PHARMACOLOGY 1 CHAPTER 1

Pharmacology - study of substances that interact with living (3) All dietary supplements and all therapies promoted as
systems through chemical processes. Occur by binding of the health-enhancing should meet the same standards of efficacy
substance to regulatory molecules and activating or inhibiting and safety as conventional drugs and medical therapies.
normal body processes.
All nutritional and botanical substances should be tested by
Medical pharmacology - science of substances used to the same types of randomized controlled trials (RCTs) as
prevent, diagnose, and treat disease. synthetic compounds.

Toxicology - branch of pharmacology that deals with the Drug - any substance that brings about a change in biologic
undesirable effects of chemicals on living systems, from function through its chemical actions.
individual cells to humans to complex ecosystems.
Drug molecule interacts as an agonist (activator) or
END OF THE 17th CENTURY antagonist (inhibitor) with a specific target molecule that
plays a regulatory role in the biologic system. This target
Reliance on observation and experimentation began to molecule is called a receptor.
replace theorizing in physiology and clinical medicine.
Drugs known as chemical antagonists may interact directly
Materia medica - science of drug preparation and the with other drugs, whereas a few drugs (osmotic agents)
medical uses of drugs; precursor to pharmacology. interact almost exclusively with water molecules.

LATE 18th AND 19th CENTURIES Drugs synthesized within the body (hormones)
Chemicals not synthesized in the body (xenobiotics)
François Magendie & Claude Bernard (student) began to
develop the methods of experimental physiology and Poisons - drugs that have almost exclusively harmful effects.
pharmacology.
Paracelsus (1493–1541) stated that “the dose makes the
The concepts of rational therapeutics, especially controlled poison,” meaning that any substance can be harmful if taken
clinical trial, were reintroduced into medicine—only about in the wrong dosage.
60 years ago—did it become possible to adequately evaluate
therapeutic claims. Toxins - poisons of biologic origin, synthesized by plants or
animals, in contrast to inorganic poisons such as lead and
1940s AND 1950s arsenic.

Information accumulated about drug action and the biologic To interact chemically with its receptor, a drug molecule must
substrate of that action, the drug receptor. In fact, the use of have:
receptor identification methods has led to the discovery of Appropriate size
many orphan receptors. Electrical charge
Atomic composition
Orphan receptors - receptors for which no ligand has been Shape
discovered and whose function can only be guessed.
Receptors and effectors do not function in isolation; they are Furthermore, a drug is often administered at a location distant
strongly influenced by companion regulatory proteins. from its intended site of action. A useful drug must have the
necessary properties to be transported from its site of
Pharmacogenomics - the relation of the individual’s genetic administration to its site of action. A practical drug should
makeup to his or her response to specific drugs. be inactivated or excreted from the body at a reasonable rate
so that its actions will be of appropriate duration.
Small segments of RNA can interfere with protein synthesis
with extreme selectivity has led to investigation of Drugs may be solid at room temperature (aspirin, atropine),
therapeutic agents: liquid (nicotine, ethanol), or gaseous (nitrous oxide).

Small interfering RNAs (siRNAs) The various classes of organic compounds: carbohydrates,
Micro-RNAs (miRNAs) proteins, lipids, and smaller molecules—are all represented
in pharmacology.
Short nucleotide chains called antisense oligonucleotides
(ANOs), synthesized to be complementary to natural RNA or Oligonucleotides, in the form of small segments of RNA,
DNA, can interfere with the readout of genes and the have entered clinical trials and are on the threshold of
transcription of RNA. introduction into therapeutics.

GENERAL PRINCIPLES: Dangerous drugs are inorganic elements, (lithium, iron, and
heavy metals). Many organic drugs are weak acids or bases.
(1) All substances can under certain circumstances be toxic;
(2) Chemicals in botanicals (herbs and plant extracts,
“nutraceuticals”) are no different from chemicals in
manufactured drugs except for the much greater proportion of
impurities in botanicals
DRUG SIZE RATIONAL DRUG DESIGN

The molecular size of drugs varies from very small Rational drug design - ability to predict the appropriate
(lithiumion, molecular weight 7) to very large (alteplase [t- molecular structure of a drug on the basis of information
PA], a protein of MW 59,050). about its biologic receptor.

Alteplase - clot-dissolving enzyme, the drug is administered DRUG-BODY INTERACTIONS

directly into the vascular compartment by intravenous or
intra-arterial infusion. Pharmacodynamic processes - actions of the drug on the
body.
Drugs interact with receptors by means of chemical forces or
bonds. These are of three major types: covalent, electrostatic, Pharmacokinetic processes - actions of the body on the
and hydrophobic. drug: absorption, distribution, and elimination of drugs.

Covalent bonds - very strong and not reversible under PHARMACODYNAMIC PROCESSES
biologic conditions. Covalent bond formed between the acetyl
group of acetylsalicylic acid (aspirin) and cyclooxygenase, Most drugs must bind to a receptor to bring about an effect.
its enzyme target in platelets, is not readily broken. The However, at the cellular level, drug binding is only the first in
platelet aggregation–blocking effect of aspirin lasts long a sequence of steps:
after free acetylsalicylic acid has disappeared from the blood-
stream (about 15 minutes) and is reversed only by the • Drug (D) + receptor-effector (R) → drug-receptor-effector
synthesis of new enzyme in new platelets. complex → effect
• D + R → drug-receptor complex → effector molecule →
Highly reactive, covalent bond-forming drugs: effect
DNA-alkylating agents used in cancer • D + R → D-R complex → activation of coupling molecule
chemotherapy to disrupt cell division in the tumor. → effector molecule → effect
• Inhibition of metabolism of endogenous activator →
Electrostatic bonding - more common than covalent bonding increased activator action on an effector molecule →
in drug-receptor interactions. increased effect

Electrostatic bonds - vary from relatively strong linkages Final change in function is accomplished by an effector
between permanently charged ionic molecules to weaker mechanism. The effector may be part of the receptor
hydrogen bonds and very weak induced dipole interactions molecule or may be a separate molecule. Receptors
such as van der Waals forces. Weaker than covalent bonds. communicate with their effectors through coupling
molecules.
Hydrophobic bonds - Usually quite weak and important in
the interactions of highly lipid-soluble drugs with the lipids A. TYPES OF DRUG-RECEPTOR INTERACTIONS
of cell membranes and in the interaction of drugs with the
internal walls of receptor “pockets.” Agonist drugs bind to and activate the receptor in some
fashion, which directly or indirectly brings about the effect.
Xenon - inert gas, has anesthetic effects at elevated pressures.
Receptor activation involves a change in conformation in the
DRUG SHAPE cases that have been studied at the molecular structure level.

Chirality (stereoisomerism) can exist as enantiomeric pairs. Pharmacologic antagonist drugs, by binding to a receptor,
Drugs with two asymmetric centers have four compete prevent binding by other molecules.
diastereomers, (ephedrine - a sympathomimetic drug).
Acetylcholine receptor blocker, atropine are antagonists
Carvedilol - a drug that interacts with adrenoceptors, has a because they prevent access of acetylcholine to the
single chiral center and thus two enantiomers. One of these acetylcholine receptor site and they stabilize the receptor in its
enantiomers, the (S)(–) isomer, is a potent β-receptor blocker. inactive state. These agents reduce the effects of acetylcholine
The (R)(+) isomer is 100-fold weaker at the β receptor. but their action can be overcome by increasing the dosage of
However, the isomers are approximately equipotent as α- agonist. Some antagonists bind very tightly to the receptor site
receptor blockers. in an irreversible or pseudoirreversible fashion and cannot be
displaced by increasing the agonist concentration.
Ketamine - an intravenous anesthetic. The (+) enantiomer is a
more potent anesthetic and is less toxic than the (–) Drugs that bind to the same receptor molecule but do not
enantiomer. Used as the racemic mixture. prevent binding of the agonist are said to act allosterically
and may enhance or inhibit the action of the agonist molecule.
Allosteric inhibition is not usually overcome by increasing the
dose of agonist.

Constitutive activity - Even in the absence of any agonist,

some of the receptor pool must exist in the Ra form some of
the time and may produce the same physiologic effect as
agonist-induced activity.
Full Agonists - Agonist drugs, when administered at Many cells also contain less selective membrane carriers that
concentrations sufficient to saturate the receptor pool, can are specialized for expelling foreign molecules. One large
activate their receptor-effector systems to the maximum family of such transporters binds adenosine triphosphate
extent of which the system is capable; that is, they cause a (ATP) and is called the ABC (ATP-binding cassette) family.
shift of almost all of the receptor pool to the Ra–D pool. This family includes the P-glycoprotein or multidrug
resistance type 1 (MDR1) transporter found in the brain,
Partial Agonists - Bind to the same receptors and activate testes, and other tissues, and in some drug-resistant neoplastic
them in the same way but do not evoke as great a response, cells.
no matter how high the concentration. Do not stabilize the Ra
configuration as fully as full agonists, so that a significant
fraction of receptors exists in the Ri–D pool. Such drugs are
said to have low intrinsic efficacy.

Pindolol - β-adrenoceptor partial agonist; act either as an

agonist (if no full agonist is present) or as an antagonist

Intrinsic efficacy is independent of affinity (as usually

measured) for the receptor.

Neutral Antagonism - Presence of the antagonist at the

receptor site will block access of agonists to the receptor and
prevent the usual agonist effect. Multidrug resistance-associated protein (MRP)
transporters - Excrete drugs or their metabolites into urine
Inverse Agonists - The drug will reduce any constitutive and bile and in the resistance of some tumors to
activity, thus resulting in effects that are the opposite of the chemotherapeutic drugs.
effects produced by conventional agonists at that receptor.
Endocytosis and exocytosis - Substances are so large or
Benzodiazepines - Conventional exogenous agonists; impermeant that they can enter cells only by endocytosis, the
facilitate the receptor-effector system and cause GABA-like process by which the substance is bound at a cell-surface
inhibition with sedation as the therapeutic result. This sedation recetor, engulfed by the cell membrane, and carried into the
can be reversed by conventional neutral antagonists such as cell by pinching off of the newly formed vesicle inside the
flumazenil. membrane.

To function as a receptor, an endogenous molecule must first The substance can then be released into the cytosol by
be selective in choosing ligands (drug molecules) to bind; and breakdown of the vesicle membrane. This process is
second, it must change its function responsible for the transport of vitamin B12, complexed
with a binding protein (intrinsic factor) across the wall of the
Binding of a drug to a non-regulatory molecule such as gut into the blood. Similarly, iron is transported into
plasma albumin will result in no detectable change in the hemoglobin-synthesizing red blood cell precursors in
function of the biologic system, so this endogenous molecule association with the protein transferrin.
can be called an inert binding site.
The reverse process (exocytosis) is responsible for the
Prodrug - Precursor: chemical that is readily absorbed and secretion of many substances from cells. For example, many
distributed must be administered and then converted to the neurotransmitter substances are stored in membrane-bound
active drug by biologic processes inside the body. vesicles in nerve endings to protect them from metabolic
destruction in the cytoplasm. Appropriate activation of the
1. Aqueous diffusion - Occurs within the larger aqueous nerve ending causes fusion of the storage vesicle with the cell
compartments of the body (interstitial space, cytosol, etc) membrane and expulsion of its contents into the extracellular
and across epithelial membrane tight junctions and the space.
endothelial lining of blood vessels through aqueous pores
that in some tissues permit the passage of molecules as large
as MW 20,000–30,000.

2. Lipid diffusion - Most important limiting factor for drug

permeation because of the large number of lipid barriers that
separate the compartments of the body. Because these lipid
barriers separate aqueous compartments, the lipid: aqueous
partition coefficient of a drug determines how readily the
molecule moves between aqueous and lipid media. C1 is the higher concentration
C2 is the lower concentration
3. Special carriers - Exist for many substances that are
important for cell function and too large or too insoluble in
lipid to diffuse passively through membranes, eg, peptides,
amino acids, and glucose.
Ionization of Weak Acids and Weak Bases; the
Henderson-Hasselbalch Equation The no-effect dose - the maximum dose at which a specified
toxic effect is not seen
Electrostatic charge - attracts water dipoles and results in a
polar, relatively water-soluble and lipid-insoluble complex. The minimum lethal dose - the smallest dose that is
observed to kill any experimental animal
Weak acid - Neutral molecule that can reversibly dissociate
into an anion (a negatively charged molecule) and a proton (a The median lethal dose (LD50) - the dose that kills
hydrogen ion). approximately 50% of the animals in a test group.

Weak base - Neutral molecule that can form a cation (a

positively charged molecule) by combining with a proton.

Sto mach (normal pH 1.9–3)

Small intestine (pH 7.5–8)
Breast milk (pH 6.4–7.6)
Aqueous humor (pH 6.4–7.5)
Vaginal and prostatic secretions (pH 3.5–7)

A truly new drug (one that does not simply mimic the
structure and action of previously available drugs) requires the Further protection against errors of interpretation
discovery of a new drug target, ie, the pathophysiologic caused by disease fluctuations is sometimes provided by using
process or substrate of a disease. a crossover design, which consists of alternating periods of
administration of test drug, placebo preparation (the control),
and the standard treatment (positive control), if any, in each
subject.

Placebo response - (Latin, “I shall please”); patients respond

in a positive way to any therapeutic intervention by interested,
caring, and enthusiastic medical personnel. The manifestation
of this phenomenon in the subject is the and may involve
objective physiologic and biochemical changes as well as
changes in subjective complaints associated with the disease.

Single-blind design - Subject bias effects can be quantitated

and minimized relative to the response measured during active
therapy

Observer bias can be taken into account by disguising the

identity of the medication being used—placebo or active form
—from both the subjects and the personnel evaluating the
Translational research involves the preclinical and clinical subjects’ responses (double-blind design).
steps.
Adherence - Confirmation of compliance with protocols
Drug screening - involves a variety of assays at the
molecular, Phase 1 - Effects of the drug as a function of dosage are
cellular, organ system, and whole animal levels to define the established in a small number (20–100) of healthy volunteers.
pharmacologic profile.
Phase 2 - Drug is studied in patients with the target disease to
The need for further chemical modification (compound determine its efficacy (“proof of concept”)
optimization) to achieve more desirable pharmacokinetic or
pharmacodynamic properties.  Pure Food and Drug Act of 1906 Prohibited mislabeling
and adulteration of drugs.
The desired result of this screening procedure (which may  Opium Exclusion Act of 1909 Prohibited importation of
have to be repeated several times with congeners of the opium.
original molecule) is a lead compound, a leading candidate  Amendment (1912) to the Pure Food and Drug Act
for a successful new drug.
Prohibited false or fraudulent advertising claims.
A patent application would be filed for a novel compound (a
composition of matter patent) that is efficacious, or for a new Harrison Narcotic Act of 1914 Established regulations for
and nonobvious therapeutic use (a use patent) for a previously use of opium, opiates, and cocaine (marijuana added in 1937).
known chemical entity.
Food, Drug, and Cosmetic Act of 1938 Required that new
drugs be safe as well as pure (but did not require proof of
efficacy).
Durham-Humphrey Act of 1952 Vested in the FDA the
power to determine which products could be sold without Avoid adverse drug reactions and optimize a drug’s
prescription. therapeutic index is an increasing focus of pharmacogenetic
and personalized (also called “precision”) medicine.
Kefauver-Harris Amendments (1962) to the Food, Drug,
and Cosmetic Act Orphan drugs - Drugs for rare diseases, can be difficult to
research, develop, and market.
Required proof of efficacy as well as safety for new drugs and
for drugs released since 1938; established guidelines for The Orphan Drug Amendment of 1983 provides incentives
reporting of information about adverse reactions, clinical for the development of drugs for treatment of a rare disease
testing, and advertising of new drugs.
Adverse drug event (ADE) or reaction to a drug (ADR) a
Comprehensive Drug Abuse Prevention and Control Act - Harmful or unintended response. Adverse drug
(1970) Outlined strict controls in the manufacture, reactions are claimed to be the fourth leading cause of death,
distribution, and prescribing of habit-forming drugs; higher than pulmonary disease, AIDS, accidents, and
established drug schedules and programs to prevent and treat automobile deaths.
drug addiction.

Orphan Drug Amendment of 1983 Provided incentives for

development of drugs that treat diseases with fewer than
200,000 patients in

Drug Price Competition and Patent Restoration Act of

1984 Abbreviated new drug applications for generic drugs.
Required bioequivalence data.

Prescription Drug User Fee Act (1992, reauthorized 2007,

2012) Manufacturers pay user fees for certain new drug
applications. “Breakthrough” products may receive special
category approval after expanded phase 1 trials (2012).

Dietary Supplement Health and Education Act (1994)

Established standards with respect to dietary supplements but
prohibited full FDA review of supplements and botanicals as
drugs.

Bioterrorism Act of 2002 Enhanced controls on dangerous

biologic agents and toxins. Seeks to protect safety of food,
water, and drug supply.

Food and Drug Administration Amendments Act of 2007

Granted FDA greater authority over drug marketing, labeling,
and direct-to-consumer advertising; required post-approval
studies, established active surveillance systems, made clinical
trial operations and results more visible to the public.

Biologics Price Competition and Innovation Act of 2009

Authorized the FDA to establish a program of abbreviated
pathways for approval of “biosimilar” biologics (generic
versions of monoclonal antibodies, etc).

FDA Safety and Innovation Act of 2012 Renewed FDA

authorization for accelerated approval of urgently needed
drugs; established new accelerated process, “breakthrough
therapy,” in addition to “priority review,” “accelerated
approval,” and “fast-track” procedures.

Phase 3 - difficult to design and execute and are usually

expensive because of the large numbers of patients involved
and the masses of data that must be collected and analyzed.

Trademark - Drug’s proprietary trade name and is usually

registered; this registered name may be legally protected as
long as it is used.
 Enzymes may be inhibited (or, less commonly, activated) by
binding a drug. Examples include dihydrofolate reductase,
Receptor - The component of a cell or organism that the receptor for the antineoplastic drug methotrexate;
interacts with a drug and initiates the chain of events leading
to the drug’s observed effects. 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA)
reductase, the receptor for statins; and various protein and
PHARMACOLOGY
Receptors have become the central focus of investigation of 1 CHAPTER
lipid 2
kinases. Transport proteins can be useful drug
drug effects and their mechanisms of action targets.
(pharmacodynamics).
Na+/K+ATPase - Membrane receptor for cardioactive
Receptors largely determine the quantitative relations digitalis glycosides
between dose or concentration of drug and pharmacologic
effects. The receptor’s affinity for binding a drug determines Norepinephrine and serotonin transporter proteins that are
the concentration of drug required to form a significant membrane receptors for antidepressant drugs
number of drug-receptor complexes, and the total number of
receptors may limit the maximal effect a drug may produce. Dopamine transporters that are membrane receptors for
cocaine and a number of other psychostimulants.
Receptors are responsible for selectivity of drug action.
The molecular size, shape, and electrical charge of a drug Structural proteins are also important drug targets, such as
determine whether—and with what affinity—it will bind to a tubulin, the receptor for the anti-inflammatory agent
particular receptor among the vast array of chemically colchicine.
different binding sites available in a cell, tissue, or patient.
Concentration-Effect Curves & Receptor Binding of
Changes in the chemical structure of a drug can Agonists
dramatically increase or decrease a new drug’s affinities for
different classes of receptors, with resulting alterations in Even in intact animals or patients, responses to low doses of a
therapeutic and toxic effects. drug usually increase in direct proportion to dose. As doses
increase, however, the response increment diminishes;
Receptors mediate the actions of pharmacologic agonists finally, doses may be reached at which no further increase in
and antagonists. Many natural ligands, such as hormones and response can be achieved.
neurotransmitters, regulate the function of receptor
macromolecules as agonists; this means that they activate the This relation between drug concentration and effect is
receptor to signal as a direct result of binding to it. traditionally described by a hyperbolic curve

Drugs as pharmacologic antagonists; bind to receptors but do

not activate generation of a signal; consequently, they
interfere with the ability of an agonist to activate the
receptor.

Still other drugs bind to a different site on the receptor than

that bound by endogenous ligands; such drugs can produce
useful and quite different clinical effects by acting as so-called
allosteric modulators of the receptor.
E - effect observed at concentration C
Macromolecular Nature of Drug Receptors Emax - maximal response that can be produced by the drug,
EC50 - Concentration of drug that produces 50% of maximal
Most receptors for clinically relevant drugs, are proteins. effect.

Drug binding - Used to identify or purify receptor proteins This hyperbolic relation resembles the mass action law that
from tissue extracts; consequently, receptors were discovered describes the association between two molecules of a given
after the drugs that bind to them. affinity. This resemblance suggests that drug agonists act by
binding to (“occupying”) a distinct class of biologic
This effort revealed that many known drugs bind to a larger molecules with a characteristic affinity for the drug.
diversity of receptors than previously anticipated and Radioactive receptor ligands have been used used to confirm
motivated efforts to develop increasingly selective drugs. It this occupancy.
also identified a number of orphan receptors, so-called
because their natural ligands are presently unknown. In these systems, drug bound to receptors (B) relates to the
concentration of free (unbound) drug ©
The best-characterized drug receptors are regulatory
proteins,
which mediate the actions of endogenous chemical signals
such as neurotransmitters, autacoids, and hormones. This
class of receptors mediates the effects of many of the most
useful therapeutic agents.
 all receptors. In other cases, “spareness” of receptors appears
Bmax - total concentration of receptor sites (ie, sites bound to to be temporal.
the drug at infinitely high concentrations of free drug)

Kd (the equilibrium dissociation constant) represents the Competitive & Irreversible Antagonists
concentration of free drug at which half-maximal binding is
observed. This constant characterizes the receptor’s affinity Receptor antagonists bind to receptors but do not activate
for binding the drug in a reciprocal fashion: If the Kd is low, them; the primary action of antagonists is to reduce the effects
binding affinity is high, and vice versa. of agonists (other drugs or endogenous regulatory molecules)
that normally activate receptors. While antagonists are
The EC50 and Kd may be identical but need not be. traditionally thought to have no functional effect in the
absence of an agonist, some antagonists exhibit “inverse
Dose-response data are presented as a plot of the drug effect agonist” activity because they also reduce receptor activity
(ordinate) against the logarithm of the dose or concentration below basal levels observed in the absence of any agonist at
(abscissa), transforming the hyperbolic curve of into a all.
sigmoid curve with a linear midportion
In the presence of a fixed concentration of agonist, increasing
Receptor-Effector Coupling & Spare Receptors concentrations of a competitive antagonist progressively
inhibit the agonist response; high antagonist concentrations
When an agonist occupies a receptor, conformational changes prevent the response almost completely. Conversely,
occur in the receptor protein that represent the fundamental sufficiently high concentrations of agonist can surmount the
basis of receptor activation and the first of often many steps effect of a given concentration of the antagonist.
required to produce a pharmacologic response. The overall
transduction process that links drug occupancy of receptors
and pharmacologic response is called coupling.

Full agonists tend to shift the conformational equilibrium of

receptors more strongly than partial agonist.

Coupling is also determined by “downstream” biochemical

events that transduce receptor occupancy into cellular
response.

For some receptors, such as ligand-gated ion channels, the

relationship between drug occupancy and response can be
simple because the ion current produced by a drug is often
directly proportional to the number of receptors (ion
channels) bound.

For other receptors, such as those linked to enzymatic signal

transduction cascades, the occupancy-response relationship is
often more complex because the biologic response reaches a
maximum before full receptor occupancy is achieved.

Many factors can contribute to nonlinear occupancy-

response coupling. A useful concept for thinking about this is
that of receptor reserve or spare receptors.

Receptors are said to be “spare” for a given pharmacologic

response if it is possible to elicit a maximal biologic response
at a concentration of agonist that does not result in occupancy
of all of the available receptors.

Spare receptors may be demonstrated by using irreversible

antagonists to prevent binding of agonist to a proportion of
available receptors and showing that high concentrations of
agonist can still produce an undiminished maximal response.
For example, the same maximal inotropic response of heart
muscle to catecholamines can be elicited even when 90% of β
adrenoceptors to which they bind are occupied by a quasi-
irreversible antagonist. Accordingly, myocardial cells are said
to contain a large proportion of spare β adrenoceptors.

Receptors may be simply spare in number relative to the

total number of downstream signaling mediators present in the
cell, so that a maximal response occurs without occupancy of