaluate the quality of infor-
mation provided by each source.
Sources are considered primary, secondary, or tertiary d ­epending
on the originality of the information and their proximity or closeness
to the source of information. Primary sources constitute papers or
technical reports or case studies published in a journal article. Once
published, the information may be commented on by other research-
ers and/or professionally indexed in a database that comprises sec-
ondary sources (for ­example, review article, textbook specialized to a
narrow topic or a more broader overview, article indexes/databases
such as Biological Abstracts/MEDLINE). Tertiary sources are when
the information from primary and secondary sources is summarized
into a textbook or full-text databases or r­eference book format, drug
reference books, drug compendia, etc. Tertiary sources provide infor-
mation about the established drugs as well as newer drugs and treat-
ment options.
Generally, the best method to find authentic information includes a
stepwise approach moving first through tertiary sources, then through
secondary sources, and finally through primary source literature. The
tertiary source initially provides the required information to familiarize
the reader with the topic, the disease or drug in question, which will ulti-
mately result in a more structured and productive and effective search.
In case the information obtained from the tertiary resources is not recent
or comprehensive enough, a secondary database may be employed.
Primary resources include published meta-analyses, randomized
controlled trials, observational trials, and case reports. There is a
wide range of journals available that can assist one in keeping up
to date in the different aspects of medical practice. The information
obtained from this literature is the basis for developing guidelines for
evidence-based practice. Although good medical journals are peer-­
reviewed, a review article or researched study appearing in print
does not necessarily mean good science. Though primary resources
are most up-to-date information, they require critical skills in inter-
pretation and evaluation of the strength of evidence (described as
above). Moreover, decisions should not be based on a single piece of
­evidence, but rather on a compilation of all the available evidence.
1. Internet sources of drug information: The Internet is the most
readily accessible and widely used source of information includ-
ing primary, secondary, and tertiary data but due to the unregu-
lated nature of the Internet, it is of utmost importance to critically
evaluate information obtained by this method. With the increas-
ing popularity of the Internet, many primary resources may be
accessed directly from the web site of the publisher or medical or
a pharmacy journal. The majority of journals require a subscrip-
tion but some journals may be open access. Often, access to the
abstract is free of charge even in subscription journals. Due to the

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 14 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

limited information provided and inherent bias in an abstract, it is

critical to ascertain whether obtaining the article may be of value
before making a therapeutic decision.

K. Essential Medicines List

Essential medicines are those that satisfy the priority healthcare
needs of the population. They are selected with due regard to d
­ isease
prevalence, evidence on efficacy, safety, and comparative cost-­
­
effectiveness. Essential medicines are intended to be available within
the context of functioning health systems at all times in adequate
amounts, in the appropriate dosage forms, with assured quality, and
at a price the individual and the community can afford.
Implementation of the concept of essential medicines is intended to
be flexible and adaptable to many different situations; exactly which
medicines are regarded as essential remains the responsibility of
states within a national framework.
Essential drugs are neither to be understood as only consisting of
life-saving drugs nor as medicines for the treatment of rare diseases.
The concept of essential drugs includes all the drugs needed for most
commonly encountered diseases including life-saving conditions. The
concept was mentioned in 1 of the 10 points of the 1978 Alma Ata
Declaration on primary health care.
1. Impact of essential medicines: A limited range of carefully
selected essential medicines leads to
• better health care,
• better drug management and health outcome (including pro-
curement, storage and distribution, and improved quality of
prescribed medicines),
• cost-effective use of health resources.
Access to essential drugs, high expenditure on drugs, and irra-
tional competition of unscientific or even hazardous drugs are
the three problems people face and public systems are chal-
lenged to response to. Nonavailability of medicines can block
the operation of the healthcare system. Attendance at health
services, credibility, and effectiveness of the healthcare system
depend to a large extent on the patient being able to obtain rel-
evant drugs at the right time. A patient values services only if he/
she obtains necessary treatment and medicines. A good diagno-
sis is of not much use if the patient cannot obtain the necessary
treatment.
The WHO Model List of Essential Medicines is a list of essential
medicines created by the World Health Organization (WHO) which
serves as a guide for the development of national and institutional
Essential Medicine Lists (EML). It is updated and revised every
2 years by the WHO Expert Committee on Selection and Use
of Medicines. The list was first published in 1977. Since 2007,
a separate list for children up to 12 years (WHO Model List of
Essential Medicines for Children) is being brought out. The 18th
edition for adults and the 4th edition for children were released
in April 2013. The WHO EML has steadily grown in terms of the
number of drugs included in the list with each update. Initially in

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 I. General Pharmacology 15

1977, the WHO EML had 204 molecules and the current list of
2013 includes 374 unique molecules. The 2013 WHO EML has Improving Health Outcomes
431 molecules with duplications across indications and includes The primary advantage is that it
both core and complimentary medicines. provides a systematic method
Worldwide, the concept of essential medicines has been accepted to review scientific evidence on
as a powerful tool to promote health equity and its impact is clinical effectiveness and cost
remarkable, as essential medicines are considered to be one of effectiveness in drug selection
the most cost-effective elements in health care. This model WHO decision, thus potentially improv-
EML is customizable to clinical guidelines for healthcare practice, ing health outcomes while reduc-
to region-specific public health issues, to least costly or most ing costs.
accessible therapeutic equivalent, and can be implemented on a Efficient Pharmacy
country, state, or institutional level. Management
2. Formulary system: The formulary system is a mechanism for the It is difficult to achieve efficiency
ongoing assessment of availability of medicines to assure safe and in the hospital pharmaceutical
effective use of drugs in a cost-conscious manner. The formulary system if there are too many
process is the cornerstone of good pharmaceutical management brands of the same medicines.
and safe use of medicines. A formulary list (also referred to as All aspects of drug management,
Essential Medicines List) is a limited list of the most cost-­effective, including procurement, storage,
safe, and available medicines of assured quality which meets the distribution, and use, are easier if
priority health needs of the population. A formulary manual is fewer items are to be dealt with,
developed and maintained based on the recommended treatments there are fewer stockouts, there
from Standard Treatment Guidelines, using explicit drug selection is containment of inventory cost,
criteria (relative efficacy, safety, suitability, and cost). and it can lead to improved drug
The formulary process consists of preparing, using, and updat- availability in hospitals. It also
ing a formulary list, a formulary manual (providing information on improves efficiency and reduce
drugs in the formulary list), and Standard Treatment Guidelines confusion and thereby medica-
(choosing the most appropriate therapies, STGs) in a hospital. tion errors.
The benefits that arise from a limited range of carefully selected Improved Quality of Care
medicines are numerous and well known and include improved
Patients are treated with fewer
drug therapy, decreased adverse drug reactions (ADRs), better
but more cost-effective medi-
health care, better drug management and health outcome (includ-
cines for which information can
ing efficiency in procurement, inventory management, storage and
be better provided. The doctors
distribution, and improved quality of prescribed medicines), and
gain more experience with fewer
decreased overall healthcare cost. The advantages of the drug
drugs and recognize drug interac-
formulary list are given in Figure 1.6. Carefully selected essential
tions and adverse drug reactions
medicines lead to cost-effective use of health resources. The for-
better. Quality of care will be fur-
mulary concept is intended to be flexible and adaptable to many
ther improved if medicine selec-
different situations. Exactly which medicines are regarded as
tion is based on evidence-based
essential remains a national responsibility as well as an individual
treatment guidelines.
hospital responsibility. The selection of essential medicines, pref-
erably linked to Standard Clinical Guidelines, is a crucial step in
ensuring access to health care and in promoting rational use by Figure 1.6
health professionals and consumers. Advantages of drug formulary list.
The factors that are critical to the use of a hospital formulary
by health workers are their involvement in the development and
updating process, the quality of the content, a user-friendly for-
mat, and adequate distribution and follow-up supervision.
The process by which the medicines are selected is critical to its
acceptance by the prescribers. An essential medicines list which is
imposed from above and does not reflect the needs of the users
will not be accepted and used by the prescribers. It is therefore very
important that the formulary development process be consultative
and transparent and that the selection be based on explicit criteria

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 16 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

Drugs are selected depending on many factors, such as the pattern of prevalent diseases, treatment facilities,
training and experience of available personnel, financial resources, and genetic, demographic, and environmen-
tal factors. WHO (1999) has developed the following selection criteria:
• Only those medicines should be selected for which sound adequate data on efficacy and safety are available
from ­clinical studies and for which evidence of performance in general use in a variety of medical settings in
terms of efficacy, suitability, safety, and cost effectiveness has been obtained (Figure 1.8).
• Each selected medicine must be available in a form in which adequate quality, including bioavailability, can be
assured; its stability under the anticipated conditions of storage and use must be established.
• When two or more medicines appear to be similar in the above respects, the choice between them should
be made on the basis of a careful evaluation of their relative efficacy, safety, quality, price, and availability.
• In cost comparison between medicines, not only the cost of the total treatment but also the unit cost of the
medicine must be considered. In cases where drugs are not entirely similar, the selection should be made on
the basis of a cost-effectiveness analysis.
• In some cases, the choice may also be influenced by other factors, such as pharmacokinetic properties, or
by local considerations, such as the availability of facilities for storage or manufacturer.
• Most essential medicines should be formulated as single compounds. Fixed-ratio combination products are
acceptable only when the dosage of each ingredient meets the requirements of a defined population and when
the combination has a proven advantage over single compounds administered separately in therapeutic effect,
safety, or compliance.
• Drugs are specified by the international nonproprietary name (INN) or generic name without reference to
brand names or specific manufacturers.

Figure 1.7
Criteria in selection of medicines for hospital formulary.

(based on efficacy, safety, quality, cost [which will vary locally]) and
cost-effectiveness. Figure 1.7 depicts the criteria for selection of
medicines for hospital formulary. Finally, selection of the medicines
For example, SIGN—Scottish
should be linked to evidence-based Standard Clinical Guidelines.
Intercollegiate Guidelines Network
Evidence-Based Medicine (EBM) is defined as “the conscientious,
(1++) High-quality meta analysis, explicit and judicious use of current best evidence in making deci-
systematic reviews of random- sions about the care of the individual patient.” EBM is the inte-
ized controlled trials (RCTs), or gration of the best available clinical evidence with an individual’s
RCTs with a very low risk of bias. ­clinical expertise and patient’s values and expectations. The hierar-
(1+) Well-conducted meta analy- chy of evidence is shown in Figure 1.8. Figure 1.9 shows catego-
sis, systematic reviews of RCTs, ries/levels of evidence. Grading of quality of evidence tells us the
or RCTs with a low risk of bias. extent to which one can be confident that an estimate of the effect
(1) Meta analysis or systematic is correct and provides confidence that the estimates are adequate
reviews of RCTs or RCTs with a to support a particular recommendation (Figure 1.9).
high risk of bias.
(2++) High-quality systematic re- L. Prescription writing
views of case-control or cohort
Prescription is a medicolegal document written by a physician, dentist,
studies; or high-quality case-con-
or any other medical practitioner to the pharmacist giving ­directions
trol or cohort studies with a very
to compound and dispense a specific medication for an individual
low risk of confounding, bias, or
patient. Prescription is actually a direct link between the physician,
chance and a high probability
pharmacist, and patient. Over the years, the demand for individually
that the relationship is causal.
compounded medicines has declined; therefore, pharmacists largely
perform the role of filling prescription and patient education ensuring
Figure 1.8 safe and appropriate use by the patient.
Categories/levels of evidence. 1. The prescription: The prescription must be accurately and legibly
(Figure continues on next page) written and identify the patient, the prescriber, the medication to

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 I. General Pharmacology 17

be dispensed, the mode of drug administration, and the duration

of treatment. Avoid abbreviations and Latin as they lead to dis- (2+) Well-conducted case-control
pensing errors. The prescription should also include the therapeu- or cohort studies with a low risk
tic purpose in the subscription (for example, “for control of blood of confounding, bias, or chance
pressure”; use of metformin for the “control of sugar”; losartan for and a moderate probability that
the treatment of hypertension) to prevent errors in dispensing. the relationship is causal.
Further including the therapeutic purpose of the prescription can (2) Case-control or cohort studies
also empower patients and improve compliance with therapy. with a high risk of confounding,
Moreover, inclusion of the patient’s weight on the prescription, bias, or chance and a significant
especially in children, can be useful in avoiding dosing errors. risk that the relationship is not
a. Parts of prescription: The prescription consists of the super- causal.
scription, the inscription, the subscription, the signa, and (3) Nonanalytic studies, for exam-
the name and signature of the prescriber, all contained on a ple, case reports.
single form. (4) Expert opinion.
[1] Superscription: The superscription includes the date
of the prescription; personal data of the patient—name,
address, weight, and age of the patient; and the Rx. Figure 1.8 (Continued)
Rx is an abbreviation for the Latin word “recipere” or Categories/levels of evidence.
“recipe,” which means “Take, thou.” The symbol is said
to designate Jupiter “The God of Healing.”
[2] Inscription: It is a main part of the prescription. It
contains the name, dosage form (such as “tablet,”
“oral solution,” “injection,” “eye ointment”), amount or
strength, and number of doses or quantity of the drug
to be dispensed. It also contains a manner in which the
medicine should be taken.
[3] Subscription: The signa or “Sig” is the instruction for
the patient (for example, how to take the medicines,
interpreted, and transposed onto the prescription label
by the pharmacist).
Historically, this was an instruction to the pharmacist
to compound medications (for example, instructions

Cochrane
Systematic Reviews

Other SRs & Meta-Analyses Strength

of LEVEL DEFINITION
Evidence evidence
High Very confident that the true
Guidelines
effect lies close to that of the
estimate of effect
Evidence Summaries
Moderate Moderately confident that the
RCTs Case Cohorts, true effect is likely to be close
Control Studies to the estimate of effect; but
there is a possibility that it is
Clinical Research Critiques substantially different
Very low Confidence in the effect esti-
Other Reviews of the Literature mate is limited: the true effect
may be substantially different

Case Reports, Case Series, Practice Guidelines, etc. Low Very little confidence in the
effect estimate: the true effect
is likely to be substantially
Clinical Reference Texts
different

Figure 1.9
Evidence-based medicine pyramid.

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 18 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

regarding the fortification of tobramycin eye drops for

Name: XYZ treating a corneal ulcer) since these days, most medi-
Age: 60 years cations are pre-compounded preparations. Subscription
Sex: Female now indicates the quantity of medication (number of
capsules or tablets) such as “dispense 30 tablets” or
Date: 7/05/18
the size of the bottle to be dispensed (5 mL, 10 mL, or
15 mL). Typically, Latin or English abbreviations are used
Diagnosis: Parkinsonism to provide specific instructions translated by the phar-
macist for patient use. Typical instructions on the pre-
scription used to include use of Latin abbreviations such
Rx
as BD for twice daily, TDS for thrice daily, HS at night,
and SOS for as and when required. It also provides for
Tab Levodopa 100 mg plus the number of refills the patient should need to complete
Tab Carbidopa 25 mg 2 ­ tablets the cycle of drug treatment. Most antibiotic and steroid
by mouth 3 times daily for one prescriptions need no refills or one refill only.
month. Take with food. [4] Signature of the physician: The prescription must be
signed in the prescriber’s own hand and dated. Address,
Dr. XYZ telephone number, and registration number should be
clearly stated in the prescription which could either be
Assistant Professor of Neurology,
preprinted on the prescription or stamped with all these
Reg. No. 1345 details. This will allow either the patient or the dispenser
Date to contact the prescriber for any clarification or potential
problem with the prescription.
Prescriptions should preferably be written in the domi-
nant language of the patient or English. Latin is no ­longer
the international language of medicine, but a number
of prescribers continue to use obsolete Latin usage.
Avoid using them. Latin abbreviations, for example,
“1 cap q1d,” should be interpreted by the pharmacist
as “take one capsule once a day” but this can easily be
mistaken for QID leading to four times the dose. Clear
and explicit directions specifying the route, dose, and
frequency should be written; avoid using of phrases
such as “take as directed” or “take as before.” For med-
icines which are to be taken on an “as required” basis,
the minimum dose interval should be stated together
along with the maximum permissible daily dose. It is
a good practice to qualify such prescriptions with the
purpose of the medication (for example, “every 6 hours
as required for pain” or “at night as required to sleep”).
It is a good dispensing practice to explain these direc-
tions to the patient; these directions should then be
reinforced by the label on the medicine.
[5] Quantity to be dispensed: The quantity of the med-
icine to be supplied should be clearly stated in such
a manner that it does not get confused with either
the strength of the product or the dosage directions.
Alternatively, the length of the treatment course may be
stated (for example, “for 5 days”). Whenever possible,
the quantity dispensed should be adjusted to avoid strip
cutting. Medicines with a single-dose regimen should
be procured matching the pack size facilitating dis-
pensing of single dose (without strip cutting) or in other
cases adjusted to match the available pack size (for

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 I. General Pharmacology 19

example, if medicines are prescribed in a dose of three

times a day for 7 days which makes the total quantity
to be dispensed as 21 tablets and the available pack
size is of 10 tablets in each strip, then 20 tablets could
be dispensed to avoid strip cutting). Strip cutting is an
error-prone activity and can be dangerous if it involves
high-alert or look-alike, sound-alike drug. For liquid
preparations, the quantity should be stated in milliliters
(abbreviated as “ml”) or liters (abbreviated as “L,” since
the letter “l” could be confused with the figure “1”).
[6] Narcotics and controlled substances: The prescrib-
ing of a medicine that is liable to abuse requires spe-
cial attention and may be subject to specific statutory
requirements. Practitioners may need authorization to
prescribe controlled substances; in such cases, it might
be necessary to indicate details of the authority on the
prescription. In particular, the strength, directions, and
the quantity of the controlled substance to be dispensed
should be stated clearly, with all quantities written in
words as well as in figures to prevent alteration. Other
Principles of prescription writing
details such as patient particulars and date should also
be filled in carefully to avoid alteration and unauthorized
refills. The prescription for controlled substances is valid Define patient problem
for up to 14 days. The prescription for narcotics should
be rewritten and should not be refilled by “continue Select the correct drug
same treatment as above.”
[7] Off-label prescribing: “Off-label” means the licensed Identify all possible factors
medicine is used in a manner not specified in the DRA’s
approved packaging label or insert. For example, botu-
Consider patient’s beliefs,
linum toxin has been approved for use in treatment of concerns and expectations
spasm but its use to treat migraine is off-label use; che-
motherapy is approved to treat one type of cancer, but
Select safe and cost-effective
if it is used to treat a different type of cancer or when drugs
given in a different way from the approved dose or dos-
age form, it would amount to off-label use. Adhere to national and
2. Principles of prescription writing (Figure 1.10): In modern med- local guidelines
icine, prescribing medicines is the main approach to the treatment
and prevention of disease. Though medicines have the capacity to Write unambiguous legal
enhance health or sometimes are life-saving, at the same time all prescription
have the potential to cause harm and could be life-­threatening, if
used inappropriately (for example, adverse drug reactions, under- Monitor both beneficial and
or overdose, and medication errors). One of the basic principles in adverse drug effects
treatment is “First do no harm” as stated by Hippocrates. Stories
of medical remedies causing more harm than good have been Communicate the actual reason
recorded from time immemorial. An iatrogenic disorder occurs
when the deleterious effects of the therapeutic or diagnostic reg- Prescribe within limitations
imen cause pathology independent of the condition for which the of knowledge and skills
initial regimen was advised, for e ­xample, extrapyramidal symp-
toms seen with antipsychotic agents. Iatrogenic disease is one of Monitor and evaluate the
the most frequent causes of hospital admissions and constitutes treatment
a growing public health problem. Polypharmacy (patients receiv-
ing multiple drugs) and potentially inappropriate medications have
been associated with many negative health outcomes, including Figure 1.10
adverse drug reactions, falls, nonadherence, reduced quality of Principles of prescription writing.

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 20 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

life, addiction, hospitalizations, and mortality. Efficacy and safety

do not lie solely with the drug but the successful pharmacotherapy
depends on the application of pharmacodynamic and pharmaco-
kinetic principles in light of knowledge gained in clinical medicine.
It requires critical thinking skills to maximize therapeutic benefits
weighing drug- and patient-related variables.
Certain principles of prescription writing have been laid out as
below for safe use of medicines:
a. Define the patient’s problem and be clear about the rea-
sons for prescribing:
• Establish an accurate diagnosis (although this may at
times be difficult) whenever possible.
• Specify a clear therapeutic objective based on the underly-
ing pathophysiology. Sometime, more than one therapeu-
tic goal may be set for a given patient.
• Select the therapeutic strategy. It should be a shared
­decision involving patients.
The select treatment can be nonpharmacological and/or
pharmacological. Nonpharmacological treatment is equally
important as very often, health problems can be resolved by
a change in lifestyle, diet, exercise, or psychological support.
b. Select the correct drug considering the patient’s history
before prescribing:
• Obtain an accurate list of current and recent medications
(including over-the-counter and alternative medicines) and
a history of prior adverse drug reactions and drug aller-
gies and undertake medication reconciliation, especially at
transition points.
• Drugs sometimes are a cause of a disease but withdrawal
of drug, if abrupt, can also cause disease. For example,
sudden withdrawal of benzodiazepines and antiepileptic
agents can lead to withdrawal syndrome.
• The sources of this information/history may come from
patients, family/carers, or other healthcare practitioners.
c. Identify other factors that might alter the benefits and
risks of treatment:
• Consider individual risk factors that might influence the
prescription (for example, genetics, physiological changes
with age and pregnancy, concomitant diseases, or impaired
liver, kidney, or heart function).
d. Take into consideration the patient’s beliefs, concerns,
and expectations:
• While selecting treatments, make sure that the patient under-
stands and agrees with the reasons for taking the medication.
e. Select efficacious, safe, and cost-effective drugs appro-
priate for the patient:
• The likely beneficial effects of a drug should outweigh any
potential harms. At the same time, also consider the likely
harms of treating versus likely harms of not treating, when-
ever possible, this decision should be based on published
evidence.

LIR_CH01.indd 20 16/10/18 12:04 PM

 I. General Pharmacology 21

• Choose the most suitable formulation, dose, frequency,

route of administration, and duration of treatment.
• Prescribe medicines for their approved indications only.
Pay special attention to drugs that are liable to abuse
which come under specific statutory requirements. Do
not p­ rescribe medicines for conditions other than those
approved by the DRA (also called “off-label” use) or out-
side standard practice as far as possible unless satisfied
that no effective alternative is available or when avail-
able would not meet the patient’s needs. This decision
should be based on explicit evidence and/or experience
of the likely benefit–harm balance of all available options.
• In most cases, treatment should be started with a low
dose and the dose gradually increased by monitoring the
patient’s response or a loading dose may be administered
as may be needed (for example, glucocorticosteroids,
phenytoin, valproic acid, warfarin, and amiodarone).
f. Adhere to the national or local guidelines where appropriate:
• Be aware of evidence-based recommendations developed
by respected professional organizations.
• Balance specific drug selection considering the needs of
the patient and cost and verify the suitability of the cho-
sen medicine for each patient. Select medicine may be the
best medicines for a given patient; however, a final decision
while selecting medicines should be taken with regard to
overall costs and needs of other patients considering pub-
lic health requirements as healthcare resources are finite.
• Access, identify, and use only reliable and validated
sources of information, and evaluate potentially less reli-
able, such as Internet, information critically.
g. Write unambiguous legal prescriptions using the correct
documentation:
• Write the drug name by the generic name in Capitals.
• Be aware of the medicines and common factors that
cause medication errors (such as high-alert, look-alike and
sound-alike medicine [LASA], and abbreviations) and know
how to avoid them.
• Avoid abbreviations and Latin to prevent dispensing errors.
Do not write abbreviated drug names.
• Do not use unapproved, nonstandard, or error-prone abbre-
viations, symbols, and dose designations. Avoid decimal
wherever possible (write 125 micrograms instead of 1.25 mg)
and do not write naked or trailing decimals (for example,
“.5 or 1.0” mg). Do not abbreviate micrograms and nano-
grams. State strength in standard units using abbreviations
those are consistent with the System Internationale (SI).
Further, hand-written U can easily be mistaken for “0 or 4.”
h. Monitor both the beneficial and the adverse drug effects
of medicines:
• Understand how to alter the therapeutic regimen as a
result of this information.
• Know the system to report adverse drug reactions.

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 22 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

i. Communicate the reasons for and document prescribing

decisions:
• Communicate clearly with the patient as well as the phar-
macist in the language which the patient understands.
• Give information to patients about how to take the med-
icine correctly, its potential benefits, and adverse effects
(especially those that will require urgent attention), and
any monitoring that is required. Use patient education aids
when possible, such as patient information leaflets, dose
organizers, and posters.
• Document prescribing decisions in the health record accu-
rately and in real time.
j. Prescribe within your limitations of knowledge, skills, and
experience:
• Always keep relevant knowledge and skills up to date.
• Be prepared to seek the advice and support of qualified
professional colleagues, if required.
• Verify all information on prescriptions before handing over
to the patient.
k. Monitoring treatment and de-prescribing or de-escalation
when necessary:
• Evaluate the outcome of treatment on follow-up visits to
Polypharmacy
allow the stopping of the drug (if the patient’s problem is
solved) or to modify it when necessary providing important
information about the adverse effects of drugs contribut-
ing to building up the body of knowledge of pharmacovig-
ilance and promoting rational use of drugs.
Beware of look-alike,
sound-alike (LASA) • De-prescribing is a process of tapering, discontinuing, or
combinations withdrawing unnecessary drugs with the goal of managing
polypharmacy and improving patient outcomes. The pro-
cess of de-prescribing can be planned and supervised by
healthcare professionals.
PCM
Avoid use of drug
CPM
name abbreviations M. Medication errors
CPZ
Every step in patient care involves a potential for error and some
degree of risk to patient safety. Errors in ambulatory and ICU pre-
scribing are a major public health problem. On average, more than
0.125mg → 125 mcg
Avoid use of one medication error each day is expected. The real key to patient
BT → Bedtime
error-prone
1.0 mg → 1 mg
abbreviations safety is reducing or eliminating harm to patients. Medication error
OD → Once daily
d → Day/dose
and trailing can occur in the process of ordering, transcribing, dispensing, admin-
QID → 6 hourly decimal istering, and monitoring of medication. A medication error may or may
not result in an actual adverse drug event.
1. Risk factors (Figure 1.11):
“1” and number “1” a. Polypharmacy and irrational use of medicines: Polypharmacy
Avoid errors due
“0” and number “0”
to mixups
is the largest risk factor, which on one hand increases the
“Z” and number “2” chance of adverse drug reactions and on the other hand
makes it vulnerable to medication errors.
b. Look-alike, sound-alike (LASA) combinations: Confusing
drug names, particularly sound-alike names, is one of the
Figure 1.11 most common causes of medication error and is of concern
Risk factors of medication errors. worldwide. This includes confusion between nonproprietary

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 I. General Pharmacology 23

names and proprietary (brand or trademarked) names. Many

drug names look or sound like other drug names (for example,
Glynase [glyburide], and Zinase [combination of diclofenac
potassium and serratiopeptidase]; Daonil [glibenclamide],
Duodil [chlorzoxazone], and Diovol [antacid]; Lasix [furose-
mide], and Lorax [lorazepam]. Illegible handwriting and incom-
plete knowledge of drug names further add to this confusion.
Availability of the products with similar packaging or labeling,
and the failure of manufacturers and regulatory authorities to
recognize prior to approving new product names and packing
continue to threat prescribing and administration errors.
c. Use of abbreviations for drug names: Acronyms such as
PCM (paracetamol), CPM (chlorpheniramine), CPZ (chlor-
promazine), CBZ (carbamazepine), THP (trihexyphenidyl),
TFP (trifluoperazine), ASA (aspirin), and 5-ASA (5-aminosalicylic
acid) are an important source of errors. Moreover, a prescrip-
tion is a medicolegal document, and these acronyms are not
standard abbreviations used by all and may be interpreted
differently, for example, MS (magnesium sulfate or morphine
sulfate). The full drug name should be written out.
d. Use of error-prone abbreviations: Use of error-prone abbre-
viations, symbols, and dose designations.
e. Errors due to mixups: Between “l” and the number “1”; “O”
and “0”; “Z” and “2”; “1” and “7.” For example, Q1d can
easily be mistaken for QID leading to four times the dose
and hand-written “U” could easily be interpreted as “0 or 4.”
Therefore, “Unit” should always be written.

N. Irrational, nonessential, and hazardous drugs

in the market
Tremendous transformation has been witnessed in the pharmaceutical
industry since the 1950s leading to its increasing profits; at the same
time, huge numbers of irrational, nonessential, and hazardous drugs
have flooded the market. It needs to be clearly understood that as little
as about 300 to 400 pharmaceuticals are capable of providing all the
useful therapeutic value that any medicine can provide for any type of
illness. This is what the “Essential Medicines List” is really. Even if we
include a number of drugs which are safe and efficacious but duplicate
the effects provided by one of these 300 chemicals, still we should have
maximum 750 to 1000 drugs on Essential Medicines List. Yet, it is esti-
mated that there are as many as 70,000 formulations available in the
market today. This is a source of tremendous confusion for both the
doctors and the patients, since in any case the patients would have little
knowledge of what drug has been prescribed to them and even doctors
would not easily be able to interpret the prescription of another doctor. It
is estimated that as many as 90% of the drugs sold in the market today
and consumed by people are the same essential drugs being sold under
different brand names, or they may be inessential drugs, or worse they
may even be irrational/unscientific or hazardous drugs.
1. Sources of these drugs: Most formulations are brand names
given by companies for the same drug. Another large set of

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 24 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

formulations are what are called fixed-dose combinations (FDCs)

of one or more of the drugs.
Cough syrup It must be noted that except for about 10 drug combinations where
there is a pharmacologic synergy in combining the drugs in a cer-
tain dosage form, most FDCs are irrational and inadvisable. This is
because the dose of each of the drugs in the combination may
have to be altered at different rates at different times, or because
the combination is with an inessential or even hazardous drug.
Pain killer
Combinations of allopathic drugs with AYUSH drugs, almost all of
which are neither tested nor certified, form another major group
of irrational drugs. Another large set of formulations are made of
drugs which have no therapeutic value or have much less value
than the generic preparation of the active ingredient. A large num-
Energizers ber of cough syrups, pain killers, tonics, gripe waters, digestives,
energizers, and so on are examples of this category (Figure 1.12).
Another large set are basically drugs which are minor and less
effective drugs, or more hazardous drugs, or more costly variants
of other active drugs available for that purpose. Most of these
Tonic water drugs comprise antibiotics, vitamins, and anti-inflammatory anal-
gesics. There are also, surprisingly, a number of drugs that have
been clearly banned by the Drug Control Authority of India, but
which still continue to be available in the market and continue to
be prescribed/used. Most of them are there through some weak-
Figure 1.12
ness in the banning order or some technical device that has been
Commonly available fixed-dose used to contravene the order.
combinations.

O. Fixed-dose combinations
Fixed-dose combinations (FDCs) are formulations of two or more
active ingredients combined in a single dosage form available in cer-
tain fixed doses. Fixed ratio combination products are acceptable
only when the dosage of each ingredient meets the requirement of
a defined population group and when the combination has a proven
advantage over single compounds administered separately in thera-
peutic effect, safety, or compliance (The Use of Essential Drugs. Model
List of Essential Drugs [Seventh List]. Fifth report of the WHO Expert
Committee. World Health Organ Tech Rep Ser. 1992; 825:1–75). FDCs
by simplifying the medication regimen may improve medication com-
pliance by reducing the pill burden of patients. However the data
on comparison of fixed-dose combination with free-drug regimen
to improve a patient’s medication compliance is limited except in
some conditions only in patients with chronic conditions like hyper-
tension for improving medication compliance which can translate into
better clinical outcomes. On the other hand, there are concerns about
increased adverse effects, particularly postural hypertension, among
drug-naive patients treated initially with two antihypertensive agents.
Most of the pharmaceutical companies manufacture a wide number
of FDCs as novel products without adequate supporting evidence of
proven better efficacy over single drugs, safety, and cost advantage.
1. Concerns with FDCs (Figure 1.13): FDCs are highly popular
in India and a large numbers of FDCs are available in the phar-
maceutical market. Apart from these, most of the FDCs are not
only unnecessary but are also big public health problems as they

LIR_CH01.indd 24 16/10/18 12:04 PM

 I. General Pharmacology 25

are heavily promoted and prescribed to cover up for diagnostic

imprecision and lack of access to laboratory facilities. Such inju-
Concerns related to FDCs
dicious use of FDCs of antibiotics can rapidly give rise to resistant
strains of organisms, which is a matter of serious concern, espe-
cially in resource-poor settings. The problem gets worsened as Safety concern
these FDCs are freely available as over-the-counter products.
a. Safety concern: Some fixed-dose combinations avail- Increased potential for
able in the market are unsafe and even dangerous: The medication error
most serious concern with irrational FDCs is that they expose
patients to an unnecessary risk of adverse drug reactions Prescription from AYUSH
(ADRs). In case a patient suffers from any ADRs, it is diffi- practitioners/quacks
cult to pinpoint the offending agent, for example, in an FDC
such as phenacetin + aspirin + caffeine (APC; additive toxic- Ineffective combination
ity potential, for example, with anti-TB drugs, streptomycin,
kanamycin, and capreomycin when combined, as they have Difference in their response
the same side effects [oto and nephrotoxicity]). and sensitivity to drugs

Some FDCs are unsafe and may be even dangerous when mul-
tiple drugs from the same therapeutic group are combined and Ineffective dosage
particularly when centrally acting drugs are clubbed together.
If the former compounds the risk of adverse effects, the latter Abuse liability
makes it difficult to undertake separate dose adjustments of
the drugs that are combined. FDCs containing two or more Difference in biological half-life
antiepileptic drugs to treat epilepsy; FDCs containing antipsy-
chotics, antidepressants, and sedatives; antidepressants + FDCs and pharmaceutical
antipsychotics + sedatives + anticholinergic; p ­ aracetamol and industry
codeine in older people; and pediatric formulations of nime-
sulide + paracetamol. Nimesulide alone has greater antipyretic FDCs vis-a-vis copacked drugs
properties than paracetamol, more anti-­ inflammatory prop-
erties than aspirin, and equivalent in analgesia to any of the
FDC vis-a-vis step-up therapy
NSAIDS alone, so there is no gain in efficacy with the added
paracetamol in the FDC. However, the patient may be subject
to increased hepatotoxic effects from the combination. FDCs
of diclofenac + serratopeptidase do not offer any particular Figure 1.13
advantage over the individual drugs given separately despite Concerns with fixed-dose combina-
the claim of rapid resolution of inflammation with serratopep- tions (FDCs).
tidase. On the other hand, the patient is exposed to a greater
risk of gastrointestinal (GI) irritation and serious bleeding from
unsuspected peptic ulceration.
FDCs of quinolones and nitroimidazoles (for example, combina-
tions of [antiamoebic] with tinidazole + loperamide; norfloxacin +
tinidazole + dicyclomine; norfloxacin + tinidazole; norfloxacin +
metronidazole; ciprofloxacin + tinidazole; ofloxacin + ornida-
zole) have not been recommended, but continue to be heavily
prescribed drugs in GI infections, pelvic inflammatory disease,
dental infection, etc., to cover up for diagnostic impreci-
sion and lack of access to laboratory facilities. Such injudi-
cious use of antibiotic FDCs can rapidly give rise to resistant
strains of microorganisms, which is a matter of serious con-
cern in a resource-poor setting. Emergence of ciprofloxacin-­
resistant Salmonella typhi strains made treatment of typhoid
fever more difficult and expensive in India.
Absence of information on adverse effects of the FDCs avail-
able in market with the pharmacovigilance program being at

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 26 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

a nascent stage and low reporting of adverse events further

hamper safety data collection.
b. Increased potential for medication errors: Multifold use of
drugs compounded by confusion generated by multiple brand
names, especially many FDC formulations, gave rise to mul-
tiple branded products. For example, 211 antipsychotic FDC
products from 10 formulations to 2,739 NSAID FDC products
from 124 formulations are available in the market.
Sometimes even approved FDC formulations contain banned,
restricted, or never-approved drugs; for example, phenylpro-
panolamine is a banned drug in other countries due to the
risk of stroke. Nimesulide containing formulations have been
banned from use in children below 12 years of age in India.
Phenylpropanolamine and its formulations have also been
banned in India. Recently, nimesulide and phenylpropanol-
amine containing formulations has been banned from use in
children below 12 years of age in India.
Irrational FDCs not only impose unnecessary financial burden
on consumers but also are misleading. The patient has to pay
for two drugs when one (or even none) may be needed for the
patient. The FDCs are marketed with slogans such as “ibu-
profen for pain and paracetamol for fever” and “ibuprofen for
peripheral action and paracetamol for central action” which
are misleading and unsafe. Similarly, there is no synergism
when two drugs acting on the same enzyme are combined.
Thus, combining two NSAIDs does not and cannot improve
the efficacy of treatment.
c. Prescription from AYUSH quacks: Ayush practitioners are
not knowledgeable about the principles of modern medicine
and do not have the capability to rationally choose and pre-
scribe individual components separately.
d. Ineffective combinations: Combination of Vitamin B series
with an inadequate dose below RDA of each vitamin is an
ineffective combination
e. Patients differ in their response and sensitivity to drugs:
Adjustment in dosage and dose interval may be necessary.
f. Ineffective dosage adjustments: Dosage of some of the
drugs needs to be adjusted depending on the response to
drug therapy and stage of the disease. For example, epileptic
and cardiovascular drugs are not suitable for patients who
take different doses at different stages, such as initial and
maintenance phases.
g. Abuse liability: Some combinations have abuse liability, for
example, FDCs containing dextropropoxyphene, phenobarbi-
tone, and corticosteroid.
h. Difference in biological half-life and quality of FDCs:
Rifampicin has variable bioavailability from solid oral dosage
forms; thus, its potency will be severely affected by using
­formulations with poor bioavailability.
i. FDCs and pharmaceutical industry: FDCs is one of the
ways to extend the patent and marketability of a drug product.

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 I. General Pharmacology 27

FDCs may be protected by patents, even though the individ-

ual active ingredients may be off-patent.
j. FDCs vis-a-vis copacked drugs: FDCs should be distinguished
from copacked drugs and combination therapy. For example,
some medicines, such as for the treatment of AIDS and tuber-
culosis, are copackaged as unit-of-use to target a single disease
to delay the emergence of resistance; ­atorvastatin + amlodipine
is combined to target multiple diseases. Combination therapy
refers to treatment with two or more active drugs, administered
at one time in their individual formulations.
k. FDC vis-a-vis step-up therapy: Sometimes, FDCs are con-
sidered to be essential as a measure for improving compli-
ance but should be delineated from step-up therapy where
medicines are added to the regimen over time depending on
the progress of the patient. However, physicians should be
familiar with individual components. Switching to FDC may
be considered once the dose of the individual medicines is
established and the regimen is well tolerated to overcome
compliance issue.
2. Rationality of FDCs: The rationality of FDCs is based on certain
aspects which are as follows:
• The pharmacokinetics of the drugs combined in a formulation
must not be widely different.
• The fixed-dose combination should not have supra-additive
toxicity of the ingredients as a combination of the two drugs
may increase the side effects of both the drugs such as com-
binations of NSAIDs and cough and cold formulations.
The World Health Organization’s (WHO) model list of Essential
Drugs provides examples of some rational FDCs such as:
• sulfamethoxazole + trimethoprim,
• antitubercular FDCs like rifampicin + isoniazid + ethambutol,
and pyrazinamide
• antiparkinsonism FDCs like levodopa + carbidopa.

P. The Menace of Fake Drugs: Consequences, Causes,

and Possible Solutions:
Quality control and assurance play an essential role in the
­pharmaceutical manufacturing process, to ensure that safe, effective
medications of good quality are available. Quality issues with medi-
cines are a frequent occurrence, resulting in recalls, withdrawals, or
harm to patients despite advances in technology in the manufacturing
sector. Some commonly used terms are given in Figure 1.14.
DRA maintains and enforces regulatory requirements for quality
of pharmaceuticals manufactured through a group of regulations
known collectively as Good Manufacturing Practices (GMP). Despite
government control on the quality of production, import/export,
­
­storage, ­supply, and distribution through prescribed norms and stan-
dards, substandard and counterfeit drugs proliferate primarily in the
environment where the drug regulation implementation is lax. Both
branded and generic products are subject to counterfeiting. Both
developed and developing countries face the problem of counterfeit

LIR_CH01.indd 27 16/10/18 12:04 PM

 28 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

A substandard medicine is a drug that does not meet quality stan-

dards. It may contain too much or too little of the active ingredient,
may be contaminated, may be poorly packaged, or fail to meet quality
standards in other ways. These medicines may be a result of negli-
gence or of mistakes during the manufacturing process or may have
been deliberately produced. Both originator and generic medicines
can be found to be substandard. Substandard medicines are products
whose composition and ingredients do not meet the correct scientific
specifications as per pharmacopoeia and which may consequently be
ineffective and often dangerous to the patient.
A fake medicine is deliberately and fraudulently mislabeled medicine,
giving false information on where it was made or by whom, in order to
appear as a legitimate medicine. Fake medicines are unlikely to con-
tain the active pharmaceutical ingredient needed to make the medi-
cine effective and may even contain harmful substances.
Spurious drugs: If it is marketed under a name which belongs to
Drug at site of another drug; or if it is an imitation of, or a substitute for, another drug or
administration resembles another drug in a manner likely to deceive or bears upon it or
upon its label or container the name of another drug.
Counterfeit medicines are part of the broader phenomenon of substan-
1 Absorption dard pharmaceuticals. The difference is that they are deliberately and
(input)
fraudulently mislabeled with respect to identity and/or source. The term
counterfeit medicine is overly broad and creates confusion because it
Drug in conflates intellectual property issues with public health problems.
plasma
2 Distribution Spurious/falsely labeled/falsified/counterfeit (SFFC) medicines
may include products with the correct ingredients or with the wrong
ingredients, without active i­ngredients, with insufficient or too much
Drug in active ingredient, or with fake packaging.
tissues
Figure 1.14
3 Metabolism Commonly used terms for reflecting drug quality issues.

Metabolite(s) drugs but the magnitude of the problem is not really known because
in tissues
of nonavailability of global study and nonuniformity in the definitions
used. Different countries and organizations use different definitions
to define the quality of medicines, making it hard to know exactly
4 Elimination which problem is being referred to when this term is used. For all
(output)
practical purposes, WHO describes spurious/falsely labeled/falsified/­
counterfeit (SFFC) medicines that are deliberately and fraudulently
mislabeled medicines with respect to identity and/or source.

Drug and/or metabolite(s) in

urine, bile, tears, breast milk, II. OVERVIEW OF PHARMACOKINETICS
saliva, sweat, or feces
Pharmacokinetics refers to what the body does to a drug, whereas phar-
macodynamics (see Chapter 2) describes what the drug does to the body.
Figure 1.15 Four pharmacokinetic properties determine the onset, intensity, and dura-
Schematic representation of drug tion of drug action (Figure 1.15):
absorption, distribution, metabolism, • Absorption: First, absorption from the site of administration permits
and elimination. entry of the drug (either directly or indirectly) into plasma.

LIR_CH01.indd 28 16/10/18 12:04 PM

 Whalen7-ch001-fig002_v2

III. Routes of Drug Administration 29

• Distribution: Second, the drug may reversibly leave the bloodstream

and distribute into the interstitial and intracellular fluids. Otic
Ocular
• Metabolism: Third, the drug may be biotransformed through metabo-
lism by the liver or other tissues. Nasal Parenteral:
IV, IM, SC
• Elimination: Finally, the drug and its metabolites are eliminated from the Inhalation
body in urine, bile, or feces.
Using knowledge of pharmacokinetic parameters, clinicians can design Oral
optimal drug regimens, including the route of administration, dose, fre- Sublingual
quency, and duration of treatment. Buccal

Transdermal
patch Topical
III. ROUTES OF DRUG ADMINISTRATION
Epidural
The route of administration is determined by the properties of the drug
(for example, water or lipid solubility, and ionization) and by the therapeu-
tic objectives (for example, the need for a rapid onset, the need for long-
term ­treatment, or restriction of delivery to a local site). Major routes of
drug administration include enteral, parenteral, and topical, among others Rectal
(Figure 1.16). or
vaginal

A. Enteral
Enteral administration (administering a drug by mouth) is the most
common, convenient, and economical method of drug administra- Figure 1.16
tion. The drug may be swallowed, allowing oral delivery, or it may be
Commonly used routes of drug
placed under the tongue (sublingual) or between the gums and cheek
administration. IM = intramuscular;
(buccal), facilitating direct absorption into the bloodstream.
IV = intravenous; SC = subcutaneous.
1. Oral: Oral administration provides many advantages and is
the most convenient dosage form. Oral drugs are easily self-­
administered, and toxicities and/or overdose of oral drugs may be
overcome with antidotes, such as activated charcoal. However,
the pathways involved in oral drug absorption are the most com-
plicated, and the low gastric pH inactivates some drugs.
A wide range of oral preparations is available including enteric-
coated and extended-release preparations.
a. Enteric-coated preparations: An enteric coating is a chemi-
cal envelope that protects the drug from stomach acid, deliv-
ering it instead to the less acidic intestine, where the coating
dissolves and releases the drug. Enteric coating is useful for
certain drugs (for example, erythromycin and omeprazole)
that are acid labile for drugs that are irritating to the stomach
(for example, aspirin) and to delay the onset of action to a
specific site within the gastrointestinal tract (sulfasalazine in
the treatment of Crohn’s disease).
b. Extended-release preparations: Extended-release (abbrevi-
ated SR, CR, ER, XR, XL, etc.) medications have special coat-
ings or ingredients that control drug release, thereby allowing
for slower absorption and prolonged duration of action. ER
formulations can be dosed less frequently and may improve
patient compliance. In addition, ER formulations may main-
tain concentrations within the ­therapeutic range over a longer
duration, as opposed to immediate-­ release dosage forms,
which may result in larger peaks and troughs in plasma con-
centration. ER formulations are advantageous for drugs with

LIR_CH01.indd 29 16/10/18 12:04 PM

 30 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

short half-lives. For example, the half-life of oral morphine is

A 2 to 4 hours, and it must be administered six times daily to
Subcutaneous
provide continuous pain relief. However, only two doses are
Intravenous injection
injection needed when extended-release tablets are used.
Intramuscular
Dermal injection 2. Sublingual/buccal: The sublingual route involves placement of
injection drug under the tongue. The buccal route involves placement
of drug between the cheek and gum. Both the sublingual and
Epidermis buccal routes of absorption have several advantages, including
Dermis ease of administration, rapid absorption, bypass of the harsh
gastrointestinal (GI) environment, and avoidance of first-pass
metabolism (see discussion of first-pass metabolism in the fol-
lowing text).

B. Parenteral
The parenteral route introduces drugs directly into the systemic cir-
culation. Parenteral administration is used for drugs that are poorly
Muscle Subcutaneous absorbed from the GI tract (for example, heparin) or unstable in the
tissue GI tract (for example, insulin). Parenteral administration is also used
for patients unable to take oral medications (unconscious patients)
and in circumstances that require a rapid onset of action. Parenteral
B administration provides the most control over the dose of drug deliv-
ered to the body. However, this route of administration is irreversible
200 and may cause pain, fever, local tissue damage, and infections. The
four major parenteral routes are intravascular (intravenous or intra-­
Plasma concentration

5 mg intravenous midazolam
arterial), intramuscular, subcutaneous, and intradermal (Figure 1.17).
Other ­parenteral routes are intra-arterial, intraperitoneal, intra-articular,
(ng/mL)

100 intramedullary, etc.

1. Intravenous (IV): IV injection is the most common parenteral
route. It is useful for drugs that are not absorbed orally, such as
5 mg intramuscular midazolam
0 the neuromuscular blocker rocuronium. IV delivery permits a rapid
0 30 60 90 effect and a maximum degree of control over the amount of drug
Time (minutes)
delivered. When injected as a bolus, the full amount of drug is
delivered to the systemic circulation almost immediately. If admin-
Figure 1.17 istered as an IV infusion, the drug is infused over a longer period,
A. Schematic representation of resulting in lower peak plasma concentrations and an increased
subcutaneous and intramuscular duration of the circulating drug.
injection. B. Plasma concentrations 2. Intramuscular (IM): Drugs administered IM can be in aqueous
of midazolam after intravenous and solutions, which are absorbed rapidly, or in specialized depot
intramuscular injection. preparations, which are absorbed slowly. Depot preparations often
consist of a suspension of drug in a nonaqueous vehicle, such as
polyethylene glycol. As the vehicle diffuses out of the muscle, the
drug precipitates at the site of injection. The drug then dissolves
slowly, providing a sustained dose over an extended interval.
3. Subcutaneous (SC): Like IM injection, SC injection provides
absorption via simple diffusion and is slower than the IV route.
SC injection minimizes the risks of hemolysis or thrombosis asso-
ciated with IV injection and may provide constant, slow, and sus-
tained effects. This route should not be used with drugs that cause
tissue irritation, because severe pain and necrosis may occur.
4. Intradermal (ID): The intradermal (ID) route involves injection into
the dermis, the more vascular layer of skin under the epidermis.

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 IV. Absorption of Drugs 31

Agents for diagnostic determination and desensitization are usu-

ally administered by this route. A Clear backing
Drug reservoir
C. Other Skin Drug-release
membrane
1. Oral inhalation and nasal preparations: Both the oral inhalation
and nasal routes of administration provide rapid delivery of drug Contact
adhesive
across the large surface area of mucous membranes of the respi-
ratory tract and pulmonary epithelium. Drug effects are almost as
rapid as those with IV bolus. Drugs that are gases (for example,
some anesthetics) and those that can be dispersed in an aerosol
are administered via inhalation. This route is effective and con-
venient for patients with respiratory disorders such as asthma
or chronic obstructive pulmonary disease, because the drug is
delivered directly to the site of action, thereby minimizing sys-
temic side effects. The nasal route involves topical administration BLOOD VESSEL

of drugs directly into the nose, and it is often used for patients
with allergic rhinitis.
Drug diffusing from reservoir
2. Intrathecal/intraventricular: The blood–brain barrier typically into subcutaneous tissue
delays or prevents the absorption of drugs into the central ner-
vous system (CNS). When local, rapid effects are needed, it is
necessary to introduce drugs directly into the cerebrospinal fluid. B
3. Topical: Topical application is used when a local effect of the drug
is desired, for example, skin, eye, ear, nose, vaginal, and urethral.
4. Transdermal: This route of administration achieves systemic
effects by application of drugs to the skin, usually via a transder-
mal patch (Figure 1.18). The rate of absorption can vary markedly,
depending on the physical characteristics of the skin at the site of
application, as well as the lipid solubility of the drug.
5. Rectal: Because 50% of the drainage of the rectal region
bypasses the portal circulation, the biotransformation of drugs by
the liver is minimized with rectal administration. The rectal route
has the additional advantage of preventing destruction of the
drug in the GI environment. This route is also useful, if the drug Figure 1.18
induces vomiting when given orally, if the patient is already vom- A. Schematic representation of a
iting, or if the patient is unconscious. Rectal absorption is often transdermal patch. B. Transdermal
erratic and incomplete, and many drugs irritate the rectal mucosa. nicotine patch applied to the arm.
Figure 1.19 summarizes characteristics of the common routes of
administration, along with examples of drugs.

IV. ABSORPTION OF DRUGS

Absorption is the transfer of a drug from the site of administration to the

bloodstream. The rate and extent of absorption depend on the e­ nvironment
where the drug is absorbed, chemical characteristics of the drug, dosage
form, and route of administration (which influences bioavailability). Routes
of administration other than intravenous may result in partial absorption
and lower bioavailability. The choice of an appropriate route in a given
­situation depends on the drug and also depends on patient-related fac-
tors. For example,
• physical and chemical characteristics of the drug and its formulation
(solid/liquid/gas or aqueous solution, suspension, or oil); accuracy of
the dosage, and

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 32 1. General Pharmacology, Pharmacotherapeutics, and Pharmacokinetics

ROUTE OF ABSORPTION
ADVANTAGES DISADVANTAGES EXAMPLES
ADMINISTRATION PATTERN
Oral • Variable; affected by many • Safest and most common, • Limited absorption of some drugs • Acetaminophen
factors convenient, and economical • Food may affect absorption tablets
route of administration • Patient compliance is necessary • Amoxicillin
• Drugs may be metabolized before suspension
systemic absorption

Sublingual • Depends on the drug: • Bypasses first-pass effect • Limited to certain types of drugs • Nitroglycerin
Few drugs (for example, • Bypasses destruction by stomach • Limited to drugs that can be • Buprenorphine
nitroglycerin) have rapid, acid taken in small doses
direct systemic absorption • Drug stability maintained because • May lose part of the drug dose if
the pH of saliva relatively neutral swallowed
Most drugs erratically or • May cause immediate
incompletely absorbed pharmacological effects

Intravenous • Absorption not required • Can have immediate effects • Unsuitable for oily substances • Vancomycin
• Ideal if dosed in large volumes • Bolus injection may result in • Heparin
• Suitable for irritating substances adverse effects
and complex mixtures • Most substances must be slowly
• Valuable in emergency situations injected
• Dosage titration permissible • Strict aseptic techniques needed
• Ideal for high molecular weight
proteins and peptide drugs

Intramuscular • Depends on drug diluents: • Suitable if drug volume is moderate • Affects certain lab tests (creatine • Haloperidol
Aqueous solution: prompt • Suitable for oily vehicles and certain kinase) • Depot
irritating substances • Can be painful medroxy-
Depot preparations: • Preferable to intravenous if patient • Can cause intramuscular progesterone
slow and sustained must self-administer hemorrhage (precluded during
anticoagulation therapy)

Subcutaneous • Depends on drug diluents: • Suitable for slow-release drugs • Pain or necrosis if drug is irritating • Epinephrine
Aqueous solution: prompt • Ideal for some poorly soluble • Unsuitable for drugs administered • Insulin
suspensions in large volumes • Heparin
Depot preparations:
slow and sustained

Inhalation • Systemic absorption may • Absorption is rapid; can have • Most addictive route (drug can enter • Albuterol
occur; this is not always immediate effects the brain quickly) • Fluticasone
desirable • Ideal for gases • Patient may have difficulty
• Effective for patients with respiratory regulating dose
problems • Some patients may have
• Dose can be titrated difficulty using inhalers
• Localized effect to target lungs: lower
doses used compared to that with
oral or parenteral administration
• Fewer systemic side effects

Topical • Variable; affected by skin • Suitable when local effect of drug is • Some systemic absorption can occur • Clotrimazole
condition, area of skin, and desired • Unsuitable for drugs with high cream
other factors • May be used for skin, eye, intra- molecular weight or poor lipid • Hydrocortisone
vaginal, and intranasal products solubility cream
• Minimizes systemic absorption • Timolol eye
• Easy for patient drops

Transdermal • Slow and sustained • Bypasses the first-pass effect • Some patients are allergic to • Nitroglycerin
(patch) • Convenient and painless patches, which can cause irritation • Nicotine
• Ideal for drugs that are lipophilic • Drug must be highly lipophilic • Scopalamine
and have poor oral bioavailability • May cause delayed delivery of drug
• Ideal for drugs that are quickly to pharmacological site of action
eliminated from the body • Limited to drugs that can be
taken in small daily doses

Rectal • Erratic and variable • Partially bypasses first-pass effect • Drugs may irritate the rectal • Bisacodyl
• Bypasses destruction by stomach acid mucosa • Promethazine
• Ideal if drug causes vomiting • Not a well-accepted route
• Ideal in patients who are vomiting,
or comatose

Figure 1.19
The absorption pattern, advantages, and disadvantages of the most common routes of administration.
(Figure continues on next page)

LIR_CH01.indd 32 16/10/18 12:04 PM

 IV. Absorption of Drugs 33

FORMS ABSORPTION PATTERN ADVANTAGES DISADVANTAGES

Vaginal douche (for Washing or cleaning out the • Helps to remove unpleasant odors, • Vaginal infection as it upsets
example, Betadine inside of the vagina with water or wash away menstrual blood, avoid the natural balance of bacteria
douche) other mixtures of fluids getting sexually transmitted dis- in the vagina—that is, vaginal
eases, and prevent pregnancy after flora
intercourse • Pelvic inflammatory disease
Pharmaceutical pessary It is a device that is placed into • Easy to use • Difficulty in getting pregnant in
the vagina for local action (for • Local action women who douche more than
example, Clotrimazole vaginal once a week. May increase the
pessary) incidence of complications in
pregnancy—ectopic pregnancy
Support/therapeutic It is a device to provide support • Vaginal support pessary is a useful • Increased risk of vaginal
pessary (for example, to the uterus or bladder and nonsurgical treatment for the man- discharge, vaginal irritation,
Ring, Shaatz, Gellhorn, rectum agement of pelvic support defects ulceration, bleeding, and dys-
Ring with support) such as cystocele, rectocele, stress, pareunia
and urinary incontinence • A neglected pessary can be-
• Support pessaries fit by trial and come embedded in the vaginal
error of several sizes and/or styles. In mucosa and may be difficult to
patients who use a diaphragm, the remove
size of the diaphragm does not cor- • Improperly fitted ring pessary
relate with the size of the pessary can lead to strangulation and
necrosis of the cervix and uterus

Figure 1.19 (Continued)

The absorption pattern, advantages, and disadvantages of the most common routes of administration.

• the speed with which the drug is absorbed and/or released; the time ROUTE OF VARIABLE (MIN-
until effect for different routes of drugs is given in Figure 1.20. ­ADMINISTRATION UTES TO HOURS)
• The desired action (local or systemic or to achieve high concentration Oral ingestion 30–90 minutes
at a particular site) Rectal 5–30 minutes
Subcutaneous 15–30 minutes
• Clinical emergency or routine treatment Intramuscular 10–20 minutes
• Condition of the patient (unconscious or vomiting) Sublingual 3–5 minutes
Inhalation 2–3 minutes
Whether the drug is absorbed from the stomach and intestine or whether it is Endotracheal 2–3 minutes
liable to first-pass degradation, knowledge of the characteristics of a drug is Intraosseous 30–60 seconds
must for appropriate drug administration and improving patient compliance. Intravenous 30–60 seconds

A. Determinants of absorption Figure 1.20

Route of administration and time to
The general determinants of the absorption rate of drugs include the
effect.
following:
• Routes of drug administration
• Dissolution into aqueous fluids at the absorption site
• Lipid solubility
• Concentration gradient
• Blood flow at the absorption site
• Surface area of the absorption site

B. Mechanisms of absorption of drugs from the GI tract

Depending on their chemical properties, drugs may be absorbed from
the GI tract by passive diffusion, facilitated diffusion, active transport,
or endocytosis (Figure 1.21).

LIR_CH01.indd 33 16/10/18 12:04 PM

Discovering Diverse Content Through
Random Scribd Documents
 House owner, Breitenfeld No. 9.

Benedikt Gaber, m. p.
House owner, Breitenfeld No. 25.

Johann Naumann, m. p.
House No. 5, Breitenfeld.
(“This testament was delivered under seal to the R. I. L. Austrian
General Court, by the Karl Scheffer Solicitor Dr. Schönauer, on
November 17, 1815, etc.”)
Codicil to my Will
Having learned that my brother, Hr Ludwig van Beethoven, desires
after my death to take wholly to himself my son Karl, and wholly to
withdraw him from the supervision and training of his mother, and
inasmuch as the best of harmony does not exist between my brother
and my wife, I have found it necessary to add to my will that I by no
means desire that my son be taken away from his mother, but that
he shall always and so long as his future career permits remain with
his mother, to which end the guardianship of him is to be exercised
by her as well as my brother. Only by unity can the object which I
had in view in appointing my brother guardian of my son, be
attained, wherefore, for the welfare of my child, I recommend
compliance to my wife and more moderation to my brother.
God permit them to be harmonious for the sake of my child’s
welfare. This is the last wish of the dying husband and brother.
Vienna, November 14, 1815.
Karl van Beethoven
m. p.
We, the undersigned, certify in consonance with truth that Karl van
Beethoven declared in our presence that he had read the statement
on the opposite page and that the same is in accordance with his
will, finally we certify that he signed it with his own hand in our
presence and requested us to witness the act.
Thus done on November 14, 1815.
Carl Gaber, m. p.
Benedikt Gaber, m. p.
Johann Neumann, m. p.
(“This codicil was delivered under seal to the R. I. L. Austrian
General Court by the Karl Scheffer Solicitor Dr. Schönauer, on Nov.
17, 1815, etc.”)
On November 20, 1815, the “Wiener Zeitung” printed the
announcement: “Died on November 16, Hr. Karl van Beethoven,
Cashier in the R. I. Bank and Chief Treasury, aged 38 years,[156] of
consumption.” And so in his own house died the brother Karl whose
last moments came with a suddenness which aroused his brother’s
suspicions that the end had been hastened by poison! Nor would he
be satisfied upon the matter until his friend Bertolini had made a
post mortem examination “whereby the lack of foundation for the
suspicion was proved.”
A few weeks before his death, Karl had applied for leave of absence
from his office on the score of his feeble condition; but his petition
was harshly refused in a document on which Beethoven afterwards
wrote: “This miserable financial product caused the death of my
brother.” In fact, however, it made probably little difference; his was
evidently one of those common cases of phthisis, where the patient,
except to the experienced eye, shows no signs of immediate danger;
who at the last moments finds himself free from pain and blessed
with a buoyancy of spirit that gives him vain hopes of prolonged life.
It is the last flickering of the flame, as the skillful physician well
knows.
As above noted, Karl van Beethoven’s will was deposited with the
proper authorities on the 17th, and “the R. I. L. Austrian Landrecht
(General Court) on November 22, 1815, appointed the widow of the
deceased, Johanna van Beethoven, guardian, the brother of the
deceased, Ludwig van Beethoven, associate guardian of the minor
son Karl.” And so, for the present, we will leave the matter.[157]
And Breuning? Why during these years and especially in this time of
sorrow does his name nowhere meet us? His son answers the
question in that extremely interesting little volume “Aus dem
Schwarzspanierhause.”[158]
Jacob Rösgen, an employee in the office of the Minister of War in
which Breuning was a Secretary, had learned certain facts, or
suspicions, in relation to Karl van Beethoven’s integrity, which he
thought should be communicated to Ludwig as a warning “not to
have anything to do with him in financial matters.” To this end he,
having obtained Breuning’s word of honor not to make known the
source of the information, imparted to him the whole matter.
“Breuning faithfully performed the task which he had assumed; but
Ludwig, in his tireless endeavor to better his brother, hastened to
take him to task for his conduct and charge him with the acts which
had been reported to him; he went so far, when pressed by his
brother for the source of his information, as to mention the name of
his friend Steffen. Kaspar (Karl) then appealed directly to my father
and asked the name of the author of the ‘denunciation,’ and when
my father resolutely declined to give the name (Rösgen) Kaspar
indulged himself in abuse to such an extent that he left insulting
letters addressed to him and unsealed with the portier of the
Ministry of War. My father, angered and pained at this impertinence
and Ludwig’s breach of confidence, read the latter a sharp lecture
which ended with the declaration that because of such unreliability it
would be impossible longer to hold association with him.”[159] It will
be long before we meet Breuning again.
There is a striking incongruity between Beethoven’s pleas of poverty
in his letters to correspondents in England at this period and the
facts drawn from official and other authentic sources. Let us tarry a
moment on this point.
He was now, at the end of 1815, in the regular
receipt of his annuity, 3400 florins in notes of A Period of
Prosperity
redemption; in March and April the arrears, 4987
florins in such notes, had been paid him; the profits of his concerts
since January 1, 1814, with presents from crowned heads and others
were, if we may trust Schindler, who appears to speak from accurate
knowledge, sufficient in amount to purchase somewhat later the
seven bank-shares, which at his death, “according to the price
current on the day of his death,” had a value in convention-coin of
7441 florins; Neate had paid him 75 guineas; for the works sold to
Steiner and Co. he had “been wholly compensated”; in March (1816)
he received from Mr. Birchall 65 pounds sterling; and there were
payments to him from Thomson and others, the aggregate of which
cannot be determined.
This incongruity is not essentially diminished either by his taxes—
sixty pounds for 1814, he tells Thomson—nor by the 10,000 florins
W. W. expended for the benefit of his brother, whether the “Wiener
Währung” in the letter to Ries be understood as the old five for one,
or the new in notes of redemption; for this fraternal charity extended
back over a series of years. In this letter to Ries, the reader will
observe also a remarkable instance of its writer’s occasional great
carelessness of statement, where he speaks of his “entire loss of
salary” for several years; for the Archduke’s share had throughout
been punctually paid; not to mention again the receipt of what had
for a time been withheld of the Kinsky and Lobkowitz subscriptions.
The omission of these facts in this and other letters, imparted to
Ries an utterly false impression; and on their publication in 1838, to
the public also. Hence the general belief that Beethoven was now in
very straitened circumstances, and that Karl’s widow and child had
been left in abject poverty; the truth as to them being this: that the
property left them produced an annual income, which with the
widow’s pension amounted at this time to above 1500 florins. From
the day that Beethoven assumed the office of guardian and took
possession of the child, he had a valid claim upon the mother for a
part of the costs of maintaining him—a claim soon made good by
legal process. If he afterward elected to suffer in his own finances
rather than press his sister-in-law, this is no justification of the
heedless statements in some of his letters now—a truth to be held in
mind. And now the letter to Ferdinand Ries:
 Wednesday, November 22, Vienna, 1815.
Dear R!
I hasten to write you that I to-day sent the pianoforte arrangement
of the Symphony in A by post to the house of Thomas Coutts and
Co., as the Court is not here, couriers go not at all or seldom, and
this besides is the safest way. The Symphony should appear toward
the end of March, I will fix the day, it has occupied too much time
for me to make the term shorter,—more time may be taken with the
Trio and the Sonata for violin, and both will be in London in a few
weeks—I urgently beg of you, dear Ries! to make this matter your
concern and to see that I get the money; it will cost a great deal
before everything gets there and I need it—I had to lose 600 fl.
annually of my salary, at the time of the bank-notes it was nothing
then came the notes of redemption and because of them I lost the
600 fl. with several years of vexation and entire loss of salary—now
we have reached a point where the notes of redemption are worse
than the bank-notes were before; I pay 1000 fl. for house-rent;
figure to yourself of the misery caused by paper money. My poor
unfortunate brother has just died; he had a bad wife, I may say he
had consumption for several years, and to make life easier for him I
gave what I may estimate at 10,000 fl. W. W. True, that is nothing
for an Englishman, but very much for a poor German, or rather
Austrian. The poor man had changed greatly in the last few years
and I can say that I sincerely lament him, and I am now glad that I
can now say to myself that I neglected nothing in respect of care for
him. Tell Mr. Birchall to repay Mr. Salomon and you the cost of
postage for your letters to me and mine to you; he may deduct it
from the sum which he is to pay me, I want those who labor for me
to suffer as little as possible.
Wellington’s Victory at the Battle of Vittoria, this is also the title on
the pianoforte arrangement, must have reached Th. Coutts and Co.
long ago. Mr. Birchall need not pay the honorarium until he has
received all the works, make haste so that I may know the day when
Mr. Birchall will publish the pianoforte arrangement. For to-day, no
more except the warmest commendation of my affairs to you; I am
always at your service in all respects. Farewell, Dear R!
On the same day he wrote to Birchall:
Vienna, November 22, 1815.
Enclosed you are receiving the pianoforte arrangement of the
Symphony in A. The pianoforte arrangement of the Symph.
Wellington’s Victory at the Battle of Vittoria was dispatched 4 weeks
ago by the business messenger, Hrn. Neumann, to Messrs. Coutts
and Co., and therefore must long ago have been in your hands.
You will receive also the Trio and Sonata in a fortnight in exchange
for which you will please pay to Messrs. Thomas Coutts and Co. the
sum of 130 gold ducats. I beg of you to make haste with the
publication of these musical compositions and to inform me of the
day of publication of the Wellington Symphony, so that I may make
my arrangements here accordingly. With great respect I remain,
Yours truly,
Ludwig van Beethoven, m. p.
The Trio and Sonata, however, were not forwarded until the 3d of
the next February—a decidedly long “fortnight.”
In those days £65 was no small sum for the mere right of
republication in England of these pianoforte works and
arrangements, and Ries richly merited these words of his old master:
“And now my heartiest thanks, dear Ries, for all the kindness you
have shown to me, and particularly for the corrections. Heaven bless
you and make your progress even greater, in which I take a cordial
interest.”
About the first of December, “a magisterial
deputation solemnly delivered” into the hands of Becomes an
Honorary Citizen
Beethoven a certificate conferring upon him the of Vienna
citizenship of Vienna in acknowledgment of his
benevolent services in behalf of St. Mark’s Hospital. Ries, writing on
September 29th for Salomon, who had broken his right shoulder in a
fall from his horse, informs Beethoven that at that date the three
overtures purchased by Neate for the Philharmonic Society had not
reached London. Beethoven, in December, repeats this to Neate,
who was still in Vienna, adding, in substance, his readiness to make
any desired written agreement about these things in England.
Salomon’s misfortune occurred in August; he lingered only until the
25th of November. No higher proof of his reputation in England can
be given than the fact that the remains of this Bonn violinist rest
near those of Handel in Westminster Abbey.
Schindler somewhere censures the Gesellschaft der Musikfreunde for
its long delay in making Beethoven an honorary member. It did what
was better. Hardly was it organized, when its directors turned their
attention to him; and, in the second year of its legal existence,
proposed to him through Zmeskall to compose an oratorio for its
use. On the 22d of December, Count Appony reported: “that Hr. L. v.
Beethoven, through Hrn. v. Zmeskall, had declared his readiness to
deliver a large work to the society and that the Board of
Management were awaiting his conditions.” It was but the course of
common propriety—of ordinary delicacy—to leave him free of all
obligation to the society until this matter of business should be
settled; indeed, that Streicher was one of the principal founders and
most influential members of the society is a sufficient pledge, that
no disrespect for, nor indifference to, his great merits, had aught to
do with the delay, which Schindler blames. We shall find that, so
soon as it was certain that Beethoven could not live to fulfill his
engagement, the society sent him its honorary diploma. Could it well
do this before?
Of noteworthy new friends and acquaintances may be mentioned
here Peters, tutor of the young Princes Lobkowitz, and Carl Joseph
Bernard, a young literateur and poet—the reviser of Weissenbach’s
poem—a great admirer of Beethoven’s music, soon to be appointed
Editor of the official “Wiener Zeitung.” He is the “Bernardus non
Sanctus” of the Conversation Books; and the two are the friends
whom Beethoven set to music in the text:
 Sanct Petrus war ein Fels!
Bernardus war ein Sanct??[160]

Another was Anton Halm, “in whose fresh military nature Master
Ludwig took delight,” says Schindler. He was a native of Styria, and
now but twenty-six years of age. After some years’ service against
Napoleon, he had resigned (1812) his lieutenancy in the 44th
Regiment. He was a pianoforte player of very respectable rank, and
even before entering the army had appeared in public in Beethoven’s
C minor Trio, Op. 1, and the C major Pianoforte Concerto, Op. 15.
He had now been three years in Hungary, living during the third with
his friend, Brunswick, who gave him a letter to Beethoven upon his
departure for Vienna, whither he had come to be tutor in a Greek
family named Gyike. “Halm once brought a sonata of his own
composition to him,” says Czerny, “and when Beethoven pointed out
a few errors, Halm retorted that he (B.) had also permitted himself
many violations of the rules, Beethoven answered: ‘I may do it, but
not you.’”
Young Schindler’s acquaintance with Beethoven
had now advanced a step: Growing
Intercourse with
Toward the end of February, 1815 (Schindler Schindler
writes), I accepted an invitation to become tutor at
Brünn. Scarcely arrived there, I was summoned before the police
officials. I was questioned as to my relations with some of the
tumultuaries of the Vienna University as also certain Italians in
whose company I had often been seen in Vienna. As my
identification papers, especially the statement concerning the
different lectures which I had attended, were not in good order, the
latter really faulty—through no fault of mine—I was detained,
notwithstanding that a government officer of high standing offered
to become my bondsman. After several weeks of correspondence
back and forth it was learned that I was not a propagandist and was
to be set at liberty. But a whole year of my academic career was
lost.
Again returned to Vienna, I was invited by one of Beethoven’s
intimate acquaintances to come to an appointed place, as the
master wanted to hear the story of the Brünn happening from my
own lips. During the relation, Beethoven manifested such
sympathetic interest in my disagreeable experiences that I could not
refrain from tears. He invited me to come often to the same place
and at the same hour, 4 o’clock in the afternoon, where he was to be
found nearly every day—reading the newspapers. A handgrasp said
still more. The place was a somewhat remote room in the beer-
house “Zum Rosenstock” in the Ballgässchen. I was there right often
and came to know the place as a quasi-crypt of a number of
Josephites of the first water, to whom our master presented no
discordant note, for his republican creed had already received a
considerable blow through a more intimate acquaintance with the
English Constitution. A captain of the Emperor’s bodyguard and Herr
Pinterics, widely known in musical Vienna, who played an important
rôle in the life of Franz Schubert, were the closest companions of the
master and, in the exchange of political views, his seconds actively
and passively. From this place I soon began to accompany him on
his walks.
But Schindler’s intimacy with Beethoven was not yet such as to save
him from errors when writing of this time. Thus he gravely assures
us that a concert which took place on the 25th of December
“provided the impulse which led the Magistracy of Vienna to elect
our master to honorary citizenship.” And yet the “solemn delivery” of
the diploma is already an item of news in the Vienna newspapers of
December 15. This concert, in the large Ridotto room, conducted by
Beethoven was for the benefit of the Bürgerspitalfond (Citizens’
Hospital Fund) and the works performed were “an entirely new
overture” (that in C, known as the “Namensfeier”); “a new chorus on
Goethe’s poem ‘Die Meeresstille’”; “Christus am Ölberg.” Between
the cantata and the oratorio, Franz Stauffer, “the twelve-year-old son
of a citizen of Vienna,” played a “Rondo brillant” by Hummel.
The compositions which are known or, on good grounds, are
supposed to belong to the year 1815 are:
1. “15 Scottish Songs, in the month of May,” arranged for Thomson;
but they are not all Scottish.
2. Chorus: “Es ist vollbracht”; for Treitschke’s “Ehrenpforte.”
3. Two Sonatas for Pianoforte and Violoncello; C major and D major,
Op. 102; in July and August.
4. Chorus with orchestra: “Meeresstille und glückliche Fahrt”; text by
Goethe; Op. 112.
5. Song: “Das Geheimniss”; text by Weissenberg.
6. Song: “An die Hoffnung”; text by Tiedge; Op. 94 (probably
finished).
7. Canons: “Das Reden,” “Das Schweigen” and “Glück zum neuen
Jahre.”[161]
The ascertained publications of the year are:
1. Polonaise, in C major, Op. 89; published by Mechetti, in March.
2. Sonata for Pianoforte, E minor, Op. 90; by Steiner, in June.
3. Song: “Des Kriegers Abschied,” text by C. L. Reissig; by Mechetti,
in June.
4. Chorus: “Es ist vollbracht,” pianoforte arrangement; by Steiner in
July.
 Chapter XVI
The Year 1816—Guardianship of the Nephew—Giannatasio del Rio—
Beethoven’s Works in London—Birchall and Neate—New Distinctions.
Compared with the years immediately preceding, the year 1816 is
comparatively barren of large incidents in the life of Beethoven; its
recorded history, therefore, is to be found to a still larger extent than
before in the composer’s extended correspondence together with
explanatory annotations. Some of the letters, especially those
written to his English friends, are likely to make a somewhat
melancholy, and to that extent erroneous, impression. The real
record of the writer finds expression in the letters which he wrote to
Steiner and Co. and Zmeskall. These are bubbling over with
playfulness and jocularity, proving that the writer was generally in a
cheerful humor and in this year was anything but the melancholy
Beethoven of the romance writers. He seems to have endured the
rapid and disquieting increase in his malady, an inevitable
consequence of the exertions and excitement attending the
rehearsing and conducting of so many large concerts, with surprising
patience and resignation. And why not? His pecuniary affairs were in
good condition, notwithstanding his lamentations to Ries and others;
he had won his lawsuit with his brother’s widow, and his artistic
ambition must have found complete satisfaction in the great fame
which he had won. A letter concerning a new operatic project first
invites attention. The eight rôles which Madame Milder had played in
the past summer in Berlin, had given such keen delight that she had
been reëngaged for a second and much longer series. Domestic
troubles and sorrows, in which her husband, the jeweler
Hauptmann, appears to have been entirely the guilty party and
which embittered all her future life, rendered her utterly unable for
the present to appear upon the stage; and “because of illness and
weakness” it was not until several weeks after her return from the
baths at Pyrmont that she could begin the new engagement on
October 3d. Meantime “Fidelio” had been put upon the boards and
“given for the first time on October 11th with great success.” “This
opera,” said the Berlin “Dramaturgisches Wochenblatt” in its notice
of the event, “bears within itself the seeds of a dramatico-musical
reformation and will hasten the end of the bastard music.” And yet
on this evening, the Leonore was Mad. Schultze—Schuppanzigh’s
sister-in-law. When, three days after, Mad. Milder took the part, its
greatness was for the first time fully appreciated; and of the twenty-
four evenings to which her engagement extended, this greatest
representative then living of Gluck’s grandest inspirations devoted
eleven to “Fidelio.” This triumph of his opera in Berlin, drew from the
composer a letter (dated January 6, 1816) full of expressions of
gratitude and enthusiastic appreciation of the singer’s talents, and
giving voice too, to a rekindled dramatic ambition. He says:
If you were to beg Baron de la Motte Fouqué—in my name—to
invent a grand opera subject which would at the same time be
adapted to you, you would do a great service to me and the German
stage. I should like, moreover, to compose it exclusively for the
Berlin stage as I shall never bring about another opera for the
parsimonious management here.
The next letter relates to the oratorio for the Gesellschaft der
Musikfreunde:
My dear Zmeskall!
With dread I observe for the first time to-day that I have not yet
answered the application of the Gesellschaft der Musif. of the
Austrian capital for an oratorio.
The death of my brother two months ago, the guardianship of my
nephew which thereby devolved upon me, together with many other
unpleasant circumstances and occurrences are the cause of my tardy
writing. Meanwhile the poem by H. von Seyfried is already begun
and I shall also soon set the same to music. That the commission is
highly honorable, I scarcely need tell you; that is self-evident and I
shall try to execute it as worthily as my small powers will allow.
As regards the artistic means to be employed in the performance I
shall be considerate, but do not wish not to be allowed to depart
from those already introduced. I hope that I have made myself
understood in this matter. As they insist upon knowing what
honorarium I ask, I inquire in turn whether the Society thinks 400
ducats in gold agreeable for such a work. I again beg pardon of the
society for the tardiness of my answer; meanwhile, you my dear
friend have at least reported by word of mouth my readiness to
compose the work, before this, which sets my mind measurably at
ease—My dear Z.
Your B.
The next selections require the preliminary statement of certain
facts. Beethoven’s dissatisfaction at the appointment (on November
22d) of his sister-in-law as the guardian of her son—now nine years
old—was expressed in an appeal to the Upper Austrian Landrecht on
the 28th, to transfer the guardianship to himself. Next day, the 29th,
that tribunal ordered the petitioner and Dr. Schönauer to appear
before it in this matter on December 2d at 10 o’clock a. m. At that
time the subject was deferred to the same hour on the 13th.
Beethoven then appeared and declared that he could produce
“weighty reasons why the widow should be entirely excluded from
the guardianship.” Whereupon, on the 15th, it was ordered that he
produce those grounds within three days, “failing which, the
preparation of the guardianship decree to the widow would be
proceeded with without further delay.” The same day Beethoven
signed a petition to the City Magistrates for an official certificate
concerning the “condemnation of his (Karl’s) mother, Johanna van
Beethoven, on an investigation for infidelity.” The magistrate
answered him on the same day through their secretary that they
could not legally grant him a copy of the judgment against her, but
would communicate the “necessary disclosures” to the tribunal. This
was done on the 21st. Then came the Christmas holidays, and no
further action was taken until the 9th of January, when a decision
was rendered in Beethoven’s favor, and he was ordered to appear on
the 19th to take the “vows for the performance of his duties.” He
complied, and on the outside of this order is written:
To-day appeared Ludwig van Beethoven as the legally appointed
guardian of his nephew Carl and vowed with solemn handgrasp
before the assembled council to perform his duties.
This document also empowered the new guardian
to take possession of the boy, who of course was The Nephew Taken
from His Mother
still with his mother. But what to do with him?
Beethoven could not take him into his own lodging; a child of that
age needs a woman’s care and tenderness.
A certain Cajetan Giannatasio del Rio was at that time proprietor and
manager of a private school in the city for boys, which enjoyed a
high and deserved reputation. His family consisted of his wife and
two highly accomplished daughters, young women of fine talents, of
much musical taste and culture, and—especially the eldest—
enthusiasts for Beethoven’s music. The composer, accompanied by
Bernard and the boy, visited and inspected the school, and was so
much pleased with it and the family, that he determined to withdraw
his nephew from the public school, and place him there as pupil and
boarder. On February 1st, he wrote to Giannatasio:
With sincere pleasure I inform you that at last on to-morrow I shall
bring to you the precious pledge that has been intrusted to me.
Moreover I beg of you again under no circumstances to permit the
mother to exercise any influence, now or when she may see him, all
this I will talk over with you to-morrow. You may impress this also
on your servants, for mine in another matter was bribed by her!
More by word of mouth though silence would be preferable to me—
but for the sake of your future citizen of the world, this melancholy
communication is necessary.
[In Karl’s hand]: I am very glad to come to you, and am your Carl
van Beethoven.
The next day, February 2, the boy was taken from his mother. The
intolerable annoyance caused by her appearing in person or sending
a messenger daily to take him from the school, drew from
Giannatasio on the 11th a written application to the guardian for “a
formal authority in a few lines for refusing without further ado to
permit her to fetch her son.” In his reply, Beethoven writes: “as
regards the mother I request that on the plea that he is busy you do
not admit her to him at all.” He then consulted Joseph Edler von
Schmerling, a member of the Landrecht, upon the measures proper
for him to adopt, and communicated that gentleman’s advice to
Giannatasio by letter, on the morning of the 15th. The same day,
taking Bernard with him, he went to the school, and there meeting
Giannatasio, the three prepared a formal petition to the Landrecht,
praying that tribunal to grant the guardian plenary authority to
exclude the widow and her agents from all or any direct
communication with the boy. This was signed by Beethoven and
immediately presented. On the 20th, the Landrecht granted,
essentially, this petition; but its decree contained this proviso: that
the mother might still visit her son “in his leisure hours, without
disturbing the course of his education or the domestic arrangements,
in the company of a person to be appointed by the guardian or the
director of the educational institution.” Armed with this authority,
Giannatasio on March 8th informed in writing “Madame Jeannette de
Beethoven, Vorstadt, Alsergasse, No. 121,” that she has in future “to
apply solely to the uncle as to whether, how and when” she can see
her son. And thus this wretched business again for the present
rested. In these days belongs a letter by Beethoven to Giannatasio:
The Queen of Night surprised us yesterday and also delivered a
veritable anathema against you; she showed her usual impertinence
and malice against me and set me back for a moment and I almost
believed that what she said was right, but when I reached home
later I received the result of the decision of the L. R. which turns out
to be just what was desired and I communicate the most necessary
point, although you will probably receive a copy of it towards
evening....
Neate was now gone to London. On his departure Beethoven wrote
in his album two canons entitled “Das Schweigen” (Silence) and
“Das Reden” (Speech), adding with the date, “January 24, 1816,” the
words:
My dear English compatriot in silence and in speech remember your
sincere friend
Ludwig van Beethoven.
The document concerning the sale of the three
overtures to the Philharmonic Society which The London
Philharmonic Buys
Beethoven promised to give Neate (which Overtures
Moscheles printed in his paraphrase of Schindler’s
biography in translation, as if it had been written in English and not
altogether correctly)[162] ran as follows:
In the month of July, 1816 [sic] Mr. Neate in the name of the
Philharmonic Society in London, received from me 3 overtures and
paid me for the same an honorarium of 75 guineas in consideration
of which I bind myself not to permit them to be published in
parts[163] anywhere, though the right is reserved by me to perform
them wherever I please as well as to publish them in pianoforte
arrangement though not before Mr. Neate shall have written to me
that they have been performed in London. Moreover, Mr. Neate has
assured me that he will kindly take it upon himself (to assure me)
that the Philharmonic Society will give me permission after a lapse of
one or two years to publish the 3 overtures in score and parts,
inasmuch as I can do this only with their consent, with which I
present my compliments to the P. S.
Ludwig van Beethoven.
Vienna, February 5, 1816.
The three overtures had already been sold to Steiner, but were not
published till six years later. The works entrusted to him, as
remembered by Mr. Neate forty-five years afterwards, were: 1. A
copy of the Violin Concerto, Op. 61, with a transcription of the solo
for Pianoforte on the same pages, which Beethoven said he himself
had arranged and was effective; 2. The two Sonatas for Pianoforte
and Violoncello, Op. 102, with a dedication to Neate; 3. The Seventh
Symphony in score; 4. “Fidelio” in score; and 5. The String Quartet
in F minor, Op. 95—all in manuscript. There is some reason to think
that besides these works Neate also took a copy of “Der glorreiche
Augenblick.” On January 20, Beethoven wrote the following letter to
Ries in London:[164]
Vienna, January 20, 1816.
My dear Ries:
I see from your letter of January 18, that you have safely received
the two things—as no couriers are going, the post is safest, but it
costs a great deal, I will send you the bill for what I have paid here
for copying and postage soon, it is very little for an Englishman but
all the more for a poor Austrian musician!
See that Mr. B.[165] recompenses me for this, since he has the
compositions for England very cheaply. Neate, who has been about
to go every moment, but always remains, will bring the overtures
with him, I have always communicated to him the injunctions
touching them given by you and our deceased S.[166]—the
symphony will be dedicated to the Empress of Russia. The pianoforte
arrangement of the Symphony in A must not be published before the
month of June, the publisher cannot be earlier—tell this at once to
B. my dear good R.
The Sonata with violin, which will go from here by the next post,
may also be published in London in the month of May—but the Trio
later. (It will also arrive by the next post) I will fix the date myself
later.
And now my heartiest thanks dear Ries, for all the kindness you
have shown to me and particularly for the corrections. Heaven bless
you and make your progress ever greater in which I take a cordial
interest—commend me to your wife.
It is necessary here to state certain facts, both to explain the failure
of Mr. Neate to sell any of these works to the London publishers, and
to render some of the letters to come intelligible.
The Philharmonic Society was an association of the
first musicians of London and its vicinity, and no The Philharmonic
Society
city on earth could at that time present such an Disappointed
array of great names. Here are a few of them
taken alphabetically from its roll: Atwood, Ayrton, Bridgetower,
Clementi, Cramer, Carnaby, Dragonetti, Horsley, Lindley, Mazzinghi,
Mori, Naldi, Novello, Ries, Shield, Smart, Spagnoletti, Viotti, Watts, S.
Webbe, Yanewicz. Imagine the disappointment of these men, fresh
from the performance of the C minor Symphony, when they played
through the overtures to “The Ruins of Athens” and “King Stephen,”
which, however interesting to a Hungarian audience as introductions
to a patriotic prologue and epilogue in the theatre, possess none of
those great qualities expected from Beethoven and demanded in a
concert overture! Nor was the “Namensfeier” thought worthy of its
author. Ries speaks thus of this matter:
After I had with much trouble persuaded the Philharmonic Society to
permit me to order three overtures from him, which should remain
its property, he sent me three, not one of which, in view of
Beethoven’s great name and the character of these concerts, could
be performed, because expectation was tense and more than the
ordinary was asked of Beethoven. A few years later he published all
three and the Society did not think it worth while to complain.
Amongst them was the overture to “The Ruins of Athens,” which I
consider unworthy of him.
But when it became known that neither of the three—Op. 115
possibly excepted—was new, and that not one of them had been
composed to meet the Society’s order, is it surprising that this act of
Beethoven’s was deemed unworthy of him, disrespectful, nay, an
insult to the Society, and resented accordingly?
Another matter was personal with Mr. Birchall. That publisher, having
at last (early in February) received the last of the works purchased
by him, immediately deposited with Coutts and Co. the sum agreed
upon, to the composer’s credit, and forwarded the following
“Declaration” to Vienna for signature, leaving the day of the month
blank—as it still remains—to be inserted when signed:
Received ... March, 1816, of Mr. Robert Birchall—Music Seller, 133
New Bond Street, London—the sum of One Hundred and thirty Gold
Dutch Ducats, value in English Currency Sixty-five Pounds, for all my
Copyright and Interest, present and future, vested or contingent, or
otherwise within the United Kingdom of Great Britain and Ireland in
the four following Compositions or Pieces of Music composed or
arranged by me, viz.:
1st. A Grand Battle Sinfonia, descriptive of the Battle and Victory at
Vittoria, adapted for the Pianoforte and dedicated to his Royal
Highness, the Prince Regent—40 Ducats.
2nd. A Grand Symphony in the Key of A, adapted to the Pianoforte
and dedicated to
3rd. A Grand Trio for the Pianoforte, Violon and Violoncello in the
Key of B.
4th. A Sonata for the Pianoforte with an Accompaniment for the
Violin in the Key of G, dedicated to
And, in consideration of such payment I hereby for myself, my
Executors and Administrators promise and engage to execute a
proper Assignment thereof to him, his Executors and Administrators
or Assignees at his or their Request and Costs, as he or they shall
direct. And I likewise promise and engage as above, that none of the
above shall be published in any foreign Country, before the time and
day fixed and agreed on for such Publication between R. Birchall and
myself shall arrive.
Instead of this document, so indispensable for his security, the
publisher received a new demand from Beethoven!—one for five
pounds additional, as per memorandum:
Copying 1.10.0
 Postage to Amsterdam 1. 0.0
Trio 2.10.0
£5. 0.0
The very unfavorable impression which this proceeding made upon
the mind of Mr. Birchall may readily be conceived. These £5 are the
10 ducats mentioned in the following letter, portions of which were
suppressed when printed by Ries:
Vienna, May 8, 1816.
My answer comes somewhat tardily; but I was ill, had much to do
and it was impossible for me to answer you sooner; now only the
most necessary things—not a Heller of the 10 ducats in gold has as
yet arrived, and I am already beginning to believe, that the
Englishmen, too, are only magnanimous in foreign lands; so also
with the Prince Regent from whom I have not even received the
copyist’s fees for my Battle sent to him, not even written or oral
thanks;[167] Fries here deducted 6 fl. Convention money. On the
receipt of the money from Birchall, besides 15 fl. Convention money
for postage, tell B. this—and see that you yourself get the draft for
the 10 ducats, otherwise it will go like the first time—what you tell
me about Neate’s undertaking would be desirable for me. I need it,
my salary amounts to 3400 florins in paper, I pay 1100 house-rent,
my servant and his wife nearly 900 fl. Calculate what remains.
Moreover, I have got to care wholly for my little nephew. He is till
now still in the Institute; this costs me close to 1100 fl. and is poor
besides, so that I must establish myself in decent housekeeping so
that I can have him with me. How much one must earn in order to
live here; and yet there is never an end for—for—for—you know it
already. As to the dedications another time. A few orders besides the
concert would also be welcome from the Philharmonic Society—
besides my dear pupil Ries ought to sit down and dedicate
something good to me to which the master would also respond and
repay kind with kind. How shall I send you my portrait! I hope too,
to have news from Neate, urge him on a bit, be assured of my
sincere interest in your futures. Urge Neate on to work and
composition. All things lovely to your wife. Unfortunately I have
none. I found only one, whom I shall doubtless never possess; but
am not a woman hater on that account.
Your true friend,
Beethoven.
Immediately upon the receipt of this letter, Ries Ungrounded
spoke with Mr. Birchall, who next day (March 15), Suspicion of Neate
deposited the £5 with Coutts and Co.; but month
after month passed and still the “Declaration” with Beethoven’s
signature did not arrive. Of the justice, propriety, delicacy of this
new demand, nothing need be said; its historical importance is due
entirely to the very unfavorable effect which it and the
correspondence relating to it produced upon the minds of the
London publishers. Mr. Neate was in some degree prepared for the
coldness with which those gentlemen received his proposals in
Beethoven’s behalf, by a letter written to him after the trial of the
overtures. One sentence in it he remembered word for word: “For
God’s sake, don’t buy anything of Beethoven!” But he was not
prepared for the utter refusal in all quarters to listen to him. He
besought Mr. Birchall to purchase the overtures. The reply was: “I
would not print them, if you would give me them gratis.”
As to the score of the Symphony in A (the Seventh), it was folly to
expect that the Philharmonic Society would pay a large sum for the
manuscript of a work already (March 6) advertised in Vienna for
subscription at the price of twenty-five florins.
It is another instance of Beethoven’s unlucky tendency to suspect
the conduct and motives of others, that seeing in a newspaper a
notice of the production of one of his Symphonies by the
Philharmonic Society, he at once assumed that it was the Seventh
and that Neate had given the use of his manuscript!
Under such circumstances Neate could do nothing for Beethoven;
nor could he well disclose the true causes of his failure; so the
composer characteristically assumed that he would do nothing, and,
as will be seen, gave vent to his wrath in terms equally bitter and
unjust. The letters selected pertaining to these transactions are
reserved for their places in chronological order.
Linke’s departure with the Erdödys to Croatia was noted in the last
chapter; he returned to Vienna in the Autumn in season to enable
Schuppanzigh to begin his winter season of quartets in November.
They were given in the hall of the hotel “Zum Römischen Kaiser,”
and had now ended. So, too, had ended the engagement of
Schuppanzigh, Weiss and Linke with Rasoumowsky. The destruction
of his palace, the approach of old age, and failing sight, induced him
now to dismiss them with suitable pensions from his service.
Schuppanzigh went to Russia; Linke returned to the Erdödys and
Weiss remained in Vienna. Before their departure the first two gave
each a farewell concert. Schuppanzigh’s took place in the palace of
Count Deym, the programme being made up entirely of Beethoven’s
works, viz: Quartet C major, Op. 59; Quintet for Wind-instruments
and Pianoforte, Op. 16, Carl Czerny, pianist; and the Septet, Op. 20.
Beethoven “entered at the beginning of the quartet” and shared in
the deafening applause of the crowded audience. Czerny relates:
“When I played the Quintet with Wind-instruments at
Schuppanzigh’s concert, I allowed myself in my youthful frivolity,
many changes—increasing the difficulty of passages, using the
higher octaves, etc. Beethoven very properly and severely upbraided
me for it in the presence of Schuppanzigh, Linke and the other
players. The next day I received from him the following letter, which
I copy exactly from the original lying before me”:
I cannot see you to-day, to-morrow I will come to you in person to
talk with you. I burst out so yesterday, I was very sorry after it had
happened, but you must pardon it in an author who would have
preferred to hear his work just as he wrote it, beautifully as you
played otherwise. I will make it good publicly to-morrow at the
Violoncello Sonata.
Be assured that as an artist I cherish the best of good feeling for you
and shall always strive to manifest it.
Linke’s concert took place on the 18th of February in the hall of the
“Römischer Kaiser,” the programme, except a Rondoletto for the
Violoncello by Romberg, being also entirely Beethoven. Stainer von
Felsburg played the new Sonata, Op. 101, and Czerny the pianoforte
part of one of the Sonatas, Op. 102, on which occasion the
composer “made it good publicly.” And so, except for an occasional
visit to Vienna by Linke, two more of our old acquaintances
disappear for several years; also Hummel and Wild. Hummel we
shall meet again beside Beethoven’s death-bed; Wild no more. An
album-leaf containing a canon, “Ars longa, vita brevis est” and “A
happy journey, my dear Hummel, think occasionally of your friend,
Ludwig van Beethoven, Vienna, April 4, 1816,” was the farewell to
the pianist and composer. On the 20th, Wild gave a little musical
festival “in the home of an art-lover,” at which he sang the “Adelaide”
and “An die Hoffnung,” Op. 94. Beethoven was present and played
the accompaniments. And this was his farewell to the singer. On
April 3d, Beethoven wrote the following letter to Ries:
My dear Ries:
Hr. B. has probably received the Trio and Sonata by this time, in the
last letter I asked 10 ducats more for copying and postage, probably
you will work out these 10 ducats for me—I always have some
worriment lest you are spending a great deal for me for postage, I
greatly wish that you would be so kind to charge up to me all my
letters to you as I want to have you reimbursed from here by the
house of Fries to the house of Coutts in London. Unless the
publisher B. objects, in which case he must send me notice
immediately by post, the Sonata with violin will appear here on June
15th, the Trio on July 15th, concerning the pianoforte arrangement
of the Symphony, I will inform Herr B. when it is to come out. Neate
must now be in London; I gave him to carry with him a number of
my compositions; and he promised to put them to the best use for
me, greet him for me. Archduke Rudolph also plays your works with
me, my dear Ries, of which Il sogno pleases me particularly.
Farewell, my dear R., commend me to your dear wife as well as all
the pretty English women to whom it might give pleasure.
On May 15, a letter of condolence to Countess
Erdödy was called out by the sudden death of her Appeals to Charles
Neate
son Fritzi. At the countryseat in Croatia, the lad
burst one morning into his sister’s room and, complaining of his
head, with a cry of anguish sank dead at her feet. Beethoven labors
sadly in his effort to find words of comfort for the stricken mother:
“Reflect that your son might have been forced to go into battle and
might then, like millions of others, have met his death, besides you
are still the mother of two dear, hopeful children.” On the same day
he wrote a French letter to Neate which, because of its characteristic
style and unconventional spelling, Moscheles reproduced literally. A
paragraph will suffice us here:
Avanthier on me portait un extrait d’une Gazette anglaise nommée
Morning cronigle, ou je lisoit avec grand plasir, que la societé
philharmonique à donné ma sinfonie in A ♯ ; c’est une grande
satisfaction pour moi, mais je souhais bien d’avoir de vous même
des nouvelles, que vous ferez avec tous les compositions, que j’ai
vous donnés; vous m’avez promis ici, de donner un concert pour
moi, mais ne prenez mal, si je me méfis un peu, quand je pense que
le Prince regent d’angleterre ne me dignoit pas ni d’une reponse ni
d’une autre reconnaissance pour la Bataile que j’ai envoyé a son
Altesse, et lequelle on a donnée si souvent a Londre, et seulement
les gazettes annoncoient le reussir de cet œuvre et rien d’autre
chose....
The following letter of a few days later was written in English,
probably by Häring, and only signed by Beethoven:
Vienna, May 18, 1816.
My dear Neate:
By a letter of Mr. Ries, I am acquainted with your happy arrival at
London. I am very well pleased with it, and still better I should be
pleased if I had learned it by yourself.
Concerning our business, I know well enough that for the
performance of the greater works, as the Symphony, the Cantata,
the Chorus, and the Opera, you want the help of the Philharmonic
Society, and I hope your endeavour to my advantage will be
successful.
Mr. Ries gave me notice of your intention to give a concert to my
benefit. For this triumph of my art at London I would be indebted to
you alone; but an influence still wholesomer on my almost indigent
life, would be to have the profit proceeding from this enterprise. You
know, that in some regard I am now father to the lovely lad you saw
with me; hardly I can live alone three months upon my annual salary
of 3400 florins in paper, and now the additional burden of
maintaining a poor orphan—you conceive how welcome lawful
means to improve my circumstances must be to me. As for the
Quartet in F minor, you may sell it without delay to a publisher, and
signify me the day of its publication, as I should wish it to appear
here and abroad on the very day. The same you be pleased to do
with the two Sonatas, Op. 102, for pianoforte and violoncello; yet
with the latter it needs no haste.
I leave entirely to your judgment to fix the terms for both works, to
wit, the Quatuor and the Sonatas, the more the better. Be so kind to
write me immediately for two reasons; 1st, that I may not be obliged
to shrink up my shoulders when they ask me if I got letters from
you; and 2dly, that I may know how you do, and if I am in favour
with you. Answer me in English if you have to give me happy news
(for example, those of giving a concert to my benefit), in French if
they are bad ones.
Perhaps you find some lover of music to whom the Trio and the
Sonata with violin, Mr. Ries had sold to Mr. Birchall, or the Symphony
arranged for the Pianoforte, might be dedicated, and from whom
there might be expected a present. In expectation of your speedy
answer, my dear friend and countryman, I am, yours truly,
Ludwig van Beethoven
We can follow the progress of the business in connection with the
compositions to be published in London in the following letter to
Ries:
Vienna, June 11, 1816.
My dear R.!
I am sorry that because of me, you are again compelled to pay out
some postage money, willing as I am to help and serve others it
gives me equal pain to burden others with my affairs. Of the 10
ducats nothing has appeared up-to-date and the conclusion to be
formed from this is that in England as here there are wind-bags and
people who do not keep their word. I charge nothing against you in
this. Nevertheless I must beg of you to go to Mr. Birchall again in the
matter of the 10 ducats, and to collect them yourself, I assure you
on my honor that I paid the 21 fl. in Convention coin for expenses
outside the copyist’s fee and several postages in bank-notes. The
money was not even paid in ducats, though you yourself wrote me
that it would be paid in Dutch ducats—therefore there are also in
England such conscientious persons to whom keeping their word is
nothing?!! The publisher here has applied to me to have the Trio
published in London on the last of August, for which reason I beg of
you kindly to speak with Mr. B. Mr. B. can get himself in readiness
concerning the pianoforte arrangement of the Symphony in A, since
as soon as the publisher here tells me the day I shall immediately let
you or B. know.
As I have not heard a syllable from Neate since his arrival in London,
I beg you to tell him to give you an answer whether he has sold the
Quartet in F minor as I want to publish it here simultaneously, and
what I may expect in reference to the Violoncello Sonatas? Of all the
other works which I sent by him I am almost ashamed to speak,
even to myself for having again been so trustful to give them to him
wholly without conditions trusting that his friendship and care for my
interests would find a way. I was given to read a translation of a
report in the Morning Chronicle about the performance of a
Symphony (probably in A). The same thing will probably happen to
this as well as all the other works which I gave to N. as happened to
the Battle, I shall probably get nothing for them as I got nothing for
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