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Comprehensive Dermatologic
Drug Therapy
FOURTH EDITION
Stephen E. Wolverton, MD
Theodore Arlook Professor of Clinical Dermatology
Department of Dermatology
Indiana University School of Medicine
Indianapolis, Indiana, USA
Associate Editor
Jashin J. Wu, MD
Founder and Course Director
San Diego Dermatology Symposium
May 29-31, 2020;
Founder and CEO
Dermatology Research and Education Foundation
Irvine, California, USA
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
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Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Notice
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. Because of rapid advances
in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be
made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors, or con-
tributors for any injury and/or damage to persons or property as a matter of products liability, negligence
or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in
the material herein.
Printed in China
v
Contributors
vi
Contributors vii
This fourth edition of Comprehensive Dermatologic Drug Therapy Section 6—Drug interactions (20 questions)b
has been both a challenge and a joy to edit. The challenge has been Section 7—Miscellaneous issues (6 questions)
primarily in keeping up with the rapidly changing landscape of Appendix 2 The most potentially serious drug interactions con-
dermatologic therapy. The joy has been the continued refinement tains 35 categories of serious/potentially life-threatening drug
of an approach to summarizing vast quantities of information on interactions condensed from the almost 30 fully updated drug
dermatologic drugs in various formats that have been consistently interaction tables throughout this book.
popular with readers. This preface will include describing new
chapters, appendices, and special features to enhance learning and New features in this edition
retrieval of information in this book.
Counting the original book, Systemic Drugs for Skin Diseases, • Drug Risks Profile boxes—at a glance the reader can quickly
published in 1991, the contents have grown from 17 chapters to review a drug’s (a) Contraindications, (b) Boxed Warnings,
70 chapters in this fourth edition of Comprehensive Dermatologic (c) Warnings & Precautions, and (d) Pregnancy Prescribing
Drug Therapy. Status (both traditional ratings and our summation of 2015
US Food and Drug Administration updates)
New chapters in this edition • General updates—include (a) typically 2 to 4 new questions at
the beginning of each chapter, and (b) substantial updating of
Chapter 5 Medical decision- references in all chapters
making principles
Chapter 18 PDE-4 inhibitors apremilast, tofacitinib Traditional features continued in this edition
and JAK inhibitors
Chapter 28 IL 17 inhibitors secukinumab, ixeki-
• Monitoring guidelines boxes: This feature has been a long-term
zumab, brodalumab
favorite for clinicians
• Drug interactions tables: These fully updated tables are derived
Chapter 29 IL 23 inhibitors guselkumab, tildraki-
from Facts and Comparisons e-answers and Hansten and Horn’s
zumab, risankizumab
Top 100 Drug Interactions databases, formatted in a new fash-
Chapter 31 Other biologic dupilumab, omalizum- ion with interactions listed with overall descending order of
agents ab, newer agents risk
Chapter 38 Hedgehog inhibitors vismodegib, sonidegib • Drug structures
• Drug mechanism flow diagrams
• Key pharmacology concepts
New appendices in this edition • Adverse effects boxes
Appendix 1 Core questionsa for understanding systemic derma- … and many other features continued from prior book
tology drugs (“Review test”) editions!
Section 1—Pharmacology basic science (67 questions) Enjoy the learning and information retrieval process!
Section 2—Clinical use (75 questions)
Section 3—Severe adverse effects (61 questions) Stephen E. Wolverton, MD (Senior Editor, SEW)
Section 4—Less serious adverse effects (24 questions) Jashin J. Wu, MD (Associate Editor, JJW)
Section 5—Drug safety monitoring (27 questions)
a280 open-ended high-yield questions selected from the roughly 800 ques-
tions at the beginning of each chapter, many of which have 2 to 4 components
to the questions. Each question lists the book page number(s) for the answer.
bSee also Appendix 2 for the highest-risk drug interactions
xiii
Acknowledgments
We would like to sincerely thank and applaud the following indi- Lockshin, Lawrence Mark, Ginat Mirowski, Sahand Rahnama,
viduals for their energetic and kind support of our journey through Elizabeth Rancour, Kaitlin Schiavo, Michael Sheehan, Ally-Khan
the book development and editorial process for the fourth edition Somani, and Najwa Somani.
of Comprehensive Dermatologic Drug Therapy. We are indebted to
all of you for your time and expertise. To the ‘States’ and the World (the authors)
I am very grateful for the expert assistance from my Associate
Editor Jashin J. Wu, MD. Jay was the primary editor for 12 chap- The 128 authors for this edition responded very, very well to the
ters including all but one of the six new chapters. Jay’s extensive task of updating earlier chapters and creating totally new ones.
experience in clinical trials was of great value! These authors responded in a superb fashion to the challenges
we set for them. In particular, we wish to highlight the following
To Elsevier individuals:
• The five authors who contributed to all five versions of the books
We are most grateful to the book Acquisitions Editors Char- I have edited (including the original title Systemic Drugs from
lotta Kryhl and Nancy Duffy, the Senior Content Development Skin Diseases, 1991 edition): Jeff Callen, Charles Camisa, Loree
Specialists Humayra Khan and Rae Robertson and the Project Davis, Marshall Kapp, and Carol Kulp-Shorten.
Manager Beula Christopher. These individuals have been remark- • The international cast of 12 authors from Canada and Europe:
able in the author communications, attention to detail in editing, Stewart Adams, Robert Bissonnette, Tobias Goerge, Aditya
and accommodating to our planning strategies and subsequent Gupta, Sandra Knowles, Thomas Luger, Christian Murray,
adjustments. Jaggi Rao, Lori Shapiro, Neil Shear, Nowell Solish, and Math-
Thanks to Elsevier for the broader role in oversight from the ias Sulk.
beginning of book development through marketing the final • The senior authors who contributed to two chapters: Jeff Cal-
product. len, Charles Camisa, Seth Forman, Melanie Kingsley, John
Koo, Megan Landis, Ben Lockshin, Kiran Motaparthi, Kather-
ine Roy, and Neil Shear.
To the Indiana University Department of Thanks to all remaining authors who took time away from
Dermatology their full-time roles as clinicians and educators, while providing
fresh ideas along with tremendous personal experience and exper-
My colleagues (current and past) from Indiana University Depart- tise for the remaining chapters of this fourth edition of Compre-
ment of Dermatology who contributed chapters: Candace Brous- hensive Dermatologic Drug Therapy. We acknowledge the entire list
sard-Steinberg, Gabriella Duprat, Jeff Gehlhausen, Daniel Grove, of authors who spent countless of hours writing and editing their
Anita Haggstrom, Kate Hrynewicz, Michael Isaacs, Prasanthi chapters for this textbook.
Kandula, Swetha Kandula, Melanie Kingsley, Kathy Lee, Ben
xiv
PART I Introduction
1
Basic Principles of
Pharmacology
STEPHEN E. WOLVERTON
QUESTIONS
Q1.1 What are the simplest definitions of ‘pharmacokinetics’, Q1.7 What are several important examples of active drug and
‘pharmacodynamics’, and ‘pharmacogenetics’? (Pg. 1, Table 1.1) active metabolite relationships? (Pg. 7, Table 1.9)
Q1.2 What are several drugs or drug families for which the absorp- Q1.8 What are several of the most important examples of prodrug
tion may be altered by (1) food, (2) cations such as iron, calcium, and active drug relationships? (Pg. 8, Table 1.8)
and magnesium, and (3) variations in gastric pH? (Pg. 2) Q1.9 Pertaining to drug excretion, (1) what are three important
Q1.3 What are some of the pros and cons to the decision of routes of drug excretion, and (2) what is the overall general
whether to calculate drug dose on (1) actual body weight, change in the active drug properties that makes excretion
(2) ideal body weight? (Pg. 3) possible? (Pg. 8)
Q1.4 What are several examples in which sustained exposure to Q1.10 What are five of the most important basic components that
a drug may give reduced positive or negative pharmacologic determine percutaneous absorption of topical medications in
effects at the drug receptor level? (Pg. 4, Table 1.4) general? (Pg. 8)
Q1.5 What are several of the most important agonists and Q1.11 What are the some of the additional cutaneous properties
antagonists at the level of specific receptors? (Pg. 4, Table 1.5) and therapeutic maneuvers that alter the degree of percutane-
Q1.6 What are several of the most important examples in which ous absorption in individual patients? (Pg. 9, Table 1.10)
drugs inhibit specific enzymes? (Pg. 6, Table 1.6)
Introduction of this chapter (and for the rest of the book) is to describe and
illustrate pharmacologic principles that will enable the clinician
This chapter is a relatively brief overview of basic principles of to maximize the efficacy and minimize the risk (adverse effects
pharmacology, intended as a primer to maximize understand- [AE], drug interactions) of dermatologic drug therapy. It is my
ing of the remaining chapters of the book. There is by design hope that this chapter will provide a broad foundation for true
some overlap with other chapters in the book, in order to address understanding of pharmacology to enable clinicians to achieve:
relevant issues from a number of vantage points. Of particular 1. More efficient assimilation of new information on medica-
relevance to this chapter are the following: Chapter 2 Principles tions;
for Maximizing the Safety of Dermatologic Drug Therapy; Chap- 2. Adaptability to the many unpredictable responses of patients
ter 62 Hepatotoxicity of Dermatologic Drug Therapy (contains to medications;
detailed information on hepatic metabolism of drugs); and Chap- 3. Better long-term retention of important information on all
ter 66 Drug Interactions. The reader is encouraged to pursue fur- aspects of drug therapy.
ther detailed information and references (cited in the respective
chapters for specific drugs) for drug examples used to illustrate
basic principles of pharmacology in this chapter. In this chapter,
Outline for the Chapter
only a bibliography format for references on pharmacologic gen- Q1.1 Traditionally, discussions on basic pharmacology divide
eral principles is used. the topic into two domains (Table 1.1): pharmacokinetics (what
The primary focus of this chapter will be on pharmacologic the body does to the drug) and pharmacodynamics (what the drug
principles related to systemic drugs. A relatively brief section on does to the body). As a relatively novel way of presenting this
percutaneous absorption will conclude the chapter. The basic goal information, I will discuss topics in sequence as seen through the
1
2 PA RT I Introduction
TABLE TABLE
1.1 Three ‘Entry Level’ Definitions 1.2 Pharmacokinetics—Major Components
TABLE
1.3 Definitions and Concepts Central to Understanding Pharmacokinetics
Term Definition
Bioactivation Either (1) conversion of prodrug to any active drug, or (2) conversion of the active drug to a reactive, electrophilic meta-
bolic intermediate
Bioequivalencea Generally referring to overall ‘equal’ bioavailability between two comparable drugs; usually between generic and trade
name formulations of a drug
Biotransformation In general, the metabolic change of a lipophilic drug to a more hydrophilic metabolite allowing renal or biliary excretion
Blood–brain barrier Protective mechanism for brain neurons; due to tight junctions (and lack of intercellular pores) in brain capillaries; highly
lipophilic drugs may ‘overcome’ this barrier
Detoxification The metabolic conversion of a reactive, electrophilic intermediate to a more stable, usually more hydrophilic compound
Enteral GI administration of a drug
Enterohepatic recirculation Sequence of initial GI absorption of drug followed by hepatic excretion into bile and small bowel, followed by subsequent
GI reabsorption
First-pass effect Drugs which have significant metabolism in the liver, before widespread systemic distribution—occurs after GI absorp-
tion, by way of portal vein to liver
Half-life Duration of time for 50% of the absorbed and bioavailable drug to be metabolized and excreted
Parenteral Literally ‘around enteral’; either intravenous, intramuscular, or subcutaneous administration
Pharmacogenetics The inherited aspects of drug pharmacokinetics and pharmacodynamics which alter the likelihood of various pharmaco-
logic effects (positive or negative)
Prodrug A pharmacologically inactive precursor of the biologically active ‘drug’
Steady state A balance between the amount of drug being absorbed and the amount being excreted; in general the time to reach
steady state is four to five ‘half-lives’
Terminal elimination Elimination/clearance of drug from all body compartments to which the drug is distributed
Therapeutic index The ratio of (1) the drug dose required to give a desired pharmacologic response, to (2) the drug dose that leads to
significant adverse effects
Therapeutic range Range of circulating drug levels deemed to give optimal efficacy and minimal adverse effects
Tissue reservoirs Body locations to which a given drug is distributed, from which the drug is very slowly released—includes sites such as
fatty tissues, stratum corneum
aThe US Food and Drug Administration definition for ‘bioequivalence’ requires that the bioavailability of the proposed generic drug must have a 95% confidence interval between 80% and 120% of the
trade name drug’s bioavailability.
GI, Gastrointestinal.
Fortunately, there are alternatives to the above drugs that do perhaps allowing for a small ‘fudge factor’ on the high side for
not readily cross the blood–brain barrier (second-generation H1 very heavy patients who do not respond to traditional doses.
antihistamines; doxycycline, tetracycline). One set of formulas from the life insurance industry for calculat-
Q1.3 Many systemic drugs discussed in this book have dos- ing ‘ideal weight’ is as follows: (1) females IBW = 100 lb for 5 ft
ages based on body weight. Included are drugs with doses calcu- tall + 5 lb/inch over 5 ft, and (2) males IBW = 106 lb for 5 ft tall
lated per kilogram of body weight (isotretinoin, etretinate) and + 6 lb/inch over 5 ft, and (3) an upward ‘adjustment’ up to 10%
dose calculated per meter squared (bexarotene—Targretin). The based on a ‘large frame.’
question arises as to what to do with dosage calculations for very Conceptually, there are three drug ‘reservoirs’ of significant
obese patients. There are both drug cost implications and poten- interest to dermatology. The first is in systemic circulation, in the
tial AE implications for very high drug doses. I tend to calculate form of drug-protein binding. The bound drug is pharmacologi-
dosages based more on ‘ideal weight’ for several reasons. Aside cally inactive, whereas the unbound drug = free drug = pharmaco-
from treatment of panniculitis, there are virtually no indications logically active drug. Acidic drugs are most commonly bound to
for which the site of desired pharmacologic effect is in fatty tis- albumin, whereas basic drugs bind preferentially to α-1 acidic gly-
sue. Highly lipid-soluble drugs are readily distributed to fatty coprotein. There are noteworthy exceptions regarding lipophilic
tissues, but when a steady state is reached, there is steady release drugs with intracellular physiologic receptor–effector systems
back into the circulation. When considering efficacy, risk, and such as corticosteroids (CS) and retinoids. There is a large circula-
cost, all three point toward maximizing the dosage using cal- tory reservoir for highly protein-bound drugs such as methotrex-
culations based on ideal (or close to ideal) body weight (IBW), ate. Sudden increases in the free drug levels due to displacement
4 PA RT I Introduction
TABLE
1.4 Definitions and Concepts Central to Understanding Pharmacodynamics
Term Definition
Active metabolite A drug metabolite which retains the same/similar pharmacologic properties as the parent drug
Affinity (binding) A physical measurement which reflects the attraction of the drug ligand to a given receptor molecule
Agonist Drug which binds to a given receptor initiating an effector mechanism → pharmacologic response
Antagonist Drug which binds to a receptor, but fails to activate the effector mechanism
Cross tolerance (see Tolerance) Reduced pharmacologic effect when exposed to a new, chemically related drug
Downregulation Reduced receptors number/availability, presumably due to a negative feedback mechanism
Inverse agonist Drug which stabilizes receptors which have some constitutive activity to an inactive conformation
Ligand Any molecule (drug) which binds to the drug receptor; binding can be by hydrogen bonds, ionic forces, or covalent forces
Partial agonist Drug which binds to a receptor and weakly initiates an effector mechanism and resultant response
Receptor The molecule to which the drug (ligand) binds to initiate its effector response; location can be cell membrane, cytosolic, or
intranuclear
Refractoriness (synonyms—desensitization, tachyphylaxis) Temporary lack of responsiveness to a drug, subsequent to prior drug efficacy
Second messenger Biochemical mediator (commonly calcium or cyclic adenosine monophosphate) that serves to relay the signal initiated by the
receptor/effector in signal transduction
Signal transduction Cellular biochemical pathways which relays a second messenger ‘signal’ from the receptor to the effector mechanism
Tachyphylaxis A diminished pharmacologic response after repeated drug administration; can be due to down regulation or receptor seques-
tration (transiently ‘unavailable’ to the drug)
Tolerance Diminished effect (generally adverse effect) after repeated drug administration (most common is tolerance to sedating drugs
such as antihistamines)
TABLE
1.5 Pharmacodynamics—Selected Receptor Antagonists and Agonists
Retinoids Retinoic acid receptor (RAR) Augment various vitamin A-mediated effects via gene response ele-
Retinoid X receptor (RXR) ments
aPrimary pharmacologic (diuretic) effects of spironolactone are mediated through the mineralocorticoid receptor; antiandrogen effects are mediated via the androgen receptor for dihydrotestosterone and
testosterone.
6 PA RT I Introduction
as doxepin) and first-generation H1 antihistamines (such as nucleotide synthesis have significant potential for use in neoplastic
diphenhydramine, hydroxyzine) to also bind muscarinic anti- diseases or as immunosuppressants in autoimmune dermatoses.
cholinergic receptors can produce objectionable anticholinergic A number of drugs representing antimicrobial agents for bacte-
AE such as dry mouth, blurred vision, and orthostatic hypo- rial, viral, and fungal infections capitalize on vital enzyme systems,
tension. Relatively selective drug receptor binding was achieved which are more readily inhibited in the infectious organism than
in later ‘generations’ of related drug groups. Selective serotonin in the human host. Finally, a number of drugs inhibit enzyme
reuptake inhibitors (such as fluoxetine, sertraline) and second- systems that contribute important downstream mediators to an
generation H1 antihistamines (such as fexofenadine, loratadine) inflammatory response. For all three categories of enzyme listed in
have had a significant improvement in the AE profile due to this table, the drug receptor may be the enzyme itself (methotrex-
much more selective drug receptor binding. It is of interest to ate and DHFR) or may work indirectly through another receptor/
note that ‘tolerance’ to the sedative AE can occur with prolonged effector mechanism (as with CS inhibition of phospholipase A2,
use of the first-generation H1 antihistamines. probably mediated through lipomodulin-1).
TABLE
1.6 Pharmacodynamics—Selected Examples of Enzymes that Specific Drugs Inhibit
drug-initiated signal or message to the definitive effector mecha- reactions) and phase II (conjugation and detoxification reac-
nism. Tremendous details on the various receptor/signal transduc- tions). The initial oxidation reactions in phase I are accomplished
tion categories (six main families) are beyond the scope of this by various CYP isoforms, which are largely present in the liver
chapter but are available in the Bibliography. This definitive effector (but also available in many other organ sites, including the skin
mechanism is commonly accomplished through deoxyribonucleic and GI tract). The result of these enzymes is a somewhat more
acid (DNA) transcription and subsequent new protein translation. hydrophilic (water-soluble) metabolite, which may provide a site
In many cases the signal transduction ‘passes through’ a DNA tran- of attachment for subsequent conjugation reactions. To compli-
scription factor. This sequence and the resultant overlap of topics cate matters, reactive electrophilic intermediates are often created,
is best illustrated by the so-called ‘signal one’ in activated T-cells which in the absence of adequate phase II detoxification systems
upon T-cell receptor binding to antigen, which is amplified by may induce important metabolic or immunologic complications
subsequent IL-2 binding to the IL-2 receptor. The rough sequence (Table 1.7). Phase II conjugation reactions (glucuronidation, sul-
of steps is as follows: (1) T-cell receptor binding to antigen, fonation, acetylation) and the various detoxification systems (such
(2) CD3 molecule-based T-cell activation, and (3) calcineurin- as glutathione and epoxide hydrolase) will generally accomplish
based production of nuclear factor activated T-cell 1 (NFAT-1), a the production of both significantly increased hydrophilicity of
DNA transcription factor important to IL-2 upregulation. Cyclo- the drug metabolites and stabilization of the aforementioned
sporine and tacrolimus both interfere with this signal transduction reactive intermediates, respectively. Q1.7 It is important to note
pathway through inhibition of calcineurin activity, with a resultant here that many drug metabolites retain the parent drug’s pharma-
decrease in activity of the transcription factor NFAT-1. cologic activity (Table 1.8). An example of this principle would
Second messengers are also important to this discussion. be the itraconazole metabolite hydroxyitraconazole, which also
Probably the two most important second messengers pertinent has significant antifungal activity. In the great majority of drugs
to pharmacology are calcium and cyclic adenosine monophos- metabolism renders the drug inactive.
phate (cAMP). Calcium is an important component of the above The topic of pharmacogenetics largely addresses genetically
T-cell signal transduction system in two locations; calcineurin is based variations in the above metabolic enzyme systems. At times,
a calcium-dependent enzyme, with a calcium-binding protein these genetic alterations can explain idiosyncratic AE of medica-
(calmodulin) playing an important role as well. Although not tions. Examples pertinent to the above phase I and phase II meta-
directly related to dermatology, the role of cAMP as a second mes- bolic systems include the following genetic polymorphisms:
senger in the beneficial effects of β-agonists in therapy of asthma 1. CYP2D6 polymorphisms with at least 50-fold variation in the
is of interest. The concept of tachyphylaxis as defined in Table 1.4 activity of this important isoform: One result is unexpected
has been well characterized for β-agonists used in this setting. profound sedation from various antidepressants (including
Two more examples of important drugs and their effects on doxepin) and other sedating medications in ‘poor metabolizers.’
signal transduction (retinoids) and transcription factors (CS) can 2. ‘Slow acetylators’: One result of this polymorphism is more
be presented. The polyamine pathway creates a process known frequent occurrence of drug-induced lupus erythematosus.
as inflammatory hyperplasia, which is an important component
of the pathogenesis of both psoriasis and various malignancies.
Retinoids inhibit the activity of ornithine decarboxylase, the rate-
limiting enzyme in the polyamine pathway. This signal transduc-
TABLE
tion enzyme inhibition is important to the benefits of systemic Definitions Related to Adverse Effects
1.7
retinoids in both psoriasis therapy and retinoid chemoprevention
of cutaneous malignancies in solid organ transplantation patients. Term Definition
CS inhibit the actions of the transcription factor, nuclear
factor κB (NFκB) by two mechanisms. CS both increase pro- Adverse effect Negative or undesirable effect from a drug
(either at toxic or pharmacologic drug doses)
duction of the inhibitor of NFκB (known as IκB) and directly
bind to and inactivate NFκB. This transcription factor is piv- Idiosyncratic Unexpected adverse effect from a drug
otal in the upregulation of a multitude of cytokines of central
Immunologic Unexpected adverse effect from a drug occur-
importance in the inflammatory response to a wide variety of idiosyncrasy ring on an immunologic basis (usually due to
stimuli. There is tremendous amplification potential of the hypersensitivity)a
inflammatory response through this NFκB pathway. Likewise, a
major portion of the anti-inflammatory benefits of CS (topical Metabolic idio- Unexpected adverse effect from a drug occur-
or systemic) are probably accomplished through the inhibition syncrasy ring due to a metabolic byproduct (reactive
intermediate)
of this important transcription factor. It is unclear whether the
relatively common occurrence of tachyphylaxis noted with class Pharmacologic Positive or negative effect from a drug,
I topical CS relates to downregulation of receptors involved in effect expected at normal doses and/or drug levels
this particular pathway. Side effect Synonym for adverse effect (prefer to use
‘adverse effect’ to address undesirable qual-
Pharmacokinetics—Part II ity of drug effect)
TABLE Some Examples of Prodrugs Important to TABLE Some Examples of Active Drug, Active
1.8 Dermatology 1.9 Metabolite Relationships
Prodrug Active Drug Active Drug Active Metabolite(S)
Antiviral Agents Antihistamines
Valacyclovir Acyclovir Hydroxyzine Cetirizine → levo-cetirizine
Famciclovir Penciclovir Loratadine Desloratadine
Corticosteroids Antidepressants
Prednisone Prednisolone Doxepin Nordoxepin
Cortisone Hydrocortisone (cortisol) Citalopram Escitalopram
TABLE
1.10 Percutaneous Absorption Variables
Other Variables
Additional skin hydration Hydrating skin (by various means) before application of topical medication will ↑ PCA
Occlusion of medication Topical occlusion locally (food wrap) or widespread (‘sauna suit’) with marked ↑ PCA; conceptually transdermal applica-
tion of ‘systemic medications’ utilizes somewhat similar process
Age of patient Increased total body surface area to body volume ratio in infants and young children; therefore, increased risk of sys-
temic effects from topical therapy due to relatively high absorptive surface
determinants of percutaneous absorption of topical dermatologic CS. For a short period of time there will be relatively few trade-
products are: offs. After 2 to 3 weeks or more, important systemic AE such as
1. Stratum corneum thickness and integrity of ‘barrier function’; weight gain, fluid retention, hypertension, hypokalemia, leuko-
2. Drug partition coefficient—the ability of the drug to ‘depart cytosis, and cushingoid changes are all possible with this unde-
from’ the specific vehicle and enter the stratum corneum; sirable long-term approach to topical CS administration. It is
3. Drug diffusion coefficient—the ability of the drug (due to important to note here that all topical drug absorption occurs
innate molecular properties) to penetrate through all layers of via passive diffusion.
skin once in the stratum corneum; Topical medications applied in several clinical settings can
4. Drug concentration—the specific drug concentration of a produce immediate hypersensitivity (Coombs-Gell type I) reac-
given topical product; and, tions. In particular, topical application to ulcerated skin can give
5. Superficial dermal vascular plexus—site of systemic absorption the applied medication almost immediate access to systemic
for topically applied drugs. circulation. There have been reports of anaphylaxis to topical
Q1.11 Measures that increase percutaneous absorption can bacitracin or neomycin in this setting. Likewise, mucosal appli-
always be considered a ‘two-edged sword.’ The desired pharma- cations of medications (such as eyedrops, vaginal suppositories,
cologic result is enhanced by these measures. For instance, use and rectal foam or suppositories) can result in significant sys-
of a high-potency topical CS in an ointment base, after skin temic levels of various drugs and freedom from ‘first-pass effect’
hydration, and with total body occlusion will do wonders for due to the small intestine and liver. Although the risk from
extensive psoriasis. The counterpoint is that all of these measures topical application of medications to these above sites is usually
will markedly increase systemic absorption of the topical CS, small, the clinician should always be mindful of this systemic
potentially giving a net prednisone-like effect from the topical absorption potential.
10 PA RT I Introduction
TABLE
1.11 Clinical Comparisons of Various Vehicles—Generalities
Patient preference Often dislike greasiness High rate patient accep- Variable High rate patient
tance acceptance
vehicle to the optimal clinical response. Each chapter in the three Gonzales FJ, Coughtrie M, Tukey RH. Drug metabolism. In: Brunton
major book sections on topical medications (Chapters 41–57) LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s The
will expand on and illustrate these principles of percutaneous Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw Hill;
absorption. 2011:123–143.
Relling MV, Giacomina KM. Pharmacogenetics. In: Brunton LL, Chab-
ner BA, Knollman BC, eds. Goodman and Gilman’s The Pharmacologic
Bibliography: Important Reviews and Chapters Basis of Therapeutics. 12th ed. New York: McGraw Hill; 2011:145–
168.
Systemic drugs Percutaneous Absorption
Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorp- Burkhart C, Morell D, Goldsmith L. Dermatogic pharmacology. In:
tion, distribution, metabolism, and elimination. In: Brunton LL, Brunton LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s
Chabner BA, Knollman BC, eds. Goodman and Gilman’s The Phar- The Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw
macologic Basis of Therapeutics. 12th ed. New York: McGraw Hill; Hill; 2011:1803–1832.
2011:17–39.
Blumenthal DK, Garrison JC. Pharmacodynamics: molecular mecha-
nisms of drug action. In: Brunton LL, Chabner BA, Knollman BC,
eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics.
12th ed. New York: McGraw Hill; 2011:41–72.
2
Principles for Maximizing
the Safety of Dermatologic
Drug Therapy
STEPHEN E. WOLVERTON
QUESTIONS
Q2.1 What four words characterize the overall approach to Q2.7 When considering a ‘teamwork’ approach to maximize drug
maximizing drug safety, and what general concepts are safety, name at least five different ‘individuals’ with a key role in
represented by these words? (Pg. 12) this drug safety process for a given patient. (Pg. 17)
Q2.2 How are the ‘standards of care’ for drug therapy monitoring Q2.8 What are the most important common clinical scenarios
determined? (Pg. 13) which require more frequent (compared with normal
Q2.3 What are several of the typical characteristics of the most monitoring frequencies) laboratory monitoring? (Pg. 18)
worrisome adverse effects to systemic drug therapy (Pg. 13) Q2.9 What are some important examples of ‘thresholds of
Q2.4 In general, what are the most important issues to discuss concern’ and ‘critical values’ for laboratory tests commonly used
with a patient before initiating systemic drug therapy which has in drug monitoring (Table 2.1)? (Pg. 18)
a significant element of risk? (Pg. 14) Q2.10 What are several important clinical strategies available for a
Q2.5 What are three broad categories for mechanisms for drug specific abnormal lab value? (Pg. 18)
interactions which can assist clinicians in anticipating important Q2.11 In the event a potentially serious complication of drug
potential drug interactions? (Pg. 15) therapy does occur, what are some of the most important
Q2.6 What are three to four examples of major drug risks management options available to clinicians? (Pg. 19)
‘discovered’ many years after the drug’s release? (Pg. 15)
12
CHAPTER 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy 13
patients with more serious, possibly life-threatening, illnesses than the 3. no predictive laboratory tests;
majority of conditions for which dermatologists prescribe the various 4. potentially irreversible; and
systemic drugs. Clinicians in any field are obliged to avoid creating 5. a potentially serious outcome.
a greater risk with drug therapy than the innate risk (in that specific Examples of such high-priority AE include (1) hematologic
patient) of the underlying disease to be treated. This statement is the complications (pancytopenia from azathioprine or methotrexate,
underlying principle behind the need for careful monitoring of sys- agranulocytosis from dapsone), (2) isotretinoin teratogenesis, (3)
temic drug therapy in dermatology. It is essential to maximize the corticosteroid (CS) osteonecrosis, (4) opportunistic infections
safety and minimize the risk of this drug therapy. from tumor necrosis factor (TNF) inhibitors and other biologic
How to optimally anticipate, prevent, diagnose, and manage therapeutics, and progressive multifocal leukoencephalopathy
specific drug AE to maximize drug safety is a central theme of from rituximab and efalizumab (off the market). Principles to
this chapter and of the book as a whole. This is a broader view- minimize the likelihood of these and other complications follow
point than merely ‘monitoring’ for AE. The goals of this broader in the four major sections of this chapter.
approach are to (1) maximize overall drug safety for the patient, (2) First, a few ‘baseline concepts.’ No matter how careful a physi-
improve the ‘emotional comfort’ of systemic drug therapy for the cian may be, sooner or later ‘bad things’ will happen to a patient
patient and physician, and (3) follow the appropriate ‘standards from drug therapy that he or she initiates. No medical risk reduc-
of care’ to minimize medicolegal risk. These overlapping goals are tion system is perfect, given the unpredictabilities of the human
interdependent. For example, when appropriate standards of care body. If the patient and physician can form a strong therapeu-
are followed, the patient safety is the focus of these standards. In tic partnership, and if the physician continues to work with the
addition, when the patient’s safety and emotional comfort during patient to promptly diagnose and manage any drug-induced
drug therapy are truly of central importance to the physician, the complications, there can be a number of positive results: (1) the
medicolegal risk is negligible. This is particularly true if the patient patient’s medical outcome is optimized, (2) the physician’s ethical
assumes an active role in the decision making process for all aspects obligations are met, and (3) the medicolegal risk is minimized.
of any systemic drug therapy regimen, in turn forming a ‘therapeu- Nevertheless, the physician must take a ‘lifelong learner’ approach
tic partnership’ with the prescribing physician. to any such unexpected complications, carefully analyzing the
It is somewhat challenging to define the definitive sources of events leading to the specific drug complication, and learning how
these so-called ‘standards of care.’ Q2.2 In general, such stan- to minimize the likelihood of a similar therapeutic outcome in the
dards come from one or more of the following sources: future.
1. Specialty-based formal guidelines such as the American Acad- On the following pages of this chapter, 33 ‘principles,’ with
emy of Dermatology ‘Guidelines of Care’; over 90 specific drug therapy examples, are used to illustrate
2. Individual pharmaceutical company guidelines for specific the clinical approach for maximizing the safety of dermatologic
drugs, such as the therapeutic guidelines and informed consent drug therapy.
packet for isotretinoin (iPLEDGE) in women of childbearing
potential; Anticipation
3. The US Food and Drug Administration (FDA) Advisory Com-
mittee recommendations, such as those guidelines proposed in This section is broken down into five subsections: (1) patient selec-
the early 1980s for monitoring the hematologic complications tion, (2) patient education, (3) baseline laboratory and related
of dapsone; tests, (4) concomitant drug therapy—drug interactions, and
4. Consensus conference publications, such as the consensus (5) evolving guidelines—risk factors.
guidelines published in 2004 for isotretinoin therapy in acne
patients; and Patient Selection
5. ‘Dear Health Care Professional’ letters (formerly ‘Dear
Doctor’ letters) from pharmaceutical companies, with care- Principle #1. Carefully compare the ‘risk’ of the disease to be
ful oversight by the FDA, updating physicians and other treated with the ‘risk’ of the drug regimen planned (in that
health care providers nationally regarding recent findings particular patient); thus a ‘risk–risk’ assessment:
for specific AE. • The risk of high-dose systemic CS in severe pemphigus vul-
The reality is that the standards of care for a given drug are garis versus the risk from the same CS regimen in patients with
often a blend of several of these sources, with a certain amount of either pemphigus foliaceus or localized epidermolysis bullosa
ambiguity as would be expected from such a mix. acquisita.
Historically, these standards of care were based on local prac- • The risk of 6 to 12 months of cyclosporine for a patient with
tices in the ‘community’ in which the physician practiced. Cur- limited plaque-type psoriasis versus the risk of the same regi-
rently the realities of the ‘information age’ in which we practice men in a patient with debilitating and extensive pyoderma gan-
tend to create a trend towards national, if not global, standards grenosum.
of care. Such standards should be considered guidelines, and not • The risk of 1 to 2 weeks of cyclosporine for a patient with Ste-
mandates, with room for flexibility as the patient’s individual cir- vens-Johnson syndrome versus the risk of burn unit therapy.
cumstances, clinician’s experience, and scientific ‘evidence’ justify. • The risk of an interleukin IL-17 or IL-23 inhibitor in a patient
As far as possible, special efforts must always be made to ensure with severe psoriasis with components of metabolic syndrome
that the most serious adverse effects (SAE) ‘never’ occur. Q2.3 versus therapy with methotrexate or cyclosporine.
Characteristics of the most SAE given the highest priority in this
Principle #2. Choose patients who can comprehend and com-
chapter, and throughout the book, include at least several of the
ply with important instructions for preventing and monitor-
following:
ing the most serious potential complications of systemic drug
1. a sudden, precipitous onset;
therapy. Examples in which this principle is most important
2. no early warning symptoms;
include the following:
14 PA RT I Introduction
• The importance of avoiding abrupt cessation of long-term, what would a ‘reasonable patient’ want to know as a rough
high-dose prednisone therapy—risk of hypothalamo-pituitary guide.
axis (HPA) complications such as an addisonian crisis.
Principle #5. Use patient handouts, written at a very under-
• The pregnancy prevention measures which are of central
standable level, to reinforce important information and instruc-
importance in isotretinoin therapy for women of childbearing
tions concerning the drug therapy chosen:
potential.
• The physician must emphasize the key information contained
• The importance of avoiding significant amounts of alcohol
in the handout, but handouts are never a substitute for appro-
with long-term methotrexate therapy for severe psoriasis or in
priate physician-patient communication.
women of childbearing potential on long-term acitretin ther-
• The patient should be instructed to notify the physician if there
apy for psoriasis.
are any questions pertinent to the handout provided.
Principle #3. All patients are not ‘created equal’ regarding the risk • The patient should be instructed to report any significant new
for various AE. Examples of patients at significantly increased symptoms that may develop subsequently (even if they are not
risk for the following AE (beyond the specifics of the drug sure these symptoms are attributed to the specific drug).
regimen) include: • Sources for these handouts include National Psoriasis Founda-
• Methotrexate hepatotoxicity: obesity, alcohol abuse, diabetes tion (major systemic therapies for psoriasis, including biolog-
mellitus, renal insufficiency. ics), various pharmaceutical companies (acitretin/Soriatane),
• CS osteoporosis: postmenopausal women, especially those who the American Medical Association (CS and many others), and
are thin and inactive. various online sources. Consider creating your own personal-
• CS osteonecrosis: recent significant local trauma, alcohol ized patient education handouts regarding specific drugs you
abuse, cigarette smoking, and presence of underlying hyperco- commonly prescribe.
agulable conditions.
Principle #6. Educate your patients regarding groups or clus-
• TNF inhibitor use in patients with a personal or family history
ters of symptoms, which together are important for the detec-
of multiple sclerosis.
tion of potentially serious drug-induced complications. The
The bottom line is that individual patients must be carefully
grouping of these symptoms may not be emphasized in the
‘matched’ with the safest and most effective drug regimen for the
above-mentioned handouts:
unique presentation of their dermatosis. This ‘match’ hinges on
• CS osteonecrosis: focal, significant joint pain (especially hip,
the various risk factors and demographic variables with which a
knee, shoulder) with decreased range of motion of the affected
specific patient presents. Perhaps the best example is the lesson
joint.
provided by the specialty of rheumatology regarding the apparent
• Isotretinoin pseudotumor cerebri: headache, visual change,
lesser risk of methotrexate in rheumatoid arthritis (RA) patients
nausea, and vomiting.
compared with the historical risk of the same methotrexate ther-
• All current biologic therapeutics and opportunistic infections:
apy in psoriasis patients. This risk reduction was accomplished by
fever plus localizing symptoms such as a cough.
(1) more careful patient selection of patients by rheumatologists,
• Dapsone (or minocycline) hypersensitivity syndrome (DRESS):
and (2) by the much lower risk of ‘metabolic syndrome’ in RA
fever, fatigue, sore throat, adenopathy, and morbilliform eruption.
patients than in psoriasis patients.
A ‘two-way street’ of open communication between patient
and physician is essential in maximizing the safety of systemic
Patient Education drug therapy. Any extra time the physician spends in this com-
munication process should pay great dividends with regard to
The multiple variables regarding a given course of systemic drug
improved therapeutic outcomes.
therapy are often very difficult for physicians to master. Thus,
it should come as no surprise that the specific drug regimens
and risks of these various therapies discussed are much more Baseline Laboratory and Related Tests
difficult for patients (who typically lack medical training) to
Any organ system with potential for drug-induced complications
understand. Q2.4 The patient needs to understand at least the
requires a baseline evaluation before initiating therapy. There are
following information: (1) how to take the medication, specifi-
very few exceptions to this principle. It stands to reason that exist-
cally the correct dose and timing, (2) the expected AE, (3) what
ing pathology in an organ system, for which a given drug has the
symptoms to report, and (4) the specific monitoring using labora-
potential to induce abnormalities, will increase the likelihood of
tory and related diagnostic tests. Particularly when significant risks
further injury to this organ system.
to important organs or body systems are discussed, the under-
standable emotional reaction of most patients makes long-term Principle #7. Assess the baseline status of any potential target
retention very difficult. The above points and other concepts form organ or site of excretion for a given drug. Similarly, if a drug
the basis of the following principles. can induce a metabolic abnormality, check for baseline presence
of this metabolic defect if such testing is currently available:
Principle #4. Careful and reasonably thorough patient educa-
• Baseline liver function tests and hepatitis viral serology: metho-
tion is essential to truly ‘informed consent’ (see Chapter 68):
trexate hepatotoxicity (methotrexate ‘target’ organ) and with
• Patients need to be active participants in therapeutic decision-
the full spectrum of biologics.
making, which requires physicians to present the information
• Baseline renal function assessment; at least testing serum cre-
in an understandable fashion.
atinine, and possibly creatinine clearance: methotrexate hepa-
• In addition, the patient must be provided the opportunity to
totoxicity or pancytopenia (site of methotrexate excretion).
ask questions and be given adequate time to consider the thera-
• Baseline (at least in the first month) comprehensive eye exami-
peutic options presented.
nation, including visual fields, in patients to receive hydroxy-
• The ‘perpetual’ question of what risks need to be discussed dur-
chloroquine therapy.
ing informed consent always needs to be carefully considered;
CHAPTER 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy 15
• Baseline testing for hyperglycemia or hyperlipidemia: pred- • Azathioprine and allopurinol or febuxostat: increased risk for
nisone therapy (metabolic abnormalities aggravated by pred- hematologic complications, as these drugs affect parallel purine
nisone). metabolic pathways.
• Baseline testing for latent tuberculosis for all biologic therapeu-
Principle #11. Anticipate (and avoid) drug combinations metab-
tics regardless of the indication. The choice of tuberculosis test-
olized by the same cytochrome P-450 (CYP) pathway, particu-
ing method (tuberculin test or interferon-γ release assay such
larly if there is a narrow therapeutic index for one of the drugs
as T-spot TB or Quantiferon Gold) is not yet fully clarified.
involved:
Principle #8. Use the most optimal tests that predict which • Rifampin (CYP3A4 enzyme inducer) plus hormonal contra-
patients are at increased risk for a specific AE. Typically such ceptives: loss of efficacy of the contraceptive with the potential
tests are ordered only at baseline. (Ideally many more of these for an unintended pregnancy.
predictive tests will be available in the future.): • Ketoconazole or erythromycin (CYP3A4 enzyme inhibitors)
• Baseline glucose-6-phosphate dehydrogenase (G6PD) level: plus cyclosporine: increased risk for renal toxicity because of
predicts magnitude of risk for dapsone hemolysis. (This test increased cyclosporine blood levels.
does not predict which patients are at risk for dapsone agranu- This area of medicine is very complicated and it is very difficult
locytosis or dapsone hypersensitivity syndrome.) to stay ‘current’ (see Chapter 66). At times, recently released drugs
• Baseline thiopurine methyltransferase level: predicts risk for have important, potentially life-threatening interactions which are
azathioprine hematologic complications as well as guiding discovered only years later. The potential for torsades de pointes with
optimal azathioprine dosing. (This test does not predict azathi- life-threatening cardiac arrhythmias from terfenadine, astemizole, or
oprine hepatotoxicity or hypersensitivity syndrome reactions.) cisapride (elucidated several years after the drugs’ release) in the pres-
There are a few select tests for which a baseline determination ence of certain CYP enzyme inhibitors illustrates this point. Do your
is not required. Near the end of long-term high-dose prednisone best to stay current: liberally use the numerous electronic resources
therapy, a morning cortisol determination (usually ∼8:30 AM) for information on drug interactions. As a backup, use of your hos-
may be of value in assessing HPA function; a baseline determina- pital’s drug information pharmacists is highly recommended to
tion is virtually never indicated. Some tests may require a delayed more effectively deal with this challenging area of medicine.
baseline determination. I formerly requested a ‘delayed baseline’
ultrasound-guided liver biopsy for methotrexate patients after 6 to Evolving Guidelines—Risk Factors
12 months of therapy, once it is clear that the patient tolerates the
drug, benefits from the drug, and requires long-term methotrexate Typically, with the passage of time the magnitude of risk for vari-
therapy. In current practice, a fibroscan after 6 to 12 months of ous systemic drugs becomes clarified. The level of concern can
therapy is appropriate. Still, overall the general rule holds: if you go in one of two directions: over time there is either increased
plan on monitoring a specific test during therapy with a given concern or decreased concern about various risks subsequent upon
systemic drug, it is prudent to determine the baseline status of that the publication of new data. Furthermore, specific new risk factors
specific test. can be elucidated as new scientific information is reported.
Principle #12. Q2.6 Certain risks or risk factors for systemic
Concomitant Drug Therapy—Drug Interactions therapies may be discovered many years after a specific drug is
released. It is imperative to ‘stay tuned’ regarding standards of
Chapter 66 is devoted entirely to the subject of drug interac-
care, as discussed in the Introduction:
tions of importance to the dermatologist and other physicians
• Psoralen and Ultraviolet A (PUVA) therapy: an increased risk
using similar medications. However, a few principles must still
for squamous cell carcinoma of the male genitalia (specific risk
be addressed in this setting. The vast majority of drug interac-
factor—male gender, without clothing protection for the groin
tions can be anticipated, and thus prevented. Truly life-threat-
region during PUVA treatments).
ening drug interactions are quite uncommon and virtually
• PUVA-induced melanoma: probably an increased risk in patients
always have been well publicized. Q2.5 The following are
receiving more than 250 to 350 treatments over a lifetime (spe-
principles dealing with three categories of drug interactions of
cific risk factor—very large number of PUVA treatments).
central importance to maximizing the safety of systemic drug
• Minocycline drug reaction with eosinophils and systemic
therapy.
symptoms (DRESS) or minocycline-induced lupus erythema-
Principle #9. Anticipate (and avoid) drug combinations that tosus: the magnitude of risk for these complications was not
have overlapping target organs of potential toxicity: clarified until over a decade after the drug’s release.
• Tetracycline or minocycline plus isotretinoin: pseudotumor • Ketoconazole hepatotoxicity: magnitude of risk overall and
cerebri. potential for fatal outcomes were not clarified until several
• Hydroxychloroquine plus chloroquine: antimalarial retinopathy. years after the drug’s release.
(It is acceptable practice to combine quinacrine with either of these • Boxed warnings for tumor necrosis factor (TNF) inhibitors concern-
two drugs, as quinacrine alone does not induce a retinopathy.) ing ‘opportunistic’ (bacterial, fungal, and parasitic) infections were
• Methotrexate and a second-generation retinoid (previously expanded in the package insert many years after the drugs’ release.
etretinate, now acitretin): probably an increased risk for hepa-
Principle #13. In contrast, the perceived magnitude of risk for
totoxicity.
a particular AE may decrease over time as new scientific evi-
Principle #10. Anticipate interactions involving two drugs that dence accumulates:
alter the same metabolic pathway: • Antimalarial retinopathy: markedly lower risk than originally
• Methotrexate and trimethoprim/sulfamethoxazole: increased perceived, largely because of more careful antimalarial dosing
risk for pancytopenia, given that these drugs inhibit folate schemes, and perhaps also to greater use of hydroxychloro-
metabolism. quine rather than chloroquine.
16 PA RT I Introduction
• PUVA cataracts: primarily a risk in patients who fail to comply Principle #16. Use all reasonable adjunctive therapeutic mea-
with current regimens regarding Ultraviolet A (UVA)-protec- sures to minimize the risk of various AE:
tive wraparound sunglasses. • Daily folic acid therapy in patients receiving methotrexate:
• Prednisone bursts and osteonecrosis risk: although this issue prevention of gastrointestinal (GI) AE and minimization of
is still cloudy in the legal system, the scientific evidence ‘rules pancytopenia risk. (Ideally, folic acid should be used in all
against’ there being a true risk of this bone complication with methotrexate patients; the benefits easily outweigh the theo-
short courses (‘bursts’) of systemic CS. retical risk of loss of efficacy in psoriasis.)
• Calcium, vitamin D, and possibly estrogens, bisphosphonates,
Principle #14. In many clinical scenarios, physicians must
PTH analogs or nasal calcitonin: use in patients receiving long-
make decisions about measures to prevent important potential term systemic CS therapy at or above physiologic doses. (Use
drug risks before all necessary information is published con- a greater number of these preventative therapies in higher-risk
cerning whether there truly is an increased risk of a specific patients.)
complication:
• TNF inhibitors (etanercept, adalimumab, infliximab, certoli-
zumab) and IL-12/23, IL-17, and IL-23 inhibitors tuberculosis Timing of Risk and Medication Errors
(TB) risk: at least order a baseline purified protein derivative The prevention of many AE requires either heightened awareness
(PPD) or interferon-γ release assay such as T-spot TB (and with more frequent monitoring (drugs with a specific timing of
selectively order a chest x-ray in higher-risk patients or in posi- greatest risk) or careful patient education (for potentially serious
tivity with the above tests) before initiating therapy. medication errors). In either setting a proactive physician style is
• TNF inhibitors (etanercept, adalimumab, infliximab, cer- preferred to maximize safety.
tolizumab) and risk of demyelinating diseases: at least check
personal and family history closely for multiple sclerosis and Principle #17. For the most potentially SAE of systemic drugs,
related demyelinating disorders before initiating therapy. learn the timing of greatest risk for the drug-induced compli-
• Isotretinoin, apremilast, and brodalumab risk of suicide; in cation while monitoring the patient most carefully during this
each case all three drugs may at least induce severe depression period:
if patient baseline depression is present (even if population • Dapsone agranulocytosis or dapsone-induced DRESS is pri-
studies do not show a direct connection with these drugs and marily an issue between weeks 3 and 12 of therapy. (Minocy-
suicide). Avoid these drugs when moderate-severe depression cline-induced DRESS: timing of greatest risk is roughly in the
(or a history of same) is present. same interval, particularly in the first 2 months of therapy.)
As challenging as it may be, physicians are obliged to stay ‘cur- • Methotrexate or azathioprine pancytopenia: the risk is greatest
rent’ with the latest published information on the magnitude of primarily in the first 4 to 6 weeks of therapy, unless a drug inter-
risk from the drugs we use. Truly important ‘new risks’ tend to action is a precipitating factor later in the course of therapy.
be widely and repeatedly disseminated to physicians, with the so- • Prednisone osteonecrosis: the risk begins to increase substan-
called ‘Dear Health Care Professional’ letters from the FDA being tially by months 2 to 3 of pharmacologic dose CS therapy.
a common vehicle for the dissemination of such information. (This risk tends to parallel the overall development of cushin-
goid changes in the patient.)
Prevention • Timing of rituximab-induced expected CD20 marked reduc-
tion and recovery in pemphigus vulgaris therapy; the recovery
This section of the chapter will be divided into three subsections may help determine the optimal timing of a subsequent ritux-
as follows: (1) patient measures to reduce risks, (2) therapeutic imab course.
interventions to minimize drug risk, and (3) timing of risk and
Principle #18. Medication errors are largely preventable with
medication errors.
careful patient education and, if necessary, cross-checks on
potentially unreliable patients. These medication errors can be
Patient Measures to Reduce Risks caused by either dose omissions or dose duplications:
• Methotrexate weekly dosing scheme: the literature has many
Principle #15. Patients should take all reasonable protective
reports of pancytopenia caused by inadvertent daily dosing of
measures to prevent important AE:
methotrexate. If necessary, another caregiver or family member
• Prevention of squamous cell carcinoma of male genitalia caused
should place the drug in the slot for just one specific day each
by PUVA therapy: wearing a ‘jockstrap’ or underwear during a
week in a weekly pill container, particularly for older patients.
PUVA treatment.
• Hormonal contraceptives and isotretinoin or thalidomide:
• Prevention of cataracts in PUVA therapy: wearing opaque
pregnancy prevention is critical in women of childbear-
goggles during the PUVA treatment and wearing wraparound
ing potential. Omission of oral contraceptives for even a day
UVA-protective sunglasses when exposed to outdoor light, at
can lead to unintended pregnancy in women of childbearing
least until sundown the day of the PUVA treatment.
potential prescribed these potent teratogens.
Evolving Guidelines for Monitoring • Full skin examination for PUVA/NB-UVB (narrow-band
ultraviolet B) or patients on systemic immunosuppressive ther-
As discussed under the section ‘Anticipation’, newer scientific evi- apy: detection of melanoma, squamous cell carcinoma, and
dence commonly leads to new or revised guidelines for standards basal cell carcinoma (and precursors thereof ).
of care. As before, the level of concern can increase or decrease • Neurologic examination (screening style) for dapsone motor
over time with the release of this new scientific information. neuropathy or thalidomide sensory neuropathy: screening
Principle #19. Stay current with changing guidelines for diag- done by the prescribing physician, possibly verified by a con-
nosing important complications of systemic drug therapy at sultant.
an early, reversible stage: • Morbilliform eruption and related DRESS syndrome findings
• Methotrexate chest x-rays for pneumonitis: pneumonitis from caused by dapsone, minocycline, or azathioprine: reported by
methotrexate is a significant risk in RA patients. In contrast, the patient but verified by the prescribing physician.
the negligible risk for this complication in psoriasis patients led Principle #22. Comanagement with another consultant is com-
to elimination of a previous yearly requirement for chest X-rays monly an essential part of this ‘teamwork’ approach to maxi-
in more recent methotrexate guidelines. mizing the safety of systemic drug therapy:
• TNF inhibitors (etanercept, adalimumab, infliximab, cer- • Gastroenterologist: for recent trend of using fibroscans in
tolizumab) and subsequent biologics and tuberculin skin test detection of fatty liver or fibrosis in long-term methotrexate
or interferon-γ releasing assay (IGRA): the somewhat recent therapy.
overall resurgence in incidence of TB and the TNF-α role in • Ophthalmologist: integral part of monitoring guidelines for
stabilizing granulomatous responses leads to this guideline for PUVA and antimalarial therapy.
screening patients for TB before initiating therapy. • Primary physician: for management decisions regarding ele-
• There is inconsistent package insert requirements for follow-up of vated blood glucose or blood pressure with CS therapy or for
latent TB screening for all four subgroups of biologics for moder- management of hyperlipidemia in patients on long-term sys-
ate-severe psoriasis. A significant number of clinicians (including temic retinoid or cyclosporine therapy.
myself) have adopted yearly latent TB screening for all biologic
therapeutics (and most oral immunosuppressive agents).
Use of Optimal Diagnostic Tests
A Teamwork Approach for Maximizing the Safety Principle #23. Stay current regarding optimal diagnostic tests
of Drug Therapy that have improved sensitivity and precision for early diagno-
sis of important AE at a reversible stage:
Despite recent trends in managed care to fragment care and limit • CS osteonecrosis diagnosis: magnetic resonance imaging is far
access to various medical specialties in the name of cost savings, superior to conventional X-rays for early diagnosis, and can
a teamwork approach for risk reduction is imperative. Q2.7 A allow timely performance of core decompression to salvage the
‘team’ consisting of the prescribing physician, the patient (includ- affected bone or joint.
ing their family), and, in many cases, the patient’s primary physi- • CS osteoporosis diagnosis: dual-energy X-ray absorptiometry
cian or another specialist, is of central importance. In addition, (Dexascan) has much greater sensitivity than conventional
pharmacists and members of the physician’s office staff have key X-rays for early recognition of bone density loss.
roles in this team. Each member of the team has an important role • Methotrexate hepatotoxicity diagnosis: as discussed previously
in maximizing the safety of systemic drug therapy. with fibroscan largely replacing ultrasound-guided liver biopsies.
Principle #20. In addition to the importance of patient aware- Principle #24. Realize that many diagnostic tests provide com-
ness of reporting symptoms suggesting the early phases of plementary information for the clinician:
selected complications, the patient often has a role in home • Transaminase values and liver histology for methotrexate
monitoring for selected complications: hepatotoxicity: one method of testing (transaminases) assesses
• Cyclosporine or CS and hypertension: with a growing number hepatocellular toxicity, whereas the other method (liver biopsy/
of patients using home blood pressure cuffs or electronic blood histology) assesses the potential for slow progression from fatty
pressure monitoring devices, this is a relatively easy area of home liver changes to focal fibrosis to cirrhosis; both tests in combi-
surveillance for AE. The patient merely needs to be told what nation are essential for proper hepatic monitoring.
levels of blood pressure elevation should be reported to the pre- • Ordering both transaminases (SGOT/AST and SGPT/ALT) for
scribing physician and/or primary physician. detection of dapsone, azathioprine, and methotrexate hepatotoxic-
• CS and home glucose monitoring: even though the history of ity: improved sensitivity and specificity when ordering both tests;
diabetes mellitus should lead to careful scrutiny regarding the subsequently, tests for hepatobiliary obstruction (bilirubin, alka-
appropriateness of systemic CS, there are many circumstances line phosphatase, gamma-glutamyl transpeptidase) can be useful
in which prednisone therapy is essential in diabetic patients. adjuncts if significant transaminase elevation has already occurred.
Home glucose monitoring provides for relatively easy surveil-
lance and follow-up.
• CS and weight gain: the simple bathroom scale can provide Higher-Risk Scenarios
useful information on the progression of cushingoid changes or As discussed earlier, patients are not ‘all created equal’ when it
for signs of increasing fluid overload in patients with previously comes to risk factors for AE from systemic drug therapy. The
well-compensated congestive heart failure. more a physician knows about relatively high-risk clinical sce-
Principle #21. The prescribing physician’s examination is essen- narios (with corresponding increased surveillance for AE in these
tial for detection or verification of important early signs of settings), the more that physician can maximize the safety of the
various drug complications: drug therapy in that particular patient.
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wools crossed with Scotch—are on the Moor, and we'll ride out Sunday and
have a look at 'em. I'm buying pigs next week at a sale over to Holne. The
cows are a very fine lot indeed. We sell our milk to Ashburton and Totnes."
He proceeded amiably until the cows were lowing at the farmyard gate.
Then Maynard departed with Neddy Tutt to the milking, and Palk, who
would begin to plough the stubble on the following day, started alone to
walk round the yard and inspect the horses and machinery.
"A quiet couple of men," said Joe to his daughter, when they had gone;
"but I like the quiet ones. They save their wind for their work, which is
where it ought to be."
"Don't he? To my eye he's the wiry sort, that wear as well and better
than the mighty men. Don't you go axing him after his health whatever you
do. It often puts wrong ideas in their heads. We take health for granted. I'm
the only person in this house where health comes in I should hope."
"You'd best turn 'em on to the fern so soon as you can," answered Susan.
"Landlord was round again, when you were up over, seeing hounds meet at
eight o'clock last week."
"Yes, and he said he'd hoped to see the work begun, because it frets him
a lot that any land of his should go to rack. And he said that he'd have
thought one like you, with a name for high farming, would have hated it as
much as him."
"That's his cunning. The Honourable Childe's a very clever man, and I
respect him for it. He knows me and I know him. The field will be as clean
as a new pin before Christmas, I shouldn't wonder."
"You won't get your regular box of cigars from the man if it ain't, I
expect."
"Oh yes, I shall. He's large-minded. He knows his luck. I like him very
well, for he sees the amusing side of things."
"What a damper you are, Soosie-Toosie! Was ever the like? You always
take the dark view and be grim as a ghost under the ups and downs of life.
If you'd only copy me there. But 'tis your poor mother in you. A luckier
woman never walked you might say; yet she was never hopeful—always on
the look out for the rainy day that never came."
"I'm hopeful enough to-day anyhow. I think the new men be the sort to
suit you."
Susan reminded her father that a kinsman was coming in the evening.
"So he did. The man's affairs hang fire by the look of it. When's he
going to be married I wonder?"
"Might ask him," answered Susan. "Not that he knows I reckon. It's up
to her."
When night came John Bamsey duly arrived and shared the last meal of
the day.
He was one of the water-bailiffs on the river—a position he had held for
six months. But he had already given a good account of himself, and his
peculiarities of character were such that they made him a promising keeper.
He was keen and resolute, with the merciless qualities of youth that knows
itself in the right. He was also swift of foot and strong. A poacher, once
seen, never escaped him. John entertained a cheerful conceit of himself, and
his career was unsullied. He echoed his mother's temperament and was
religious-minded, but he had a light heart. He had fallen in love with a girl
two years older than himself, and she had accepted him. And now, at
twenty-two, John's only trouble was that Dinah Waycott would not name
the day.
He was a fair, tall man, with a solid, broad face, small grey eyes and an
expression that did not change. He wore an old-fashioned pair of small
whiskers and a tawny moustache in which he took some pride.
"And when's the wedding going to be?" asked Mr. Stockman. "Don't
know; but it's about time I did; and I mean to know inside this month.
Dinah must make up her mind, Cousin Joe. Wouldn't you say that was fair?"
"Certainly she should. Orphan Dinah took you very near a year ago, and
the marriage ought to be next spring in my opinion."
"No doubt it will be," answered John; "but I will have something
definite. Love-making is all right, but I want to be married and take the
lodge at Holne Chase."
"Yes; and by the same token, Neddy, your mother expects you Sunday."
"I be coming," said Neddy Tutt, and John continued. "I'm lodging with
'em, but they're very wishful to be off, and they will be so soon as ever I'm
spliced. The Honourable Childe wants me at the lodge and I want to be
there."
Susan, who had a mind so sensitive that she often suspected uneasiness
in other minds where none existed, was reflecting now, dimly, that the
newcomers would not find this subject very interesting. They sat stolidly
and quietly listening and eating their supper. Occasionally Maynard spoke
to Susan; Palk had not made a remark since he came to the meal.
"We be talking in the air no doubt for your ears," he said "But I hope
you'll feel yourselves interested in my family before long, just as I shall be
in your families, if you've got relations that you like to talk about. Me and
this young man's father are cousins in a general way of speaking, and his
father, by name Benjamin Bamsey, was married twice. First time he married
the widow of Patrick Waycott, who was a footman at the Honourable
Childe's, lord of Holne Manor, and she come to my cousin Benjamin with
one baby daughter, Dinah by name. So the girl, now up home twenty-three,
is just 'Orphan Dinah,' because her mother died of consumption a year after
she married Mr. Bamsey. Then Benjamin wedded again—a maiden by the
name of Faith West; and she's the present Mrs. Ben Bamsey, and this chap
is her son, and Jane Bamsey is her daughter. And now Johnny here be
tokened to his foster sister, 'Orphan Dinah,' who, of course, ain't no relation
of his. I hope I make myself clear."
"Consumption, same as his wife. In fact the seeds was in the poor girl
when Ben took her. But she done very well with him as long as she lived,
and he's terrible fond of Dinah."
"Father's too fond of Dinah for my peace in a way. You know father—
how he dashes at a thing. The moment he heard from mother, who'd found
out, that I was gone on Dinah, he swore as nothing would please him better.
And he was on my side from the first. In fact if Dinah hadn't wanted me for
myself, I believe father would have driven her to take me, for she'd do
anything for him. She couldn't love a real father better. She doats upon
him."
"He can't spoil her, however. Nothing would spoil Dinah," said Susan.
"And now," continued John, "now that the time's in sight and changes
have got to come, father begins to sing small at the thought of losing her.
He seemed to have a sort of notion I'd live on at home for ever, and Dinah
too. He's like that. He dashes at a thing and forgets how it will touch him
when it happens. He don't look all round a subject."
Maynard spoke.
"I hope the young woman is strong," he said. "'Tis rather serious for
both parents to have died so young."
"A very natural and thoughtful thing to say," declared Joe. "It shows
you've got intellects, Maynard. But, thank God, the girl is sound every way;
in fact, out of the common hearty and nice-looking too—at least Johnny
reckons she is."
"If she's got a fault, she's too plain-spoken," said Mr. Stockman. "I'm all
for direct speech myself and there's nothing like making your meaning
clear. It saves time better than any invention. But Dinah—how can you put
it? She's got such a naked way of talking. I don't say that the gift of
language was given us to conceal our thoughts, because that's a very hard
saying, though I know what it means; but I do say it was given us so as we
should present our thoughts to our fellow creatures in a decent shape. She's
a bit startling at times, Dinah is."
"It ain't she says anything to shock you, when you come to think over
it," argued Susan. "It's just plain thinking and going to the root of the
matter, which ain't common with most people."
"If the young woman says just what she means, it's a very rare thing,"
he said.
"Of course there are," chaffed Joe. "You that have missed the state,
Soosie-Toosie, and don't know no more about love than a caterpillar, no
doubt think that a lovers' quarrel be a very parlous thing. But it's no more
parlous than the east wind in March—is it, Johnny? A frosty breeze may be
very healthy and kill a lot of grubs and destroyers, if the ground be properly
worked over and the frost can get into it. And so with lovers' quarrels, they
do good, if both sides take 'em in a proper spirit."
Maynard laughed.
"I reckon that's true, Mr. Stockman," he said.
"What might you think, Mr. Palk?" asked Susan. She felt the heavy
silence of Thomas and knew not, as yet, that he often clothed himself in
silence for his own comfort. But he had listened with attention and she
thought he must probably have experience.
"You're a loser and a gainer, Thomas," said his new master genially.
"You may lose the blessing of a good son, or daughter, and a valuable wife;
and you gain also, because you might not have had those fine things, but
found yourself in a very different position. You might have had what's
better than freedom; but on the other hand you might have had what's a long
sight worse."
"All the same, father reckons you're the sort will marry again, Cousin
Joe," Johnny told him. "He says that such a good-looking man as you, and
so popular with the ladies, will surely take another some day, when you'm
tired of sporting."
"That's like Benjamin—to judge by the outside and never sound the
depths. He thinks that his own pattern of mind be the pattern of all. And not
a word against him, for a finer pattern of mind and one fuller of the milk of
human kindness don't live; but let nobody hope, or fear, any such adventure
for me. Me and Soosie-Toosie will go our way, all in all to each other; and
the less we have to trouble about ourselves, the more time and thought we
can give to our neighbours."
Susan displayed her wan smile at these sentiments. She was in stark fact
her father's slave and John well knew it; but he made no comment. Mr.
Stockman seldom said a word that was open to comment on any subject. He
gave his views and opinions for what they were worth, but quarrelled with
none who might differ from him. Indeed, he never quarrelled with anybody.
It was his genius invariably to give the soft answer; and this he did from no
particular moral conviction, but as a matter of policy. Life had taught him
that friction was seldom worth the trouble; and he had an art to get his way
rather by geniality of manner than force of character. He achieved his
purpose, and that frequently a hard and selfish purpose, as often as a more
strenuous man; but, such was his hearty humanity of approach, that people
for the most part found themselves conceding his wishes. He did not,
however, hoodwink everybody. A bad bargain is a bad bargain, no matter
how charming may be the man with whom it is made; and there were
neighbours who did not hesitate to say that Joe was a humbug always
playing for his own hand, and better able so to do than many far less
gracious and genial.
John Bamsey departed presently, and after he had gone the master of
Falcon Farm praised him generously.
"A four-square, fine chap that," he said. "An example to the young
fellows. A proper glutton for work. He'll be down on the river for hours to-
night, to keep off they baggering salmon poachers. And he goes to church
Sundays with his parents and always keeps his temper well in hand. For that
matter a water-watcher ought to have a temper, so as the doubtful characters
shall know he's not to be trifled with. A forceful chap—a little narrow in his
opinions I dare say; but that don't matter when his opinions are sound and
on the side of morals and good order. He gets 'em from both parents. And
the larger charity will come in time. That's a question of mellowing and
years. I can see you men are charitable minded, for I'm a student of
character and read people pretty clever, owing to my large experience. Have
a spot out of my bottle to-night for luck. Then, I dare say, you won't be
sorry to turn in. We're early birds by night and early birds in the morning. I
always say the hours before breakfast lay the foundation of the day and
break the back of it."
Maynard took no liquor, but drank a cup of tea with Susan, whose
solitary dissipation was much tea taken at all possible times. Thomas Palk
accepted a glass of whisky and water.
"Soosie-Toosie will call you at half after five," said Joseph, "and I like,
in a general way, to hear Ned start with the milk cart to Ashburton before
seven for the milk train. It's always a pain to me not to stir myself till
breakfast. I lie awake and hunger for the hour; but lifelong rules have often
got to be broke for failing health's sake in sight of seventy, as you'll find in
your turn no doubt. Life, as I always say, be all cakes and cream to youth;
but it's little more than physic when you be nearing the allotted span. Well, I
wish you good night, and if there's anything you lack, tell my daughter to-
morrow. I hope we shall be good friends and a lot more than master and
man pretty soon."
He shook hands with them both, and while Palk contented himself by
saying, "Good night, master," Maynard, who was clearly moved by such
comfortable words, echoed them and thanked Mr. Stockman for the manner
of his reception.
CHAPTER IV
AT BUCKLAND-IN-THE-MOOR
Like beehives cluster the thatched roofs of Buckland, for the cottages
are dwarfed by the lofty trees which soar above them. Oak and ash, pine
and beech heave up hugely to their canopies upon the hill slope, and the
grey roofs and whitewashed walls of the hamlet seem little more than a
lodge of pygmies sequestered in the forest. The very undergrowth of laurel
has assumed giant proportions and flings many a ponderous bough across
the highway, where winds a road with mossy walls through the forest and
the village. Here and there green meadows break the woods and lay broad,
bright tracts between the masses of the trees; then glimpses of the Vale
beneath are visible through woodland rifts.
The cottage coverings were old and sombre of tone; but on this
September day, before the great fall of the leaf, destined presently to sweep
like a storm from tree top to earth, sunshine soaked through the interlacing
boughs and brought light to the low-browed windows, to the fuchsias and
purple daisies in the gardens. It flashed a ruby on the rays of Virginian
creepers that sometimes clothed a wall and brightened the white faces of the
little dwellings to pale gold. All was very silent about the hour of noon. For
a few moments no human form appeared; only a brook poured down from
the hills, foamed through its dark, hidden ways, rested at a granite drinking
trough beside the road, then trickled on again. A robin sang, and far distant
throbbed the note of a woodman's axe.
Though the houses were few and small, great distinction marked them.
They held themselves as though conscious of their setting, and worthy of it.
They fitted into the large and elaborate moulding of the hillside and by their
human significance completed a vision that had been less without them.
There was a quality of massive permanence in the scene, imparted by the
gigantic slope of the hill whereon it was set. It fell with no addition of
abrupt edge or precipice, but evenly, serenely from its crown on the naked
Beacon above, by passages of heath and fern, by the great forests and
sweeps of farmland and water meadows that broke them, down and down
past the habitations, assembled like an ants' nest on its side to the uttermost
depths of the river valley and the cincture of silver Dart winding through
the midst of it.
At a point where the road fell and climbed again through the scattered
dwellings there stood two cottages under the trees together. They adjoined,
and one was fair to see—well-kept and prosperous, with a tidy scrap of
garden before it and a little cabbage patch behind. The straw of the roof was
trimly cut and looped heavily over the dormer windows, while above, on a
brick stack, four slates were set instead of a chimney pot. But the neighbour
cottage presented a forlorn appearance. It was empty; its thatch was
scabbed and crusted with weeds and blobs of moss; at one place it had
fallen in and the wooden ribs of the roof protruded. A mat of neglected ivy
covered the face of the cot and thrust through broken windows into the little
chambers. Damp and decay marked all, and its evil fame seemed reflected
in its gloomy exterior. For the house was haunted, and since Mrs. Benjamin
Bamsey had seen a "wishtness" peering through the parlour window on two
successive evenings after the death of the last tenant, none could be found
to occupy this house, though dwellings in Buckland-in-the-Moor were far to
seek.
Now a man appeared in the road from the direction of the church. He
was of an aspect somewhat remarkable and he came from Lower Town, a
hamlet sunk in the Vale to the west. Arthur Chaffe combined many trades,
as a carpenter in a small village is apt to do. He attended to the needs of a
scattered community and worked in wood, as the smith, in iron. He boasted
that what could be made in wood, from a coffin to a cider cask, lay in his
power. And beyond the varied and ceaseless needs of his occupation, he
found time for thought, and indeed claimed to be a man above the average
of intelligence. His philosophy was based on religious principle and
practice; but he was not ungenial for an old bachelor. He smiled upon
innocent pleasure, though the lines that he drew round human conduct were
hard and fast.
He was eight and fifty, and so spare that the bones of his face gave it
expression. Upon them a dull, yellowish skin was tightly drawn. He was
growing bald and shaved his upper lip and cheeks, but wore a thin, grey
beard. His teeth were few and his mouth had fallen in. His cheeks puffed
out when he ate and spoke, but sank to nothing under the cheek bones when
he sucked his pipe. He had a flat nose, and his long legs suggested an
aquatic bird, while his countenance resembled a goat and his large and pale
brown eyes added to the likeness. His expression was both amiable and
animated, and he could laugh heartily. Mr. Chaffe's activities were
centripetal and his orbit limited. It embraced Lower Town and Buckland,
and occasionally curved to Holne and outlying farms; but he was a
primitive, and had seldom stirred out of a ten-mile radius in his life. Had he
gone much beyond Ashburton, he had found himself in a strange land. He
employed three men, and himself worked from morning to night. His
highest flights embraced elementary cabinet-making, and when he did make
a piece of furniture on rare occasions, none denied that it was an enduring
masterpiece.
He left the high road now, approached the pair of cottages and knocked
at the door of the respectable dwelling.
"So you've come then, Mr. Chaffe. What a man of your word you are!"
"I hope so, Mrs. Honeysett. And very pleased to do anything for you
and your father."
"Come in and sit down for five minutes. 'Tis a climb from Lower Town.
But people say you can fly so easy as you can walk, and a hill's nought to
you."
"We thin blades have the pull of the beefy ones in this country. I
sometimes think I'll start a pony; but I like to use my legs and ban't often
too tired."
"Will you have a drink and a piece of my seedy cake?"
"I will then and gladly. Milk for choice. How's the Governor?"
"Pretty middling for him. You must see him afore you go. You're one of
his pets."
"I'm none so sure of that. But 'tis a longful time since we met. I've been
busier than ever this summer. I surprise myself sometimes what I get into
twenty-four hours."
"I hear from Ben Bamsey that his cousin have got two new men at
Falcon Farm, and foreigners both."
"So they are. One's youngish, t'other's middle-aged; and Joe says they
promise to be treasures. He's much pleased about them."
"Because he's got the wit to choose where he will fall," answered Mrs.
Honeysett. "Joe Stockman has gifts. He's a master of the soft answer."
"I wouldn't say I didn't like him. As a man of intellects myself I value
brains. He's a clever man."
"He's spoilt a bit. He gets round one you know. There's a great power in
him to say the word to a woman he always knows will please her. I properly
like him some days; then other days he drives me frantic."
The gruff voice of Mrs. Honeysett's father intruded upon them. It came
from a little chamber which opened out of the kitchen and had been
converted into his bedroom. His lower limbs were paralysed, but he had a
vehicle which he moved by handles, and could thus steer himself about the
ground floor of his home.
"I hear Arthur Chaffe," rumbled the voice. "I'll see you, Arthur, afore
you go, and larn if you've got more sense than when you was here last."
A gurgle of laughter followed this remark and the visitor echoed it.
"Ah! You bad old blid! No more of your sense, I promise you. We know
where your sense comes from!"
"Don't you charge too much for my new gate then—sense, or no sense."
Again the slow, heavy laughter followed; but Mr. Chaffe did not laugh.
He shook his head.
That matter settled and the price determined, Arthur Chaffe returned to
the cottage and found that Mr. Withycombe had travelled in upon his little
trolley and lifted himself into a large, dog-eared chair beside the hearth.
He was a heavy man with a big, fresh face that had been exceedingly
handsome in his prime, but was now a little bloated and discoloured, since
fate had ended for the old sportsman his hard and active existence. He had
hunted the Dart Vale Foxhounds for thirty years; then, maimed in the back
by a fall, for five years he had occupied the position of indoor servant to a
master who was deeply attached to him. Finally had come a stroke, as the
result of the old injury, and Enoch was forced to retire. He had now reached
the age of sixty-six and was a widower with two sons and one daughter.
One boy was in the Royal Navy, the other lived at home and worked in the
woods.
Mr. Withycombe had grey eyes, a Roman nose and cheeks of a ruddy
complexion. He wore whiskers, but shaved his mouth and chin. He was a
laughing philosopher, admired for his patience and unfailing good temper,
but distrusted, because he permitted himself opinions that did not conform
to the community in which he dwelt. These were suspected to be the result
of his physical misfortunes; in reality they were but the effect of his
environment. An admiration amounting to passion existed in the large heart
of Mr. Withycombe for his former master, and during those years when he
worked under his roof, the old fox-hunter had learned educated views on
various subjects and modified his own to match them. The Honourable
Ernest Childe, of Holne Chase, a lord of three manors, could neither do nor
think wrong in Enoch's opinion. He was the paragon, and the more nearly
did his fellow creatures take their colour from such a man and such a mind,
the better it must be for all—so Mr. Withycombe declared. Others, however,
did not agree with him. They followed parson rather than squire, and while
admitting that the latter's sterling practice left little to be desired, yet
suspected his principles and regretted that his pew in church was invariably
empty. They puzzled at the discrepancy and regretted it, because it appeared
a danger to the rising generation.
Mr. Chaffe shook the heavy and soft hand that Enoch extended to him.
"Half dead, half alive, Arthur. But, thanks be, the half that matters most
is alive."
"Now it do," admitted Enoch. "But I won't pretend. When this blow first
fell upon me and I knew that my legs would be less use in the world than
rotten wood, which at least be good for burning, then I cursed God to hell.
However, that's past. I've got my wits and now, along of these spectacles, I
can read comfortable again."
He pointed to a little shelf within reach of his hand where stood various
works.
"I could wish you'd read some books of mine, Enoch," said Arthur
Chaffe.
"Mr. Chaffe be going to ax seventeen and six for the gate and five
shillings for the hinges and lachet," said Melinda.
He handed his tobacco pouch to the visitor. It was covered with otter
skin now grown shabby.
Arthur filled his pipe.
"We stand for different things, you and me," he said, "yet, thank God,
agree in the virtues. Duty's duty, and a man that's honest with himself can't
miss it."
"Oh yes he can, Arthur. There's plenty that be honest enough and don't
want to shirk, yet miss the road."
"She's very well. Passed the time of day yesterday. Been helping in the
harvest. Ben Bamsey have had the best wheat he remembers. 'Tis harvest
thanksgiving with us Sunday week. And something out of the common to
thank for this year."
"No, no; his wife's his right hand. But we'm like brothers I grant. In fact,
few brothers neighbour so close I dare say. No news of the wedding; and
that don't worry Ben. You know what Dinah is to him."
"Mustn't say that; but—well, now that the date is only waiting for
Dinah, Ben begins to feel what her going will be. No doubt we shall hear
soon. Faith Bamsey's at Dinah about it. She reckons it's not fair to Johnny to
keep him on the hooks longer."
"More it is."
"Well, I dare say you're right, Mrs. Honeysett. Dinah's the sort that loves
liberty; but the maids have got to come to it, and she's a good girl and will
go into matrimony fearless."
"Fearless enough," said Enoch. "If she'd been born in a different station
of life, how that creature would have rode to hounds!"
"It's something that a man who knows human nature so well as you
should be surprised, Arthur," said the old hunter.
Enoch laughed.
"One for him sure enough. Funny word, 'undertaker.' A good chap is
Andrew Gaunter. Many a flip of sloe-gin I've had at his door when hounds
met that way. He'd bring it out himself, just for the pleasure of 'good
morning.'"
He looked up to where his hunting horn hung from a nail above the
mantel shelf.
"Is it true old Sparrow be gone to the workhouse?" asked Melinda, who
loved facts concerning fellow creatures and reduced conversation to
personalities when she could.
"It is true," answered Chaffe.
"A sparrow as fell to the ground uncounted then," said Enoch, but the
carpenter denied it.
"You mustn't think that. What be the workhouse but a sign of the
everlasting mercy put in our minds by a higher power?"
"Many never know happiness till they get there. Human life have
always been a hand to mouth business for most of us. It's meant to be, and I
don't believe myself that Providence likes us to look much farther than the
points of our noses."
"The great man is him that can, however," argued Mr. Withycombe.
"Him as looks a few yards deeper into the mirk of the future than we can
soon rises to be famous. He knows there can be no security against nature;
but, outside that, he sees there did ought to be security between man and
man, since we are reasoning creatures. And he thinks reasoning creatures
did ought to be reasonable and he tries to help 'em to be—man and man and
nation and nation."
"To do it, you must come with clean hands, Arthur; but all the nations'
hands are dirty. They look back into each other's histories and can't trust.
Man's a brigand by nature. It's the sporting instinct as much as anything,
and the best sporting nations are the best fighting nations. That's why we're
up top."
"Are we?"
"The Honourable Childe always says so. He has chapter and verse for
all his opinions."
"He'll drop in on the way home and tell you about a run now and again,
same as he did last year, I shouldn't wonder."
"What's this a little bird has whispered to me about Jane Bamsey?" she
asked.
"I've guessed it. Jerry's moonstruck and always looking that way."
"I hope it ain't true," said Enoch. "I don't much care for that maiden.
She's spoiled, and she's shifty. She came to see us with her mother. Hard
hearted."
"Yes; but the sort of kitten that grows into a cat devilish quick. I
wouldn't wish it for Jerry's sake. He's a man likely to be under the thumb of
his wife, so I'd hope a different sort for him."
"Jane's too young for Jerry," declared Melinda. "He's over thirty and
she's but eighteen or so. Besides, when Dinah marries John and goes, then
Jane will have to turn to and be more to her mother. She's terrible lazy."
"They don't know what it will mean to that house when Dinah leaves
it."