Essentials of Pathophysiology for Pharmacy, Ostalo' predlog Patofiziologija. Wisdom University
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Essentials of Pathophysiology for Pharmacy, Ostalo' predlog Patofiziologija. Wisdom University

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of

for PATHOPHYSIOLOGY

PHARMACY

ESSENTIALS

Pharmaceutical Care: Insights from Community Pharmacists William N. Tindall and Marsha K. Millonig

Essentials of Law and Ethics for Pharmacy Technicians Kenneth M. Strandberg

Essentials of Pharmacy Law Douglas J. Pisano

Essentials of Pathophysiology for Pharmacy Martin M. Zdanowicz

Pharmac y: What It Is and How It Works William N. Kelly

Pharmacokinetic Principles of Dosing Adjustments: Understanding the Basics Ronald Schoenwald

Strauss’s Federal Drug Laws and Examination Review, Fifth Edition Steven Strauss

Pharmaceutical and Clinical Calculations, Second Edition Mansoor Khan and Indra Reddy

Inside Pharmacy: Anatomy of a Profession Ray Gosselin, Jack Robbins, and Joseph Cupolo

Understanding Medical Terms: A Guide for Pharmacy Practice, Second Edition Mary Stanaszek, Walter Stanaszek, and Robert Holt

Pharmacokinetic Analysis: A Practical Approach Peter Lee and Gordon Amidon

Guidebook for Patient Counseling Harvey Rappaport, Tracey Hunter, Joseph Roy, and Kelly Straker

CRC PRESS PHARMACY EDUCATION SERIES

CRC PR ESS Boca Raton London New York Washington, D.C.

MARTIN M. ZDANOWICZ

of

for PATHOPHYSIOLOGY

PHARMACY

ESSENTIALS

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.

Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher.

The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying.

Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.

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Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe.

Visit the CRC Press Web site at www.crcpress.com

© 2003 by CRC Press LLC

No claim to original U.S. Government works International Standard Book Number 1-58716-036-6

Library of Congress Card Number 2002067061 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0

Printed on acid-free paper

Library of Congress Cataloging-in-Publication Data

Zdanowicz, Martin M. Essentials of pathophysiology for pharmacy / by Martin M. Zdanowicz

p. ; cm.-- (CRC Press pharmacy education series) Includes bibliographical references and index. ISBN 1-58716-036-6 (alk. paper) 1. Physiology, Pathological. I. Title. II. Series. [DNLM: 1. Pathology--methods. 2. Physiology--methods. 3. Drug Therapy--methods.

QZ 140 Z396e 2002] RB113 .Z337 2002 616.07--dc21 2002067061

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Dedication

This book is lovingly dedicated to my wife Christine, my son Alex, and my daughter Olivia, who are my constant

joy and inspiration. I would also like to dedicate this book to the students for constantly bringing out the best in me. I only hope that I am able to bring out the best in them…

You cannot depend on your eyes when your imagination is out of focus.

— Mark Twain

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Preface

This book was written as a clear, concise learning instrument for students in pharmacy or sciences. Many of the large pathophysiology textbooks used today are very detailed works that often include chapters on normal physiology and function, topics that are redundant for pharmacy or health science students who will take separate courses in human physiology as part of their curriculum.

The book begins with an overview of tissue injury and mechanisms of tissue repair to provide students with a foundation of key concepts in injury and repair that appear throughout subsequent chapters. A detailed discussion of the immune system is also included early on because this system plays a key role in a number of important disease processes. The discussion of the immune system is followed by an up-to-date discussion of HIV that includes important information regarding HIV mutation and drug resistance.

The book continues with a detailed presentation of diseases affecting the main organ systems including cardiovascular, respiratory, renal, gastrointes- tinal, hepatic and endocrine disorders. The book concludes with a compre- hensive look at diabetes mellitus.

The presentation of material within the chapters is designed to maxi- mize clarity and facilitate conveyance of key points to the students. Sub- sections, bulleted lists, tables and definitions of key terms are included in each chapter along with study objectives that are designed to focus stu- dents on important concepts within each chapter. Each chapter includes a rationale for drug therapy section that allows students to correlate infor- mation they have learned on selected diseases to the clinical application of drugs. The author’s experience in teaching both pathophysiology and pharmacology has made it clear that the time to introduce pharmacy and health science students to therapeutics is with the study of pathophysiol- ogy, where the mechanism and effects of disease are explored in detail. The presentation of drug therapy in this book is general and in most cases does not focus on the uses of specific drugs within a class but rather on a class of drugs as a whole. The goal of the drug therapy section is to expose students to various drug classes with emphasis on how these drug classes are used to treat a specific disease state. Major side effects of these drug classes are also included. However, specific drug nomenclature and dosing

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are not included, nor are detailed mechanisms of drug action because these topics will be covered in detail in subsequent pharmacology and therapeu- tics classes.

Although this book was designed as a stand-alone text for a pathophys- iology course in a pharmacy or health sciences program, it may also be useful as a clear and concise supplement to some of the larger, more comprehensive textbooks that are currently available. This book may also serve as an excel- lent review of pathophysiology for students preparing for standardized exams or for anyone who needs to update his or her knowledge in this area.

Martin M. Zdanowicz

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Contents

Chapter 1 Cellular injury

Study objectives..............................................................................................1 Introduction ....................................................................................................3

Cellular adaptation..............................................................................3 Cellular injury ................................................................................................4

Free radical injury ...............................................................................5 Hypoxic cell injury ..............................................................................5

Manifestations of cellular injury .................................................................6 Cell death ........................................................................................................6

Apoptosis ..............................................................................................6 Necrotic cell death...............................................................................7

Tissue repair....................................................................................................7 Types of tissue repair ..........................................................................8 Steps in tissue (wound) repair ..........................................................8

Chapter 2 Cancer

Study objectives............................................................................................ 11 Introduction ..................................................................................................13 Cancer terminology .....................................................................................13 Theories of oncogenesis ..............................................................................14

Abnormalities of tumor suppressor/inducer genes....................14 Mutation of DNA ..............................................................................15 Hereditary...........................................................................................15

Manifestations of cancer .............................................................................15 Tumor staging...............................................................................................16 Cancer detection...........................................................................................16

Tumor cell markers ...........................................................................16 Visualization .......................................................................................18 Biopsy ..................................................................................................18

Rationale for therapy...................................................................................18 Treatment of cancer .....................................................................................18

Surgical removal ................................................................................18 Chemotherapy....................................................................................18 Hormonal therapy .............................................................................18 Radiation therapy ..............................................................................19 Immune-based therapies ..................................................................19

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Chapter 3 Disorders of hemostasis and coagulation

Study objectives............................................................................................21 Introduction ..................................................................................................23 Steps in hemostasis......................................................................................23

Vascular spasm...................................................................................23 Formation of platelet plug ...............................................................23 Activation of blood coagulation cascades .....................................24

Intrinsic pathway..................................................................24 Extrinsic pathway.................................................................25

Formation of fibrin clot ....................................................................25 Clot retraction .......................................................................25 Fibrinolysis (clot dissolution) .............................................25

Conditions leading to decreased coagulation.........................................25 Genetic defects ...................................................................................25

Hemophilia ............................................................................25 von Willebrand’s disease ....................................................26

Autoimmune defects.........................................................................27 Idiopathic thrombocytopenia purpura .............................27

Thrombocytopenia.............................................................................27 Acquired deficiencies ........................................................................27

Vitamin K deficiency............................................................27 Liver disease..........................................................................28

Drug-induced alterations in hemostasis and coagulation..........28 Conditions leading to increased blood coagulation ..............................28

Chapter 4 Alterations in hematologic function and oxygen transport

Study objectives............................................................................................29 Introduction ..................................................................................................31 Hematopoiesis ..............................................................................................31 Anemia...........................................................................................................33

General manifestations of anemia ..................................................33 Types of anemia .................................................................................33

Hemolytic anemia ................................................................33 Blood loss anemia.................................................................34 Iron-deficiency anemia ........................................................34 Cobalamin-deficiency or folate-deficiency anemia.........34 Inherited anemia...................................................................34 Manifestations of thalassemia ............................................36 Aplastic anemia ....................................................................36

Polycythemia ................................................................................................37 Manifestations ....................................................................................37 Treatment ............................................................................................38

Chapter 5 Immune response and inflammation

Study objectives............................................................................................39 Introduction ..................................................................................................41

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Components of the immune system.........................................................41 Antigens ..............................................................................................41 Major histocompatability complex (MHC) ...................................41

MHC I.....................................................................................42 MHC II ...................................................................................42

Monocytes and macrophages ..........................................................42 Lymphocytes ......................................................................................42

T lymphocytes (T cells) .......................................................43 B lymphocytes (B cells) .......................................................43

Antibodies...........................................................................................44 Natural killer cells .............................................................................46 Cytokines ............................................................................................46 Complement proteins .......................................................................46

The inflammatory reaction .........................................................................47 Hypersensitivity reactions..........................................................................48

Chapter 6 Acquired immune deficiency syndrome (AIDS)

Study objectives............................................................................................51 Introduction ..................................................................................................53 HIV structure ................................................................................................53 Stages in an HIV infection..........................................................................54 Epidemiology of HIV infection .................................................................55 Laboratory diagnosis of HIV .....................................................................56 Rationale for treatment of HIV..................................................................56 Treatment of HIV .........................................................................................56

Chapter 7 Diseases of the vascular system

Study objectives............................................................................................59 Introduction ..................................................................................................61 Arterial disease.............................................................................................61

Atherosclerosis ...................................................................................61 Manifestations of atherosclerosis ....................................................62 Aneurysm............................................................................................64

Clinical manifestations of aneurysm.................................65 Treatment of aneurysms......................................................66

Vasospastic conditions ......................................................................66 Arterial inflammation .......................................................................66

Disease of the veins .....................................................................................66 Varicose veins.....................................................................................66 Chronic venous insufficiency ..........................................................67 Venous thrombus...............................................................................68

Treatment and prevention of venous thrombus .............68 Embolism ............................................................................................68

Anticoagulant and thrombolytic drug therapy ......................................69

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Chapter 8 Alterations in blood pressure

Study objectives............................................................................................71 Introduction ..................................................................................................73 Primary or essential hypertension ............................................................73

Manifestations of essential hypertension ......................................74 Rationale for treatment of essential hypertension .......................75 Treatment ............................................................................................75

Secondary hypertension .............................................................................76 Malignant hypertension..............................................................................76 Hypotension..................................................................................................76

Manifestations ....................................................................................77 Treatment ............................................................................................77

Chapter 9 Diseases of the heart

Study objectives............................................................................................79 Introduction ..................................................................................................81 Disorders of the pericardium.....................................................................81

Acute pericarditis ..............................................................................81 Manifestations.......................................................................81

Pericardial effusion............................................................................81 Manifestations.......................................................................82

Constrictive (chronic) carditis..........................................................82 Rationale for treatment of pericarditis...........................................83

Diseases of the myocardium......................................................................83 Myocarditis .........................................................................................83

Manifestations.......................................................................83 Cardiomyopathies .............................................................................83

Types of cardiomyopathy ...................................................83 Rationale for treatment of cardiomyopathy ....................85

Disorders of the endocardium and heart valves....................................85 Infectious endocarditis......................................................................85

Manifestations.......................................................................86 Treatment ...............................................................................86

Rheumatic heart disease...................................................................86 Manifestations.......................................................................86

Disorders of the heart valves...........................................................86 Mitral valve prolapse...........................................................88 Rationale for treatment of valvular disease.....................88

Congenital heart defects .............................................................................89 Patent ductus arteriosus ...................................................................89

Chapter 10 Myocardial ischemia

Study objectives............................................................................................91 Introduction ..................................................................................................93 Manifestations of myocardial ischemia....................................................93 Rationale for treatment of myocardial ischemia ....................................94

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Treatment of myocardial ischemia............................................................94 Nonpharmacologic treatment..........................................................94 Pharmacologic treatment..................................................................95 Surgical treatment..............................................................................96

Chapter 11 Myocardial infarction

Study objectives............................................................................................97 Introduction ..................................................................................................99 Coronary blood flow and myocardial infarction....................................99 Manifestations of myocardial infarction ..................................................99 Complications of myocardial infarction.................................................100 Compensatory mechanisms for myocardial infarction .......................100 Rationale for therapy.................................................................................101 Treatment for myocardial infarction.......................................................101

Chapter 12 Heart failure and shock

Study objectives..........................................................................................103 Introduction ................................................................................................105 Manifestations of heart failure.................................................................105

Left heart failure ..............................................................................105 Right heart failure ...........................................................................106

Systolic failure vs. diastolic failure .........................................................108 Systolic failure ..................................................................................108 Diastolic failure ................................................................................108

Physiologic compensation for heart failure...........................................108 Rationale for treatment of heart failure ................................................. 110 Circulatory shock ....................................................................................... 112

Physiologic responses to shock ..................................................... 113 Stages of shock................................................................................. 113

Complications of shock............................................................................. 114 Rationale for therapy................................................................................. 114

Treatment of shock .......................................................................... 115

Chapter 13 Abnormalities of cardiac conduction

Study objectives.......................................................................................... 117 Introduction ................................................................................................ 119 Cardiac conduction system ...................................................................... 119 Cardiac action potentials ..........................................................................120

Phases of cardiac muscle cell action potential............................120 Phases of action potential for cardiac pacemaker cells.............120

Electrocardiography ..................................................................................122 Components of a normal ECG......................................................122 Factors that may contribute to the development of a cardiac arrhythmia ..................................................................122

Mechanisms of cardiac arrhythmia.........................................................122 Ectopic pacemakers .........................................................................122

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Reentry impulses .............................................................................123 Types of arrhythmia ..................................................................................124

Sinus node arrhythmia ...................................................................124 Atrial arrhythmia.............................................................................124 Ventricular arrhythmia ...................................................................125 Heart block .......................................................................................126

Diagnosis of arrhythmia ...........................................................................127 Rationale for the treatment of cardiac arrhythmia...............................127 Treatment of cardiac arrhythmia.............................................................128

Pharmacologic treatment................................................................128 Nonpharmacologic treatment of arrhythmia..............................129

Chapter 14 Disorders of the respiratory system

Study objectives..........................................................................................131 Introduction ................................................................................................133 Respiratory infections ...............................................................................133

Infections of the upper respiratory tract .....................................133 The common cold...............................................................133 Influenza ..............................................................................134

Infections of the lower respiratory tract ......................................135 Pneumonia...........................................................................135 Tuberculosis.........................................................................137 Obstructive respiratory disorders....................................139 Restrictive pulmonary disorders .....................................144 Respiratory failure..............................................................149

Chapter 15 Abnormalities of the kidney and urinary tract

Study objectives..........................................................................................151 Introduction ................................................................................................153 Disorders of the kidney ............................................................................153

Acute glomerulonephritis ..............................................................154 Rapidly progressing glomerulonephritis.....................................154 Chronic glomerulonephritis...........................................................155

Manifestations of glomerulonephritis.............................155 Treatment of glomerulonephritis .....................................156

Urinary tract infections...................................................................156 Manifestations.....................................................................156 Treatment .............................................................................156

Renal calculi (kidney stones) .........................................................156 Manifestations.....................................................................157 Treatment .............................................................................157

Renal tumors ....................................................................................157 Manifestations.....................................................................157 Treatment .............................................................................158

Polycystic kidney disease...............................................................158 Manifestations.....................................................................158

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Treatment .............................................................................158 Renal failure .....................................................................................158

Acute renal failure..............................................................159 Chronic renal failure ..........................................................160 Manifestations.....................................................................160

Disorders of the bladder and urethera...................................................162 Urine reflux.......................................................................................162 Neurogenic bladder.........................................................................163

Chapter 16 Gastrointestinal disorders

Study objectives..........................................................................................165 Introduction ................................................................................................167 Abnormalities of the esophagus..............................................................167

Dysphagia .........................................................................................167 Achalasia ...........................................................................................168 Esophageal diverticulum................................................................168 Gastroesophageal reflux disease ...................................................168

Manifestations.....................................................................168 Treatment .............................................................................169

Disorders of the stomach..........................................................................169 Gastritis .............................................................................................169

Acute gastritis .....................................................................169 Chronic gastritis..................................................................169

Peptic ulcers......................................................................................170 Manifestations of peptic ulcer disease............................170 Treatment of peptic ulcer disease ....................................171

Disorders of the intestines........................................................................171 Irritable bowel syndrome...............................................................171 Inflammatory bowel disease..........................................................171

Crohn’s disease ...................................................................172 Ulcerative colitis .................................................................173

Disorders of the gall bladder.........................................................174 Gallstone formation (cholelithiasis) ................................174 Cholecystitis ........................................................................174

Diverticular disease.........................................................................175 Manifestations of diverticular disease ............................175 Treatment of diverticular disease ....................................176

Colorectal cancer..............................................................................176 Manifestations of colorectal cancer .................................176

Chapter 17 Disease of the liver and exocrine pancreas

Study objectives..........................................................................................177 Introduction ................................................................................................179 Viral hepatitis..............................................................................................179

Epidemiology ...................................................................................180 Manifestations of viral hepatitis ...................................................180

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Possible complications of hepatitis...............................................181 Treatment of hepatitis .....................................................................182

Cirrhosis ......................................................................................................182 Stages of alcoholic liver disease....................................................182 Manifestations of alcoholic cirrhosis ............................................183 Treatment of cirrhosis .....................................................................184

Liver cancer.................................................................................................184 Disorders of the pancreas — Pancreatitis..............................................184

Manifestations ..................................................................................184 Treatment ..........................................................................................185

Chapter 18 Endocrine disorders

Study objectives..........................................................................................187 Introduction ................................................................................................189 Abnormalities of the hypothalamus/pituitary glands........................189

Hypopituitarism ..............................................................................190 Disorders of the anterior pituitary gland....................................191

Alterations of growth hormone secretion ......................191 Growth hormone hyposecretion......................................191 Growth hormone hypersecretion — Gigantism and acromegaly...............................................192

Disorders of the posterior pituitary .............................................193 Syndrome of inappropriate ADH (SIADH)...................193 Diabetes insipidus ..............................................................193

Alteration of thyroid function .................................................................194 Hypothyroidism...............................................................................194

Manifestations.....................................................................194 Myxedema ...........................................................................195 Treatment .............................................................................195

Hyperthyroidism .............................................................................195 Grave’s disease ...................................................................195

Disorders of the adrenal glands ..............................................................196 Hyposecretion of adrenal hormones ............................................196

Congenital adrenal hypoplasia (CAH) ...........................196 Addison’s disease...............................................................197 Cushing’s disease ...............................................................198

Disorders of the adrenal medulla .................................................199 Pheochromocytoma............................................................199

Chapter 19 Diabetes mellitus

Study objectives..........................................................................................201 Introduction ................................................................................................203 Endocrine pancreas....................................................................................203 Types of diabetes mellitus ........................................................................204

Type I diabetes (insulin-dependent diabetes).............................204 Manifestations.....................................................................204

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Treatment .............................................................................204 Type II diabetes mellitus (non-insulin-dependent diabetes)....206

Manifestations.....................................................................207 Treatment .............................................................................207

Long-term complications of diabetes mellitus......................................208 Gestational diabetes...................................................................................210

References............................................................................................................. 211

Selected bibliography.........................................................................................213

Index .....................................................................................................................215

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1

chapter one

Cellular injury

Study objectives

• Compare and contrast the various forms of cellular adaptation. What is the purpose of these adaptive changes?

• Discuss the two underlying mechanisms by which cellular injury can occur.

• List the various classifications of cellular injury that can occur and give examples of each.

• Describe the major manifestations that present when cells are injured. Why does each of these manifestations occur?

• Define apoptosis and necrotic cell death. How do they differ? • List the specific types of cellular necrosis that may occur along with

their distinct characteristics. • Define gangrene and gas gangrene. • Discuss the two mechanisms by which tissue repair occurs. Give

examples of specific cell types that will utilize each repair mechanism. • List the steps involved in wound repair along with the key features

of each step. • List various factors that can impair wound healing. • What is a keloid scar? Why does it occur?

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Chapter one: Cellular injury 3

Introduction

The environment around cells is dynamic and constantly changing. In this fluid environment, cells are exposed to numerous stimuli, some of which may be injurious. To survive, cells must have the ability to adapt to variable conditions. This process of adaptation can involve changes in cellular size, number or type.

Cellular adaptation (see Figure 1.1)

1. Atrophy • Decrease in size of a cell or tissue. • Decreased size results in decreased oxygen consumption and met-

abolic needs of the cells and may increase the overall efficiency of cell function.

• Atrophy is generally a reversible process, except for atrophy caused by loss of nervous innervation to a tissue.

• Causes of atrophy include prolonged bed rest, disuse of limbs or tissue, poor tissue nutrition and ischemia.

2. Hypertrophy • Increase in cell size and tissue mass. • Occurs when a cell or tissue is exposed to an increased workload. • Occurs in tissues that cannot increase cell number as an adaptive

response. • Hypertrophy may be a normal physiologic response, such as

the increase in muscle mass that is seen with exercise, or it may

Figure 1.1

Adaptive changes in cells.

Atrophy

Metaplasia

Hypertrophy

Dysplasia

Hyperplasia

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4 Essentials of Pathophysiology for Pharmacy

be pathologic as in the case of the cardiac hypertrophy that is seen with prolonged hypertension. Hypertrophy may also be a compensatory process. When one kidney is removed, for exam- ple, the remaining kidney hypertrophies to increase its func- tional capacity.

3. Hyperplasia • Increase in the number of cells in an organ or tissue. • Can only occur in cells capable of mitosis (therefore, not muscle

or nerve cells). • Hyperplasia may be a normal process, as in the breast and uterine

hyperplasia that occurs during pregnancy, or pathologic such as the gingival hyperplasia (overgrowth of gum tissues) that may be seen in certain patients receiving the drug phenytoin.

1

As with hypertrophy, hyperplasia may also be a compensatory mech- anism. For example, when a portion of the liver is surgically removed, the remaining hepatocytes (liver cells) increase in num- ber to preserve the functional capacity of the liver.

4. Metaplasia • The conversion of one cell type to another cell type that might

have a better chance of survival under certain circumstances. • Metaplasia usually occurs in response to chronic irritation or in-

flammation. • An example of metaplasia occurs in the respiratory passages of

chronic cigarette smokers. Following years of exposure to irritat- ing cigarette smoke, the ciliated columnar epithelium lining the respiratory passages gradually converts to stratified squamous epithelium. Although the stratified squamous cells may be better able to survive the constant irritation of cigarette smoke, they lack the cilia of the columnar epithelial cells that are necessary for clearing particulates from the surfaces of the respiratory passages.

5. Dysplasia • A derangement of cell growth that leads to tissues with cells of

varying size, shape and appearance. • Generally occurs in response to chronic irritation and inflammation. • Dysplasia may be a strong precursor to cancer in certain instances

such as in the cervix or respiratory tract.

Cellular injury

Cellular injury can occur in a number of different ways. The extent of injury that cells experience is often related to the intensity and duration of exposure to the injurious event or substance. Cellular injury may be a reversible process, in which case the cells can recover their normal function, or it may be irreversible and lead to cell death. Although the causes of cellular injury are many (see Table 1.1), the underlying mechanisms of cellular injury usu- ally fall into one of two categories:

free radical injury

or

hypoxic injury

.

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Chapter one: Cellular injury 5

Free radical injury

• Free radicals are highly reactive chemical species that have one or more unpaired electrons in their outer shell.

• Examples of free radicals include

superoxide

(O

2

−),

hydroxyl radicals

(OH

−) and

hydrogen peroxide

(H

2

O

2

). • Free radicals are generated as by-products of normal cell metabolism

and are inactivated by free radical–scavenging enzymes within the body such as

catalase

and

glutathione peroxidase

. When excess free radicals are formed from exogenous sources or the free radical pro- tective mechanisms fail, injury to cells can occur.

• Free radicals are highly reactive and can injure cells through: 1. Peroxidation of membrane lipids 2. Damage of cellular proteins 3. Mutation of cellular DNA

• Exogenous sources of free radicals include tobacco smoke, organic solvents, pollutants, radiation and pesticides.

• Free radical injury has been implicated as playing a key role in the normal aging process as well as in a number of disease states such as diabetes mellitus, cancer, atheroscelrosis, Alzheimer’s disease and rheumatoid arthritis.

2,3

Hypoxic cell injury

• Hypoxia is a lack of oxygen in cells and tissues that generally results from ischemia.

• During periods of hypoxia, aerobic metabolism of the cells begins to fail. This loss of aerobic metabolism leads to dramatic decreases in energy production (ATP) within the cells. Hypoxic cells begin to swell

Table 1.1

Classification of Cellular Injury

Physical injury Mechanical trauma Temperature extremes (burn injury, frostbite) Electrical current

Chemical injury Chemicals, toxins, heavy metals, solvents, smoke, pollutants, drugs, gases

Radiation injury Ionizing radiation — gamma rays, X rays Non-ionizing radiation — microwaves, infrared, laser

Biologic agents Bacteria, viruses, parasites

Nutritional injury Malnutrition Obesity

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6 Essentials of Pathophysiology for Pharmacy

as energy-driven processes (such as ATP-driven ion pumps) begin to fail. The pH of the extracellular environment begins to decrease as waste products (such as lactic acid, a product of anaerobic metabo- lism) begin to accumulate. The cellular injury process may be revers- ible, if oxygen is quickly restored, or irreversible and lead to cell death. Certain tissues such as the brain are particularly sensitive to hypoxic injury. Death of brain tissues can occur only 4 to 6 minutes after hypoxia begins.

• The loss of ionic balance in hypoxic cells can also lead to the accu- mulation of intracellular calcium, which is normally closely regulated within cells. There are a number of

calcium-dependent

protease

enzymes present within cells that become activated in the presence of excess calcium and begin to digest important cellular constituents.

Manifestations of cellular injury

1. Cellular swelling • Caused by an accumulation of water due to the failure of energy-

driven ion pumps. Breakdown of cell membrane integrity and accumulation of cellular electrolytes may also occur.

• Cellular swelling is considered to be a reversible change. 2. Cellular accumulations

• In addition to water, injured cells can accumulate a number of different substances as metabolism and transport processes begin to fail.

• Substances that can be accumulated in injured cells may include fats, proteins, glycogen, calcium, uric acid and certain pigments such as melanin.

• These accumulations are generally reversible but can indicate a greater degree of cellular injury. Accumulation of these substances can be so marked that enlargement of a tissue or organ may occur (for example, fatty accumulation in an injured liver).

Cell death

Cell death falls into two main categories:

apoptosis

and

necrotic cell death

.

Apoptosis

• A controlled, “preprogrammed” cell death that occurs with aging and normal wear and tear of the cell.

• Apoptosis may be a mechanism to eliminate worn-out or genetically damaged cells. Certain viral infections (the Epstein–Barr virus, for example) may activate apoptosis within an infected cell, thus killing both the host cell and infecting virus.

TX366_book Page 6 Friday, July 12, 2002 1:00 PM

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