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BRS Pharmacology, Seventh Edition, equips medical, dental, and other health professions students with the preparation needed to excel on licensing examinations and confidently transition to healthcare practice.

The popular BRS series format presents concise coverage of the general principles of drug mechanisms and detailed descriptions of how drugs act on major body systems, delivering vital information in a succinct, streamlined approach favored by today’s students. This trusted review also familiarizes students with the pharmacologic principles of toxicology and details essential information on drugs used to treat anemia, disorders of hemostasis, infectious diseases, and cancer.

Updated with powerful mnemonics and vibrant illustrations, the seventh edition strengthens students’ retention and reinforces challenging concepts to help students ensure success from the USMLE to clinical practice.

Dozens of new and updated illustrations clarify sites and mechanisms of action, relationships between drug classes, interactions and more.
New cross references in the Comprehensive Examination point students to specific content for fast, efficient remediation.
Concise outline format offers an efficient review of high-yield topics.
Enhanced review questions emphasize USMLE format for the most effective board preparation.

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BRS Pharmacology


BRS Pharmacolo

Sarah Lerchenfeldt, PharmD
Asatatant Professor
Department of Foundational Medical Studies
Oakland University William Beaumont School of Medicine
Rochestelf Miclllgan

Authors ofFirst-Sixth Editions

Gary C. Rosenfeld, PhD
David S. Loose, PhD

• •Wolters Kluwer
Philadelphia • Baltimore • New York• London
Buenos Aires • Hong Kong• Sydney •Tokyo

Acquisitions Editor. Matt Hauber
Development Editor: Andrea Vosburgh
Editorial Coordinator. Julie Kostelnik
Marketing Manager: Phyllis Hitner
Production Project Manager. Bridgett Dougherty
Design Coordinator. Joan Wendt
Art Director: Jennifer Clements
Manufacturing Coordinator: Margie Orzech
Prepress Vendor. SPi Global

Seventh Edition
Copyright© 2020 Wolter• Kluwer

Copyright© 2014, 2010, 2007, 1998 Llppincott Williams & Wtlkins, a Wolters Kluwer business. All rights reserved.
This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any
means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage
and retrieval system without written permission from the copyright owner, except for brief quotations embodied
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please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email
at permissions@lww.com, or via our website at shop.lww.com (products and services).
9 8 7 6 5 4 3 2 1

Printed in China
Ubrary of CongreH Cai.loglng-1n-Publk:atl.on Data
Names: Lerchenfeldt, Sarah, author. IPreceded by (work): Rosenfeld, Gary C. Pharmacology.
Title: BRS pharmacology I Sarah Lerchenfeldt
Other titles: Pharmacology
Description: Seventh edition. IPhiladelphia : Wolters Kluwer, [2020] IPreceded by Pharmacology I
Gary C. Rosenfeld, Davi; d S. Loose. 6th ed. 2014.
Identifiers: LCCN 2019013763 I ISBN 9781975105495
Subjects: IMESH: Pharmacological Phenomena I Pharmaceutical Preparations IExamination Question
Classification: LCC RM301.13 I NLM QV 18.2 I DDC 615.1076-dc23 LC record available at https://lccn.Ioc.

This work is provided •as is," and the publlsher disclaims any and all warranties, express or implied, including
any warranties as to accuracy, comprehensiveness, or currency of the content ofthis work.
This work is no substitute for individual patient assessment based upon healthcare professionals' examination
of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide
medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the
publisher, are solely responsible for the use of this work including all medical judgments and for any resulting
diagnosis and treatments.
Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment
options should be made and healthcare professionals should consult a variety of sources. When prescribing
medication, healthcare professionals are advised to consult the product information sheet (the manufacturer's
package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side
effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be
administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted
under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or
property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any
person of this work.


This concise review of medical pharmacology ill designed for health professions students, including
medical students, dental students, and those enrolled in physician asaistant or nurse practitioner
programs. It ill intended primarily to help students prepare for course examinations and licensing
examinations, including the United States Medical LicensJng Examl.Datlon (USMLE) Step 1. This book
presents condensed and succinct descriptions of relevant and current board-driven information pertaining to pharmacology without the usual associated details. It is not meant to be a substitute for the
comprehensive presentation of information and difficult concepts found in standard pharmacology


The seventh edition begins with a chapter devoted to the general principles of drug action, followed
by chapters concerned with drugs acting on the major body systems. Other chapters discuss anti.inflammatory and immunosuppreasive agents, drugs used to treat anemia and disorders ofhemosta11is, infectious diseases, cancer, and toxicology.
Each chapter includes a presentation of specific drugs with a discuasion of their general properties,
mechanism of action, pharmacologic effects, therapeutic uses, and adverse effects. A drug list, tables,
and figures summarize essential drug information included in all chapters.

Clinically oriented, USMLE-style review questions and answers with explanations follow each
chapter to help students assess their understand.IDg of the information. Similarly, a comprehensive
examination consisting ofUSMLE-style questions is included at the end of the book. This examination serves as a self-assessment tool to help students determine their fund of knowledge and diagnose
any weaknesses in pharmacology.


Updated with current drug information
End-of-chapter review tests feature updated USMLE-style questions
Several tables and figures summarize essential information for quick recall
Updated drug lists for each chapter
Additional USMLB-style comprehensive examination questiom and explanatiom

Sarah Lerchenfeldt, PharmD



I would like to extend my sincere thank& to Dr. Gary C. Rosenfeld and Dr. David S. Loose for writing
the first six editions of BRS Pharmacology. I would also like to thank the Wolters Kluwer staffand their
a880ciates for their contributions to this edition.



Preface v

Acknowledgments vi




I. Dose-Response Relationships 1
II. Pharmacokinetics and Pharmacodynamics 6
Ill. Drug Absorption 7
IV. Drug Distribution 10
V. Metabolism (Biotransformation) of Drugs 11
VI. Drug Elimination and Termination of Action 13
VII. Pharmacokinetic Principles 15
RaviawTall 19




I. 'Ihe Nervous System 24
II. 'Ihe Peripheral Efferent Nervous System 24
Ill. Parasympathomimetic Drugs 30
IV. Anticbolinergic Drugs 34
V. Sympathomimetic Drugs 40
VI. Adrenergic Receptor Antagonists 44
R1viawT111 48




I. Diuretics 55
II. Antidiuretic Drugs 60
R1vi1wT111 63




I. Antihypertensive Drugs 67
II. Agents Used to Treat Congestive Heart Failure 73
Ill. Antianginal Agents 76
IV. Anti.anhythmic Drugs 77
V. Drugs that Lower Plasma lipids 83
Review Tell 87






Sedative-Hypnotic Drugs 92
Antipsychotic (Neuroleptic) Drugs 96
Antidepressant Drugs 100
lithium (and Anticonvulsants Used to Treat Bipolar Disorder)
Drugs Used to Treat Parkinson Disease 106
Drugs Used to Treat Alzheimer Disease 109
Antiepileptic Drugs llO
General Anesthetics ll3
Local Anesthetics 117
Opioid Analgesics and Antagonists 119
Drugs of Abuse 123

Review Test





Histamine and Antihistamines 138
Serotonin Agonists and Antagonists 140
Ergot Alkaloids 141
Eicosanoids 142
Salicylates and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Drugs Used for Gout 147
Immunosuppressive Drugs 148

Raviaw Tast









I. Drugs Used in the Treatment of Anemia 158
II. Drugs Acting on Myeloid Cells 162
Ill. Drugs Used in Hemostatic Disorders 162
Raviaw Tast



I. Antiemetics


Drugs Used to Manage Obesity 179
Drugs Used to Increase Appetite 180
Agents Used for Upper GI Tract Disorders 180
Drugs Used to Dissolve Gallstones 183
Digestive Enzyme Replacements 183
Agents that Act on the Lower GI Tract 183









I. Introduction to Pulmonary Disorders 193
II. Agents Used to Treat Asthma and Other Bronchial Disorders 194
Ill. Drugs Used to Treat Rhinitis and Cough 199
Review Test 202




Hormone Receptors 205
Tue Hypothalamus 205
Tue Anterior Pituitary 209
Tue Posterior Pituitary 211
Drugs Acting on the Gonadal and Reproductive System 213
Tue Adrenal Cortex 219
Tue Thyroid 223
Tue Pancreas and Glucose Homeostasis 226
Tue Calcium Homeostatic System 232
Retinoic Acid and Derivatives 235

Review Test 238




Infectious Disease Therapy 241
Antibacterial Agents: Inhibitors of Bacterial Cell Wall Biosynthesis 242
Antibacterial Agents: Inhibitors ofBacterial Protein Synthesis 248
Antibacterial Agents: Inhibitors of DNA Synthesis and Integrity 252
Antibacterial Agents: Miscellaneous Drugs 254
Antimycobacterial Agents 254
Antifungal Agents 256
Antiparasitic Drugs 258
Antiviral Drugs 262
Antiretroviral Drugs 264

Review Test 269



Principles of Cancer Chemotherapy 274
Alkylating Agents 277
Antimetabolites 279
Microtubule Damaging Agents 281
Topoisomerase Inhibitors 282
Antitumor Antibiotics 283
Miscellaneous Antineoplastic Agents 284
Targeted Therapy 284
Corticosteroids 287
Hormone Therapy 287

Review Test 291





I. Principles and Terminology 296
II. Air Pollutants 298
Ill. Solvents 300
IV. Insecticides and Herbicides 301
V. Heavy Metal Poisoning and Management 302
VI. Drug Poisoning 305
Review Test 307

Camp18hensiv11 Examination 310
Index 331


Fundamental Principles of

A. Dnig dtctL Drug effects are produced by altering the normal functions of cells and tissues in the


body via oue of the four general mechanisms:
1. /ammo• wilt
1. Receptors are natunilly occurring target macromolecules that mediate the effects of endogenowi physiologic substances such as neurotransmitters or hormones.
II. Figure 1.1 illustrates the four major classes of drug- receptor interactions, uaing specific
examples of endogenous ligands.
(1) Lig1nd-actiV1ted ion chlnnels. Figure l.lA illwitrates acetylcholine interacting with a
nicotinic receptor that la a nonspecific Na+/.K+tranamembrane ion channel. Interaction
of a molecule of acetylcholine with each subunit of the channel produces a conformational change that permits the passage ohodium (Na~) and potassium (X•). Other channels that are targets for various drop include specific calcium (eas.) and K• channels.
(Z) G-protein-coupl1d r1c1ptors (Fig. l.lB-D). G-protein- coupled receptors compose the
largest class of receptors. All the receptors have seven tranamembrane segments, three
intracellular loops, and an intracellular carboxy-terminal tail. The biologic activity of
the receptors la mediated via interaction with a number of G (guanoslne triphosphate
binding) proteins.
(•) Ga.-caupled receptors. Figure 1.18 illustrates that a fJ-adrenoceptor, which when
activated by ligand binding (e.g., epinephrine), exchanges GDP for GTP. This facilitates the migration of Gu, (Ga..m...i.""') and its interaction with adenylyl cyclue (AC).
Ga.-bound AC catalyzes the production of cyclic AMP (cAMP} from adenosine
triphosphate (ATP}; cAMP activates protein kinase A, which subsequently acts to
phosphorylate and activate a number of effector proteins. The f:Jy dimer may also
activate some effectors. Hydrolyais of the guanosine triphosphate (GTP) bound to
the Ga to guanosine diphosphate (GDP) terminates the signal.
(II) Ga1 (Ga.,..111oy)-caupl1d rectptars (Fig. UC}. Ugand binding (e.g., somatostatin) to
G11i-coupled receptors similarly exchanges GTP for GDP, but G11t inhibits AC, leading to reduced cAMP production.
(c) G• (and G11 )-caupl•d rac1ptan {Fig. l.lD). G, (and G11) interact with ligand (e.g.,
serotonin)-activated receptors and Increase the activity of phoaphollpaae C (PLC).
PLC cleaves the membrane phospholipid phosphatidylinosl.tol 4,5-bisphosphate
(Pn>2) to diacylglyalrol (DAG} and inosllol l,4,5-triphosphate (lPJ. DAG activates
protein kinase C, which can subsequently phosphorylate and activate a number of
cellular proteins; D>s causes the release of ea>+ from the endoplasmic reticulum into
the cytoplasm, where it can activate many cellular proce&ae&
(3) R1c1pter-1ctiv1l8d tyrosin• kin1111 (Fig. l .lB). Many growth-related signals (e.g.,
insulin) are mediated via membrane receptors that possess intrinsic tyrosine kinase
activity as illustrated for the insulin receptor. IJgand binding causes conformational
changes in the receptor; some receptor tyrosine kinases are monomers that dlmerize



BRS Phannacology
upon ligand binding. The liguded receptors then autophosphorylate tyrosine residues,

which recruit cytoplasmic proteins to the plasma membrane where they are also tyro·
sine phosphorylated and activated.
(4) lntrac1llular nuclaar receptors (Fig. l.lF). lJgands (e.g., cortisol) for nuclear receptors
are llpophillc and can diffuse rapidly through the plasma membrane. In the absence
of ligand, nuclear receptors are inactive because of their interaction with chaperone
proteins such as heat-shock proteins like HSP-90. Bind.Ing ofligand promotes structural
changes in the receptor that facilitate dissociation ofchaperones, entry of receptors into
the nucleus, hetero- or homodimerization of re<:eptors, and high-affinity interaction
with the DNA of target genes. DNA-bound nuclear ret:eptors are able to recruit a diverse
number of proteins called coactivators, which subsequendy act to increase transcrip·
of the target gene.


ACh nlcotlnlc receptor
-Ion channel



p-adrenoreceptor coupled to Ga.


RP c.AMP -...PKA



Multiple cellular

Olher cellular




SomatDstatln receptor
coupled to G17;


Other cellular



RGUllE 1.1. Four major cluH• of drug-receptor interactions, with •pacific examples of endogenous ligands.
A. Acetylcholine interaction with a nicotinic receptor, a ligend·activeted ion channel. B-D. G·protei11-coupled receptor'$.
a. Epinephrine interaction with a Ga,,·coupled ~adrenoceptor. C. Somatostatin interaction with a Ga. {Ga.,u,..,,l·coupled
recepmr. D. Serotonin interaction with a G, (and G11l·coupled recepmr. E. Insulin interaction with a receptor-activated
tyrosine kinue. F. Cortisol intlraction with an intracellular nuclear receptor.


Fundamental Principles of Pharmacology


Serotonin receptor
caupled Gq




Insulin receptor-ectivaled tyrosine

kinase actlv1ty


Insulin receptor

y y







I \

Multiple cellular

FIGURE 1.1. fcontinued)

2. A""'1tios ofthe actirify of IBZJ1DNbyactivation or inhibition of the enzyme's catalytic activity.
3. Antimetabolill etiOB, in which the drug, acting as a nonfunctional analog of a naturally occurring metabolite, interferes with normal metabolism.
4. Noaapscilit: cb1111itel orpllysit:ll inllnlttiou, such as those caused byantacids, osmotic agents,
or chelators.
B. The graded dose-response curwe. The graded dose-response curve expressea an individual's
response to increasing doses of a given drug. The magnitude of a phannaoologic response ls
proportional to the number of receptors with which a drug effectively interact& (Fig. 1.2). The

graded dose-response curve includes the following parameters:
1. ltlagnilrnhJ l1f tupona is graded; it continuously increases with the dose up to the maximal
capacity of the system and is often depicted as a function of the logarithm of the dose administered (to see the relationship over a wide range of doses).


BRS Ph•rmacalalJJ
Cortisol activation ol
glucocortlcold receptor


Q Cortisol


t '


HSP90 ~

FIGURE U. (cantinued)

2. M1di1s 1tftlr:tin dOll (ED.J is the dose that produces the half-maximal response; the threshold dose is that which produces the first noticeable effect
1 lntrinlic 1cliritris the ability of a drug. once bound, to activate the receptor.
a. Agonists are drugs capable of binding to, and activating, a receptor.
(1) Full aganists occupy receptors to cause max1mal activation.
la) Intrinsic activity= 1
(Z) Partial aganists can occupy R!ceptors but cannot ellclt a maximal responae.
la) Intrinsic activity of <l (Fig. 1.3; drug C)
b. Antagonists bind to the receptor but do not initiate a response; they block the action of an
agonist or endogenous substance that works through the receptor.
(1) Competitive antagonists combine with the same site on the receptor but their binding
does not activate the receptor.

Intrinsic activity











Log (drug dose)

FIGURE 1.2. Graded dose-response


Drug A


FIGURE 1.3. Graded dose-response
curves for two agonists (A and Bl and
a partial agonist (C).


Fundamental Principles of Pharmacology
Drug B

ED 50 (B)

50 (A)

= ED50 (C)

Log (drug dose)

(a) Intrinsic activity= 0
(b) They may inhibit the actions of endogenous substances or other drugs.
(c) Competitive antagonists may be reversible or irreversible.
i. Reversible, or equilibrium, competitive antagonists are not covalently bound.
They shift the dose-response curve for the agonist to the right and increase the
ED 50, in which more agonist is required to elicit a response in the presence of the
antagonist (Fig. 1.4). Because higher doses of agonist can overcome the inhibition, the maximal response can still be obtained.
(2) Noncompetitive antagonists bind to the receptor at a site other than the agonist-binding
site (Fig. 1.5) and either prevent the agonist from binding correctly or prevent it from activating the receptor. Consequently, the effective amount of receptor is reduced. Receptors
unoccupied by antagonist retain the same affinity for agonist, and the ED 50 is unchanged.
4. Potency of a drug is the relative measure of the amount of a drug required to produce a specified level of response (e.g., 50%) compared with other drugs that produce the same effect via
the same receptor mechanism.
a. The potency of a drug is determined by the affinity of a drug for its receptor and the amount
of administered drug that reaches the receptor site.
b. The relative potency of a drug can be demonstrated by comparing the ED 50 values of two full
agonists; the drug with the lower ED 50 is more potent (e.g., in Fig. 1.3, drug A is more potent
than drug B).
5. The efficacy of a drug is the ability of a drug to elicit the pharmacologic response.
a. Efficacy may be affected by such factors as the number of drug-receptor complexes formed,
the ability of the drug to activate the receptor once it is bound (i.e., the drug's intrinsic activity), and the status of the target organ or cell.

Drug X alone

Drug X plus antagonist

Maximum response

EDso -

FIGURE 1.4. Graded dose-response
curves illustrating the effects of competitive antagonists.

Drug X dose (log scale)



BRS Phannacology


ED50 unchanged
FIGURE 1.5. Graded dose-response

Drug X dose (log Kale)

curves illustrating the effects of non·
competitive antagonists.

8.. Slop•V> measured at the mid-portion ohhe dose-response curve.
a. The slope varies for different drugs and different responses.
b. Steep dose-response curves indicate that a small change in dose produces a large change in
'J. V•ti•bilityretlect.B the differences between individuals in response to a given drug.
8.. 11IB18p•utit: i11d•x (Tl} relates the desired therapeudc effect to undesired toxicity; it ls deter·
mined using data provided by the quanta! dose-response curve.
a. The TI is defined as TDeo/EDao (i.e., the ratio of the dose that produces a toxic effect in halfof
the population to the dose that produces the desired effect in half of the population).
b. Note that the TI should be used with caution in instances when the quanta! dose-response
curves for the desired and toxic effect.Bare not parallel.
c. The therapeutic range (therapeutic window) ii> the serum concentration ofdrug required to
achieve therapeutic effects without toxicity.
(1) Serum concentrations for drugs with a narrow therapeutic range must be monitored
closely; small changes in dose or organ dysfunction may lead to therapeutic failure or

C. The quantal dose-response curYe
1. The quanta! dose-response curve (Fig. l.6AandB) relates the dosage of a drug to the frequency
with which a designated response will occur within a population.
a. The response may be an "all-or-none" phenomenon (e.g., individuals either do or do not fall
asleep after receiving a sedative) or a predetermined intensity ofetfect.
Z. It is obtained via transformation of the data used for a frequency distribution plot to reOect the
cumulative frequency of a response.
1. In the context of the quantal dose-response curve, ED50 indicates the dose of a drug that pro·
duces the response in half of the population. (Note that this differs from the meaning of Enso in
a graded dose-response curve.)
a. For example, in Figure l.6B, the ED611 would be 1. The TD00 for a drug would be determined
from the midpoint of a similar curve indicating the cumuladve percent of the population
showing a toxic response to a drug.

A. Phannacokinl1ics. Pharmacokinetics is conc:emed with the tfftct of the body on drugs, or the
movement of drugs throughout the body, including absorption, distribution, metabolism, and

B. Phannacadynamics. Pharmacodynamics is concerned with the affect of drugs an the body, including the physiologic and molecular effects.


Fundamental Principles of Pharmacology



34.0% 34.0%









Drug dos• (log scale)



FIGURE 1.&. A. Frequency distribution
plot. Number of individuals las percentage of the population) who require the
indicated drug dose to exhibit an identi·
cal response. As illustrated. 2.3% of the
population require 0.01 units ID exhibit
the retponse, 13.7% require 0.1 unitl,
end so on. B. Quental dose-response
curve. The cumulative number of individuals (as a percentage of the population) who will respond if the indicated
dose of drug is administered to ttle
entire population.






Drug dos• (log scale)


Drug absorption Is the movement of a drug from its site of adminiattation Into the bloodstream.
In many cases, a drug must be transported across one or more biologic membranes to reach the
A. Drug transport across membranes
1. Diffllsion of 1111iosized d11191 is the most common and most important mode ofttaversiDg biologic membranes.
a. Drugs diffuse passively down their concentration gradient
b. Diffusion can be influenced siguilicantly by the lipid-water partition cotfficient of the drug,
which is the ratio of solubility in an organic solvent to solubility in an aqueous solution.


In general, absorption increases as lipid solubility (partition

cotfficient) increases.

c. Other factors that can also 1Dfluence diffusion include the concentration gradient of the drug
across the cell membrane and the swface area of the cell membrane.
2. Dilfulion of dtup lll1t 111 w.ak •l•t:llofytn
a. Only the unionized form of a drug can diffuse to any significant degree across biologic


BRS Ph1nn1calagy
b. The degree of ionization of a weak acid or base is determined by the pK of the drug and pH of
its environment according to the Henderson-Hasselba lch equation.
(1) For a weak acid (A):
where HA is the concentration ofthe protonated, or unionized, form ofthe acid and A- is
the concentration of the ionized, or unprotonated, form.
(2) For a weak base (B):
BH+ pH++B,
log[B]/[BH+] = pH-pK
where BH+ is the concentration of the protonated form of the base and Bis the concentration of the unprotonated form.
c. When the pK of a drug equals the pH of the surroundings, 50% ionization occurs, in which
equal numbers of ionized and unionized species are present.
(1) A lower pK reflects a stronger acid.
(2) A higher pK corresponds to a stronger base.
d. Drugs with different pK values will diffuse across membranes at different rates.
e. The pH of the biologic fluid in which the drug is dissolved affects the degree of ionization
and, therefore, the rate of drug transport.
f. Ion trapping occurs when a drug that is a weak acid or weak base moves between fluid compartments with different pHs; for example, when an oral drug is absorbed from the stomach
(pH ofl-2) to plasma (pH of7.4).
(1) The drug will tend to accumulate in the fluid compartment in which it is most highly
(a) Weak acids tend to accumulate in the fluid with the higher pH.
(b) Weak bases tend to accumulate in the fluid with the lower pH.
3. Active transport is an energy-dependent process that can move drugs against a concentration
gradient through protein-mediated transport systems.
a. Active transport occurs in only one direction and is saturable.
b. It is usually the mode of transport for drugs that resemble actively transported endogenous
substances such as sugars, amino acids, and nucleosides.
c. Some transport systems increase drug transport and entry into cells to increase drug effects.
Others cause active efilux of drugs from target cells and decrease their activity.
4. Filtration is the bulk flow of solvent and solute through channels in the membrane.
a. It is seen with small molecules (usually with a molecular weight <100 Dalton [Da]) that can
pass through the channels (pores),
b. Some substances with a greater molecular weight, like certain proteins, can be filtered
through intercellular channels.
c. Concentration gradients affect the rate of filtration.
5. F1ci/iflltfld diffusion is movement of a substance down a concentration gradient.
a. It is carrier mediated, specific, and saturable; it does not require energy.

B. Routes of administration
1. Or11/ sdmini1tntion
a. Sites of absorption
t1) Stomach
(a) Lipid-soluble drugs and weak acids, which are normally unionized at the low pH of
gastric contents, may be absorbed directly from the stomach.
(b) Weak bases and strong acids (pK = 2-3) are not normally absorbed from this
site since they tend to exist as ions that carry either a positive or negative charge,

l!1[Jt1lll Fundamental Principles of Pharmacology


12) Small intestine
la) The small intestine is the primary site af absarptian of most drugs because of the
very large surface area across which drugs, including partially ionized weak acids
and bases, may diffuse.
lb) Acids are normally absorbed more extensively from the small intestine than from
the stomach, even though the intestine has a higher pH of 5-7.
b. The biaavailability of a drug is the fraction of drug (administered by any route) that
reaches the bloodstream unaltered (bioavailability = 1 for intravenous administration).
Bioequivalence refers to the condition in which the plasma concentrations versus time profiles of two drug formulations are identical.
11) The first-pass effect influences drug absorption by metabolism in the liver or by biliary secretion. After absorption from the stomach or small intestine, a drug must pass
through the liver before reaching the general circulation and its target site.
la) If the capacity ofliver metabolic enzymes to inactivate the drug is great, only limited
amounts of active drug will escape the process.
i. During the first pass, the liver metabolizes some drugs so extensively that it precludes their use.
12) Other factors that may alter absorption from the stomach or small intestine include the
(a) Gastric emptying time and passage of drug to the intestine may be influenced by
gastric contents and intestinal motility.
i. A decreased emptying time generally decreases the rate af absarptian
because the intestine is the major absorptive site for most orally administered drugs.
lbl Gastrointestinal (GI) blaad flaw plays an important role in drug absorption
by continuously maintaining the concentration gradient across epithelial
i. The absorption of small, very lipid-soluble molecules is "blood flow limited;'
whereas highly polar molecules are "blood flow independent."
le) Stomach acid and enzyme inactivation may destroy certain drugs. Enteric coating
prevents breakdown of tablets by the acidic pH of the stomach.
ldl Interactions with food, drugs, and other constituents of the gastric milieu may influence absorption.
(el Inert ingredients in oral preparations may alter absorption.
2. Patentenl administration includes three major routes: intravenous UVJ, intramuscular llM),
and subcutaneous ISC). Parenteral administration generally results in more predictable bioavailability than oral administration.
a. With IV administration, the drug is injected directly into the bloodstream (100% bioavailable). It represents the most rapid means of introducing drugs into the body and is particularly useful in the treatment of emergencies.
b. After IM and SC administration, many drugs can enter the capillaries directly through pores
between endothelial cells.
3. Other routes of administr1tion
a. Inhalation results in rapid absorption because of the large surface area and rich blood supply
of the alveoli.
11) It is frequently used for gaseous anesthetics and for other drugs that act on the airways,
such as the glucocorticoids used to treat bronchial asthma.
b. Sublingual administration is useful for drugs with high first-pass metabolism, since hepatic
metabolism is bypassed.
c. lntrathecal administration is useful for drugs that do not readily cross the blood-brain
d. Rectal administration minimizes first-pass metabolism. It may be useful when oral drugs
cannot be taken due to nausea and vomiting,
e. Topic aI administration is used widely when a local effect is desired or to minimize systemic
effects, especially in dermatology and ophthalmology.


BRS Phannacology

Drug distribution is the movement of a drug from the bloodstream to the various tissues of the body.

A. Distribution of drugs. Distribution of drugs is the process by which a drug leaves the bloodstream
and enters the exttacellular fiuids and tissues. A drug must diffuse across cellular membranes if
its site ofaction is intracellular. In this case, lipid solubility is important for effective distribution.

1. lmpoltfnt:• of blood flow
1. In most tissues, drugs can leave the circulation readily by diffusion across or between capil·
lary endothelial cells. Thus, the initial rate of distribution ofa drug depends heavily on blood
flow to various organs (brain, liver, kidney> muscle, skin > fat, bone).
b. At equilibrium, or stBedy state, the amount of drug in an organ ls related to the mass of the
organ and l.tB properties, as well as the properties of the specific drug.
2. Volum• ofdmnbulios (Vjla the volume of tatal body fluid into which a drug appears to dlatrlbute after It reaches equilibrium in the body. Volume of distribution la determined by administering a known dose of drug (expressed in units of mass) intravenously and measuring the
initial plasma concentration (expressed in units of mass/volume):
Vc1 = amount of drug admlnlstered (mg)/initial plasma concentration (mg/L)
Volume of distribution is egpressed in units of volume. In most cases, the initial plasma concentration, Ca. is determined by extrapolation from the elimination phase.
1. Standard valu• of volumes oftluid compartments in an average 70-kilogram (kg) adult are
as follows: plasma= 3 Liters (L); extracellular tluid = 12 L; and total body water= 41 L.
b. Features of volume of distribution.
(1) The use ofV.i values is primarily conceptual, in which dnags that distribute extensively
have relatively large nlues and vice versa.
{a) A low Vc1 value may indicate extensive plasma protein binding of the drug.
{b) A high V4 may indicate that the drug is extensively bound to tissue sites.
(2) Among other variables, V4 may be JnDuenced by age, sex, weight, and disease processes
(e.g., edema, ascites).
3. Drug tedidlibutio11 describes when the relative distribution of a drug in diJierent tissues or
tluid compartments of the body changes with time. This is usually seen with highly lipophllic
drugs, such as thiopental, that initially enter tissues with high blood tlow (e.g., the brain) and
then quickly redistribute to tissues with lower blood tlow (e.g., skeletal muscle and adipose
4. B•ni•ts to dlflll didliblllion
a. Blood-brain barrier
(1) Ionized or polar drugs distribute poorly ta the CNS, because they must pass through,
rather than between, endothelial cells.
(2) Inflammation, such as that resulting from meningitis, may increase the ability of ionized,
poorly soluble drugs to cross the blood-brain barrier.
(3) The blood-brain barrier may not be fully developed at the time of birth.
b. Placental barrier
(1) lipid-t0lubl1 dnags cross the placental barrier more easily than polar drugs.
(2) Drugs with a molecular weight of <600 Da pass the placental barrier more readily than
larger molecules.
(3) The possibility that drugs administered to the mother may cross the placenta and reach
the fetus is always an important consideration in therapy.


B. Binding of drugs by plesma proteins
1. Drugs in the plasma may e:idat in the free form or may be bound to plasma proteins or other
blood components, such as red blood cells.
plam• protlitt binding
1. The extent of plasma protein binding is highly Ylriable; depending on the drug, it may range
from 0% to more than 99% bound. Binding is generally reversible.



Fundamental Principles of Pharmacology


b. Only free drug is small enough to pass through the spaces between the endothelial cells that
form the capillaries; extensive binding slows the rate at which the drug reaches its site of
action and may prolong duration of action.
c. Some plasma proteins bind many different drugs, whereas other proteins bind only one or
a limited number. For example, urum albumin tends to bind many acidic drugs, whereas
exi,-acid gl.ycoprotein tends to bind many basic drugs.

A. General proper1i11
1. Most drugs undergo biotransformation, or metabolism, after they enter the body.
1. It almost always produces metabolites that are more polar than the parent drug. often tenninating the pharmacologic action and increasing removal of the drug from the body (via acretion).

b. Mataboli111 cany ionizable groups and are often more charged and more polar than the
parent compounds.
Thia increased charge may lead to a more rapid rate of clearance because of possible
secretion by acid or base carriers in the kidney; it may also lead to decreased tnbular
c. Possible consequences of biot:ran&formation include the production of the following:
11) Inactive malabolitas (most common)
121 Metabolites with increased or decreased potencies
(a) The active parent drugs may be metabolized to active metabolites.
(b) Prod rugs are inactive compounds that are metabolized to active drugs.
131 Metabolites with qualitatively different pharmacologic actions
141 Toxic metabolites
2. Many drugs undergo several sequential biotransformation reactions, which are catalyud by
specific enzyme sygtems.
3. The liYer i1 lh1 major site of metabolism, although specific drugs may undergo biotransfonnation in other tissues.
4. Drug metabolism can be affected by many parameters, including the following:
a. Drugs {drug-drug interactions} and diet (food-drug interactions)
b. Organ function and various disease state&
111 Dacraased liver function may lead to decreased metabolism of certain drugg.
121 Drug metabolism may decrease in cardiac and pulmonary disease.
c. Age and developmental status
111 Very young children and elderly indMduals may be more sensitive to drugg due to
undeveloped or decreased levels of drug-metabolizing enzymes.
121 Hormonal status and genetics may also affect drug metabolism.


B. Cl1aific1tion of biotranlfonnation reactions
1. l'h•se I (nossyntllelir:} TUr:lions involve enzyme-catalyzed biotransformation of the drugwithout any conjugations.

a. They often convert the parent drug to a more polar (water soluble} compound.



They frequently introduce a polar functional group, such as -OH, -SH, or -Nlli,
which serves as the active center for sequential conjugation in phase D reactions.
12) These include oxidalians, reductions, and hydrolysis raactions.
b. Although phase I products may be excreted. in many cases, they undergo phase II reactions.
c. Bnzymes catalyzing phase I include cytochrome P-450, aldehyde and alcohol dehydrogenase,
deaminasa, esterases, amidases, and epoxide hydratases.
Pbau 11 (qnrlumt:) tHt:U0/1$ include conjugation reactions, which involve the enzyme-catalyzed combination of a drug with an endogenous substance.
I. The polar functional group of phase I products is often combined with glucuronic acid
(glucuronidation), acetic acid (acetylation), or sulfuric acid (sulfation).
b. The final product is a highly polar conjugate that can be readily eliminated.


BRS Ph1nn1calagy
c. Enzymes catalyzing phase II biotransformation reactions include glucuronyl transferase
{glucuronide conjugation), sulfotransferase {sulfate conjugation), transacylases {amino
acid conjugation), acetylases, ethylases, methylases, and glutathione transferase.

C. Cytochrome P-450 monooxygenase (mixed function oxidase)
1. General features

a. Cytochrome P-450 monooxygenase plays a central role in drug biotransformation.
(1) This enzyme system is the one most frequently involved in phase I raactions.
(2) It catalyzes numerous reactions, including aromatic and aliphatic hydroxylations; dealkylation at nitrogen, sulfur, and oxygen atoms; heteroatom oxidations at nitrogen and
sulfur atoms; reductions at nitrogen atoms; and ester and amide hydrolysis.
b. There are many types of cytochrome P-450 {CYP) enzymes.
c. Each type catalyzes the biotransformation of a unique spectrum of drugs, although there
is some overlap with substrate specificities. The CYP families are referred to using Arabic
numerals {e.g., CYPl, CYP2, etc.).
(1) Each family has a number of subfamilies denoted by an upper case letter {e.g., CYP2A,
CYP2B, etc.).
(2) The individual enzymes within each subfamily are denoted by another Arabic numeral
{e.g., CYP3Al, CYP3A2, etc.).
d. The CYPZC, CYPZD, and CYP3A enzymes are responsible for the metabolism of most drugs.
(1) CYP3A4 is the most abundant hepatic enzyme and is involved in the metabolism of over
half of clinically important drugs.
2. The primary location of cytochrome P-450 is the liver, although significant levels are also found
in the small and large intestine.
a. P-450 activity is also found in many other tissues, including the adrenals, ovaries and testis,
and tissues involved in steroidogenesis and steroid metabolism.
b. The enzyme's subcellular location is the endoplasmic reticulum.
c. Lipid membrane location facilitates the metabolism oflipid-soluble drugs.

3. Mechanism of reaction

a. In the overall reaction, the drug is oxidized and oxygen is reduced to water.
b. Reducing equivalents are provided by nicotinamide adenine dinucleotide phosphate
(NADPH), and generation of this cofactor is coupled to cytochrome P-450 reductasa.
c. The overall reaction for aromatic hydroxylation can be described as
Drug+ 0 2 + NADPH + H• -+ Drug - OH+ NADP• + H20

4. Genetic polymorphism of several clinically important cytochrome P-450s, particularly CYP2C
and CYP2D, is a source of variable metabolism in humans, including differences among racial
and ethnic groups. These enzymes have substantially different properties (Vma or K.i,).

5. Induction
a. Enzyme induction may occur due to drugs and endogenous substances, such as hormones;
they can preferentially induce one or more forms of CYP-450.

b. When caused by drugs, induction is pharmacologically important as a major source of drug
interactions. A drug may induce its own metabolism (metabolic tolerance) or that ofother drugs.
(1) Induction can be caused by a wide variety of drugs, such as quinidine, phenytoin, phenobarbital, rifampin, and cartJamazepine.
(2) Environmental agents, such as tobacco smoke, may also induce CYP-450 enzymes.
c. Some of the same drugs that induce CYP3A4 can induce the drug efflux transporter
P-glycoprotein, such as rifampin and St John's wort
&. Inhibition

a. Competitive or noncompetitive {clinically more likely) inhibition of P-450 enzyme activity can result in the reduced metabolism of other drugs or endogenous substrates, such as
b. Enzyme inhibition is a maior source of drug-drug interactions. It is caused by a number
of commonly used drugs, including cimetidine, fluconazole, fluoxetine, and erythromycin.
Environmental or dietary agents (e.g., grapefruit juice) can also cause enzyme inhibition.
c. Some of the same drugs that inhibit CYP3A4 can inhibit the drug efflux transporter
P-glycoprotein, including amiodarone, clarithromycin, erythromycin, and ketoconazole.


Fundamental Principles of Pharmacology


D. Glucuranyl transfara•
1. General features
a. Glucuronyl transferase is a set of enzymes with unique, but overlapping, spedflcities that are
involved in phaM II reaction•.
b. It catalyzes the conjugation of gluCW'Onic acid to a variety of active centers, including
-OH,-COOH,-SH, and-NHi.
Z. Location and induction
a. Glucuronyl transferase is located in the endoplasmic reliculwn.
b. It is the only phase Il reaction that is inducible by dnigs and is a possible site of drug

E. Hepatic extraction of drugs
1. General extraction by the liver occws because of the liver's large size (1,500 g) and high blood
flow (1 mL/g/mln).
Z. The extraction ratio is the amount of drug removed in the liver dMded bythe amount of drug
entering the organ; a drug completely extracted by the liver would have an extraction ratio ofl.
Highly extracted drugs can have a hepatic clearance approaching 1,500 ml/min.
3. Fim-p111 effect. Drugs taken orally pass across membranes of the GI tract into the portal vein
and through the liver before entering the general circulation.
a. Bioavailability of orally administered drugs is decreased by the fraction of drug removed by
the first pass through the liver. For example, a drug with a hepatic extraction ratio of 1 would
have 0% bioavailabillty; a drug such as lldocaine, with an extraction ratio of 0.7, would have
30% bioavailabWty.
b. In the presence ofhepatic disease, drugs with a high first-pass extraction may reach the systemic circulation in higher than normal amounts, and dose adjustment may be required.

A. Mechani•m• of drug elimination and tenninatian of action
1. In most cases, the action of a drug is terminated by enzyme-catalyzed conversion to an inactive
(or less active) compound and/or elimination from the body via the kidney or other routes.
2. Redistribution of drugs from the site of action may umninate the action of a drug, although this
occurs infrequently. For example, the action of the anesthetic thiop1ntal Is umnlnated largely
by lb redistribudon from the brain (where it Initially accumulates as a result of lb high Upid
solubility and the h1gh blood flow to that orpn) to the more poorly perfused adipose tissue.

B. Routn of excretion
1. Routes of excretion may include urine, feces (e.g., unabsorbed drugs and drugs secreted in
bile), saliva, sweat, tears, milk(with possible ttansrerto neonates), and lungs (e.g., alcohols and
2. Any route may be important for a given drug, but the kidney is 1he maior site of excretion for
most drugs.
3. Some drugs are secreted by liver cells into the bile, pass into the intestine, and are eliminated
in the feces (e.g., rifampin, indomethacin, estradiol).
4. Some drugs undergo enterah1patic circulation (reabsorbed from the intestine); in this case,
the drug effect may be prolonged.

C. General principles for drug clearance (CL)
1. Conceptually, clearance is a measure of the capacity of the body to remove a drug.

Z. Mathematically, clearance is the proportionality constant that relates the rate of drug elimination to the plasma concenttation of the drug.
The units of clearance are volume/time.
b. Drugs with high clearance are rapidly removed from the body.
c. Drugs with low clearance are removed slowly from the body.



BRS Ph1nn1calagy

3. Specific organ clearance is the capacity of an individual organ to eliminate a drug. It may be
due to metabolism (e.g., hepatic clearance by the liver) or excretion (e.g., renal clearance by
elimination in the urine).
Rate of elimination by organ= CL- x [Drug]plum•~or
CL.,,.,.= Rate of elimination by organ/[Drug]plum•porl\QinM-

4. Whal• body clsar1nc1 is the capacity of the body to eliminate the drug by all mechanisms.
Therefore, whole body clearance is equal to the sum of all of the specific organ clearance
mechanisms by which the active drug is eliminated from the body:

er........ body= c1_. + c1_ 2+ ci._N
The term "clearance" generally refers to whole body clearance unless otherwise specified. In
this case,
Rate of elimination from body = CI....mo.. body x [Drug] p1uma
CL= Rate of elimination from body/[Drug]p1uma

5. Plasma clearance is numerically the same as whole body clearance, but this terminology is
sometimes used because clearance may be viewed as the volume of plasma that contains the
amount of drug removed per unit time (recall that the units of clearance are volume/time).
a. If not specified, this term refers to the volume of plasma "cleared" of drug by all bodily mechanisms (i.e., whole body clearance).
b. The term may also be applied to clearance by specific organs; for example, renal plasma
clearance is the volume of plasma containing the amount of drug eliminated in the urine
per unit time.

D. Net renal excretion of drugs
1. Net renal excretion of drugs is the result of three separate processes: (1) the amount of drug
filtered at the glomerulus, (2) plus the amount of drug secreted by active transport mechanisms
in the kidney (3) minus the amount of drug passively reabsorbed throughout the tubule.

a. Filtration
(1) Most drugs have low molecular weights and are freely filtered from the plasma at the
(2) Serum protein binding reduces filtration since plasma proteins are too large to be filtered.
(3) Compared to adults, the glomerular filtration rate (GFR) is 30%-40% lower during a
child's first year of life.
b. Secretion
(1) The kidney proximal tubule contains two transpon systems that may secrete drugs into
the ultrafiltrate, one for organic acids (organic acid transporters or OATs) and a second
for organic bases (organic base transporters or OBTs).
(a) There are multiple OATs and OBTs with specificities for different organic molecules
in the tubule.
lb) They require energy for active transpan against a concentration gradient.
(c) They are also a site for potential drug-drug interactions; drugs may compete with
each other for binding to the transporters.
(Z) Plasma protein binding does not normally have a large effect on secretion because the
affinity of the transport systems for most drugs is greater than the affinity of plasmabinding proteins.
c. Reabsorption
(1) Reabsorption may occur throughout the tubule; some compounds, including endogenous compounds such as glucose, are actively reabsorbed.
(Z) Reabsorption of the unionized fann of drugs that are weak acids and bases can occur by
simple passive diffusion, the rate of which depends on the lipid solubility and pK of the
drug, as well as the concentration gradient ofthe drug between the urine and the plasma.


Fundamental Principles of Pharmacology


(3) Reabsorption may be affected by alterations of urinary pH, which affects elimination of
weak acids or bases by altering their ionization (ie., ion trapping).
{a) For example, alkallnlzation of the wine will result in a higher proportion of the Ionized form of an acidic drug that will decrease its reabsorption and hence Increase
its elimination.
2. Re11•I r:le.rance ofd111gs
a. Renal clearance measures the volume of plasma that is cleared ofdrug per unit time:
CL(mL/min) =U x V/P
where Uis the concentration of drug per mllllliter of urine, Vthe wolume of the urine ezcreted
per minute, and P the concentration of drug per milliliter of plasma.
(1) A drug excreted byfiltndion alone will h8ve a clearance equal to the GFR (125-130 mIJmin).
(2) A drug excreted by filtration and complete 11cretion will have a clearance equal to renal
plasma clearance (650 mL/min).
(3) Clearance values between 130 and 650 mL/min suggest that a drug is filtered, secreted,

and partially reabsorbed.
b. A variety offactors influence renal clearance, including age, other drugs, and disease.
c. In the presence of renal failure, the clearance of a drug may be reduced slgntflcantly, resulting in higher plasma levels (dose reductions may be required).

A. General ph1nnacokinatic principl"
1. Pharmacokineti.cs describes changes in plasma drug concentration over time.
2. Although it is ideal to determine the amount ofdrug that reaches its site of action as a function
of time after administration, it is usually impractical or not feasible.
a. The plasma drug concentration ls measured since the amount of drug in the tissues is generally related to plasma concentration.

B. Distribution and elimination
1. 011•-campaltm•11t nrad•/(Fjg.1.7)
a. The drug appears to distribute Instantaneously after IV administration of a single dose. 1f
the mechanisms for drug elimination, such as biotransfonnatl.on by hepatic enzymes and

renal secretion, are not saturated. following the therapeutic dose, a semilog plot of plasma
concentration versus time will be linear.



Slope =-k



RCURE 1.7. Ona·cCJmpartmant model of
drug diltriblltion.



BRS Ph1nn1calagy

b. Drug elimination is first order, in which a constant friction of drug is eliminated per unit

(1) For example, one-half (50%) of the drug is eliminated every 8 hours.
(2) Elimination of most drugs is a first-order process.

c. The slope of the semilog plot is -k, where k is Iha rite constant of elimination and has units
of time and the intercept on the y axis is C0 • (Note: C0 is used to calculate Vd for drugs that
obey a one-compartment model.)
d. The plasma drug concentration (Ci) relative ta the initial concentration (C.,) at any time (t)
after administration is given by
ln4=lnC0 -kt
and the relationship of the plasma concentr1tions at any two points in time is given by

In Ca= In C1 - k (ta - t1)

2. Two-compartment model (Fig. 1.8)
a. The two-compartment model is a more common model for distribution and elimination of drugs.
b. Initial rapid decreases in lhe plasma concentration of a drug are observed because of a
distribution phase, which is the time required for the drug to reach an equilibrium distribution between a central compartment, such as the plasma space, and a second compartment,
such as the aggregate tissues and fluids to which the drug distributes.
(1) During this phase, plasma drug concentrations decrease very rapidly because the drug
is being eliminated from the body (e.g., by metabolism and renal elimination), as well
as exiting the plasma space as it distributes to other tissues and fluid compartments.
c. After distribution, a linear decrease in the log drug concentration is observed ifthe elimination phase is first order. The curve is less steep in this phase because there is no longer
a net decrease in plasma levels of drug due to distribution to the tissues (which has been
d. For drugs that obey a two-compartment model, the value of C0 obtained by extrapolation of
the elimination phase is used to calculate Vc11 and the elimination rate constant, k, is obtained
from the slope of the elimination phase.
a. The expressions for In Ct and clearance (CL) shown above for a one-compartment model also
apply during the elimination phase for drugs that obey a two-compartment model.

3. Fint-onlsr elimin•tion
a. The elimination of most drugs at therapeutic doses is first order, where a constant fraction
of drug is eliminated per unit time.
(1) It occurs when the drug does not saturate elimination systems.
(2) The rate of elimination is a linear function of the plasma drug concentration.


FIGURE 1.8. Two-compartment model of drug

l!1[Jt1lll Fundamental Principles of Pharmacology


b. The rate of elimination depends on the concentration of drug in the plasma and is equal to
the plasma concentration of the drug multiplied by a proportionality constant:
Rate of elimination from body(mass/time) =Constant x [Drug]p1uma(mass/vol)
Because the rate of elimination is given in units of mass/time and concentration is in units
of mass/volume, the units of the constant are volume/time. This constant is referred to as
the clearance of the drug.

4. Zero-an/et eliminstian
a. Zaro-order elimination occurs when a constant amount of the drug is eliminated per unit
time; it does not depend on plasma concentration.
(1) It may occur when therapeutic doses of drugs axcaed the capacity of elimination
mechanisms (the mechanism by which the body eliminates the drug, such as hepatic
metabolism or kidney secretion, is saturated).
b. In this model, the plot of the log of the plasma concentration versus time will decrease in a
concave upward manner (e.g., 10 mg of drugwill be eliminated every 8 h). (Note that after
an interval of time sufficient to reduce the drug level below the saturation point, first-order
elimination occurs.)
c. Examples of drugs removed by zero-order kinetics include phenytoin and ethanol.

C. Half-life (t,11)
1. Half-life is the time it takes for the plasma drug concentration to be reduced by 50%. This concept only applies to drugs eliminated by tint-order kinetics.
2. Half-life is determined by the following:
a. Log plasma drug concentration versus time profile for drugs fitting a one-compartment
b. Elimination phase for drugs fitting the two-compartment model.
c. If the dose administered does not exceed the capacity of the elimination systems {i.e., the
dose does not saturate those systems), the half-life will remain constant
3. The half-life is related to the elimination rate constant (k) by the equation t,11 0.693/k (i.e., for
a steep decrease in concentration, k is high; therefore, t112 is short).
4. It is related to the volume of distribution (V,J and clearance (CL) bythe equation t112 = 0.693 VjCL.
a. This relationship emphasizes that drugs that are widely distributed in the body {i.e., a high V.i)
will take longer to be eliminated and drugs for which the body has a high capacity to remove
(i.e., a high CL) will take a short time to be eliminated.
5. In most cases, over 95% of the drugwill be eliminated in a time interval equal to five half-lives;
this applies for therapeutic doses of most drugs.


D. Multidose kinetics
1. Infusion and multidose repest sdministntian
a. If a drug is given by continuous IV infusion at a constant dose rate and elimination is first
order, it will eventually reach a constant steady-state plasma concentration.
(1) The steady-state concentration occurs when the rate of elimination is equal to the rate

of administration.
b. If a drug that is eliminated by first-order kinetics is administered repeatedly (e.g., one tablet
or injection every 8 h), the average plasma concentration of the drug will increase until a
mean steady-state level is reached.
(1) This will not occur for drugs that exhibit zero-order elimination.
c. The time required to reach steady state is equal to five half-lives regardless of whether
administration is via continuous infusion or repeated administration.
(1) Whenever a dose rate is changed, it will take five half-lives for a new steady-state level to
be reached for any route of administration.

2. Stesdy state after repest administntion
a. Some tluctuation in plasma concentration will occur even at steady state.
b. Levels will be at the high point of the steady-state range shortly after a dose is administered;
levels will be at the low point immediately before administration of the next dose. Hence,
steady state designates an average plasma concentration and the range of fluctuations
above and below that level.


BRS Ph1nn1calagy
c. The magnitude offluctuations can be controlled by the dosing interval.
(1) A shorter dosing interval decreases fluctuations, and a longer dosing interval increases
d. On cessation of multidose administration, over 95% of the drug will be eliminated in a time
interval equal to five half-lives if first-order kinetics applies.
3. M11inten11nce dose 111te
a. The maintenance dose rate is the dose ofa drug required per unit time to maintain a desired
staady-state level in the plasma to sustain a specific therapeutic effect
b. To determine the dose rate required to maintain an average steady-state plasma concentration of drug, multiply the desired plasma concentration by the CL:
Maintenance dose rate= Desired [drug]p1uma x Clearance (CL)
(amount/time) =(amount/ volume) x (volume/time)
This yields dose rate in units of amount per time (e.g., mg/h).
(1) To remain at steady state, the dose rate must equal the elimination rate.
(a) The rate at which the drug is added to the body must equal the rate at which it is
(2) The elimination rate= CL x [Drug]plumai therefore, because the dose rate must equal
the elimination rate to be at steady state, dose rate also equals CL x Desired [drug]p1uma.
c. If the drug is administered at the maintenance dose rate, a steady-state plasma concentration
will be reached in four to five half-lives. (Note: This is four to five half-lives, not four to five
4. Lo11ding dose
a. For certain drugs, an initial loading dose may be given to achieve rapid levels and earlier therapeutic effects; this may be useful in potentially life-threatening situations, such as a severe
infection (e.g., aminoglycosides, vancomycin) or pulmonary embolism (e.g., heparin).
b. To calculate the loading dose, the desired plasma concentration of drug can be multiplied
Loading dose= Desired [drug] 1uma x V4
c. After administration of the loading dose (which rapidly achieves the desired plasma concentration of drug), the drug is administered at the maintenance dose rate to maintain the drug
concentration at the desired steady-state level.

Review Test

Dirutians: Select the beat answer for each question.

1. Somatostatin interacts with which of the
following receptors?


G1-protein- coupled receptor
G,-protein- coupled receptor
Intracellular nuclear receptor
Ligand-activated ion channel
(E) Receptor-activated tyrosine kinaee

2. What characteristic gives cortisol the ability
to target intranuclear receptors?
(Al Dlft'uae through lipid membranes
(Bl Interact with adenylyl cyclase
(C) Interact with G-proteln-coupled receptors
(DI Recruit intracellular ldnases
(E) Undergo autophoaphorylation

3. A 66-year-old man is admitted to the ho1pi-

(Cl Destruction of drug by stomach acid
(DI Increased first-pass effect
(El Increased protein binding of the drug
5. An 82-year-old woman ls admitted to the
hoapital for management of a heart failure exacerbatloo. She baa peripheral edema and aaclte&
due to the exacerbation. Further evaluadon
also reveals a urinary tract infection requiring
antibiotic treatment Due to her history of heart
failure, change& in what phannacodynamic
parameter should be considered prior to choosing the most appropriate antibiotic dose?


Impaired blood flow to the inteatlne

(Bl Increased protein binding ofvarlous


Increased volume of di.sttibution
ID) Increased drug elimination

tal with confusion, nausea, and blurred vision.
He is currendy on digoDn for the treatment of
heart failure. On phyaical eum, hie heart mte is
120 bpm. Further evaluation reveals a cligoxin

6. Which of the following term& is used to

level of5.3 ng/mL {normal amge: 0.5-2 og/m.L).
The doctor belleve1 hia symptom& are due to
d1goxio toxicity. Which parameter la uaed to
indicate the ability of digoDn to produce the
deaired effect relative to a toxic effect?




(Bl Bllicacy


Intriruiic activity
(E) Therapeutic indez


4. A 64-year-old woman pre1ents to the
emergency room with aevere abdominal pain
and feculent emeaia. She ha& a history of
multJple abdominal surgeries due to Crohn
disease. Further evaluation reveals a small
bowel obstruction. A few hours later, she
undergoes aurgery for lysis of adhesions and
resection of the small bowel. Why should the
use ofoml medications be avoided in this
patie nt?

(Al Decreaaed paaaage of drug through

(Bl Decreased gutrointestinal blood flow

describe the elimination rate via metabolism
catalyzed by alcohol dehyd.Iogenue when the
enzyme is saturated?
(Cl First-order elimination
IDI Redistribudon
IEI Zero-order .kinetics

1. Which of the following statements are true in
regard to glucuronidation reactions?
(Al Conaidered phase I reactiona
IBI Include the enzymatic activity of alcohol
IC) Require an active center aa the aite of
ID) Require nlcotinamide adenine dinucleotide phosphate

l A 38-year-old woman presents to herJ>6Y·
chiatrist for the m.aDllgertleot of depre11ion.
She feels that her current treatment is ineffec.
tive and would like to switch medications. The
patient rewala that ahe drinb alcohol every
night to relieve her feelings of sadness and
guilt. mood work Ja positive for elevated liver



BRS Ph1nn1calagy

enzymes. The doctor starts imipramine, which
has an extensive first-pass metabolism. How
would this drug be affected?


Decreased half-life
Decreased absorption
Decreased solubility
Increased concentration
Increased pH

9. A 24-year-old female is prescribed erythromycin for gastroparesis. It is prescribed four
times daily due to its short half-life. What is the
rationale for such a frequent dosing?

tA) Achieve the steady-state plasma concentration of the drug
tB) Aid more complete distribution of the drug
tC) Avoid the toxicity of the drug because of its
low therapeutic index
tD) Ensure that the drug concentration
remains constant over time
tE) Inhibit the first-pass metabolism of the

10. A 78-year-old woman is started on digoxin
for the management of congestive heart failure.
Her initial dose is 0.25 mg. The C.,, obtained by
extrapolation of the elimination phase, is determined to be 0.05 mg/L. What is the patient's
estimated volume of distribution?
tA) 0.0125 L
tB) 0.2 L
tC) 0.5 L
tD) 1 L
tE) 5 L

11. A drug has a volume of distribution of
50 L. At plasma concentrations over 2 mg/L, it
undergoes zero-order elimination at a rate of
2 mg/h. If a patient is brought to the emergency
room with a plasma concentration of 4 mg/L of
the drug, how long will it take (in hours) for the
plasma concentration to decrease by 50%?



12. A 100-mg tablet of drug Xis given to a
patient every 24 hours to achieve an average
steady-state plasma concentration of 10 mg/L.
If the dosing regimen is changed to one 50 mg
tablet every 12 hours, what will be the resulting
average plasma concentration (in mg/L) of the
drug after five half-lives?




13. A 35-year-old woman is started on ceftriaxone as empiric therapy for meningitis. Following
intravenous administration, the initial rates of
drug distribution to different tissues depend
primarily on which of the following parameters?
tA) Active transport of the drug out of different
cell types
tB) Blood flow to the tissues
tC) Degree ofionization of the drug in the
tD) Fat content of the tissues
tE) Specific organ clearances

14. A drug is administered in the form of an
inactive prodrug. The prodrug increases the
expression of a cytochrome P-450, which converts it to its active form. With chronic, longterm administration of the prodrug, which of
the following will be observed?

Efficacy will decrease
Efficacy will increase
Potency will decrease
Potency will increase

15. Which subfamily of cytochrome P-450s is
responsible for the highest fraction of clinically
important drug interactions resulting from
16. If the oral dosing rate of a drug is held
constant. what will occur if the bioavailability is
tA) Decreased first-order elimination rate
tB) Decreased total body clearance
tC) Increased half-life for first-order
tD) Increased steady-state plasma
tE) Increased volume of distribution
17. A 45-year-old man is given an oral maintenance dose of drug calculated to achieve a
steady-state plasma concentration of 5 mcg/L.

l!1[Jt1lll Fundamental Principles of Pharmacology
After dosing the patient for a sufficient amount
of time to reach steady state, the average
plasma concentration of drug is I 0 mcg/L. A
decrease in which of the following parameters
may explain the higher than anticipated plasma
drug concentration?


Volume of distribution

(A) Half-life of the drug

(Bl Rate ofrenal secretion
(Cl Receptor affinity for the drug
(DI Therapeutic index of the drug
noncompetitive antagonist?








What is the half-life (in h) of drug X?

(E) 9

19. Which of the following factors will determine the number of drug-receptor complexes

20. Which of the following is an action of a

18. Administration of an intravenous loading dose of drug X yields an initial plasma
concentration of 100 mcg/L. The table below
illustrates the plasma concentration of drug X
as a function of time after the initial loading

(Al 1
(Bl 2
(Cl 4
(DI s


(A) Alters the mechanism of action of an agonist
(Bl Alters the potency of an agonist
(Cl Binds to the same site on the receptor as
the agonist
(DI Decreases the maximum response to an
(E) Shifts the dose-response curve of an agonist to the right

21. The renal clearance ofa drug is 10 mL/min.
The drug has a low molecular weight and is 20%
bound to plasma proteins. It is most likely that
renal excretion of this drug involves which of
the following mechanisms?

(Al Active tubular secretion only
(Bl Glomerular filtration only
(Cl Glomerular filtration and active tubular

(DI Glomerular filtration and passive tubular
(E) Passive tubular reabsorption only

Answers and Explanations
1. Tha answer is A. Somatostatln binds to a Gi-coupled protein receptor, initiating exchange of
GTP for GDP, which inhibits AC and leads to reduced cAMP production. The G.-protein-coupled receptor is an example of the PLC pathway, in which interaction with the ligand leads to
increased PLC activity and eventual activation of protein ldn.ase C via the PIP2 and IP3 pathway.
This is exemplified by interaction ofepinephrine with its receptor. The ligand-activated ion
channel is an example of interaction of specific ligand with an ion channel, which permits passage of ions through the channel. Aretylcholine is an eDIDple ofsuch an interaction. Receptoractivated tyrosine kinase is exemplified by insulin, where binding of ligand activates specific
tyrosine kinase, leading to a cascade of reactions within the cell. Finally, an intracellular nuclear
receptor is eemplified by cortisol, which binds to it and exerts its effects on DNA replication.

2. Th1 answ1r is A. The ability to target intracellular receptors depends on the ligand's ability to
crou lipid barriers, such as the nuclear envelope. Recruitment of intracellular kinase5 is characterized by some receptor-activated tyrosine kinases. Autophosphorylation is a feature of many
different kinases. Interactions with G-protein and AC are characteristics of membrane receptors.

3. Tha answer is E. DigOJdn is an example of a drug with a very low therapeutic index (TI), which
requires frequent monitoring of the plasma level to achieve the balance between the desired
effect and untoward toxicity. Potency of the drug is the amount of drug needed to produce a
given response. Intrinsic activity of the drug is the ability to elicit a response. Efficacy of the
drug is the maximal drug ~t that can be achieved in a patient under a given set of conditions.
Bioavailability of the drug is the fraction of the drug that reaches the bloodstream unaltered.

4. The answer is A. Adequate passage ofdrug through the small intestine is required to observe
the effects of the drug, because most of the absorption takes place in the small intestine. After
extensive abdominal surgery, especlally that involving a resection of a portion ofsmall bowel, the
passage may be slowed, or even stopped, for a period of time. Abdominal surgery rarely results in
reduced blood ftow to the intestine, nor does such an operation influence protein binding. or the
first-paRS effect Destruction of drug by stomach acid does not depend on intra-abdominal surgery.

5. The an1w1r is C. Because of the patient's edema and ascites from heart failure, the apparent volwne of distribution will be increased, which may require small adjustments in the usual medication doses. Edematous states do not inluence gastrointestinal CGn blood Dow, nor do they affect
drug-protein interactions. Drug elimination may be slowed with a congestive heart failure {CHF)
exacerbation, not increased. Drug kinetics are generally not changed by edematous states.

8. The answar is E. Alwhol (ethanol) is one of the few drugs that follow 7.ero-order kinetics (ie., higher
drug concentrations are not metabolir.ed because the enzyme that is involved in the process is saturable). In first-order elimination, the rate of elimination actually depends on the concentration of the
drug, multiplied by the proportionality constant Clearance is a measure of the capacity of the body
to remove the drug. Biotransformati.on refers to the general mechanism of a particular drug's elimination. Redistribution is one ofthe possible fates of a drug, which usually temrlnates drug action.

7. Tha answer is C. Glucuronidation reactions, which are considered phase II reactions, require an
active center (a functional group) as the site of conjugation. Phase I reactions are biotransformation reactions, not conjugation reactions. Alcohol dehydrogenase is an example of a phase
I reaction. Nicotinamide adenine dinucleotide phosphate (NADPH) is required for aromatic
hydroxylation, an example of a phase I reaction.

8. The answer is D. First-pass metabolism. simplymeans passage through the portal circulation before
reaching the systemic circulation. In the face of liver dysfunction, drug levels may reach lllgher concentrations. Bioavailability of drugs is decreased, not increased, by the fraction removed aftEr the first
pass through the liver. Drugs are usually less rapidlymetaboli7.ed when hepatic enzymes are elevated
(which indicates hepatic dysfunction). Solubility ofdrugs is not associated with hepatic damage.

l!1[Jt1lll Fundamental Principles of Pharmacology


9. The answer is A. Dosing schedules of drugs are adjusted according to their half-lives to achieve
steady-state plasma concentration. Attempting to avoid the toxicity of the drug because of its
low therapeutic index (TI) represents an unlikely scenario; since to reduce toxicity of a drug with
a low TI, one would reduce the dosing schedule, not increase it Distribution of the drug is generally not affected by dosing schedule, nor is dose scheduling affected by first-pass metabolism.
Some tluctuation in plasma concentration occurs even at steady state; it is the average concentration over time that is the goal of steady state.

10. The answer is E. To calculate the volume of distribution, use the formula in which the dose of
the drug is divided by the plasma concentration. In this case, 0.25 mg is divided by 0.05 mg/L,
giving the result of 5 L for volume of distribution.

11. The answer is E. For the plasma concentration of drug to decrease by 50%, half the drug present
in the body initially must be eliminated. The amount of drug in the body initially is the volume of
distribution x the plasma concentration (50 L x 4 mg/L = 200 mg). When the plasma concentration
falls to 2 mg/L, the body will contain 100 mg of drug (50 L x 2 mg/L = 100 mg). Since the body eliminates the drug at a rate of 2 mg/h, it will require 50 hours for l 00 mg of the drug to be eliminated.

12. The answer is C. A 100-mg tablet every 24 hours is a dose rate of 4.17 mg/h {100/24 = 4.17),
which is the same dose rate as one 50-mg tablet every 12 hours (50/12 = 4.17). Thus, the average
plasma concentration will remain the same, but decreasing both the dose and the dose interval
will decrease the peak to trough variation of plasma concentration.

13. The answer is B. The initial rate of distribution of a drug to a tissue depends primarily on the rate of
blood tlow to that tissue. At longer times, however, a drug may undergo redistribution among various
tissues, for example, a very lipophilic drug may become concentrated in adipose tissue with time.

14. The answer is D. The induction of the cytochrome P-450 following chronic administration
will increase the conversion of the inactive prodrug to its active form. This will shift the doseresponse curve of the pro drug to the left (i.e., increase its potency) without changing its efficacy.

15. The answer is C. The CYP3A subfamily is responsible for roughly 50% of the total cytochrome
P-450 activity present in the liver and is estimated to be responsible for approximately half of all
clinically important untoward drug interactions resulting from metabolism.

16. The answer is D. If the oral dosing rate is constant but the bioavailability increases, the fraction
of the administered dose that reaches the general circulation unaltered increases. This, in turn,
will increase the steady-state plasma concentration.

17. The answer is B. Steady-state plasma concentration of drug= (dose rate)/(clearance). Thus, a
decrease in clearance will increase the plasma drug concentration, whereas an increase in any of
the other three parameters will decrease the steady-state plasma concentration.

18. The answer is C. Inspection of the plasma concentration values indicates that the half-life of
drug does not become constant until 1-9 hours after administration. The drug concentration
decreases by half (from 50 to 25 mcg/L) between l and 5 hours (a 4-hour interval) and again
decreases byhalf(from25 to 12.5 mcg/L) between 5 and 9 hours (again, a 4-hour interval). This
indicates the half-life of the drug is 4 hours. The rapid decrease in plasma concentration between
0 and l hour, followed by a slower decrease thereafter (and the constant half-life thereafter), indicates that this drug obeys a two-compartment model with an initial distribution phase followed
by an elimination phase. The half-life is always determined from the elimination phase data.

19. The answer is C. Receptor affinity for the drug will determine the number of drug-receptor
complexes formed. Efficacy is the ability of the drug to activate the receptor after binding has
occurred. Therapeutic index (TI) is related to safety of the drug. Half-life and secretion are properties of elimination and do not influence the formation of drug-receptor complexes.

20. The answer is D. A noncompetitive antagonist decreases the magnitude of the response to an
agonist but does not alter the agonist's potency (i.e., the ED50 remains unchanged). A competitive antagonist interacts at the agonist-binding site.

21. The answer is D. This drugwill undergo filtration and passive reabsorption. Since the molecular
weight of the drug is small, free drug will be filtered. Because 20% of the drug is bound to plasma
proteins, 80% of it is free and available for filtration, which would be at a rate of 100 mL/min (i.e.,
0.8 x 125 mL/min; 125 mL/min is the normal glomerular filtration rate [GFR]). A clearance of 10
mL/min must indicate that most of the filtered drug is reabsorbed.

Drugs Acting on the
Autonomic Nervous

A. General oveni1w of th1 nervous sysllm
1. The nervous syatem ia divided into the:
1. Central nervous syatem (CNS)
(1) Brain
(2) Spinal cord
b. Peripheral nervous system (PNS)
(1) Neuronal tissues outside the CNS
2. The motor (efferent) portion of the nervous system can be divided into two major subdivisions.
1. Autonomic (unconscious control)
(1) Sympathetic division: Fight m flight respon!el
(2) Parasympathetic division: Rest or ctigellt responses
(3) Bum.pie: Vuceral functions (such u cardiac output or digestion)
b. Somatic (conscious control)
(1) Example: Movement
c. Both s,_tems have important afferent (sensory) input& that provide infonnadon regarding
the internal and extern.al environments. They also modify motor output

A. Th• autonomic nervoua eptem (ANS) controls involuntary activity
(Fig. 2.1; Table 2.1)

1. P1naympltl11tic nervous sptem (PNS)
I. Long preganglionic amns originate from neuzons in the cranial and sacral areas of the spinal

cord and, with few exceptions, synapse on neurons in ganglia located close to or within the
innervated organ.
b. Short postgangllonic amna innervate cardiac muscle, bronchial smooth muscle, and exo·
ct1ne glands.
c. Parasympathetic innervation predominates over sympathetic innervation of salivary glands,
lacrimal glands, and erectile tiasue.

2. Sympltlletic nervau1 tyltem (SNS)
in the thmacic and lwnbar areas of the
spinal cord and synapae on neU?ODS in gaDgtia located outside ot but close to, the spinal
cord. The adrenal medulla, anatomically considered a modified ganglion, ia innervated by
sympathetic preganglionic axons.
b. Long postganglionic axons innervate many of the same tissues and oi;gans as the PNS.
c. Innervation ofth1nn01"111Ulltlry sw11t glands is anatomically gympathetic, but the postganglionic nerve fibers are cholinergic and release acetylcholine as the neurotransmitter.

1. Short preganglionic aiwna originate from neurons



Effector Organ


ACh _J L Nicotinic
Norepinephrine* _J L o., P1, IJ2


Sympathetic a


Drugs Acting on the Autonomic Nervous System





ACh ~ L ACh _JtL- Muscarinic

Parasympathetic ••- - - - - - - - - - - - - - - -



Adrenal gland

Adrenal ••- - - - - - - - - - - (



_J L


Epinephrine (80%)
Norepinephrine (20%)


- -----------------------<

*Except sweat glands, which use ACh.


_J L



FIGURE 2.1. 0 rganization of the autonomic nervous system.



Eye lpupill
Skin and most others
Skeletal muscle
Bronchial muscle
GI tract
Muscle wall
Urinary bladder
Fund us
Trigone; sphincter
Fat cell1

Actions of the Autonomic Nervous System on Selected Effector Organs
Action of Symplltlletic
{Th11nii::11lumb.rl Divisiu

Action of Pa111symp1thatic
ICrani11•cral) Divisi11n

Dilation lexl

Constriction lex!

Acceleration lexl
Increased lexl

Slowing Uni
Decreated linl

Constriction {ex)
Dilation lexl
Viscid secretion {exl

Watery secretion lex)
Secretion lexl

Secretioo lex)
Relaxation linl

Contraction lex)

Relaxation linl
Contraction lexl

Cootraction lex)
Relaxation {in)

Relaxati11n linl
Contraction lex!
Ejaculation {exl
Relaxati11n linl

Contracti11n lex)
Relaxation linl
Erection Uni

Gluconeogenesis lexl
Glyco11enoly1i1 lex)
Renin secretionlexl
Lipolytit lexl

ex. excitatory; in. inhibitory; -. no functionally important innervation.


BRS Ph1nn1calagy

3. Enteric nervous system

a. The enteric nervous system is considered a third branch of the ANS.
b. It is a highly organized, semiautonomous, neural complex localized in the gastrointestinal
(GI) system.
c. It receives preganglionic axons from the PNS and postganglionic axons from the SNS.
d. Nerve terminals contain peptides and purines as neurotransmitters.

B. The somatic nervous system. The somatic nervous system controls voluntary activity. This system
contains long axons that originate in the spinal cord and directly innervate skeletal striated muscle
(Fig. 2.1).

C. Genera I overview of the primary neurotransmitters of the ANS
1. Many peripheral ANS fibers synthesize and release acetylcholine.
a. These are known as cholinergic fibers, and include the following:


(1) All preganglionic efferent autonomic fibers
(2) Somatic (nonautonomic) motor fibers to skeletal muscle
b. Most efferent fibers leaving the CNS are cholinergic, in addition to most parasympathetic
postganglionic fibers and some sympathetic postganglionic fibers.
Parasympathetic postganglionic neurons also use nitric oxide or peptides as the primary transmitter or co-transmitters.
The majority of postganglionic sympathetic fibers release norepinephrine.
a. These are known as noradrenergic fibers.
Dopamine may be released by some peripheral sympathetic fibers.
Adrenal medullary cells release epinephrine and norepinephrine.

D. Neurotransmitters of the autonomic and somatic nervous systems (Fig. 2.1)
1. Acetylcholina (ACh)

a. Biosynthesis
(1) ACh is synthesized in nerve tenninals by the cytoplasmic enzyme choline acetyltransferase, which catalyzes the transfer of an acetate group from acetyl coenzyme A to choline.
(2) Synthesized ACh is transported from cytoplasm to vesicle-associated transporters.
b. Storage, release, and termination
(1) It is stored in nerve terminal vesicles and released by nerve action potentials through
calcium-dependent exocytosis.
(2) On release (a step blocked by botulinum toxin), ACh is rapidly hydrolyzed and inactivated by tissue acetylcholinesterase (AChE) and by nonspecific butyrylcholine
esterase (pseudocholinesterase) to choline and acetate.
c. ACh is the neurotransmitter across synapses:
(1) At the ganglia of the SNS and PNS
(2) In tissues innervated by the PNS and the somatic nervous system
d. It is not administered parenterally for therapeutic purposes because it is hydrolyzed nearly
instantly by butyrylcholine esterase.

2. Norepinaphrine and epinephrine
a. Norepinephrine and epinephrine are catecholamines; they possess a catechol nucleus and
an ethylamine side chain.

b. Biosynthesis (Fig. 2.2)
(1) In prejwictional nerve endings, tyrosine is hydroxylated by tyrosine hydroxylase, the
rate-limiting enzyme in the synthesis of catecholamines, to form dihydroxyphenylalanine (dopa).
(2) Dopa is decarboxylated by dopa decarboxylase to form dopamine.
(3) Dopamine is transported into vesicles (a step blocked by reserpine), where it is hydroxylated on the side chain by dopamine ~-hydroxylase to form norepinephrine.
(4) In certain areas of the brain and in the adrenal medulla, norepinephrine is methylated
on the amine group of the side chain by phenylethanolamine-N-methyltransferase
(PNMT) to form epinephrine.


Drugs Acting on the Autonomic Nervous System

H O O i CH2-rH-NH2

- - -....~

















-P"' O iCH HO


CH2 -

NH -



~-PN_M_T_ HOY')-kH- a<2- NH,


FIGURE 2.2. Biosynthasis of catecholamines. PNMT, phanylathenolemina-N-mathyltransfarasa.

c. Storage and release
(1) Norepinephrine is stored in vesicles that, through a calcium-dependent process, release
their contents by exocytosis from nerve terminals at postganglionic nerve endings of
the SNS (except at thermoregulatory sweat glands, where ACh is the neurotransmitter).
(2) Norepinephrine also exists in a nonvesicular cytoplasmic pool that is released by indirectly acting sympathomimetic amines (e.g., tyramine, amphetamine, ephedrine) by a
process that is not calcium dependent
(3) Norepinephrine and some epinephrine are released from adrenergic nerve endings in
the brain.
(4) In the periphery, epinephrine is the major catecholamine released from adrenal medullary chromaffin cells into the general circulation, where it functions as a hormone. Some
norepinephrine is also released.

d. Termination
(1) The action of norepinephrine is primarily terminated by active transport from the cytoplasm into the nerve terminal by a norepinephrine transporter (uptake 1).
la) This process is inhibited by cocaine and tricyclic antidepressants.
lb) Norepinephrine is then transported by a second carrier system into storage vesicles,
as are dopamine and serotonin (a process also blocked by reserpine).
(2) Another active transport system (uptake 2) is located on glia and smooth muscle cells.
(3) There is also some simple diffusion away from the synapse.
(4) Norepinephrine and epinephrine are also oxidatively deaminatad by mitochondrial
monoamine oxidase (MAO) in nerve terminals and effector cells, notably in the liver
and intestine.

(5) Nerve cells and effector cells contain catechol-0-methyltransferase ICOMT), which
metabolizes catecholamines.

E. Receptors of the ANS
1. Chalinac1pto11
a. Nicotinic receptors are cholinoceptors that are activated by the alkaloid nicotine (see Fig. 2.1 ).


BRS Ph1nn1calagy
(1) They are localized at myoneural junctions of somatic nerves and skeletal muscle (NM);
autonomic ganglia (Ne), including the adrenal medulla; and certain areas in the brain.
(2) Nicotinic receptors are a component ofpostjunctional transmembrane polypeptide that
forms a ligand-gated (cation-selective) ion channel (see Fig. l.lA).
(a) Binding of ACh to the receptor site causes opening of the ion channel and an influx of
positively charged ions (sodium and potassium) and across the cellular membrane.
(b) This influx of positive charge depolarizes the postsynaptic membrane.
(3) In skeletal muscle, ACh interacts with nicotinic receptors to produce membrane depolarization and a propagated action potential through the transverse tubules of skeletal
(a) This results in the release of Caz+ from the sarcoplasmic reticulum and, through a
further series of chemical and mechanical events, muscle contraction.
(b) Hydrolysis of ACh by AChE results in muscle cell repolarization.
(c) The continued presence of a nicotine agoni.st, like succinylcholina, at nicotinic
receptors, or excessive cholinergic stimulation, can lead to a •depolarizing blockade· (phase I block), in which normal depolarization is followed by persistent depolarization. During phase I block, skeletal muscle is unresponsive to either neuronal
stimulation or direct stimulation.
(d) The selective nicotinic receptor antagonists, tubocurarina and trimathaphan, can
block the effect of ACh at skeletal muscle and autonomic ganglia, respectively.
b. Muscarinic receptors are cholinoceptors that are activated by the alkaloid mu.scarine (see
Fig. 2.1; Table 2.2).
(1) Muscarinic receptors are localized on numerous autonomic effector cells, including cardiac atrial muscle and cells of the sinoatrial (SA) and atrioventricular {AV)
nodes, smooth muscle, exocrine glands, and vascular endothelium (mostly arterioles),
although the latter does not receive parasympathetic innervation, as well as certain
areas in the brain.
(2) They consist of at least five receptor subtypes (M1-M5).
(a) M1-receptors are found in sympathetic postganglionic neurons.
(b) M2-receptors are found in cardiac and smooth muscles.
(c) M3-receptors are found in glandular cells (e.g., gastric parietal cells), and the vascular endothelium and vascular smooth muscle.
(d) M5-receptors are found in the vascular endothelium.
(a) All receptor subtypes are found in CNS neurons.
(3) ACh interacts with M,, M1, and Ms muscarinic cholinoceptors to increase phosphatidyl inositol (Pl) turnover and Caa+ mobilization (see Fig. 1.lD; Table 2.2).
(a) By activation of the G protein (Gq), the interaction of ACh with M 1 and M3 muscarinic
cholinoceptors stimulates polyphosphatidylinositol phosphodiesterase (phospholipasa C), which hydrolyzes PI to inositol trisphosphate UP1) and diacylglycerol

(b) IP1 mobilizes intracellular caa. from the endoplasmic and sarcoplasmic reticula,
and activates Ca2•-regulated enzymes and cell processes.
(c) DAG activates protein kinase C, which results in phosphorylation of cellular
enzymes and other protein substrates and the influx of extracellular calcium that
results in activation of contractile elements in smooth muscle.
t a b I e


Effects of G-Protein Coupled Receptors


G, coupled

Increase phospholipase C--+ Increase IP:s. DAG, Ca 1+


G, coupled

D•creaH adenylyl cyclase--+ decreaH cAMP

Bata· 1. Beta-2

G, coupled

Increase adenylyl cyclase--+ increase cAMP

Muscarinic-1, Muscarinic-3, ind
Muscarinic-2 and Muscarinic-4

G~ coupled

Increase phospholipase C--+ Increase IPa. DAS, Ca"

G; coupled

Decrease adenylyl cyclase --1- decrease cAMP


Drugs Acting on the Autonomic Nervous System


14) ACh also interacts with M2 and M4 muscarinic cholinoceptors to activate G proteins
IG;J, which leads to inhibition af adenylyl cyclase activity with decreased levels of cyclic
AMP (cAMP) and to increased potassium (K+) conductance with effector cell hyperpolarization (Table 2.2).
15) Cholinergic agonists act on M1 muscarinic receptors of endothal ial calls to promote the
release of nitric oxide (NO), which diffuses to the vascular smooth muscle to activate
guanylyl cyclase and increase cyclic GMP (cGMP), and to produce relaxation.
2. Adfllnot:eptors
a. 11-Adrenoceptars (see Fig. 2.1)
11) a-Adrenoceptors are classified into two major receptor subgroups (there are subtypes
of each group).
la) 11.-Receptors are located in postjunctional effector cells, notably vascular smooth
muscle, where responses are mainly excitatory.
lb) ai-Receptors are located primarily in prajunctional adrenergic nerve terminals, and
also in fat cells and in the pcells of the pancreas.
12) They mediate many functions, including the following:
lal Vasoconstriction (a.1)
lb) Gastrointestinal (GI) relaxation (a1)
le) Mydriasis (a1)
Id) Prejunctional inhibition of release of norepinephrine and other neurotransmitters

le) Inhibition of insulin release(~)
If) Inhibition oflipolysis (~)
13) a-Adrenoceptors are distinguished from p-adrenoceptors by their interaction (in
descending order of potency), with the adrenergic agonists epinephrine= norepinaphrine :> :> isoproterenol, and by their interaction with relatively selective antagonists such
as phantalamine.
(41 ~-Adrenoceptors, like muscarinic M1 cholinoceptors, activate guanine nucleotidebinding proteins (Gq) in many cells, which results in activation ofphospholipase C and
stimulation ofphosphoinositide (PI) hydrolysis that leads to increased formation oflP1,
mobilization of intracellular stores of Ca2•, increased DAG, and activation of protein
kinase C.
15) az-Adrenoceptan, like muscarinic M2-cholinoceptors, activate inhibitory guanine
nucleotide-binding proteins (G1), inhibit adanylyl cyclase activity, and decrease intracellular cAMP levels and the activity of cAMP-dependent protein kinases (see Fig. 1.lC).
b. j>Adrenoceptan (see Fig. 2.1)
11) P-Adrenoceptors, located mostly in postjunctional effector cells, are classified into two
major receptor subtypes, p1-receptors (primarily excitatory) and ~-receptors (primarily
la) ~-Receptor subtype
i. p1 -Receptors mediate increased contractility and conduction velocity, and renin
secretion in the kidney.
ii. The Pi-receptor subtype is defined by its interaction (in descending order of
potency) with the adrenergic agonists isoproterenol :>epinephrine= norepinephrina and by its interaction with relatively selective antagonists such as atenolol.
lbl Pz-Receptor subtype
i. P2 -Receptors mediate vasodilation and intestinal, bronchial, and uterine smooth
muscle relaxation.
ii. The~- receptor subtype is defined byitsinteraction (in descendingorderofpotency)
with the adrenergic agonists isoproterenol = epinephrine :>:> norepinephrine.
12) f3-Receptar activation
la) P-Receptors activate guanine nucleotide-binding protains (GJ (see Fig.1.lB; Table 2.2).
lb) Activation stimulates adenylate cyclase activity and increases intracellular CAMP
levels and the activity of cAMP-dependent protein kinases.
le) Adrenoceptor-mediated changes in the activity of protein kinases (and also levels of
intracellular Caz+) bring about changes in the activity of specific enzymes and structural and regulatory proteins, resulting in modification of cell and organ activity,


BRS Phannacology

A. Direct...cting muscarinic cholinaceptor agonists
1. Mecll8Bi1111 ofaction and chemic•/ :rtlllcture


Direct-acting parasympadtomlmetlc drugs act at muscar1nlc chollnoceptors to mimic many
of the physiologic effects dtat result from stlmuladon of the parasympathetic division of the
ANS (see Fig. 2.1).
b. Bethanechol and methacholine are choline esters widt a quaternary ammonium group dtat
are structurally similar to ACh.
c. They have substantially reduced activity at nicotinic recepiors and are more resistant to
hydrolysis by AChE.
2. Pll•1111•t:alagit: •llBt:ls (Tubles 2.3 and 2.4)

a. Eye
(1) Direct-acting muscarln1c chollnoceptor agonJsts contract th• circular smooth muscle
fibers of dt1 ciliary muscl1 and iris to produce a spasm of accommodation and an
increased outtlow of aqueous humor into the canal of Schlemm, respectively. This
results in a reduction in intraocular pressure.
(2) These drugs contract the smooth muscle of the iris sphincter to cause miHil.

b. Cardiovascular 1J1t9m
(1) Direct-acting muscarinic cholinoceptor agonists produce a negative chronatropic
effect (reduced SA node activity).
(2) These drugs decrease conduction velocity through the atrioventricular (AV) node.
(a) They have no effect on force of contraction because there are no muscarinlc receptors on (or parasympathetic Innervation of) ventr:l.cles.
(3) Direct-acting muscarlnic cholinoceptor agonlats produce vasodilation dtat results
primarily from their action on endothellal cella to promote the release of NO, which diffuses to die vascular smooth muscle and produces relaxation.
(a) Vascular smoodt muscle has muscarin.1c receptors but no pamsympadtetic innervadon.
(b) The decrease in blood pressure can result in a reDex increase in heart rate.

c. Gltract
(1) Direct-acting muscarinic cholinoceptor agonists increase smooth muscle contractions
and tone, with increased peristaltic activity and motility.
(2) These drugs increase salivation and acid secretion.

d. Urinary tract
(1) Direct-acting muscarinic chollnoceptor agonists incrnse contraction of the ureter and

bladdtr smooth muscle.
(2) These drugs increase sphincter relaxation.


a bIe


Actions of Cholinoceptor Agonists


Eft1ct1 of M11e1ri1ic Aga1iltl

Heart {rate, conduction velocity!•


Arteriolet (tonal
Blood PrtHUtt
Pupil •ize


Bronchial tDnu
Intestine (motility!
GI Hcrations
Urin1ry bl1ddar

'Rupons1111 !e~ .. heart retB) may be allectEd by 111fle10111.



t a b I e


Type of Drug
Muscarinic agr:mist
Muscarinic antagonist
a-Adrenergic agonist

Drugs Acting on the Autonomic Nervous System


Effects of Muscarinic Cholinoceptor Agonists and Antagonists and Adrenoceptor
Agonists on Smooth Muscles of the Eye



Iris circular {constrictorl


Cilia ry circular



Iris circular {constricto rl



Ciliery circular


Cyclo plegia

Iris radial {dilatorl



Ciliary circular



a. Respiratory system
11) These drugs can cause bronchoconsb'iction with increased resistance and increased
bronchial secretions.
t. Other effects
11) They can increase the secretion of tears from lacrimal glands and increase sweat gland
12) These drugs produce tremor and ataxia.
3. Specific drugs and their indications
a. These drugs are used primarily for diseases of the eye, GI tract, urinary tract, the neuromuscular junction, and the heart (Table 2.5).
b. Bethanechol
11) This agent increases bladder muscle tone and causes contractions to initiate urination.
It also stimulates GI motility and can help restore peristalsis. It has limited distribution
to the CNS.
12) It is approved for the management of postoperative and postpartum urinary retention
and neurogenic bladder.
13) It has the potential to cause a reflux infection if the patient has bacteriuria (when the
sphincter fails to relax as bethanechol contracts the bladder).
c. Methacholine
11) This agent is only used to diagnose bronchial airway hyperreactivity in patients with no
clinically apparent asthma.
12) Since severe bronchoconstriction and reduced respiratory function may occur, it should
not be used in patients with clinically apparent asthma, wheezing, or a low baseline
pulmonary function test.
d. Pilocarpina
11) Pilocarpine is a tertiary amine that is well absorbed from the GI tract and enters the CNS.
12) It is occasionally used topically for opan-angla glaucoma, either as eye drops or as a
sustained-release ocular insert.
la) When used before surgery to treat acute narrow-angle glaucoma (a medical emergency), pilocarpine is often given in combination with an indirectly acting muscarinic agonist, such as physostigmine.
13) Orally, pilocarpine is used to increase salivary secretion; it used to treat xerostomia
associated with Siiigren syndrome.
a. Cavimalina is used for the treatment ofxerostomia associated with Sjogren syndrome.
t. Carbachol is used rarely as a treatment for open-angle glaucoma. It is also approved to cause
miosis during ophthalmic surgery.

a b Ie


Selected Indications of Selected Direct-Acting Cholinoceptor Agonists


Prevents urine rstantion; postoperative abdominal distension; gastric atony


Diagnostic for bronchial hyp1rsensitivity


Open-angle glaucoma; acute narrow-angle glaucoma; SjCgren syndrome


BRS Ph1nn1calagy

4. Advsrss sffsr:ts
a. The adverse effects associated with direct-acting muscarinic cholinoceptor agonists are
extensions of their pharmacologic activity.

b. Adverse effects may include nausea, vomiting, diarrhea, sweating. and salivation. More serious effects include bronchoconstriction and decreased blood pressure. These effects can be
reversed by atropine.

c. Systemic effects are minimal for drugs applied topically.
5. Prer:.utions
a. Caution must be used in patients with asthma and cardiac disease.
(1) They are not recommended in hyperthyroidism since they predispose patients to
b. They are also not recommended when there is mechanical obstruction of the GI or urinary tract

B. Acetylcholinestarase inhibitors (indirect-acting parasympalhomimetic agents)
1. ACh interacts with AChE at two sites.
1. The N+ of choline (ionic bond) binds to the anionic site, and the acetyl ester binds to the este-

ratic site (serine residue).

b. As ACh is hydrolyzed, the serine-OH side chain is acetylated and free choline is released.

c. Acetylserine is hydrolyzed to serine and acetate.
d. The half-life (t11J of acetylserine hydrolysis is 100-150 microseconds.
2. Phosphoric acid esters (organophosphates)
a. Specific agents
(1) Insecticides: Parathion and malathion
(2) Nerve gases: Sarin and tabun

b. Msr:hanism at action. These drugs bind to AChE and render Iha enzyme nonfunctional; this
leads to increased ACh at the neuronal synapses at the neuromuscular junction.
(1) They bind to AChE and undergo prompt hydrolysis.
(2) The phosphate ion is released slowly from the enzyme active site, preventing the binding and hydrolysis of endogenous ACh.
(3) Compared to the carbamates, the organophosphates are long-acting drugs that form a
very stable phosphate complex with AChE.
(a) They undergo 1 conformational change known as ·aging,· causing AChE to
become irreversibly resistant to reactivation by the antidote (pralidoxime).
(4) They prolong the peripheral and central effects of ACh.
c. Indications. These agents are not used in a clinical setting. They are pesticides that are used in
agriculture and nerve agents that may be used in terrorism or chemical warfare.
(1) Echothiophate is an irreversible and toxic organophosphate cholinesterase inhibitor;
it results in phosphorylation of AChE rather than acetylation. It is an ophthalmic agent
approved for the treatment of e