Case Files

™

Pharmacology

Second Edition

EUGENE C. TOY, MD

The John S.Dunn Senior Academic Chief and Program

Director

Obstetrics and Gynecology Residency Program

The Methodist Hospital,Houston

Clerkship Director and Clinical Associate Professor

Department of Obstetrics and Gynecology

University of Texas Medical School at Houston

Houston,Texas

GARY C. ROSENFELD,PHD

Professor

Department of Integrative Biology and Pharmacology

Assistant Dean for Educational Programs

University of Texas Medical School at Houston

Houston,Texas

DAVID S.LOOSE, PHD

Associate Professor

Department of Integrative Biology and Pharmacology

University of Texas Medical School at Houston

Houston,Texas

DONALD BRISCOE, MD

Program Director

Family Medicine Residency

The Methodist Hospital,Houston

Medical Director

Houston Community Health Centers,Inc.

Denver Harbor Clinic

Houston,Texas

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DOI: 10.1036/0071488588

To Dr. Larry C. Gilstrap III, whose encouragement is largely responsible for

my writing this series of books. He has been a personal inspiration, mentor,

and role model of an outstanding physician, teacher, and leader;

and to Dr. Edward Yeomans who has been a dear friend and

gleaming light of brilliance in obstetrics.

—ECT

To Dr. George Stancel who encouraged my passion for education;

to the medical students of the University of Texas, Medical School at Houston

who have consistently and constructively challenged me to be the

best teacher that I can be;

and to my special children and grandchildren,

Sydney, Stephanie, and Jacob.

—GCR

To the medical and graduate students of the

University of Texas Health Science Center in Houston who continually challenge

and make both teachingand research far more interesting;

and to William and Jane

for their patience and encouragement during the writing

and editing of the manuscript.

—DSL

To the dedicated staff, residents and faculty of the

Methodist Hospital Family Medicine Residency and Denver Harbor Clinic,

with whom I am privileged to work.

—DB

❖

DEDICATION

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❖

CONTENTS

CONTRIBUTORS vii

ACKNOWLEDGMENTS ix

INTRODUCTION xi

SECTION I

Applying the Basic Sciences to Clinical Medicine 1

Part 1. Approach to Learning Pharmacology 3

Part 2. Approach to Disease 4

Part 3. Approach to Reading 5

SECTION II

Clinical Cases 11

Fifty-Three Case Scenarios 13

SECTION III

Listing of Cases 401

Listing by Case Number 403

Listing by Disorder (Alphabetical) 404

INDEX 407

For more information about this title, click here

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❖

CONTRIBUTORS

Jeané Simmons Holmes, MD, FACOG

Assistant Clinical Professor

Obstetrics and Gynecology Residency Program

The Methodist Hospital, Houston

Houston, Texas

Polycystic Ovarian Syndrome

Lacy Kessler

Medical Student

Class of 2008

The University of Texas Medical School at Houston

Houston, Texas

Ergot Akyloids

Eicosanoids

Priti P. Schachel, MD

Assistant Professor

Department of Obstetrics and Gynecology

Weill Medical College of Cornell University

The Methodist Hospital, Houston

Houston, Texas

Polycystic Ovarian Syndrome

vii

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❖

ACKNOWLEDGMENTS

The inspiration for this basic science series occurred at an educational retreat

led by Dr. L. Maximilian Buja, who at the time was the dean of the medical

school. It has been such a joy to work together with Drs. Gary Rosenfeld and

David Loose, who are both accomplished scientists and teachers. It has been

rewarding to collaborate with Dr. Donald Briscoe, a scholar and an excellent

teacher. I would like to thank McGraw-Hill for believing in the concept of

teaching by clinical cases. I owe a great debt to Catherine Johnson, who has

been a fantastically encouraging and enthusiastic editor.

At the University of Texas Medical School at Houston, we would like to

recognize the bright and enthusiastic medical students who have inspired us to

find better ways to teach. At The Methodist Hospital, I appreciate the support

from Dr. Mark Boom, Dr. Karin Larsen Pollock, Mr. Reggie Abraham, Mr.

John Lyle, and our fabulous Department Chair, Dr. Alan Kaplan. At St. Joseph

Medical Center, I would like to recognize some of the finest administrators I

have encountered: Phil Robinson, Pat Mathews, Laura Fortin, Dori Upton,

Cecile Reynolds, John Bertini, MD, and Thomas V. Taylor, MD. I appreciate

Marla Buffington’s excellent advice and assistance. Without the help from my

colleague and friend, Dr. John C. McBride, this book could not have been writ-

ten. Most importantly, I am humbled by the love, affection, and encouragement

from my lovely wife, Terri, and our four children, Andy, Michael, Allison, and

Christina.

Eugene C. Toy

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❖

INTRODUCTION

Often, the medical student will cringe at the “drudgery” of the basic science

courses and see little connection between a field such as pharmacology and

clinical problems. Clinicians, however, often wish they knew more about the

basic sciences, because it is through the science that we can begin to under-

stand the complexities of the human body and thus have rational methods of

diagnosis and treatment.

Mastering the knowledge in a discipline such as pharmacology is a formi-

dable task. It is even more difficult to retain this information and to recall it

when the clinical setting is encountered. To accomplish this synthesis, phar-

macology is optimally taught in the context of medical situations, and this is

reinforced later during the clinical rotations. The gulf between the basic sci-

ences and the patient arena is wide. Perhaps one way to bridge this gulf is with

carefully constructed clinical cases that ask basic science-oriented questions.

In an attempt to achieve this goal, we have designed a collection of patient

cases to teach pharmacology-related points. More importantly, the explanations

for these cases emphasize the underlying mechanisms and relate the clinical

setting to the basic science data. The principles are explored rather than

overemphasizing rote memorization.

This book is organized for versatility: to allow the student “in a rush” to go

quickly through the scenarios and check the corresponding answers and to

provide more detailed information for the student who wants thought-

provoking explanations. The answers are arranged from simple to complex: a

summary of the pertinent points, the bare answers, a clinical correlation, an

approach to the pharmacology topic, a comprehension test at the end for rein-

forcement or emphasis, and a list of references for further reading. The clini-

cal cases are arranged by system to better reflect the organization within the

basic science. Finally, to encourage thinking about mechanisms and relation-

ships, we used open-ended questions in the clinical cases. Nevertheless, sev-

eral multiple-choice questions are included at the end of each scenario to

reinforce concepts or introduce related topics.

HOW TO GET THE MOST OUT OF THIS BOOK

Each case is designed to introduce a clinically related issue and includes open-

ended questions usually asking a basic science question, but at times, to break

up the monotony, there will be a clinical question. The answers are organized

into four different parts:

xii INTRODUCTION

PART I

1. Summary

2. A straightforward answer is given for each open-ended question.

3. Clinical Correlation—A discussion of the relevant points relating the

basic science to the clinical manifestations, and perhaps introducing

the student to issues such as diagnosis and treatment.

PART I I

An approach to the basic science concept consisting of three parts:

1. Objectives—A listing of the two to four main knowledge objectives

that are critical for understanding the underlying pharmacology to

answer the question and relate to the clinical situation.

2. Definitions of basic terminology.

3. Discussion of the specific class of agents.

PART III

Comprehension Questions—Each case includes several multiple-choice

questions that reinforce the material or introduces new and related concepts.

Questions about the material not found in the text are explained in the answers.

PART I V

Pharmacology Pearls—A listing of several important points, many clinically

relevant, reiterated as a summation of the text and to allow for easy review,

such as before an examination.

SECTION I

Applying the

Basic Sciences to

Clinical Medicine

Part 1. Approach to Learning Pharmacology

Part 2. Approach to Disease

Part 3. Approach to Reading

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PART 1. APPROACH TO LEARNING PHARMACOLOGY

Pharmacology is best learned by a systematic approach, understanding the

physiology of the body, recognizing that every medication has desirable and

undesirable effects, and being aware that the biochemical and pharmacologic

properties of a drug affects its characteristics such as duration of action, volume

of distribution, passage through the blood-brain barrier, mechanism of elimi-

nation, and route of administration. Rather than memorizing the characteris-

tics of a medication, the student should strive to learn the underlying rationale

such as, “Second-generation antihistamine agents are less lipid soluble than

first-generation antihistamines and therefore do not cross the blood-brain bar-

rier as readily; thus, second-generation antihistamines are not as sedating.

Because they both bind the histamine H

receptor, the efficacy is the same.”

KEY TERMS

Pharmacology: The study of substances that interact with living systems

through biochemical processes.

Drug:A substance used in the prevention, diagnosis, or treatment of disease.

Toxicology:A branch of pharmacology that studies the undesirable effects

of chemicals on living organisms.

Food and Drug Administration (FDA):The federal agency responsible

for the safety and efficacy of all drugs in the United States, as well as

food and cosmetics.

Adverse effect:Also known as side effect; all unintended actions of a drug

that result from the lack of specificity of drug action. All drugs are capa-

ble of producing adverse effects.

Pharmacodynamics: The actions of a drug on a living organism, includ-

ing mechanisms of action and receptor interaction.

Pharmacokinetics:The actions of the living organism on the drug, includ-

ing absorption, distribution, and elimination.

Volume of distribution (V

): The size of the “compartment” into which a

drug is distributed following absorption and is determined by the equation:

= Dose (mg) drug administered/Initial plasma concentration (mg/L)

Potency of drug: Relative amount of drug needed to produce a given

response, determined largely by the amount of drug that reaches the site

of action and by the affinity of the drug for the receptor.

Efficacy:Drug effect as the maximum response it is able to produce and is

determined by the number of drug-receptor complexes and the ability of

the receptor to be activated once bound. EC-50 refers to the drug con-

centration that produces 50 percent of the maximal response, whereas

ED-50 refers to the drug dose that is pharmacologically effective in

50 percent of the population.

APPLYING THE BASIC SCIENCES TO CLINICAL MEDICINE 3

Absorption:The movement of a drug from the administration site into the

blood stream usually requiring the crossing of one or more biologic

membranes. Important parameters include lipid solubility, ionization,

size of the molecule, and presence of a transport mechanism.

Elimination:Process by which a drug is removed from the body, generally

by either metabolism or excretion. Elimination follows various kinetic

models. For example, first-order kinetics describes most circum-

stances, and means that the rate of drug elimination depends on the con-

centration of the drug in the plasma as described by the equation:

Rate of elimination from body= Constant× Drug concentration

Zero-order kinetics:It is less common and means that the rate of elimina-

tion is constant and does not depend on the plasma drug concentration.

This may be a consequence of a circumstance such as saturation of liver

enzymes or saturation of the kidney transport mechanisms.

Bioavailability:The percentage of an ingested drug that is actually absorbed

into the bloodstream.

Route of administration:Drug may be delivered intravenously (IV or iv) for

delivery directly into the bloodstream, intramuscularly(IM), and subcu-

taneously (SC). The medication may be depot and slow release, inhalant

for rapid absorption and delivery to the bronchi and lungs, sublingual to

bypass the first-pass effect, intrathecal for agents that penetrate the

blood-brain barrier poorly, rectal to avoid hepatic first-pass effect and

for nausea, and topical administration when local effect is desired such

as dermatologic or ophthalmic agents.

PART 2. APPROACH TO DISEASE

Physicians usually tackle clinical situations by taking a history (asking

questions), performing a physical examination, obtaining selective labora-

tory and imaging tests, and then formulating a diagnosis. The synthesis of

the history, physical examination, and imaging or laboratory tests is called

the clinical database. After reaching a diagnosis, a treatment plan is usu-

ally initiated, and the patient is followed for a clinical response. Rational

understanding of disease and plans for treatment are best acquired by learn-

ing about the normal human processes on a basic science level; likewise,

being aware of how disease alters the normal physiologic processes is also

best understood on a basic science level. Pharmacology and therapeutics

require also the ability to tailor the correct medication to the patient’s situ-

ation and awareness of the medication’s adverse effect profile. Sometimes,

the patient has an adverse reaction to a medication as the chief complaint,

and the physician must be able to identify the medication as the culprit. An

understanding of the underlying basic science allows for more rational

analysis and medication choices.

4 CASE FILES: PHARMACOLOGY

PART 3. APPROACH TO READING

There are seven key questions that help to stimulate the application of basic

science information to the clinical setting. These are:

1. Which of the available medications is most likely to achieve the

desired therapeutic effect and/or is responsible for the described

symptoms or signs?

2. What is the likely mechanism for the clinical effect(s) and adverse

effect(s) of the medication?

3. What is the basic pharmacologic profile (e.g., absorption, elimina-

tion) for medications in a certain class, and what are the differ-

ences among the agents within the class?

4. Given basic pharmacologic definitions such as therapeutic index

(TI) or certain safety factor (TD

/ED

), or median lethal dose

(LD

), how do medications compare in their safety profile?

5. Given a particular clinical situation with described unique patient

characteristics, which medication is most appropriate?

6. What is the best treatment for the toxic effect of a medication?

7. What are the drug-drug interactions to be cautious about regard-

ing a particular medication?

1. Which of the following medications is most likely to be responsible

for the described symptoms or signs?

The student must be aware of the various effects, both desirable and

undesirable, produced by particular medications. Knowledge of desir-

able therapeutic effects is essential in selecting the appropriate drug for

the particular clinical application; likewise, an awareness of its adverse

effects is necessary, because patients may come into the physician’s

office with a complaint caused by a drug effect unaware that their

symptoms are because of a prescribed medication. It is only by being

aware of the common and dangerous effects that the clinician can

arrive at the correct diagnosis. The student is encouraged not to merely

memorize the comparative adverse effect profiles of the drugs, but

rather to understand the underlying mechanisms.

2. What is the likely mechanism for the clinical effect(s) and adverse

effect(s) of the medication?

As noted above, the student should strive to learn the underlying

physiologic, biochemical, or cellular explanation for the described

drug effect. This understanding allows for the rational choice of an

alternative agent or the reasonable choice of an agent to alleviate the

symptoms or explanatory advice to the patient regarding behavioral

changes to diminish any adverse affects. For example, if a 60-year-old

woman who takes medications for osteoporosis complains of severe

“heartburn,” one may be suspicious, knowing that the bisphosphonate

APPLYING THE BASIC SCIENCES TO CLINICAL MEDICINE 5

medication alendronate can cause esophagitis. Instruction to the

patient to take the medication while sitting upright and remaining

upright for at least 30 minutes would be the proper course of action,

because gravity will assist in keeping the alendronate in the stomach

rather than allowing regurgitation into the distal esophagus.

3. What is the basic pharmacologic profile (absorption, elimination,

volume of distribution) for medications in a certain class, and what

are differences among the agents within the class?

Understanding the pharmacologic profile of medications allows

for rational therapeutics. However, instead of memorizing the sepa-

rate profiles for every medication, grouping the drugs together into

classes allows for more efficient learning and better comprehension.

An excellent starting point for the student of pharmacology would be

to study how a prototype drug within a drug class organized by

structure or mechanism of action may be used to treat a condition

(such as hypertension). Then within each category of agents, the stu-

dent should try to identify important subclasses or drug differences.

For example, hypertensive agents can be categorized as diuretic

agents, β-adrenergic-blocking agents, calcium-channel-blocking

agents, and renin-angiotensin system inhibitors. Within the subclas-

sification of renin-angiotensin system inhibitors, the angiotensin-

converting enzyme inhibitors can cause the side effect of a dry cough

caused by the increase in bradykinin brought about by the enzyme

blockade; instead, the angiotensin-1 receptor blockers do not affect

the bradykinin levels and so do not cause the cough as often.

4. Given basic pharmacologic definitions such as therapeutic index

(TI) or certain safety factor (TD

/ED

), or median lethal dose

(LD

), how do medications compare in their safety profile?

Therapeutic index (TI): Defined as the TD

/ED

(the ratio of the

dose that produces a toxic effect in half the population to the dose that

produces the desired effect in half the population).

Certain safety factor (TD

/ED

): Defined as the ratio of the dose that

produces the toxic effect in 1 percent of the population to the dose that

produces the desired effect in 99 percent of the population; also known

as standard safety measure.

Median lethal dose (LD

): Defined as the median lethal dose, the

dose that will kill half the population.

Based on these definitions, a desirable medication would have a high

therapeutic index (toxic dose is many times that of the efficacious

dose), high certain safety factor, and high median lethal dose (much

higher than therapeutic dose). Likewise, medications such as digoxin

that have a low therapeutic index require careful monitoring of levels

and vigilance for side effects.

6 CASE FILES: PHARMACOLOGY

5. Given a particular clinical situation with described unique patient

characteristics, which medication is most appropriate?

The student must weigh various advantages and disadvantages, as

well as different patient attributes. Some of those may include compli-

ance with medications, allergies to medications, liver or renal insuffi-

ciency, age, coexisting medical disorders, and other medications. The

student must be able to sift through the medication profile and identify

the most dangerous adverse effects. For example, if a patient is already

taking a monoamine-oxidase-inhibiting agent for depression, then

adding a serotonin reuptake inhibitor would be potentially fatal, because

serotonin syndrome may ensue (hyperthermia, muscle rigidity, death).

6. What is the best treatment for the toxic effect of a medication?

If complications of drug therapy are present, the student should know

the proper treatment. This is best learned by understanding the drug

mechanism of action. For example, a patient who has taken excessive opi-

oids may develop respiratory depression, caused by either a heroin over-

dose or pain medication, which may be fatal. The treatment of an opioid

overdose includes the ABCs (airway, breathing, circulation) and the

administration of naloxone, which is a competitive antagonist of opioids.

7. What are the drug-drug interactions to be concerned with regard-

ing a particular medication?

Patients are often prescribed multiple medications, from either the

same practitioner or different clinicians. Patients may not be aware of

the drug-drug interactions; thus, the clinician must compile, as a com-

ponent of good clinical practice, a current list of all medications (pre-

scribed, over-the-counter, and herbal) taken by the patient. Thus, the

student should be aware of the most common and dangerous interac-

tions; once again, understanding the underlying mechanism allows for

lifelong learning rather than short-term rote memorization of facts that

are easily forgotten. For example, magnesium sulfate to stop preterm

labor should not be used if the patient is taking a calcium-channel-

blocking agent such as nifedipine. Magnesium sulfate acts as a com-

petitive inhibitor of calcium, and by decreasing its intracellular

availability it slows down smooth muscle contraction such as in the

uterus. Calcium-channel blockers potentiate the inhibition of calcium

influx and can lead to toxic effects, such as respiratory depression.

COMPREHENSION QUESTIONS

[I.1] Bioavailability of an agent is maximal when the drug has which of the

following qualities?

A. Highly lipid soluble

B. More than 100 Daltons in molecular weight

C. Highly bound to plasma proteins

D. Highly ionized

APPLYING THE BASIC SCIENCES TO CLINICAL MEDICINE 7

[I.2] An agent is noted to have a very low calculated volume of distribution

). Which of the following is the best explanation?

A. The agent is eliminated by the kidneys, and the patient has renal

insufficiency.

B. The agent is extensively bound to plasma proteins.

C. The agent is extensively sequestered in tissue.

D. The agent is eliminated by zero-order kinetics.

[I.3] Which of the following describes the first-pass effect?

A. Inactivation of a drug as a result of the gastric acids.

B. Absorption of a drug through the duodenum.

C. Drug given orally is metabolized by the liver before entering the

circulation.

D. Drug given IV accumulates quickly in the central nervous system

(CNS).

[I.4] A laboratory experiment is being conducted in which a mammal is

injected with a noncompetitive antagonist to the histamine receptor.

Which of the following best describes this agent?

A. The drug binds to the histamine receptor and partially activates

it.

B. The drug binds to the histamine receptor but does not activate it.

C. The drug binds to the receptor, but not where histamine binds, and

prevents the receptor from being activated.

D. The drug irreversibly binds to the histamine receptor and renders it

ineffective.

[I.5] A 25-year-old medical student is given a prescription for asthma,

which the physician states has a very high therapeutic index. Which

of the statements best characterizes the drug as it relates to the ther-

apeutic index?

A. The drug’s serum levels will likely need to be carefully monitored.

B. The drug is likely to cross the blood-brain barrier.

C. The drug is likely to have extensive drug-drug interactions.

D. The drug is unlikely to have any serious adverse effects.

[I.6] A drug M is injected IV into a laboratory subject. It is noted to have

high serum protein binding. Which of the following is most likely to be

increased as a result?

A. Drug interaction

B. Distribution of the drug to tissue sites

C. Renal excretion

D. Liver metabolism

8 CASE FILES: PHARMACOLOGY

[I.7] A bolus of drug K is given IV. The drug is noted to follow first-order

kinetics. Which of the following describes the elimination of drug K?

A. The rate of elimination of drug K is constant.

B. The rate of elimination of drug K is proportional to the patient’s

renal function.

C. The rate of elimination of drug K is proportional to its concentra-

tion in the patient’s plasma.

D. The rate of elimination of drug K is dependent on a nonlinear rela-

tionship to the plasma protein concentration.

Answers

[I.1] A. Transport across biologic membranes and thus bioavailability is

maximal with high lipid solubility.

[I.2] B. The volume of distribution is calculated by administering a known

dose of drug (mg) IV and then measuring an initial plasma concen-

tration (mg/L). The ratio of the mass of drug given (mg) divided by

the initial plasma concentration (mg/L) gives the V

. A very low V

may indicate extensive protein binding (drug is sequestered in the

bloodstream), whereas a high V

may indicate extensive tissue bind-

ing (drug is sequestered in the tissue).

[I.3] C. The first-pass effect refers to the process in which following oral

administration a drug is extensively metabolized as it initially passes

through the liver, before it enters the general circulation. Liver

enzymes may metabolize the agent to such an extent that the drug

cannot be administered orally.

[I.4] C. A noncompetitive antagonist binds to the receptor at a site other

than the agonist-binding site and renders it less effective by prevent-

ing agonist binding or preventing activation.

[I.5] D. An agent with a high therapeutic index means the toxic dose is

very much higher than the therapeutic dose, and it is less likely to

produce toxic effects at therapeutic levels.

[I.6] A. High protein binding means less drug to the tissue, the kidney, and

the liver. Drug interaction may occur if the agent binds to the same

protein site as other drugs, thus displacing drugs and increasing

serum levels.

[I.7] C. First-order kinetics means the rate of elimination of a drug is pro-

portional to the plasma concentration.

APPLYING THE BASIC SCIENCES TO CLINICAL MEDICINE 9

REFERENCES

Braunwald E, Fauci AS, Kasper KL, et al., eds. Harrison’s Principles of Internal

Medicine, 16th ed. New York: McGraw-Hill, 2004.

Rosenfeld GC, Loose-Mitchell DS. Pharmacology, 4th ed. Philadelphia, PA:

Lippincott, Williams & Wilkins, 2007:1.

10 CASE FILES: PHARMACOLOGY

PHARMACOLOGY PEARLS

❖ Understanding the pharmacologic mechanisms of medications allows

for rational choices for therapy, fewer medication errors, and rapid

recognition and reversal of toxic effects.

❖ The therapeutic index, certain safety factor (TD

/ED

), and median

lethal dose are various methods of describing the potential toxic-

ity of medications.

❖ There are seven key questions to stimulate the application of basic

science information to the clinical arena.

SECTION II

Clinical Cases

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❖

CASE 1

A 12-year-old girl presents to your office with a sore throat and fever. You

diagnose her with pharyngitis caused by group A β-hemolyticStreptococcus.

She is given an IM injection of penicillin. Approximately 5 minutes later, she

is found to be in respiratory distress and audibly wheezing. Her skin is mot-

tled and cool, she is tachycardic (rapid heart rate), and her blood pressure has

fallen to 70/20 mm Hg. You immediately diagnose her as having an anaphy-

lactic reaction to the penicillin and give an SC injection of epinephrine.

◆

What effect will epinephrine have on this patient’s vascular system?

◆

Which adrenoceptor primarily mediates the vascular response?

◆

What effect will epinephrine have on her respiratory system?

◆

Which adrenoceptor primarily mediates the respiratory system

response?

ANSWERS TO CASE 1: AUTONOMIC SYMPATHETIC

NERVOUS SYSTEM

Summary:A 12-year-old girl with “strep throat” is given an injection of peni-

cillin and develops an acute anaphylactic reaction.

◆

Effect of epinephrine on vascular system:Vasoconstriction.

◆

Adrenoceptor which primarily mediates the vascular response:

Alpha-1 (α

◆

Effect of epinephrine on the pulmonary system: Bronchial muscle

relaxation.

◆

Adrenoceptor which primarily mediates the pulmonary response:

Beta-2 (β

CLINICAL CORRELATION

Anaphylaxis is an acute, immune-mediated response to an allergen character-

ized by bronchospasm, wheezing, tachycardia, and hypotension. Epinephrine is

the drug of choice used to treat this condition because it appears, through the

activation of alpha (α)- and beta (β)-adrenoceptors, to counteract the patho-

physiologic processes underlying anaphylaxis. As with all emergencies, the

ABCs (airway, breathing, circulation) should be addressed first. Occasionally,

the anaphylaxis causes laryngeal edema to the extent that the airway is com-

promised, and intubation (placement of a tube in the trachea) is impossible. In

these circumstances, an emergency airway, such as a surgical cricothyroido-

tomy (creating an opening from the skin through the cricoid cartilage), is

required.

APPROACH TO THE AUTONOMIC SYMPATHETIC

NERVOUS SYSTEM

Objectives

1. List the neurotransmitters of the autonomic sympathetic nervous sys-

tem and describe their anatomical localization.

2. List the receptors and receptor-subtypes of the autonomic sympathetic

nervous system.

3. Predict the responses to activation and inhibition of autonomic sympa-

thetic nervous system receptors.

CASE FILES: PHARMACOLOGY

Definitions

Autonomic nervous system: Subdivision of the efferent peripheral nerv-

ous system that is largely under unconscious control (the somatic subdi-

vision of the peripheral nervous system is largely under conscious

control), shown in Figure 1-1.

Sympathetic nervous system:A division of the autonomic nervous system

(the other is the parasympathetic nervous system) that originates in nuclei

of the CNS. Preganglionic fibers exit through the thoracic and lumbar

spinal nerves to synapse on ganglia close to the spinal cord and also on

the adrenal medulla (considered modified ganglia). Postganglionic fibers

innervate a wide variety of effector organs and tissues, including arteriole

and bronchial smooth muscles.

Agonist: A drug that activates a receptor and results in a pharmacologic

response.

Antagonist:A drug that binds to receptors with little or no effect of its own,

but that can block the action of an agonist that binds to the same receptors.

DISCUSSION

Class

The neurotransmitter norepinephrine is released from the efferent nerves of

the sympathetic autonomic nervous system at postganglionic sympathetic

(also known as “adrenergic”) nerve endings, whereas epinephrine and some

norepinephrine are released from the adrenal medulla.

These endogenous catecholamine neurotransmitter agonists interact at

postjunctional specialized cell membrane components called adrenoceptors

(named after the adrenergic nerves that innervate them) that are classified as

either alpha (α) or beta (β).

There are two subtypes of the a-adrenoceptor, a

and a

, each of which

has variants of unclear pharmacologic importance. Activation of the autonomic

sympathetic nervous system α

-adrenoceptors by adrenergic agonists results in,

among other effects, contraction of most vascular smooth muscle (a

) caus-

ing increased peripheral resistance and blood pressure, contraction of the

pupillary dilator muscle resulting in mydriasis, an indirectly mediated

(through inhibition of acetylcholine [Ach] release) relaxation of gastrointesti-

nal smooth muscle and contraction of gastrointestinal sphincters (α

), and

activation of the seminal vesicles, prostate gland, and ductus deferens that

results in ejaculation. Activation of prejunctional adrenoceptor autoreceptors

(α

) by catecholamines results in (feedback) inhibition of the release of norep-

inephrine and other neurotransmitters from their respective nerve endings.

There are also three subtypes of the b-adrenoceptor, b

, b

, and b

Activation of the autonomic sympathetic nervous system α-adrenoceptors by

adrenergic agonists results in, among other effects, increased rate and force of

CLINICAL CASES 15

contraction of the heart (b

), smooth muscle relaxation of bronchi causing

bronchodilation (b

), and activation of fat cell lipolysis (b

Because the catecholamines epinephrine and norepinephrine have

important physiologic roles, drugs that block their actions, that is, adreno-

ceptor antagonists, can have important pharmacologic effects, many of

which are clinically useful. a-Adrenoceptor nonselective antagonists

(e.g., phentolamine) are used to treat the hypertension of pheochromocy-

toma (a tumor that secretes catecholamines) and male erectile dysfunc-

tion, whereas the more selective a

-adrenoceptor antagonists (e.g.,

prazosin, terazosin, doxazosin) are used to treat hypertension and benign

prostatic hyperplasia(Table 1-1).

CASE FILES: PHARMACOLOGY

Constricts

pupil of eye

Stimulates

salivary glands

Slows heart

Constricts bronchii

in lungs

Stimulates activity

of stomach

and intestines

Stimulates activity

of pancreas

Stimulates

gallbladder

Promotes voiding

from bladder

Promotes erection

of genitals

Dilates

pupil of eye

Sympathetic

Nervous System

Parasympathetic

Nervous System

Inhibits

salivary gland

secretion

Accelerates heart

Relaxes bronchii

in lungs

Inhibits activity

of stomach

and intestines

Inhibits activity

of pancreas

Stimulates

glucose release

from liver; inhibits

gallbladder

Inhibits voiding

from bladder

Stimulates

adrenal medulla

Promotes

ejaculation and

vaginal

contractions

Figure 1-1. Schematic of autonomic nervous system.

Structure

Epinephrine and norepinephrine are catecholamines, synthesized from

tyrosine, that possess a catechol nucleus with an ethylamine side chain (epi-

nephrine is the methylated side chain derivative of norepinephrine). The rate-

limiting enzyme in this process is tyrosine hydroxylase.

Mechanism of Action

Epinephrine binds to α

-adrenoceptors and, through a G-protein (Gq-type

GTP-binding protein [Gq])-mediated activation of phospholipase C and stimu-

lation of polyphosphoinositide hydrolysis, results in formation of inositol 1,4,5-

trisphosphate (IP

) that promotes the release of stored intracellular Ca

Epinephrine interaction with α

-adrenoceptors results in activation of a Gi-type

GTP-binding protein (Gi) to inhibit adenylyl cyclase activity, thereby decreas-

ing cyclic adenosine monophosphate (cAMP) levels. Epinephrine perhaps also

increases β

-adrenoceptor-mediated influx of Ca

across membrane channels.

In addition to the increased formation of the “second messenger” IP

, epi-

nephrine also increases the phospholipase-mediated formation of another sec-

ond messenger diacylglycerol (DAG) that activates protein kinase C that

influences the activity of a number of other signaling pathways. Epinephrine

also activates b

- and b

-adrenoceptors to increase a G-protein-mediated

stimulation of adenylyl cyclase activity, thereby increasing intracellular

cAMP levelsand the activity of cAMP-dependent protein kinases.

CLINICAL CASES 17

Table 1-1

SELECTED EFFECTS OF ADRENOCEPTOR ACTIVATION

ORGAN EFFECTS (ADRENOCEPTOR SUBTYPE)

Bronchial smooth muscle Dilates (β

)

Heart rate and contractile force Increases (β

)

Eye (pupil size) Dilates (α

)

Blood vessels Constrict (α

)

†,‡

Gastrointestinal tract Decrease (α

,β

)

(tone, motility, secretions)

Pancreas (insulin release) Decrease (α

)

∗

Dilation (mydriasis)results from α

-adrenoceptor stimulation of the radial muscle.

†

Skeletal muscle blood vessels have β

-adrenoceptors that, when activated, result in vessel

constriction.

‡

Coronary arteries also have β-adrenoceptors that, when activated, result in vessel dilation,

whichis the dominant effect.

Administration

Epinephrine is generally administered parenterally (IM) for treatment of

anaphylactic shock. For this and other conditions, it is also available as IV, SC,

ophthalmic, nasal, and aerosol preparations. Norepinephrine is only available

for parenteral, generally IV, administration.

Pharmacokinetics

Epinephrine released from the adrenal gland is metabolized primarily by

catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).

The action of norepinephrine released from nerve endings is terminated

primarily by reuptake into nerve terminals (uptake 1) and other cells

(uptake 2).

COMPREHENSION QUESTIONS

[1.1] A patient with septic shock is noted to have persistent hypotension

despite dopamine infusion. Epinephrine in an IV infusion is used.

With which adrenoceptor does epinephrine act to constrict vascular

smooth muscle?

A. α

-Adrenoceptors

B. α

-Adrenoceptors

C. β

-Adrenoceptors

D. β

-Adrenoceptors

[1.2] A 16-year-old male is having an acute asthmatic attack. Epinephrine is

given SC. With which of the following adrenoceptors does epinephrine

act to dilate bronchial smooth muscle?

A. α

-Adrenoceptors

B. α

-Adrenoceptors

C. β

-Adrenoceptors

D. β

-Adrenoceptors

[1.3] Which of the following best describes the cellular action of epinephrine?

A. Activation of adenylyl cyclase

B. Decreased activity of cAMP-dependent protein kinases

C. Increased intracellular stores of Ca

D. Inhibition of the activity of phospholipase

[1.4] Epinephrine-mediated β

-adrenoceptor activation results in which of

the following?

A. Constriction of bronchial smooth muscle

B. Decreased gastrointestinal motility

C. Dilation of the pupils

D. Increased heart rate

CASE FILES: PHARMACOLOGY

Answers

[1.1] A.α

-Adrenoceptors mediate vasoconstriction in many vascular beds.

In skeletal muscle, epinephrine can act at β

-adrenoceptors to cause

vasodilation.

[1.2] D. Epinephrine acts on β

-adrenoceptors to cause smooth muscle

relaxation of bronchi resulting in bronchodilation. Because of

adverse cardiovascular effects of epinephrine (β

), more selective β

adrenoceptor agonists are now used (e.g., albuterol).

[1.3] A.Epinephrine activates α

-adrenoceptors to cause a release of intra-

cellular stored Ca

andβ

- and β

-adrenoceptors to activate adenylyl

cyclase.

[1.4] D. Epinephrine activation of β

-adrenoceptors results in an

increase in heart rate. Activation of α

-adrenoceptors results in

dilation of the pupil. Activation of β

-adrenoceptors causes dila-

tion of bronchial smooth muscle and decreased gastrointestinal

(GI) motility.

CLINICAL CASES 19

PHARMACOLOGY PEARLS

❖ Physiologically epinephrine acts as a hormone on distant cells after

its release from the adrenal medulla.

❖ As exceptions, sympathetic postganglionic neurons that innervate

sweat glands and renal vascular smooth muscle release, respec-

tively, ACh and dopamine rather than norepinephrine.

❖ Exogenously administered epinephrine increases blood pressure

through its action on β

-adrenoceptors in the heart, resulting in

increased heart rate and force of contraction and through its

action on α

-adrenoceptors in many vascular beds that results in

vasoconstriction.

❖ In skeletal muscle, epinephrine injection can result in vasodilation

(β

) that in some cases may lead to a decreased total peripheral

resistance and a decrease in diastolic pressure.

❖ Norepinephrine has little, if any, effect on β

-adrenoceptors (nor-

epinephrine and epinephrine have similar effects on α- and β

adrenoceptors), thus increasing both systolic and diastolic

blood pressure.

20 CASE FILES: PHARMACOLOGY

REFERENCES

Goldstein DS, Robertson D, Straus SE, et al. Dysautonomias: clinical disorders of

the autonomic nervous system. Ann Intern Med 2002;137(9):753–63.

Brown SG. Cardiovascular aspects of anaphylaxis: implications for treatment and

diagnosis. Curr Opin Allergy Clin Immunol 2005;5(4):359–64.

Clark AL, Cleland JG. The control of adrenergic function in heart failure: thera-

peutic intervention. Heart Fail Rev 2000;5(1):101–14.

August P. Initial treatment of hypertension. N Engl J Med 2003;348(7):610–7.

❖

CASE 2

A 61-year-old man is noted to have increased intraocular pressure on a routine

eye examination. The visual acuity is normal in both eyes. The dilated eye

examination reveals no evidence of optic nerve damage. Visual field testing

shows mild loss of peripheral vision. He is diagnosed with primary open-angle

glaucoma and is started on pilocarpine ophthalmic drops.

◆

What is the action of pilocarpine on the muscles of the iris and cilia?

◆

What receptor mediates this action?

◆

Is pilocarpine the appropriate first-line drug for treatment of

primary open-angle glaucoma?

ANSWERS TO CASE 2: MUSCARINIC

CHOLINOMIMETIC AGENTS

Summary: A 61-year-old man with open-angle glaucoma is prescribed pilo-

carpine ophthalmic drops.

◆

Action of pilocarpine on muscles of the iris and cilia: Constriction of

the muscles

◆

Receptor that mediates this action: Muscarinic cholinoreceptor

◆

First-line drugs to treat primary open-angle glaucoma:

Prostaglandin analogs

CLINICAL CORRELATION

Open-angle glaucoma is a disease caused by obstruction of the outflow of

aqueous humor into the canal of Schlemm, causing an increase in intraocu-

lar pressure. The use of a direct-acting muscarinic agonist, such as pilo-

carpine, causes contraction of the muscles of the cilia and iris. Because

these are circular muscles, the pupil is constricted, which helps to relieve

the outflow obstruction and lower the intraocular pressure. Although not

common with the use of topical ophthalmic drops, bronchospasm and pul-

monary edema has been noted with the use of pilocarpine drops. More com-

monly, blurred vision and myopia (nearsightedness) occur as a result of the

impairment of accommodation caused by the contraction of the iris and cil-

iary muscles.

The use of a direct-acting muscarinic agonist such as pilocarpine to

treat open-angle glaucoma is now not common due to its numerous side

effects, the need to administer it up to four times per day, and the avail-

ability of other agents. Prostaglandin analogs such as latanoprost are now

considered first-line therapy for this condition followed by β-adrenoceptor

agonists.

APPROACH TO MUSCARINIC

CHOLINOMIMETIC AGENTS

Objectives

1. Be able to list the receptors of the parasympathetic nervous system.

2. Contrast the actions and effects of direct and indirect stimulation of

muscarinic cholinoreceptors.

3. List the therapeutic uses of parasympathomimetic agents.

4. List the adverse effects of parasympathomimetic agents.

CASE FILES: PHARMACOLOGY

Definitions

Parasympathetic nervous system:An anatomic division of the autonomic

nervous system (the other is the sympathetic nervous system) that orig-

inates in nuclei of the CNS. Preganglionic fibers exit through cranial

and sacral spinal nerves to synapse via short postganglionic nerve

fibers on ganglia, many of which are in the organs they innervate.

Cholinomimetic agents: Agents that mimic the action of ACh.These

act directly or indirectly to activate cholinoreceptors. Some directly

acting agents (pilocarpine, bethanechol, carbachol) are designed to act

selectively on either muscarinic or nicotinic cholinoreceptors, whereas

indirectly acting agents (such as neostigmine, physostigmine, edro-

phonium, demecarium), which inhibit the enzyme acetylcholinesterase

(AChE) that is responsible for the inactivation of ACh, can activate

both. Pilocarpine is a directly acting cholinomimetic agent that acts

chiefly at muscarinic cholinoreceptors. Additional selectivity of pilo-

carpine and other cholinomimetics in the treatment of glaucoma is

achieved by the use of an ophthalmic (topical) preparation.

DISCUSSION

Class

The efferent nerves of the parasympathetic autonomic nervous system

release the neurotransmitter AChat both preganglionic and postganglionic

(i.e., “cholinergic”) nerve endings, and also at somatic nerve endings. Nitric

oxide is a cotransmitter at many of the parasympathetic postganglionic sites.

TheAC h released from nerve endings of the parasympathetic nervous system

interacts at specialized cell membrane components called cholinoreceptors

that are classified as either nicotinic or muscarinicafter the alkaloids initially

used to distinguish them.

Nicotinic cholinoreceptors are localized at all postganglionic neurons

(the autonomic ganglia), including the adrenal medulla, and skeletal muscle

endplates innervated by somatic nerves. Muscarinic cholinoreceptors are

localized at organs innervated by parasympathetic postganglionic nerve end-

ings, for example, on cardiac atrial muscle, sinoatrial node cells, and atri-

oventricular node cells,where activation can cause a negative chronotropic

effect and delayed atrioventricular conduction. Cholinergic stimulation of

muscarinic receptorsin the smooth muscle, exocrine glands, and vascular

endothelium can cause, respectively, bronchoconstriction, increased acid

secretion, and vasodilation (Table 2-1).

There are two subtypes of the nicotinic cholinoreceptors: N

, localized to

postganglionic neurons, and N

, localized to the skeletal muscle endplates.

There are three pharmacologically important subtypes of the muscarinic choli-

noreceptors, M

, M

, and M

(two additional subtypes have been identified by

CLINICAL CASES 23

cloning), that alone or in combination are localized to sympathetic postganglionic

neurons (and the CNS), to the atrial muscle, sinoatrial (SA) cells, and atrioven-

tricular (AV) node of the heart, to smooth muscle, to exocrine glands, and to the

vascular endothelium that does not receive parasympathetic innervation.

Directly and indirectly acting parasympathetic cholinomimetic agents,

primarily pilocarpine and bethanechol, and neostigmine, are used most

often therapeutically to treat certain diseases of the eye (acute angle-closure

glaucoma), the urinary tract (urinary tract retention), the gastrointestinal

tract (postoperative ileus), salivary glands (xerostomia), and the neuromus-

cular junction (myasthenia gravis). The ACh is generally not used clinically

because of its numerous actions and very rapid hydrolysis by AChE and

pseudocholinesterase.

The adverse effects of direct- and indirect-acting cholinomimetics result

from cholinergic excess and may include diarrhea, salivation, sweating,

bronchial constriction, vasodilation, and bradycardia. Nausea and vom-

iting are also common. Adverse effects of cholinesterase inhibitors (most

often as a result of toxicity from pesticide exposure, e.g., organophos-

phates) also may include muscle weakness, convulsions, and respiratory

failure.

Structure

ACh is a choline ester that is not very lipid soluble because of its charged qua-

ternary ammonium group. It interacts with both muscarinic and nicotinic

cholinoreceptors. Choline esters similar in structure to ACh that are used thera-

peutically include methacholine, carbachol, and bethanechol. Unlike ACh and

24 CASE FILES: PHARMACOLOGY

Table 2-1

EFFECTS OF CHOLINORECEPTOR ACTIVATION

ORGAN EFFECTS

Bronchial smooth muscle Contracts

Heart rate Decreases

Eye smooth muscles Contracts

Pupil size Contracts

Accommodation

Blood vessels Dilate

Gastrointestinal tract (tone, motility, secretions) Increase

∗

There is no parasympathetic innervation of blood vessels. However, they have cholinoreceptors

that when activated result in their dilation.

carbachol, methacholine and bethanechol are highly selective for muscarinic

cholinoreceptors.Pilocarpine is a tertiary amine alkaloid.

Mechanism of Action

Muscarinic cholinoreceptors activate inhibitory G-proteins (G

) to stimu-

late the activity of phospholipase C, which, through increased phospholipid

metabolism, results in production of inositol triphosphate (IP

) and DAG

that lead to the mobilization, respectively, of intracellular calciumfrom the

endoplasmic and sarcoplasmic reticulum and, through activation of protein

kinase C (PK-C), the opening of smooth muscle calcium channels with an

influx of extracellular calcium. Activation of muscarinic cholinoreceptors also

results in altered potassium flux that results in cell hyperpolarization, and in

inhibition of adenylyl cyclase activity and cAMP accumulation induced by

other hormones, including the catecholamines.

The nicotinic receptor functions as a cell membrane ligand-gated ion

channel pore. On interaction with ACh, the receptor undergoes a conforma-

tional change that results in influx of sodium with membrane depolarization

of the nerve cell or the skeletal muscle neuromuscular endplate.

Indirectly acting parasympathetic cholinomimetic agents inhibit AChE and

thereby increase ACh levels at both muscarinic and nicotinic cholinoreceptors.

Administration

Directly acting muscarinic cholinomimetic agents may be administered topically

as ophthalmic preparations (pilocarpine, carbachol), orally (bethanechol, pilo-

carpine), or parenterally (bethanechol). Depending on the agent, an indirectly act-

ing cholinesterase inhibitor may be administered topically, orally, or parenterally.

Pharmacokinetics

ACh is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by

the enzyme choline acetyltransferase and then transported into nerve end-

ing vesicles. Like ACh, methacholine, carbachol, and bethanechol are

poorly absorbed by the oral route and have limited penetration into the

CNS. Pilocarpine is more lipid soluble and can be absorbed and can

penetrate the CNS.

After release from nerve endings, ACh is rapidly metabolized into choline and

acetate, and its effects are terminated by the action of the enzymes AChE and

pseudocholinesterase. Methacholine and particularly carbachol and bethanechol

are resistant to the action of cholinesterases.

CLINICAL CASES 25

COMPREHENSION QUESTIONS

[2.1] A 62-year-old woman is noted to have open-angle glaucoma. She inad-

vertently applies excessive pilocarpine to her eyes. This may result in

which of the following?

A. Bronchial smooth muscle dilation

B. Decreased gastrointestinal motility

C. Dilation of blood vessels

D. Mydriasis

[2.2] Muscarinic cholinergic agonists

A. Activate inhibitory G-proteins (G

)

B. Decrease production of IP

C. Decrease release of intracellular calcium

D. Inhibit the activity of phospholipase C

[2.3] Choline esters like carbachol are most likely to cause which of the

following adverse effects?

A. Anhydrosis (dry skin)

B. Delirium

C. Salivation

D. Tachycardia (rapid heart rate)

Answers

[2.1] C. Excessive pilocarpine may initially result in dilation of blood vessels

with a drop in blood pressure and a compensatory reflex stimulation of

heart rate. Higher levels will directly inhibit the heart rate. In addition,

pilocarpine stimulation of muscarinic cholinoreceptors can result in

miosis, bronchial smooth muscle dilation, and increased GI motility.

[2.2] A. In addition to activating inhibitory G-proteins (G

), muscarinic

cholinergic agonists stimulate the activity of phospholipase C, increase

production of IP

, and increase release of intracellular calcium.

[2.3] C.Diarrhea, salivation, and lacrimation may be seen. The heart rate

is usually slowed. Choline esters do not cross the blood-brain barrier,

and therefore delirium is not an adverse effect.

CASE FILES: PHARMACOLOGY

REFERENCES

Felder C. Muscarinic acetylcholine receptors: signal transduction through multiple

effectors. FASEB J 1995;9(8):619–25.

Marquis RE, Whitson JT. Management of glaucoma: focus on pharmacological

therapy. Drugs Aging 2005;22(1):1–21.

Millard CB, Broomfield CA. Anticholinesterases: medical applications of neuro-

chemical principles. J Neurochem 1995;64(5):1909–18.

CLINICAL CASES

PHARMACOLOGY PEARLS

❖ Cholinoreceptors are classified as either nicotinic or muscarinic.

❖ Muscarinic cholinoreceptors are localized at organs such as the

heart, causing a negative chronotropic effect.

❖ Stimulation of muscarinic receptors in the smooth muscle, exocrine

glands, and vascular endothelium cause bronchoconstriction, incr-

eased acid secretion, and vasodilation.

❖ Methacholine and bethanechol are highly selective for muscarinic

cholinoreceptors.

❖ Cholinomimetic agents, including anticholinesterase inhibitors, are

precluded for treatment of gastrointestinal or urinary tract disease

because of mechanical obstruction, where therapy can result in

increased pressure and possible perforation. They are also not

indicated for patients with asthma.

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❖

CASE 3

A 53-year-old woman comes to see you for a consultation. She is scheduled to

take a Caribbean cruise in 2 weeks but is concerned about sea sickness. She

has been on boats before and is very sensitive to motion sickness. A friend

mentioned to her that there is a patch that is effective for this problem. She is

in good health and takes no medications regularly. Her examination is normal.

You prescribe a scopolamine transdermal patch for her.

◆

What is the mechanism of action of scopolamine?

◆

What are the common side effects of this medication?

◆

What are some relative contraindications to its use?

ANSWERS TO CASE 3: MUSCARINIC

CHOLINORECEPTOR ANTAGONISTS

Summary:A 53-year-old woman with motion sickness is prescribed transder-

mal scopolamine before she takes a sea cruise.

◆

Mechanism of action of scopolamine: Competitive antagonist of

muscarinic cholinoreceptors in the vestibular system and the CNS

◆

Common side effects: Mydriasis, dry mouth, tachycardia, urinary

retention, confusion, drowsiness

◆

Relative contraindications: Glaucoma, urinary obstruction, heart

disease

CLINICAL CORRELATION

Scopolamine, like other antimuscarinic agents, including the prototype

atropine, is a selective competitive (surmountable) antagonist of ACh at mus-

carinic cholinoreceptors. Its actions can be overcome by increased concentra-

tions of ACh or other muscarinic cholinoreceptor agonists. Scopolamine

blocks muscarinic cholinoreceptors in the vestibular system and CNS to

prevent motion sickness.It has a relatively long duration of action and can be

given as a transdermal patch, making it well suited for the treatment of motion

sickness. Histamine H

-receptor antagonists, such as cyclizine, are also used

to treat motion sickness.

In addition to motion sickness, muscarinic cholinoreceptor antagonists

(e.g., benztropine) are used therapeutically to treat Parkinson disease. Short-

acting topical agents or ointments are used to facilitate ophthalmoscopic

examination (e.g., cyclopentolate, tropicamide). Ipratropium bromide, a qua-

ternary ammonium compound that does not cross the blood-brain barrier, is

used to treat asthma and has efficacy in chronic obstructive pulmonary disease

(COPD). They (e.g., trospium, tolterodine) are also used to treat certain blad-

der disorders. Because it penetrates the CNS, the tertiary amine atropine is

used to counter the muscarinic cholinoreceptor effects of cholinergic excess

resulting from organophosphate insecticide poisoning.

Theadverse effects of scopolamine and other muscarinic cholinoreceptor

antagonists are related to inhibition of muscarinic cholinoreceptors in organ

systems of the body. Drowsiness and sedation are caused by actions on the

CNS. Mydriasis is caused by blocking parasympathetic tone in the muscles of

the cilia and iris. This could increase intraocular pressure in a person with glau-

coma. Cholinoreceptor blockade at the sinoatrial node results in tachycardia.

This could cause arrhythmias,especially in someone with underlying heart dis-

ease. The urinary bladder is relaxed and the urinary sphincter constricted,

which may promote urinary retention.Blockade of muscarinic cholinoreceptors

CASE FILES: PHARMACOLOGY

in the salivary glands reduces salivation,causing dry mouth. Blockade of other

muscarinic cholinoreceptors in the CNS can lead to impairment of memory,

confusion, restlessness, drowsiness, or hallucinations.

Muscarinic cholinoreceptor antagonist drugs are used cautiously in

patients with angle-closure glaucoma (contraindicated), open-angle glau-

coma, urinary tract obstruction (e.g., prostatic hypertrophy), cardiac dis-

ease, and gastrointestinal infections, among other conditions. Elderly

patients are particularly sensitive to CNS effects.

APPROACH TO MUSCARINIC CHOLINORECEPTOR

ANTAGONISTS

Objectives

1. Describe the mechanism of action of muscarinic cholinoreceptor

antagonists.

2. Describe the physiologic effects of muscarinic cholinoreceptor antag-

onists.

3. List important therapeutic uses of muscarinic cholinoreceptor antagonists.

4. List the adverse effects and contraindications for muscarinic choli-

noreceptor antagonists.

Definitions

Chronic obstructive pulmonary disease [COPD]: Progressive, inflam-

matory lung conditions, including both chronic bronchitis and emphy-

sema, which result in airway obstruction that is not fully reversible.

Most COPD is due to smoking.

Asthma:An inflammatory lung condition characterized by reversible airway

obstruction that can be precipitated by irritants such as environmental

allergens, cigarette smoke, cold air or exercise.

Muscarinic Cholinoreceptor antagonists: Drugs that block the actions of

acetylcholine.

DISCUSSION

Class

Cholinoreceptor antagonists are distinguished by their specificity for mus-

carinic and nicotinic cholinoreceptors. Muscarinic cholinoreceptor antago-

nists block the effects of ACh at muscarinic cholinoreceptors in the

parasympathetic autonomic nervous system and in the CNS. Nicotinic

cholinoreceptor antagonists block the effects of ACh at ganglia of the

parasympathetic and sympathetic nervous system (and medulla), and at the

neuromuscular junction.

CLINICAL CASES 31

32 CASE FILES: PHARMACOLOGY

Structure

Like atropine, the prototype muscarinic cholinoreceptor antagonist scopo-

lamine is a tertiary amine. As such, it has ready access to the CNS when

administered parenterally, and it can be absorbed across the skin when com-

bined with a suitable vehicle in a transdermal patch. Quaternary amine

antimuscarinic agents,including tiotropium bromide, have limited access to

the CNS and thus are used therapeutically for their peripheral effects.

Mechanism of Action

Interaction of scopolamine, atropine, or other antimuscarinic agents with mus-

carinic cholinoreceptors prevents the typical actions of ACh, such as activation

of G-proteins and subsequent production of IP

, and DAG that results in mobi-

lization of calcium.

Administration

The patch formulation of scopolamine for motion sickness provides for up to

72 hours of pharmacologic activity. Scopolamine can also be administered IV,

IM, or PO. Ipratropium bromide and tiotropium are administered topically to

the airways as a metered-dose inhaler for COPD.

Pharmacokinetics

The duration of action of antimuscarinic agents ranges from less than a day

(tropicamide) to 3–10 days (scopolamine, atropine).

COMPREHENSION QUESTIONS

[3.1] Prescription of a muscarinic cholinoreceptor antagonist with a quater-

nary amine group is most appropriate for the patient with which of the

following conditions?

A. A 50-year-old woman with angle-closure glaucoma

B. A 34-year-old man with gastrointestinal infectious enteritis

C. A 66-year-old man with mild dementia

D. A 56-year-old diabetic woman with urinary tract obstruction

[3.2] A 16-year-old teenager is going on his first deep sea fishing trip and is

using a scopolamine patch to ward off sea sickness. Which of the fol-

lowing is the most likely adverse effect he will experience?

A. Bradycardia

B. Drowsiness

C. Miosis

D. Urinary urgency

[3.3] Cholinergic excess resulting from organophosphate insecticide poison-

ing can be treated with which of the following?

A. Atropine

B. Digoxin

C. Ipratropium bromide

D. Tropicamide

Answers

[3.1] C. Muscarinic cholinoreceptor antagonists with quaternary amine

groups do not penetrate the CNS and are therefore unlikely to impair

memory. By blocking gastrointestinal motility, these agents can cause

increased retention of infecting organisms.

[3.2] B.Scopolamine penetrates the CNS and can cause drowsiness and seda-

tion. It also can cause mydriasis, tachycardia, and urinary retention.

[3.3] A.Atropine is a tertiary amine that can penetrate the CNS. In addi-

tion to its peripheral blocking actions, it can also block the adverse

CNS effects as a result of cholinergic excess. Tropicamide is also a

tertiary amine. However, it has a very short duration of action and

would be an unsuitable antidote. Ipratropium bromide is a charged

quaternary ammonium compound that does not penetrate the CNS.

CLINICAL CASES 33

PHARMACOLOGY PEARLS

❖ Many antihistaminic agents, antipsychotic agents, and antidepres-

sant agents have muscarinic cholinoreceptor antagonist (antimus-

carinic) activity.

❖ Scopolamine is a tertiary amine and has ready access to the CNS

when administered parenterally, whereas quaternary amine

antimuscarinic agents, such as ipratropium bromide, have limited

access to the CNS.

❖ Scopolamine can cause drowsiness and sedation, as well as mydria-

sis, tachycardia, and urinary retention.

❖ Cholinoreceptor agonists cause symptoms of SLUD—salivation,

lacrimation,urination, diarrhea—whereas cholinoreceptor antag-

onists have the opposite effects—dry mouth, dry eyes, urinary

retention, constipation.

34 CASE FILES: PHARMACOLOGY

REFERENCES

Alhasso AA, McKinlay J, Patrick K et al. Anticholinergic drugs versus non-drug

active therapies for overactive bladder syndrome in adults. Cochrane Database Syst

Rev 2006;18(4):CD003193.

Eglen RM, Choppin A, Watson N. Therapeutic opportunities from muscarinic

receptor research. Trends Pharmacol Sci 2001;22(8):409–14.

Nachum Z, Shupak A, Gordon C. Transdermal scopolamine for prevention of

motion sickness: clinical pharmacokinetics and therapeutic applications. Clin

Pharmacokinet 2006;45(6):543–66.

❖

CASE 4

A healthy 25-year-old man is undergoing a brief surgical procedure requiring

general anesthesia. He underwent an unremarkable intubation and induction of

anesthesia using IV succinylcholine and inhaled halothane. During the surgery

the patient develops muscle rigidity and tachycardia, and his temperature rap-

idly rises.

◆

What is the mechanism of action of succinylcholine?

◆

What reaction is occurring in the patient?

◆

What drug should immediately be given to the patient, and what is

its mechanism of action?

ANSWERS TO CASE 4: SKELETAL MUSCLE

RELAXANTS

Summary:A 25-year-old man develops muscle rigidity, tachycardia, and high

fever during surgery.

◆

Mechanism of action of succinylcholine: Nicotinic receptor agonist at

the motor endplate of the neuromuscular junction, which causes

persistent stimulation and depolarization of muscle cells.

◆

Reaction that is occurring: Malignant hyperthermia.

◆

Drug given for treatment and its mechanism of action:Dantrolene,

which acts by interfering with calcium release from the sarcoplasmic

reticulum.

CLINICAL CORRELATION

Succinylcholine is the only depolarizing neuromuscular agent in wide clini-

cal use. It is used for the rapid induction of a brief flaccid paralysis. It works

as an agonist of the nicotinic receptor at the motor endplate of the neuro-

muscular junction. This causes a persistent stimulation and depolarization of

the muscle, preventing stimulation of contraction by ACh. It has a rapid

onset and short duration of action because it is quickly hydrolyzed by plasma

and liver cholinesterase. Malignant hyperthermia, a rare but significant

cause of anesthetic morbidity and mortality, is an inherited autosomal dom-

inant disorder that results in tachycardia, muscle rigidity, and high body

temperatures in response to the use of certain inhaled anesthetics in com-

bination with muscle relaxants, usually succinylcholine. It is caused by a

release of calcium ions from the sarcoplasmic reticulum in muscle cells.

Dantrolene interferes with this release and is therefore the treatment of

choice for this condition.

APPROACH TO PHARMACOLOGY OF SKELETAL

MUSCLE RELAXANTS

Objectives

1. Contrast the mechanism of action of depolarizing and nondepolarizing

neuromuscular junction-blocking agents.

2. List the therapeutic uses and adverse effects of skeletal muscle

relaxants.

CASE FILES: PHARMACOLOGY

Definitions

Hyperkalemia: Elevated levels of the electrolyte potassium in the serum

Myalgia: Pain originating in skeletal muscle

Depolarizing neuromuscular agent:A drug that acts at the neuromuscular

junction to prevent the initiation of an action potential by ACh.

DISCUSSION

Class

Neuromuscular blocking agentsare classified as either depolarizing or non-

depolarizing (Table 4-1) and are used mostly as adjuncts with general anes-

thetics to block motor endplate activity of ACh at the neuromuscular junction.

Succinylcholine is the prototype for depolarizing agents and used for brief

paralysis for surgery and for intubation. Tubocurarine, the prototype, and

other nondepolarizing agents (e.g., cisatracurium, vecuronium, rocuronium)

are used for longer term paralysis for surgery.

In addition to malignant hyperthermia, succinylcholine administration may

result in hyperkalemia,particularly in patients with burn and trauma, which

could result in cardiac arrest. Myalgia is also commonly reported.

Certain nondepolarizing agents may produce hypotension, as a result of

histamine release and some ganglionic blocking activity, and tachycardia as a

result of vagolytic activity.

Numerous drug interactions between neuromuscular blocking agents and

other drugs have been reported that lead to increased neuromuscular blockade,

particularly with certain antibiotics and inhaled anesthetics.

CLINICAL CASES 37

Table 4-1

SELECTED SKELETAL MUSCLE RELAXANTS

MECHANISM SELECTED

TYPE OF AGENT OF ACTION ADVERSE EFFECTS

Depolarizing agents Persistent endplate Malignant hyperthermia,

(succinylcholine) depolarization and hyperkalemia, myalgia

desensitization

Nondepolarizing agents Reversible competitive Hypotension, tachycardia

(tubocurarine, cisatracurium antagonists that block the

vecuronium, rocuronium) action of ACh at nicotinic

cholinoreceptor

Structure

The neuromuscular blocking agents resemble ACh (succinylcholine con-

tains two linked ACh molecules) and contain one or two quaternary nitro-

gens that limit entry into the CNS.

Mechanism of Action

After a single dose, succinylcholine occupies the nicotinic receptor to pro-

duce a persistent endplate depolarization(phase I block) that results in flac-

cid paralysis because the muscles become unresponsive to endogenously

released ACh. The initial depolarization is accompanied by muscle fascicula-

tions. Continued exposure of endplates to succinylcholine results in their

repolarization. However, through an unclear mechanism, they become rela-

tively insensitive to subsequent depolarization (so-called desensitization, or

phase II block).

Nondepolarizing blocking agents act as reversible competitive antagonists

that block the action of ACh at nicotinic cholinoreceptors in muscle endplates

and autonomic ganglia.

Cholinesterase inhibitors (e.g., neostigmine, pyridostigmine) can effec-

tively antagonize and reverse the neuromuscular blocking action of non-

depolarizing agents and succinylcholine during phase II. However, they

will augment the action of succinylcholine during phase I.

Administration

The neuromuscular blocking agents are highly polar and therefore must be

administered parenterally. Most nondepolarizing agents are eliminated

through the kidney. Succinylcholine is eliminated by the hydrolytic action of

plasma butyrylcholinesterase (pseudocholinesterase).

Pharmacokinetics

Neuromuscular blocking agents are highly ionized and therefore have limited

volume of distribution and limited access to the CNS.

COMPREHENSION QUESTIONS

[4.1] The use of succinylcholine as an adjunct to general anesthetics during

surgery is based on its ability to:

A. Block the action of ACh at the motor endplate

B. Increase release of ACh from autonomic ganglia

C. Increase release of histamine from mast cells

D. Inhibit cholinesterase

CASE FILES: PHARMACOLOGY

[4.2] Continued exposure of muscle endplates to succinylcholine results

in their:

A. Conversion to ion channels

B. Enhanced sensitivity to ACh

C. Regeneration of ACh receptors

D. Repolarization

[4.3] Cholinesterase inhibitors can reverse the action of which of the following?

A. Cisatracurium

B. Succinylcholine

C. Both A and B

D. Neither A or B

[4.4] A 35-year-old man undergoes surgery for a hernia repair. After the surgery,

he complains of diffuse muscle aches, which the anesthesiologist states is

likely caused by the skeletal muscle relaxant. He has a temperature of

37.8°C (100°F). Which of the following is the most accurate statement?

A. The agent also commonly causes hypokalemia.

B. The agent blocks ACh at the nicotinic receptor.

C. The agent causes persistent endplate depolarization and desen-

sitization.

D. The patient likely has malignant hyperthermia.

Answers

[4.1] A.Succinylcholine acts like ACh to cause depolarization of the mus-

cle endplate. However, unlike ACh, succinylcholine is not metabo-

lized at the synapse. Therefore, the endplate remains depolarized and

unresponsive to endogenous ACh, resulting in muscle paralysis.

[4.2] D. Continued exposure of the muscle endplate to succinylcholine

results in desensitization (phase II block) where the endplate repolar-

izes but cannot readily be depolarized.

[4.3] C.Cholinesterase inhibitors like neostigmine can effectively antago-

nize and reverse the neuromuscular blocking action of nondepolariz-

ing agents and succinylcholine during phase II. However, they will

augment the action of succinylcholine during phase I.

[4.4] C.Myalgia (muscle aches) is a common adverse reaction of depolar-

izing agents such as succinylcholine; these agents also may induce

hyperkalemia and malignant hyperthermia.

CLINICAL CASES 39

REFERENCES

Bowman WC. Neuromuscular block. Br J Pharmacol 2006;147(Suppl 1):S277–86.

Lee C. Structure, conformation, and action of neuromuscular blocking drugs. Br J

Anaesth 2001;87(5):755–69.

Sparr HJ, Beaufort TM, Fuchs-Buder T. Newer neuromuscular blocking agents.

How do they compare with established drugs? Drugs 2001;61(7):919–42.

40 CASE FILES: PHARMACOLOGY

PHARMACOLOGY PEARLS

❖ Malignant hyperthermia is a rare autosomal dominant disorder char-

acterized by tachycardia, muscle rigidity, and high body temper-

atures, which occurs when the patient is exposed to inhaled

anesthetics in combination with muscle relaxants, usually suc-

cinylcholine.

❖ Dantrolene interferes with the release of intracellular calcium and is

therefore used to treat the muscle rigidity and hyperthermia asso-

ciated with malignant hyperthermia.

❖ The neuromuscular blocking agents are highly polar and highly ion-

ized and therefore, must be administered parenterally and have

limited volume of distribution and limited access to the CNS.

❖ A small number of patients (1:10,000) with atypical cholinesterase

experience long-lasting apnea of 1–4 hours following succinyl-

choline (or the nondepolarizing neuromuscular blocking drug

mivacurium that is also eliminated by the action of butyryl-

cholinesterase). Mechanical ventilation is used to manage the

apnea even though prescreening could detect this rare condition.

❖

CASE 5

A 65-year-old woman is admitted to the intensive care unit (ICU) of the hos-

pital with sepsis caused by a urinary tract infection. She is hypotensive, with

a blood pressure of 80/40 mm Hg and has an elevated heart rate (tachycardia)

and decreased urine output (oliguria). Along with the institution of appropri-

ate antibiotic therapy and IV fluids, a decision is made to start her on an IV

infusion of dopamine to attempt to raise her blood pressure.

◆

What effects can be expected with low-dose dopamine?

◆

Which receptors mediate these effects?

◆

What effects occur with higher dose dopamine and which receptors

mediate these?

ANSWERS TO CASE 5: SYMPATHOMIMETIC AGENTS

Summary: A 65-year-old woman in septic shock has persistent hypotension

and oliguria requiring IV dopamine.

◆

Effects of low-dose dopamine: Reduces arterial resistance and

increases blood flow in renal, coronary, and splanchnic systems;

positive inotropic effect.

◆

Receptors involved:β

-receptors and specific dopamine receptors.

◆

Effects of higher dose dopamine and receptors involved:

Vasoconstriction mediated by α-receptors.

CLINICAL CORRELATION

Dopamine is frequently used to treat cardiogenic or septic shock. The β

adrenoceptor-mediated effects in the heart result in an increase in cardiac

output with minimal peripheral vasoconstriction. This contributes to

dopamine’s ability to raise systolic blood pressure with no effect or only a

slight effect on diastolic pressure. Specific dopamine receptors in the vascu-

lature of the renal, coronary, and splanchnic systems allow for reduced arte-

rial resistance and increased blood flow. At higher doses there is a peripheral

α-adrenoceptor effect that overrides dopamine receptor-mediated vasodila-

tion and results in vasoconstriction. The combination of renal blood-flow

preservation, while supporting the blood pressure, is desirable in conditions

of shock. This also contributes to increasing blood pressure. Prolonged high

doses of dopamine can result in peripheral tissue necrosis because of the

α-adrenoceptor-mediated vasoconstriction that reduces blood flow to the

extremities, particularly in the digits.

APPROACH TO PHARMACOLOGY OF AUTONOMIC

SYMPATHETIC AGENTS

Objectives

1. Outline the effects of sympathomimetic agents on peripheral organ

systems.

2. List the major sympathomimetic agonists and their routes of adminis-

tration.

3. Describe the therapeutic and adverse effects of the major sympath-

omimetic drugs.

CASE FILES: PHARMACOLOGY

Definitions

Sympathomimetic agents: Drugs that either directly or indirectly mimic

all or some of the effects of epinephrine or norepinephrine.

Receptor selectivity: Preferential binding (greater affinity) of a drug to a

specific receptor group or receptor subtype at concentrations below which

there is little, if any, interaction with another receptor group or subtype.

DISCUSSION

Class

Sympathomimetic agents act directly (e.g., epinephrine, norepinephrine,

dopamine, dobutamine, phenylephrine, metaraminol, methoxamine,

albuterol, terbutaline) or indirectly (amphetamine, ephedrine) to activate

a- and b-adrenoceptors (Table 5-1). Sympathomimetic agent adrenoceptor

CLINICAL CASES 43

Table 5-1

AUTONOMIC NERVOUS SYSTEM EFFECTS*

ADRENERGIC MUSCARINIC CHOLINERGIC

ORGAN RECEPTOR/ACTION RECEPTOR/ACTION

Heart β

—increased heart rate and Decreased heart rate and

contractility contractility

Blood vessels

†

—constriction Dilation

—dilation

Bronchi β

—bronchial smooth muscle Bronchial smooth muscle

relaxation contraction

GI tract α

—sphincter contraction Overall contraction relaxation

—relaxation of sphincter

Kidney β

—renin release No effect

Urinary bladder α

—sphincter contraction Wall contraction sphincter

—wall relaxation relaxation

Adipose tissue β

—increased lipolysis No effect

Eye α

—radial muscle contraction Sphincter muscle contraction

with pupil dilation with pupil constriction ciliary

muscle contraction

See also Figure 1-1.

†

No direct parasympathetic innervation.

selectivity varies. Some are nonselective (e.g., ephedrine), whereas some

have greater affinity for α-adrenoceptors (e.g., phenylephrine, metaraminol,

methoxamine) or β

-adrenoceptor (e.g., dobutamine) or β

-adrenoceptor

(e.g., terbutaline, albuterol) subgroups. However, selectivity is often lost as

the dose of a sympathomimetic agent is increased. Compared to nonselective

β-receptor agonists (isoproterenol), b

-selective sympathomimetic agents

may increase cardiac output with minimal reflex tachycardia. a

-Selective

agents, which decrease blood pressure by a prejunctional action in the CNS

(clonidine, methyldopa), are used to treat hypertension. Fenoldopam is a

potent D

agonist with a short half-life, useful in severe hypertension; its

effects include decreasing systemic vascular resistance.

Dopamine interacts with specific subtypes of dopamine receptors in the

periphery (D

and D

). Stimulation of the D

receptor on the vasculature is

principally vasodilation, and on the renal proximal tubules leads to natriuresis

and diuresis; stimulation of the D

receptor on the presynaptic sympathetic

nerve endings inhibits norepinephrine release. It also has direct and indirect

sympathomimetic activity where, at lower doses, it has greater affinity for β-

adrenoceptors than it does for α-adrenoceptors.

The clinical utility of a particular sympathomimetic agent depends on,

among other factors, the specific organ system and receptor subtypes that are

involved. In the cardiovascular system, a reduction in blood flow by rela-

tively selective α-adrenoceptor sympathomimetic agents is used to achieve

surgical hemostasis, reduced diffusion of local anesthetics, and a reduction of

mucous membrane congestion in hay fever and for the common cold. An

increase in blood flow or blood pressure by α-adrenoceptor sympathomimetic

agents is beneficial for the management of hypotensive emergencies (e.g.,

phenylephrine, methoxamine, norepinephrine) and chronic orthostatic

hypotension (oral ephedrine). Sympathomimetic agents such as isoproterenol

(and epinephrine) are also used for emergency short-term treatment of com-

plete heart block and cardiac arrest.

Treatment of bronchial asthmarepresents a major use of b

-selective sym-

pathomimetic agents (e.g., terbutaline, albuterol). Its effect is bronchodilation

and relaxation of the smooth muscles of the bronchioles.

Ophthalmic examination is facilitated with the use of the directly acting

a-adrenoceptor sympathomimetic agonist, phenylephrine. Phenylephrine

(and the indirectly acting sympathomimetic agent, cocaine) is also used to

localize the lesion in Horner syndrome. In addition to β-adrenoceptor-blocking

agents, α

-selective agents (e.g., apraclonidine) are used to lower intraocular

pressure in glaucoma.

The peripheral adverse effects of the sympathomimetic agents are gen-

erally an extension of their pharmacologic effects. These are most often

cardiovascular in nature, particularly when they are administered parenter-

ally, and may include increased blood pressure, arrhythmias, and cardiac

failure.

44 CASE FILES: PHARMACOLOGY

Structure

Sympathomimetic agents, as well as norepinephrine and epinephrine, are

derived from phenylethylamine.Substitutions on the amino group, the ben-

zene ring or the α- or β-carbon, markedly alter the selectivity, activity, and

metabolism of the sympathomimetic agents. For example, alkyl substitutions

on the amino group tend to markedly increase β-adrenoceptor selectivity.

Mechanism of Action

Directly acting sympathomimetic agents bind to and activate adrenoceptors to

mimic the actions of epinephrine or norepinephrine. Indirectly acting sympa-

thomimetic agents mimic the actions of norepinephrine by either displacing it

or inhibiting its reuptake from adrenergic nerve endings.

Administration

Sympathomimetic agents are available for administration by topical, nasal,

oral, ophthalmic, and parenteral routes depending on the drug and condi-

tion being treated.

Pharmacokinetics

Like the catecholamines norepinephrine and epinephrine, direct and indirect

sympathomimetic agent may be subject to metabolism and inactivation by

COMT and MAO. Phenylephrine is not metabolized by COMT, whereas

metaraminol and methoxamine are not substrates for either COMT or MAO.

Their durations of action, therefore, are relatively long (20–60 minutes).

COMPREHENSION QUESTIONS

[5.1] A 25-year-old man is noted to be in septic shock. A low-dose dopamine

infusion is administered, and will likely result in which of the following?

A. Decrease cardiac output

B. Decrease systolic blood pressure

C. Increase renal blood flow

D. Produce significant peripheral vasoconstriction

[5.2] In contrast to norepinephrine, metaraminol, and methoxamine are

metabolized by which of the following?

A. COMT

B. MAO

C. Both

D. Neither

CLINICAL CASES 45

[5.3] Which of the following is the most accurate statement?

A. α-Adrenoceptor sympathomimetic agonists are used to reduce

mucous membrane congestion.

B. α-Adrenoceptor agonists are used to treat bronchospasm.

C. β-Adrenoceptor agonists are used to reduce surgical bleeding.

D. β

-Adrenoceptor agonist agents are used to prolong local anesthesia.

Answers

[5.1] C.Dopamine binding to specific dopamine receptors in the vascula-

ture in the kidney increases renal blood flow. Cardiac output is

increased by dopamine action on β

-adrenoceptors. Dopamine causes

minimal peripheral vasoconstriction.

[5.2] D. Metaraminol and methoxamine are not substrates for either

COMT or MAO and have a longer duration of action than norepi-

nephrine, which is a substrate for both.

[5.3] A.α-Adrenoceptor sympathomimetic agents will cause vasoconstric-

tion and thereby reduce mucous membrane congestion.

46 CASE FILES: PHARMACOLOGY

PHARMACOLOGY PEARLS

❖ β

-Selective sympathomimetic agents may increase cardiac output

with minimal reflex tachycardia.

❖ α

-Selective agents decrease blood pressure by a prejunctional

action in the CNS.

❖ Terbutaline and albuterol are preferred over ephedrine for relieving

the bronchoconstriction of asthma, and other bronchial condi-

tions, because of their greater bronchiolar selectivity.

❖ Dopamine binding to specific dopamine receptors in the vasculature in

the kidney increases renal blood flow. Cardiac output is increased

by dopamine action on β

-adrenoceptors. Low-dose dopamine

causes minimal peripheral vasoconstriction.

REFERENCES

Cleland JG. Beta-blockers for heart failure: why, which, when, and where. Med Clin

North Am 2003;87(2):339–71.

Graham RM, Perez DM, Hwa J, et al. Alpha

-adrenergic receptor subtypes.

Molecular structure, function and signaling. Circ Res 1996;78(5):737–49.

Mann HJ, Nolan PE. Update on the management of cardiogenic shock. Curr Opin

Crit Care 2006;12(5):431–6.

❖

CASE 6

A 70-year-old man is seen in follow-up at your office after he has been hospi-

talized for a myocardial infarction (MI). He underwent successful angioplasty

and is currently asymptomatic. Prior to his MI, he was not on medications. He

is not a smoker and is not diabetic. During his hospitalization, he was noted

to have persistently elevated blood pressure readings. He had asthma as a

child, but has not had any recent wheezing episodes. While in the hospital, he

was started on oral metoprolol.

◆

Metoprolol is selective for which adrenoceptor?

◆

What effects do agents such as metoprolol have on the

cardiovascular system?

◆

In which organ is metoprolol primarily metabolized?

◆

Why must b-adrenergic antagonists be used with caution in

asthmatics?

ANSWERS TO CASE 6: ADRENOCEPTOR

ANTAGONISTS

Summary:A 70-year-old hypertensive man with a childhood history of asthma

had a recent myocardial infarction and is prescribed metoprolol.

◆

Adrenoceptor selectively antagonized by metoprolol:β

◆

Effect of b-adrenoceptor antagonists on the cardiovascular system:

Reduction of sympathetic-stimulated increases in heart rate,

contractility, and cardiac output; lower blood pressure as a result of

effects on the heart, renin-angiotensin system, and CNS; increased

atrioventricular (AV) conduction time and refractoriness.

◆

Organ in which metoprolol is metabolized:Liver.

◆

Reason for caution in use in asthmatics: Blockade of β

-adrenoceptor

in bronchial smooth muscle may cause increased airway resistance and

bronchospasm.

CLINICAL CORRELATION

β-Adrenergic receptor antagonists are widely used in medicine, primarily for

their beneficial effects on the cardiovascular system and for lowering intraoc-

ular pressure in patients with glaucoma. Both the nonselective β-adrenorecep-

tor antagonists and the relatively β

-adrenoceptor selective antagonists are

used to treat hypertension. The mechanism of their action is multifactorial,

probably including reduction in cardiac output, reduction in renin release, and

some CNS effect. They are also beneficial for treating coronary artery disease

and postmyocardial infarction patients as they reduce sympathetic-stimulated

increases in heart rate and contractility. This helps to reduce myocardial oxy-

gen demand, providing prophylaxis for angina. b-Adrenoceptor antagonists

have a proven benefit in prolonging survival after heart attacks. They

lengthen AV conduction time and refractoriness and suppress automaticity.

This helps to prevent both supraventricular and ventricular arrhythmias.

Caution must be used when giving β-blockers to patients with asthma, COPD,

and diabetes. All β-adrenoceptor blockers, including those that are β

-adreno-

ceptor selective, have some β

-adrenoceptor antagonist activity and may

cause bronchospasm by their effects on bronchial smooth muscle. They can

also mask the symptoms of hypoglycemia in a diabetic by blocking the

adrenergic stimulated symptoms of tremor, tachycardia, and nervousness that

would normally occur.

CASE FILES: PHARMACOLOGY

APPROACH TO PHARMACOLOGY

OF ADRENOCEPTOR AGONISTS

Objectives

1. Describe the therapeutic uses and adverse effects of α-adrenoceptor

antagonists.

2. Describe the therapeutic uses and adverse effects of β-adrenoceptor

antagonists.

3. Contrast the differences between the nonselective and relatively

-selective adrenoceptor antagonists.

Definitions

Pheochromocytoma:A tumor of the adrenal medulla that releases excess

levels of epinephrine and norepinephrine that can result in hypertension,

cardiac anomalies, and severe headache.

Myocardial infarction:Death of cardiac muscle as a result of ischemia.

DISCUSSION

Class

There are two classes of clinically important α-adrenoceptor antagonists: non-

selective antagonists and selective α

-antagonists. Phentolamine, a nonselec-

tive, competitive a-adrenoceptor antagonist, and phenoxybenzamine, a

nonselective, noncompetitive a-adrenoceptor antagonist are used for the

preoperative management of the marked catecholamine-induced vasoconstric-

tionassociated with pheochromocytoma. Prazosin and other a

-adrenoceptor

selective antagonists(doxazosin, terazosin) are used to manage chronic mild-

to-moderate hypertension and benign prostatic hypertrophy.

In addition to the nonselective β-adrenoceptor antagonists, there are two

classes of clinically important selective β-adrenoceptor antagonists, β

and β

(Table 6-1). The major clinical uses for β-adrenoceptor antagonists include

ischemic heart disease, cardiac arrhythmias, hypertension, hyperthyroidism, and

glaucoma. Ischemic heart disease is managed with nonselective β-adrenoceptor

antagonists, propranolol, timolol, and nadolol, as well as β

-adrenoceptor selec-

tive antagonists, metoprolol, atenolol, and esmolol. Cardiac arrhythmias are

managed, depending on the arrhythmia, with propranolol and esmolol.

Hypertension is managed with a wide variety of nonselective and b

-adreno-

ceptor selective antagonists, except esmolol. Timololand other β-adrenocep-

tor antagonists are used to manage glaucoma by decreasing aqueous humor

production and thereby reducing intraocular pressure.

CLINICAL CASES 49

Labetalol (and several other agents, including carvedilol), in formulations

used clinically, blocks both b- and a

-adrenoceptors in a 3:1 ratio. It also

has some β

-adrenoceptor agonist activity. Labetalol lowers blood pressure

bydecreasing systemic vascular resistance without any major effect on heart

rate or cardiac output. It is used to treat hypertensive emergencies and hyper-

tension from pheochromocytoma. Table 6-2 has a listing of selected sympa-

thomimetic agents.

The major adverse effects of nonselective α-adrenoceptor antagonists

arecardiac stimulation, primarily tachycardia because of baroreflex-mediated

sympathetic discharge, and postural hypotension.Additional cardiac stimu-

lation by phentolamine may be caused by antagonist activity at prejunctional

-adrenoceptors that result in increased norepinephrine release. (Prazosin and

other selective α

-adrenoceptor selective antagonists are less likely to cause

reflex tachycardia.) A β-adrenoceptor antagonist may be required to counter

the cardiac effects. α-Antagonists are rarely used as first-line agents for hyper-

tension, as they are associated with a higher rate of congestive heart failure

than other agents.

The major adverse effects of nonselective b-adrenoceptor antagonists

are related to their effects on bronchial smooth muscle and on carbohydrate

metabolism. Blockade of b

-receptors in smooth muscle may increase air-

way resistance in patients with asthma or other airway obstruction dis-

eases.Although the clinical use of a selective β

-adrenoceptor antagonist may

offer some protection in patients with asthma, the selectivity of these agents is

not great, and therefore they should be used judiciously, if at all. In patients

with insulin-dependent diabetes, nonselective b-adrenoceptor antagonists

increase the incidence and severity of hypoglycemic episodes. The use of

selective β

-adrenoceptor antagonists in patients with this condition offers

some potential benefit.

50 CASE FILES: PHARMACOLOGY

Table 6-1

β-ADRENOCEPTOR ANTAGONIST SELECTIVITY

Nonselectiveb-Adrenoceptor Antagonists

Propranol

Nadolol

Timolol

Selectiveb

-Adrenoceptor Antagonists

Atenolol

Metoprolol

Esmolol

Nonselectiveb- and a

-Adrenoceptor Antagonists

Labetalol

Carvedilol

Mechanism of Action

α-Adrenoceptor antagonists and β-adrenoceptor antagonists interact directly,

and either competitively or irreversibly with, respectively, α-adrenoceptors

andβ-adrenoceptors to block actions of the endogenous catecholamines (nor-

epinephrine and epinephrine), and exogenously administered sympath-

omimetic agents.

Administration

α- and β-adrenoceptor antagonists are administered orally or parenterally.

β-Adrenoceptor antagonists are also available for ophthalmic application.

CLINICAL CASES 51

Table 6-2

SELECTED DRUGS AND THEIR EFFECTS ON THE AUTONOMIC

NERVOUS SYSTEM

ADRENOCEPTOR MECHANISM OF

DRUG ACTIVITY ACTION CLINICAL USE

Epinephrine Nonselective α- Bronchial smooth Asthma and other

andβ-adrenoceptor muscle dilation allergic diseases to

agonist relax airways and

reduce swelling

Phenylephrine α

-Adrenoreceptor Vasoconstriction Rhinitis and colds as

stimulation decongestant

Propranolol Nonselective β- Decreases heart Hypertension, coronary

adrenoceptor rate, cardiac heart disease

agonist contractility

Albuterol β

-Adrenoceptor Bronchial smooth Asthma

agonist muscle dilation

Phentolamine Nonselective Vasodilation Preoperative manage-

competitive α- ment of the marked

adrenoceptor catecholamine-induced

antagonist vasoconstriction

associated with

pheochromocytoma

Prazosin α

-Adrenoreceptor Vasodilation Chronic mild to

selective moderate hypertension

antagonists and benign prostatic

hypertrophy

Pharmacokinetics

Metoprolol and propranolol undergo extensive and variable interindividual

first-pass hepatic metabolism resulting in relatively low bioavailability. Oral

sustained-release preparations of these agents are available. Drugs that inhibit

cytochrome P

450

2D6 may decrease the metabolism of carvedilol. Esmolol is

ultra-short-acting as a result of its ester linkage that is rapidly metabolized by

plasma esterases.

COMPREHENSION QUESTIONS

[6.1] Which of the following actions of epinephrine are blocked by prazosin?

A. Bronchial dilation

B. Increased cardiac stroke volume

C. Increased heart rate

D. Mydriasis

[6.2] A 34-year-old man is prescribed labetalol for hypertension. The effect

on the cardiovascular system is a result of its action as an antagonist at

which of the following?

A. α-Adrenoceptors

B. β-Adrenoceptors

C. Both α- and β-adrenoceptors

D. Muscarinic cholinoreceptors

[6.3] Which of the following is the least likely clinical use for β-adrenoceptor

antagonists?

A. Benign prostatic hypertrophy

B. Cardiac arrhythmias

C. Hypertension

D. Ischemic heart disease

Answers

[6.1] D.Prazosin is an α-adrenoceptor antagonist that will block epinephrine-

mediated contraction of the radial smooth muscle of the eye that

results in mydriasis. All the other actions listed are mediated by β-

adrenoceptors, which would be blocked by β-adrenoceptor antago-

nists like propranolol.

[6.2] C. Labetalol blocks both β- and α-adrenoceptors. It lowers blood

pressure by decreasing systemic vascular resistance (α-adrenoceptor

antagonist activity), without any major effect on heart rate or cardiac

output (β-adrenoceptor antagonist activity).

CASE FILES: PHARMACOLOGY

[6.3] A. β-Adrenoceptor antagonists are used therapeutically to manage

ischemic heart disease, cardiac arrhythmias, and hypertension. α

Adrenoceptor selective antagonists are used to manage benign pro-

static hypertrophy.

CLINICAL CASES 53

PHARMACOLOGY PEARLS

❖ α

-Adrenoceptor selective antagonists, such as doxazosin and tera-

zosin, are used for mild chronic hypertension and benign prosta-

tic hypertrophy.

❖ The major clinical uses for β-adrenoceptor antagonists include

ischemic heart disease, cardiac arrhythmias, hypertension, hyper-

thyroidism, and glaucoma.

❖ The major adverse effects of nonselective b-adrenoceptor antag-

onists are related to their effects on bronchial smooth muscle

(increased airway resistance in asthmatics) and on carbohydrate

metabolism (hypoglycemia in insulin-dependent diabetics).

REFERENCES

Shin J, Johnson JA. Pharmacogenetics of beta-blockers. Pharmacotherapy

2007;27(6):874–87.

Piascik MT, Perez DM. Alpha 1-adrenergic receptors: new insights and directions.

J Pharmacol Exp Ther 2001;293(2):403–10.

This page intentionally left blank

❖

CASE 7

A 64-year-old woman with a history of two previous myocardial infarctions

(MIs) comes to the emergency room with shortness of breath. In the previous

2 weeks, she has developed dyspnea with exertion and swelling of her legs.

She sleeps on three pillows because she coughs and gets short of breath if she

tries to lie flat. In the emergency department, she is sitting upright, appears to

be in moderate respiratory distress, and is tachycardic and hypertensive. She

has jugular venous distension to the angle of her jaw. On auscultation of her

lungs, wet rales are heard bilaterally. She has pitting edema of both lower legs

up to her knees. A chest x-ray confirms the diagnosis of pulmonary edema.

She is placed on oxygen and immediately given an IV injection of furosemide.

◆

What is the mechanism of action of furosemide?

◆

What electrolyte abnormalities can be caused by furosemide?

ANSWERS TO CASE 7: DIURETICS

Summary: A 64-year-old woman with pulmonary edema is prescribed

furosemide.

◆

Mechanism of action of furosemide: Inhibit active NaCl reabsorption

in the ascending limb of the loop of Henle, increasing water and

electrolyte excretion.

◆

Potential electrolyte abnormalities:Hypokalemia, hypomagnesemia,

and metabolic alkalosis because of enhanced H

excretion.

CLINICAL CORRELATION

Loop diuretics given intravenously promote diuresis within minutes, mak-

ing them ideal for the treatment of acute pulmonary edema. Furosemide

is the prototype and most widely used drug in this class. Loop diuretics inhibit

NaCl reabsorption in the ascending limb of the loop of Henle. This causes a

marked increasein the excretion of both water and electrolytes. The excretion

of potassium, magnesium, and calcium ions are all increased, which may

cause clinically significant adverse effects. A metabolic alkalosis may also

occur as a result of the excretion of hydrogen ions. However, the ability to

cause excretion of these electrolytes may also provide a clinical benefit in cer-

tain situations. Forced diuresis by giving IV saline and furosemide is a pri-

mary method of treatment of hypercalcemia.

APPROACH TO PHARMACOLOGY OF THE

LOOP DIURETICS

Objectives

1. Know the site and mechanism of action of diuretic agents.

2. Know the electrolyte effects of the various diuretic agents.

3. Know the therapeutic uses, adverse effects, and contraindications to

diuretic use.

Definitions

Diuretic:An agent that increases the production of urine. The most com-

mon are natriuretic diuretics, agents that increase urine production by

interfering with sodium reabsorption in the kidney.

Edema: Accumulation of water in interstitial spaces. Causes include ele-

vated blood pressure, a decrease in plasma oncotic pressure caused by a

reduction in hepatic protein synthesis, or an increase in the oncotic pres-

sure within the interstitial space.

CASE FILES: PHARMACOLOGY

DISCUSSION

Class

Natriuretic diuretics all act within the kidney to reduce the reabsorption

of Na

ⴙ

and Cl

ⴚ

.There are four sites within the kidney where various diuret-

ics act; these correspond to four anatomic regions of the nephron. The proxi-

mal tubule (site 1)is the site of approximately 60 percent Na

reabsorption, but

diuretics acting here are relatively ineffective because of the sodium-reabsorbing

capacity in more distal regions of the nephron. The ascending loop of Henle

(site 2)has active reabsorption of approximately 35 percent of the filtered Na

This is mediated by a cotransporter termed NKCC2 that transports 1 Na

, 1 K

and 2 Cl

−

, and this is the molecular target of furosemide and other loop or

“high-ceiling” diuretics. The distal convoluted tubule (site 3)is responsible

for transport of approximately 15 percent of filtered sodium. Thiazidediuret-

ics act in this segment of the nephron by interfering with another cotransporter,

NCC, which cotransports Na

and Cl

−

. Site 4 diuretics act in the collecting

tubule by interfering with Na

reabsorption through a specific channel, the

epithelial sodium channel (ENaC), also called the amiloride-sensitive sodium

channel (Figure 7-1).

Loop diuretics—furosemide, ethacrynic acid, bumetanide, and

torsemide—are highly acidic drugs that act on the luminal side of the

tubule. They reach this site by being secreted into the tubule by anion secre-

tion in the proximal tubule. Compared with other diuretics, loop diuretics

cause the greatest diuresis because the Na

−

2Cl

−

transporter is responsible

for a large fraction of Na

reabsorption, and regions distal to the ascending

limb have more limited capacity for sodium transport. Loop diuretics are use-

ful for the treatment of peripheral and pulmonary edema, which may occur

secondarily as a consequence of cardiac failure, liver failure, or renal failure.

Loop diuretics increase the excretion of Na

, Cl

−

, K

, Mg

, Ca

and decrease

the excretion of Li

. The increased excretion of Ca

is clinically relevant, and

loop diuretics can be used to treat hypercalcemia. Some of the diuretic actions

of furosemide are mediated via prostaglandins because inhibitors of

prostaglandin biosynthesis diminish the increase in diuresis produced by the

drug. In addition, furosemide has actions on the vascular system that occur

prior to diuresis and this action may be mediated by prostaglandins. Other

effects include changes in renal blood flow and a reduction in left-ventricular-

filling pressure. Loop diuretics increase urine production and decrease plasma

in patients with acute renal failure.

Major adverse effects of loop diuretics are electrolyte imbalances.

Increased delivery of Na

to the collecting duct increases K

and H

excretion.

Loop diuretics therefore cause hypokalemia, hypochloridemia, and meta-

bolic alkalosis. Hyperuricemiamay be caused by the volume contraction and

enhanced uric acid reabsorption by the proximal tubule. Loop diuretics can

produce dose-dependent ototoxicity.

CLINICAL CASES 57

Figure 7-1. Sites of action of the nephron and diuretic agents.

Distal convoluted tubule

Proximal convoluted tubule

Proximal straight tubule

Descending limb

of loop of Henle

Ascending limb

of loop of Henle

Collecting

tubule

2Cl

−

Site 1

Carbonic anhydrase

inhibitors

Site 3

Thiazide

diurectics

Site 4

Aldosterone

antagonists

Site 2

Loop

diurectics

Structure

Most loop diuretics are sulfonamide derivatives;the exceptions are ethacrynic

acid, which is a phenoxyacetic acid derivative, and torsemide, which is a

sulfonylurea.

Mechanism of Action

The molecular target of furosemide and other loop or high-ceiling diuretics is the

sodium-potassium-2 chloride cotransporter (NKCC2), which transports 1 Na

1 K

, and 2 Cl

−

. The activity of this transporter is blocked by loop diuretics.

CASE FILES: PHARMACOLOGY

Administration

All loop diuretics can be administered orally, and their onset of action is

approximately 1 hour (torsemide) to 2 hours (furosemide). Loop diuretics can

also be administered IV, and for furosemide, this produces vasodilation in as

little as 5 minutes and diuresis in 20 minutes.

Pharmacokinetics

All loop diuretics are extensively bound to plasma proteins. Half-lives vary

from 45 minutes (bumetanide) to 3.5 hours (torsemide). Approximately

65 percent of a dose of furosemide is eliminated by the kidney, and the

remainder is metabolized. Only 20 percent of torsemide is eliminated by the

kidney, and 80 percent is metabolized.

COMPREHENSION QUESTIONS

[7.1] Furosemide acts to inhibit Na

reabsorption in which of the following

locations?

A. Ascending limb of the loop of Henle

B. Collecting duct

C. Descending limb of the loop of Henle

D. Distal convoluted tubule

[7.2] A patient arrives in the emergency room in a coma and has a serum Ca

of 4.5 mM. You start a saline infusion of which of the following drugs?

A. Calcitonin

B. Ethacrynic acid

C. Hydrochlorothiazide

D. Spironolactone

[7.3] A 55-year-old man with congestive heart failure is noted to be taking

furosemide each day. Which of the following is most likely to be found

in the serum?

A. Decreased potassium level

B. Decreased uric acid level

C. Elevated magnesium level

D. Low bicarbonate level

Answers

[7.1] A.Furosemide acts specifically on a Na

2Cl

−

transporter in the

ascending limb of the loop of Henle.

[7.2] B.Loop diuretics such as ethacrynic acid increase the excretion of Ca

[7.3] A. Furosemide leads to hypokalemia, hypomagnesemia, and meta-

bolic alkylosis (elevated bicarbonate level).

CLINICAL CASES 59

REFERENCES

Paul RV. Rational diuretic management in congestive heart failure: a case-based

review. Crit Care Nurs Clin North Am 2003;15(4):453–60.

Padilla MC, Armas-Hernandez MJ, Hernandez RJ, et al. Update of diuretics in the

treatment of hypertension. Am J Ther 2007;14(4): 331–5.

60 CASE FILES: PHARMACOLOGY

PHARMACOLOGY PEARLS

❖ Furosemide, which acts on the loop of Henle, is the most efficacious

diuretic.

❖ Hypokalemia is a frequent adverse effect encountered with loop

diuretics, and this can be managed with the concomitant use of

potassium-sparing diuretics such as triamterene or spironolactone.

❖ Loop diuretics can produce dose-dependent ototoxicity.

❖

CASE 8

Following his third episode of gouty arthritis, a 50-year-old man sees you in

the clinic. Each case was successfully treated acutely; however, your patient is

interested in trying to prevent future episodes. He is not on regular medications

and has a normal physical examination today. Blood work reveals an elevated

serum uric acid level and otherwise normal renal function and electrolytes. A

24-hour urine collection for uric acid reveals that he is under-excreting uric

acid. Suspecting that this is the cause of his recurrent gout, you place him on

probenecid.

◆

What is the mechanism of action of probenecid?

◆

Which drugs could have their excretion inhibited by probenecid?

ANSWERS TO CASE 8: NONDIURETIC INHIBITORS

OF TUBULAR TRANSPORT

Summary: A 50-year-old man with recurrent gout is prescribed probenecid.

◆

Mechanism of action of probenecid: Inhibits secretion of organic

acids and decreases reabsorption of uric acid, causing a net increase in

secretion.

◆

Other drugs whose secretion could be inhibited: Penicillin,

indomethacin, and methotrexate.

CLINICAL CORRELATION

Gout is a disease in which uric acid crystals deposit in joints, causing an

extremely painful acute inflammatory arthritis. Persons with recurrent gout

often have chronically elevated levels of uric acid in their blood. This hyper-

uricemia is frequently caused by either overproduction of uric acid or under-

excretion of uric acid by the kidneys. Probenecid (and other uricosuric drugs)

promotes the excretion of uric acid. It works by inhibiting the secretion of

organic acids from the plasma into the tubular lumen and blocking the reup-

take of uric acid. The net result of this is an increase in the secretion of uric

acid. The benefit of this is the prevention of recurrent gout attacks in chronic

underexcreters of uric acid. In those individuals who overproduce uric acid,

allopurinol is used. This inhibits xanthine oxidase, a key enzyme in the pro-

duction of uric acid.

APPROACH TO PHARMACOLOGY

OF URICOSURIC AGENTS

Objectives

1. Understand the mechanism of action of uricosuric agents.

2. Know the therapeutic uses, adverse effects, and contraindications to

uricosurics.

3. Know the mechanism of action and use of allopurinol.

Definitions

Uricosuric agents: Increase the mass of uric acid that is excreted in the

urine.

Renal secretion: Moves solutes such as urate from the plasma into the

urine.

Renal reabsorption:Moves solutes from the urine back into the plasma.

62 CASE FILES: PHARMACOLOGY

DISCUSSION

Class

Urate is both secreted and reabsorbed by at least three independent molecular

transporters located in the proximal tubule. Urate is nearly completely secreted

into the lumen of the nephron against an electrochemical gradient by the

action of organic acid transporter-1 (OAT-1) and organic acid transporter-3

(OAT-3).These cotransporters exchange α-ketoglutarate and urate (or other

organic anions) and move urate from the plasma into the tubular cell. The pro-

tein UAT is an electrically neutral channel that permits uric acid to leave tubu-

lar cells and enter either the tubular lumen or the plasma. URAT1, located on

the apical membrane of tubular cells, is thought to be responsible for most of

the reabsorption of urate from the filtrate. URAT1 is a transporter that is capa-

ble of exchanging a variety of anions with urate in an electrically neutral manner.

Interaction of uricosuric agents such as probenecid with URAT1 diminishes the

reabsorption of urate and increases urate excretion. All of these transporters or

channels are relatively nonselective with respect to the organic acid transported.

OAT-1 and OAT-3 are capable of secreting most organic acids including

probenecid, penicillin, aspirin, furosemide, and hydrochlorothiazide.

In patients with gout, probenecid can be used prophylactically; urico-

suric drugs will not diminish the severity of an acute attack. An acute

gouty attackmay be precipitated by the initiation of probenecid treatment

as uric acid is mobilized out of joints. Adequate hydrationshould be ensured,

because probenecid predisposes patients to the formation of uric acid kidney

stones.

The alternate therapeutic approach to the treatment of gout is to reduce the

production of uric acid with allopurinol. The enzyme xanthine oxidase

produces uric acid in a two-step reaction from the purine hypoxanthine.

Allopurinol is metabolized to alloxanthine by xanthine oxidase, and this

metabolite is a long-lasting inhibitor of the enzyme.

Probenecid is also useful for decreasing the excretion of penicillin,

because penicillin is eliminated primarily by renal secretion mediated by

OAT-1 and OAT-3. Probenecid competes for this secretion and thereby

reduces the rate of elimination and increases both the biological half-life of

penicillin and the plasma concentrationof the antibiotic more than twofold.

This adjunct use of probenecid is particularly useful in single-dose regimens

for the treatment of gonococcal infections with long-acting penicillins such as

penicillin G.

Secretion of organic acids is quite nonspecific, and most acidic drugs are

secreted by the same transporters OAT-1 and OAT-3. This implies that nearly

any combination of acidic drugs will compete for elimination at the level of

the transporters, and the effects on elimination of each individual drug must be

considered. For example, the half-life of diuretics such as furosemide will be

increased by probenecid, and this may require dosage adjustment. Aspirin,

CLINICAL CASES 63

another acidic drug, will compete with probenecid for secretion. This

reduces the action of probenecid to increase uric acid excretion and thus

increases plasma urate. Therefore aspirin is contraindicated in patients with

gout who are taking probenecid.

The most common adverse effect of probenecid is gastrointestinal (GI)

upset, and approximately 2 percent of patients experience a hypersensitivity

reaction usually manifest as a skin rash. The incidence of hypersensitivity is

lower with sulfinpyrazone, but the incidence of GI upset is higher.

Structure

Probenecid is a lipid-soluble benzoic acid derivative with a pKa of 3.4.

Another agent in this class is sulfinpyrazone, a pyrazolone derivative similar

to the anti-inflammatory agent phenylbutazone. It has a pKa of 2.8 but is no

longer marketed in the United States.

Mechanism of Action

Both probenecid and sulfinpyrazone are secreted into the lumen of the nephron

via OAT-1 and OAT-3 where the drugs can diminish the ability of URAT1 to

reabsorb urate.

Administration

Both drugs are active orally, and both are nearly completely absorbed.

Pharmacokinetics

The half-life of probenecid is 5–8 hours; sulfinpyrazone is approximately 3 hours,

but its uricosuric actions can last as long as 10 hours. Increased excretion of

uric acid occurs promptly after oral administration. Both agents are eliminated

in the urine.

COMPREHENSION QUESTIONS

[8.1] Probenecid is effective in treating gout because it decreases which of

the following?

A. Inflammation in affected joints

B. Production of uric acid

C. Reabsorption of uric acid

D. Secretion of uric acid

64 CASE FILES: PHARMACOLOGY

[8.2] Which of the following describes the action of allopurinol?

A. Inhibits metabolism of purines to uric acid

B. Inhibits prostaglandin biosynthesis

C. Inhibits uric acid reabsorption

D. Interferes with cytokine production

[8.3] An 18-year-old man who is known to have non-penicillinase-producing

gonococcal urethritis is given an injection of penicillin and probenecid.

What is the mechanism used by probenecid that makes penicillin more

efficacious?

A. Decreases the bacterial resistance by inhibiting penicillinase

production

B Increases the half-life and serum level by decreasing the renal

excretion of penicillin

C. Prolongs the duration of action by affecting the liver metabolism of

penicillin

D. Promotes entry of the penicillin into the bacteria

Answers

[8.1] C. Probenecid does inhibit renal tubular secretion of urate, but at

therapeutic doses it inhibits reabsorption to a greater degree, thereby

increasing net excretion urate.

[8.2] A.Allopurinol interferes with the metabolism of purines by inhibit-

ing the enzyme xanthine oxidase.

[8.3] B. Probenecid decreases the renal excretion of penicillin, thereby

increasing both the half-life and the serum level.

PHARMACOLOGY PEARLS

❖ At low doses, probenecid inhibition of urate secretion predominates,

and this paradoxically increases plasma urate.

❖ At higher doses, inhibition of reabsorption predominates, leading to

the therapeutically useful increased excretion of urate.

❖ An acute gouty attack may be precipitated by the initiation of

probenecid treatment as uric acid is mobilized out of joints.

❖ Probenecid is also useful for decreasing the excretion of penicillin

and cephalosporins.

❖ Patients are typically begun on a high loading dose to ensure the

action on reabsorption is achieved.

CLINICAL CASES 65

REFERENCES

Dantzler WH. Regulation of renal proximal and distal tubule transport: sodium,

chloride and organic ions. Comp Biochem Physiol Part A 2003;136:453–78.

Stamp LK, O’Donnell JL, Chapman PT. Emerging therapies in the long-term man-

agement of hyperuricemia and gout. Intern Med J 2007;37:258–66.

66 CASE FILES: PHARMACOLOGY

❖

CASE 9

A 72-year-old man presents to the office for routine follow-up. He is under

treatment for hypertension and congestive heart failure with enalapril and a

diuretic. His blood pressure is under acceptable control and he has no symp-

toms of heart failure at present. He does complain that he has been coughing

frequently in the past few months. History and examination reveal no other

cause of a chronic cough, so you decide to discontinue his enalapril and start

him on losartan.

◆

What is the mechanism of action of enalapril?

◆

By what mechanism does enalapril convert to its active form

enalaprilat?

◆

What is the likely cause of the cough?

◆

What is the mechanism of action of losartan?

ANSWERS TO CASE 9: DRUGS ACTIVE ON THE

RENIN-ANGIOTENSIN SYSTEM

Summary: A 72-year-old man with hypertension and congestive heart failure

presents with an ACE inhibitor-induced cough, and is switched to losartan.

◆

Mechanism of action of enalapril: Inhibits the conversion of

angiotensin I to angiotensin II, this also inhibits the angiotensin

II-stimulated release of aldosterone. Angiotensin-converting enzyme

(ACE) inhibitors also impair the inactivation of bradykinin.

◆

Mechanism of converting enalapril to enalaprilat:Deesterification in

the liver.

◆

Mechanism of ACE inhibitor-induced cough:Secondary to the

increased bradykinin levels, which is caused by reduction in the

inactivation of bradykinin.

◆

Mechanism of action of angiotensin receptor blockers (ARBs):

Antagonists of angiotensin-1 (AT-1) receptors which mediate the

pressor effects of angiotensin II.

CLINICAL CORRELATION

ACE inhibitors have gained wide-scale use in medicine for their effectiveness

in hypertension, congestive heart failure, coronary artery disease, and renal

protection in diabetics. They inhibit the conversion of angiotensin I to

angiotensin II. Angiotensin II is a potent vasoconstrictor and stimulates the

release of aldosterone, which promotes sodium retention. Angiotensin II also

increases catecholamine release by the adrenal medulla and at sympathetic

nerves. Inhibition of the production of angiotensin II reduces vascular resist-

ance and sodium and water retention. Another effect of ACE inhibitors is to

reduce the inactivation of bradykinin. Active bradykinin is a vasodilator, pro-

viding an additive effect in lowering blood pressure. However, raising

bradykinin levels contributes to one of the ACE inhibitors’most bothersome

side effects, chronic dry cough. ACE inhibitors in general are well tolerated,

but along with cough, can cause hyperkalemia and should be used with cau-

tion with potassium-sparing diuretics or in persons with impaired renal func-

tion. ARBs are antagonists of the angiotensin I receptor, which mediates the

direct vasoconstrictor effect of angiotensin II. This also blocks the release of

aldosterone. ARBs do not affect the bradykinin system and therefore do not

cause a cough. They are also well tolerated but, like ACE inhibitors, can cause

hyperkalemia. Aliskiren (Tekturna), a renin inhibitor has recently been intro-

duced in the United States. It appears to be as efficacious as ACE inhibitors or

ARBs, but clinical experience is limited.

CASE FILES: PHARMACOLOGY

APPROACH TO PHARMACOLOGY OF THE

RENIN-ANGIOTENSIN SYSTEM

Objectives

1. Know the mechanism of action of ACE inhibitors.

2. Know the therapeutic uses, side effects, and contraindications to ACE

inhibitor use.

3. Know the mechanism of action of ARBs.

4. Know the therapeutic uses, side effects, and contraindications to ARB

use.

Definitions

Hypertension: From the Seventh Report, Joint National Committee on

Detection, Evaluation, and Treatment of High Blood Pressure, normal

blood pressure is 120/80 mm Hg. Progressive disease may be staged as

prehypertensive (120–139/80–89), Stage 1 (140–159/90–99), and Stage

2 (>160/> 100).

Bradykinin:A member of a class of peptides, the kinins, that have a vari-

ety of effects on the cardiovascular system, including vasodilatation and

inflammation.

ARB:Angiotensin receptor blocker, more precisely angiotensin AT-1 receptor

blockers.

DISCUSSION

Class

The renin-angiotensin-aldosterone system provides a humoral system for

controlling blood pressure and electrolyte levels.The “sensors” in this sys-

tem monitor Na

, K

, vascular volume, and blood pressure.A reduction in

blood pressure, detected by intrarenal stretch receptors, or a fall in the deliv-

ery of Na

to the distal portions of the nephron results in release of renin from

the juxtaglomerular apparatus (JGA). Renin secretion can also be increased

through the baroreceptor reflex mediated by increased central nervous system

(CNS) outflow and β

-adrenergic receptors on the JGA. Renin is an aspartyl

protease that cleaves angiotensinogen, a 56-kD polypeptide produced in the

liver, to the decapeptide angiotensin I (Figure 9-1, “classic” pathway).

Angiotensin I is biologically inactive and is rapidly converted to the

octapeptide angiotensin II by the action of ACE, a dipeptidyl peptidase.

Angiotensin II is further metabolized within the brain and in the plasma by

aminopeptidase A, which removes the N-terminal aspartic acid to produce

angiotensin III, which may itself be further metabolized by aminopeptidase

N, which removes the N-terminal arginine yielding angiotensin IV. The latter

CLINICAL CASES 69

Figure 9-1. Schematic of angiotensin pathway.

“CLASSIC” INTRAVASCULAR

PRODUCTION OF AGII

LOCAL TISSUE

PRODUCTION OF AGII

Angiotensin

(56 Kd, liver)

Angiotensin I

(10 amino acids)

Angiotensin II

(8 amino acids)

Angiotensin III

(AgII 2–8)

Angiotensin IV

(AgII 3–8)

Renin

Local

Renin

ACE (dipeptidyl-peptidase)

Aminopeptidase A

Aminopeptidase N

Aminopeptidase A

Aminopeptidase N

Local ACE

Cathepsin G

Chymase

t-PA

Cythepsin G

70 CASE FILES: PHARMACOLOGY

two metabolites may play a critical role in regulating blood pressure in the

brain. Distinct from this classic intravascular pathway for the formation of

angiotensins, evidence has accumulated indicating that angiotensins can also

be produced within various tissues by a local conversion to angiotensins II, III,

and IV (see Figure 9-1).

Angiotensin II has multiple actions that act in concert to increase blood

pressure and alter electrolyte levels. Angiotensin II is a potent vasoconstric-

tor,10–40 times more potent than epinephrine, an effect mediated by recep-

tor-coupled Ca

2ⴙ

channels in vascular smooth muscle cells, as described

below. Angiotensin II enhances the release of catecholaminesfrom both the

adrenal medulla and at peripheral nerve endings. Within the adrenal cortex,

angiotensin II increases the biosynthesis of aldosterone, which leads to an

increase in Na

and water reabsorption in the kidneys and volume expansion.

Angiotensin II has several actions within the CNS including altering vagal

tone to increase blood pressure, increasing thirst, and increasing the release of

antidiuretic hormone.

Angiotensin II also has effects on the heart and the vasculature that do not

directly affect blood pressure. Angiotensin II induces cardiac hypertrophy,

is proproliferative, and enhances matrix remodeling and the deposition of

matrix proteins, which leads to increased myocardial stiffness.Within vessel

walls, angiotensin II is proinflammatory and can stimulate the release of sev-

eral chemokines.

Three angiotensin receptors mediate these actions. The AT-1 and

angiotensin-2 (AT-2) receptors have been described in various tissues. Both

are seven-transmembrane receptors that appear to couple to various signaling

pathways. AT-1 receptors bind angiotensin II, angiotensin III, and angiotensin

IV. This receptor mediates most of the cardiovascular and central responses to

angiotensin II, including vasoconstriction of vascular smooth muscle and

aldosterone biosynthesis in the adrenal medulla. AT-1 receptors also mediate

the cardiac hypertrophic and proproliferative responses to angiotensin II. AT-2

receptors also bind angiotensin II and play a role in the development of the car-

diovascular system. In general, activation of AT-2 receptors is physiologically

antagonistic to the action of AT-1 receptors. Activation of AT-2 receptors is

hypotensive and antiproliferative and is coupled to distinctly different signal-

ing pathways compared to AT-1 receptors. Angiotensin-4 (AT-4) receptors

appear to be identical to transmembrane aminopeptidase insulin-regulated

aminopeptidase (IRAP) and have a single transmembrane domain. AT-4 recep-

tors are expressed in the numerous tissues and bind angiotensin IV. Activation

of these receptors has been reported to regulate cerebral blood flow, and to

stimulate endothelial cell expression of plasminogen activator inhibitor, and

has effects on both memory and learning.

Inhibition of the renin-angiotension system (RAS) is accomplished phar-

macologically in three ways: inhibition of the production of angiotensin II,

blockade of AT-1 receptors, or inhibition of renin activity. ACE inhibitors, or

peptidyl dipeptidase (PDP) inhibitors, include enalapril, lisinopril, fosinopril,

CLINICAL CASES 71

captopril, and seven others. These drugs differ in their chemistry and phar-

macokinetic properties, but all are orally active, have the same range of activ-

ities, and are equally effective clinically. ACE is the enzyme responsible for

both activation of angiotensin I (metabolism to angiotensin II) and inacti-

vation of bradykinin. The decreased metabolism of bradykinin is partly

responsible for the hypotensive action of ACE inhibitors, and is also responsi-

ble for enhancing the irritability of airways that leads to the dry cough asso-

ciated with ACE inhibitors.

ARBs block the action of angiotensin II by acting as antagonists at AT-1

receptors. These nonpeptide antagonists include losartan, valsartan, can-

desartan, and others. ARBs bind with high affinity to AT-1 receptors without

interfering with AT-2 or AT-4 receptors.

The ACE inhibitors and ARBs are equally effective in reducing blood

pressure. More clinical experience exists with the ACE inhibitors and it has

been well established that this class of drugs reduces the risk of second events

in patients who have had an MI and in reducing renal damage in patients with

diabetic nephropathy. Hypotension and hyperkalemia are adverse effects

seen with both classes of RAS inhibitors. Cough and angioedema, caused

by increased bradykinin levels, are more frequently seen with the ACE

inhibitors.

A newly approved agent, aliskiren, has been approved for use in the treatment

of hypertension. Aliskiren is a small molecule inhibitor of renin. In clinical trials

of more than 2000 patients, aliskiren was effective in 24-hour blood pressure

control. The effect was maintained for at least a year. Aliskiren was about as

effective as ACE inhibitors or ARBs but may cause a greater rebound in renin

production when discontinued than the other agents.

Structure

Although the various ACE inhibitors have different chemical structures, they

are mostly based on extensive modifications of L-proline. The ARBs are also

quite distinct chemically: Valsartan is an L-valine derivative, and losartan is an

imidazole derivative. Aliskiren was designed based on the crystal structure of

renin and is a nonpeptide, small molecule, transition-state mimetic that binds

to the active site of the enzyme.

Mechanism of Action

ACE inhibitors are all competitive inhibitors of angiotensin-converting enzyme.

ARBs are competitive antagonists of the angiotensin II type 1 receptor (AT-1)

Administration

All ACE inhibitors are available for oral administration. Enalaprilat, the active

metabolite of enalapril, is available for intravenous infusion. Aliskiren is an

oral agent.

72 CASE FILES: PHARMACOLOGY

Pharmacokinetics

Most of the current ACE inhibitors are prodrugs and require conversion to the

active metabolite in the liver. For example, enalapril is converted to enalapri-

lat, fosinopril is converted into fosinoprilat. Captopril and lisinopril are active

drugs that do not require metabolism. The onset of action of ACE inhibitors is

0.5–2 hours, and the duration of action is typically 24 hours (captopril is 6 hours).

Most are eliminated in the urine.

COMPREHENSION QUESTIONS

[9.1] Losartan acts to decrease which of the following?

A. AT-1 receptor activity

B. Bradykinin production

C. Production of angiotensin II

D. Renin production

[9.2] Which of the following is a limiting adverse effect of ACE inhibitors?

A. Acidosis

B. Hyperkalemia

C. Hypernatremia

D. Hypokalemia

E. Hyponatremia

[9.3] Which of the following is an advantage of losartan over enalapril?

A. Better efficacy in lower blood pressure

B. Better prevention of secondary myocardial events

C. Less cost

D. Less incidence of angioedema

Answers

[9.1] A.Losartan is a prototypical angiotensin AT-1 receptor antagonist.

[9.2] B.By reducing aldosterone levels, ACE inhibitors decrease K

excre-

tion in the distal nephron.

[9.3] D.Losartan does not lead to elevated bradykinin levels; thus, there is

less of an incidence of angioedema and dry cough. The effects on

blood pressure are equal. The track record for prevention of secondary

cardiovascular events is well established for ACE inhibitors, although

the same is speculated for ARBs.

CLINICAL CASES 73

74 CASE FILES: PHARMACOLOGY

PHARMACOLOGY PEARLS

❖ Elevation of the bradykinin levels is thought to be the etiology of the

dry cough and angioedema of ACE inhibitors.

❖ ACE inhibitors improve outcome in patients with cardiovascular dis-

ease and have been recommended as therapy in several guide-

lines.

❖ Clinical experience suggests that inhibitors of the renin-angiotensin

system are somewhat less effective in African Americans.

❖ ARBs block the action of angiotensin II by acting as antagonists at

AT-1 receptors.

REFERENCES

Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme

inhibitor, ramipril, on cardiovascular events in high-risk patients: the heart out-

comes prevention evaluation study investigators. N Engl J Med 2000;342:

145–53.

Stojiljkovic L, Behnia R. Role of angiotensin system inhibitors in cardiovascular

and renal protection: a lesson from clinical trials. Curr Pharm Des 2007;13:

1335–45.

❖

CASE 10

A 69-year-old man sees you in the office for follow-up of his chronic conges-

tive heart failure. He has a marked reduction in his ejection fraction following

a series of MIs. He also has hypertension and type II diabetes mellitus. His

symptoms include dyspnea on exertion, orthopnea, paroxysmal nocturnal dys-

pnea, and peripheral edema. He has normal renal function. He is on appropriate

treatment of his diabetes, along with an ACE inhibitor and a loop diuretic. You

decide to add digoxin to his regimen.

◆

What is the effect of digoxin on the normal heart?

◆

What is the effect of digoxin on the failing heart?

◆

What neural effects does digoxin have?

◆

What are the side effects and toxicities of digoxin?

ANSWERS TO CASE 10: AGENTS USED TO TREAT

CONGESTIVE HEART FAILURE

Summary:A 69-year-old man with congestive heart failure, hypertension, and

diabetes mellitus has a markedly low ejection fraction and is prescribed

digoxin.

◆

Effect on a normal heart: Increased systemic vascular resistance and

constriction of smooth muscle in veins, which may decrease cardiac

output.

◆

Effect on a failing heart: Increased stroke volume and increased

cardiac output.

◆

Neural effects: Decreased sympathetic tone and increased vagal

activity, resulting in inhibition of sinoatrial (SA) node and delayed

conduction through atrioventricular (AV) node.

◆

Side effects and toxicities: Induction of arrhythmias, anorexia, nausea,

vomiting, diarrhea, disorientation, and visual disturbance.

CLINICAL CORRELATION

Digoxin can be useful in improving some of the symptoms of congestive heart

failure, but its use must be closely monitored. Digoxin works by inhibiting the

sodium-potassium adenosine triphosphatase (ATPase), primarily in cardiac

muscle cells. This causes increased intracellular sodium and decreased intra-

cellular potassium. The increased sodium reduces the exchange of intracellu-

lar calcium for extracellular sodium, causing an increased intracellular

calcium level. The overall effect of this is to allow for a greater release of cal-

cium with each action potential. This has a positive inotropic effect. In a fail-

ing heart, stroke volume and cardiac output are increased. End-diastolic

volume, venous pressure, and blood volume are decreased. These circulatory

improvements also result in a reduction of sympathetic tone. This further

improves circulation by lowering systemic vascular resistance. Digoxin also

has the effect of increasing vagal activity,which inhibits the SA node and

slows conduction through the AV node. This is beneficial in patients with

atrial tachyarrhythmias such as atrial fibrillation, atrial flutter, and atrial tachy-

cardias. Digoxin has a narrow therapeutic index, and its level in the blood

must be closely monitored.The dose must be adjusted for renal impairment,

because it is cleared by the kidney. Toxic digoxin levels may produce many

types of arrhythmias, with AV blocks and bradycardia being common.

Mental status changes and gastrointestinal symptoms are common as well.

Asymptomatic elevations in digoxin levels are usually treated by discontinu-

ing or reducing the drug’s dosage. Symptomatic toxicity, particularly arrhyth-

mias, is most often treated by the IV infusion of digoxin-binding

antibodies.

CASE FILES: PHARMACOLOGY

APPROACH TO PHARMACOLOGY

OF THE CARDIAC GLYCOSIDES

Objectives

1. Know the mechanism of action of the cardiac glycosides.

2. Know the therapeutic uses, adverse effects, and toxicities of cardiac

glycosides.

3. Know the other agents used frequently in the treatment of congestive

heart failure.

Definitions

Cardiac glycosides:The cardenolides include digitalis, digoxin, digitoxin,

and ouabain.

Inotropic:Affecting myocardial contractility.

Chronotropic:Affecting heart rate.

Congestive heart failure:A syndrome with multiple causes that may affect

either systole or diastole. Left heart failure leads to pulmonary conges-

tion and reduced cardiac output and appears in patients with MI, aortic

and mitral valve disease, and hypertension. Right heart failure leads to

peripheral edema and ascites and appears in patients with tricuspid valve

disease, cor pulmonale, and prolonged left heart failure. The New York

Heart Association classification of congestive heart failure includes class I

(mild disease) to class IV (severe disease).

DISCUSSION

Class

The medicinal actions of the cardiac glycosides, digitalis, have been used suc-

cessfully for over 200 years, and they have both positive inotropic and antiar-

rhythmic properties. Digoxin is the most commonly used cardiac

glycoside. Cardiac glycosides act to indirectly increase intracellular cal-

cium (Figure 10-1). Digitalis binds to a specific site on the outside of the

ⴙ

-K

ⴙ

-ATPaseand this reduces the activity of the enzyme. All cells express

-ATPase but there are several different isoforms of the enzyme; the iso-

forms expressed by cardiac myocytes and vagal neurons are the most sus-

ceptible to digitalis. Inhibition of the enzyme by digitalis causes an increase

in intracellular Na

and decreases the Na

concentration gradient across the

plasma membrane. It is this Na

concentration that provides the driving force

for the Na

-Ca

antiporter. The rate of transport of Ca

out of the cell is

reduced, and this leads to an increase in intracellular Ca

, greater activation

of contractile elements, and an increase in the force of contraction of the

heart. The electrical characteristics of myocardial cells are also alteredby

CLINICAL CASES 77

Figure 10-1. Digoxin acts to indirectly increase intracellular calcium levels

by binding to the Na

-K

-ATPase.

Digoxin

Outside

Inside

Outside

Inside

the cardiac glycosides. The most important effect is a shortening of the

action potential that produces a shortening of both atrial and ventricular

refractoriness. There is also an increase in the automaticity of the heart,

both within the AV node and in the cardiac myocytes.

Within the nervous system cardiac glycosides affect both the sympathetic

and parasympathetic systems, and parasympatheticomimetic effects predomi-

nate at therapeutic doses. Increased vagal activity inhibits the SA node and

delays conduction through the AV node.

Inacute heart failure, digitalis clearly improves contractility. Ejection frac-

tion and cardiac output is increased and symptoms are decreased. In congestive

78 CASE FILES: PHARMACOLOGY

heart failure, digitalis is used primarily in patients who are symptomatic

after optimal therapy with diuretics, ACE inhibitors, and beta blockers.

In this setting, digitalis decreases symptoms and increases exercise tolerance.

However, in patients with normal sinus rhythm,there is no decline in over-

all mortality because of deaths associated with digitalis toxicity.

Because of its action in increasing vagal tone, cardiac glycosidesare use-

ful in the treatment of several supraventricular arrhythmias including

atrial flutterand atrial fibrillation. Digitalis can control paroxysmal atrial

and AV nodal tachycardia.Its use is contraindicated in Wolff-Parkinson-

White syndrome, where it can induce arrhythmias in the alternate pathway.

Cardiac glycosides have a narrow therapeutic index. Toxic levels of car-

diac glycosides lead to depletion of intracellular K

ⴙ

and accumulation of

ⴙ

(because of inhibition of Na

-ATPase). This leads to partial depolar-

ization of the cell and increased excitability, both of which can lead to arrhyth-

mias including supraventricular and ventricular tachyarrhythmias. Bradycardia

and heart block are also manifestations of digitalis toxicity in the heart.

Adverse effects of digitalis on the gastrointestinal (GI) tract are common

including anorexia, vomiting, pain, and diarrhea. Central nervous system

effects include yellowed and blurred vision, dizziness, fatigue, and delir-

ium. At very high toxic ranges digitalis inhibits Na

-ATPase in skeletal

muscle, resulting in hyperkalemia.

competes with digitalis for binding to the Na

-ATPase;

hypokalemia increases the effectiveness of digitalis and increases toxicity.

Hypercalcemia can also increase the action of digitalis and increase toxicity.

Dopamine and dobutamine are positive inotropic agents that can be

used on a short-term basis in congestive heart failure. Dobutamine stimu-

lates D

- and D

-adrenergic receptors.The action on b

-adrenoreceptorsis

responsible for most of the beneficial actions of dobutamine.It is useful in

patients with acute left ventricular failure or to prevent pulmonary edema in

heart failure. At sufficient doses, dopamineinteracts with b

receptors and

increases myocardial contractility. It is useful in the treatment of cardio-

genic and septic shock.

Structure

These compounds share two structural features: an aglycone steroid nucleus

with a lactone at carbon 17 in the D ring, which confers the cardiotonic prop-

erties, and polymeric sugar moieties attached to carbon 3 of the A ring. Both

features are necessary for pharmacologic activity; the sugar groups are largely

responsible for the pharmacokinetic properties of these drugs.

Mechanism of Action

Inhibition of the activity of the Na

ⴙ

-K

ⴙ

-ATPase; this indirectly increases

intracellular Ca

2ⴙ

CLINICAL CASES 79

Administration

Digoxin can be administered IV or orally. Oral bioavailability is approxi-

mately 75 percent. Digitoxin is available only as an oral agent and its bioavail-

ability is greater than 90 percent. Ouabain has limited bioavailability and is not

used clinically.

Pharmacokinetics

Digoxin is excreted by the kidney and is not metabolized. Patients with com-

promised renal function must be monitored carefully for digoxin toxicity.

Digitoxin is metabolized in the liver and renal impairment does not affect the

half-life of the drug.

COMPREHENSION QUESTIONS

[10.1] Digoxin increases cardiac contractility by directly engaging in which

of the following?

A. Activating L-type Ca

channels

B. Inhibiting cardiac phosphodiesterase

C. Inhibiting myocardial Na

/Ca

-ATPase

D. Inhibiting myocardial Na

-ATPase

[10.2] Which of the following drugs may be used to increase cardiac output

in a patient with pulmonary edema secondary to MI?

A. Captopril

B. Dobutamine

C. Metoprolol

D. Verapamil

[10.3] Which of the following is the most accurate statement regarding

digoxin?

A. Decreased mortality in patients with congestive heart failure with

normal sinus rhythm

B. Increases vagal tone and decreases AV node conduction

C. Lengthens the action potential and increases the refractoriness of

the heart

D. Useful in the treatment of Wolff-Parkinson-White syndrome

Answers

[10.1] D. While digoxin reduces the amount of Na

-Ca

exchange, this

effect is indirect and mediated by the inhibition of the Na

-ATPase.

[10.2] B. Dobutamine is useful in this setting; the other choices would not

increase cardiac output.

CASE FILES: PHARMACOLOGY

[10.3] B. Cardiac glycosides increase vagal tone and decrease AV node con-

duction. The action potential is decreased and the refractoriness of

the heart is decreased. Mortality is not decreased in patients with nor-

mal sinus rhythm because of digoxin toxicity. Digoxin is contraindi-

cated in Wolff-Parkinson-White syndrome.

PHARMACOLOGY PEARLS

❖ Cardiac glycosides inhibit the activity the Na

-K

-ATPase; this

indirectly increases intracellular Ca

❖ While several studies have found that digitalis does not improve

mortality, it is still useful in reducing symptoms in congestive

heart failure.

❖ The increased effectiveness of digitalis as serum K

falls is signifi-

cant because most patients with congestive heart failure are also

frequently treated with diuretics that cause potassium loss.

❖ Hypokalemia exacerbates digoxin toxicity.

REFERENCE

Hood W, Jr, Dans A, Guyatt G, et al. Digitalis for treatment of congestive heart failure

in patients in sinus rhythm. Cochrane Database Syst Rev 2004;2:CD002901.

CLINICAL CASES

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❖

CASE 11

A 62-year-old man is being managed in the intensive care unit following a

large anterior wall MI. He has been appropriately managed with oxygen,

aspirin, nitrates, and β-adrenergic receptor blockers but has developed recur-

rent episodes of ventricular tachycardia. During these episodes he remains

conscious but feels dizzy, and he becomes diaphoretic and hypotensive. He is

given an IV bolus of lidocaine and started on an IV lidocaine infusion.

◆

To what class of antiarrhythmic does lidocaine belong?

◆

What is lidocaine’s mechanism of action?

ANSWERS TO CASE 11: ANTIARRHYTHMIC DRUGS

Summary: A 62-year-old man develops symptomatic ventricular tachycardia

after an MI. He is begun on IV lidocaine.

◆

Class of antiarrhythmic to which lidocaine belongs: Ib.

◆

Mechanism of action: Specific Na

channel blocker, reduces the rate of

phase 0 depolarization, primarily in damaged tissue.

CLINICAL CORRELATION

Lidocaine is a common treatment for ventricular tachycardia in a patient who

is symptomatic and remains conscious. It works by blocking Na

channels and

is highly selective for damaged tissue. This makes it useful for the treatment

of ventricular ectopy associated with an MI. It is administered as an IV bolus

followed by a continuous drip infusion. It is metabolized in the liver and

undergoes a large first-pass effect. It has many neurological side effects,

including agitation, confusion, and tremors, and can precipitate seizures.

APPROACH TO PHARMACOLOGY

OF THE ANTIARRHYTHMICS

Objectives

1. Know the classes of antiarrhythmic agents and their mechanisms of action.

2. Know the indications for the use of antiarrhythmic agents.

3. Know the adverse effects and toxicities of the antiarrhythmic agents.

Definitions

Paroxysmal atrial tachycardias (PAT):Arrhythmia caused by reentry

through the AV node.

Heart block: Failure of normal conduction from atria to ventricles.

WPW:Wolff-Parkinson-White syndrome.

DISCUSSION

Class

Arrhythmias arise as a result of improper impulse generation or improper

impulse conduction. The abnormal action potentials cause disturbances in the

rate of contraction or in the coordination of myocardial contraction. The

molecular targets of antiarrhythmics are ion channels in the myocardium or

conduction pathways; these may be direct or indirect effects.

CASE FILES: PHARMACOLOGY

There are four ion channels of pharmacologic importance in the heart:

Voltage-activated Na

channel—SCN5A

Voltage-activated Ca

channel—L-type

Voltage-activated K

channel—IKr

Voltage-activated K

channel—IKs

Most antiarrhythmic drugs either bind directly to sites within the pore of a

channel or indirectly alter channel activity. There are approximately 20 antiar-

rhythmics approved for use today. They are classified according to which

of the ion channels they affect and their mechanism of action (Table 11-1).

CLINICAL CASES 85

Table 11-1

SELECTED ANTIARRHYTHMIC AGENTS

PROTOTYPE

CLASS DRUG Na

EFFECT

Ia Quinidine X X Increases refractory period,

slows conduction

Ib Lidocaine X Shortens duration of

refractory period

Ic Flecainide X X Slows conduction

II Propranolol X

Blocksβ

-adrenergic receptors

III Amiodarone X X Increases refractory period

IV Verapamil X Increases refractory period

AV node

Other

Adenosine X X

Decreases AV node conduction

Moricizine X

†

Atropine Decreases vagal tone

Digoxin Increases vagal tone

Sotalol X

‡

Also nonselective beta blocker

Indirect effect mediated by decreasing cAMP.

†

Moricizine blocks Na

channels and is usually considered a class 1 antiarrhythmic, but it has

properties of Ia, Ib, and Ic drugs.

‡

Solotol has α- and β-adrenergic antagonist properties and also inhibits K

channels.

The major arrhythmias of clinical concern are ventricular arrhythmias, atrial

arrhythmias, bradycardias, and heart blocks. There is also the pharmacologic

need to convert an abnormal rhythm to normal sinus rhythm (cardioconver-

sion). The class of antiarrhythmics used for any particular arrhythmia depends

on the clinical circumstances. The treatment of acute, life-threatening disease,

in contrast with the long-term management of chronic disease, requires a dif-

ferent selection of antiarrhythmics.

Class I Antiarrhythmics

Class I antiarrhythmics bind to Na

channels and prevent their activation.

This increases their effective refractory period and decreases conduction

velocity. Class I antiarrhythmics have a greater effect on damaged tissue com-

pared to normal tissue. This may be because of several factors:

Depolarization. Damaged tissues tend to be depolarized because of K

leakage—many class I antiarrhythmics preferentially bind to depolar-

ized tissues.

pH. Ischemic tissues are more acidic, and many class I antiarrhythmics

preferentially bind to membranes at low pH.

Inactivation frequency. During arrhythmias, Na

channels undergo more

rapid cycles of activation/inactivation. At any given time there will be an

increase in the number of inactive channels compared to normal tissues

in a normal rhythm. Class I antiarrhythmics generally bind preferentially

to Na

channels in the inactive state.

The subclasses a, b, and c of class I antiarrhythmics are distinguished based on

their ability to inhibit K

channels.

Class Ia. Procainamide is a prototype class Ia antiarrhythmic that sup-

presses the activity of Na

and also suppresses K

-channel activity.

Administered IV, it is used for the acute suppression of supraventricu-

lar and ventricular arrhythmias and for suppressing episodes of atrial

flutter and atrial fibrillation. It may be administered orally for the

long-term suppression of both supraventricular and ventricular

arrhythmia, but toxicity limits this application. Procainamide can

suppress sinoatrial (SA) and AV nodal activity, especially in patients

with nodal disease, and cause heart block. Prolonged use of pro-

cainamide is associated with increased risk of ventricular tachycar-

dias. Procainamide has some ganglionic blocking activity and can

cause hypotension and decreased myocardial contractility.A limit-

ing adverse effect of procainamide is the development of lupus-like syn-

drome characterized by skin rash, arthritis, and serositis. All patients on

procainamide will develop antinuclear antibodies within 2 years.

Procainamide is metabolized to N-acetyl procainamide (NAPA), which

has K

ⴙ

-channel-blocking effects. NAPA is excreted by the kidney,

and plasma levels of procainamide and NAPA should both be moni-

tored especially in patients with renal disease.

86 CASE FILES: PHARMACOLOGY

Class Ib. Lidocaine is very specific for the Na

channel and it blocks both

activated and inactivated states of the channel. It must be administered

parenterally. Lidocaine has been used extensively to suppress ven-

tricular arrhythmias associated with acute MI or cardiac damage

(surgery). It has been used prophylactically to prevent arrhythmias

in patients with MI, but there is controversy as to the overall bene-

fit in decreasing mortality. Lidocaine is metabolized in the liver and

has relatively short half-life (60 minutes). This limits its adverse

effects which generally are mild and rapidly reversible.Overdose can

produce sedation, hallucinations, and convulsions.

Class Ic. Flecainide inhibits both Na

and K

channels but shows no pref-

erence for inactivated Na

channels. It delays conduction and increases

refractoriness.It is effective for the control of atrial arrhythmias and

it is very effective in suppressing supraventricular arrhythmias.A

recent large clinical trial with patients with ischemic heart disease

demonstrated that flecainide is associated with increased mortality.

Currently its use is restricted to patients with atrial arrhythmias

without underlying ischemic heart disease.

Class II Agents

Endogenous catecholamines increase myocardial excitability and can

trigger ventricular arrhythmias. β-Adrenergic receptor blockade indirectly

suppresses L-type Ca

-channel activity. This slows phase 3 repolarization and

lengthens the refractory period. Reduction in sympathetic tone depresses auto-

maticity, decreases AV conduction, and decreases heart rate and contractility.

Beta blockers are useful for the long-term suppression of ventricular

arrhythmias particularly in patients at risk for sudden cardiac arrest.

Beta blockers are most effective in patients with increased adrenergic activity:

• Surgical or anesthetic stress.

• Anginal pain and MI.

• Congestive heart failure and ischemic heart disease.

• Hyperthyroidism.

• Beta blockers have been shown to reduce mortality and second cardio-

vascular events by 25–40% in patients with post-MI.

There are a large number of beta blockers approved for use as antiarrhyth-

mics. Two of particular interest are

1. d,l-sotalol, which is particularly effective as an antiarrhythmic agent

because it combines inhibition of K

channels with beta-blocker activity

2. Metoprolol, a specific β

antagonist, which reduces the risk of pul-

monary complications

d,l-sotalol is a racemic mixture; l-sotalol is an effective, nonselective β-

adrenergic antagonist;and d-sotalol is a class III antiarrhythmic that inhibits K

channels. It is an oral agent with a long half-life (20 hours) that can maintain

CLINICAL CASES 87

therapeutic blood levels with once a day dosing. d,l-sotalol is useful for the

long-term suppression of ventricular arrhythmias, especially in patients at risk

of sudden death. It is also used to suppress atrial flutter and fibrillation and

paroxysmal atrial tachycardia. It is a valuable adjunct in the use of implantable

cardiac defibrillators, decreasing the number of events that require defibrilla-

tion. At low doses, the β-adrenergic-blocking activity, and associated adverse

effects, predominates. At higher doses, the K

-channel inhibitory effects pre-

dominate with the risk of developing ventricular tachycardia.

Class III Antiarrhythmics

Drugs in this class include bretylium, dofetilide, and amiodarone.These

agents act predominantly to inhibit cardiac K

ⴙ

channels (IKr). This length-

ens the time to repolarize and prolongs the refractory period. Amiodarone is

also a potent inhibitor of Na

channels and has α- and β-adrenergic antagonist

activity.

Amiodarone has an unusual structure related to thyroxine. It can be

administered IV or orally, but its actions differ depending on route of admin-

istration. IV-administered amiodarone has acute effects to inhibit K

-channel

activity, slowing repolarization, and increasing the refractory period of all

myocardial cell types. Administered orally in a more chronic setting, it leads

to long-term alterations in membrane properties with a reduction in both Na

and K

-channel activity and decrease in adrenergic receptor activity.

Amiodarone is used extensively for ventricular and atrial arrhythmias

and has little myocardial depressant activity, allowing it to be used in

patients with diminished cardiac function. Administered IV, amiodarone is

effective in treating ventricular tachycardia and to prevent recurrent ventricu-

lar tachycardia, and to suppress atrial fibrillation. Oral amiodarone is useful

for arrhythmias that have not responded to other drugs (such as adenosine) and

for long-term suppression of arrhythmias in patients at risk of sudden cardiac

death.

Amiodarone has little myocardial toxicity, does not impair contractility,

and rarely induces arrhythmias. Most of the adverse effects of amiodarone

result from its long half-life (13–103 days) and poor solubility. Amiodarone

deposits in the lung and can cause irreversible pulmonary damage.

Similarly, amiodarone can be deposited in the cornea causing visual dis-

turbances or in the skin where it can cause a bluish tinge.

Class IV Antiarrhythmics

The class IV antiarrhythmics act by directly blocking the activity of L-

type Ca

2ⴙ

channels. Verapamiland diltiazem are the major members of this

class, and they have a similar pharmacology. Verapamil blocks both active

and inactive Ca

2ⴙ

channels and has effects that are equipotent in cardiac and

peripheral tissues. The dihydropyridinessuch as nifedipine have little effect

on Ca

2ⴙ

channels in the myocardium, but are effective in blocking Ca

2ⴙ

88 CASE FILES: PHARMACOLOGY

channels in the vasculature. Verapamilhas marked effects on both SA and

AV nodesbecause these tissues are highly dependent on Ca

currents. AV

node conduction and refractory period are prolonged and the SA node is

slowed. Verapamil and diltiazem are useful for reentrant supraventricu-

lar tachycardias and can also be used to reduce the ventricular rate in atrial

flutter or fibrillation. The major adverse effect of verapamilis related to its

inhibition of myocardial contractility.It can cause heart block at high doses.

Other Antiarrhythmics

Adenosine is a very short-acting drug (approximately 10 seconds) used

specifically to block PAT. Adenosine binds to purinergic A1 receptors.

Activation of these receptors leads to increased potassium conductance and

decreased in calcium influx. This results in hyperpolarization and a decrease

in Ca

-dependent action potentials. The effect in the AV node is marked with

a decrease in conduction and an increase in nodal refractory period. Effects on

the SA node are smaller. Adenosine is nearly 100 percent effective in convert-

ing PAT to sinus rhythm. Adenosine must be given IV, and because of its short

half-life, it has few adverse effects. Flushing and chest pain are frequent but

typically resolve quickly.

Digoxin (see Case 10) blocks Na

-K

-ATPase and indirectly increases

intracellular Ca

. In the myocardium this causes an increase in contractility;

in nerve tissue the predominant effect is to increase neurotransmitter release;

and the parasympathetic system (vagus) is affected more than the sympathetic

system. The increased vagal tone results in increased stimulation of mus-

carinic acetylcholine receptors that slow conduction in the AV node. Digoxin

is very effective controlling the ventricular response rate in patients with

atrial fibrillation or flutter.Digoxin can be administered IV to acutely treat

atrial arrhythmias or orally for long-term suppression of abnormal atrial

rhythms. Digitalis is less effective than adenosine in PAT and should not be

used in Wolff-Parkinson-White syndrome.

Atropine is a muscarinic antagonist that can be used in some brady-

cardias and heart blocks. It can be administered to reverse heart block

caused by increased vagal tone such as an MI or digitalis toxicity.

Atropine is administered IV, and it exerts its effect within minutes.

COMPREHENSION QUESTIONS

[11.1] Which of the following is the most effective agent for converting

paroxysmal atrial tachycardia to normal sinus rhythm?

A. Adenosine

B. Atropine

C. Digoxin

D. Lidocaine

CLINICAL CASES 89

[11.2] Which of the following best describes a pharmacologic property of

amiodarone?

A. α-Adrenergic agonist

B. β-Adrenergic agonist

C. Activation of Ca

channels

D. Inhibition of K

channels

[11.3] A 45-year-old man is noted to have dilated cardiomyopathy with atrial

fibrillation and a rapid ventricular rate. An agent is used to control the

ventricular rate, but the cardiac contractility is also affected, placing

him in pulmonary edema. Which of the following agents was most

likely used?

A. Amiodarone

B. Digoxin

C. Nifedipine

D. Verapamil

Answers

[11.1] A. Adenosine is nearly 100 percent effective in converting PAT.

Digoxin could be used but is less effective.

[11.2] D. Amiodarone blocks both Na

and K

channels and has α- and β-

adrenoreceptor antagonist activities. The latter would indirectly

decrease Ca

-channel activity.

[11.3] D. Verapamil is a calcium-channel-blocking agent that slows conduc-

tion in the AV node, but it also has a negative inotropic effect on the

heart.

PHARMACOLOGY PEARLS

❖ Amiodarone is typically the first choice in acute ventricular arrhyth-

mias.

❖ Adenosine is the best choice to convert PAT to sinus rhythm.

❖ Long-term benefit of using class I antiarrhythmics is uncertain, but

mortality is not decreased.

❖ Beta blockers have been shown to reduce mortality and second

cardiovascular events by 25–40% in patients post-MI.

CASE FILES: PHARMACOLOGY

REFERENCES

Cooper HA, Bloomfield DA, Bush DE, et al. Relation between achieved heart rate

and outcomes in patients with atrial fibrillation (from the atrial fibrillation follow-

up investigation of rhythm management [AFFIRM] study): AFFIRM investiga-

tors. Am J Cardiol 2004;93(10):1247–53.

Boriani G, Diemberger I, Biffi M et al. Pharmacological cardioversion of atrial fib-

rillation: current management and treatment options. Drugs 2007;64:2641–62.

CLINICAL CASES

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❖

CASE 12

A 50-year-old man presents for follow-up of his hypertension. He is main-

taining a low-sodium diet, exercising regularly, and taking metoprolol at max-

imum dosage. He is on no other medications. His blood pressure remains

elevated at 150/100 mm Hg. His examination is otherwise unremarkable. You

decide to add a thiazide diuretic to his regimen.

◆

What is the mechanism of action of metoprolol?

◆

What is the mechanism of action of thiazide diuretics?

◆

What electrolyte abnormalities commonly occur with thiazide

diuretics?

ANSWERS TO CASE 12: ANTIHYPERTENSIVE

AGENTS

Summary: A 50-year-old man with inadequately controlled hypertension is

prescribed a thiazide diuretic.

◆

Mechanism of action of metoprolol:β

-Selective adrenoreceptor antagonist.

◆

Mechanism of action of thiazide diuretics: Inhibit active reabsorption

of NaCl in the distal convoluted tubule by interfering with a specific

/Cl

−

cotransporter.

◆

Electrolyte abnormalities seen with thiazide diuretics:Hypokalemia,

hyponatremia, hypochloremia.

CLINICAL CORRELATION

Thiazide diuretics are the recommended first-line agents for most people

with hypertension. They are frequently used in combination with other

classes of antihypertensives. Thiazides inhibit the active reabsorption of Na

This causes an increase in the excretion of Na

, Cl

−

, and K

. They also reduce

the excretion of Ca

by increasing its absorption. The excretion of sodium and

water reduces intravascular volume and contributes to their antihypertensive

effect. Thiazides are used as single agents primarily in mild to moderate hyper-

tension. They are often added as second agents when other drugs alone cannot

control a patient’s hypertension. The electrolyte abnormalities caused by thi-

azides can be clinically important. Hypokalemia occurs frequently, especially

when higher doses of thiazides are used. Patients need to be instructed to fol-

low a high potassium diet and frequently require potassium supplementation.

Thiazides can also elevate serum uric acid levels, which can precipitate gout

in susceptible individuals.

APPROACH TO PHARMACOLOGY

OF ANTIHYPERTENSIVE AGENTS

Objectives

1. Know the classes of antihypertensive medications and their mecha-

nisms of action.

2. Know the common side effects of the antihypertensive agents.

Definitions

Hypertension: Blood pressure continuously elevated to levels greater than

120/80 mm Hg. Pressures of 130/90 mm Hg are considered prehyper-

tensive.

CASE FILES: PHARMACOLOGY

Essential hypertension: Hypertension of unknown etiology makes up

approximately 90 percent of hypertensive patients.

DISCUSSION

Class

There are 12 major classes of drugs that are used as oral antihypertensive

drugs, and these include drugs that act centrally and those that work in the

periphery. Antihypertensive drugs may cause vascular smooth-muscle relax-

ation, vascular volume reduction, or a decrease in cardiac output. This is

accomplished by decreasing Ca

in vascular smooth muscle cells or by reduc-

ing Na

reabsorption on the kidney. Table 12-1 lists these major classes.

Lifestyle modifications include smoking cessation, weight management,

and commencement of an exercise program.

The Joint National Commission (JNC) also emphasized the need to recog-

nize and treat systolic hypertension,which is associated with a higher degree

of risk of MI in patients older than 45 years. Systolic hypertension is more

difficult to treat than diastolic hypertension and frequently requires multiple

drugs acting via different mechanisms.

The JNC-7 report and other recent studies recommend thiazide diuretics as

the first-line agent for the treatment of hypertension in most cases(Table 12-2).

This conservative approach is based on data supporting the fact that these

agents decrease morbidity and mortality in clinical trials. The other

agents that should be considered for initial monotherapy include the beta

blockers, the renin-angiotensin system inhibitors (either ACE inhibitors or

ARBs), α-adrenoreceptor antagonists, calcium-channel antagonists, and

arterial vasodilators. All have been shown to reduce blood pressure by

10–15 mm Hg.

Diuretics

Diuretics cause an initial reduction in blood pressure by facilitating loss of

ⴙ

and water.This leads to a decrease in cardiac output and blood pressure.

However, after 8 weeks, cardiac output returns to normal while blood pressure

remains reduced. This is thought to be caused by a reduction in the vasocon-

strictive activities of Na

ⴙ

on vascular smooth musclesthat include elevation

of intracellular Ca

2ⴙ

via the Ca

2ⴙ

/Na

ⴙ

antiporter. Thiazidediuretics, which

reduce the activity of a specific Na

−

cotransporter (NCC2) in the distal

convoluted tubule,are the class of diuretics most often used for hypertension.

In refractory cases or in patients with concomitant edema, loop diuretics can

be used with caution. Loop diuretics reduce Na

reabsorption in the ascending

limb of the loop of Henle by reducing the activity of another Na

-K

-2Cl

−

cotransporter (NKCC) and can produce a profound loss of Na

and K

. Both

thiazides and loop diuretics can cause hypokalemia and hyponatremia. A

common complaint associated with diuretic use is the increased frequency of

CLINICAL CASES 95

96 CASE FILES: PHARMACOLOGY

Table 12-1

SELECTIVE CLASSES OF ANTIHYPERTENSIVE AGENTS

COMMON

PROTOTYPE ADVERSE

CLASS DRUG MOA EFFECT

Beta blocker Propranolol Adrenergic Fatigue, reduction

β-receptor antagonist on libido

-Antagonist Prazosin Adrenergic receptor Orthostatic

antagonist hypotension

ACE inhibitor Enalapril Reduces production Hyperkalemia

of angiotensin II

ARB (angiotenson Losartan AT-1 receptor Hyperkalemia

receptor blocker) antagonist

Renin Aliskiren Inhibits renin Angioedema,

inhibitor activity headache, dizziness,

gastrointestinal

events

Specific Eplerenone Aldosterone-receptor Hyperkalemia

aldosterone- antagonists

receptor antagonist

Diuretic—loop Furosemide Reduces Na

Hypokalemia

reabsorption in

loop of Henle

Diuretic—distal Hydrochlorothiazide Reduces Na

Hypokalemia

tubule reabsorption at site 3

channel Nifedipine Blocks Ca

entry Hypotension

blocker in vascular smooth arrhythmias

muscle cells

Arterial Minoxidil Hyperpolarizes Orthostatic

vasodilators VSMC hypotension

Central acting Clonidine α

-Adrenergic Sedation,

vasodilator agonist, I

-receptor depression

agonist

Adrenergic Guanethidine Inhibits release of Postural

neuron blockers norepinephrine hypotension

Neuronal Reserpine Depletes neurons of Sedation

uptake inhibitor neurotransmitters

urination. Spironolactone and eplerenone are antagonists of the aldosterone

receptor and are weakly diuretic. Eplerenone is much more specific for

the alososterone receptor compared to spironolactone.

Beta (␤) Blockers

Use of β-adrenoreceptor blockers for hypertension relies on decreasing

cardiac output and decreasing peripheral vascular resistance. The vari-

ous drugs in this class vary in their potency on β

receptors; metoprolol is

more than 1000 times more potent in blocking β

compared to β

receptors,

giving this drug a relative cardioselectivity.Blockade of β

-adrenoreceptors

in the JGA of the kidney reduces renin secretion, and this reduces the pro-

duction of angiotensin II. Nonselective beta blockers such as propranolol

cause a number of predictable adverse effects including bronchoconstriction

(contraindicating use in asthmatics); a decrease in the production of insulin

(contraindicating use in diabetics); and central nervous system (CNS) effects

including depression, insomnia, and a decline in male potency. In addition,

the nonselective agents increase both triglycerides and low-density lipopro-

tein (LDL). These effects are reduced but not eliminated with the more β

selective agents.

Alpha

(␣

) Blockers

Prazosin, doxazosin, and terazosin reduce blood pressure by antagoniz-

ing α

-adrenoreceptors in vascular smooth muscle.Blockade of this recep-

tor reduces intracellular cyclic adenosine monophosphate (cAMP) and leads

to a reduction in intracellular Ca

. Orthostatic hypotension is common on

initiation of therapy but diminishes. Dizziness and headache are also adverse

effects. α

-Blockers appear to reduce LDL cholesterol. Alphablockers are used

CLINICAL CASES 97

Table 12-2

THE JOINT NATIONAL COMMITTEE ON HYPERTENSION HAS

DEFINED FOUR CATEGORIES OF HYPERTENSION

BLOOD BLOOD

PRESSURE PRESSURE

SYSTOLIC DIASTOLIC RECOMMENDED

STAGE (mm Hg) (mm Hg) TREATMENT

Normal <120 and <80 —

Prehypertensive 120–139 or 80–89 Lifestyle

modification

Hypertensive stage 1 140–159 or 90–99 Lifestyle modification, R

Hypertensive stage 2 ≥160 or ≥100 Lifestyle modification, R

primarily for hypertension in patients who also have symptomatic prostatic

hyperplasia. Because of excess cases of congestiveheart failurein users of

alpha blockers, these agents should not be used as first-line therapy in hyper-

tension.

Calcium Channel Blockers

Calcium channel (Ca

2ⴙ

-channel) blockers are useful antihypertensives

and can reduce blood pressure by 10–15 mm Hg. These agents exert their anti-

hypertensive effect by blocking L-type (voltage-sensitive) Ca

2ⴙ

channels.

By blocking the entry of Ca

into the cell, less is available to activate the con-

tractile apparatus, and within vascular smooth muscle, this produces a reduc-

tion in vascular tone. Three distinct chemical classes comprise the

-channel antagonists, dihydropyridinesinclude nifedipine, diphenylalky-

lamines include verapamil, and benzothiazepines include diltiazem. All are

approved for treating hypertension. Nifedipine and the other dihydropyridines

have less of an effect on the heart than verapamil and diltiazem. Verapamil

has the greatest effect on the heart and can significantly reduce contrac-

tility. Because of its effect on the heart, verapamil can be used to treat

supraventricular arrhythmias as well as variant angina. Depression of cardiac

function is the greatest adverse effect of the Ca

-channel blockers, and this is

markedly diminished with the dihydropyridines. Dihydropyridines can induce

a reflex tachycardia in response to their blood pressure–lowering effect.

However, clinical trials with short-acting nifedipine suggested that there was

an increase in the risk of MI in patients treated for hypertension, and these

agents should not be used to treat the disease.

Renin-Angiotensin System Inhibitors

Inhibitors of the renin-angiotensin system, both ACE inhibitors and ARBs

are effective for hypertension monotherapy. ACE inhibitors block the conver-

sion of the inactive angiotensin I to the potent angiotensin II. Angiotensin II

acts to increase blood pressure in several ways. In vascular smooth muscle it

increases intracellular Ca

and produces pronounced vasoconstriction. At

peripheral nerve endings and in the adrenal medulla it increases the amount of

catecholamines released on stimulation. In the zona glomerulosa of the adre-

nal cortex it acts to stimulate the biosynthesis of aldosterone, which increases

renal Na

and water retention. Adverse effects include hypotension, dizziness,

and fatigue; rarely, hyperkalemia may occur. A dry cough and angioedema

may occur as a result of the reduction in degradation of bradykinin that is

brought about by these drugs.

Aliskiren (Tekturna) reduces the activity of renin; this in turn causes a

reduction in the production of angiotensin II. Clinical experience is lacking for

aliskiren, but it appears about as effective as ACE inhibitors and has fewer side

effects. During clinical trials, headache, dizziness, and some gastrointestinal

CASE FILES: PHARMACOLOGY

events were the most common side effects, and angioedema was observed in a

few patients.

Angiotensin II acts through AT-1 and AT-2 receptors, which in turn couple to

numerous signal transduction pathways. The hypertensive actions of angiotensin

II are mediated by AT-1 receptors. Losartan, valsartan, and other AT-1 receptor

blockers are also effective in reducing blood pressure by 10–15 mm Hg. The

adverse-effect profile is similar to the ACE inhibitors but without the cough or

angioedema.

Direct Arterial Vasodilators

Arterial vasodilators act by increasing the efflux of potassium from the

cell. This causes hyperpolarization across the plasma membrane that dimin-

ishes the activity of the voltage-regulated L-type calcium channel. In vascular

smooth muscle cells this produces a reduction in vascular tone. Minoxidil and

hydralazine are the two most commonly used oral vasodilators used to treat

hypertension. Both have pronounced effects on the resistance vessels and little

effect on veins. Because of their predominant effect on arterioles, these agents

provoke the baroreceptor reflex that includes tachycardia, vasoconstric-

tion, and the release of renin.For this reason, these agents are usually com-

bined with a beta blocker and a diuretic.

Centrally Acting Agents

Centrally acting vasodilators such as clonidine and methyldopa act as

␣

-adrenergic receptor agonists in the vasomotor center within the

medulla. These agents decrease sympathetic outflow and thereby decrease

vascular tone and cardiac output. The use of these agents as antihypertensives

has been overshadowed by the introduction of ACE inhibitors and ARBs and

-channel blockers. This is largely a result of the adverse effects, which are

mostly in the CNS and include sedation, depression, and dry mouth. However,

they are still used in cases of refractory hypertension.

Peripheral Sympathetic Inhibitors

Peripheral sympatholytic agents used for hypertension include guanethi-

dine and reserpine. Guanethidine enters sympathetic nerve terminals by trans-

port and replaces norepinephrine in transmitter vesicles. Release of

norepinephrine is thereby diminished. Reserpine blocks the uptake and storage

of biogenic amines, and this diminishes the amount of transmitter released on

stimulation. Because of much higher rates of adverse effects, these agents are

rarely used to treat simple hypertension but may be combined in the treatment

of refractory hypertension.

CLINICAL CASES 99

COMPREHENSION QUESTIONS

[12.1] The inclusion of spironolactone with a thiazide diuretic in a regimen to

treat hypertension is done to achieve which of the following?

A. Reduce hyperuricemia

B. Reduce Mg

loss

C. Decrease the loss of Na

D. Reduce K

loss

[12.2] Which of the following drugs would be the best to treat moderate

hypertension in a diabetic patient with mild proteinuria?

A. Enalapril

B. Propranolol

C. Hydrochlorothiazide

D Nifedipine

[12.3] A 33-year-old man is diagnosed with essential hypertension. He is

started on a blood pressure medication, and after 6 weeks, he notes

fatigue, rash over his face, joint aches, and effusions. A serum antinu-

clear antibody (ANA) test is positive. Which of the following is the

most likely agent?

A. Hydralazine

B. Propranolol

C. Thiazide diuretic

D. Nifedipine

E. Enalapril

Answers

[12.1] D. Spironolactone is a “potassium-sparing” diuretic that reduces K

excretion in the collecting duct. It diminishes the K

-wasting effects

of thiazide diuretics.

[12.2] A. ACE inhibitors, such as enalapril, have been shown to reduce the

progressive loss of renal function that is often seen in diabetic

patients. The nonselective beta blocker, propranolol, would worsen

the diabetes.

[12.3] A. Hydralazine is associated with a lupus-like presentation, with pho-

tosensitivity, malar rash, joint pain, and sometimes pericardial effu-

sion or pleural effusion.

100

CASE FILES: PHARMACOLOGY

PHARMACOLOGY PEARLS

❖ The ALLHAT clinical trial (Antihypertensive and lipid-lowering

treatment to prevent heart attack) compared amlodipine, a dihy-

dropyridine Ca

-channel blocker, lisinopril, an ACE inhibitor,

doxazosin, an α

-adrenergic antagonist with chlorthalidone, a

thiazide diuretic.

❖ Thiazide diuretics are the preferred initial therapy for hypertension

in most cases.

❖ Beta-blocking agents can cause depression, insomnia, male impo-

tency, bronchoconstriction, and decreased production of insulin.

REFERENCES

Kostis JB. The importance of managing hypertension and dyslipemia to decrease

cardiovascular disease. Cardiovasc Drugs Ther Epub; 21(4):297–309:2007.

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research

Group. Major outcomes in moderately hypercholesterolemic, hypertensive

patients randomized to pravastatin vs usual care: the antihypertensive and lipid-

lowering treatment to prevent heart attack trial (ALLHAT-LLT). The antihyper-

tensive and lipid-lowering treatment to prevent heart attack trial. JAMA

2002;288(23):2998–3007.

CLINICAL CASES

101

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❖

CASE 13

A 60-year-old man with hypertension and type II diabetes comes in for a

follow-up visit. Along with making appropriate diet and lifestyle changes, he

is taking an ACE inhibitor-thiazide diuretic combination for his hypertension

and metformin for his diabetes. His blood pressure and diabetes are under

acceptable control. Routine blood work revealed normal electrolytes, renal

function, and liver enzymes. He is noted to have elevated total cholesterol and

low-density lipoprotein (LDL) levels, which have remained high in spite of

his lifestyle changes. In an effort to reduce his risk of developing coronary

artery disease, you start him on a 3-hydroxy-3-methylglutaryl-coenzyme A

(HMG-CoA) reductase inhibitor.

◆

What is the mechanism of action of HMG-CoA reductase

inhibitors?

◆

What effect do they have on total and LDL cholesterol levels?

◆

What are the common adverse effects of HMG-CoA reductase

inhibitors?

ANSWERS TO CASE 13: LIPID-LOWERING AGENTS

Summary:A 60-year-old man has hypertension, diabetes, and hyperlipidemia

and is started on an HMG-CoA reductase inhibitor.

◆

Mechanism of action of HMG-CoA reductase inhibitors:

Competitive inhibition of the rate-limiting enzyme in cholesterol

biosynthesis results in compensatory increase in plasma cholesterol

uptake in the liver mediated by an increase in the number of LDL

receptors.

◆

Effect on total cholesterol: Up to 30 percent reduction.

◆

Effect on LDL cholesterol: Up to 50 percent reduction.

◆

Common adverse events:Elevated liver enzymes and hepatotoxicity,

myalgia and myositis, irritability, sleep disturbance, anxiety.

CLINICAL CORRELATION

HMG-CoA reductase inhibitors are in wide clinical use with proven benefit in

lowering cholesterol levels and reducing the risk of coronary artery disease in

susceptible individuals. They competitively antagonize the rate-limiting

enzyme in cholesterol biosynthesis. Reduced cholesterol synthesis spurs a

compensatory increase in hepatic uptake of plasma cholesterol mediated by an

increase in the number of LDL receptors. The net effect of this is to lower the

plasma levels of lipoproteins, especially LDL cholesterol. The effect on high-

density lipoprotein (HDL) cholesterol is less pronounced. Although generally

very well tolerated, severe hepatotoxicity has occurred, and monitoring of

liver enzymes is mandatory while taking these medications. Myalgiais a com-

mon side effect, but rarely severe, myositis and rhabdomyolysis have occurred.

Hepatotoxicity and myositis can occur while using an HMG-CoA reductase

inhibitor alone, but they become more likely when combinations of medica-

tions are used.

APPROACH TO PHARMACOLOGY

OF LIPID-LOWERING DRUGS

Objectives

1. Know the drugs used to treat hyperlipoproteinemias.

2. Know the adverse effects and toxicities of the drugs.

3. Know the therapeutic uses of each of the lipid-lowering agents.

104

CASE FILES: PHARMACOLOGY

Definitions

Hyperlipidemia: An elevation in either plasma cholesterol or plasma

triglycerides or both.

Myopathy:General term for any disease of muscle.

Myositis: Muscle pain with increased creatinine kinase levels.

Rhabdomyolysis: Muscle pain accompanied by a greater than tenfold

increase in creatinine kinase above upper limits of normal, indicating

serious muscle damage.

LDL cholesterol: Low-density lipoprotein. Atherogenic lipoprotein parti-

cle. Several subfractions have been identified, and the smallest are the

most atherogenic. It contains apolipoproteins B

100

(apo B

100

; interacts

with LDL receptor), Apo E (interacts with LDL receptor and Apo E

receptor), and Apo C (activates lipoprotein lipase).

HDL cholesterol: High-density lipoprotein particle involved in transport-

ing cholesterol from the periphery back to the liver. Has antiatheroscle-

rotic activity. Contains Apo A, C, and D.

VLDL:Very-low-density lipoprotein, a triglyceride-rich lipoprotein particle

synthesized in the liver.

DISCUSSSION

Class

Drugs that decrease plasma lipids are among the most commonly prescribed

today. Some of these affect primarily cholesterol (e.g., the statins) and are use-

ful in the treatment of hypercholesterolemia while other agents affect primarily

triglycerides (e.g., gemfibrozil).

The National Cholesterol Education Program (NCEP) has classified

levels of plasma cholesterol (Table 13-1). The LDL cholesterol treatment

goal is determined by assessing the risk of cardiovascular disease of indi-

vidual patients. The major risk factors that modify LDL goals are listed in

Table 13-2.

Known CHD include patients who have had an infarction or angina or a

surgical procedure for cardiovascular disease. In addition, patients with

peripheral arterial disease, abdominal aortic aneurism, or symptomatic

carotid artery disease or diabetes are considered to have known CHD or a

high risk for CHD. The NCEP classification and the risk assessment are

combined and used to modify the LDL cholesterol goals as illustrated in

Table 13-3.

CLINICAL CASES 105

106 CASE FILES: PHARMACOLOGY

Table 13-2

RISK FACTORS FOR CARDIOVASCULAR DISEASE

Clinical CVD

Cigarette Smoking

Hypertension (BP >140/90 mm Hg) or on an antihypertensive drug

Low HDL cholesterol (<40 mg/dL)

Family history of premature coronary heart disease

Age (men >45 years, women > 55 years)

Poor nutrition

Table 13-1

NATIONAL CHOLESTEROL EDUCATION PROGRAM (NCEP) LEVELS

OF PLASMA CHOLESTEROL

LDL CHOLESTEROL (mg/dL) CATEGORIZATION

<100 Optimal

100–129 Near/above optimal

130–139 Borderline high

160–189 High

>190 Very high

TOTAL CHOLESTEROL (mg/dL)

<200 Desirable

200–239 Borderline high

>240 High

HDL CHOLESTEROL (mg/dL)

<40 Low

>60 High

Agents Used for Hypercholesterolemia

Statins

Of the drugs that decrease plasma cholesterol, the statins have gained the

widest use. The statins are structural analogs of the substrate HMG-CoA

that inhibit the activity of the enzyme HMG-CoA reductase at nanomolar

concentrations. This enzyme is required for the synthesis of isoprenoids and

cholesterol. By inhibiting de novo biosynthesis of cholesterol, cellular uptake

of cholesterol from plasma via the LDL receptor is increased, reducing plasma

cholesterol levels. Because statins have additional actions to inhibit the

production of the triglyceride-rich VLDL, this makes them useful in the

management of patients with hypertriglyceridemia; atorvastatin and rosuvas-

tatin are particularly effective in this regard. There is evidence that statins also

have anti-inflammatory activity, and this may contribute to their reduction in

cardiovascular events. Statins may also reduce the rate of bone resorption

and thereby lessen osteoporosis. This effect is thought to be caused by the

inhibition of isoprenoid biosynthesis in osteoclast precursors, which inhibits

their differentiation into mature osteoclasts. Six statins are approved in the

United States: lovastatin, rosuvastatin, fluvastatin, atorvastatin, pravas-

tatin, and simvastatin. They differ in efficacy: Rosuvastatin has been

reported to reduce LDL cholesterol by more than 60 percent; atorvastatin,

approximately 50 percent; and pravastatin and fluvastatin, approximately

35 percent. All of the statins are active orally. Lovastatin and simvastatin are

prodrugs that are converted to their active metabolite by the liver.

The two major adverse effects associated with statin use are hepato-

toxicity and myopathy.Hepatotoxicity was initially thought to be as high as

1 percent with elevations in hepatic transaminases as high as three times the

upper limits. Subsequent clinical trials indicate that the actual incidence of

hepatotoxicity is much lower. Hepatic transaminase levels should be moni-

tored on initiation of therapy and at least yearly thereafter. The myopathy asso-

ciated with statin use occurs in less than 0.1 percent of patients. However,

severe rhabdomyolysis has occurred rarely, and one statin, cerivastatin, was

removed from the market after several rhabdomyolysis-associated deaths.

CLINICAL CASES 107

Table 13-3

CARDIOVASCULAR RISK AND LDL GOAL

LDL GOAL

RISK LEVEL (mg/dL)

Known CHD <100

≥2 risk factors <130

0–1 risk factors <160

Bile-Acid-Binding Resins

The bile acid sequestrants are also useful in reducing plasma cholesterol.

Cholestyramine, colestipol, and colesevelam are ion-exchange resins that

nonspecifically bind bile acids within the intestine and thereby reduce their

enterohepatic circulation. This increases de novo hepatic bile acid synthesis

and the cholesterol for this synthesis comes, in part, from the plasma via the

LDL receptor. Bile acid sequestrants typically reduce plasma cholesterol

by 15–20 percent with no effect on triglycerides. Because they are not

absorbed, the bile acid sequestrants are quite safe, and adverse effects are typ-

ically gastrointestinal and include bloating and constipation. In the intestine,

these agents bind many molecules other than bile acids and they impair the

absorption of lipid-soluble vitamins and many drugs including digoxin,

furosemide, thiazides, coumarin, and some statins. Patient adherence with

these drugs is poor.

Inhibitors of Cholesterol Absorption

Ezetimibe is a new class of cholesterol-lowering drug that acts within

the intestine to reduce cholesterol absorption.Cholesterol is absorbed from

the small intestine by a process that includes specific transporters that have not

been completely characterized. Ezetimibe appears to block one or more of

these cholesterol transporters, thereby reducing cholesterol absorption.

Ezetimibe used alone produces a reduction in plasma cholesterol of approxi-

mately 19 percent and an approximate 10 percent decline in triglyceride

levels. When combined with a statin, reductions in plasma cholesterol as

high as 72 percent have been reported in clinical trials. The complementary

mechanisms—inhibition of cholesterol biosynthesis by statins and inhibition

of cholesterol absorption by ezetimibe—may be useful in treating patients

with refractory hypercholesterolemia. Few adverse effects have been reported

with ezetimibe, but clinical experience is limited. The most frequently

reported adverse effects are back and joint pain.

Nicotinic Acid

Niacin, at doses well beyond those used as a vitamin, has effects on all

plasma lipids. It reduces LDL cholesterol by 20–30 percent and reduces

triglycerides by 35–45 percent. It is the best agent available for increasing

HDL. Niacin inhibits VLDL production in the liver by inhibiting both the syn-

thesis and esterification of fatty acids. LDL levels are reduced as a consequence

of the decline in VLDL synthesis. Niacin inhibits lipolysis in adipose tissue

which reduces the supply of fatty acids to the liver, further decreasing VLDL

synthesis. HDL levels are increased because niacin decreases the catabolism of

Apo A

. Niacin is useful in treating hypertriglyceridemia as well as hypercho-

lesterolemia especially in the presence of low HDL. The limiting adverse effect

of niacin is cutaneous flushing and itching, and dyspepsia is common at the

doses (1 g/day) necessary to affect lipids. More medically serious adverse

108

CASE FILES: PHARMACOLOGY

effects include hepatotoxicity and hyperglycemia. Niacin induces an insulin-

resistant state causing hyperglycemia. For this reason niacin should not be

used in diabetic patients.

Agents Used for Hypertriglyceridemia—Fibrates

The fibrates include clofibrate, fenofibrate, ciprofibrate, bezafibrate,

and gemfibrozil.These agents predominantly cause a decline plasma triglyc-

eridesand a small decrease in LDL cholesterol. HDL levels are increased. The

fibrates bind to a nuclear receptor peroxisomal proliferator-activator receptor γ

(PPAR-γ) mostly in liver and skeletal muscle. Agonist-bound PPAR-γ induces

lipoprotein lipase (LPL), which increases the lipolysis of triglyceride-rich

VLDL and chylomicrons. Fibrates reduce triglycerides by 35–50 percent and

LDL cholesterol by 10–20 percent. HDL levels are increased by 10–15 percent.

All of the fibrates are orally active, but their absorption is decreased by food.

The major adverse effect is gastrointestinal upset, cutaneous rash, and itching.

Fibrates should not be used in patients with compromised renal function.

COMPREHENSION QUESTIONS

[13.1] Lovastatin reduces plasma cholesterol by which of the following

processes?

A. Inhibiting Apo B

100

biosynthesis

B. Inhibiting cholesterol absorption

C. Inhibiting cholesterol biosynthesis

D. Interfering with bile acid reabsorption

[13.2] Which of the following is a usual effect of niacin?

A. Increases HDL

B. Increases LDL

C. Increases total cholesterol

D. Increases triglycerides

[13.3] A 33-year-old man has been prescribed medication for hyperlipidemia.

He has been noted to have bleeding from his gums and easy bruisability.

His prothrombin time is elevated. Which of the following agents is

most likely to be involved?

A. Atorvastatin

B. Cholestyramine

C. Gemfibrozil

D. Niacin

CLINICAL CASES 109

Answers

[13.1] C. The statins are competitive inhibitors of HMG-CoA reductase and

thereby inhibit de novo cholesterol biosynthesis.

[13.2] A. Niacin increases HDL, decreases total and LDL cholesterol, and

decreases triglycerides.

[13.3] B. Cholestyramine interferes with the absorption of lipid-soluble

vitamins such as vitamin K, leading to decreased levels of vitamin

K–dependent coagulation factors.

PHARMACOLOGY PEARLS

❖ The HMG-CoA reductase inhibitors, the statins, are the initial

choice of drug for the treatment of hypercholesterolemia.

❖ The statins are structural analogs of the substrate HMG-CoA

(3-hydroxy-3-methylglutaryl-coenzyme A) that inhibit the activ-

ity of the enzyme HMG-CoA reductase.

❖ The two major adverse effects associated with statin use are hepato-

toxicity and myopathy.

❖ Bile acid sequestrants impair the absorption of lipid-soluble vita-

mins and many drugs including digoxin, furosemide, thiazides,

coumarin, and some statins.

❖ The fibrates including clofibrate, fenofibrate, ciprofibrate, bezafi-

brate, and gemfibrozil predominantly cause a decline in plasma

triglycerides.

❖ Niacin has effects on all plasma lipids and has side effects of flush-

ing and itching.

REFERENCES

NCEP Report. Implications of recent clinical trials for the National Cholesterol

Education Program Adult Treatment Panel III guidelines. Circulation

2004;110:227–39.

Wierzbicki AS, Mikhailidis DP, Wray R. Drug treatment of combined hyperlipi-

demia. Am J Cardiovasc Drugs 2001;1(5):327–36.

110 CASE FILES: PHARMACOLOGY

❖

CASE 14

A 19-year-old man is brought to the physician’s office by his very concerned

mother. He has been kicked out of the dormitory at college for his “bizarre”

behavior. He has accused several fellow students and professors of spying on

him for the CIA. He stopped attending his classes and spends all of his time

watching TV because the announcers are sending him secret messages on how

to save the world. He has stopped bathing and will only change his clothes

once a week. In your office you find him to be disheveled, quiet, and unemo-

tional. The only spontaneous statement he makes is when he asks why his

mother brought him to the office of “another government spy.” His physical

examination and blood tests are normal. A drug screen is negative. You diag-

nose him with acute psychosis secondary to schizophrenia, admit him to the

psychiatric unit of the hospital, and start him on haloperidol.

◆

What is the mechanism of therapeutic action of haloperidol?

◆

What mediates the extrapyramidal side effects (EPSs) of the

antipsychotic agents?

◆

Which autonomic nervous system receptors are antagonized by

antipsychotic agents?

112 CASE FILES: PHARMACOLOGY

ANSWERS TO CASE 14: ANTIPSYCHOTIC DRUGS

Summary:A 19-year-old man with acute psychosis from schizophrenia is pre-

scribed haloperidol.

◆

Mechanism of therapeutic action of haloperidol:Antagonist activity at

postjunctional dopamine D

-receptors in the mesolimbic and mesocortical

areas of the brain.

◆

Mechanism of EPSs:Antagonist activity at dopamine receptors in the

basal ganglia and other dopamine receptor sites in the central nervous

system (CNS).

◆

Autonomic nervous system receptors blocked by antipsychotic

agents: α-Adrenoceptors and muscarinic cholinoreceptors.

CLINICAL CORRELATION

Schizophrenia is a chronic thought disorder that often presents in adolescence

or early adulthood. It is characterized by the presence of “positive symptoms,”

which include delusions, hallucinations, and paranoia, and “negative symp-

toms,” which include blunt affect, withdrawal, and apathy. The therapeutic

effects of the antipsychotic agents result from their antagonist actions on

postjunctional dopamine D

receptors in the mesolimbic and mesocortical

areas of the brain, although their benefits may also be related to their antago-

nist activity at dopamine receptors in other areas of the CNS; additionally,

atypical antipsychotic agents have efficacy at serotonin receptors. The

dopamine receptor antagonist activity of antipsychotic agents at multiple sites

in the CNS, and their antagonist activity at various other receptors in the CNS

and throughout the body, contributes to the presence of numerous adverse

effects. The presence of so many, and frequently severe, side effects makes

patient compliance with long-term antipsychotic therapy an important clinical

issue. However, newer, “atypical” agents are now available with greater speci-

ficity for the receptors that mediate antipsychotic actions than for the receptors

that mediate adverse effects.

APPROACH TO PHARMACOLOGY

OF ANTIPSYCHOTIC DRUGS

Objectives

1. List the classes and specific drugs that have antipsychotic activity.

2. Describe the mechanism of therapeutic action of antipsychotic agents.

3. Describe the common side effects of antipsychotic agents and indicate

the receptors that mediate them.

112

CASE FILES: PHARMACOLOGY

CLINICAL CASES 113

Definitions

Acute dystonia: Sustained painful muscle spasms producing twisting

abnormal posture usually occurring shortly after taking an antipsychotic

medication.

Akathisia: Characterized by feelings of intense muscle restlessness or

strong desire to move about, usually during the first 2 weeks of treatment

with an antipsychotic medication.

Parkinson syndrome: Characterized by flat affect, shuffling gait, joint

rigidity, and tremor that occurs weeks to months after treatment.

Neuroleptic malignant syndrome: Characterized by the acute onset of

hyperthermia, muscle rigidity, tremor, tachycardia, mental status changes,

diaphoresis, labile blood pressure, and exposure to a neuroleptic. This

syndrome is associated with a significant mortality rate and usually

occurs within the first few weeks of therapy.

DISCUSSION

Class

Antipsychotic drugscan be classified according to chemical structure as phe-

nothiazines, butyrophenones, and an important group with diverse atypical

structures. The phenothiazines are further subdivided according to side-chain

constituents: aliphatic, piperidine, and piperazine (Table 14-1).

Although very similar in their therapeutic efficacy, the “low- (oral-)

potency” aliphatic and piperidine phenothiazines have a somewhat different

Table 14-1

REPRESENTATIVE ANTIPSYCHOTIC DRUGS (SIDE CHAINS)

Phenothiazines

Chlorpromazine, triflupromazine (aliphatic)

Thioridazine, mesoridazine (piperidine)

Fluphenazine, trifluoperazine (piperazine)

Butyrophenone

Haloperidol

Atypical

Clozapine

Risperidone

Olanzapine

Quetiapine

Aripiprazole

Ziprasidone

adverse effect profile than the “high-potency” agents that include the piper-

azine phenothiazines, and also thiothixene, and haloperidol.

The newer, atypical agents have generally unique structures; some studies

have suggested that they may have greater therapeutic efficacy with regard to

the negative symptoms of schizophrenia. They also have been documented to

have superior adverse effect profiles. Recent clinical trials have called into

question the safety of several of the newer agents. In summary, individual

patient response to antipsychotic agents varies widely and often dictates drug

selection.

Administration of the low-potency antipsychotic agents is more likely to

result in autonomic adverse effects that include orthostatic hypotension

caused by

-adrenoceptor blockade, and dry mouth, urinary retention,

and tachycardia resulting from blockade of muscarinic cholinoreceptors.

Their blockade of histamine H

receptors in the CNS results in sedation.

The still widely used high-potency agents, for example, haloperidol,are more

likely to result in adverse neurologic effects. Among these are the EPSs, acute

dystonia, akathisia, and Parkinson syndrome, which occur relatively early

in therapy and are thought to be primarily mediated by blockade of dopamine

receptors in the nigrostriatal dopamine pathway of the basal ganglia. A

late-occurring tardive dyskinesiathat is often irreversible and that may be a

result of the slow development of dopamine receptor supersensitivity also in

the basal ganglia is more or less likely to occur with all antipsychotic agents

except clozapine. A potentially fatal neuroleptic malignant syndrome is

another serious adverse effect of antipsychotic agents in sensitive patients

(1%).Also, hyperprolactinemia in women may occur as a result of enhanced

prolactin release from the posterior pituitary, because of antipsychotic drug

blockade (phenothiazines, butyrophenones, risperidone) of dopamine D

receptors of the tuberoinfundibular dopaminergic pathway, which may lead to

amenorrhea, galactorrhea, gynecomastia, decreased libido, and impotence.

Weight gain is also a likely effect of many of these antipsychotic agents.

Theatypical agents are less likely than the conventional agents to result in

adverse EPSs. However, weight gain (clozapine, olanzapine, quetiapine),

hypotension, and sedation are not uncommon events. Seizures (2–5%) and

agranulocytosis (2% risk, 10% fatality) limit the use of clozapine to patients

unresponsive to other agents.

Mechanism of Action

All clinically useful antipsychotic drugs block postjunctional dopamine D

recep-

tors,although the degree of blockade among the drugs varies greatly in relation to

their action on other neuroreceptors, particularly serotonin 5-hydroxytryptamine

2A (5-HT

) receptors and certain other dopamine receptor subtypes.

Antipsychotic drugs appear to exert their therapeutic effect, at least in part, by inhi-

bition of dopamine’s action in the mesocortical and mesolimbic dopaminer-

gic pathways of the CNS.

114 CASE FILES: PHARMACOLOGY114 CASE FILES: PHARMACOLOGY

CLINICAL CASES 115

Administration

All antipsychotic agents can be administered by either the oral or parenteral

route or both. Fluphenazine decanoate and haloperidol decanoate are available

as parenteral depot preparations.

Pharmacokinetics

Most antipsychotic agents are readily but incompletely absorbed. They are

highly lipid soluble and have longer clinical duration of action than would be

expected from their plasma half-life, probably as a consequence of their dep-

osition in fat tissue.

Thioridazine, which is metabolized to mesoridazine, is the exception to the

rule that hepatic metabolism of the antipsychotic agents results in less active

metabolites.

Concurrent use of certain antipsychotic agents with other drugs that also

block cholinoreceptors may result in additive peripheral and CNS dysfunction.

COMPREHENSION QUESTIONS

[14.1] Haloperidol-induced Parkinson syndrome is a result of haloperidol’s

action in which of the following tracts?

A. Mesocortical tract

B. Mesolimbic tract

C. Nigrostriatal tract

D. Tuberoinfundibular tract

[14.2] The therapeutic effect of haloperidol is mediated, at least in part, by its

blockade of which of the following receptors?

A. α-Adrenoceptors

B. Dopamine D

receptors

C. Histamine H

receptors

D. Muscarinic receptors

[14.3] Compared to the low-potency phenothiazine antipsychotic agents,

haloperidol is more like to cause which of the following adverse effects?

A. Akathisia

B. Orthostatic hypotension

C. Sedation

D. Urinary retention

Answers

[14.1] C. Haloperidol-induced Parkinson syndrome is a result of inhibition

of dopamine D

receptors in the nigrostriatal tract of the CNS.

[14.2] B. Antipsychotic drugs like haloperidol exert their therapeutic effect,

at least in part, by inhibition of dopamine’s action at dopamine D

116 CASE FILES: PHARMACOLOGY

receptors in the mesocortical and mesolimbic dopaminergic path-

ways of the CNS. A number of adverse effects of these drugs are

caused by inhibition of dopamine action in the nigrostriatal and

tuberoinfundibular dopaminergic pathways of the CNS; blockade of

histamine, muscarinic, cholinergic, and α-adrenergic receptors in the

CNS and the peripheral nervous system are also contributory.

[14.3] A. Haloperidol is most likely to cause dystonia, akathisia, and

Parkinson syndrome, whereas the low-potency phenothiazines are

more likely to cause autonomic adverse effects that include orthosta-

tic hypotension, sedation, and urinary retention.

116 CASE FILES: PHARMACOLOGY

PHARMACOLOGY PEARLS

❖ The low-potency antipsychotic agents are more likely to result in

autonomic adverse effects that include orthostatic hypotension as

a consequence of α-adrenoceptor blockade, dry mouth, urinary

retention, and tachycardia resulting from blockade of muscarinic

cholinoreceptors, and sedation (histamine H

-receptor blockade).

❖ High-potency agents, for example, haloperidol, are more likely to

result in EPSs, acute dystonia, akathisia, and Parkinson syn-

drome, mediated by blockade of dopamine D

receptors in the

nigrostriatal pathway of the basal ganglia.

❖ A late-occurring tardive dyskinesia is often irreversible and is a seri-

ous effect of many antipsychotic agents.

❖ A potentially fatal neuroleptic malignant syndrome is another seri-

ous adverse effect of antipsychotic agents in sensitive patients.

❖ Hyperprolactinemia may occur as a result of enhanced prolactin

release from the posterior pituitary, as a result of antipsychotic

drug blockade of dopamine D

receptors in the tuberoinfundibu-

lar tract.

❖ Agranulocytosis may occur in patients treated with clozapine.

REFERENCES

Ananth J, Burgoyne KS, Gadasalli R, et al. How do atypical antipsychotics work? J

Psychiatry Neurosci 2001;26(5):385–94.

Freedman R. Schizophrenia. N Engl J Med 2003;349(13):1738–49.

Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in

patients with chronic schizophrenia. N Engl J Med 2005;353:1209–23.

Thacker GK, Carpenter WT. Advances in schizophrenia. Nature Med 2001;7(6):

667–71.