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 PREFACE

The second edition of Pharmacology for Rehabilitation In addition to the new chapters, all original chapters
Professionals presents basic pharmacological principles have been updated with the newest drug information with
along with the mechanism of action and side effects of emphasis on marketed drugs as opposed to those in the
major drug categories seen in rehabilitative practice. pipeline. The discussion activities have also been expanded
Similar to the first edition, the chapters are organized with new cases and questions that will spur some debate
using the systems approach. Each section begins with and promote integration into practice. Boxes have been
the pathophysiology and continues with a discussion of inserted providing generic and brand names of drugs along
the drug groups used for treatment. Most sections end with special comments for easy reference, and many fig-
with a discussion about how drugs affect rehabilitation ures have been redrawn. Specifically the cardiovascular
and how therapeutic interventions may affect drug pharmacology chapters and the diabetes section have been
effectiveness. Drug-exercise interactions, when known, expanded and further debate has been provided on the
are discussed. The chapters conclude with discussion affects of non-steroidal anti-inflammatory agents on the
activities that help the student learn the material and cardiac system and even the role that diuretics and
apply it to practice. The title has been changed to re- ␤ blockers may have in increasing the risk of diabetes.
flect the inclusion of coverage of other rehabilitation The chapter, “Exploring Drug-Exercise Interaction”
professionals. (chapter 28) follows the model presented in the first edi-
New to this edition are chapters on vitamins and min- tion by specifically reviewing exercise-drug implications
erals (including their interactions with drugs), comple- for cardiovascular disease, pulmonary disease, and diabe-
mentary and alternative agents, drugs used to facilitate tes, discussing red flags particularly related to drug treat-
wound healing, and drugs of abuse and doping ment and exercise, and presenting sample exercise pre-
agents. In particular the chapter on alternative medicine scriptions. Additionally the chapters on chemotherapeutic
(chapter 26), provides an in-depth review of the support- drugs and antimicrobials/antiviral agents have been
ing evidence, or lack thereof, of the supplements com- expanded. There is further discussion on monoclonal anti-
monly used by patients with cardiovascular disease and bodies in the prescription of exercise while cycling on
women undergoing menopause. The chapter on wound chemotherapy. Treatment sections for HIV disease and
healing (chapter 25), specifically discusses venous stasis hepatitis have also been expanded to reflect the newest
ulcers, and arterial and diabetic ulcers. Cleansing agents, drug regimens.
antimicrobials for wounds, and enzymatic agents are The book continues to be written on a level commen-
discussed as are pressure dressings. The chapter on abuse surate with rehabilitation education, while offering a mix
(chapter 27) reviews the physiological effects of alcohol, of basic and clinical science following the knowledge re-
heroin, marijuana, and hallucinogenic agents and the quirements of a Doctorate in Physical Therapy. The web-
pharmacological management of these addictions. An site companion to the book offers answers to many of the
extensive review of methadone treatment has been added discussion activities, sample test questions, image library,
to the chapter on pain. updates, and links to supplemental resources.

vii
 ACKNOWLEDGMENTS

I wish to acknowledge the continuing efforts of the staff chapters. Additionally I would like to thank my col-
at Elsevier who managed to keep calm when the author leagues at the University of Medicine & Dentistry whose
did not always display proper decorum. A special thanks scholarship continues to amaze me and provides me with
also goes to my contributing authors who brought everlasting goals.
expert knowledge and practical experience to their Barbara Gladson

viii
 CONTENTS

SECTION ONE
Principles of pharmacology
1. Introduction 2
Barbara Gladson

2. Pharmacodynamics: Mechanism of Action 12

Barbara Gladson

3. Pharmacokinetics and Drug Dosing 21

Barbara Gladson
4. Adverse Drug Reactions 37
Barbara Gladson

SECTION TWO
Autonomic and Cardiovascular Pharmacology
5. Drugs Acting on the Autonomic Nervous System 48
Barbara Gladson

6. Antihypertensive Agents 66
Barbara Gladson

7. Drug Therapy of Coronary Atherosclerosis and Its Repercussions 86

Barbara Gladson

8. Drug Therapy for Congestive Heart Failure and Cardiac Arrhythmias 109
Barbara Gladson
9. Drug Therapy for Pulmonary Disorders 125
Barbara Gladson

ix
x CONTENTS

SECTION THREE
Pain Control
10. Anesthetic Agents 142
Barbara Gladson

11. Drugs for the Treatment of Pain and Inflammation 152

Barbara Gladson

12. Drug treatment for Arthritis-Related Conditions 174

Barbara Gladson

SECTION FOUR
Endocrine Pharmacology
13. Selective Topics in Endocrine Pharmacology 191
Barbara Gladson

14. Drug Treatment for Osteoporosis and Diabetes 216

Barbara Gladson

SECTION FIVE
Neurologic Pharmacology
15. Drugs for Epilepsy and Attention Deficit/Hyperactivity Disorder 249
Barbara Gladson

16. Antispasticity Medications and Skeletal Muscle Relaxants 262

Sue Ann Sisto

17. Pharmacologic Management of Degenerative Neurologic Disorders 279

Lee Dibble
18. Drug Treatment for Depression and Anxiety 300
Giovanni Carracci and Arnold Williams

19. Drug Treatment for Schizophrenia and Bipolar Illness 317

Najeeb Hussain and Carlos Jordan
 CONTENTS xi

SECTION SIX
Anti-Infective and Anti-Cancer Agents
20. Antimicrobial Agents 334
Wolfgang Vogel

21. Antiviral Agents and Selected Drugs for Fungal Infections 353
Barbara Gladson and Wolfgang Vogel

22. Cytotoxic Agents and Immune Modulation 376

Lillian Pliner and Tracie Saunders

SECTION SEVEN
Special Topics in Pharmacology
23. Drugs for Gastrointestinal Disorders 412
Barbara Gladson

24. Vitamins and Minerals 427

Jane Ziegler

25. Topical Drugs and Treatments Used in Wound Management 437

Sue Paparella-Pitzel and Leslie-Faith Morritt Taub

26. Complementary and Alternative Medicine in Pharmacology 448

Lisa Dehner

27. Drugs of Abuse: Anabolic Steroids and Other Doping Agents 478
Wolfgang Vogel

28. Exploring Drug-Exercise Interactions 485

Mary Jane Myslinski
This page intentionally left blank
 SE C T I O N I
Principles of Pharmacology

1
 CHAPTER

1
Introduction
Barbara Gladson

WHAT IS PHARMACOLOGY?
Pharmacogenomics examines how our genetic makeup
Pharmacology is defined as the study of how chemical produces unexpected and peculiar reactions to drugs and
substances affect living tissue, and it includes the moni- helps direct therapeutics according to a person’s geno-
toring of how these agents bind to receptors to enhance type.5,6 The science of pharmacogenomics has its roots
or inhibit normal function.1,2 The study of pharmacol- as far back as 1948 when it was descovered that some
ogy may be divided into two main areas: pharmaco- patients suffered fatal reactions to the local anesthetic
therapeutics (also known as medical pharmacology) and drug procaine. It was later discovered that these indi-
toxicology. Pharmacotherapeutics is the use of chemical viduals had a genetic alteration that produced a low af-
agents to prevent, diagnose, and cure disease, whereas finity between the drug and its metabolizing enzyme. We
toxicology is the study of the negative effects of chemi- now know that there are many variations in both gene
cals on living things, including cells, plants, animals, and sequence and expression that alter responses to drugs
humans. Pharmacology is separate from pharmacy, and that these variabilities appear more common in cer-
which refers to the mixing and dispensing of drugs, as tain races and ethnicities. It has been accepted that ge-
well as to clinical functions, including monitoring drug netic variations exist in drug receptors, ion channels, and
prescriptions for appropriateness and monitoring pa- other drug targets. And, in fact, genetic tests are avail-
tients for adverse drug interactions.3 able that help identify if a patient will respond to certain
Pharmacotherapeutics may be further divided into medications or not.7 Tests can help determine whether a
two domains: pharmacokinetics and pharmacodynamics. woman with breast cancer would respond to either of
When we think of the word kinetics, we think of mathe- the breast cancer drugs tamoxifen and trastuzumab
matical formulas and rates. When the word kinetics is (Herceptin) and if a patient with a coagulation disorder
applied to pharmacology, it refers to the study of how would receive adequate anticoagulation from the drug
fast and how much of a drug is absorbed into the body, warfarin. From a clinical perspective, genetics is why
how it is distributed to the various organs, and how it is Asians and Hispanics diagnosed with schizophrenia
ultimately metabolized and excreted by the body. Com- have significantly higher serum drug levels than white
puting the concentration of drug absorbed or excreted is individuals, which results in a greater incidence of extra-
part of a pharmacokinetic study. pyramidal symptoms, and why angiotensin-converting
Pharmacodynamics describes what the drug does to enzymes are less effective in blacks than in whites.8 The
the body and its beneficial or adverse effects at the cel- recognition of these genetic polymorphisms has led to
lular or organ level. Pharmacodynamic studies identify the development and marketing of pharmacodiagnostic
the mechanism of action and compare effects of different tests to help determine which drug to choose for an in-
drugs for potency and efficacy. Pharmacodynamic prin- dividual patient.9
ciples are often presented in a graphic form called a Pharmacoepidemiology is concerned with the effec-
dose-response curve.2 This curve demonstrates the effect tiveness of a drug in large populations compared with
of increasing drug doses on a particular response (see that in individuals.10 This discipline utilizes all the tools
Figures 2-10 and 2-11). The dose-response curve helps for studying epidemics and chronic diseases to evaluate
explain the nature of the drug-receptor interaction and the use and effectiveness of medicines. Particular empha-
is useful for comparing drugs in similar categories for sis is placed on determining the frequency of adverse
strength and effectiveness (see Chapter 2). drug reactions by adopting a systematic approach after
Although this schema for describing the basis of phar- spontaneous postmarketing reporting. The true value of
macology is simple and easily understood, it should, in pharmacoepidemiology is that it provides information
fact, be expanded to include not only the traditional about drug effectiveness and safety.
areas of pharmacology driven by a systems approach but Pharmacoeconomics is the area of pharmacology that
also some new specialty areas such as pharmacogenom- quantifies in dollar amounts the cost versus benefit of
ics, pharmacoepidemiology, and pharmacoeconomics.4 therapeutics.11 Pharmacoeconomic studies have been
2 Copyright © 2011, Elsevier Inc.
 CHAPTER 1 Introduction 3

used to contain health care costs and are favored by

DRUG DEVELOPMENT
governments and insurance companies to encourage
AND REGULATION PROCESS
changes in prescribing patterns. These entities have
placed limits on the amount of reimbursable dollars for The FDA is the administrative arm of the U.S. govern-
medications and encourage generic substitutions. ment that directs the drug development process and gives
approval for marketing a new drug or approves a new
use for an older drug. The FDA’s power comes from a
WHY SHOULD PHYSICAL THERAPISTS series of legislation enacted since the passage of the Pure
STUDY PHARMACOLOGY? Food and Drug Act of 1906.19 This Act represented the
The field of pharmacology is constantly changing. Al- U.S. government’s earliest attempts to protect public
most daily, new drugs appear on the market, and new health, following the discovery of unsanitary practices in
information about older drugs is presented in medical the meat-packing industry. Next came the Sherley Amend-
journals. Drug therapy is pervasive among our physical ment of 1912 which prohibited companies from making
therapy patients, and therefore we must have some un- fraudulent claims for drug products. Later on, the Food,
derstanding of mechanisms of action and adverse reac- Drug, and Cosmetic Act of 1938 was passed. This was
tions of drugs. Perhaps even more important is an under- prompted by the deaths of 107 individuals (mostly
standing of how drugs affect physical therapy practice. children) who ingested a medication, diethylene glycol
Some beneficial effects of drugs may be enhanced by our solution that was mixed with the powdered antibiotic
interventions, and in some cases, our interventions may sulfanilamide, which was marketed for the treatment of
be able to lessen some of the negative effects of medica- streptococcal infections. The sweet raspberry taste of the
tion. However, we must also be aware that physical liquid was thought to be appealing to children. This new
therapy intervention may exacerbate some of the adverse formulation was tested for flavor, appearance, and fra-
effects of drugs and necessitate a change in treatment. grance but not toxicity. The victims were sick for about
Excellent examples of interventions that may produce 7 to 21 days showing signs of kidney failure, abdominal
adverse effects include massage procedures and strength- pain, nausea, vomiting, and convulsions. Numerous let-
ening exercises performed in an area recently injected ters from parents who lost their children arrived at Pres-
with insulin.12,13 ident’s Franklin Roosevelts’s office and also at the FDA.
There are four specific reasons that physical thera- The result was the new Food, Drug, and Cosmetic Act,
pists should study pharmacology. First, physical thera- which mandated that drugs be safe and of good quality
pists must understand patients’ responses to different but did not require evidence of efficacy. It was not until
drugs. Drugs often cause fatigue and can interfere with the Kefauver-Harris Amendments to the Food, Drug, and
cognitive and motor functions. Examples of drugs Cosmetic Act were signed in 1962 that drug approval
that cause fatigue are sedatives, opioids, and muscle was contingent upon both safety and efficacy. This legis-
relaxants; however, many other drugs also produce lation was a reaction to the evidence that thalidomide, a
sedation and affect muscle strength.14,15 A second rea- supposedly nontoxic hypnotic, when taken during preg-
son to study pharmacology is to determine the ideal nancy was responsible for phocomelia, a rare birth defect
treatment schedule. A therapist may want to see a pa- involving the shortening or absence of limbs.
tient when the patient’s pain medication has reached Additional legislative Acts that have since been passed
its peak effect; however, the therapist would not want include the Comprehensive Drug Abuse Prevention and
to treat a patient at peak sedation. The same is true for Control Act of 1970, which limits access to drugs of
a patient taking antiparkinsonian medication; the pa- abuse, and the Expedited Drug Approval Act of 1992,
tient may be experiencing the peak antitremor effect fueled by the acquired immune deficiency syndrome
during the scheduled therapy session. The third reason (AIDS) crisis, which helped shorten the drug develop-
for studying pharmacology is to learn to recognize ment process for certain life-saving medications. How-
drug–therapy interactions. Whirlpool treatments and ever, it was not until 1997 that legislation requiring
other heat-related modalities produce peripheral vaso- pharmaceutical companies to provide information on the
dilation, which can exacerbate the orthostatic hypo- adverse effects of drugs to consumers was passed (Agri-
tension produced by certain antihypertensive agents culture, Rural Development, Food and Drug Administra-
and lead to syncope.16,17 Lastly, from 1998 to 2005, tion and Related Agencies Appropriations Act, 1997).20
the number of serious adverse drug reactions (ADRs) Senator Edward Kennedy, in his amendment speech to
reported to the U.S. Food and Drug Administration this bill, said, “Millions of Americans are affected and
(FDA) increased approximately 2.6 times to 89,842 billions of dollars are spent on medical problems caused
cases and the number of fatal adverse drug events by prescription drugs. The nation spends as much to cure
was reported to be 15,107.18 Many of these ADRs are the illnesses caused by prescription drugs as we spend on
preventable, and therapists must recognize these reac- the drugs themselves.” 21
tions and report them immediately to the patient’s Drug regulation is essential to ensure a safe and
physician. effective product. The purposes of regulation include
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4 CHAPTER 1 Introduction

balancing the need of the pharmaceutical companies to The chemists recruited have knowledge of the structure
show a profit with the need of patients to have easy ac- of the insulin receptor and develop chemical compounds
cess to safe medications, especially nonprofitable drugs that bind to the receptor. These compounds are then
or “orphan drugs” (drugs for rare diseases). The regula- passed along to the pharmacologist for drug screening. A
tory process is designed to ensure drug safety and variety of biological assays are used to test the com-
efficacy by a detailed review of all research studies, both pounds at the molecular and cellular levels as well as at
preclinical and clinical, to scrutinize product labeling to the organ and animal levels. The tissues selected for test-
prevent fraud and to make sure directions are accurate ing are those influenced by insulin, and the animals cho-
and easily understood by patients, and to ensure quality sen for testing are those that have insulin receptors simi-
in the manufacturing process.22 In the United States, the lar to those of humans. An evaluation of cardiovascular
FDA is charged with this responsibility, but in Europe and renal functions are performed on healthy animals for
and the rest of the world, there are both centralized and safety. Specifically, acute and chronic toxicity tests are
decentralized procedural methods for drug approval. In performed; as well, the drug’s effect on reproduction and
the European Union, the European Medicines Evalua- its mutagenic and carcinogenic potentials are evaluated.
tion Agency (EMEA), has replaced the previously indi- Efficacy testing is conducted on animals bred to become
vidual country approval process.23 Individual countries diabetic. Additional testing on the respiratory, gastroin-
still have the authority to grant national licenses, but testinal, reproductive, and central nervous systems is
there is a significant “harmonization of practice” at the performed. These experiments constitute the preclinical
global level. Harmonization of regulations was more testing phase, usually lasting 2 to 6 years.26 At the end of
formally accepted in 1990 with the establishment of the this phase, representatives from Drug Company X take
International Conference on Harmonisation of Techni- the data on their lead compound to the FDA and seek
cal Requirements for Registration of Pharmaceuticals approval to begin testing the oral insulin in humans. If
for Human Use (ICH).24 The ICH is a group of pharma- the compound is believed to be safe for humans, a Notice
ceutical regulators and companies from Europe, the of Claimed Investigational Exemption for a New Drug
United States, and Japan that produce guidance docu- (IND) is filed with the FDA. Human testing begins once
ments addressing how clinical trial data obtained in one the FDA approves the investigational new drug (IND)
country might be used to support the regulatory applica- and consists of four phases as described below.
tion in another country so that trials need not be dupli- Phase 1 is the safety assessment study. In this study,
cated. There are, however, exceptions to harmonization. the oral insulin is given to a small number of healthy
The Japanese Pharmaceutical Affairs Bureau requires volunteers (about 25 to 50), and a safety profile is estab-
most prescription drugs to be first studied in Japan prior lished.27 These studies are conducted to identify any toxic
to regulatory approval. The reason for this tighter con- effects and to begin to establish a safe dosage range.
trol is due to differences in the metabolism and body size Pharmacokinetic studies are also performed. If the drug
of Japanese individuals compared with those of individ- is thought to have significant toxic effects, testing will be
uals who originate from the United States or Europe. conducted on volunteer patients with the disease being
Although some centralized control over drug regula- targeted instead of on healthy control subjects. This is
tion is exercised, individual countries have their own often the case for AIDS drugs or drugs designed for resis-
rules regarding possession and prescription of drugs, and tant types of cancers. This phase lasts up to 2 years.
these rules vary greatly. In some countries, patients can Phase 2 is the drug effectiveness study.27 In this phase,
obtain drugs without a prescription, whereas in others a small number of patients (approximately 200) who
purchase of drugs by individuals is tightly controlled. In have the targeted disease receive the new drug. The study
addition, vitamins, dietary supplements, and herbal rem- design is usually single-blinded, and the new drug is
edies are not regulated as drugs in the United States and compared with a placebo (a nonactive compound) or
many other countries, so manufacturers of these items with an older active agent with known safety and
do not have to abide by the strict regulations for safety, efficacy. Therefore a phase 2 study using the above ex-
purity, and efficacy governing prescription drugs.25 ample would compare glucose levels in patients admin-
stered the gold standard, that is, injectable insulin, with
those in patients taking the experimental version. The
Drug Development questions that would be addressed by this study include:
The first step in the drug development process is the de- Is the experimental drug safe for patients with diabetes,
termination of a target market by the drug company. For and is it more effective than the injectable form of the
example, let us say that Drug Company X decides that drug in lowering blood glucose levels? This phase may
there is a need for an oral form of insulin. Insulin is com- last for another 1 to 2 years but the duration can vary,
monly delivered by means of a subcutaneous injection, a depending on the specific endpoint being studied. In our
form of drug delivery that is less desirable to patients. example, lowered blood glucose level is the endpoint,
First, the drug company enlists some chemists to perform but the study might track the time to development of
research on and provide support to the new proposal. cardiovascular complications or other secondary sequela
 CHAPTER 1 Introduction 5

of the disease, such as retinal damage, which would ex- drug prescription should be viewed as a therapeutic ex-
tend the length of the study. periment and that we are all subjects in drug studies.
Phase 3 is a much larger study, including many more The time it takes to bring a drug to market is long, as
subjects with diabetes than in the previous phase just the clinical phases (phases 1 to 3) take, on average,
(5000 to 10,000 subjects or more).28 In addition, the 8.6 years and the entire process may take between
duration of the study is usually extended, perhaps up to 10 and 15 years in the United States.30,31 In 2001, the
as long as 3 to 6 years. Investigators and study sites for total cost from molecule to marketing was estimated to
these trials are chosen from all over the world. Safety and be $802 million, and there is no evidence that this cost
effectiveness are again studied but on a much larger scale. has been reduced.30 It is a labor-intensive process that
Phase 3 trials tend to be double-blinded randomized con- does not always lead to success. One of the major bottle-
trolled trials (RCTs) that are either parallel or crossover necks in the process is subject recruitment. Trials are
in design. Parallel designs test at least two therapies at the often delayed or abandoned due to poor enrollment of
same time, but each patient group is assigned only one subjects. Eighty-six percent of studies conducted in the
drug. In studies with crossover designs, patients act as United States do not recruit the required number of sub-
their own control subjects by receiving therapies in se- jects in a timely manner.32 In addition, the United States
quence. Some patients may receive Drug A first and then ranks behind Asia, Western Europe, Eastern Europe, and
Drug B, and other patients may receive Drug B first and South America in the number of subjects recruited into
then Drug A. Phase 3 studies tend to be performed in trials per month.33 Between 2003 and 2006, the average
larger tertiary care centers by experts in the targeted dis- trial time increased by 74%, compared with data col-
ease. Again, in our example of oral insulin, test sites lected between 1999 and 2003.34 This delay has led to a
would be set up around the country and in Europe and growing number of trials being conducted abroad.35
Japan, preferably at centers for the study of diabetes. Due to the tremendous costs and time involved in
These centers receive funding from the pharmaceutical drug discovery, pharmaceutical companies maintain
company to recruit and pay subjects, set up data collec- some exclusivity on their products through patents. Pat-
tion systems, and obtain any other supplies or equipment ents are filed usually around the end of the preclinical
needed to support the research. Clinical researchers from studies and are in place for 20 years.28 However, since
the drug company will closely monitor all the data to the clinical phases take time, the patent owner has only
make sure that the oral insulin is effective and safe a limited amount of time to market the drug before the
throughout phase 3. generic forms begin to appear in pharmacies. The drug
If phase 3 studies are successful, the drug company companies therefore fight hard to extend their patents by
files a New Drug Application (NDA) with the FDA.28 As coming up with new uses for their drugs to balance out
part of this application, the company submits all pre- the lengthy review process and the cost of failed
clinical and clinical data on the oral insulin. The FDA compounds.
then reviews the materials, and if the drug seems to be When the patent expires, any company may produce
effective and without significant adverse effects, the FDA and sell the drug as a generic without having to pay any
gives permission to the company to market the oral fees to the original company, but the licensed trade name
insulin to the public. given to the drug remains the property of the original
Phase 4 begins when the drug is approved for public drug maker. In the case of a lengthy FDA review process,
use. It is called the postmarketing surveillance phase and the patent may be extended for up to 5 years.
is a much larger study than any previously performed.29 Although the FDA approves drugs for specific indica-
This phase constitutes monitoring the drug for safety in tions, which then become listed on the package insert, it
large numbers of patients under real-life conditions. Dur- does not limit the use of drugs to these described condi-
ing this phase, members of the public who have diabetes tions. Physicians have the final say on how a drug may
become study subjects without their knowledge. If many be used. Prescribing a drug for off-label or unapproved
adverse drug reactions are discovered during this phase, uses is common and legally permitted.
and if they present significant health risks, the drug may
be recalled. Technically, phase 4 has infinite duration
Orphan Drugs and Treatment
because the drug company will continue monitoring for
Investigational New Drugs
any problems throughout the marketing process. How-
ever, even though the drug has been released for public Because drug development is an extremely expensive and
consumption after phase 3, it is prudent to wait until it lengthy process, drugs for rare diseases, the so-called
has been on the market for at least 2 years before using “orphan drugs,” tend not to be researched or marketed
it. It is responsible health care to prescribe an older drug by drug companies. Therefore, in 1983, the Orphan Drug
with a proven track record first and then to switch to a Act was passed to provide research grants for the study of
newer drug after all the adverse drug reactions (ADRs) diseases affecting fewer than 200,000 patients in the
have been identified. This process underscores the atti- United States.19 This Act provides special financial incen-
tude among many health care professionals that every tives to companies to help offset their development costs.
6 CHAPTER 1 Introduction

However, lack of profit is not the only reason that orphan incomplete understanding of pathophysiology, we can
drugs are rarely studied. These drugs present some hope that in the future further study in this area will lead
scientific dilemmas because it is difficult to establish safety to more effective drugs.
and effectiveness in small numbers of patients. In addi- Another problem with the drug discovery process, in
tion, many rare diseases occur in children, and investiga- the case of many diseases, is the lack of animal models
tors prefer not to include children in early clinical trials. for drug screening.37 Even though there are animals that
The FDA has also provided guidelines to streamline can grow specific tumors, animals that are bred to have
the development of certain drugs for life-threatening diabetes, and even animal models for epilepsy, animal
conditions such as AIDS and certain cancers.36 These models are lacking for many other illnesses. Again, men-
drugs receive Treatment Investigational New Drugs tal illness is a good example because no animal model
(IND) status, allowing them special priority throughout exists for the testing of different compounds.
the review procedure. This status also allows patients Reluctance to include women and children in clinical
outside the ongoing studies to be treated with investiga- trials, largely because of differences in pharmacokinetics
tional drugs. Treatment IND status is issued for a drug and pharmacodynamics in these populations, represents
designed to treat serious life-threatening illnesses when another impediment to clinical trials. One solution to
no other acceptable alternative is available in the mar- this has been the establishment of the Office of Women’s
ket. The drug must already be involved in a clinical trial, Health within the FDA in 1994.40 This office has pro-
and the pharmaceutical company must show that it is moted the development and approval of drugs for dis-
proceeding with the normal steps involved in the drug eases affecting women. In addition, this office is dedi-
approval process. If a physician wants to prescribe a cated to identifying how drugs affect women because
drug that is in clinical study but lacks the treatment IND traditionally most clinical trials have been conducted
status, the drug may still be obtained for a patient under only on men. Governmental groups have attempted to
a “compassionate use” clause. provide incentives to the pharmaceutical industry to in-
clude more minorities and women into clinical trials.
The National Institutes of Health (NIH) Revitalization
Barriers to Drug Development Act of 1993 (Public Law 103-43) requires that all studies
Many barriers to development of new drugs exist, par- funded by the NIH include representations of women
ticularly for diseases that progress over time, such as and minority groups.41 However, despite this legislation,
multiple sclerosis and Parkinson’s disease. Foremost several populations remain under-represented in clinical
among the barriers, of course, is the issue of funding. This trials.42-45 Minorities and women are still less likely to
barrier affects studies of rare diseases much more than enroll in studies compared with white males, particularly
studies of the more common diseases; but the discovery of in cancer and HIV clinical trials. In the future, the U.S.
new drugs even for common illnesses is risky and quite House of Representatives is expected to consider legisla-
expensive. Drug researchers suggest that charity organiza- tion that would extend patent rights to companies that
tions and government support programs continue to be run clinical trials that are ethically and racially focused.46
emphasized as funding sources.37 Additional barriers include the lack of experienced prin-
Another barrier to development is the fact that many cipal investigators, and lack of coordinated data collec-
diseases lack specific markers of identification or there is tion systems, greater protocol complexity.47,48
lack of consensus regarding clinical trial endpoints, which Drug development is a labor-intensive, expensive,
makes it difficult to document treatment progress. Ex- risky, and time-consuming process. Although this proc-
amples include Alzheimer’s disease and some mental ill- ess is widely accepted and adhered to, there is growing
nesses such as bipolar disorder and schizophrenia. Mental discussion regarding alternative methods to prove drug
illness tends to be a multifactorial condition demonstrat- safety and efficacy.49 Improved postmarketing surveil-
ing impairments in language, memory, motor planning, lance, which involves a coordinated data collection sys-
and cognitive domains.38 Functional testing in all these tem from around the world, has been suggested to detect
areas is necessary to prove that a medication is effective. unanticipated events, both positive and negative, that
Even when markers have been identified, researchers in could lead to greater accuracy in identifying treatment
the field do not always agree on the level of significance options.50,51 The use of meta-analyses for analyzing
that these markers provide in terms of documenting im- many trials simultaneously has also been suggested as a
provement. For example, manufacturers of arthritis drugs way of improving therapy. In some cases, a meta-analy-
may claim that their drugs are effective by showing a re- sis of multiple small trials can be used to identify a drug
duction in the signs and symptoms of rheumatoid arthritis effect not previously recognized by individual trials.
(e.g., redness, swollen joints), but others may insist that Pharmacoeconomics, which consists of studies that deter-
effectiveness claims be based on a slowing of disease pro- mine the cost/benefit ratio of drugs, is likely to become a
gression as determined by radiography.39 Because the growing field as research dollars continue to shrink.
lack of a specific drug target or marker is a result of our Pharmacoeconomic studies examine overall outcome in
 CHAPTER 1 Introduction 7

clinical practice and are used to inform changes in prac- 6. The Signa or Sig, which gives directions to the pa-
tice. These suggestions are not likely to become standard tient, including how often to take the drug, how
operating procedures in the drug delivery process yet, much drug to take, and additional instructions such
but the FDA has instituted a number of changes that will as “shake well” or “take with food.” Signa is Latin
ultimately benefit patients. Approvals of drugs via the for “label.” The patient instructions are usually writ-
“fast-track” and greater inclusion of women in clinical ten with Latin abbreviations.
trials represent two recent changes in the drug discovery 7. Refill information.
process. In addition, the FDA has begun using outside 8. Prescriber’s signature.
help, groups of clinical specialists in a variety of fields, 9. Drug Enforcement Administration (DEA) number,
in evaluating studies to hasten the review process. Fur- which is required for controlled substances, as well as
ther changes focused on streamlining the process and for insurance claims processing.
improving data collection are expected as time goes on. In the past, many adverse drug events have occurred
due to prescribing errors. Quickly scribbled prescriptions
that omit important information are illegible or contain
ELEMENTS OF A PRESCRIPTION the wrong dose or dose units and can be disastrous. A
The prescription is an order written by a licensed practitio- misplaced decimal point is not uncommon and can lead to
ner (e.g., physician, dentist, veterinarian, or podiatrist, a 10-fold difference in dose, which is why, for example,
and, in some states, the physician assistant and nurse “.1 mg” should always be preceded by a zero, “0.1 mg”.
practitioner) to instruct the pharmacist to provide a specific Another recommendation is to avoid using the abbrevi-
medication needed by a patient. The elements contained in ated form of micrograms, “␮g” since this can be read as
the prescription include the following52 (Figure 1–1): “mg” which would produce a 1000-fold error. U for Units
1. The prescribing physician’s name, credentials, address, should also not be used since it may be mistaken as a zero,
and telephone number. and QD, QOD, and qd can all be mistaken for one an-
2. The date the prescription was written and the other, so these instructions should be written out as
patient’s full name and address. “daily” and “every other day.” Box 1–1 lists acceptable
3. Rx, called the superscription, which tells how the abbreviations.
drug is to be administered to the patient (e.g., orally
or by injection). Rx is an abbreviation of the Latin
CONTROLLED SUBSTANCES
word for “recipe” and “receive thou.”
4. Inscription, which includes the drug name (either Controlled substances are drugs classified according to
brand or generic), dose, and quantity to dispense. their potential for abuse. They are regulated under the
5. Subscription, which gives directions to the pharma- Controlled Substances Act (CSA), which classifies these
cist regarding the mixing instructions (compound- compounds into schedules (levels) from I to V.52 This
ing), IF NEEDED. law, which was enacted in 1971, also makes provisions
for research into drug abuse and treatment programs for
dependency. This Act, along with assistance from the
Don Dose, MD DEA, controls the manufacture, distribution, and dis-
65 South Lake Drive
Capsule, Ca 07008 pensing of drugs that have the potential to be abused.
(282) 233-2748

FOR: DATE:

ADDRESS:
Schedule I
Rx Schedule I drugs are available only for research. They
Drug Name, Strength (Metric Units), have the highest abuse potential, leading to dependence
& Quantity without any acceptable medical indication. Some exam-
ples include heroin, LSD (lysergic acid diethylamide),
and mescaline. Special approval is necessary before any
SIG: (how drug is taken, e.g. at meals or 2 tab BID)
of these agents can be used.
REFILL______
OR
UNTIL_______ Schedule II
Schedule II drugs also have a high abuse potential with
Warning: ,MD
the likelihood of physical and psychological dependence,
but unlike schedule I drugs, they have accepted medical
DEA#
State License # uses. Drugs classified at this level include stimulants such
as amphetamines; opioids, including morphine, fentanyl,
FIGURE 1-1 Sample drug prescription. and oxycodone; and some barbiturates. Automatic refills
8 CHAPTER 1 Introduction

BOX 1- 1 Common Abbreviations used Schedule III

in Prescription Writing
Schedule III drugs have a lower abuse potential than
those in schedules I or II; however, they may also be
a before
ac before meals abused, resulting in some physical and psychological
bid twice a day dependence. Refills are allowed, but no more than five
cap capsule refills are permitted within a 6-month period. Mild to
dil dissolve, dilute moderately strong opioids, barbiturates, and steroids are
disp, dis dispense categorized at this level. Opioids that are formulated
elix elixir with aspirin and acetaminophen as well as anabolic ste-
g gram roids are also included under schedule III.
gtt dros
h hour
hs at bedtime Schedule IV
IA intra-arterial
Schedule IV drugs have less abuse potential than those in
IM intramuscular
IV intravenous schedule III; however, this does not mean that they are
IVPB IV piggyback not popular among drug abusers. They include opioids
kg kilogram such as propoxyphene (Darvon), benzodiazepines such
mEq, meq milliequivalent as diazepam (Valium), and some stimulants. No more
mg milligram than five refills within 6 months are allowed under one
mcg, ␮g microgram (always write) prescription.
OD right eye
OS, OL left eye
OTC over-the-counter Schedule V
OU both eyes
Schedule V drugs have the lowest abuse potential and
p after
may even be available without a prescription. Actual
pc after meals
PO by mouth availability without a prescription is state regulated, so
PR per rectum laws governing their use vary. Various cold and cough
prn when needed medicines containing codeine are listed in this category.
q every
qam, om every morning
ad every day (write “daily”)
Rules Governing Narcotics
qh, q1h every hour It is against the law for any person to possess a sched-
q2h, q3h, etc every 2 hours, every 3 hours, etc uled drug unless it has been obtained with a prescription.
qhs every night at bedtime It is also illegal to transfer possession of any scheduled
qid
drug to another person.53 In the hospital setting if a nar-
qod (do not use)
cotic is ordered for a patient and then not used, it must
every other day
qs sufficient quantity be returned to the hospital pharmacy. In addition, if a
rept, repet may be repeated narcotic falls on the floor and becomes contaminated, it
Rx take must also be returned to the pharmacy. Every dose of a
SC, SQ subcutaneous schedule II drug ordered for a patient must be accounted
Sig, S label for. For this reason, any drug found by the therapist on
Sos if needed the floor, table, or anywhere else in a patient’s room
stat at once must be turned in to the nursing station so that proper
sup, supp suppository accounting of these drugs can be made.
susp suspension
tab tablet
tbsp, T tablespoon (write out 15 ml) DRUG NAMING AND CLASSIFICATION
tid three times a day SYSTEMS
tsp teaspoon (write out 5 ml)
U units (write out units) Drugs have chemical, generic (nonproprietary), and trade
(proprietary) names. The chemical name is based on the
specific structure of the compound.54 It tends to be long,
are not allowed, and the prescriber must write a new and this name is often not used by either the public or the
prescription each time a refill is needed. In the hospital health care team. The generic name is considered the
setting, if an order is written on an as-needed basis, it is official name of the compound and may have some resem-
only valid for 72 hours. Prescription scripts older than blance to the names of other drugs that fall within the
6 months cannot be filled. same category or have the same purpose. It is the name
 CHAPTER 1 Introduction 9

listed in the official drug compendia, The United States enzyme inhibitors. The last method for categorizing
Pharmacopeia, and stays with the compound, no matter drugs is a classification based on either the chemical
how many trade names it accumulates. The generic names makeup or the source for the drug. Plant material pro-
are also the only names recognized for use in scientific jour- vides a good natural source for many compounds. Atro-
nals, although these names, too, can vary from one country pine is named after the plant species Atropa. Penicillin is
to another; for example, acetaminophen in the United part of a group of compounds described as ␤-lactam
States is known as paracetamol in the United Kingdom. antibiotics because they contain a ␤-lactam ring, a four-
The trade name or brand name is the name given to the member nitrogen-containing carbon structure.
drug by the pharmaceutical company and is copyrighted The system that is currently in place for classifying
to that company. In recent years, there has been a push for and naming drugs is imprecise, confusing, and implies
trendy names that the public will recognize. An example that all drugs within the same classification group act in
is the drug Singulair. Singulair, taken from the word a similar manner.56 In light of the potential for mistakes
“single,” is supposed to remind the public that it has when trade or proprietary names are used and the inac-
once-a-day dosing and is thus a more desirable drug than curacies implied in using functional categories for nam-
one that must be administered several times a day. These ing, there is a push toward using the official or generic
names, although they are helpful in steering the public names of drugs when speaking to patients and health
toward a particular drug, actually add more confusion to care professionals or when writing prescriptions. How-
the system of naming and increase the possibility that ever, pharmaceutical companies continue to market their
someone might make a mistake when writing a prescrip- drugs with trendy trade names.
tion. Once a patent expires, other pharmaceutical compa-
nies have a right to market the drug and assign their own
ACTIVITIES 1
trade names. Because there may be several trade names
given to one generic drug, use of trade names should be 1. This chapter has reviewed the phases of clinical drug
avoided while writing prescriptions. development. Outline some elements that must be
taken into consideration to ensure that this is an
ethical process.
Drug Classification 2. Discuss the key questions that should be answered
Drugs are often classified into specific categories. These concerning a drug during the development process.
categories do not represent a universally accepted sys- 3. Look-alike/sound-alike drugs are responsible for
tem, and one drug may be placed into a variety of differ- many medication errors.
ent classes.55 The classes do, however, provide a useful A. Name a few sound-alike drugs, and give their
framework for studying pharmacology. Drugs may be indications.
classified according to the body system being treated, for B. Discuss some strategies that can be used to reduce
example, cardiovascular drugs, pulmonary drugs, and look-alike and sound-alike medication errors.
gastrointestinal drugs. Drugs may also be classified ac- 4. Describe the following drugs using the pharmaco-
cording to their pharmacotherapeutic actions, or the therapeutic, pharmacologic, and molecular categories
overall pharmacologic actions of the drugs on specific of drug naming:
disease processes. Examples of drugs classified in this Propranolol
manner are antidepressants and antihypertensives. A Prazosin
mistake that is often made when medicines are delin- Captopril
eated in this manner is the assumption that all the drugs Losartan
classified under the same heading act in the same man- Nifedipine
ner. However, this is not always true. Diuretics and cal- Hydrochlorothiazide
cium channel blockers are both antihypertensives, but
they have very different mechanisms of action.
Drugs may also be categorized according to their
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 CHAPTER 1 Introduction 11

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 CHAPTER

2
Pharmacodynamics:
Mechanism of Action
Barbara Gladson

concentration.3,4 Ion specificity is determined by the

TARGETS FOR DRUG ACTION structural configuration of the amino acids (pore size)
As discussed in the previous chapter, drugs are classified and the charge on the molecule. Both the charge and size
according to their actions. The main emphasis of this of the pore vary for each type of ion channel. Common
chapter will be to describe these actions on both molecular voltage-gated channels include sodium (Na) and cal-
and cellular levels. Later chapters will deal with the effects cium (Ca2) channels in which these cations diffuse into
of these actions at tissue and system levels. When a drug the cell, causing a depolarization (Figure 2–2). When
acts at a molecular level, its target is usually a protein mol- potassium (K) channels open, the ion tends to flow out
ecule containing a binding site for the drug. Previously, a of the cell causing the cytosol to become more negative.
receptor was considered to be a distinct protein channel A well-known ligand-gated receptor is the nicotinic
imbedded in the cell’s phospholipid membrane whose acetylcholine (ACh) receptor consisting of five protein
function was to open and close in response to drug binding subunits arranged around a central pore. When two
(Figure 2–1). However, not all drugs have this type of dis- ACh molecules bind to the  subunit, the channel opens
tinct receptor. Other molecular targets or receptors include (Figure 2–3). Other ligand-gated channels include -
transport molecules, enzymes that catalyze chemical reac- aminobutyric acid (GABA), glycine, and serotonin re-
tions, nucleic acids, some miscellaneous targets such as ceptors. Several different subtypes exist for each of these
metal ions, or gastrointestinal contents.1 There are also main types of channels; however, they all share a prop-
drugs for which a distinct single molecular or chemical erty for quick activation, that is, the channel opens in a
binding entity has yet to be descovered.2 But, in general, millisecond timescale. The patch-clamp technique devel-
the sites for drug action include specific binding sites on oped by Neher and Sakmann is a way to measure the ion
proteins that undergo a conformational change in the pres- flow that occurs through the channel during opening.
ence of a ligand (drug) to initiate a cascade of events lead- Neher, E., Ion channels for communication between and
ing to the drug’s action called transduction. Identifying the within cells. Science, 1992. 256: p. 498-502.
drug–receptor interaction has been critical to the under- A tight seal is formed between a micropipette contain-
standing of how a drug works. ing an electrode and a cell membrane (Figure 2–4).
When the cell is exposed to a neurotransmitter or to a
voltage change, the pipette is able to measure the current
Receptor Types passing through a single channel. Many drugs are tested
Four receptor superfamilies have been identified: ion in this manner to determine their effects on specific ion
channel–linked receptors (ligand-gated and voltage-gated), channels. This has become a very important tool in the
G-protein–coupled receptors, deoxyribonucleic acid drug discovery process because there is evidence to sup-
(DNA)-coupled receptors, and kinase-linked receptors.1 port ion-channel mutations in a number of diseases (e.g.,
All except the intracellular DNA-coupled receptor are cystic fibrosis, long QT syndrome, and several types of
transmembrane receptors in that they contain receptors myopathies).5,6 In addition, targeting ion channels for
responding to ligands outside the cell but contain struc- treatment in cardiovascular and neurodegenerative dis-
tural proteins that link this region to the intracellular eases has become common. Examples of drugs that bind
domain. to ion channels include vasodilator drugs that inhibit the
Ligand- and voltage-gated receptors are transmem- opening of L-type calcium channels in cardiac and
brane proteins arranged around a central aqueous channel smooth muscles and the benzodiazepine tranquilizers
(pore). The channel opens in response to a ligand or a that bind to the GABAA receptor.
voltage change in the membrane, allowing the selective G-protein–linked receptors consist of a transmembrane
transfer of ions from a greater concentration to a lesser receptor coupled to an intracellular system by a special
12 Copyright © 2011, Elsevier Inc.
 CHAPTER 2 Pharmacodynamics: Mechanism of Action 13

Drug Molecules contractile proteins, ion channels, and cytokine produc-

tion. Examples of receptors that are linked to G-proteins
include subtypes of the muscarinic acetylcholine receptor,
Receptors dopamine receptor, and norepinephrine receptor, as
Extracellular well as a variety of hormone receptors.8-10 In addition,
G-protein–linked receptors function as targets for drugs
for approximately 30 currently available medications, in-
cluding montelukast (Singulair), losartan (Cozaar), and
loratadine (Claritin). It is expected that therapeutic inter-
vention with these receptors will have a major impact on
a variety of diseases in the future.
Intracellular DNA-coupled receptors are intracellular receptors that
FIGURE 2-1 A protein embedded in a cell membrane containing stimulate gene transcription, leading to the synthesis of
an extracellular binding site for a drug. proteins and enzymes.11-13 Because most are located intra-
cellularly in the nucleus, the ligands must be lipophilic to
facilitate crossing the cell membrane. Many of the ligands
Resting Open Inactivated
that activate this type of receptor are steroid hormones,
including estrogen, progesterone, cortisol, and thyroid
Na+
Favoured by hormone. Each receptor contains two regions, one for
depolarization
binding to DNA and the other for binding to the hor-
fast slow mone. When the hormone binds to the receptor on the
nuclear membrane, it interacts with a hormone response
element on the genome to either activate or depress gene
expression. If gene expression is activated, an increase in
Inactivated particle
ribonucleic acid (RNA) polymerase activity is detected
within a few minutes. The result is altered protein synthe-
sis. Mineralocorticoids act at these receptors to stimulate
Blocking
the production of new carrier proteins involved in trans-
drug port of ions through the kidney tubules.14
A B C The last type of receptor to be discussed is the kinase-
linked receptor. Kinase-linked receptors have a single
transmembrane helical region with a larger extracellular
domain for ligand binding.1,15 The size of the extracellular
region is related to the size of the endogenous ligand, an
example of which is the insulin molecule.16 Insulin binding
produces a dimerization, that is, a linkage of two kinase
FIGURE 2-2 Resting, activated, and inactivated states of voltage-
gated channels, exemplified by the sodium channel.
receptors that then phosphorylate each other. The auto-
phosphorylation of the tyrosine amino acids further pro-
vides strong binding sites for other intracellular proteins.
These intracellular proteins vary, depending on the recep-
protein called guanosine-binding protein (G-protein).1,7 tor involved, but are usually related to cell division and
The actual receptor crosses the membrane seven times, growth, with the final product being transcription of genes.
with the outer loops containing the active site for ligand Tyrosine kinase receptors have become recent targets for
binding (Figure 2–5). The inner loops are involved in ac- new and innovative treatments for cancer, including lung,
tivating of the G-protein. Once the appropriate ligand or breast, and gastrointestinal stromal tumors.17-20
drug binds to the extracellular side, a change occurs in the
three-dimensional structure of the receptor that activates
the G-protein, which then activates other effectors such as
Other Sites of Drug Action
ion channels and enzymes. G-proteins consist of three In addition to the receptors discussed previously, drugs
protein subunits: -, -, and -subunits. Once activated, may bind to several other specific sites. In the kidney
the -subunit binds guanosine triphosphate (GTP) and tubules, in particular, specific cell membrane ion pumps
loses its affinity for the -subunit (joined subunit). The and carrier proteins act as sites of drug action. Many
-subunit bound to GTP dissociates from the -subunit, diuretics bind to Na transporters in the renal tubules to
and each exerts its influence on a second messenger sys- block reabsorption of NA.21 If Na is not reabsorbed,
tem. There are several types of G-proteins, the functions water is lost (excreted), and plasma volume is decreased,
of which are determined by the type of -subunit. resulting in a lowering of blood pressure. Digoxin binds
The ultimate effects may be seen on enzyme activity, to the Na/K-adenosine triphosphatase pump in
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 CHAPTER XII.
The Difficulties of Diplomacy.

Courteous Reception in Paris.—Compliment of the King.—Principles of Prize

Division.—Embarrassing Questions.—Interesting Correspondence.—The Final
Settlement.—Modest Claims of Commodore Jones.—Plan for a Commercial
Speculation.—Its Failure.—The Mission to Denmark.—Return to America.

Commodore Jones, upon his arrival in Paris, was invited to dine

with Marshal Castries, Minister of Marine. After dinner the marshal
took the commodore aside, and said to him:
“I am requested by his majesty the king to say to you that it will
afford him much satisfaction to be able, in any way, to promote your
future fortune.”
The commodore immediately entered, with all his energies, upon
the arduous duties of his mission. There is no diplomacy equal that
of a straight-forward, honest purpose. There was never a shrewd
manœuvrer who did not eventually manœuvre himself out of all
influence. The reader would be weary of the detail of all the
embarrassments which, through the labors of two years,
Commodore Jones encountered, and over which, one by one, he
triumphed. And his success was never owing to cunning or intrigue,
but to the frank and manly pursuit of that which was just.
A careful examination of the diplomatic correspondence, which
was long-continued and with great ability on both sides, shows that
he was ever courteous, and that he held his own spirit under such
control, that rarely could any annoyance provoke him to utter an
irritable or a hasty word.
 On the 20th of December Paul Jones was introduced to the king.
He presented his credentials, and was received with the cordiality of
established friendship. The following letter to the Minister of Marine
will show the style and literary ability with which he conducted the
correspondence. It was addressed to “My Lord Maréchal,” under date
of February 1st, 1784.

“As I wish to give your excellency as little trouble as may be,

respecting the money arising from prizes taken by the squadron I
had the honor to command in Europe, I have waited, since the day
you did me the honor to present me to his majesty, until this
moment, in order to give you sufficient time for any arrangement
you might find essential, before the division should take place
between the ships and vessels that composed the force under my
command when the prizes were taken.
“I now do myself the honor to transmit you the enclosed official
letter on that subject, from Mr. Franklin, Minister Plenipotentiary of
the United States, containing a copy of my credentials as agent from
Congress, of which I had occasion to offer an account upon my
arrival. I also enclose a statement of the force, in guns and men, of
each ship and vessel that composed the squadron I commanded,
which is the only paper essential to the first division of the prize-
money.
“It is the custom, in cases like the present, to multiply the number
of the crew by the sum of the calibre of the cannon mounted on
board each ship. The product gives the intrinsic force in proportion
to which the share of the prize-money arising to each ship is
determined. On that ground it is my duty to claim the proportion
arising to the Bon Homme Richard and the Alliance. Their
proportions will afterward be divided by the American
Superintendent of Finance, agreeably to the rules of the American
navy, between the officers and the crews of the two ships.
“The subdivision of the shares of the other ships and vessels, in
proportion to their force in men and metal, of the prizes in which
they are concerned, will remain with your excellency to determine,
as may be most agreeable to the respective officers and men. As
those ships and vessels were entirely his majesty’s property, and
their officers and men composed of French subjects, I do not
presume to interfere in their respect any further than to pray your
excellency, in the most earnest manner, to render them, and all
concerned, that immediate justice to which all Europe knows their
distinguished services so highly entitle them. As nearly four years
and a half have already elapsed since those captures were made, I
rely on the kind promise you gave me, that the prize-money shall
now be immediately settled.
“I am, with profound respect, my lord maréchal, your most
obedient and most humble servant,
”John Paul Jones.”

The prize ships had been sold in France, and the money had been
placed in the hand of Monsieur de Chaumont, one of the crown
officers of finance. But the treasury was in debt to him. He therefore
took the liberty of keeping the money in payment of that debt,
leaving it for the claimants to draw upon the empty treasury for
whatever sum might be due them. In reference to this aspect of
affairs, Commodore Jones wrote to the minister.
“Whether Monsieur de Chaumont is indebted to the government,
or the government is, as he says, indebted to him, is a matter which
does not concern the captors of the prizes. But they have a right to
claim the protection of government to force Monsieur de Chaumont
to render the money, with interest, which he has unjustly detained
from them, for four years and a half, while many of them are
perishing with cold and hunger.”
This point he successfully carried. He had very wisely arranged
with Congress that all the money he might recover should be
transmitted by him to the Congressional treasury, to be paid by the
minister to the individual claimants. According to the concordat or
agreement which was entered upon with the French government
when the little squadron sailed, it was settled:
“That the division of prizes should be made agreeably to the
American laws; but that the proportion of the whole, coming to each
vessel in the squadron, should be regulated by the minister of the
Marine Department of France and the minister plenipotentiary of the
United States of America.”
But here there were conflicting principles. By the laws of France a
certain proportion of all prize-money was set apart for the support of
the Hospital of Invalids, from which institution American sailors could
derive no benefit. The American prize laws gave captors the whole
value of ships of war, and half the value of merchantmen. After long
negotiation the French government yielded this point also, and
allowed the distribution to be made according to American law.
There were, it will be remembered, five hundred British prisoners,
captured by Jones, maintained at very considerable expense for
some time by the French government, at the Texel. The British
government refused to surrender, in exchange for these men,
American prisoners. They did, however, give up French prisoners, in
exchange for them. When Commodore Jones passed over these men
to the French authorities, it was with the distinct understanding that
they, in conference with the British government, should obtain for
them an equal number of American captives, to be delivered to
Commodore Jones. But the spirit of the British cabinet was so
implacable toward the Americans, that the French government could
not accomplish this.
Marshal Castries now contended that the expenses attending the
maintenance of these prisoners at the Texel, and their transportation
to England, should be deducted from the prize-money. With
justifiable intensity of purpose, Commodore Jones combated this
claim. Dr. Franklin, then in Paris, was in entire accord with
Commodore Jones upon this question, as upon all the other
principles Jones had insisted upon in the adjustment. On the 25th of
March he wrote, in a letter addressed to “Honorable Paul Jones,
Esq.”:
“I certainly should not have agreed to charge the American
captors with any part of the expense of maintaining the five hundred
prisoners in Holland till they could be exchanged, when none of
them were exchanged for the Americans in England, as was your
intention, and as we both had been made to expect.”
 The commodore immediately enclosed this letter in another, which
he addressed to Marshal de Castries. He wrote:
“The within copy of a letter which I had the honor to receive
yesterday from Mr. Franklin, will convince you that he never
consented, and could not consent, to the manner proposed by your
predecessor and by M. de Chaumont for settlement of the prize-
money due to the American officers and men who served under my
orders in Europe.
“I will not complain that the prisoners which I took and carried to
Holland were not exchanged for the Americans, who had been taken
in war upon the ocean, and were long confined in the English
dungeons by civil magistrates, as traitors, pirates, and felons. I will
only say I had such a promise from the minister of marine.
“It was all the reward I asked for the anxious days and sleepless
nights I passed, and the many dangers I encountered in glad hope
of giving them all their liberty. And if I had not been assured that Mr.
Franklin had made an infallible arrangement with the courts of
France and England, for their immediate redemption, nothing but a
superior force should have arrested them out of my hands, till they
had been actually exchanged for the unhappy Americans in
England.”
This claim the French government also yielded. But still the weary
months rolled on, and no payment was made. The simple fact was
that there was no money in the treasury. The government was in a
condition of a man, struggling and floundering amidst all the
intolerable embarrassments of approaching bankruptcy. There were
claims upon them vastly more pressing than the payment of a few
thousand livres to a few hundred poor foreign seamen. Commodore
Jones was fully aware of all this. With characteristic courtesy,
kindness, and yet firmness, he addressed a letter, as follows, to the
marshal on the 23d of June, 1785.
“By the letter your excellency did me the honor to write me on the
13th of May last, you were pleased to promise that as soon as M. de
Chardon should have sent you the liquidation of my prizes, which
you expected without delay, you would take measures for the
payment, and you would let me know.
 “From the great number of affairs more important that engage
your attention, I presume this little matter, which concerns me in a
small degree personally, but chiefly as the agent of the brave men
who served under my orders in Europe, may have escaped your
memory. Since the first of November, 1783, when I received
authority to settle this business with your excellency, I have been
waiting here for no other purpose, and constantly expecting it to be
concluded from month to month. To say nothing of my expenses
during so long an interval, the uncertainty of my situation has been
of infinite prejudice to my other concerns. My long silence is a proof
that nothing but necessity could have prevailed on me to take the
liberty of reminding your excellency of your promise. I hope for the
honor of a final determination, and I am with great respect, etc.”
Still there were delays of the most annoying character too
numerous and too tedious to be narrated. Through all these,
Commodore Jones retained his equanimity, and commanded the
respect of those with whom he was contending. The expenses of
Commodore Jones, as agent of the United States at the court of
Versailles, were necessarily considerable. One could not fill the post
of an ambassador there upon the wages of a day-laborer. It was
essential to his influence, as he was daily brought in contact with the
ancient nobility of France, that he should maintain the style of a
gentleman.
At length, on the 15th of July, 1785, Marshal Castries issued an
order to pay to Commodore Jones, at L’Orient the sum of one
hundred eighty-one thousand and thirty-nine livres, one sous, and
ten derniers. Thomas Jefferson was then our minister at Paris. In a
letter addressed to him about this time, Jones wrote:
“I cannot bring myself to lessen the dividend of the American
captors by making any charge either for my time or trouble. I lament
that it has not been in my power to procure for them advantages as
solid and extensive as the merit of their services. I would not have
undertaken this business from any views of private emolument that
could possibly have resulted from it to myself, even supposing I had
recovered a sum more considerable than the penalty of my bond.
The war being over I made it my first care to show the brave
instruments of my success that their rights are as dear to me as my
own. It will, I believe, be proper for me to make oath before you, to
the amount charged for my ordinary expenses.”
Our minister received a salary of ten thousand dollars a year. It
required the most rigid economy, with that sum, to meet expenses.
Mrs. Adams, the wife of our distinguished ambassador John Adams,
in her letters, gives a graphic account of their residence at the little
village of Auteuil, about four miles from Paris. The house was large,
and coldly elegant. There were massive mirrors and waxed floors,
but no air of comfort. A servant polished the floors each morning
with a brush buckled to one of his feet. The expenses of
housekeeping were enormous. A heavy tax was imposed upon
everything. All articles of domestic use about thirty per cent. higher
than in Boston. It was absolutely necessary to keep a coach. The
coachman and horses cost fifteen guineas a month. The social
customs of the country required seven servants. The inevitable
expenses of the family were so heavy that it required all Mrs.
Adams’s remarkable financial skill to save them from pecuniary ruin.
The humble style in which they lived, compared with the splendor
with which the other foreign ministers were surrounded, often
caused mortification. Mr. Jay was compelled to resign, since he could
not support himself upon his salary.
Such were the surroundings of Commodore Jones in his arduous
mission. And yet he practised such rigid economy, that he charged
but five thousand dollars a year for all his services and expenses.
Franklin and Jefferson both carefully examined his accounts and
gave them their approval. They were then sent to Congress, where
they were again subjected to a rigid scrutiny, and were again
approved. Not long after, on the 16th of October, 1787, Congress
passed the following vote:
“Resolved unanimously, that a medal of gold be struck and
presented to the Chevalier John Paul Jones, in commemoration of
the valor and brilliant services of that officer, in the command of the
squadron of American and French ships, under the flag and
commission of the United States, off the coast of Great Britain, in
the late war; and that the Honorable Mr. Jefferson, minister
plenipotentiary of the United States at the court of Versailles, have
the same executed with the proper devices.”
At the same time, Congress commended Commodore Jones to the
special regard of the king of France, and solicited permission for him
to embark in the French fleets of evolution, convinced that he can
nowhere else so well acquire that knowledge which may hereafter
render him more extensively useful.
The commodore, with his intense views of life’s duties, never
found time for conviviality or any dissipating pleasures. He employed
his otherwise unoccupied hours in writing a very carefully prepared
narrative of his past services. This was not printed, but was read in
manuscript by many distinguished personages. The illustrious
Malesherbes, after reading the journal, wrote as follows to Mr.
Jones:
“I have received with much gratitude the mark of confidence
which you have given me; and I have read, with great eagerness
and pleasure, the interesting relation. My first impression was to
desire you to have it published. But after having read it, I perceive
that you had not written it with a view to publication, because there
are things in it which are written to the king, for whom alone that
work was intended. However actions, memorable as yours are,
ought to be made known to the world, by an authentic journal
published in your own name. I earnestly entreat you to work at it as
soon as your affairs will allow. In the meantime, I hope that the king
will read this work with that attention which he owes to the relation
of the services which had been rendered to him by a person so
celebrated.”
While these scenes were transpiring, the renowned American
traveller, John Ledyard, was in Paris. He proposed to Commodore
Jones a commercial speculation, upon a scale of grandeur likely to
interest his mind, and which would call into requisition all his
administrative energies and acquired information and skill.
The plan was to fit out a vessel of two hundred and fifty tons, to
be thoroughly armed and equipped, with forty-five officers and men,
to be selected in France. She was to sail, on the first day of October,
for Cape Horn, and thence to the Sandwich Islands. There she was
to take in new stores of provisions, and continue her route to the
northwest coast of North America. She was to remain from April to
October, running up and down the coast, purchasing furs of the
Indians.
Having filled the vessel, they were to make sail across the Pacific,
for China or Japan. The rich furs would there bring a great price.
They were to be sold for gold or other commodities. With this gold
and merchandise the ship was to return to France, by way of the
Cape of Good Hope. It was thought that the whole voyage would
occupy about eighteen months. After a very close calculation it was
estimated that the profits of the enterprise would amount to a little
over one hundred and eighty thousand dollars.
Such was the plan in general, subject to various modifications,
such as whether one vessel should go alone, or whether two should
go in company. It was by a somewhat similar commercial enterprise
that John Jacob Astor subsequently laid the foundation of his
colossal fortune.
There was much to recommend this plan to enthusiastic and
enterprising men. Its novelty lent a great charm. It was considered
that the risks were small, decidedly less than those which usually
attended voyages to the East or West Indies. The expense of the
armament, and the cargo of trinkets, small ware, and cutlery, for
traffic with the Indians, was very inconsiderable. It was well known
that the northwest coast of America abounded in the richest furs,
above all other regions in the world. These furs could be purchased
for a mere trifle from the Indians. In China and Japan they would
command extravagant prices.
Jefferson was deeply interested in this plan. In his mind, as in that
of Paul Jones, it assumed a dignity far above that of a mere money-
making enterprise. It would extend our knowledge of those vast
regions, with their wild inhabitants, which both of these sagacious
men foresaw would eventually be included within the limits of the
American Union. Paul Jones was to have the supreme command,
and by his powerful influence was to obtain the vessel and the outfit.
Ledyard was to be supercargo.
 As they pondered the plan, aided by the cool judgment of Mr.
Jefferson, it assumed ever-increasing proportions. A trading post
was to be established, strongly stockaded and well garrisoned. The
Indians were to be treated with the greatest justice and humanity,
so as to secure their good-will. There were to be two vessels
employed, one of which should always be on the coast. Silks and
teas were to be purchased, upon which there would be an additional
profit in Europe.
The plan was manifestly so feasible and so full of promise, that it
was necessary to keep it as secret as possible, lest many others
should embark in the same enterprise, and the rivalry should
become great. Indeed, there were rumors, which reached Mr.
Jones’s ears, that there were other parties contemplating a similar
movement. He wrote to Dr. Bancroft upon the subject. He replied,
under date of September 9th, 1785:
“I endeavored, as early as possible, to gain information respecting
the object of your inquiry. But it was a difficult matter, none of my
acquaintance knowing anything more of it than what had appeared
in the public papers. Yesterday, however, I was informed, by a
gentleman who I believe has some more knowledge of the fact, that
the two vessels, King George and Queen Charlotte, have actually
sailed on the expedition which was thought of by Mr. Ledyard, for
furs, which I should suppose must interfere with, and very much
lessen the profits of any simular undertaking by others.”
Mr. Jones wrote to Madrid, and was informed that the court of
Spain would not allow any commercial speculation in the
neighborhood of California, by the subjects of any other nation than
her own. It is supposed that this fact mainly led to the abandonment
of the scheme. There may have been, and probably were, other
considerations. But we hear of the enterprise no more.
The reader will remember that there were three prizes sent by
Landais to Norway, and that the Danish government restored them
to the British ambassador upon the ground that the vessels had
been captured by a people not recognized by them as an
independent government. This was sustaining the British claim, that
Jones was not a legitimate naval officer, but a mere pirate, whom
they would be justified in hanging could they catch him. Every
officer in the colonial army and navy, in the view of the British
government, stood upon the same platform.
The prizes thus lost to us at Copenhagen were valued at two
hundred and fifty thousand dollars. This was five-fold the amount
recovered from the prizes sent into France. Upon the threatened
surrender of these prizes, Dr. Franklin immediately sent a memorial
to Count Bernstorf, the Danish prime minister. This admirable state
paper contained the following very characteristic sentences. After
recapitulating the circumstances of the case, he adds:
“Permit me, sir, to observe on this occasion, that the United States
of America have no war but with the English. They have never done
any injury to other nations, particularly none to the Danish nation.
On the contrary, they are in some degree its benefactors, as they
have opened a trade of which the English made a monopoly, and of
which the Danes may now have their share; and by dividing the
British empire have made it less dangerous to its neighbors. They
conceived that every nation whom they had not offended was, by
the rights of humanity, their friend. They confided in the hospitality
of Denmark, and thought themselves and their property safe when
under the roof of his Danish majesty.
“But they find themselves stripped of that property, and the same
given up to their enemies, on the principle only that no
acknowledgment had yet been formally made, by Denmark, of the
independence of the United States; which is to say that there is no
obligation of justice toward any nation, with whom a treaty,
promising the same, has not been made. This was indeed the
doctrine of ancient barbarians; a doctrine long since exploded, and
which it would not be for the honor of the present age to revive. And
it is hoped that Denmark will not, by supporting and persisting in
this decision, obtained of his majesty apparently by surprise, be the
first modern nation that shall attempt to revive it.
“The United States, oppressed by, and in war with one of the most
powerful nations of Europe, may well be supposed incapable, in their
present infant state, of exacting justice from other nations not
disposed to grant it. But it is in human nature, that injuries as well
as benefits, received in times of weakness and distress, national as
well as personal, make deep and lasting impressions. And those
ministers are wise who look into futurity, and quench the first sparks
of misunderstanding between two nations, which neglected, may in
time grow into a flame, all the consequences whereof no human
prudence can foresee, which may produce much mischief to both,
and cannot possibly produce any good to either.
“I beg, through your excellency, to submit these considerations to
the wisdom and justice of his Danish majesty, whom I infinitely
respect, and who, I hope, will consider and repeal the order above
recited; and, if the prizes which I hereby reclaim, in behalf of the
United States of America, are not actually gone to England, that they
may be stopped and redelivered to M. de Chezaulx, the consul of
France, at Bergen, in whose care they were before, with liberty to
depart for America, when the season shall permit. But if they shall
be already gone to England, I must then reclaim from his majesty’s
equity the value of the said three prizes, which is estimated at fifty
thousand pounds sterling, but which may be regulated by the best
information that can, by any means, be obtained.”
The three prizes thus surrendered, were the Betsey, the Union,
and the Charming Polly. Mr. Jones had been so successful in his
negociations with France, that it was deemed expedient to send him
to Copenhagen to seek redress from the Danish court. He obtained
the works of Grotius, and all other eminent writers upon the Law of
Nations, and, aided by Thomas Jefferson, made himself familiar with
all the principles involved in the questions at issue. Thus thoroughly
equipped, he entered upon this new and difficult enterprise. In every
movement of importance, at this time, Paul Jones conferred with his
highly valued friends, Thomas Jefferson and Benjamin Franklin, and
acted with their concurrence. A little before this, the Danish
government had so far recognized the injustice of its acts, and the
validity of our claim, as to offer to pay an indemnity of forty
thousand dollars. Dr. Franklin declined this offer upon the ground
that the fair value of the prizes should be first ascertained. It was
thought best that Commodore Jones should repair, at once, to
Copenhagen.
 He left Paris, with this purpose, in the spring of 1787. At Brussels
he failed to receive an expected remittance from the sale of some
bank stock he had ordered in America. Thus he found himself out of
funds. This induced him to turn back, and take passage to the
United States, to inquire into the condition of his pecuniary affairs.
He speedily attended to his private concerns and prepared to return
to Europe. Fully aware of the difficulty of his mission, he was
anxious to fortify himself with all those moral forces which could add
to his influence. He wrote to Honorable John Jay, our Minister of
Foreign Affairs, soliciting from him such testimonials as would
commend him to the Danish court. His letter was dated New York,
July 18th, 1787. It was easy for his enemies to represent this as an
act of mere vanity. Perhaps it was. But it was certainly an act of
wisdom, thus to endeavor to secure the confidence and good-will of
the court, to which he was commissioned for the performance of
duties so arduous. In the conclusion of his letter to Mr. Jay, he
wrote:
“Since the year 1775, when I displayed the American flag, for the
first time, with my own hands, I have been constantly devoted to
the interests of America. Foreigners have perhaps given me too
much credit. This may have raised my ideas of my services above
their real value. But my zeal can never be overrated.
“I should act inconsistently, if I omitted to mention the dreadful
situation of our citizens in Algiers. Their almost hopeless fate is a
deep reflection on our national character in Europe. I beg leave to
influence the humanity of Congress in their behalf, and to propose
that some expedient may be adopted for their redemption. A fund
might be raised, for that purpose, by a duty of a shilling per month
from seamen’s wages, throughout the continent, and I am
persuaded that no difficulty would be made to that requisition.”
 CHAPTER XIII.
The Mission to Denmark.

Letter to Mr. Jefferson.—The Marquise de Marsan.—Unfounded Charges and

Vindication.—Flattering Application from Catherine II.—His Reception at the
Polish Court.—Jones receives the Title of Rear-Admiral.—English Insolence.—
Letter of Catherine II.

Just before Mr. Jones left Europe, he transmitted a letter to

Congress, informing them that the piratic regency of Algiers had
armed eight war vessels, carrying from eighteen to thirty-four guns
each, which were to cruise between Cape St. Vincent and the
Azores, to capture American ships. The French minister, M.
Soulanges, at Toulon, had ascertained this fact, and very kindly,
immediately communicated it to Mr. Jones. In writing to Mr. Jefferson
upon the subject, the commodore said:
“This event may, I believe, surprise some of our fellow-citizens.
But, for my part, I am rather surprised that it did not take place
sooner. It will produce a good effect, if it unites the people of
America in measures consistent with their national honor and
interest, and rouses them from that ill-judged security, which the
intoxication of success has produced since the revolution.”
One of his most valued lady friends in France, a daughter of Louis
XV., wrote to him, in deepest affliction. Though a daughter of the
king, and as such enjoying high rank, she was not regarded as a
member of the royal family. The king bestowed a large fortune upon
the mother, on the daughter’s account. The father died when the
daughter, who was a great favorite of his, was very young. The
mother then greatly neglected this child of a royal sire, treating her
neither with natural affection nor justice. This young lady was
adopted by the Marquise de Marsan, who became to her as a
mother, and introduced her to the highest society of the court.
She was very happily married to M. Tellison, a very worthy
gentleman, but without fortune. In this virtuous family, Commodore
Jones had found, in his lonely hours in Paris, a congenial and happy
home. The aged marquise regarded the young hero as her own son.
Monsieur and Madame Tellison treated him with truly fraternal
affection. Their little boy was a great favorite of the commodore, as
he fondled him upon his knee, and lavished caresses upon him.
Man is born to mourn. The day of sorrow came to this united and
happy family. On the 23d of June, 1787, Madame Tellison wrote to
Paul Jones, in New York, informing him of the sudden death of her
friend and protectress, the Marquise de Marsan, and of consequently
a great reverse in their pecuniary condition. Jones, writing to Dr.
Bancroft in London, alluding to this event, said:
“This is also a great grief and loss to me, as I had in that lady a
valuable friend.”
The letter Madame Tellison had written to Mr. Jones, was
forwarded to him by Thomas Jefferson. He immediately wrote to Mr.
Jefferson as follows:
“The letter you sent me, left the feeling author all in tears. Her
friend, her protectress, her introductress to the king, was suddenly
dead. She was in despair. She lost more than a mother. A loss indeed
that nothing can repair; for fortune and favor are never to be
compared to tried friendship. I hope, however, she has gone to visit
the king in July, agreeably to his appointment given to her in the
month of March. I am persuaded that he would receive her with
additional kindness, and that her loss would, in his mind, be a new
claim to protection; especially as he well knows and has
acknowledged her superior merit and just pretensions.
“As I feel the greatest concern for the situation of this worthy lady,
you will render me a great favor by writing a note requesting her to
call on you, as you have something to communicate from me. When
she comes, be so good as to deliver her the within letter, and show
her this; that she may see both my confidence in you and my advice
to her.”
The enclosed letter, full of gushing sympathies, was as follows. It
was dated New York, September 4th, 1787.
“No language can convey to the fair mourner the tender sorrow I
feel on her account. The loss of our worthy friend is, indeed, a fatal
stroke! It is an irreparable misfortune, which can only be alleviated
by this one reflection, that it is the will of God, whose providence
has, I hope, other blessings in store for us. She was a tried friend
and more than a mother to you. She would have been a mother to
me also, had she lived. We have lost her. Let us cherish her memory
and send up grateful thanks to the Almighty that we once had such
a friend.
“I cannot but flatter myself that you have yourself gone to the
king, in July, as he had appointed. I am sure your loss will be a new
inducement for him to protect you and render you justice. He will
hear you, I am sure. You may safely unbosom yourself to him and
ask his advice, which cannot but be flattering for him to give you.
Tell him you must look on him as your father and protector. If it were
necessary I think too that the Count d’Artois,[E] his brother, would,
on your personal application, render you good offices by speaking in
your favor. I should like it better, however, if you can do without him.
“I am almost without money, and much puzzled to obtain a supply.
I mention this with infinite regret, and for no other reason than
because it is impossible for me to transmit you a supply, under my
present circumstances. This is my fifth letter to you since I left Paris.
The two last were from France. But you say nothing of having
received any letters from me. Summon, my dear friend, all your
resolution. Exert yourself and plead your own cause. You cannot fail
of success. Your cause would move a heart of flint. Present my best
respects to your sister. You did not mention her in your letter. But I
persuade myself she will continue her tender care of her sweet
godson, and that you will cover him all over with kisses from me.
They come warm to you both, from the heart.”
While in New York he heard very ungenerous complaints that his
charge for services in recovering the prize-money was exorbitant.
Earnestly seeking the good-will of his fellow-citizens, these
reproaches pained him. He wrote upon the subject as follows:
“The settlement I made, with the court of France, had first Dr.
Franklin’s, and afterwards Mr. Jefferson’s approbation, in every stage
and article of the business. And I presume it will be found, so far as
depended on me, to merit that of the United States. In France I was
received and treated by the king and his ministers, as a general
officer, and a special minister from Congress. The credit with which I
was honored as an officer, in the opinion of Europe, and the personal
intimacy I have with many great characters at Paris, with my
exclusive knowledge of all circumstances relative to the business,
insured me a success which no other man could have obtained. My
situation subjected me to considerable expense. I went to court
much oftener, and mixed with the great much more frequently than
our minister plenipotentiary. Yet the gentlemen in that situation
consider their salary of two thousand pounds sterling a year as
scarcely adequate to their expenses.”
His busy mind was ever fertile in expedients for the public welfare.
In urging upon Congress immediate and effectual measures for the
rescue of the unhappy American captives in piratic and barbaric
Algiers, he had urged the establishment of a fund for that object. He
also urged that, from this fund, a great national hospital should be
established, for the benefit of invalid seamen, on the plan of the
renowned Greenwich Hospital in England, and the still more far-
famed Hotel des Invalides in Paris.
On the 11th of November, Mr. Jones sailed from New York on his
mission to Denmark. Unfavorable weather caused the ship to put
into Dover early in December, 1787. He repaired to London and
spent a few days with our minister at the court of St. James,
Honorable John Adams. He proceeded to Paris, where he arrived on
the 11th of the month. For some unexplained reason he did not wish
to have the fact of his arrival noised abroad. The day after he
reached Paris, he had a private interview with Mr. Jefferson. In this
interview he received the startling and flattering announcement, that
the Empress of Russia was anxious to engage his services as an
officer, in the war she was then carrying on against the Turks. M.
Simolin, the Russian ambassador at Versailles, had been instructed
to apply to Mr. Jones, through Mr. Jefferson, to see if the services of
the chevalier could be engaged as an officer in her navy. While this
plan was under consideration, he called upon several of the French
ministers, from whom he met a very cordial reception.
On the 4th of March, 1788, after a long and fatiguing winter
journey, Mr. Jones reached Copenhagen. He was then but forty years
of age. His health, however, was much impaired by the cares, toil,
and exposure of his stormy life. Soon after his arrival he breakfasted
with the chamberlain of the king of Poland, for the purpose of
meeting Mr. Simolin, the Russian ambassador. He informed Mr.
Jones, that in consequence of the knowledge which the empress had
obtained of his character, she wished him to take command of her
fleet in the Black Sea, and that she would soon make to him
advantageous proposals. After the Russian ambassador had retired,
the chamberlain, whose guest the commodore was, informed him
that Mr. Simolin had written to the empress:
“If your Imperial Majesty will confide to Commodore Jones the
chief command on the Black Sea, with carte blanche, I will answer
for it, that, in less than a year he will make Constantinople tremble.”
Soon after this he was presented to the royal family, to all of the
corps diplomatique, and to many other distinguished personages of
the court. In speaking of his reception by the king, the queen
dowager, and the young prince and princess royal, he wrote:
“The queen dowager conversed with me for some time, and said
the most civil things. Her majesty has a dignity of person and
deportment which become her well, and which she has the secret to
reconcile with great affability and ease. The princess royal is a
charming person; and the graces are so much her own, that it is
impossible to see and converse with her without paying her the
homage which artless beauty and good-nature will ever command.
All the royal family spoke to me except the king, who speaks to no
person when presented. His majesty saluted me with great
complaisance at first, and as often afterwards as we met in the
course of the evening. The prince royal is greatly beloved, and
extremely affable. He asked me a number of pertinent questions
respecting America. I had the honor to be invited to sup with his
majesty and the royal family. The company at table, consisting of
seventy ladies and gentlemen, including the royal family, the
ministers of state, and foreign ambassadors, was very brilliant.”
Very earnestly Commodore Jones engaged in the object of his
mission. He had a double motive to impel him to make all possible
haste. In addition to the natural desire to close up the business,
which had been thus lingering for years, he was now daily expecting
offers of employment from the Empress of Russia, which it might be
greatly for his interest to accept. The Algerines, those merciless
pirates of all seas, were united with the Turks of Constantinople, in
their warfare against Russia. An opportunity might thus be afforded
him to strike a blow for the liberation of the American captives. This
was an object very near his heart.
There is power in an illustrious name. The achievements of
Commodore Jones were well known at Copenhagen. He had
received a golden medal, for his services, from the Congress of the
United States. The king of France had honored him with a gold-
headed sword, and had conferred upon him the distinguished honor
of constituting him a Knight of the Order of Military Merit. It was also
known that he had won the esteem of the most distinguished men in
Paris, and was an honored guest in the highest circles of the court.
These considerations were all elements of power, of which Mr. Jones
very wisely availed himself. In urging the Danish minister, Count de
Bernstorf, to a prompt decision, Mr. Jones wrote under date of March
24th:
“The promise you have given me of a prompt and explicit decision,
from this court, inspires me with full confidence. I have been very
particular in communicating to the United States all the polite
attentions with which I have been honored at this court. And they
will learn, with great pleasure, the kind reception I have had from
you. I felicitated myself on being the instrument to settle the
delicate national business in question, with a minister who
conciliates the views of the wise statesman with the noblest
sentiments and cultivated mind of the true philosopher and man of
letters.”
 If any one regards this as excessive in its complimentary tone, as
it certainly appears to be, let him read the next letter to Count
Bernstorf, after a delay of six days, which indicates that he could
deal with other coin besides that of laudation. This letter was dated
March 30th.
“Your silence on the subject of my mission from the United States
to this court, leaves me in the most painful suspense; the more so
as I have made your excellency acquainted with the promise I am
under, to proceed, as soon as possible, to St. Petersburg. This being
the ninth year since the three prizes reclaimed by the United States,
were seized upon in the port of Bergen, in Norway, it is to be
presumed that this court has long since taken an ultimate resolution
respecting the compensation demand made by Congress.
“Though I am extremely sensible of the favorable reception with
which I have been distinguished at this court, and am particularly
flattered by the polite attentions with which you have honored me,
at every conference, yet I have remarked with great concern, that
you have never led the conversation to the object of my mission
here.
“A man of your liberal sentiments will not therefore be surprised,
or offended at my plain dealing, when I repeat that I impatiently
expect a prompt and categorical answer, in writing, from this court
to the Act of Congress of the 25th of October last. Both my duty,
and the circumstances of my situation, constrain me to make this
demand in the name of my sovereign the United States of America.
“But I beseech you to believe that though I am extremely
tenacious of the honor of the American flag, yet my personal
interests in the decision I now ask, would never have induced me to
present myself at this court. You are too just, sir, to delay my
business here, which would put me under the necessity to break the
promise I have made to her imperial majesty, conformable to your
advice.”
To this very decisive communication the minister returned an
answer full of compliments and full of evasions. The king had no
money to spare. Yet he was very desirous of securing the friendship
of the United States, that he might enter into a commercial treaty,
which would be of great benefit to Denmark. Amidst a vast mass of
verbiage the commodore was informed that the king thought it best
to defer a final settlement until the Constitution of the United States
was fully established; that a settlement could only be made with an
ambassador invested with plenipotentiary powers; and that, as the
negotiations were commenced with the United States ministers in
Paris, it was not expedient to transfer the seat of the suspended
negociation from Paris to Copenhagen. In conclusion, he begged
Commodore Jones to assure the government of the United States of
the cordial esteem of the king of Denmark, of the earnest desire of
his majesty to form connexions solid, useful and essential with this
country, and to assure the government that when the proper time
came, nothing should be allowed to retard the conclusion of an
amicable settlement of a question, already so far advanced toward a
solution. Under these circumstances, the only thing to be done was
to transfer the business to Mr. Jefferson. This enabled him
immediately to enter upon the service of the Empress of Russia. In
his letter, on this occasion, to Mr. Jefferson, he wrote:
“If I have not finally concluded the object of my mission it is
neither your fault nor mine. The honor is now reserved for you to
display your great abilities and integrity by the completion and
improvement of what Dr. Franklin had wisely begun. I rest perfectly
satisfied that the interests of the brave men I commanded will
experience in you, parental affection, and that the American flag can
lose none of its lustre, but the contrary, while its honor is confided to
you.
“While I express, in the warm effusions of a grateful heart, the
deep sense I feel of my eternal obligations to you, as the author of
the honorable prospect that is now before me, I must rely on your
friendship to justify to the United States the important step I now
take conformable to your advice.
“I have not forsaken a country that has had many and
disinterested proofs of my affection. And I can never renounce the
glorious title of a citizen of the United States. It is true that I have
not the express permission of the sovereignty to accept the offer of
her imperial majesty. Yet America is independent, is in perfect peace,
and has no public employment for my military talents.
“The prince royal sent me a messenger requesting me to come to
his apartment. His royal highness said a great many civil things to
me; told me that the king thanked me for my attention and civil
behavior to the Danish flag, while I commanded in the European
seas; and that his majesty wished to testify to me his personal
esteem.”
It is said that Jones was offered a pension from the Danish
government of fifteen hundred crowns a year. Jones, however, never
mentioned this circumstance to any of his most familiar
correspondents. There is no evidence that he ever received one
dollar of this money, but, on the contrary, much evidence that he
never received any.
The commodore repaired to St. Petersburg. He was received by
the empress with more flattering attentions than the court had ever
before conferred upon any stranger. The empress immediately
conferred upon him the rank of rear-admiral. He was detained in the
capital, contrary to his wishes, a fortnight, where he was introduced
to the first circles of society, feasted and caressed. Jones, speaking
of this reception, writes to Lafayette:
“You would be charmed with Prince Potemkin. He is a most
amiable man, and none can be more noble-minded. For the
empress, fame has never done her justice. I am sure that no
stranger who has not known that illustrious character, ever
conceived how much her majesty is made to reign over a great
empire, and to attach grateful and susceptible minds.”
The attentions which Paul Jones received from the Russian court
greatly annoyed the English in and about St. Petersburg. They still
insolently persisted in stigmatizing a commissioned officer in the
American navy as a renegade and a pirate, because, having been
born in Scotland, he had espoused the cause of American liberty.
Tooke, in his life of Catherine II., gives vent to all his bitter British
prejudices. Calling Admiral Jones an “English pirate and renegado,”
he adds, “Jones, not meeting with the consideration he expected in
America, made a tender of his services to the court of St.
Petersburg; and the British officers, applicants for employment, went
in a body to the amount of near thirty to lay down their
commissions, declaring it was impossibly to serve under him, or to
act with him in any measure or capacity.”
We read in an Edinburgh paper of that date the following notice of
that event, probably written by a Russian officer. “Paul Jones arrived
here a few days ago. He is to set out soon, to take command of a
squadron in the Black Sea. I had the satisfaction to see this honest
man, while he was examining one of our dock-yards. He is a well-
made man of middle size; he wears the French uniform with the
Cross of St. Louis, and a Danish order which he received at
Copenhagen, where he had the honor to dine with the king. He has
also received, since he came here, one of the first Orders of Merit in
this country, so that it is to be feared that they will spoil him by
making too much of him. The English officers in the service have
presented a memorial to Admiral Greig, refusing to serve with Jones,
and threatening to throw up their commissions. Whether they will
stand to their text, it is difficult to say.”
The empress paid no attention whatever to this petulance. Admiral
Jones treated it with profound contempt. In writing to Lafayette, in
reference to his treatment by the Russian court, he says:
“This was a cruel grief to the English, and I own that their
vexation, which was generally in and about St. Petersburg, gave me
no pain.”
The empress with her own hands wrote to the admiral. In her
letter she probably refers, though slightly, to this unmanly opposition
of the English. We give her letter.

“Sir—A courier from Paris has just brought from my envoy in

France, M. Simolin, the enclosed letter to Count Besborodko.[F] As I
believe that this letter may help to confirm to you what I have
already told you verbally, I have sent it, and beg you to return it, as
I have not even made a copy be taken, so anxious am I that you
should see it. I hope that it will efface all doubts from your mind,
and prove to you that you are to be connected only with those who
are most favorably disposed toward you. I have no doubt but that on
your side you will fully justify the opinion which we have formed of
you, and apply yourself with zeal to support the reputation and the
name you have acquired for valor and skill on the element in which
you are to serve.
“Adieu. I wish you happiness and health.
“Catherine.”
 CHAPTER XIV.
The Russian Campaign.

Admiral Jones repairs to the Black Sea.—Designs of Catherine II.—Imposing

Cavalcade.—Turkey Declares War against Russia.—Daring Conduct of Admiral
Jones.—A Greek Officer Alexiano.—The Prince of Nassau Siegen.—Annoyances
of Admiral Jones from Russian Officers.—Battle in the Black Sea.—Jones yields
the Honor to the Prince of Nassau.

At the same time when Chevalier Jones received his flattering

letter from the empress, her prime minister sent to him a despatch,
requesting him to repair to the naval headquarters on the Black Sea,
that he might take part in the opening of the campaign. The minister
also assured him, in the name of the empress, that everything
possible should be done to make his situation agreeable, and to
furnish him with opportunities for the exercise of his valor and skill.
It is not surprising that the admiral, receiving such marks of
attention from her imperial highness, should have formed a high
estimate of the excellence of her character. He wrote to Count Segur
at this time, saying:
“I shall write to the empress, who hath sent me a letter full of
goodness. But I shall never be able to express how much greater I
find her than fame reports. With the character of a very great man,
she will be always adored as the most amiable and captivating of the
fair sex.”
War had been impending for several years between Russia and
Turkey. The Turks, in the wanton spirit of barbarian conquest,
without the shadow of excuse for the invasion, had crossed the
Hellespont with an overwhelming army, had seized Constantinople,
and rushing onward in the tide of victory, had unfurled their
triumphant banners within sight of the battlements of Vienna. All
Europe had trembled beneath the tread of the terrible Moslem
armies. Catherine was anxious to drive these usurping Turks back
from Europe, across the Dardanelles and the Bosphorus, into their
Asiatic wilds. She would make the imperial city of Constantine her
maritime capital and her great naval depot, from which most
admirable point she could command the commerce of the world.
This was the real and ever-constant cause for the war, which for
nearly a century had been waged between Russia and the Porte. But
innumerable and frivolous pretexts had been brought forward, as
excuses for an appeal to arms.
About ten years before this, the empress had established a naval
depot on the right bank of the Dnieper, not very far from the
entrance of the river into the Euxine, or Black Sea. Imperial
influence soon brought a population of forty thousand to this port,
which became an important dock-yard, where the largest ships-of-
war were launched. The region around was wild, savage, filled with
wandering, half-civilized Tartar tribes. Russian gold and Russian arms
gradually gained the ascendency and the tribes, with their territory,
were gradually annexed to the majestic Russian Empire.
Catherine then contrived, by a treaty with the Porte, to obtain the
sovereignty over the immense province of the Crimea; also a sort of
dominion over the Black Sea, and the right to pass with her ships
through the Dardanelles. In anticipation of the conquest of
Constantinople, she caused her young son to be called Constantine.
The King of Poland, the Emperor of Austria, and most of the other
powers of northern Europe, were in sympathy with the ambitious
designs of Russia. They all wished to see the Turks driven back into
Asia. In that case, most of them would receive portions of the
immense territory which the Turks had overrun in Europe. But
England was intensely opposed to the designs of Russia. The Turkish
Empire, England regarded as an important and necessary barrier
between the rapidly growing power of Russia and her own
possessions in the East Indies.
 In the year 1786, Catherine projected a magnificent progress to
her new possessions on the Euxine. The enterprise was organized
with all the imposing brilliance which oriental grandeur could create.
The immense cavalcade, numbering thousands of the plumed and
gayly dressed chivalry of Europe, followed down the magnificent
valley of the Dnieper. All the most prominent members of the
Russian court accompanied the empress. The ambassadors of
France, Austria, and of England were in her train. The latter were
probably instructed, carefully to observe all the movements.
At the city of Kief, some six or seven hundred miles from the
mouth of the river, Prince Potemkin joined the imperial party with a
brilliant cavalcade of the princes, dukes, and counts of the minor
powers of Europe. The King of Poland, with a large retinue of his
nobles, commenced the journey with the empress. The Emperor of
Austria, with a still more imposing escort, joined her on the way.
The Turkish government was quite troubled, in view of this
remarkable visitation. Four of the largest ships of the line were sent
to cast anchor at the mouth of the Dnieper; though they were
instructed not to make any hostile demonstrations.
The empress returned to St. Petersburgh. Soon after this, Turkey
declared war against Russia, with England for her adviser. An army
of eighty thousand men was ordered to march instantly along the
western shore of the Euxine, to the mouth of the Dnieper. Sixteen
ships of the line, eight frigates, and a large number of gun-boats,
passed through the Bosphorus into the Euxine. The Turks had drawn
the sword, and thrown away the scabbard.
The news of this declaration of war by Turkey was received with
great joy at St. Petersburg. It was just what the empress desired. At
Cherson, Odessa, and other points at the mouth of the Dnieper, she
had created quite a formidable fleet. At very short notice, she could
launch on the waters of the Euxine, eight ships of the line, twelve
frigates, and nearly two hundred gun-boats. Joseph II. of Austria
had entered into alliance with the empress. Eighty thousand Austrian
troops were sent to coöperate with the Russian arms, in Wallachia.
Two Russian squadrons, under Admirals Kruse and Greig, were ready
to coöperate in the Mediterranean. Such was the state of affairs
between Russia and Turkey, at the time Commodore Jones accepted
the invitation of the empress. He subsequently wrote a very carefully
prepared journal of the difficulties he encountered, and of the results
of this all-important enterprise.
This journal, very handsomely executed, was engrossed in the
French language, and was accompanied by ninety-three Piéces
Justificatives, or documentary proofs, of the accuracy of all his
important statements. The truthfulness of this narrative has never
been called in question. It was not published until after his death.
Justice to Admiral Jones demands that I should quote freely from
this very important document. The reader will thus obtain a more
correct idea of the true character of the man, and of the adventures
upon which he entered, than could be gained in any other way. After
describing the circumstances under which he was led to enter into
the service of the empress, he writes:
“In Denmark I put in train a treaty between that power and the
United States, but it was interrupted by a courier from St.
Petersburg, despatched express by the empress, inviting me to
repair to her court.
“Though I foresaw many difficulties in the way of my entering the
Russian service, I believed I could not avoid going to St. Petersburg,
to thank the empress for the favorable opinion she had conceived of
me. I transferred the treaty, going forward at Copenhagen, to Paris,
to be concluded there, and set out for St. Petersburg, by Sweden. At
Stockholm I staid but one night, to see Count Rasoumorsky. Want of
time prevented me from appearing at court.
“At Gresholm, I was stopped by the ice, which prevented me from
crossing the Gulf of Bothnia, and even from approaching the first of
the isles in the passage. After having made several unsuccessful
efforts to get to Finland by the isles, I imagined that it might be
practicable to effect my object by doubling the ice to the southward,
and entering the Baltic Sea.
“This enterprise was very daring, and had never before been
attempted. But by the north, the roads were impracticable; and
knowing that the empress expected me from day to day, I could not
think of going back by Elsinore.
 “I left Gresholm early one morning, in an undecked passage-boat
about thirty feet in length. I made another boat follow of about half
that size. This last was for dragging over the cakes of ice, and for
passing from one to another to gain the coast of Finland. I durst not
make my project known to the boatmen, which would have been the
sure means of deterring them from it. After endeavoring, as before,
to gain the first isle, I made them steer for for the south, and we
kept along the coast of Sweden all the day, finding with difficulty
room enough to pass between the ice and the shore. Toward night,
being almost opposite Stockholm, pistol in hand I forced the
boatmen to enter the Baltic Sea, and steer to the east.”
Here it is obvious to remark, that this was outrageously unjust.
These poor boatmen, with parents, wives, and children perhaps,
dependent upon them, had never promised at whatever hazard, to
take him across that stormy sea. Indeed he had studiously
concealed from them the peril of the enterprise upon which he had
embarked. If the admiral were willing, in view of the fame and
fortune which were enticing him beyond those tempest-tossed ice-
fields, to incur the dreadful risks, he had no right to compel these
poor men to peril their lives in a cause in which they had nothing to
gain. If we understand the facts, as given by the commodore
himself, the course which he pursued on this occasion is entirely
unjustifiable. Admiral Jones continues:
“We ran toward the coast of Finland. All night the wind was fair,
and we hoped to land next day. This we found impossible. The ice
did not permit us to approach the shore, which we only saw from a
distance. It was impossible to regain the Swedish side, the wind
being strong and directly contrary. I had no other course but to
make for the Gulf of Finland. There was a small compass in the boat,
and I fixed the lamp of my travelling carriage so as to throw a light
on it.
“On the second night we lost the small boat, which was sunk. But
the men saved themselves in the large one, which with difficulty
escaped the same fate. At the end of four days, we landed at Revel
in Livonia, which was regarded as a kind of miracle. Having satisfied
the boatmen for their services and their loss, I gave them a good
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