Pharmacotherapy Handbook 11Th Edition Terry L Schwinghammer All Chapter

Pharmacotherapy Handbook 11th
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Pharmacotherapy
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Eleventh Edition
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Pharmacotherapy
Handbook
Eleventh Edition
Terry L. Schwinghammer, PharmD, FCCP, FASHP, FAPhA

Professor Emeritus, Department of Clinical Pharmacy
School of Pharmacy
West Virginia University
Morgantown, West Virginia
Joseph T. DiPiro, PharmD, FCCP

Professor and Dean
Archie O. McCalley Chair
School of Pharmacy
Virginia Commonwealth University
Richmond, Virginia
Vicki L. Ellingrod, PharmD, FCCP

John Gideon Searle Professor of Pharmacy
Associate Dean for Research and Graduate Education, College of Pharmacy
Professor of Psychiatry, Medical School
University of Michigan
Ann Arbor, Michigan
Cecily V. DiPiro, PharmD

Consultant Pharmacist
Richmond, Virginia
New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
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Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
INTRODUCTION
Edited by Cecily V. DiPiro and Terry L. Schwinghammer
The Patient Care Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
SECTION 1: BONE AND JOINT DISORDERS

Edited by Terry L. Schwinghammer
1. Gout and Hyperuricemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2. Osteoarthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3. Osteoporosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
4. Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
SECTION 2: CARDIOVASCULAR DISORDERS

5. Acute Coronary Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
6. Arrhythmias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
7. Cardiac Arrest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
8. Dyslipidemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
9. Heart Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
10. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
11. Ischemic Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
12. Shock Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
13. Stroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
14. Venous Thromboembolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
SECTION 3: DERMATOLOGIC DISORDERS

15. Acne Vulgaris. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
16. Dermatologic Drug Reactions and Common Skin Conditions. . . . . . . . . . . . . . 174
17. Psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
SECTION 4: ENDOCRINOLOGIC DISORDERS

18. Adrenal Gland Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
19. Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
20. Thyroid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
SECTION 5: GASTROINTESTINAL DISORDERS

Edited by Joseph T. DiPiro and Terry L. Schwinghammer
21. Cirrhosis and Portal Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
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22. Constipation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

23. Diarrhea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
24. Gastroesophageal Reflux Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
25. Hepatitis, Viral. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
26. Inflammatory Bowel Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
27. Nausea and Vomiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
28. Pancreatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
29. Peptic Ulcer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
SECTION 6: GYNECOLOGIC AND OBSTETRIC DISORDERS

Edited by Vicki L. Ellingrod
30. Contraception. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
31. Hormone Therapy in Women. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
32. Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
SECTION 7: HEMATOLOGIC DISORDERS

Edited by Cecily V. DiPiro
33. Anemias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
34. Sickle Cell Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
SECTION 8: INFECTIOUS DISEASES

Edited by Joseph T. DiPiro
35. Antimicrobial Regimen Selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
36. Central Nervous System Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
37. Endocarditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
38. Fungal Infections, Invasive. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
39. Fungal Infections, Superficial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
40. Gastrointestinal Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
41. Human Immunodeficiency Virus Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
42. Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
43. Intra-Abdominal Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
44. Respiratory Tract Infections, Lower. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
45. Respiratory Tract Infections, Upper. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
46. Sepsis and Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
47. Sexually Transmitted Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
48. Skin and Soft-Tissue Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
49. Surgical Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
50. Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
51. Urinary Tract Infections and Prostatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
52. Vaccines, Toxoids, and Other Immunobiologics. . . . . . . . . . . . . . . . . . . . . . . . . . .568
SECTION 9: NEUROLOGIC DISORDERS

53. Alzheimer Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
54. Epilepsy and Status Epilepticus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
vi
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Contents
55. Headache: Migraine and Tension-Type. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

56. Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
57. Parkinson Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
SECTION 10: NUTRITION SUPPORT

58. Obesity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
59. Nutrition Assessment and Support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
SECTION 11: ONCOLOGIC DISORDERS

60. Breast Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
61. Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
62. Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
63. Lymphomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
64. Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
SECTION 12: OPHTHALMIC DISORDERS

65. Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
SECTION 13: PSYCHIATRIC DISORDERS

66. Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
67. Bipolar Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
68. Depressive Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .783
69. Opioid Use Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
70. Schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813
71. Sleep–Wake Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830
72. Substance Use Disorders: Alcohol, CNS Depressants, Stimulants, Nicotine. . . . 839
SECTION 14: RENAL DISORDERS

73. Acid–Base Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
74. Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
75. Chronic Kidney Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872
76. Electrolyte Homeostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
SECTION 15: RESPIRATORY DISORDERS

77. Allergic Rhinitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905
78. Asthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .915
79. Chronic Obstructive Pulmonary Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
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Contents
SECTION 16: UROLOGIC DISORDERS

80. Benign Prostatic Hyperplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
81. Erectile Dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
82. Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
APPENDICES
Appendix 1. Pediatric Pharmacotherapy, Nutrition, and Neonatal Critical Care. . . . . 975
Appendix 2. Geriatric Assessment and Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . 984
Appendix 3. Critical Care: Patient Assessment and Pharmacotherapy. . . . . . . . . . . 988
Appendix 4. Drug Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
Appendix 5. Drug-Induced Hematologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 1001
Appendix 6. Drug-Induced Liver Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
Appendix 7. Drug-Induced Pulmonary Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
Appendix 8. Drug-Induced Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
Appendix 9. Drug-Induced Ophthalmic Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . 1021
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023
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Preface
The 11th edition of this companion to Pharmacotherapy: A Pathophysiologic Approach

is designed to provide practitioners and students with critical information that can be
used to guide medication decision-making in collaborative, interprofessional health-
care settings. To ensure brevity, clarity, and portability, the bulleted format provides
essential textual information, key tables and figures, and treatment algorithms.
Corresponding to the major sections in the Pharmacotherapy textbook, medical
conditions are alphabetized within the following sections: Bone and Joint Disorders;
Cardiovascular Disorders; Dermatologic Disorders; Endocrinologic Disorders;
Gastrointestinal Disorders; Gynecologic and Obstetric Disorders; Hematologic Dis
orders; Infectious Diseases; Neurologic Disorders; Nutrition Support; Oncologic
Disorders; Ophthalmic Disorders; Psychiatric Disorders; Renal Disorders; Respiratory
Disorders; and Urologic Disorders. The Handbook includes nine tabular appendices
(four more than the 10th edition) involving pediatric pharmacotherapy, nutrition, and
neonatal critical care; geriatric assessment and pharmacotherapy; critical care patient
assessment and pharmacotherapy; drug allergy; drug-induced hematologic disorders;
drug-induced liver disease; drug-induced pulmonary disease; drug-induced kidney
disease; and drug-induced ophthalmic disorders. This edition also includes new chap-
ters on the pharmacists’ patient care process, opioid use disorder, and superficial fungal
infections.
Each chapter is organized in a consistent format:
• Disease State Definition
• Pathophysiology
• Clinical Presentation
• Diagnosis
• Treatment
• Evaluation of Therapeutic Outcomes
The Treatment section may include goals of treatment, general approach to treat-
ment, nonpharmacologic therapy, drug selection guidelines, dosing recommenda-
tions, adverse effects, pharmacokinetic considerations, and important drug-drug
interactions. When more in-depth information is required, the reader is encouraged
to refer to the corresponding chapter in the primary textbook, Pharmacotherapy:
A Pathophysiologic Approach, 11th edition. These chapters now provide guidance on
application of the pharmacists’ patient care process for specific conditions.
The authors gratefully acknowledge Barbara G. Wells, PharmD, FASHP, FCCP,
retired Dean Emeritus and Professor Emeritus, School of Pharmacy, The University of
Mississippi, for her substantial contributions to the creation, design, and production
of all previous editions of this work. Her vision, insight, and passion for the provi-
sion of patient-centered medication therapy are evident throughout the pages of the
Handbook. In addition, this edition of the Handbook is dedicated to the memory of her
late husband, Richard M. Wells: pharmacist, colleague, and friend.
It is our hope that students and practitioners find this book to be helpful on their
daily journey to provide the highest quality individualized, patient-centered care. We
invite your comments on how we may improve subsequent editions of this work.
Terry L. Schwinghammer
Joseph T. DiPiro
Vicki L. Ellingrod
Cecily V. DiPiro
Please provide your comments about this book, Schwinghammer et al., Pharmacotherapy
Handbook, 11th edition, to its authors and publisher by writing to userservices@
mheducation.com. Please indicate the author and title of this handbook in the subject
line of your e-mail.
ALGRAWANY
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INTRODUCTION
Edited by Cecily V. DiPiro and Terry L. Schwinghammer
The Patient Care Process
INTRODUCTION
Health professionals who provide direct patient care are often called practitioners.
Health professionals practice when they use their unique knowledge and skills to serve
patients. A healthcare practice is not a physical location or simply a list of activities.
Rather, a professional practice requires three essential elements: (1) a philosophy of
practice, (2) a process of care, and (3) a practice management system.
A practice philosophy is the moral purpose and commonly held set of values that
guides the profession. It is the critical foundation on which the practices of pharmacy,
medicine, nursing, and dentistry are built. Although the concept of pharmaceutical
care is not formally included in the code of ethics for the pharmacy profession or the
oath of a pharmacist, pharmacists understand that they have a unique responsibility
for addressing the drug-related needs of patients and should be held accountable for
preventing, identifying, and resolving drug therapy problems.
The patient care process is a fundamental series of actions that guide the activities
of health professionals. In 2014, the Joint Commission for Pharmacy Practitioners
(JCPP)—representing 11 national pharmacy organizations—endorsed a framework
for providing clinically oriented patient care services called the Pharmacists’ Patient
Care Process. This process includes five essential steps: (1) collecting subjective and
objective information about the patient; (2) assessing the collected data to identify
problems, determine the adequacy of current treatments, and set priorities; (3) creating
an individualized care plan that is evidence-based and cost-effective; (4) implementing
the care plan; and (5) monitoring the patient over time during follow-up encounters to
evaluate the effectiveness of the plan and modify it as needed (Fig. 1). In addition to
the five fundamental steps, a patient-centered approach to decision making is essential.
A practice management system is necessary to support the efficient and effective
delivery of services, including physical, financial, and human resources with policies
and procedures to carry out the work of patient care.
This chapter provides a brief summary of the patient care process applied to drug
therapy management and the practice management issues influencing adoption and
application of this process by pharmacists.
IMPORTANCE OF A STANDARD CARE PROCESS

The stimulus for developing the patient care process for pharmacy was the wide
variation observed as pharmacists provided direct patient care, often using the same
terminology to describe diverse services or, conversely, using different terminology to
describe the same service. Without a consistent patient care process, it has been chal-
lenging for the pharmacy profession to communicate the pharmacist’s role to external
groups and establish the distinct value pharmacists bring to an interprofessional care
team. Moreover, the patient must know and understand what is to be delivered to deter-
mine how best to receive the care provided. Likewise, other members of the healthcare
team must determine how best to integrate the pharmacist’s work into their efforts car-
ing for the patient. A process of care must be built on a set of fundamental steps that can
address the wide range of complexity that exists among patients. The process needs to be
adaptable to varied settings, diverse populations, and different acuity levels.
ch00.indd 1 18-11-2020 14:16:20

| INTRODUCTION
FIGURE 1. The pharmacists’ patient care process. Joint Commission of Pharmacy

Practitioners. Pharmacists’ Patient Care Process. May 29, 2014. Available at: https://
jcpp.net/wp-content/uploads/2016/03/PatientCareProcess-with-supporting-
organizations.pdf. Reprinted with permission.
THE PATIENT CARE PROCESS TO OPTIMIZE PHARMACOTHERAPY

The application or focus of a profession-specific process of care depends upon the pro-
fession’s knowledge and expertise. For pharmacy, the patient care process is focused on
patient medication-related needs and experience with medication therapy. Each health
profession then addresses patient needs by assessing patient-specific information in a
unique manner. For pharmacists providing comprehensive medication management
(CMM), the assessment step involves a systematic examination of the indication, effec-
tiveness, safety, and adherence for each of the patient’s medications. This is a unique way
of approaching a patient’s health needs; no other discipline applies a systematic assess-
ment process to medications and the medication experience in this manner.
The pharmacists’ patient care process is standardized and is not specific to a care
setting—it can be applied wherever CMM is performed. However, the type of informa-
tion collected, its sources, and the duration of time to complete the process may vary
depending on the practice setting and acuity of care. The subsequent sections in this
chapter briefly describe the steps in the patient care process for pharmacists.
COLLECT PATIENT-SPECIFIC INFORMATION
Collect relevant subjective and objective information about the patient and analyze the
data to understand the medical/medication history and clinical status of the patient.
Information from the health record may include patient demographics, active medical
ch00.indd 2 18-11-2020 14:16:24

The Patient Care Process |
problem list, admission and discharge notes, office visit notes, laboratory values, diag-
nostic tests, and medication lists. Conduct a comprehensive medication review with
the patient that also includes alcohol, tobacco and caffeine use; immunization status;
allergies; and adverse drug effects. Ask whether the patient has questions or concerns
for the visit. Document a complete medication list that includes all prescription and
nonprescription medications as well as dietary supplements the patient is taking (ie,
name, indication, strength and formulation, dose, frequency, duration, and response
to medication). Gather past medication history, if pertinent. Collect information about
the patient’s medication experience (eg, beliefs, expectations, and cultural consider-
ations related to medications) and personal goals of therapy. Ask about the patient’s
ability to access medications, manage medications at home, adhere to the therapy, and
use medications appropriately. Gather additional important information (eg, physi-
cal assessment findings, review of systems, home-monitored blood glucose, blood
pressure readings).
ASSESS INFORMATION AND FORMULATE A
MEDICATION THERAPY PROBLEM LIST
Analyze the information collected to formulate a problem list consisting of the patient’s
active medical problems and medication therapy problems in order to prioritize
medication therapy recommendations that achieve the patient’s health goals. Assess
the indication of each medication the patient is taking, including the presence of an
appropriate indication; consider also whether the patient has an untreated medical
condition that requires therapy. Assess the effectiveness of each medication, including
progress toward achieving therapeutic goals; optimal selection of drug product, dose,
and duration of therapy; and need for additional laboratory data to monitor medication
response. Assess the safety of each medication by identifying adverse events; excessive
doses; availability of safer alternatives; pertinent drug-disease, drug-drug, or drug-food
interactions; and need for additional laboratory data to monitor medication safety.
Assess adherence and the patient’s ability to take each medication (eg, administration,
access, affordability). Ensure that medication administration times are appropriate
and convenient for the patient. From all of this information, formulate and prioritize a
medication therapy problem list, classifying the patient’s medication therapy problems
based on indication, effectiveness, safety, and adherence (Table 1).
TABLE 1 Medication Therapy Problem Categories Framework

Medication-Related Needs Medication Therapy Problem Category
Indication Unnecessary medication therapy
Needs additional medication therapy
Effectiveness Ineffective medication
Dosage too low
Needs additional monitoring
Safety Adverse medication event
Dosage too high
Needs additional monitoring
Adherence Adherence
Cost
Pharmacy Quality Alliance. PQA Medication Therapy Problem Categories Framework. August 2017.
Available at: https://www.pqaalliance.org/assets/Measures/PQA%20MTP%20Categories%20
Framework.pdf.
ch00.indd 3 18-11-2020 14:16:24

| INTRODUCTION
DEVELOP THE CARE PLAN

Working in collaboration with other healthcare professionals and the patient or care-
giver, develop an individualized, patient-centered care plan that is evidence based
and affordable for the patient. Design the plan to manage the patient’s active medical
conditions and resolve the identified medication therapy problems. Coordinate care
with the primary care provider and other healthcare team members to reach consensus
on the proposed care plan, when needed. Identify the monitoring parameters necessary
to assess effectiveness, safety, and adherence, including frequency of follow-up moni-
toring. Design personalized education and interventions for the patient, and reconcile
all medication lists (eg, from the medical record, patient, pharmacy) to arrive at an
accurate and updated medication list. Determine who will implement components of
the care plan (ie, patient, clinical pharmacist, other providers). Decide on the appropri-
ate time frame and mode for patient follow-up (eg, phone, face-to-face).
IMPLEMENT THE CARE PLAN
Implement the care plan in collaboration with other healthcare professionals and the
patient or caregiver. Discuss the care plan with the patient, educate the patient about
the medications and goals of therapy, make sure the patient understands and agrees
with the plan, and implement recommendations that are within your scope of practice.
For recommendations that cannot be independently implemented, communicate the
care plan to the rest of the team, indicating where input is required by other team mem-
bers. Document the encounter in the health record (eg, assessment, medication therapy
care plan, rationale, monitoring, and follow-up). Arrange patient follow-up based on
the determined time frame and communicate follow-up instructions with the patient.
FOLLOW-UP WITH THE PATIENT
Provide targeted follow-up and monitoring (whether in person, electronically, or via
phone) to assess the effectiveness and safety of the care plan. Modify the plan when
needed in collaboration with other team members and the patient or caregiver to
achieve patient and clinical goals of therapy. Plan for a CMM follow-up visit at least
once within a year of the initial visit, and repeat all steps of the patient care process
at that time to ensure continuity of care and ongoing medication optimization. Refer
the patient back to the provider (and document accordingly) if all medication therapy
problems have been resolved, no new problems are identified, and it is determined that
the patient no longer needs CMM services.
PRACTICE MANAGEMENT ISSUES

A practice management system is essential to the care process and includes the metrics
to ensure patient health outcomes are being achieved; efficient workflow; communica-
tion and documentation using the power of information technology (IT); and data
that accurately reflect the attribution and value the practitioner brings to patient care.
QUALITY METRICS
The patient care process sets a standard of achievable performance by defining the
parameters of the process that can be measured. With the movement toward outcome-
based healthcare models and value-based payment systems, it is critical to objectively
measure the impact a patient care service has on a patient’s health and well-being. For
the process to be measurable, each element must be clearly defined and performed in
a similar manner during each patient encounter. The lack of clarity and consistency
has hindered collection of robust evidence to support the value of pharmacists’ patient
care services. The standard patient care process gives pharmacists an opportunity to
show value on a large scale because the services are comparable and clearly understood
across practice settings.
ALGRAWANY
4
The Patient Care Process |
WORKFLOW, DOCUMENTATION, AND INFORMATION SYSTEMS

Healthcare systems are rapidly embracing the power of technology to analyze infor-
mation and gain important insights about the health outcomes being achieved. The
uniform patient care process sets a standard for the practice workflow that allows IT
systems to capture and extract data for analysis and sharing. The ability to capture
clinical data is currently available through a number of coding systems, such as the
International Classification of Diseases 10th edition (ICD-10) and the Systematized
Nomenclature of Medicine—Clinical Terms (SNOMED-CT). Practitioners need to
understand how coding systems operate behind the scenes when performing and
documenting their clinical activities. This will enable practitioners to assist informa-
tion technologists to effectively design systems to accurately document the elements of
the process that can produce the data on medication-related outcomes.
DOCUMENTATION, ATTRIBUTION, AND PAYMENT
Payment to healthcare providers for patient care services in the United States has
traditionally been based on the documentation and reporting of standard processes of
care. Rules and guidance from Medicare and the Centers for Medicare and Medicaid
Services (CMS) are considered the billing and payment standard for healthcare provid-
ers both for governmental and commercial payers. Reporting the complexity of care
provided is built on top of the documentation requirements; complexity is determined
by the number of required elements in each documentation domain. A billing code
is then assigned to the patient encounter that equates to a payment commensurate
with the level of care provided. This process is the basis for the current fee-for-service
payment structure, and it is likely that this general format will remain in any future
payment model. The traditional SOAP (Subjective, Objective, Assessment, Plan) note
format is often used by pharmacists when documenting patient care and is particularly
appropriate when providing services incident to an eligible Medicare Part B provider.
However, some elements of the SOAP note that are required when using certain bill-
ing codes are not routinely performed by pharmacists (eg, comprehensive physical
examination). The pharmacists’ patient care process establishes a standard framework
that reflects the pharmacist’s work. Using a standard care process accompanied with
a standard documentation framework will result in efficiencies of practice, enable
appropriate and accurate billing, and facilitate the attribution of care to desired patient
outcomes needed in value-based payment models.
See Chapter 1, The Patient Care Process, authored by Stuart T. Haines, Mary Ann
Kliethermes, and Todd D. Sorensen for a more detailed discussion of this topic.
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SECTION 1
BONE AND JOINT DISORDERS
1
CHAPTER
Gout and Hyperuricemia
• Gout involves hyperuricemia, recurrent attacks of acute arthritis with monosodium

urate (MSU) crystals in synovial fluid leukocytes, deposits of MSU crystals in tissues
in and around joints (tophi), interstitial kidney disease, and uric acid nephrolithiasis.
Acute Gouty Arthritis

PATHOPHYSIOLOGY
• Uric acid is the end product of purine degradation. An increased urate pool in indi-
viduals with gout may result from overproduction or underexcretion.
• Purines originate from dietary purine, conversion of tissue nucleic acid to purine
nucleotides, and de novo synthesis of purine bases.
• Overproduction of uric acid may result from abnormalities in enzyme systems that regu-
late purine metabolism (eg, increased activity of phosphoribosyl pyrophosphate [PRPP]
synthetase or deficiency of hypoxanthine-guanine phosphoribosyl transferase [HGPRT]).
• Uric acid may also be overproduced because of increased breakdown of tissue nucleic
acids, as with myeloproliferative and lymphoproliferative disorders. Cytotoxic drugs can
result in overproduction of uric acid due to lysis and the breakdown of cellular matter.
• Dietary purines are insignificant in generating hyperuricemia without some derange-
ment in purine metabolism or elimination.
• Two-thirds of uric acid produced daily is excreted in urine. The remainder is
eliminated through gastrointestinal (GI) tract after degradation by colonic bacteria.
Decline in urinary excretion to a concentration below the rate of production leads to
hyperuricemia and an increased pool of sodium urate.
• Drugs that decrease renal uric acid clearance include diuretics, nicotinic acid, salicy-
lates (<2 g/day), ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine, and
cytotoxic drugs.
• Deposition of urate crystals in synovial fluid results in inflammation, vasodilation,
increased vascular permeability, complement activation, and chemotactic activity for
polymorphonuclear leukocytes. Phagocytosis of urate crystals by leukocytes results in
rapid lysis of cells and discharge of proteolytic enzymes into cytoplasm. The ensuing
inflammatory reaction causes intense joint pain, erythema, warmth, and swelling.
• Uric acid nephrolithiasis occurs in ~10% of patients with gout. Predisposing factors
include excessive urinary excretion of uric acid, acidic urine (pH <6), and highly
concentrated urine.
• In acute uric acid nephropathy, acute kidney injury occurs because of blockage of
urine flow from massive precipitation of uric acid crystals in collecting ducts and
ureters. Chronic urate nephropathy is caused by long-term deposition of urate crys-
tals in the renal parenchyma.
• Tophi (urate deposits) are uncommon and are a late complication of hyperuricemia.
The most common sites are the base of the fingers, olecranon bursae, ulnar aspect of
forearm, Achilles tendon, knees, wrists, and hands.
CLINICAL PRESENTATION
• Acute gout attacks are characterized by rapid onset of excruciating pain, swelling,
and inflammation. The attack is typically monoarticular, most often affecting the first
7
ch01.indd 7 18-11-2020 11:49:51

SECTION 1 | Bone and Joint Disorders
metatarsophalangeal joint (podagra), and then, in order of frequency, the insteps,

ankles, heels, knees, wrists, fingers, and elbows. Attacks commonly begin at night,
with the patient awakening with excruciating pain. Affected joints are erythematous,
warm, and swollen. Fever and leukocytosis are common. Untreated attacks last from
3 to 14 days before spontaneous recovery.
• Acute attacks may occur without provocation or be precipitated by stress, trauma, alco-
hol ingestion, infection, surgery, rapid lowering of serum uric acid by uric acid-low-
ering agents, and ingestion of drugs known to elevate serum uric acid concentrations.
DIAGNOSIS
• Definitive diagnosis requires aspiration of synovial fluid from the affected joint and
identification of intracellular crystals of MSU monohydrate in synovial fluid leukocytes.
• When joint aspiration is not feasible, a presumptive diagnosis is based on presence of
characteristic signs and symptoms as well as the response to treatment.
TREATMENT
• Goals of Treatment: Terminate the acute attack, prevent recurrent attacks, and pre-
vent complications associated with chronic deposition of urate crystals in tissues.
NONPHARMACOLOGIC THERAPY
• Local ice application is the most effective adjunctive treatment.
• Dietary supplements (eg, flaxseed, cherry, celery root) are not recommended.
PHARMACOLOGIC THERAPY (FIG. 1-1)
• Most patients are treated successfully with nonsteroidal anti-inflammatory drugs
(NSAIDs), corticosteroids, or colchicine. Treatment should begin as soon as possible
after the onset of an attack.
NSAIDS
• NSAIDs have excellent efficacy and minimal toxicity with short-term use. Indometh-
acin, naproxen, and sulindac have Food and Drug Administration (FDA) approval
for gout, but others are likely to be effective (Table 1-1).
• Start therapy within 24 hours of attack onset and continue until complete resolution
(usually 5–8 days). Tapering may be considered after resolution, especially if comorbid-
ities such as impaired hepatic or kidney function make prolonged therapy undesirable.
• The most common adverse effects involve the GI tract (gastritis, bleeding, and perfo-
ration), kidneys (renal papillary necrosis, reduced glomerular filtration rate), cardio-
vascular system (increased blood pressure, sodium and fluid retention), and central
nervous system (impaired cognitive function, headache, and dizziness).
• Selective cyclooxygenase-2 inhibitors (eg, celecoxib) may be an option for patients
unable to take nonselective NSAIDs, but the risk-to-benefit ratio in acute gout is
unclear, and cardiovascular risk must be considered.
Corticosteroids
• Corticosteroid efficacy is equivalent to NSAIDs; they can be used systemically or by
intra-articular (IA) injection. If only one or two joints are involved, either IA or oral cor-
ticosteroids are recommended. Systemic therapy is necessary for polyarticular attacks.
• Prednisone or prednisolone oral dosing strategies include (1) 0.5 mg/kg daily for
5–10 days followed by abrupt discontinuation, or (2) 0.5 mg/kg daily for 2–5 days
followed by tapering for 7–10 days. Tapering is often used to reduce the hypothetical
risk of a rebound attack upon steroid withdrawal.
• Methylprednisolone dose pack is a 6-day regimen starting with 24 mg on day 1 and
decreasing by 4 mg each day that may be considered.
• Triamcinolone acetonide 20–40 mg given by IA injection may be used if gout is limited
to one or two joints; give 10–40 mg IA (large joints) or 5–20 mg IA (small joints). IA cor-
ticosteroids should be used with an oral NSAID, colchicine, or corticosteroid therapy.
8
ch01.indd 8 18-11-2020 11:49:52

ch01.indd 9
Mild/moderate Severe
Pain intensity
Initiate monotherapy:a Initiate combination therapy - examples include:

NSAID Colchicine NSAID
Colchicineb Colchicine Oral corticosteroid
Systemic corticosteroid NSAID Intra-articular corticosteroid
Colchicine Intra-articular corticosteroid
Oral corticosteroid Intra-articular corticosteroid
Successful Inadequate response
Treatment outcome Treatment outcome
Prevent recurrent attacks: Switch to alternate monotherapy

Recommend dietary modifications to
prevent hyperuricemiac
Gout and Hyperuricemia | CHAPTER 1

Educate patient about the role of uric Successful
acid excess in gout attacks Inadequate
Develop plan for patient to promptly self- response
treat any future attacks
Initiate urate-lowering therapy if indicated Off-label Interleukin-1 inhibitor
therapy
a) Recommendation for initial monotherapy with one of these medication groups supported unanimously by guidelines of the American College of Rheumatology (ACR),
European League Against Rheumatism (EULAR), and American College of Physicians (ACP)
18-11-2020 11:49:53
b) Colchicine should be started as soon as possible, ideally within 12-36 hours of pain onset
c) Noted as an area of inconclusive evidence by 2017 ACP guidelines
(Algorithm derived from 2017 ACP, 2016 EULAR, and 2012 ACR gout guidelines.)
FIGURE 1-1. Algorithm for management of an acute gout attack.
9
TABLE 1-1 Dosage Regimens of Oral Nonsteroidal Anti-inflammatory Drugs for Treatment of
Acute Gout
Generic Name Initial Dose Usual Range
Etodolac 300 mg twice daily 300–500 mg twice daily
Fenoprofen 400 mg three times daily 400–600 mg three to four times daily
Ibuprofen 400 mg three times daily 400–800 mg three to four times daily
Indomethacin 50 mg three times daily 50 mg three times daily initially
until pain is tolerable then rapidly
reduce to complete cessation
Ketoprofen 75 mg three times daily or 50 50–75 mg three to four times daily
mg four times daily
Naproxen 750 mg followed by 250 mg —
every 8 hours until the
attack has subsided
Piroxicam 20 mg once daily or 10 mg —
twice daily
Sulindac 200 mg twice daily 150–200 mg twice daily for 7–10 days
Meloxicam 5 mg once daily 7.5–15 mg once daily
Celecoxib 800 mg followed by 400 mg —
on day one, then 400 mg
twice daily for 1 week
• Methylprednisolone (a long-acting corticosteroid) given by a single intramuscular

(IM) injection followed by a short course of oral corticosteroid therapy is another rea-
sonable approach. Alternatively, IM corticosteroid monotherapy may be considered
in patients with multiple affected joints who cannot take oral therapy.
• Short-term corticosteroid use is generally well tolerated. Use with caution in patients
with diabetes, GI problems, bleeding disorders, cardiovascular disease, and psychi-
atric disorders. Avoid long-term use because of risk for osteoporosis, hypothalamic–
pituitary–adrenal axis suppression, cataracts, and muscle deconditioning.
• Adrenocorticotropic hormone (ACTH) gel: 40–80 USP units IM every 6–8 hours
for 2 or 3 days and then discontinued. Limit use to patients with contraindications
to first-line therapies (eg, heart failure, chronic kidney disease, and history of GI
bleeding) or patients unable to take oral medications. However, the high drug price
excludes ACTH as a viable treatment option.
Colchicine
• Colchicine is highly effective in relieving acute gout attacks; when it is started within
the first 24 hours of onset, about two-thirds of patients respond within hours. Use
only within 36 hours of attack onset because the likelihood of success decreases sub-
stantially if treatment is delayed.
• Colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diar-
rhea). Non-GI effects include neutropenia and axonal neuromyopathy, which may
be worsened in patients taking other myopathic drugs (eg, statins) or with impaired
kidney function. Use colchicine with caution in patients taking P-glycoprotein or
strong CYP450 3A4 inhibitors (eg, clarithromycin) due to increased plasma colchi-
cine levels and potential toxicity; colchicine dose reductions may be required. Also
use colchicine with caution in patients with impaired kidney or hepatic function.
• Colcrys is an FDA-approved colchicine product available in 0.6 mg oral tablets. The
recommended dose is 1.2 mg (two tablets) initially, followed by 0.6 mg (one tablet) 1
hour later. Although not an FDA-approved regimen, the American College of Rheu-
matology (ACR) gout treatment guidelines suggest that colchicine 0.6 mg once or
10
ch01.indd 10 18-11-2020 11:49:53

twice daily can be started 12 hours after the initial 1.2-mg dose and continued until
the attack resolves. Colchicine is also available generically.
Hyperuricemia In Gout
• Recurrent gout attacks can be prevented by maintaining low uric acid levels, but
adherence with nonpharmacologic and pharmacologic therapies is poor.
• Patient education should address the recurrent nature of gout and the objective of
each lifestyle/dietary modification and medication.
• Promote weight loss through caloric restriction and exercise in all patients to enhance
renal urate excretion.
• Alcohol restriction is important because consumption correlates with gout attacks.
ACR guidelines recommend limiting alcohol use in all gout patients and avoidance
of any alcohol during periods of frequent gout attacks and in patients with advanced
gout under poor control.
• Dietary recommendations include limiting consumption of high-fructose corn syrup
and purine-rich foods (organ meats and some seafood) and encouraging consump-
tion of vegetables and low-fat dairy products. The DASH diet (Dietary Approaches
to Stop Hypertension) may lower serum uric acid by ~1.0 mg/dL in hyperuricemic
patients who are adherent. However, no studies have demonstrated that dietary inter-
vention improves clinical outcomes such as reduction in gout flares.
• Evaluate the medication list for potentially unnecessary drugs that may elevate uric acid
levels. The ACR guidelines recommend elimination of nonessential uric acid-elevating
medications in patients with hyperuricemia when feasible (eg, thiazide and loop diuret-
ics, calcineurin inhibitors, niacin). Low-dose aspirin for cardiovascular prevention
should be continued because aspirin has a negligible effect on elevating serum uric acid.
PHARMACOLOGIC THERAPY (FIG. 1-2)
• After the first attack of acute gout, prophylactic pharmacotherapy is recommended if
patients have two or more attacks per year, even if serum uric acid is normal or only
minimally elevated. Other indications include presence of tophi, kidney disease, or
history of uric acid urolithiasis.
• Urate-lowering therapy can be started during an acute attack if anti-inflammatory
prophylaxis has been initiated.
• Apply a stepwise approach to hyperuricemia (Fig. 1-2). Xanthine oxidase inhibitors
are recommended first-line therapy, with uricosurics reserved for patients with a con-
traindication or intolerance to xanthine oxidase inhibitors. In refractory cases, combi-
nation therapy with a xanthine oxidase inhibitor plus a drug with uricosuric properties
(probenecid, losartan, or fenofibrate) is suggested. Pegloticase may be used in severe
cases in which the patient cannot tolerate or is not responding to other therapies.
• The ACR guideline goal of urate-lowering therapy is to achieve and maintain serum uric
acid <6 mg/dL (357 μmol/L), and preferably <5 mg/dL (297 μmol/L) if gout is severe or
signs and symptoms of gout persist. Urate lowering should be prescribed for long-term use.
Xanthine Oxidase Inhibitors

• Xanthine oxidase inhibitors reduce uric acid by impairing conversion of hypoxan-
thine to xanthine and xanthine to uric acid. Because they are effective in both over-
producers and underexcretors of uric acid, they are the most widely prescribed agents
for long-term prevention of recurrent gout attacks.
• Allopurinol lowers uric acid levels in a dose-dependent manner. ACR guidelines recom-
mend a starting dose no greater than 100 mg daily in patients with normal kidney function
and no more than 50 mg/day in patients with chronic kidney disease (stage 4 or worse) to
avoid allopurinol hypersensitivity syndrome and prevent acute gout attacks common dur-
ing initiation of urate-lowering therapy. The dose should be titrated gradually every 2–5
weeks up to a maximum of 800 mg/day until the serum urate target is achieved.
11
ch01.indd 11 18-11-2020 11:49:53

No Does patient have an indication for Urate Yes

Lowering Therapy (ULT)?a
Nonpharmacologic Urate ULT Initiation Anti-inflammatory Gout

Lowering Strategies First-Line Prophylaxis During ULT
Dietary Modificationsd • Allopurinol Initiation
• Reduce/avoid alcohol and First-Line
Alternative
organ meats • Low dose colchicine
• Febuxostatb
• Increase vegetable and • Low dose NSAID
• Probenecid
dairy consumption Second Line
Eliminate Urate Elevating • Low dose prednisone
Medications if Unnecessary or prednisolone
• Diuretics
• Niacin
• Calcineurin inhibitors
First-Line
• Titrate ULT to maximum dose
Consider Evidence of gout
• Add therapy with urate-lowering No Achieved Yes activity while
properties if appropriate Urate Target?e taking ULT?
comorbidities exist:c
• Losartan (hypertension) No
• Fenofibrate (Hypertriglyceridemia) Continue
prophylactic
therapy No Yes
Tophus
Achieved Yes present?
urate target? Yes
No Discontinue Discontinue
prophylactic prophylatctic
If using maximized xanthine Continue all measures therapy after the therapy
oxidase inhibitor, consider needed to maintain greater of: six months
add-on therapy: serum urate <6 mg/dL 1) Six months after
• Lesinurad (<357 µmol/L) OR achieving
• Probenecid indefintelye 2) Three months urate target
after achieving
urate target
Achieved Yes
urate target?
No
Switch to
pegloticase
a) Indications for urate-lowering therapy include: 1) presence of tophus 2) ≥ 2 gout attacks per year 3) kidney disease
4) past urolithiasis. EULAR, but not ACR or ACP Guidelines, also recognize the following indications for ULT:
1) first diagnosis of gout at age < 40 years 2) uric acid > 8.0 mg/dL 3) high-risk comorbidities (hypertension,
ischemic heart disease, hear failure)
b) Recognized as first line by ACR Guidelines but cardiovascular safety concerns have been reported
since guideline publication
c) EULAR Guidelines also recognize calcium channel blockers and statins as add-on therapy for uric acid lowering
when indicated for treatment of comorbidities
d) The effectiveness of dietary intervention in improving clinical outcomes is noted as an area of inconclusive evidence
by 2017 ACP guidelines
e) Targeting and maintaining a specific urate level is noted as an area of inconclusive evidence by 2017 ACP guidelines
NSAID, nonsteroidal anti-inflammatory drug; ULT, urate-lowering therapy; XOI, xanthine oxidase inhibitor.
(Algorithm derived from 2017 ACP, 2016 EULAR, and 2012 ACR gout guidelines.)
FIGURE 1-2. Algorithm for management of hyperuricemia in gout.
12
ch01.indd 12 18-11-2020 11:49:54

• Mild adverse effects of allopurinol include skin rash, leukopenia, GI problems,

headache, and urticaria. A more severe adverse reaction known as allopurinol
hypersensitivity syndrome, which includes severe rash (toxic epidermal necrolysis,
erythema multiforme, or exfoliative dermatitis), hepatitis, interstitial nephritis, and
eosinophilia, occurs rarely but is associated with a 20%–25% mortality rate.
• Febuxostat (Uloric) also lowers serum uric acid in a dose-dependent manner. The recom-
mended starting dose is 40 mg once daily. Increase the dose to 80 mg once daily for patients
who do not achieve target serum uric acid concentrations after 2 weeks of therapy. Adverse
events include nausea, arthralgias, and minor hepatic transaminase elevations. Febuxostat
does not require dose adjustment in hepatic or kidney dysfunction. Recent clinical trial
evidence demonstrated an increase in all-cause and cardiovascular mortality compared to
allopurinol, resulting in addition of a warning in the FDA-approved labeling. Because of
these safety concerns, lack of evidence of superior efficacy compared to equivalent-dosed
allopurinol, and increased cost, febuxostat is considered a second-line option. Due to rapid
mobilization of urate deposits during initiation, give concomitant therapy with colchicine
or an NSAID for at least the first 8 weeks of therapy to prevent acute gout flares.
Uricosurics
• Uricosuric drugs increase renal clearance of uric acid by inhibiting the postsecretory
renal proximal tubular reabsorption of uric acid. Patients with a history of urolithiasis
should not receive uricosurics. Start uricosuric therapy at a low dose to avoid marked
uricosuria and possible stone formation. Maintaining adequate urine flow and urine
alkalinization during the first several days of therapy may also decrease likelihood of
uric acid stone formation. Uricosuric treatment is limited to patients with creatinine
clearance (CrCl) >45–50 mL/min.
• Probenecid: The initial dose is 250 mg twice daily for 1–2 weeks, then 500 mg twice
daily for 2 weeks. Increase the daily dose thereafter by 500-mg increments every 1–2
weeks until satisfactory control is achieved or a maximum dose of 2 g/day is reached.
Major side effects include GI irritation, rash and hypersensitivity, precipitation of
acute gouty arthritis, and urolithiasis.
• Lesinurad (Zurampic) inhibits urate transporter 1 in proximal renal tubules, thereby
increasing uric acid excretion. It is approved as combination therapy with a xanthine
oxidase inhibitor for treatment of hyperuricemia associated with gout in patients
who have not achieved target serum uric acid concentrations with xanthine oxidase
inhibitor monotherapy. The approved lesinurad dose is 200 mg once daily in the
morning with food and water in combination with a xanthine oxidase inhibitor.
Lesinurad should not be used in patients with CrCl <45 mL/min. Adverse effects
include urticaria and elevated levels of serum creatinine, lipase, and creatine kinase.
It carries a black box warning about increased risk of acute renal failure when used in
the absence of xanthine oxidase inhibitor therapy. A combination product (Duzallo)
is available that contains two different allopurinol strengths: lesinurad 200 mg/
allopurinol 200 mg (for patients with CrCl 45–59 mL/min) and lesinurad 200 mg/
allopurinol 300 mg (for patients with CrCl >59 mL/min).
Pegloticase
• Pegloticase (Krystexxa) is a pegylated recombinant uricase that reduces serum uric
acid by converting uric acid to allantoin, which is water soluble. Pegloticase is indi-
cated for antihyperuricemic therapy in adults refractory to conventional therapy.
• The dose is 8 mg by IV infusion over at least 2 hours every 2 weeks. Because of
potential infusion-related allergic reactions, patients must be pretreated with anti-
histamines and corticosteroids. Pegloticase is substantially more expensive than
first-line urate-lowering therapies.
• The ideal duration of pegloticase therapy is unknown. Development of pegloticase
antibodies resulting in loss of efficacy may limit the duration of effective therapy.
• Because of its limitations, reserve pegloticase for patients with refractory gout who
are unable to take or have failed all other urate-lowering therapies.
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Miscellaneous Urate-Lowering Agents

• Fenofibrate is thought to increase clearance of hypoxanthine and xanthine, leading
to a sustained reduction in serum urate concentrations of 20%–30%.
• Atorvastatin and rosuvastatin have also been associated with serum uric acid lower-
ing, although the effect is less than with fenofibrate. The mechanism is unclear but is
thought to be due to decreased renal reabsorption of uric acid.
• Losartan inhibits renal tubular reabsorption of uric acid and increases urinary excre-
tion, properties that are not shared with other angiotensin II receptor blockers. It also
alkalinizes the urine, which helps reduce the risk for stone formation.
• Amlodipine, nifedipine, and diltiazem (calcium channel blockers) have been
associated with a lower risk of gout, which has been attributed to increased renal
elimination of uric acid.
ANTI-INFLAMMATORY PROPHYLAXIS DURING

INITIATION OF URATE-LOWERING THERAPY
• Initiation of urate-lowering therapy can precipitate an acute gout attack due to remod-
eling of urate crystal deposits in joints after rapid lowering of urate concentrations.
Prophylactic anti-inflammatory therapy is often used to prevent such gout attacks.
• The ACR guidelines recommend low-dose oral colchicine (0.6 mg twice daily) or
low-dose NSAIDs (eg, naproxen 250 mg twice daily) as first-line prophylactic thera-
pies, with stronger evidence supporting use of colchicine. For patients on long-term
NSAID prophylaxis, a proton pump inhibitor or other acid-suppressing therapy is
indicated to protect from NSAID-induced gastric problems.
• Low-dose corticosteroid therapy (eg, prednisone ≤10 mg/day) is an alternative for
patients with intolerance, contraindication, or lack of response to first-line therapy.
The potential severe adverse effects of prolonged corticosteroid therapy preclude
their use as first-line therapy.
• Continue prophylaxis for at least 6 months or 3 months after achieving target serum
uric acid, whichever is longer. For patients with one or more tophi, continue prophy-
lactic therapy for 6 months after achieving the serum urate target (Fig. 1-2).
EVALUATION OF THERAPEUTIC OUTCOMES

• Check the serum uric acid level in patients suspected of having an acute gout attack,
particularly if it is not the first attack, and a decision is to be made about starting pro-
phylaxis. However, acute gout can occur with normal serum uric acid concentrations.
• Monitor patients with acute gout for symptomatic relief of joint pain as well as potential
adverse effects and drug interactions related to drug therapy. Acute pain of an initial
gout attack should begin to ease within about 8 hours of treatment initiation. Complete
resolution of pain, erythema, and inflammation usually occurs within 48–72 hours.
• For patients receiving urate-lowering therapy, obtain baseline assessment of kidney
function, hepatic enzymes, complete blood count, and electrolytes. Recheck the tests
every 6–12 months in patients receiving long-term treatment.
• During titration of urate-lowering therapy, monitor serum uric acid every 2–5 weeks;
after the urate target is achieved, monitor uric acid every 6 months.
• Because of the high rates of comorbidities associated with gout (diabetes, chronic
kidney disease, hypertension, obesity, myocardial infarction, heart failure, and
stroke), elevated serum uric acid concentrations or gout should prompt evalua-
tion for cardiovascular disease and the need for appropriate risk reduction mea-
sures. Clinicians should also look for possible correctable causes of hyperuricemia
(eg, medications, obesity, malignancy, and alcohol abuse).
See Chapter 109, Gout and Hyperuricemia, authored by Michelle A. Fravel and Michael
E. Ernst, for a more detailed discussion of this topic.
ALGRAWANY
14
CHAPTER
2 Osteoarthritis
• Osteoarthritis (OA) is a common, progressive disorder affecting primarily weight-

bearing diarthrodial joints, characterized by progressive destruction of articular
cartilage, osteophyte formation, pain, limitation of motion, deformity, and disability.
PATHOPHYSIOLOGY
• Primary (idiopathic) OA, the more common type, has no known cause.
• Secondary OA is associated with a known cause such as inflammation, trauma, meta-
bolic or endocrine disorders, and congenital factors.
• OA usually begins with damage to articular cartilage through injury, excessive
joint loading from obesity or other reasons, or joint instability. Damage to car-
tilage increases activity of chondrocytes in attempt to repair damage, leading to
increased synthesis of matrix constituents with cartilage swelling. Normal balance
between cartilage breakdown and resynthesis is lost, with increasing destruction and
cartilage loss.
• Subchondral bone adjacent to articular cartilage undergoes pathologic changes and
releases vasoactive peptides and matrix metalloproteinases. Neovascularization and
increased permeability of adjacent cartilage occur, which contribute to cartilage loss
and chondrocyte apoptosis.
• Cartilage loss causes joint space narrowing and painful, deformed joints. Remaining
cartilage softens and develops fibrillations, followed by further cartilage loss and
exposure of underlying bone. New bone formations (osteophytes) at joint margins
distant from cartilage destruction are thought to help stabilize affected joints.
• Inflammatory changes can occur in the joint capsule and synovium. Crystals or
cartilage shards in synovial fluid may contribute to inflammation. Interleukin-1,
prostaglandin E2, tumor necrosis factor-α, and nitric oxide in synovial fluid may also
play a role. Inflammatory changes result in synovial effusions and thickening.
• Pain may result from distention of the synovial capsule by increased joint fluid;
microfracture; periosteal irritation; or damage to ligaments, synovium, or the
meniscus.
• Risk factors include increasing age, obesity, sex, certain occupations and sports activi-
ties, history of joint injury or surgery, and genetic predisposition.
• The predominant symptom is deep, aching pain in affected joints. Pain accompanies
joint activity and decreases with rest.
• Joints most commonly affected are the distal interphalangeal (DIP) and proximal
interphalangeal (PIP) joints of the hand, first carpometacarpal joint, knees, hips,
cervical and lumbar spine, and first metatarsophalangeal (MTP) joint of the toe.
• Limitation of motion, stiffness, crepitus, and deformities may occur. Patients with
lower extremity involvement may report weakness or instability.
• Upon arising, joint stiffness typically lasts less than 30 minutes and resolves with
motion.
• Presence of warm, red, and tender joints suggests inflammatory synovitis.
• Physical examination of affected joints reveals tenderness, crepitus, and possibly
enlargement. Heberden and Bouchard nodes are bony enlargements (osteophytes) of
the DIP and PIP joints, respectively.
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DIAGNOSIS
• Diagnosis is made through patient history, physician examination, radiologic find-
ings, and laboratory testing.
• American College of Rheumatology criteria for classification of OA of the hips,
knees, and hands include presence of pain, bony changes on examination, normal
erythrocyte sedimentation rate (ESR), and radiographs showing osteophytes or joint
space narrowing.
• For hip OA, patients must have hip pain and two of the following: (1) ESR <20 mm/hr
(5.6 μm/sec), (2) radiographic femoral or acetabular osteophytes, and/or (3) radio-
graphic joint space narrowing.
• For knee OA, patients must have knee pain and radiographic osteophytes in addition
to one or more of the following: (1) age >50 years, (2) morning stiffness lasting ≤30
minutes, (3) crepitus on motion, (4) bony enlargement, (5) bony tenderness, and/or
(6) palpable joint warmth.
• ESR may be slightly elevated if inflammation is present. Rheumatoid factor is nega-
tive. Analysis of synovial fluid reveals high viscosity and mild leukocytosis (<2000
white blood cells/mm3 [2 × 109/L]) with predominantly mononuclear cells.
TREATMENT
• Goals of Treatment: (1) Educate the patient, family members, and caregivers; (2)
relieve pain and stiffness; (3) maintain or improve joint mobility; (4) limit functional
impairment; and (5) maintain or improve quality of life.
• Educate the patient about the disease process and extent, prognosis, and treatment
options. Promote dietary counseling, exercise, and a weight loss program for over-
weight patients.
• Physical therapy—with heat or cold treatments and an exercise program—helps
maintain range of motion and reduce pain and need for analgesics.
• Assistive and orthotic devices (canes, walkers, braces, heel cups, and insoles) can be
used during exercise or daily activities.
• Surgical procedures (eg, osteotomy, arthroplasty, joint fusion) are indicated for func-
tional disability and/or severe pain unresponsive to conservative therapy.
PHARMACOLOGIC THERAPY (TABLE 2-1)

General Approach
• Drug therapy is targeted at relief of pain. A conservative approach is warranted
because OA often occurs in older individuals with other medical conditions.
• Apply an individualized approach (Figs. 2-1 and 2-2). Continue appropriate nondrug
therapies when initiating drug therapy.
Knee and Hip OA

• Acetaminophen is a preferred first-line treatment; it may be less effective than oral
nonsteroidal anti-inflammatory drugs (NSAIDs) but has a lower risk of serious
gastrointestinal (GI) and cardiovascular (CV) events. Acetaminophen is usually well
tolerated, but potentially fatal hepatotoxicity with overdose is well documented. It
should be avoided in chronic alcohol users or patients with liver disease.
• Nonselective NSAIDs or cyclooxygenase-2 (COX-2) selective inhibitors (eg,
celecoxib) are recommended if a patient fails acetaminophen. Nonselective NSAIDs
may cause minor GI complaints such as nausea, dyspepsia, anorexia, abdominal
pain, and diarrhea. They may cause gastric and duodenal ulcers and bleeding
through direct (topical) or indirect (systemic) mechanisms. Risk factors for NSAID-
associated ulcers and ulcer complications (perforation, gastric outlet obstruction, and
GI bleeding) include longer duration of NSAID use, higher dosage, age older than
16
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Osteoarthritis | CHAPTER 2
TABLE 2-1 Medications for the Treatment of Osteoarthritis

Drug Starting Dose Usual Range
Oral analgesics
Acetaminophen 325–500 mg three 325–650 mg every 4–6 hours or
times a day 1 g three to four times/day
Tramadol 25 mg in the morning Titrate dose in 25-mg increments
to reach a maintenance
dose of 50–100 mg three
times a day
Tramadol ER 100 mg daily Titrate to 200–300 mg daily
Hydrocodone/ 5 mg/325 mg three 2.5–10 mg/325–650 mg three to
acetaminophen times daily five times daily
Oxycodone/acetaminophen 5 mg/325 mg three 2.5–10 mg/325–650 mg three to
times daily five times daily
Topical analgesics
Capsaicin 0.025%–0.15% Apply to affected joint three to
four times per day
Diclofenac 1% gel Apply 2 or 4 g per site as
prescribed, four times daily
Diclofenac 1.3% patch Apply one patch twice daily
to the site to be treated, as
directed
Diclofenac 1.5% solution Apply 40 drops to the affected
knee, applying and rubbing in
10 drops at a time. Repeat for
a total of four times daily.
Intra-articular
corticosteroids
Triamcinolone 5–15 mg per joint 10–40 mg per large joint (knee,
hip, shoulder)
Methylprednisolone acetate 10–20 mg per joint 20–80 mg per large joint (knee,
hip, shoulder)
NSAIDs
Aspirin (plain, buffered, or 325 mg three 325–650 mg four times a day
enteric-coated) times a day
Celecoxib 100 mg daily 100 mg twice daily or
200 mg daily
Diclofenac IR 50 mg twice a day 50–75 mg twice a day
Diclofenac XR 100 mg daily 100–200 mg daily
Diflunisal 250 mg twice a day 500–750 mg twice a day
Etodolac 300 mg twice a day 400–500 mg twice a day
Fenoprofen 400 mg three 400–600 mg three to four
times a day times a day
Flurbiprofen 100 mg twice a day 200–300 mg/day in two to four
divided doses
(Continued)
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TABLE 2-1 Medications for the Treatment of Osteoarthritis (Continued)

Drug Starting Dose Usual Range
Ibuprofen 200 mg three 1200–3200 mg/day in three to
times a day four divided doses
Indomethacin 25 mg twice a day Titrate dose by 25–50 mg/day
until pain controlled or
maximum dose of 50 mg
three times a day
Indomethacin SR 75 mg SR once daily Can titrate to 75 mg SR twice
daily if needed
Ketoprofen 50 mg three times a day 50–75 mg three to four
times a day
Meclofenamate 50 mg three times a day 50–100 mg three to four
times a day
Mefenamic acid 250 mg three 250 mg four times a day
times a day
Meloxicam 7.5 mg daily 15 mg daily
Nabumetone 500 mg daily 500–1000 mg one to two
times a day
Naproxen 250 mg twice a day 500 mg twice a day
Naproxen sodium 220 mg twice a day 220–550 mg twice a day
Naproxen sodium CR 750–1000 mg 500–1500 mg once daily
once daily
Oxaprozin 600 mg daily 600–1200 mg daily
Piroxicam 10 mg daily 20 mg daily
Salsalate 500 mg twice a day 500–1000 mg two to three
times a day
CR, controlled-release; ER, extended-release; IR, immediate-release; SR, sustained-release;
XR, extended-release.
60 years, past history of peptic ulcer disease of any cause, history of alcohol use, and
concomitant use of glucocorticoids or anticoagulants. Options for reducing the GI
risk of nonselective NSAIDs include using (1) the lowest dose possible and only when
needed, (2) misoprostol four times daily with the NSAID, and (3) a PPI or full-dose
H2-receptor antagonist daily with the NSAID.
• COX-2 inhibitors pose less risk for adverse GI events than nonselective NSAIDs, but
this advantage is substantially reduced for patients taking aspirin. Both nonselective
and selective NSAIDs are associated with an increased risk for CV events (hyperten-
sion, stroke, myocardial infarction, and death).
• NSAIDs may also cause kidney diseases, hepatitis, hypersensitivity reactions, rash,
and CNS complaints of drowsiness, dizziness, headaches, depression, confusion, and
tinnitus. NSAIDs inhibit COX-1–dependent thromboxane production in platelets,
thereby increasing bleeding risk. Unlike aspirin, celecoxib and nonspecific NSAIDs
inhibit thromboxane formation reversibly, with normalization of platelet function
1–3 days after drug discontinuation. Avoid NSAIDs in late pregnancy because of
risk of premature closure of the ductus arteriosus. The most potentially serious
drug interactions include use of NSAIDs with lithium, warfarin, oral hypoglyce-
mics, methotrexate, antihypertensives, angiotensin-converting enzyme inhibitors,
β-blockers, and diuretics.
18
ch02.indd 18 18-11-2020 11:50:58

Patient requires
pharmacologic treatmenta
Is acetaminophen
contraindicated?
No Yes
Acetaminophenb Is treatment effective? Alternative first-line
maximum 4 g/day agents
Topical NSAIDs
No Yes (knee only) and/or
intra-articular
Alternative second-line Continue treatment
agents corticosteroids
• Opioid analgesics and/or tramadol
• Surgery and/or oral NSAIDs
• Duloxetine (knee only) (if <75 yo or low CV
• Intra-articular hyaluronates (knee only) and GI risk)c
a
Selection of a medication should consider patient-specific characteristics.
b
The patient must be counseled regarding all acetaminophen-containing products.
c
When used for chronic management of OA, consider addition of a proton-pump inhibitor.
(CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.)
FIGURE 2-1. Treatment recommendations for hip and knee osteoarthritis.
• Topical NSAIDs are recommended for knee OA if acetaminophen fails, and they are
preferred over oral NSAIDs in patients older than 75 years. Topical NSAIDs provide
similar pain relief with fewer adverse GI events than oral NSAIDs but may be associ-
ated with adverse events at the application site (eg, dry skin, pruritus, and rash). Patients
using topical products should avoid oral NSAIDs to minimize the potential for additive
side effects. Use of topical NSAIDs has not been linked with increased risk of CV events.
• Intra-articular (IA) corticosteroid injections are recommended for both hip and
knee OA when analgesia with acetaminophen or NSAIDs is suboptimal. They can
provide excellent pain relief, particularly when joint effusion is present. Local anes-
thetics such as lidocaine or bupivacaine are commonly combined with corticosteroids
to provide rapid pain relief. Injections may also be given with concomitant oral
analgesics for additional pain control. After aseptic aspiration of the effusion and
corticosteroid injection, initial pain relief may occur within 24–72 hours, with peak
relief occurring after 7–10 days and lasting for 4–8 weeks. Local adverse effects can
include infection, osteonecrosis, tendon rupture, and skin atrophy at the injection
site. Do not administer injections more frequently than once every 3 months to mini-
mize systemic adverse effects. Systemic corticosteroid therapy is not recommended in
OA, given lack of proven benefit and well-known adverse effects with long-term use.
• Tramadol is recommended for hip and knee OA in patients who have failed scheduled
full-dose acetaminophen and topical NSAIDs, who are not appropriate candidates
for oral NSAIDs, and who are not able to receive IA corticosteroids. Tramadol can be
added to partially effective acetaminophen or oral NSAID therapy. Tramadol is associ-
ated with opioid-like adverse effects such as nausea, vomiting, dizziness, constipation,
headache, and somnolence. However, tramadol is not associated with life-threatening
GI bleeding, CV events, or renal failure. The most serious adverse event is seizures.
Tramadol is classified as a Schedule IV controlled substance due to its potential for
dependence, addiction, and diversion. There is increased risk of serotonin syndrome
when tramadol is used with other serotonergic medications, including duloxetine.
• Opioids should be considered in patients not responding adequately to nonphar-
macologic and first-line pharmacologic therapies. Patients who are at high surgical
risk and cannot undergo joint arthroplasty are also candidates for opioid therapy.
Use opioid analgesics in the lowest effective dose and the smallest quantity needed.
Avoid combinations of opioids and sedating medications whenever possible.
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ch02.indd 19 18-11-2020 11:50:58

Patient requires
pharmacologic treatmenta
Is patient ≥75 years of

age?
No Yes
First-line agents
Oral NSAIDsb (if First-line agents
low CV and GI risk) Topical NSAIDs
Topical NSAIDs or
or Topical capsaicin
Topical capsaicin and/or
and/or Tramadol
Tramadol
Is treatment Yes Yes Is treatment

Continue treatment
effective? effective?
No No
Alternative regimens
Alternative regimens
Combined therapy
Combined therapy
with two first-line
with two first-line
agentsc
agentsc
(ie, oral NSAIDs
(ie, topical NSAIDs
and topical capsaicin
and tramadol)
or tramadol)
a
Selection of a medication should consider patient-specific characteristics.
b
When used for chronic management of OA, consider addition of a proton-pump inhibitor.
c
Should not combine topical NSAIDs and oral NSAIDs.
(CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.)
FIGURE 2-2. Treatment recommendations for hand osteoarthritis.
Inform patients on how to use, store, and dispose of opioid medications. Sustained-
release compounds usually offer better pain control throughout the day. Common
adverse effects include nausea, somnolence, constipation, dry mouth, and dizziness.
Opioid dependence, addiction, tolerance, hyperalgesia, and issues surrounding drug
diversion may be associated with long-term treatment. Assess opioid use at least
every 3 months, evaluating patient progression toward functional treatment goals,
risks of harm, and adverse effects.
• Duloxetine can be used as adjunctive treatment of knee (not hip) OA in patients
with partial response to first-line analgesics (acetaminophen, oral NSAIDs). It may
be a preferred second-line medication in patients with both neuropathic and muscu-
loskeletal OA pain. Pain reduction occurs after about 4 weeks of therapy. Duloxetine
may cause nausea, dry mouth, constipation, anorexia, fatigue, somnolence, and
dizziness. Serious rare events include Stevens-Johnson syndrome and liver failure.
Concomitant use with other medications that increase serotonin concentration
(including tramadol) increases risk of serotonin syndrome.
• IA hyaluronic acid (sodium hyaluronate) is not routinely recommended because
injections have shown limited benefit for knee OA and have not been shown to
benefit hip OA. Injections are usually well tolerated, but acute joint swelling, effu-
sion, stiffness, and local skin reactions (eg, rash, ecchymoses, or pruritus) have been
reported. IA preparations and regimens for OA knee pain include:
✓ Cross-linked hyaluronate 30 mg/3 mL (Gel-One) single injection
✓ Hyaluronan 30 mg/2 mL (Orthovisc) once weekly for three injections
✓ Hyaluronan 88 mg/4 mL (Monovisc) single injection
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ch02.indd 20 18-11-2020 11:50:59

✓ Hylan polymers 16 mg/2 mL (Synvisc) once weekly for three injections

✓ Hylan polymers 48 mg/6 mL (Synvisc-One) single injection
✓ Sodium hyaluronate 20 mg/2 mL (Hyalgan) once weekly for five injections
✓ Sodium hyaluronate 20 mg/2 mL (Euflexxa) once weekly for three injections
✓ Sodium hyaluronate 25 mg/2.5 mL (Supartz FX) once weekly for five injections
✓ Sodium hyaluronate 25 mg/2.5 mL (GenVisc 850) once weekly for five injections
• Glucosamine and/or chondroitin and topical rubefacients (eg, methyl salicylate,
trolamine salicylate) lack uniform improvement in pain control or functional status
for hip and knee pain and are not preferred treatment options. Glucosamine adverse
effects are mild and include flatulence, bloating, and abdominal cramps. The most
common adverse effect of chondroitin is nausea.
Hand OA
• Topical NSAIDs are a first-line option for hand OA. Topical diclofenac has efficacy
similar to oral NSAIDs with fewer adverse GI events, albeit with some local applica-
tion site events. Efficacy with topical NSAIDs typically occurs with 1–2 weeks.
• Oral NSAIDs are an alternative first-line treatment for patients who cannot toler-
ate the local skin reactions or who received inadequate relief from topical NSAIDs.
• Capsaicin cream is an alternative first-line treatment; small clinical trials have dem-
onstrated about 50% reduction in pain scores. It is a reasonable option for patients
unable to take oral NSAIDs. Capsaicin must be used regularly to be effective, and
it may require up to 2 weeks to take effect. Adverse effects are primarily local and
include burning, stinging, and/or erythema that usually subsides with repeated
application. Warn patients not to get cream in their eyes or mouth and to wash hands
after application. Application of the cream, gel, solution, or lotion is recommended
four times daily.
• Tramadol is an alternative first-line treatment and is a reasonable option for patients
who do not respond to topical therapy and are not candidates for oral NSAIDs
because of high GI, CV, or renal risks. Tramadol may also be used in combination
with partially effective acetaminophen, topical therapy, or oral NSAIDs.

• To monitor efficacy, assess baseline pain with a visual analog scale, and assess range
of motion for affected joints with flexion, extension, abduction, or adduction.
• Depending on the joint(s) affected, measurement of grip strength and 50-ft walking
time can help assess hand and hip/knee OA, respectively.
• Baseline radiographs can document extent of joint involvement and follow disease
progression with therapy.
• Other measures include the clinician’s global assessment based on patient’s history of
activities and limitations caused by OA, the Western Ontario and McMaster Univer-
sities Arthrosis Index, Stanford Health Assessment Questionnaire, and documenta-
tion of analgesic or NSAID use.
• Ask patients about adverse effects from medications. Monitor for signs of drug-
related effects, such as skin rash, headaches, drowsiness, weight gain, or hypertension
from NSAIDs.
• Obtain baseline serum creatinine, hematology profile, and serum transaminases with
repeat levels at 6- to 12-month intervals to identify specific toxicities to the kidney,
liver, GI tract, or bone marrow.
See Chapter 106, Osteoarthritis, authored by Lucinda M. Buys and Sara A. Wiedenfeld,
for a more detailed discussion of this topic.
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3
00
CHAPTER
Osteoporosis
Chapter_Title
• Osteoporosis is a bone disorder characterized by low bone density, impaired bone

architecture, and compromised bone strength predisposing to fracture.
PATHOPHYSIOLOGY
• Bone loss occurs when resorption exceeds formation, usually from high bone turn-
over when the number or depth of bone resorption sites greatly exceeds the ability of
osteoblasts to form new bone. Accelerated bone turnover can increase the amount of
immature bone that is not adequately mineralized.
• Men and women begin to lose bone mass starting in the third or fourth decade
because of reduced bone formation. Estrogen deficiency during menopause
increases osteoclast activity, increasing bone resorption more than formation. Men
are at a lower risk for developing osteoporosis and osteoporotic fractures because
of larger bone size, greater peak bone mass, increase in bone width with aging,
fewer falls, and shorter life expectancy. Male osteoporosis results from aging or
secondary causes.
• Age-related osteoporosis results from hormone, calcium, and vitamin D deficiencies;
decreased production or function of cytokines; decreased body water; less exercise;
and other factors that result in accelerated bone turnover and reduced osteoblast
formation.
• Drug-induced osteoporosis may result from systemic corticosteroids, excessive thy-
roid hormone replacement, antiepileptic drugs (eg, phenytoin, phenobarbital), depot
medroxyprogesterone acetate, and other agents.
• Many patients are unaware that they have osteoporosis and only present after frac-
ture. Fractures can occur after bending, lifting, or falling or independent of any
activity.
• The most common fractures involve vertebrae, proximal femur, and distal radius
(wrist or Colles fracture). Vertebral fractures may be asymptomatic or present with
moderate to severe back pain that radiates down a leg. Pain usually subsides after
2–4 weeks, but residual back pain may persist. Multiple vertebral fractures decrease
height and sometimes curve the spine (kyphosis or lordosis).
• Patients with a nonvertebral fracture frequently present with severe pain, swelling,
and reduced function and mobility at the fracture site.
DIAGNOSIS
• The FRAX tool uses the following risk factors to predict the percent probability of
fracture in the next 10 years: age, race/ethnicity, sex, previous fragility fracture, par-
ent history of hip fracture, body mass index, glucocorticoid use, current smoking,
alcohol (≥3 drinks per day), rheumatoid arthritis, and select secondary causes with
femoral neck or total hip bone mineral density (BMD) data optional.
• The Garvan calculator uses four risk factors (age, sex, low-trauma fracture, and falls)
with the option to also use BMD. It calculates 5- and 10-year risk estimates of any
osteoporotic/fragility fracture and hip fracture. This tool corrects some disadvantages
of FRAX because it includes falls and number of previous fractures, but it does not
use as many other risk factors.
• Physical examination findings may include bone pain, postural changes (ie, kyphosis),
and loss of height (>1.5 in [3.8 cm]).
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Osteoporosis | CHAPTER 3
• Laboratory testing: complete blood count, serum creatinine, calcium, phosphorus,

electrolytes, alkaline phosphatase, albumin, thyroid-stimulating hormone, total
testosterone (for men), 25-hydroxyvitamin D, and 24-hour urine concentrations of
calcium and phosphorus.
• Measurement of central (hip and spine) BMD with dual-energy x-ray absorptiometry
(DXA) is the diagnostic standard. Measurement at peripheral sites (forearm, heel,
and finger) with DXA or quantitative ultrasonography is used only for screening and
for determining need for further testing.
• A T-score compares the patient’s BMD to the mean BMD of a healthy, young (20- to
29-year-old), sex-matched, white reference population. The T-score is the number of
standard deviations from the mean of the reference population.
• Diagnosis of osteoporosis is based on low-trauma fracture or femoral neck, total hip,
and/or spine DXA using World Health Organization (WHO) T-score thresholds.
Normal bone mass is T-score above −1, low bone mass (osteopenia) is T-score
between −1 and −2.4, and osteoporosis is T-score at or below −2.5.
TREATMENT
• Goals of Treatment: The primary goal of osteoporosis care is prevention. Optimiz-
ing peak bone mass when young reduces the future incidence of osteoporosis. After
low bone mass or osteoporosis develops, the objective is to stabilize or improve bone
mass and strength and prevent fractures. Goals in patients with osteoporotic frac-
tures include reducing pain and deformity, improving function, reducing falls and
fractures, and improving quality of life.
• Figure 3-1 provides an osteoporosis management algorithm for postmenopausal
women and men ages 50 and older.
• All individuals should have a balanced diet with adequate intake of calcium and
vitamin D (Table 3-1). Achieving daily calcium requirements from calcium-
containing foods is preferred.
✓ Consumers can calculate the amount of calcium in a food serving by adding a zero
to the percentage of the daily value on food labels. One serving of milk (8 oz or
240 mL) has 30% of the daily value of calcium; this converts to 300 mg of calcium
per serving.
✓ To calculate the amount of vitamin D in a food serving, multiply the percent daily
value of vitamin D listed on the food label by 4. For example, 20% vitamin D = 80
units.
• Protein is required for bone formation; the recommended dietary allowance (RDA)
is 0.8 g/kg body weight per day for adults, increasing to 1–1.2 g/kg body weight in
older adults.
• Alcohol consumption should not exceed 1–2 drinks per day for women and 2–3
drinks per day for men.
• Ideally, caffeine intake should be limited to 2 or fewer servings per day.
• Smoking cessation helps optimize peak bone mass, minimize bone loss, and ulti-
mately reduce fracture risk.
• Weight-bearing aerobic and strengthening exercises can decrease risk of falls and
fractures by improving muscle strength, coordination, balance, and mobility.
• Fall prevention programs that are multifactorial can decrease falls, fractures, other
injuries, and nursing home and hospital admissions.
• Vertebroplasty and kyphoplasty involve injection of cement into fractured vertebra(e)
for patients with debilitating pain from compression fractures. Although intended to
stabilize damaged vertebrae, reduce pain, and decrease opioid intake, recent research
demonstrated only short-term benefit with no major pain relief and the potential for
post-procedure complications.
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SECTION 1 | BONE AND JOINT DISORDERS
• Woman ≥65 years of age

• Man ≥70 years of age
• Postmenopausal woman <65 years of age
with a FRAX 10-year major osteoporotic
fracture score >8.4%
• Man 50 to 69 years old with clinical risk
factors for fracturea
• Abnormal peripheral BMD test
Presence of a low-trauma • Radiographic evidence of low bone mass
No • Medical conditions or medications known
fracture (vertebrae or hip)
to increase the risk for bone loss and
fracture (eg, rheumatoid arthritis,
Yes glucocorticoids ≥3 months, certain
chemotherapies)
• Evaluate for secondary

Yes Osteoporosis or high
causes
fracture risk
• Bone healthy lifestyleb
T-score ≤–2.5 at femoral
• Dietary calcium 1,000 to Normal BMD neck or spine OR
1,200 mg dailyc T-score ≥ –1.0 Send for central DXA testing
T-score –1.1 to –2.4
• Vitamin D at least 800 to
at femoral neck or
1,000 units daily
spine AND a FRAX 10-year
• Medication therapyd –
Low bone mass probability of hip
treatment dosed • Bone healthy lifestyleb fracture ≥3% or all major
• First line: alendronate, T-score –1.1 to –2.4 at
• Dietary calcium 1,000 to osteoporosis-related
femoral neck or spine AND
risedronate, 1,200 mg dailyc fracture ≥20%h
zoledronic acid a FRAX 10-year probability
• Vitamin D 800 to
or denosumab of hip fracture ≤3% or all
1,000 units daily
• Alternate therapy: major osteoporosis-related
abaloparatide,e
Re-evaluate BMD using fracture ≤20%h • Evaluate for secondary
central DXA in 5 years or as causes
ibandronate,
appropriate • Bone healthy lifestyleb
raloxifene,f
romosozumab,e • Dietary calcium 1,000 to
or teriparatideg • Bone healthy lifestyleb 1,200 mg dailyc
• Last line: intranasal • Dietary calcium 1,000 to • Vitamin D at least 800 to
calcitonin 1,200 mg dailyc 1,000 units daily
Obtain baseline • Vitamin D 800 to • Medication therapy –
central BMD testing 1,000 units daily treatment dosesd
for monitoring • Medication therapy – • First line: alendronate,
response to therapy. prevention doses risedronate,
• Considered if risk zoledronic acid
Re-evaluate BMD using or denosumab
factors exist
central DXA in 2 to 5 years • Alternate therapy:
• Generally not for
women who are or are abaloparatide,e
considering pregnancy ibandronate,
raloxifene,f
Re-evaluate BMD using central romosozumab,e
DXA in ≥2 years or as
or teriparatideg
appropriate
• Last line:
intranasal calcitonin
Re-evaluate BMD using
central DXA in 2 to 5 years
or as appropriate
a Major clinical risk factors for fracture: current smoker, low body weight or body mass index, personal
history of fracture as an adult (after age 50 years), history of osteoporosis/low trauma fracture in a
first-degree relative, excessive alcohol intake.
b
Bone-healthy lifestyle includes well-balanced diet with adequate calcium, vitamin D, and protein intakes;
smoking cessation; limited alcohol intake; weight-bearing/resistance exercises; and fall prevention.
c Dietary calcium preferred. If diet is inadequate, supplement as necessary.
d Sometimes men with hypogonadism also receive testosterone replacement; sometimes women with
menopausal symptoms receive low-dose hormone therapy for a short time.

e Newer agents marketed after osteoporosis guidelines published; similar uses as teriparatide.
f Raloxifene can be a good option in women at high risk for breast cancer.
g Teriparatide can be considered a first-line option in patients with a very high risk of fracture
(e.g, T-score ≤3.5 or multiple low trauma fractures) or intolerant to other medications.
h Some providers use age-adjusted FRAX thresholds versus set thresholds for all age groups.
(BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; FRAX, World Health Organization
Fracture Risk Assessment Tool.)
FIGURE 3-1. Algorithm for the management of osteoporosis in postmeno-
pausal women and men aged 50 and older.
ALGRAWANY
24
TABLE 3-1 Calcium and Vitamin D Recommended Dietary Allowances (RDAs) and Tolerable
Upper Intake Levels (ULs)
Calcium Vitamin D
Elemental Tolerable Tolerable
Calcium Upper Intake Vitamin D Upper Intake
Group and Ages RDA (mg) Level (mg) RDA (Units)a Level (Units)
Infants
Birth–6 months 200b 1000 400b 1000
7–12 months 260b 1500 400b 1500
Children
1–3 years 700 2500 600 2500
4–8 years 1000 2500 600 3000
9–18 years 1300 3000 600 4000
Adults
19–50 years 1000 2500 600b,c 4000
51–70 1000 2000 600b,c 4000
years (men)
51–70 years 1200 2000 600b,c 4000
(women)
>70 years
1200 2000 800b,c 4000
a
Some guidelines recommend intake to achieve a 25(OH) vitamin D concentration >30 ng/mL
(mcg/L; 75 nmol/L), which is higher than the Institute of Medicine goal of >20 ng/mL (mcg/L;
50 nmol/L).
b
Adequate intake (evidence insufficient to determine an RDA).
c
Guidelines recommend 800–1000 units or 1000–2000 units for adults with osteoporosis.
PHARMACOLOGIC THERAPY
GENERAL APPROACH
• Combined with adequate calcium and vitamin D intakes, alendronate, risedronate,
zoledronic acid, and denosumab are the prescription medications of choice because
they reduce both hip and vertebral fracture risks.
• Abaloparatide, bazedoxifene/conjugated equine estrogens, ibandronate, raloxifene,
romosozumab, and teriparatide are second-line alternatives because they decrease
vertebral but not hip fracture risks.
• Calcitonin is last-line therapy.
• Estrogen and testosterone are not used for osteoporosis treatment but can have a
positive bone effect when prescribed for other conditions.
ANTIRESORPTIVE THERAPY
Calcium Supplementation
• Calcium generally maintains or increases BMD slightly, but its effects are less than
those of other therapies. There are insufficient data to support using calcium and
vitamin D supplementation to reduce fracture incidence. Because the fraction of
calcium absorbed decreases with increasing dose, maximum single doses of 600 mg
or less of elemental calcium are recommended.
• Calcium carbonate is the salt of choice because it contains the highest concentration
of elemental calcium (40%) and is typically least expensive. It should be ingested with
meals to enhance absorption in an acidic environment.
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• Calcium citrate (21% calcium) has acid-independent absorption and need not be
taken with meals. It may have fewer GI side effects than calcium carbonate.
• Tricalcium phosphate contains 38% calcium, but calcium-phosphate complexes
could limit overall calcium absorption. It may be useful in patients with hypophos-
phatemia that cannot be resolved with increased dietary intake.
• Constipation is the most common calcium-related adverse reaction; treat with
increased water intake, dietary fiber (given separately from calcium), and exercise.
Calcium carbonate can sometimes cause flatulence or upset stomach. Calcium causes
kidney stones rarely.
• Calcium can decrease the oral absorption of some drugs including iron, tetracyclines,
quinolones, bisphosphonates, and thyroid supplements.
Vitamin D Supplementation
• Vitamin D supplementation using 700–800 units per day has been shown to sig-
nificantly reduce the incidence of both hip and nonvertebral fractures with small
increases in BMD.
• Supplementation is usually provided with daily nonprescription cholecalciferol
(vitamin D3) products. Higher-dose prescription ergocalciferol (vitamin D2) regi-
mens given weekly, monthly, or quarterly may be used for replacement and main-
tenance therapy. The RDAs in Table 3-1 should be achieved through food and
supplementation.
• Current guidelines recommend treating patients with osteoporosis to a
25-hydroxyvitamin D concentration of at least 30 ng/mL (mcg/L; 75 nmol/L) or
30–50 ng/mL.
• Because the half-life of vitamin D is about 1 month, recheck the vitamin D concentra-
tion after about 3 months of therapy.
• Medications that can induce vitamin D metabolism include rifampin, phenytoin, bar-
biturates, valproic acid, and carbamazepine. Vitamin D absorption can be decreased
by cholestyramine, colestipol, orlistat, and mineral oil. Vitamin D can enhance
the absorption of aluminum; therefore, aluminum-containing products should be
avoided to prevent aluminum toxicity.
Bisphosphonates
• Bisphosphonates (Table 3-2) mimic pyrophosphate, an endogenous bone resorption
inhibitor. Therapy leads to decreased osteoclast maturation, number, recruitment,
bone adhesion, and life span. Incorporation into bone gives bisphosphonates long
biologic half-lives of up to 10 years.
• Bisphosphonates consistently increase BMD and reduce fracture risk, with differ-
ences in sites of fracture reduction among agents. Ibandronate is not a first-line
therapy because of the lack of hip fracture reduction data.
• BMD increases are dose dependent and greatest in the first 12 months of therapy.
After discontinuation, the increased BMD is sustained for a prolonged period that
varies per bisphosphonate.
• Alendronate, risedronate, and IV zoledronic acid are Food and Drug Administration
(FDA) indicated for postmenopausal, male, and glucocorticoid-induced osteoporosis.
IV and oral ibandronate are indicated only for postmenopausal osteoporosis. Weekly
alendronate, weekly and monthly risedronate, and monthly oral and quarterly IV iban-
dronate therapy produce equivalent BMD changes to their respective daily regimens.
• Oral bisphosphonates must be administered correctly to optimize clinical benefit
and minimize adverse GI effects. Each oral tablet should be taken in the morning
with at least 6 oz (180 mL) of plain water (not coffee, juice, mineral water, or milk)
at least 30 minutes (60 minutes for oral ibandronate) before consuming any food,
supplements, or medications. An exception is delayed-release risedronate, which is
administered immediately after breakfast with at least 4 oz (120 mL) of plain water.
The patient should remain upright (sitting or standing) for at least 30 minutes after
alendronate and risedronate and 1 hour after ibandronate to prevent esophageal
irritation and ulceration.
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ch03.indd 27
TABLE 3-2 Medications Used to Prevent and Treat Osteoporosis

Drug Brand Name Dose Comments
Antiresorptive Medications—Nutritional Supplements
Calcium Various Adequate daily intake: IOM: 200–1200 mg/day, Recommend food first to achieve goal intake. Available
varies per age); supplement dose is difference in different salts including carbonate and citrate,
between required adequate intake and dietary absorption of other salts not fully quantified. Different
intake. formulations including chewable, liquid, gummy,
Immediate-release doses should be softgel, drink, and wafer; different combination
<500–600 mg. products. Review package to determine number of
units to create a serving size and desired amount
of elemental calcium. Give calcium carbonate with
meals to improve absorption.
Vitamin D Over the counter: Adequate daily intake: IOM: 400–800 units/day Vegetarians and vegans need to read label to determine
D3 (cholecalciferol) Tablets, 400, 1000, and 2000 units to achieve adequate intake; NOF: 800–1000 if a plant-based product.
Capsule, 400, 1000, 2000, 5000, and units orally daily; if low 25(OH) vitamin D Slight advantage of D3 over D2 for increasing serum
D2 (ergocalciferol) concentrations, malabsorption, or altered
10,000 units 25(OH) vitamin D concentrations.
Gummies, 300, 500, 1000 units metabolism higher doses (>2000 units daily)
might be required. For drops, make sure measurement is correct for
Drops 300, 400, 1000, and 2000 desired dose.
units/mL or drop Vitamin D deficiency: 50,000 units orally once to
twice weekly for 8–12 weeks; repeat as needed Ability of sprays, lotions, and creams to resolve
Solution, 400 and 5000 units/mL
until therapeutic concentrations. deficiencies or maintain adequate intakes is
Spray 1000 and 5000 units/spray unknown.
Creams and lotions 500 and 1000
units per ¼ teaspoonful
Prescription:
18-11-2020 15:46:43
Capsule, 50,000 units

Solution, 8000 units/mL
(continued )
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ch03.indd 28
28

TABLE 3-2 Medications Used to Prevent and Treat Osteoporosis (Continued )
Antiresorptive Prescription Medications
Bisphosphonates
Alendronate Fosamax Treatment: 10 mg orally daily or 70 mg orally Generic available for weekly tablet product.
Fosamax Plus D weekly 70 mg dose is available as a tablet, effervescent tablet,
Binosto (effervescent tab) Prevention: 5 mg orally daily or 35 mg orally oral liquid or combination tablet with 2800 or 5600
weekly units of vitamin D3.
Administered in the morning on an empty stomach
with 6–8 ounces of plain water. Do not eat and
remain upright for at least 30 minutes following
administration.
Do not coadminister with any other medication or
supplements, including calcium and vitamin D.
Ibandronate Boniva Treatment: 150 mg orally monthly, 3 mg Generic available for oral product.
IV quarterly Administration instructions same as for alendronate,
Prevention: 150 mg orally monthly except must delay eating and remain upright for at
least 60 minutes.
Risedronate Actonel Treatment and prevention: 5 mg orally daily, Generic available for immediate-release product.
Atelvia (delayed-release) 35 mg orally weekly, 150 mg orally monthly 35 mg dose is also available as a delayed-release
product.
Administration instructions same as for alendronate,
except delayed-release product is taken immediately
18-11-2020 15:46:43
following breakfast.
ch03.indd 29
Zoledronic acid Reclast Treatment: 5 mg IV infusion yearly Can premedicate with acetaminophen to decrease
Prevention: 5 mg IV infusion every 2 years infusion reactions.
Contraindicated if CrCl <35 mL/min
Also marketed under the brand name Zometa (4 mg)
for treatment of hypercalcemia and prevention of
skeletal-related events from bone metastases from solid
tumors with different dosing.
RANK Ligand Inhibitor
Denosumab Prolia Treatment: 60 mg SC every 6 months Administered by a healthcare practitioner.
Correct hypocalcemia before administration.
Also marketed under the brand name Xgeva (70 mg/mL)
for treatment of hypercalcemia and prevention of
skeletal-related events from bone metastases from solid
tumors with different dosing.
Estrogen Agonist/Antagonist and Tissue Selective Estrogen Complex
Raloxifene Evista 60 mg orally daily Generic available
Bazedoxifene with Duavee 20 mg plus 0.45 mg CEE orally daily For postmenopausal women with a uterus; no
conjugated progestogen needed. Bazedoxifene monotherapy
equine estrogens available in some countries.
(CEE)
Calcitonin (salmon) Fortical 200 units (1 spray) intranasally daily, alternating Generic available. Also available as an SC injection.
nares every other day. Refrigerate nasal spray until opened for daily use, then
18-11-2020 15:46:43
room temperature.
Prime with first use.
(continued )
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ch03.indd 30
30

TABLE 3-2 Medications Used to Prevent and Treat Osteoporosis (Continued )
Formation Medications
Recombinant human parathyroid hormone (PTH 1–34 units)
Teriparatide Forteo 20 mcg SC daily for up to 2 years First dose sitting or lying. Refrigerate before and after
PF708 approved biosimilar; under each use. Use new needle with each dose. Inject
investigation to determine thigh or stomach. Discard after 28 days or if cloudy.
therapeutic equivalence
Human parathyroid hormone–related peptide (PTHrP[1–34]) analog
Abaloparatide Tymlos 80 mcg SC daily for up to 2 years First dose sitting or lying. Refrigerate before use then keep
at room temperature. Use new needle with each dose.
Inject in abdomen. Discard after 30 days.
Formation and Antiresorptive Medication
Sclerostin inhibitor
Romosozumab Evenity 210 mg SC monthly for 1 year; administered as Correct hypocalcemia before administration.
two single-use 105-mg/1.17-mL prefilled Refrigerate. Leave at room temperature for at least 30
syringes minutes before use.
Inject in abdomen, thigh, or upper arm; preferably each
injection at a different site.
IOM, Institute of Medicine; IV, intravenously; NOF, National Osteoporosis Foundation; NSAID, nonsteroidal anti-inflammatory drug; SC, subcutaneously.
Data from product prescribing information.
18-11-2020 15:46:43
• If a patient misses a weekly dose, it can be taken the next day. If more than 1 day has
elapsed, that dose is skipped. If a patient misses a monthly dose, it can be taken up to
7 days before the next scheduled dose.
• The most common bisphosphonate adverse effects include nausea, abdominal pain,
and dyspepsia. Esophageal, gastric, or duodenal irritation, perforation, ulceration,
or bleeding may occur. The most common adverse effects of IV bisphosphonates
include fever, flu-like symptoms, and local injection-site reactions.
• Rare adverse effects include osteonecrosis of the jaw (ONJ) and subtrochanteric
femoral (atypical) fractures. ONJ occurs more commonly in patients with cancer
receiving higher-dose IV bisphosphonate therapy and other risk factors including
glucocorticoid therapy and diabetes mellitus.
• The optimal duration of bisphosphonate therapy is unknown. Some experts recom-
mend considering a bisphosphonate holiday (defined as disruption of therapy during
which medication effects exist with a plan for medication reinstitution) in postmeno-
pausal women after 5 years of oral bisphosphonates or 3 years of IV bisphosphonates
if no significant fracture history, hip BMD T-score is above –2.5, and fracture risk is
not high. In women with a high fracture risk or lower hip BMD T-scores, continuing
oral bisphosphonates for 10 years or IV bisphosphonates for 6 years should be con-
sidered. A bisphosphonate holiday should last for ≤5 years with BMD and patient
assessment done every 2–4 years.
Denosumab
• Denosumab (Prolia) is a RANK ligand inhibitor that inhibits osteoclast formation
and increases osteoclast apoptosis. It is indicated for treatment of osteoporosis in
women and men at high risk for fracture, for glucocorticoid-induced osteoporosis,
to increase bone mass in men receiving androgen-deprivation therapy for nonmeta-
static prostate cancer, and in women receiving adjuvant aromatase inhibitor therapy
for breast cancer who are at high risk for fracture.
• Over 3 years, denosumab significantly decreased vertebral fractures, nonvertebral
fractures, and hip fractures in postmenopausal women with low bone density. Con-
tinued increases in BMD occur with long-term treatment with no plateau in BMD
effects over 10 years.
• Denosumab is administered as a 60-mg subcutaneous (SC) injection in the upper
arm, upper thigh, or abdomen once every 6 months.
• Adverse reactions not associated with the injection site include back pain, arthralgia,
and infection. ONJ and atypical femoral shaft fracture occur rarely. Denosumab is
contraindicated in patients with hypocalcemia until the condition is corrected.
• After 5–10 years of therapy, patients should be reevaluated for medication continua-
tion, discontinuation, or switching to a different medication.
Mixed Estrogen Agonists/Antagonists and Tissue-Selective

Estrogen Complexes
• Raloxifene (Evista) is an estrogen agonist/antagonist that is an estrogen agonist on
bone receptors but an antagonist at breast receptors, with minimal effects on the
uterus. It is approved for prevention and treatment of postmenopausal osteoporosis
and for reducing the risk of invasive breast cancer in postmenopausal women with
and without osteoporosis.
• Bazedoxifene is an estrogen agonist/antagonist that is an agonist at bone and antago-
nist at the uterus and breast; however, it has no breast cancer prevention effects. The
proprietary product Duavee is combined with conjugated equine estrogens (CEE),
making it a tissue-selective estrogen complex. It is approved for prevention of post-
menopausal osteoporosis and vasomotor menstrual symptoms.
• Raloxifene and bazedoxifene decrease vertebral but not hip fractures. The drugs
increase spine and hip BMD, but to a lesser extent than bisphosphonates. Data for
both drugs support beneficial effects for up to 7–8 years of use. However, the benefit
is lost after discontinuation, and bone loss returns to age- or disease-related rates.
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• Hot flushes are common with raloxifene but decreased with bazedoxifene/CEE. Ral-
oxifene rarely causes endometrial thickening and bleeding; bazedoxifene decreases
these events making progestogen therapy unnecessary when combined with CEE.
Leg cramps and muscle spasms are common with these agents. Thromboembolic
events are uncommon (<1.5%) but can be fatal. Bazedoxifene/CEE has all of the
contraindications and precautions for estrogens as a class.
Calcitonin
• Calcitonin is an endogenous hormone released from the thyroid gland when serum
calcium is elevated. Salmon calcitonin is used clinically because it is more potent and
longer lasting than the mammalian form.
• Calcitonin is indicated for osteoporosis treatment for women at least 5 years past
menopause. An FDA Advisory Committee Panel voted against continued use for post-
menopausal osteoporosis, but it can be used if alternative therapies are not appropriate.
• Only vertebral fractures have been documented to decrease with intranasal calcitonin
therapy. Calcitonin does not consistently affect hip BMD. No calcitonin data exist
for men. Intranasal calcitonin may provide some pain relief in patients with acute
vertebral fractures, but such use should be short-term (4 weeks) and not in place of
other more appropriate analgesic or osteoporosis therapy.
Hormone Therapies
• Hormone therapies (estrogen and testosterone) are not recommended solely for osteo-
porosis but have positive bone effects when used for other indications. Estrogen therapy
can be a good choice for women going through early menopause when protection against
bone loss is needed in addition to reduction of vasomotor symptoms, reserving other
osteoporosis therapy until treatment is reassessed closer to the average age of menopause.
• Estrogen with or without a progestogen significantly decreases fracture risk and bone
loss in women. Oral and transdermal estrogens at equivalent doses and continuous
or cyclic regimens have similar BMD effects. Effect on BMD is dose dependent, with
some benefit seen with lower estrogen doses. When estrogen therapy is discontinued,
bone loss accelerates and fracture protection is lost.
• Testosterone is used to treat hypogonadism in men, but an osteoporosis medication
should be added when risk for osteoporotic fracture is high. No fracture data are
available, but some data support minor bone loss prevention for testosterone use in
men and women.
FORMATION MEDICATIONS
Parathyroid Hormone Analogs
• Abaloparatide (Tymlos) is an analog of parathyroid hormone-related peptide
(PTHrP), and teriparatide (Forteo) and PF708 (approved with Forteo [teriparatide
injection] as the reference drug) are analogs of parathyroid hormone (PTH); these
agents are indicated for the treatment of postmenopausal women with osteoporosis
at high risk for fracture, defined as multiple risk factors for fracture, history of osteo-
porotic fracture, or failure or intolerance to other therapies. Teriparatide is also FDA
approved for men with idiopathic or hypogonadal osteoporosis who are at high risk
for fracture, men intolerant to other osteoporosis medications, and patients with
glucocorticoid-induced osteoporosis.
• Teriparatide increases bone formation with a minor increase in bone resorption for a
net anabolic effect when administered intermittently (ie, subcutaneously once daily).
Abaloparatide has a greater anabolic effect with less activation of bone resorption and
remodeling than teriparatide. Both medications improve bone mass.
• Two years of teriparatide or abaloparatide reduces vertebral and nonvertebral frac-
ture risk in postmenopausal women. Observational teriparatide data suggest a similar
fracture benefit in men, whereas no data are available regarding abaloparatide use in
men. Discontinuation of PTH analog therapy results in decreased BMD, which can
be alleviated with subsequent antiresorptive therapy.
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• Transient hypercalcemia can occur and is less common with abaloparatide than teripa-
ratide (3.4% vs 6.4%, respectively). Because of an increased incidence of osteosarcoma
in rats, both medications contain a box warning against use in patients at increased risk
for osteosarcoma; this adverse effect has not occurred in people. PTH analogs should
not be used in patients with hypercalcemia, metabolic bone diseases other than osteopo-
rosis, metastatic or skeletal cancers, or premenopausal women of childbearing potential.
FORMATION AND ANTIRESORPTIVE MEDICATION

Romosozumab
• Romosozumab (Evenity) is a humanized monoclonal antibody that binds to scleros-
tin to prevent inhibition of bone formation and decrease bone resorption, an activity
that differentiates this medication from other anabolic therapies. It indicated for
postmenopausal women at high risk for fracture defined as multiple risk factors for
fracture, a history of osteoporotic fracture, or failure or intolerance to other therapies.
• After 1 year of therapy in postmenopausal women, vertebral fractures decreased
by 73%, with a nonsignificant decrease in nonvertebral fractures of 25%; lumbar
spine and hip BMD statistically increase after 1 year of treatment. To prevent BMD
loss after discontinuation, 1 year of denosumab or alendronate after romosozumab
resulted in BMD continuing to increase at both sites.
• The most common adverse effects are headache and arthralgia; hypercalcemia occurs
in <1% of patients. Mild injection site irritation occurs in 6%–8% of patients. Romo-
sozumab antibodies may occur in 10%–20% of patients but are generally not neutral-
izing and do not reduce efficacy. Serious cardiovascular events have been reported,
and the labeling contains a boxed warning of an increased risk of myocardial infarc-
tion (MI), stroke, and cardiovascular death. Romosozumab should not be used
within 1 year of an MI or stroke, and benefit–risk evaluation should be conducted in
patients with or at risk for these conditions. Rare cases of ONJ and atypical femoral
fractures have been reported.
• Therapy should be limited to 12 monthly doses. If osteoporosis therapy remains war-
ranted, continued therapy with an antiresorptive agent should be considered.
SEQUENTIAL AND COMBINATION THERAPY

• In sequential therapy, an anabolic agent is given first to increase bone remodeling
units and bone mass, followed by an antiresorptive agent to continue with bone
formation. This regimen is generally reserved for patients with severe osteoporosis
because of the cost of anabolic agents.
✓ Starting with an antiresorptive first and then switching to teriparatide results in
lower BMD increases but may be especially useful for patients who have fractured
or continue to lose bone mass while on antiresorptive therapy.
✓ Small increases in BMD can occur after switching from an oral bisphosphonate
to denosumab. This sequential therapy can be used during a bisphosphonate drug
holiday or for bisphosphonate treatment failures (ie, no BMD changes or fracture).
• Combination therapy is rarely used because of no documented fracture benefit,
increased cost, concern for dual suppression of bone turnover, and potential for
more adverse effects. When raloxifene is used for breast cancer prevention, another
antiresorptive agent is sometimes prescribed, especially if hip fracture risk is high.
GLUCOCORTICOID-INDUCED OSTEOPOROSIS
• Glucocorticoids decrease bone formation through decreased proliferation and differ-
entiation as well as enhanced apoptosis of osteoblasts. They also increase the number
of osteoclasts, increase bone resorption, decrease calcium absorption, and increase
renal calcium excretion.
• All glucocorticoid doses and formulations have been associated with increased bone
loss and fractures; however, risk is much greater with oral prednisone doses ≥5 mg
daily (or equivalent) and oral therapy vs inhaler or intranasal therapy.
33
ch03.indd 33 18-11-2020 15:46:45

• Bone losses are rapid, with up to 12%–15% loss over the first year; the greatest
decrease occurs in the first 6 months of therapy. Bone loss is about 2%–3% per year
after the first year.
• Perform an initial BMD assessment prior to or within 6 months of glucocorticoid
initiation for adults ≥40 years of age and for adults <40 years of age with a history
of fragility fracture or other risk factors. Repeat BMD testing is recommended every
2–3 years during osteoporosis therapy for those taking very high glucocorticoid doses
(≥30 mg prednisone per day or a cumulative dose >5 g in the past year), a fracture
18 months or more after starting osteoporosis therapy, medication adherence or
absorption concerns, or other risk factors for osteoporosis.
• All patients starting or receiving systemic glucocorticoid therapy (any dose or dura-
tion) should practice a bone-healthy lifestyle and ingest 1000–1200 mg elemental cal-
cium and 600–800 units of vitamin D daily to achieve therapeutic 25-hydroxyvitamin
D concentrations. Use the lowest possible corticosteroid dose and duration.
• Treatment guidelines divide recommendations for prescription medication use by
fracture risk and age. Alendronate, risedronate, zoledronic acid, denosumab, and
teriparatide are FDA approved for glucocorticoid-induced osteoporosis.
• Standard osteoporosis therapy doses are used. Oral bisphosphonates are recom-
mended first-line, although IV bisphosphonates can be used in nonadherent patients
or those unable to take the oral preparations. Teriparatide is recommended for
patients who cannot use a bisphosphonate, and denosumab is recommended if
neither a bisphosphonate nor teriparatide can be used. Denosumab is not recom-
mended as first-line therapy due to limited safety data in this population. Raloxifene
does not have an FDA indication for this use, but there are clinical data documenting
improved BMD at the lumbar spine in patients taking glucocorticoids.

• Assess medication adherence and tolerability at each visit.
• Ask patients about possible fracture symptoms (eg, bone pain, disability) at each
visit. Assessment of fracture, back pain, and height loss can help identify worsening
osteoporosis.
• Obtain a central DXA BMD measurement after 1–2 years or 3–5 years after initiat-
ing a medication therapy to monitor response. Repeat a central DXA every 2 years
until BMD is stable, at which time the reassessment interval can be lengthened. More
frequent monitoring may be warranted in patients with conditions associated with
high rates of bone loss (eg, glucocorticoid use).
See Chapter 108, Osteoporosis, authored by Mary Beth O’Connell, Jill S. Borchert, Erin M.
Slazak, and Joseph P. Fava for a more detailed discussion of this topic.
ALGRAWANY
34
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This passive or defensive policy did not suit the Spaniards, while
it encouraged the Aztecs. Therefore two corps were formed, each of
two hundred men, besides allies, under Cortés and Ordaz. Clearing
a path with a volley of artillery, they sallied in different directions to
drive back the assailants, who hurried for safety into lanes and
houses, and behind barricades. This comparative freedom of
advance appears to have been permitted to entice the Spaniards
into a disadvantageous position, for soon the natives reappeared in
swarms in the rear and along the flanks, showering arrows and
stones, and coming to close quarters with spears and swords. The
heaviest attack was from the roofs, on which large supplies of
missiles had been collected, and from which commanding position
the enemy was able to direct the discharges with terrible effect,
particularly upon the naked Tlascaltecs. Several Spaniards also fell,
and the greater number were wounded. Ordaz received three cuts,
and Cortés a wound which maimed two fingers of the left hand.[767]
The assailants were comparatively safe, for those on the roofs could
be picked off only by archers and musketeers, and those below took
refuge when pressed, only to return to fresh attack. Efforts were
made to fire the houses, but this was slow work, since they were
constructed almost wholly of adobe or stone, and were filled with
defenders. Nor would the fire spread, owing to the detached form of
the buildings, separated by alleys or canals, so that the torch had to
be applied to each.
Thus matters continued until Ordaz, who was engaged on the
street to the west of the fort, sent word to Cortés, who was pressing
forward in the direction of the Iztapalapan causeway, that he was
losing ground. Leaving his own forces, the general hurried to the
scene with a few horsemen, and heading the charge, drove back the
warriors at the most exposed point, so as to relieve the infantry in the
retreat which was now found necessary. Returning to his men he
found them also retreating, those who headed the column, including
Andrés Duero, the Cuban secretary, having been cut down. “Shame
upon you!” exclaimed Cortés to the corps, as he led the horsemen to
the rescue of the fallen cavaliers. He was just in time to save them,
for a moment more and Duero, at least, would have been slain. The
elated warriors fell back before the charge of the terrible Malinche,
although they soon recovered. Cortés then concluded to retreat, but
this proved no less dangerous than the advance, and among others
Lezcano was dragged from his horse and killed, after having
distinguished himself for bravery and execution. The fort had
meanwhile sustained an active siege, and when the retreating corps
approached it they found more enemies in waiting, who, fearful of
losing their prey, rushed forward with greater fury than ever. An
entrance was finally effected, the forces in the temple being at the
same time withdrawn for the greater safety of themselves and the
fort.[768]
Swelling with triumph the Aztecs now directed all their efforts
against the Spanish quarters. Burning arrows and whirling brands
began to mingle with their missiles. Although the building itself was
of stone, the roof and portions of the outwork, and the Tlascaltec
camp in the yards, were of inflammable material, and more than
once the flames burst forth, filling the whole place with suffocating
smoke, and calling for the greatest exertions to subdue them. The
little water at hand could not be spared, and so earth was cast up,
and portions of the wall were torn down to check the fire and to stop
the gaps. The assault continued all day, till darkness sent most of the
warriors to their homes.[769]
FOOTNOTES
[744] Which speaks little to the credit of either Mary or Santiago. Bernal Diaz, Hist.
Verdad., 102. ‘Otro miraglo ... é fué muy notorio.’ ‘Ya sé que los incrédulos ... dirán
que mi ocupaçion en esto de miraglos, pues no los ví, es supérflua ... é yo hablo
que esto é más se puede é debe creer;’ for did the Indians have mysteries and
miracles, surely God, the virgin, and the saints could effect greater deeds. Oviedo,
iii. 511. He quotes from Livy and others concerning the reliable miracles of Roman
times. Prescott and others transfer the miracles to the siege under Cortés for
greater effect. Bustamante, the modern champion of the shrines of Mexico, who is
ready to uphold any deed attributed to these images, is rather incredulous about
miracles recorded in favor of Spanish cutthroats. See Chimalpain, Hist. Conq., i.
283 et seq. ‘Si no oviéssemos miedo de esse del caballo blanco, ya vosotros
estaríedes coçidos,’ cried some, Oviedo, iii. 511, while the more valiant added that
‘con todo esto si no soltays a Motecçumacin, y os vays luego, presto sereys
muertos.’ Gomara, Hist. Mex., 152.
[745] Cortés, Cartas, 127. Bernal Diaz, Hist. Verdad., 101-2, says seven, two
having been taken alive. ‘Mataron a Peña, el querido de Motezuma,... Valdibia, y
Juan Martin Narizes.’ Herrera, dec. ii. lib. x. cap. vii.
[746] ‘Tuvieron guerra con los yndios en esta Cibdad dos medios dias que fueron
jueves e viernes.’ ‘Guerra casy dos dias.’ Lopes and Flores, in Ramirez, Proceso
contra Alvarado, 131, 134. ‘Dieron bateria los Mexicanos á los Españoles siete
dias, y los tuvieron cercados veinte y tres dias.’ Sahagun, Hist. Conq., 29.
‘Cercados los españoles ocho dias.’ Id. (ed. 1840), 105. ‘Pelearõ y combatieron la
casa diez dias arreo.’ Gomara, Hist. Mex., 151. Torquemada explains this by
assuming two days of fighting and eight days of close siege, with attacks upon all
who sallied, i. 490. Sahagun states that Itzquauhtzin, governor of Tlatelulco,
accompanied Montezuma to the roof and spoke to the people, representing that
the Spaniards, as the mightier race, would inflict great injury on them unless they
ceased to fight, and that the emperor would be murdered. The Mexicans
responded with insults and missiles, but as the soldiers interposed their shields no
harm was done. They appear to have stopped active operations, however. Hist.
Conq., 28-9. The insults and missiles belong no doubt to the later siege under
Cortés. Duran states, however, that Montezuma was henceforth looked on as an
accomplice of the Spaniards, and discarded as a ruler, it being resolved to kill him
and his family. Hist. Ind., MS., ii. 463. According to Oviedo the news came at this
time of the victory over Narvaez, ‘é Monteçuma mandó á los indios que dexassen
de pelear é dexassen venir los otros chripstianos, porque á todos juntos
matassen; é aquesto se cree que fué su intento.’ iii. 512. That he may have urged
this with intent or as a bait is not unlikely, but it should apply equally to Narvaez’
men, since it appears that their defeat could not yet have been known. When
known, however, it must have had its effect. ‘Quando supieron nuestra vitoria,
cessarõ de dalle guerra.’ Bernal Diaz, Hist. Verdad., 101. Yet Gomara writes that
on learning of the large forces coming against them, the besiegers resumed the
attack at one time. Hist. Mex., 151.
[747] This spring was rediscovered during the reign of Viceroy Revilla Gigedo.
Bustamante, Mem. Piedad Mex., 7. A pool of sweet water was the chief
inducement for founding the city on this site in 1325. Native Races, ii. 559-61; v.
345 et seq.
[748] Cortés, Cartas, 126. The Spanish messenger from Mexico returned
wounded. Peter Martyr, dec. v. cap. v. With him, or about the same time, arrived
four chiefs sent by Montezuma to complain that Alvarado had attacked the nobles
without cause. While defending themselves six soldiers had fallen. Cortés told the
chiefs with stern countenance that he was returning to investigate the matter. A
letter was sent to Alvarado enjoining him to guard the emperor closely. Bernal
Diaz, Hist. Verdad., 101.
[749] And the zealous aid of Velazquez de Leon, who did so much toward
securing the Goazacoalco command for Cortés when Narvaez sent letters to win it
over. Cortés, Residencia, i. 409; ii. 6, 31, 165-6. He is accused by his enemies of
impiety and licentiousness, and as one whom the general favored above more
worthy men. Solis assumes that Sandoval nominally retained the command of the
coast province, Rangel being merely his lieutenant. Hist. Mex., ii. 108.
[750] ‘Llegò aquel dia [the first] à la Rinconada, el segundo caminò siete Leguas
... llegò à Tlaxcalla à diez y siete de Junio.’ Torquemada, i. 492. Herrera tells a
long story of suffering from hunger and thirst during the march through the desert.
Marquez and Ojeda were sent ahead to Tlascala for supplies, and came back with
1200 carriers laden with fowl, bread, fruit, and other refreshments. Cortés, among
others, was found starving, and a number were discovered on the road almost
dead. All, it seems, were rescued. dec. ii. lib. x. cap. vii. There are several reasons
for believing that Herrera, who is somewhat confused about this period, has
confounded the present march with the flight from Mexico to Tlascala of a month
later, when the people were really starving. This seems confirmed by the
erroneous statement that the troops arrived at Tlascala July 17th, the time,
according to Herrera’s own later statement, when they reached that place after the
flight. The account also intimates that the starving army was met among the Otomí
settlements, where food could readily be obtained, without the necessity for
Marquez and Ojeda to go ten leagues farther, to the capital, to obtain it. These and
other discrepancies are overlooked by all who refer to the march. Prescott dwells
in particular on the suffering from thirst, forgetful of the statement on a previous
page that the rainy season had begun about three weeks before, and that water
must have been abundant along the whole route. Solis finds that the effeminate
followers of Narvaez endured the suffering remarkably well. Hist. Mex., ii. 109.
[751] ‘Embiò a fray Bartolome de Olmedo ... a Motezuma.’ Herrera, dec. ii. lib. x.
cap. vii. It is unlikely that so valuable a man would have been sent while affairs
were threatening.
[752] Narvaez landed with about 900 soldiers, including 80 horsemen, 120 with
bows, and 80 with fire-arms. A number had been picked up at Cozumel, but an
equal proportion perished by shipwreck. Cortés had about 250 men, and 200 were
probably left on the coast, of garrison, guards, and invalids. To the 950 soldiers
thus taken may be added at least 150 from the crews of the dismantled or
destroyed vessels. Prescott manages to mysteriously increase the horses and
projectile arms beyond what he previously assigns to Narvaez and Cortés. One
thousand infantry, 100 horsemen, and many allies, say Gomara and Herrera. The
Probanza de Lejalde, in Icazbalceta, Col. Doc., i. 425, indicates 80 horses. Bernal
Diaz places the figures as high as 1300 soldiers, including 96 or 97 horsemen, 80
archers, 80 musketeers, and 2000 Tlascaltec warriors; while Cortés, with a
prudent desire to cover the subsequent losses at Mexico, reduces them to 500
infantry and 70 cavalry. Solis gives the reason of the profound historian for the
small number of allies taken to Mexico: ‘Por no escandalizar á Motezuma, ó poner
en desesperacion á los rebeldes.’ Hist. Mex., ii. 111.
[753] The arrival at Tezcuco is evidence enough that a more northern road was
taken than the one previous. The middle route by Telapon appears somewhat
more direct for Mexico, but requires a detour to reach the Acolhua capital, and it is
not likely that an army in hurried march could afford to go out of its way. Hence the
Calpulalpan road must have been followed.
[754] See Native Races, ii. 162-3, 168-73, 569; v., passim; Motolinia, Hist. Ind.,
181-3.
[755] Cortés writes that he was on the point of sending a Spaniard to Mexico with
Tezcucan rowers, a chief being taken as hostage, but just then came this canoe.
Cartas, 127.
[756] Two, named Santa Clara and Pedro Hernandez, says Herrera, dec. ii. lib. x.
cap. vii.
[757] ‘Parò en Tepeaquilla, lugar a legua de Mexico.’ Id. Now the shrine of
Guadalupe. Prescott assumes that the Iztapalapan road was taken, as before, but
it was avoided probably because Cortés feared the fort Xoloc, which guarded the
centre. It was also longer, and had more movable bridges than the other
causeways.
[758] ‘Riñas por San Iuan pazes para todo el año.’ Vetancvrt, Teatro Mex., pt. iii.
139. The following day a dress was found hanging from a beam, and in a square a
pile of bread, with over 500 fowl, without a guard. This Cortés considered less
favorable, and said ‘que serian riñas de por San Iuan.’ Herrera, dec. ii. lib. x. cap.
vii.-viii.
[759] ‘Para dar á entender con esto que ellos estaban de guerra y muy ofendidos
de los españoles que él habia dejado.’ Sahagun, Hist. Conq. (ed. 1840), 108. His
account of deserted streets, applied to Cortés’ first arrival in Mexico, belongs no
doubt to this occasion. Duran argues that had the massacre taken place before
Cortés’ arrival he would not have been allowed to enter. Hist. Ind., MS., ii. 470.
Equally in the dark is Acosta, who assumes that the Indians were openly at war,
but the custom being to rest every fourth day, Cortés managed to enter during the
cessation of hostilities. Hist. Ind., 522. Oviedo looks on the non-resistance of the
Indians as a wile to entrap all the Spaniards. iii. 510.
[760] Herrera writes amusingly that Cortés shouted before the closed gates,
‘Open!’ ‘Who is there?’ demanded Alvarado. ‘I,’ replied Cortés. ‘Do you come with
full liberty, and power to command, as before?’ ‘Yes, and with victory, and greater
forces.’ Alvarado thereupon opened, kissed his hand, and surrendered the keys!
dec. ii. lib. x. cap. viii.
[761] ‘Con que aventuró la mayor parte de sus fuerzas.’ Solis, Hist. Mex., ii. 120.
Or perhaps because he had not had recourse to some safer measure, such as
arresting the leaders of the proposed plot, for hostages. ‘Le dixo muy enojado, q̄
era muy mal hecho, y grande desatino, y poca verdad ... no le hablò mas en ello.’
Bernal Diaz, Hist. Verdad., 102. Cortés would hardly have told him that he lied,
since his statements were confirmed by so many; they certainly were years after.
Vetancurt supposes that Cortés told him he should have allowed the emperor to
attend the festival, and should have awaited the attack rather than opened the
war. Teatro Mex., pt. iii. 140. ‘Dissimulo por no enojar a los que lo hizieron.’
Gomara, Hist. Mex., 151.
[762] Solis supposes, however, that the two met in friendly intercourse, and takes
Bernal Diaz and Herrera to task for asserting the contrary. Hist. Mex., ii. 112-14.
He refers to Cortés’ friendly message from Tezcuco, which is doubtful, and to
Gomara, who certainly allows Cortés to refer to Montezuma and his courtiers as
‘dogs.’ Hist. Mex., 153. In the testimony during Cortés’ residencia the discourtesy
is asserted. Cortés, Residencia, i. 42 etc. Clavigero suggests ‘ch’era d’uopo il far
sembianza di credere il Re colpevole dell’inquietudine.’ Storia Mess., iii. 121.
[763] Native Races, ii. 134-6; v. 462-4; ‘Il y joignait, comme de coutume, la charge
du grand prêtre de Huitzilopochtli.’ Brasseur de Bourbourg, Hist. Nat. Civ., iv. 309.
Gomara assumes that Cortés orders a chief to open the market. He, offended at
the insults used, goes only to rouse the people. Hist. Mex., 153. Ixtlilxochitl
supposes that the chief is offended at the reprimand administered for delaying to
open the market. Hist. Chich., 301. ‘Mandò Hernando Cortes llamar a los mas
principales caualleros, hizoles vna larga platica diziẽdo, que les perdonaua lo
passado, con que para adelãte fuessen ... amigos: ... sin responder ... se fueron.’
Herrera, dec. ii. lib. x. cap. viii.
[764] Duran enumerates some of the provinces summoned, as Xilotepec and

Matlaltzinco. ‘Mandó llamar á ... Encantadores y Hechiceros para que los
asombrasen y los mostrasen algunas visiones de noche, ... para que alli muriesen
de espanto.’ Hist. Ind., MS., ii. 462-6.
[765] Cortés describes first a brief attack, then a sally, succeeded by a fresh
assault on the fort, while Bernal Diaz and Herrera let a force advance against the
Indians before they reached the palace. I follow Cortés as the chief guide,
because his account of all this period was written while quite fresh in his mind, and
appears the most sensible and correct, while the other versions depend more or
less on faint recollection and hearsay. Cortés as a rule did not wait till the enemy
approached, but he may not have been prepared for the sudden attack. Yet it is
probable that he wished in his report to lay the responsibility of the attack upon the
enemy. I do not think Cortés inclined to misrepresent in general or without an
object.
[766] For war customs see Native Races, ii. 400-32.
[767] ‘Sinistræ manus digitis duobus mutilis.’ Peter Martyr, De Insvlis, 5. Cortés
also says ‘quedé manco,’ Cartas, 142, 131, yet Cano ridicules the statement, and
declares ‘nunca fué manco dellos ni le faltan.’ Oviedo, iii. 551-2.
[768] Cortés, Cartas, 128-9. Bernal Diaz speaks of a sally by Ordaz, with 400
men, before the natives reach the fort. He is sorely beset, as related, and retires
with a loss of 23 soldiers. Hist. Verdad., 102-3. Herrera’s account, as usual, is
confused. After Rio returns wounded to report the uprising of warriors, five
horsemen rally to reconnoitre. The following day Ojeda and Marquez set out to
forage, and come to announce the approach of assailants. Two hundred men now
make a sortie and kill a multitude without losing a man. dec. ii. lib. x. cap. viii. It is
useless to follow this author here except for incidents.
[769] Bernal Diaz places the dead at 35 soldiers, besides a large number of allies.
Eight fell during the first discharge upon Ordaz’ party and fifteen more before he
regained the fort, while of the 46 wounded among the garrison twelve died. Hist.
Verdad., 103. Cortés, with his usual prudent suppression of evil news, allows four
deaths and over 80 wounded. He never refers to those who die of wounds.
Gomara follows him. Hist. Mex., 153.
CHAPTER XXIV.
FIGHT UPON THE TEMPLE SUMMIT.
June, 1520.
The Natives Continue the Assault—Their Fierce Bravery—The Spaniards

Build Turrets—Still the Mexicans Prove too Strong for Them—
Montezuma Called to Intercede—He is Insulted and Stoned by his
Subjects—Cortés Attempts Egress by the Tlacopan Causeway—Failure
of Escobar to Take the Pyramid—Cortés Gains the Slippery Height—
The Gladiatorial Combat there.
At dawn the assault was renewed with the same fierceness as

before, and with even less regard for the sweeping volleys of the
cannon, which were fired without aim into the packed masses of the
natives, bringing them down by the score. The gaps were quickly
closed, and the rapidly repeated shots seemed to make no more
impression on the surging mass than pebbles dropped into the
boiling surf. It was a critical time for Cortés, who seemed not yet to
recognize the full extent of the danger. He felt the necessity of open
communication with the mainland, for obvious reasons, and to this
end, in the course of the morning, he arranged another sortie like
that of the preceding day, but in one direction only. The Indians
retired, as before, into lanes and buildings, and beyond canals,
raising; the bridges behind them. Barricades having been thrown up
to impede the advance since the last sally, some guns were brought
to the front, and with their aid a few of the obstructions were
demolished and more than one bridge was gained, together with a
number of houses, to which the torch was applied. The discharges
from the roofs were kept up with galling pertinacity, although the
effect was not so fatal as during the preceding day, owing to the
experience then gained. The forces below, who had retired before
the charges of the advance, rolled back like recurring billows, and in
ever increasing number, upon flank and rear, as if to overwhelm
them. Such were their numbers and stubborn recklessness that ten
thousand Hectors and Rolands, says Bernal Diaz, could have
effected nothing against them, and soldiers from the Italian war
swore that never among Christians or Turks had they witnessed
such fierceness. Considerable alarm was also created by the
appearance of long pikes, like those of the Chinantecs, directed
particularly against the cavalry. Fortunately they were not numerous,
nor were the pikemen sufficiently practised to be very dangerous.
Worn out in the unequal contest Cortés turned to gain his camp,
which was no easy task, since the natives were massed in greatest
number in the rear, determined to cut off retreat. The fort was gained,
nevertheless, although hardly a man escaped uninjured, while about
a dozen were killed; one unfortunate soldier being captured and
sacrificed in full view of the garrison.[770]
It had been found that the greatest danger to the sallying parties
came from the roofs, whence discharges could be directed with
comparative impunity and with greater effect than from the ground.
In order to counteract them, three mantas, or movable turrets, were
planned, whose occupants were to devote their attention wholly to
clearing the roofs of assailants. The completing of these machines
and other preparations kept the garrison busy all the 27th of June, so
that no sally was made. Ascribing this to fear, the Indians became
more pressing in their assault, and more profuse with their insults.
“Dogs!” cried some, “of hunger and thirst shall you die!” Others
shouted, “Here is a piece of my tortilla!” at the same time flinging
them unpalatable fragments of toasted bread. “Eat it, you perjured
villains, who can fight only on the backs of animals; for soon shall
your own bodies be cut up for food and cast before the beasts!” The
enemy appeared more numerous than ever, and the roofs and yards
were literally covered with their missiles. The greatest danger to the
Spaniards lay in the operations of the battering and mining parties,
who, regardless of bullets from the wall turrets, sought steadily to
open fresh breaches. Conspicuous in the hostile camp was a richly
dressed Indian, surrounded by a staff of finely attired warriors, who
seemed to direct operations, and whose orders were received with
the deepest reverence. This personage the prisoners declared to be
Cuitlahuatzin, and the next in rank Quauhtemotzin.[771] Charge after
charge was made by his direction, and with a vehemence that
threatened to carry everything before it; and loudly rang the yells,
whether of delight at some advantage gained or of fury over a
repulse.
Thus the besieged were harassed beyond endurance. Large
numbers were wounded, and all were exhausted from vigils, hard
fighting, trying work, and the want of sufficient water and food; for in
view of the stoppage of supplies, rations had been reduced. Those
of the Narvaez expedition were particularly disheartened, and
bestowed freely their maledictions, first on Velazquez, who had sent
them to such a country, and then upon Cortés, whose promises of
golden treasures and well stocked encomiendas had lured them to
this plight. Perceiving, however, that unity of purpose alone could
save them, they stifled regrets and showed Cortés that something
must immediately be done to stay the onslaught, lest the building fall
about their ears. It was exceedingly disagreeable, but it must be
done; the proud Spanish general must sue to the greatly injured
captive king, pleading for his influence in behalf of peace.[772]
Montezuma had all these days been closely confined to his rooms
brooding over the insults offered him, and apparently indifferent to
the danger from without. When the message was brought he sullenly
said, “Why does Malinche address himself to me, who care no
longer for life? I will not listen to him, for he it is who has brought me
into this plight.” He intimated further that the promises of the general
could not be relied upon, and that his words carried a double
meaning. Olmedo and Olid, who had come to urge the request, had
recourse to soothing words and persuasion, and succeeded in
mollifying him somewhat.[773] He replied, however, that it was
probably too late to appease the Mexicans by promises. “They have
now a new leader,” he said, “who is resolved to spare no Spaniard,
and I believe that you have all to die in this city.”[774] Nevertheless he
yielded, and as befitted the momentous point at issue, he arrayed
himself in the richly bejewelled robes of state, and placed upon his
head the mitred copilli, beneath whose precious feathers gleamed
the golden plate.[775] Carefully guarded he ascended to the roof and
stepped to the parapet, preceded by a courtier who bore the triple
wand of the empire, as was customary on such occasions. Instantly
the tumult was hushed, even before the leaders could issue orders
for a stay of hostilities; instantly a thousand heads were bent in
humble adoration before the august majesty of their sovereign. This
attitude, however, was assumed but for a moment; soon these same
heads were held higher than ever. Then the chiefs drew near to
listen to the unhappy monarch.
Montezuma had appeared with a feeling of mingled fear and
doubt as to what his reception might be, and he did not fail to
observe that the accustomed reverence was shown only for an
instant, involuntarily, as it were, and that silence was prompted
rather by curiosity than respect. The urgency of the moment
demanded that he should speak, but it was rather as supplicant than
ruler that he turned to his people.
“You are in arms, my children,” he said, “in hot battle. Why is
this? You will be slain, and there will be heard throughout the land for
many years the wail of wives and little ones. You would give me my
liberty, and I thank you. You do not turn from me in anger, and I
thank you. You have not chosen another king in my stead, and I
thank you. Such an act would displease the gods, and bring
destruction on all. And see! I am no prisoner. Go your way; I am free.
By divine command I must remain the guest of the Spaniards yet a
little longer, and you must not molest them, for soon they will return
whence they came. Alas, my people, my country, my crown!”[776]
With a heavy sigh, and midst copious tears, his head fell on his
breast. The monarch’s strength had indeed departed. The people
knew that he spoke falsely, that he was little better than imbecile,
unfit to be their sovereign. Oh, if he but had the good fortune to die
while helping them to grind to powder these hated enemies! Only a
little while ago his words would have been received as the
utterances of a deity. Now the scales had fallen from their eyes, and
they saw him as he was. They could bear no more. Jeers and
groans reached him from every direction. “Coward! chicken! Woman
to the Spaniards, fit only for the gown and the spindle! Murderer of
your nobles!” Such were the cries which now reached his ears as he
stood stupefied with agony. Presently came a shower of arrows and
stones, and before the Spanish guard could interpose their shields
several missiles struck him, one on the left temple, which caused
him to fall senseless into the arms of the by-standers.[777]
Startled by the crime they had committed, awe fell upon the
multitude as the stricken sovereign was led away. Taking advantage
of this feeling Cortés beckoned the chiefs to a parley with a view to
explain what Montezuma had intended to convey. He had always
wished them well, he said, and felt grieved to wage war for what had
occurred during his absence. He desired peace, yet the desire was
not prompted by fear, but by consideration for their safety and that of
the city. The chiefs replied that the Spaniards must leave the country
to the natives, and depart at once. That was exactly what they
wished to do, replied Cortés, but they would not be driven away. If
the Mexicans desired them to go, they must abandon the siege, tear
down the barricade, and retire to their homes; they must likewise
restore the bridges and supply provisions. To this the chiefs declined
to listen, declaring that they would not lay down their arms so long as
there was a Spaniard left on whom to use them.[778] The evident
desire of the besieged for peace served only to encourage the
Indians, and the assault was renewed with an increased ardor that
taxed the defenders to the utmost.
And now, whatever the cost, a way out of this place must be
opened. Cortés knew of three causeways which led to the mainland,
the only means of exit for his forces. He knew that they were low and
narrow, exposed on both sides to the attacks of canoe fleets, and
intersected by a number of bridges which were perhaps by this time
raised. Each of these openings was an almost impassable chasm.
The southern causeway to Iztapalapan was two leagues in length,
and provided with seven drawbridges, besides a strong fortress,
which rendered it impassable to an enemy. The northern, leading to
Tepeyacac, was one league long, while the shortest, conducting
westward to Tlacopan, half a league distant, was broken by only
three bridges.[779] Cortés resolved to undertake the passage by this
last named causeway. During the night had been completed three
mantas, of light framework and planks, each to hold twenty
musketeers and archers, with which it was hoped to check the
assailants on the roofs. These mantas were built with two chambers,
provided with loop-holes; the upper ranged on a level with the
house-tops of ordinary one-story buildings of the city, and had doors,
so as to allow of sallies upon the roofs.[780]
The following morning, June 28th, Cortés placed himself at the
head of five hundred Spaniards and over three thousand allies, and
took the direction of the Tlacopan causeway.[781] By a sudden
charge the cavalry drove back the Indians and allowed the free
passage of the mantas, which were drawn and pushed by
Tlascaltecs, and protected by bodies of infantry. A corps of pioneers
accompanied them with pickaxes, mattocks, crow-bars, and ladders,
to destroy barricades and walls, and to scale buildings. Four cannon
were also brought. The rear was protected by a portion of the
cavalry. The Aztecs were at first amazed at the curious moving
turrets, and feared that they might contain more terrible destroyers
even than the grape-charged guns; but finding them less dangerous,
they continued their efforts, and fast and thick poured the stones and
arrows on the line of advance, particularly on the engines, which
were severely damaged. The march proceeded, however, with more
or less interruption till a raised bridge was reached on the main road,
where the Indians had gathered in vast numbers, with an evident
determination to check the expedition. The turrets were brought
alongside the houses adjoining the canal in order to clear the
crowded roofs, but regardless of the volleys from the firelocks, the
natives on the roofs plied their missiles only the faster, letting fly
heavy rocks[782] upon the engine coverings, so as to render them
untenable and hinder the manœuvring of the cannon. This success
enabled the warriors beyond the canal and behind the barricades to
maintain their assault with great effect, and to prevent a further
advance. They gained a considerable advantage by a change of
tactics in directing the missiles to a great extent against the legs of
the Spaniards, to their serious discomfiture.[783] After spending the
greater part of the forenoon in an unsuccessful attempt to destroy
the houses nearest the canal, and to fill a passage across it, the
troops retired to the fort greatly disheartened. Even the Tlascaltecs,
who were usually so glib of tongue in replying to Aztec taunts, for
once held their peace.[784]
Meanwhile the battle raged fiercely round the fort. The temple in
front of it, since its evacuation by the Spaniards, had been occupied
by some five hundred Mexicans, chosen men,[785] who introduced a
large quantity of ammunition and supplies, and began to batter the
besieged quarter. It was this shower which had first damaged the
turrets and harassed the march. Perceiving the danger of leaving so
commanding a position in hostile hands, Cortés had sent his
chamberlain, Escobar, with one hundred men[786] and some allies to
dispossess them. This was no easy task, for the pyramid was of
great extent and over eighty feet in height, composed of a series of
abrupt stone terraces, each receding about six feet from the one
beneath, and so arranged that the ascent led along the entire circuit
of each ledge before the steps conducting to the next could be
gained.[787] Twenty men, says Cortés, could have held it against a
thousand; yet the one hundred were to attempt it. Step by step they
fought their way, beneath showers of arrows, and against javelins,
and sword and lance thrusts from the upper ledges. More dangerous
even than these weapons were the cumbrous missiles in the shape
of heavy stones and timber which came crashing down upon them.
Three times[788] did Escobar lead his men to the charge, only to see
them repulsed and sent rolling down the steps and over the ledges.
Finally he sent word to Cortés that the task was impracticable. The
general received this notice while vainly battling at the canal, and he
eagerly seized upon it as excuse for changing his base of operation.
He hurried to the spot, threw a cordon round the pyramid, and
although badly wounded in the left hand he immediately led his men
to the charge. The Spaniards were making fair progress, when two
heavy beams, which had been reserved at the summit for the last
extremity, were loosened and sent tumbling down the side, so
directed as to sweep to destruction the assailants along its entire
length. At about the centre of their terrible passage, full before them,
stood Cortés. Immediate death for himself and his brave comrades
seemed inevitable, when behold! by some unseen finger the beams
were turned end foremost and shot harmlessly through the opening
made for them by the soldiers. “Thanks be to God and the virgin,
whose image was placed in this tower!” cried Cortés, as without the
loss of a moment he sprang forward and speedily gained the
summit. There the fight assumed the form of a gladiatorial combat, a
hand-to-hand and line-to-line conflict, poised in mid-air on this
narrow slippery summit, and in full view of the whole city. As if by
common consent the combatants below paused in their bloody work
and stood breathless, lost in the more thrilling sight above.
At the eastern end of the platform stood the two three-story
chapels, over fifty feet in height, originally dedicated to Huitzilopochtli
and Tezcatlipoca. Against this the Indians had massed themselves,
fierce in their desperation. The Castilians had taken their stand at the
other end. It was an awful situation, dire destruction being inevitable
to one side or the other. With nerves and sinews strained to their
utmost tension, they stood between attacks regarding each other,
regarding every motion, anon picking from the other’s number with
javelin, dart, or musket, as they were able. It was with difficulty the
Spaniards could stand, and there was no railing round the slippery
height; but fortune again assisted by unveiling the sun and sending
its blinding rays full in the face of the enemy. Every now and then the
soldiers charged in solid phalanx into the centre of the opposite
mass, only to be obliged to retire under the pressure of its weight,
and to receive the counter-charge, encouraged by wildly
gesticulating priests, who flitted to and fro in bloody robes and
dishevelled hair. Aware of the inferiority of their weapons, the natives
sought rather to seize hold of the Spaniards, singly or in groups, and
with the recklessness of doomed men to hurl themselves with their
victims from the dizzy height. In one instance Cortés himself was
selected for this terrible fate. Inspired to martyrdom and revenge, two
young nobles watched their opportunity, and approached him on
their knees, as if pleading for mercy. Ere he had time to consider the
situation they had seized him in their arms and were struggling to
gain the edge. One moment more and he would have been dashed
to death, but by putting forth his whole strength, nerved by
desperation, he succeeded in freeing himself from their grasp. Ojeda
was singled out for a similar attempt, and would have perished had
not a Genoese come to his aid.[789]
For three hours the struggle lasted, while one Indian after
another was picked off by the bullet and the arrow, or pierced by the
pike and sword, or sent headlong over the platform, either to be
crushed by the fall or to be transfixed by the Spaniards on the ledges
below. As their number diminished, many a one sought the higher
martyrdom by leaping from the sacred spot into paradise. Thus
melted away that fated band of Aztec warriors. At the portal of
Huitzilopochtli’s chapel fell the last defender; and two priests, one of
them the high-priest, alone remained to offer themselves as
captives. On entering the chapel consecrated to the virgin no traces
appeared of the holy emblems, only evidences of idolatrous rites,
and upon the altar stains from the blackened hands of the temple
attendants.[790] In the adjoining chapel the war-god was found
reinstalled in all its glittering hideousness. Some consolation for this
sacrilegious intrusion was offered to the victors in despoiling it of the
rich ornaments, while the cacao and other provisions stored here by
the garrison proved a prize to the half-famished Spaniards. The
Tlascaltecs, so long deprived of meat, pounced upon the bodies of
the slain heroes to secure them for a feast, which should not only
satisfy the cravings of hunger, but infuse their hearts and minds with
some of the qualities of the valiant dead.[791] The chapels were then
fired. The upper portion of the structure being of wood, the flames
rose in columns heavenward, heralding the triumph of the Spaniard,
and striking the Indian with awe. It was a great and thrilling feat, this
fight upon the temple top; and so the natives regarded it, their heart,
and mind, and paintings being all stained sanguine over its
remembrance.[792]
FOOTNOTES
[770] Bernal Diaz mentions the death of ten or twelve, but Cortés acknowledges
only three score of wounded. On this occasion, apparently, Herrera allows Cortés
to gain Tacuba, whither he might have retreated in safety with all his forces and
wealth; yet he states that the return fight proved most severe, the fort being
regained with difficulty, after the loss of two guns and several soldiers, one taken
alive. dec. ii. lib. x. cap. ix. Solis manages to transform the operation into a victory,
wherein Cortés stays the slaughter out of mercy. Prescott is quite arbitrary in the
use of the chronicles. He combines the incidents of several days into one and
transposes them at pleasure, with the sole aim apparently of presenting an
exciting description of what the siege might have been. A few facts are elaborated,
and the rest sacrificed to style.
[771] Marina asked Montezuma if a new king had been chosen, but he did not
think they would elect one while he lived. Vetancvrt, Teatro Mex., pt. iii. 141.
[772] ‘Fue acordado de demandalles pazes para salir de Mexico, ... acordò
Cortes, que el gran Monteçuma les hablasse.’ Bernal Diaz, Hist. Verdad., 104.
‘Muteczuma ... dijo que le sacasen ... y que él hablaria á los capitanes.’ Cortés,
Cartas, 129-30. The latter statement may be Herrera’s authority for saying that
Montezuma was the first to propose speaking to the Mexicans. dec. ii. lib. x. cap.
x. Observing Cuitlahuatzin’s regal authority over the besieging forces, Montezuma
was seized with a fit of jealous alarm for throne and life. ‘Chiamò Cortès, ...
pregandolo instantemente di non differir più la sua partenza.’ Clavigero, Storia
Mess., iii. 124. This implies that the emperor was not aware of the vain efforts
made to open communication with the mainland, or even to approach it. Cortés
had to urge him in any case to speak to his subjects, an unwelcome task in view of
his declining influence and of the merely partial success of the former appeal.
[773] Among other reasons it was represented that Cortés was not to blame for
the late massacre. ‘Que si la indignacion de los mexicanos podia templarse con el
castigo de los culpados ... le prometia castigar.’ So says the native version of
Tezozomoc, Recop. tradiciones, MS., cap. vi.; Chimalpain, Hist. Conq., 287-8.
[774] He felt no eagerness to plead in behalf of those who had caused all his
misfortunes, and he was only too conscious that his pusillanimity must have
degraded him in the eyes of his subjects, while the elevation of his brother to the
leadership must have diminished the influence which till then may have remained
with him. He could hardly avoid a feeling of jealousy at the thought of this
elevation; and if he, during an impulse of anger against Cortés, had counselled the
proceedings of Cuitlahuatzin, he now felt probably both grieved and terrified at the
storm he had raised. He also harbored a wholesome fear of Malinche, and the
prospect of his speedy departure helped to stir anew the embers of hope. All might
yet be well: the capital might be spared further desolation, and he again resume
his former grandeur.
[775] See description of his first meeting with Cortés, Native Races, ii. This
appearance of the emperor took place on the 27th of June, as Cortés states, but
Bernal Diaz, Herrera, and Ixtlilxochitl place it respectively on the 5th, 6th, and 7th
day of the siege.
[776] Herrera, dec. ii. lib. x. cap. x.; Bernal Diaz, Hist. Verdad., 104. ‘No
molestàsen à los estrangeros y fuésen sus amigos, pues su persona corria
riesgo.’ Tezozomoc, Recop. tradiciones, MS., cap. vi. Cortés, followed by Gomara,
gives him no time to speak ere the people assault.
[777] They would no longer recognize him as emperor, etc. Saying this, a chief
threw a stone which struck Montezuma on the forehead. Duran, Hist. Ind., MS., ii.
468. Acosta attributes this first throw to ‘Quicuxtemoc,’ the later king of Mexico.
Hist. Ind., 523. ‘Ma io nol credo,’ says Clavigero, Storia Mess., iii. 126. ‘Aunque vn
Castellano tenia cuydado de arrodelar a Motezuma ... le acertò vna piedra en las
sienes.’ Herrera, dec. ii. lib. x. cap. x. Had not the Spaniards held up a shield
before Montezuma the people would have known it was he and not thrown the
stone which killed him, says Cano, his later son-in-law. Oviedo, iii. 550. Gomara is
inclined to believe this, for his people ‘no lo quisieran hazer mas que sacarse los
ojos.’ Hist. Mex., 154. ‘Una saéta alcanzó al emperador en el estòmago que lo
atravezó por el baso, y una piedra le dió en la sien izquierda.’ The people would
never have thrown missiles, for they pitied him, and were prepared to obey his
injunctions, but Cacama, who stood behind the emperor, made signs that they
should continue the attack without regard for him or for the monarch. Tezozomoc,
Recop. tradiciones, MS., cap. vi. According to Bernal Diaz, the four chiefs who had
approached to confer with him expressed their sympathy for his misfortunes. They
had now chosen as leader ‘Coadlabacan, señor de Iztapalapa,’ and had sworn to
the gods to continue the war till all Spaniards were exterminated. Yet they prayed
daily to the gods for his safety, and if all went well he would more than ever be
their lord. They had hardly finished when showers of missiles fell, of which three
stones and an arrow hit him, on the head, arm, and leg. Hist. Verdad., 104.
‘Remorse succeeded to insult,’ and they fled, says Robertson, Hist. Am., 90, a
statement which Prescott improves by stating that the square before the fort was
left empty. But remorse must have been brief, for the main authorities, Cortés,
Gomara, Bernal Diaz, and Torquemada, either declare or intimate that the assault
never stopped. ‘No por eso cesó la guerra y muy mas recia y muy cruda de cada
dia.’ Cortés, Cartas, 130.
[778] ‘Esta Fortaleza casi no tiene exemplar,’ exclaims Lorenzana, forgetting that
Cortés’ firmness was due to the justifiable fear that a trap was intended. Cortés,
Hist. N. España, 136-7. Cortés concludes the sentence about Montezuma’s being
wounded by saying that he died within three days. He thereupon resumes the
account of parleys and siege operations, leaving the impression that these took
place after his death, while such was not the case. Nevertheless, Gomara,
Herrera, and others, Bernal Diaz not excluded, are misled, by this vagueness
evidently, into extending the siege and confounding the events, so that modern
historians have all more or less remained mystified. Solis assumes that during
Montezuma’s illness the siege was conducted only by straggling parties, the main
forces being occupied with crowning the new emperor. Hist. Mex., ii. 155-6. This is
probably due to a misconstruction of Bernal Diaz.
[779] ‘En esta auia tres no mas, y en la de Yztapalapà, siete.’ Herrera, dec. ii. lib.
x. cap. xi.; Native Races, ii. 561 et seq.
[780] Cortés, Cartas, 130, 133. ‘Quatro ingenios ... en que pudiessen yr veynte y
cinco hombres,’ says Bernal Diaz, Hist. Verdad., 103. ‘Tres mantas ... cõ sus
ruedas; leuauan treynta hombres a cada vna, cubierta con tablas gruessas de tres
dedos.’ Herrera, loc. cit. Drawn by men within, adds Peter Martyr, dec. v. cap. v.
‘Cabia cada vno veynte hombres, con picas escopetas y ballestas y vn tiro.’
Gomara, Hist. Mex., 154.
[781] Herrera unwisely assumes that the three towers with their forces were
respectively directed against the three causeway approaches.
[782] ‘De tres y quatro arrouas, que maltrataron a los que yuan en los ingenios, y
rompieron las tablas.’ Herrera, dec. ii. lib. x. cap. xi.
[783] ‘Hirieron a mas de docientos Castellanos.’ Id., cap. ix.
[784] ‘Nos mataron un español y hirieron muchos.’ Cortés, Cartas, 130-1.

Pharmacotherapy Handbook 11Th Edition Terry L Schwinghammer All Chapter

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Pharmacotherapy Handbook 11th

Edition Terry L. Schwinghammer

fm.indd 2 04-12-2020 15:14:33

Terry L. Schwinghammer, PharmD, FCCP, FASHP, FAPhA

Joseph T. DiPiro, PharmD, FCCP

Vicki L. Ellingrod, PharmD, FCCP

Cecily V. DiPiro, PharmD

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McGraw-Hill Education eBooks are available at special quantity discounts to use as

THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS

SECTION 1: BONE AND JOINT DISORDERS

SECTION 2: CARDIOVASCULAR DISORDERS

SECTION 3: DERMATOLOGIC DISORDERS

SECTION 4: ENDOCRINOLOGIC DISORDERS

SECTION 5: GASTROINTESTINAL DISORDERS

22. Constipation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

SECTION 6: GYNECOLOGIC AND OBSTETRIC DISORDERS

SECTION 7: HEMATOLOGIC DISORDERS

SECTION 8: INFECTIOUS DISEASES

SECTION 9: NEUROLOGIC DISORDERS

fm.indd 6 04-12-2020 15:14:34

55. Headache: Migraine and Tension-Type. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

SECTION 10: NUTRITION SUPPORT

SECTION 11: ONCOLOGIC DISORDERS

SECTION 12: OPHTHALMIC DISORDERS

SECTION 13: PSYCHIATRIC DISORDERS

SECTION 14: RENAL DISORDERS

SECTION 15: RESPIRATORY DISORDERS

SECTION 16: UROLOGIC DISORDERS

fm.indd 8 04-12-2020 15:14:34

The 11th edition of this companion to Pharmacotherapy: A Pathophysiologic Approach

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The Patient Care Process

IMPORTANCE OF A STANDARD CARE PROCESS

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FIGURE 1. The pharmacists’ patient care process. Joint Commission of Pharmacy

THE PATIENT CARE PROCESS TO OPTIMIZE PHARMACOTHERAPY

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TABLE 1 Medication Therapy Problem Categories Framework

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DEVELOP THE CARE PLAN

PRACTICE MANAGEMENT ISSUES

WORKFLOW, DOCUMENTATION, AND INFORMATION SYSTEMS

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Gout and Hyperuricemia

• Gout involves hyperuricemia, recurrent attacks of acute arthritis with monosodium

Acute Gouty Arthritis

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metatarsophalangeal joint (podagra), and then, in order of frequency, the insteps,

ch01.indd 8 18-11-2020 11:49:52

Initiate monotherapy:a Initiate combination therapy - examples include:

Prevent recurrent attacks: Switch to alternate monotherapy

Gout and Hyperuricemia | CHAPTER 1

• Methylprednisolone (a long-acting corticosteroid) given by a single intramuscular

ch01.indd 10 18-11-2020 11:49:53

Xanthine Oxidase Inhibitors

ch01.indd 11 18-11-2020 11:49:53

No Does patient have an indication for Urate Yes

Nonpharmacologic Urate ULT Initiation Anti-inflammatory Gout

ch01.indd 12 18-11-2020 11:49:54

• Mild adverse effects of allopurinol include skin rash, leukopenia, GI problems,

ch01.indd 13 18-11-2020 11:49:54