INTRODUCTION AND

PHARMACODYNAMICS AND
DRUG AND DEVELOPMENT
REGULATION

CHRISTINE MAY R. VALDEZ, M.D.

UNIVERSITY OF VISAYAS GULLAS COLLEGE OF MEDICINE
• Pharmacology
-body of knowledge concerned with the action of chemicals on
biologic systems
• Medical pharmacology
-area of pharmacology concerned with the use of chemicals in the
prevention, diagnosis, and treatment of disease, especially in humans
• Toxicology
-area of pharmacology concerned with the undesirable effects of
chemicals on biologic systems
• Pharmacokinetics
describes the effects of the body on drugs-- absorption,
distribution, metabolism, excretion (ADME)
• Pharmacodynamics
denotes the actions of the drug on the body, such as mechanism
of action and therapeutic and toxic effects
NATURE OF DRUGS
• Drugs in common use include inorganic ions, nonpeptide organic
molecules, small peptides and proteins, nucleic acids, lipids, and
carbohydrates
• Some are found in plants or animals, and others are partially or
completely synthetic
• Many drugs found in nature are alkaloids, which are molecules that
have a basic pH in solution--result of amine groups in their structure
A. Size and Molecular Weight
• Drugs vary in size from molecular weight (MW) 7 (lithium) to over
MW 50,000 (thrombolytic enzymes, antibodies, other proteins)
• Most drugs, however, have MWs between 100 and 1000
• Drugs smaller than MW 100 are rarely sufficiently selective in their
actions, whereas drugs much larger than MW 1000 are often poorly
absorbed and poorly distributed in the body
• Most protein drugs (“biologicals”) are commercially produced in cell,
bacteria, or yeast cultures using recombinant DNA technology
B. Drug-Receptor Bonds
• Drugs bind to receptors with a variety of chemical bonds
Includes:
very strong covalent bonds (irreversible action)
weaker electrostatic bonds (between a cation and an anion)
much weaker interactions (hydrogen, van der Waals, and
hydrophobic bonds)
PHARMACODYNAMICS
PHARMACODYNAMIC PRINCIPLES
A. Receptors
• Drug actions are mediated through the effects of drug ligand
molecules on drug receptors in the body
• Most receptors are large regulatory molecules that influence
important biochemical processes (enzymes involved in glucose
metabolism) or physiologic processes (ion channel receptors,
neurotransmitter reuptake transporters, and ion transporters)
• If drug-receptor binding results in activation of the receptor-- Agonist
• If inhibition results-- Antagonist
• Some drugs mimic agonist molecules by inhibiting metabolic enzymes
(acetylcholinesterase inhibitors)
• Quantitation of the effects of drug-receptor binding as a function of
dose yields dose-response curves that provide information about the
nature of the drug-receptor interaction
• Few drugs are enzymes themselves (thrombolytic enzymes,
pancreatic enzymes)
B. Receptor and Inert Binding Sites
• Most ligand molecules are much smaller than their receptor
molecules, specific regions of receptor molecules provide the local
areas responsible for drug binding receptor sites or recognition
sites
• Drugs bind to some nonregulatory molecules in the body without
producing a discernible effect inert binding sites
DOSE–RESPONSE RELATIONSHIPS
• Agonist drugs mimic the action of the original endogenous ligand for
the receptor (isoproterenol mimics norepinephrine on β1 receptors of
the heart)
• magnitude of the drug effect depends on the drug concentration at
the receptor site, determined by both the dose of drug administered
and by the drug’s pharmacokinetic profile
A. Graded dose–response relations
• As the concentration of a drug increases, its pharmacologic effect also
gradually increases until all the receptors are occupied (maximum
effect)
• Plotting the magnitude of response against increasing doses of a drug
produces a graded dose–response curve described as a rectangular
hyperbola
• Two important properties of drugs, potency and efficacy, can be
determined by graded dose–response curves
POTENCY
• amount of drug needed to produce a given effect
• In graded dose-response measurements effect usually chosen is
50% of the maximal effect and the concentration or dose causing this
effect is called the EC50 or ED50
• determined mainly by the affinity of the receptor for the drug and the
number of receptors available
• In quantal dose response measurement ED50, TD50, and LD50 are
also potency variables (median effective, toxic, and lethal doses,
respectively, in 50% of the population studied)
• measure of potency can be determined from either graded or
quantal dose-response curves
Potency
• measure of the amount of drug necessary to produce an effect of a
given magnitude
• Concentration of drug producing 50% of the maximum effect (EC50) is
usually used to determine potency
Eg: candesartan and irbesartan are angiotensin receptor blockers that
are used to treat hypertension
Therapeutic dose range for candesartan is 4 to 32 mg, as compared to 75
to 300 mg for irbesartan
Candesartan is more potent than is irbesartan (it has a lower EC50 value,
similar to Drug A)
Efficacy
• magnitude of response a drug causes when it interacts with a
receptor
• dependent on the number of drug–receptor complexes formed and
the intrinsic activity of the drug (its ability to activate the receptor and
cause a cellular response)
• Maximal efficacy of a drug (Emax) assumes that all receptors are
occupied by the drug, and no increase in response is observed if a
higher concentration of drug is obtained
• Maximal response differs between full and partial agonists, even
when 100% of the receptors are occupied by the drug
• Even though an antagonist occupies 100% of the receptor sites, no
receptor activation results and Emax is zero
• Efficacy is a more clinically useful characteristic than is drug potency,
since a drug with greater efficacy is more therapeutically beneficial
than is one that is more potent
EFFICACY
• often called maximal efficacy  greatest effect (Emax) an agonist can
produce if the dose is taken to the highest tolerated level
• determined mainly by the nature of the drug and the receptor and its
associated effector system
• can be measured with a graded dose-response curve
• Partial agonists have lower maximal efficacy than full agonists
GRADED DOSE-BINDING
RELATIONSHIP & BINDING AFFINITY
• measure the percentage of receptors bound by a drug, and by plotting
this percentage against the log of the concentration of the drug
dose-binding graph similar to the dose-response curve is obtained
• concentration of drug required to bind 50% of the receptor sites is
denoted by the dissociation constant (Kd) and is a useful measure of
the affinity of a drug molecule for its binding site on the receptor
molecule
Smaller the Kd greater the affinity of the drug for its receptor
INTRINSIC ACTIVITY
• Agonist binds to a receptor and produces a biologic response based
on the concentration of the agonist and the fraction of activated
receptors
• Intrinsic activity of a drug determines its ability to fully or partially
activate the receptors
A. Full agonists
• a drug binds to a receptor and produces a maximal biologic response that
mimics the response to the endogenous ligand
• bind to a receptor stabilizing the receptor in its active state and are said
to have an intrinsic activity of one
• All full agonists for a receptor population should produce the same Emax
• Eg: phenylephrine is a full agonist at α1 -adrenoceptors, because it
produces the same Emax as does the endogenous ligand, norepinephrine
• Upon binding to α1 -adrenoceptors on vascular smooth muscle,
phenylephrine stabilizes the receptor in its active state
• Diameter of the arteriole decreases, causing an increase in resistance
to blood flow through the vessel and an increase in blood pressure
• Agonist may have many measurable effects, including actions on
intracellular molecules, cells, tissues, and intact organisms
• All of these actions are attributable to interaction of the drug with the
receptor
• dose–response curves for receptor binding and each of the biological
responses should be comparable
B. Partial agonists
• have intrinsic activities greater than zero but less than one
• Even if all the receptors are occupied cannot produce the same Emax as
a full agonist
• may have an affinity that is greater than, less than, or equivalent to that of
a full agonist
• When a receptor is exposed to both a partial agonist and a full agonist, the
partial agonist may act as an antagonist of the full agonist
• As the number of receptors occupied by the partial agonist increases
Emax would decrease until it reached the Emax of the partial agonist
Eg: aripiprazole, an atypical antipsychotic, is a partial agonist at
selected dopamine receptors
Dopaminergic pathways that are overactive tend to be inhibited by
aripiprazole, whereas pathways that are underactive are stimulated
Explains the ability of aripiprazole to improve symptoms of
schizophrenia, with a small risk of causing extrapyramidal adverse
effects
Antagonists
• bind to a receptor with high affinity but possess zero intrinsic activity
• has no effect in the absence of an agonist but can decrease the effect
of an agonist when present
• may occur either by blocking the drug’s ability to bind to the receptor
or by blocking its ability to activate the receptor
1. Competitive antagonists:
• If both the antagonist and the agonist bind to the same site on the receptor
in a reversible manner, they are said to be “competitive”
• prevents an agonist from binding to its receptor and maintains the receptor in
its inactive state
Eg: the antihypertensive drug terazosin competes with the endogenous ligand
norepinephrine at α1 –adrenoceptors decreasing vascular smooth muscle
tone and reducing blood pressure
This inhibition can be overcome by increasing the concentration of agonist
relative to antagonist
• Competitive antagonists shift the agonist dose–response curve to the right
(increased EC50) without affecting Emax
2. Irreversible antagonists:
• bind covalently to the active site of the receptor reducing the
number of receptors available to the agonist
• causes a downward shift of the Emax, with no shift of EC50 values
• effect of irreversible antagonists cannot be overcome by adding more
agonist
• irreversible antagonists and allosteric antagonists are both considered
noncompetitive antagonists
competitive agonists reduce agonist potency (increase EC50)
noncompetitive antagonists reduce agonist efficacy (decrease Emax)
3. Allosteric antagonists:
• causes a downward shift of the Emax, with no change in the EC50
value of an agonist
• binds to a site (“allosteric site”) other than the agonist-binding site
and prevents the receptor from being activated by the agonist
Eg: picrotoxin, which binds to the inside of the GABA-controlled chloride
channel When bound inside the channel, no chloride can pass
through the channel, even when the receptor is fully activated by GABA
4. Functional antagonism:
• also known as “physiologic antagonism”
• An antagonist may act at a completely separate receptor, initiating
effects that are functionally opposite those of the agonist
A classic example is the functional antagonism by epinephrine to
histamine-induced bronchoconstriction
Histamine binds to H1 histamine receptors on bronchial smooth
muscle causing bronchoconstriction of the bronchial tree
Epinephrine is an agonist at β2 -adrenoceptors on bronchial smooth
muscle causes the muscles to relax
QUANTAL DOSE-RESPONSE
RELATIONSHIPS
• When the minimum dose required to produce a specified response
is determined in each member of a population
E.g. blood pressure-lowering drug might be studied by measuring the
dose required to lower the mean arterial pressure by 20 mm Hg in 100
hypertensive patients
• When plotted as the percentage of the population that shows this
response at each dose versus the log of the dose administered, a
cumulative quantal dose-response curve--sigmoid in shape
• Median effective dose (ED50), median toxic dose (TD50), and (in
animals) median lethal dose (LD50) are derived from experiments
• Because the magnitude of the specified effect is arbitrarily
determinedED50determined by quantal dose-response
measurements has no direct relation to the ED50 determined from
graded dose response curves
• data provide information about the variation in sensitivity to the drug
in a given population if the variation is small curve is steep
THERAPEUTIC INDEX & THERAPEUTIC
WINDOW
Therapeutic index
• ratio of the dose that produces toxicity in half the population (TD50)
to the dose that produces a clinically desired or effective response
(ED50) in half the population
TI = TD50 / ED50
• determined from quantal dose-response curves
• represents an estimate of the safety of a drug
• E.g. ED50 is approximately 3 mg, and the LD50 is approximately 150
mg therapeutic index is approximately 150/3, or 50, in mice
• factors such as the varying slopes of dose-response curves make this
estimate a poor safety index
• Both the therapeutic index and the therapeutic window depend on the
specific toxic effect used in the determination
Clinical usefulness of the therapeutic index
• TI of a drug is determined using drug trials and accumulated clinical
experience
• reveal a range of effective doses and a different (sometimes
overlapping) range of toxic doses
• Warfarin oral anticoagulant with a low therapeutic index
• Penicillin antimicrobial drug with a large therapeutic index
1. Warfarin
As the dose of warfarin is increased, a greater fraction of the patients
respond (for this drug, the desired response is a two- to threefold
increase in the international normalized ratio [INR]) until, eventually, all
patients respond
• At higher doses of warfarin anticoagulation resulting in hemorrhage
occurs in a small percent of patients
Therapeutic window
• more clinically useful index of safety
• a larger value indicates a wide margin between doses that are effective and
doses that are toxic
• describes the dosage range between the minimum effective
therapeutic concentration or dose, and the minimum toxic
concentration or dose
• E.g. if the average minimum therapeutic plasma concentration of
theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the
therapeutic window is 8–18 mg/L
2. Penicillin
• it is safe and common to give doses in excess of that which is
minimally required to achieve a desired response without the risk of
adverse side effects
• bioavailability does not critically alter the therapeutic or clinical
effects
II. DRUG DEVELOPMENT
& REGULATION
• Before a new drug can be approved for regular therapeutic use in
humans, a series of animal and experimental human studies (clinical
trials) must be carried out
• New drugs may emerge from a variety of sources
• Some are the result of identification of a new target for a disease
• New drugs may result from the screening of hundreds of compounds
against model diseases in animals
SAFETY & EFFICACY
• Because society expects prescription drugs to be safe and effective
governments regulate the development and marketing of new drugs
• Current regulations in the USA require evidence of relative safety
(derived from acute and subacute toxicity testing in animals) and
probable therapeutic action (pharmacologic profile in animals) before
human testing is permitted
• The development of a new drug and its pathway through various
levels of testing and regulation
ANIMAL TESTING
• required before human studies can begin
• a drug proposed for occasional topical use requires less extensive
testing than one destined for chronic systemic administration
• Because of the urgent need anticancer drugs and anti-HIV drugs
require less evidence of safety than do drugs used in treatment of less
threatening diseases
Urgently needed drugs are often investigated and approved on an
accelerated schedule
A. Acute Toxicity
• Acute toxicity studies are required for all new drugs
• involve administration of incrementing doses of the agent up to the
lethal level in at least 2 species (1 rodent and 1 nonrodent)
B. Subacute and Chronic Toxicity
• Subacute and chronic toxicity testing is required for most agents
(chronic use)
• Tests are usually conducted for 2–4 weeks (subacute) and 6–24
months (chronic), in at least 2 species
TYPES OF ANIMAL TESTS
A. Pharmacologic Profile
• a description of all the pharmacologic effects of a drug (effects on
cardiovascular function, gastrointestinal activity, respiration, hepatic
and renal function, endocrine function, CNS)
• Both graded and quantal dose response data are gathered
B. Reproductive Toxicity
• Reproductive toxicity testing involves the study of the fertility effects of the
candidate drug and its teratogenic and mutagenic toxicity
• FDA has used a 5-level descriptive scale to summarize information regarding the
safety of drugs in pregnancy
Teratogenesis
• induction of developmental defects in the somatic tissues of the fetus (exposure
of the fetus to a chemical, infection, or radiation)
• studied by treating pregnant female animals of at least 2 species at selected
times during early pregnancy when organogenesis is known to take place and by
later examining the fetuses or neonates for abnormalities
• Examples of drugs known to have teratogenic effects include
thalidomide, isotretinoin, valproic acid, ethanol, glucocorticoids,
warfarin, lithium, and androgens
• Mutagenesis  induction of changes in the genetic material of
animals of any age and therefore induction of heritable abnormalities
• Ames test standard in vitro test for mutagenicity, uses a special
strain of salmonella bacteria that depends on specific nutrients in the
culture medium
Loss of this dependence as a result of exposure to the test drug signals
a mutation
• Many carcinogens (aflatoxin, cancer chemotherapeutic drugs, and
other agents that bind to DNA) have mutagenic effects and test
positive in the Ames test
• Male animals are exposed to the test substance before mating
• Abnormalities in the results of subsequent mating (loss of embryos,
deformed fetuses) signal a mutation in the male’s germ cells
C. Carcinogenesis
• induction of malignant characteristics in cells
• Ames test is often used to screen chemicals because there is a
moderately high degree of correlation between mutagenicity in the
Ames test and carcinogenicity in some animal tests
• Agents with known carcinogenic effects include coal tar, aflatoxin,
dimethyl nitrosamine and other nitrosamines, urethane, vinyl
chloride, and the polycyclic aromatic hydrocarbons in tobacco smoke
(benzo[a]pyrene) and other tobacco products
CLINICAL TRIALS
• Human testing of new drugs in requires approval by institutional
committees that monitor the ethical (informed consent, patient
safety) and scientific aspects (study design, statistical power) of the
proposed tests
• requires the prior approval by the FDA of an Investigational New Drug
Exemption application (IND), which is submitted by the manufacturer
to the FDA
• IND includes all the preclinical data collected up to the time of
submission and the detailed proposal for clinical trials
• Major clinical testing process is usually divided into 3 phases that are
carried out to provide information for a New Drug Application (NDA)
• NDA includes all the results of preclinical and clinical testing and
constitutes the request for FDA approval of general marketing of the
new agent for prescription use
• A fourth phase of study (surveillance phase) follows NDA approval
• In particularly lethal conditions FDA may permit carefully
monitored treatment of patients before phases 2 and 3 are completed
A. Phase 1
• consists of careful evaluation of the dose-response relationship and
the pharmacokinetics of the new drug in a small number of normal
human volunteers (20–100)
• An exception is the phase 1 trials of cancer chemotherapeutic agents
and other highly toxic drugs these are carried out by administering
the agents to volunteer patients with the target disease
• acute effects of the agent are studied over a broad range of dosages,
starting with one that produces no detectable effect and progressing
to one that produces either a significant physiologic response or a
very minor toxic effect
B. Phase 2
• involves evaluation of a drug in a moderate number of sick patients
(100–200) with the target disease
• A placebo or positive control drug is included in a single-blind or
double-blind design
• carried out under very carefully controlled conditions
• patients are closely monitored (hospital research ward)
• Goal is to determine whether the agent has the desired efficacy
(produces adequate therapeutic response) at doses that are
tolerated by sick patients
• Detailed data are collected regarding the pharmacokinetics and
pharmacodynamics of the drug in this patient population
C. Phase 3
• usually involves many patients (1000–6000 or more) and many
clinicians who are using the drug in the manner proposed for its
ultimate general use (outpatients)
• include placebo and positive controls in a double-blind crossover design
• Goals are to explore further, under the conditions of the proposed
clinical use, the spectrum of beneficial actions of the new drug, to
compare it with placebo (negative control) and older therapy (positive
control), and to discover toxicities that occur so infrequently as to be
undetectable in phase 2 studies
• Very large amounts of data are collected and these studies are usually
very expensive
• few phase 3 trials include the current standard of care as a positive
control
• If the drug successfully completes phase 3  NDA is submitted to the
FDA
• If the NDA is approved drug can be marketed and phase 4 begins
D. Phase 4
• represents the post marketing surveillance phase of evaluation, in
which it is hoped that toxicities that occur very infrequently will be
detected and reported early enough to prevent major therapeutic
disasters
• Manufacturers are required to inform the FDA at regular intervals of
all reported untoward drug reactions
• has not been rigidly regulated by the FDA
DRUG PATENTS & GENERIC DRUGS
• A patent application is usually submitted around the time that a new
drug enters animal testing
• approval of the patent and completion of the NDA approval process give
the originator the right to market the drug without competition from
other firms for a period of 10–14 years from the NDA approval date
• After expiration of the patent any company may apply to the FDA for
permission to market a generic version of the same drug if they
demonstrate that their generic drug molecule is bioequivalent (meets
certain requirements for content, purity, and bioavailability) to the
original product
DRUG LEGISLATION
ORPHAN DRUGS
• a drug for a rare disease (one affecting fewer than 200,000 people)
• study of such agents has often been neglected because profits from
the sales of an effective agent for an uncommon ailment might not
pay the costs of development
• current legislation provides for tax relief and other incentives
designed to encourage the development of orphan drugs
SELF ASSESSMENT QUIZ
If 10 mg of naproxen produces the same analgesic response as 100 mg
of ibuprofen, which of the following statements is correct?
A. Naproxen is more efficacious than is ibuprofen.
B. Naproxen is more potent than ibuprofen.
C. Naproxen is a full agonist, and ibuprofen is a partial agonist.
D. Naproxen is a competitive antagonist.
E. Naproxen is a better drug to take for pain relief than is ibuprofen.
• If 10 mg of morphine produces a greater analgesic response than can
be achieved by ibuprofen at any dose, which of the following
statements is correct?
A. Morphine is less efficacious than is ibuprofen.
B. Morphine is less potent than is ibuprofen.
C. Morphine is a full agonist, and ibuprofen is a partial agonist.
D. Ibuprofen is a competitive antagonist.
E. Morphine is a better drug to take for pain relief than is ibuprofen.
• In the presence of naloxone, a higher concentration of morphine is
required to elicit full pain relief. Naloxone by itself has no effect.
Which of the following is correct regarding these medications?
A. Naloxone is a competitive antagonist.
B. Morphine is a full agonist, and naloxone is a partial agonist.
C. Morphine is less efficacious than is naloxone.
D. Morphine is less potent than is naloxone.
E. Naloxone is a noncompetitive antagonist.
• Isoproterenol produces maximal contraction of cardiac muscle in a
manner similar to epinephrine. Which of the following best describes
isoproterenol?
• A. Full agonist.
• B. Partial agonist.
• C. Competitive antagonist.
• D. Irreversible antagonist.
• E. Inverse agonist.
Sugammadex is a new drug that reverses the action of rocuronium and
certain other skeletal muscle-relaxing agents (nondepolarizing
neuromuscular blocking agents). It appears to interact directly with the
rocuronium molecule and not at all with the rocuronium receptor. Which of
the following terms best describes sugammadex?
(A) Chemical antagonist
(B) Noncompetitive antagonist
(C) Partial agonist
(D) Pharmacologic antagonist
(E) Physiologic antagonist
A 55-year-old woman with hypertension is to be treated with a thiazide
diuretic. Thiazide A in a dose of 5 mg produces the same decrease in
blood pressure as 500 mg of thiazide B. Which of the following
statements best describes these results?
(A) Thiazide A is more efficacious than thiazide B
(B) Thiazide A is about 100 times more potent than thiazide B
(C) Toxicity of thiazide A is less than that of thiazide B
(D) Thiazide A has a wider therapeutic window than thiazide B
(E) Thiazide A has a longer half-life than thiazide B
The Ames test is frequently carried out before clinical trials are begun.
The Ames test is a method that detects
(A) Carcinogenesis in primates
(B) Carcinogenesis in rodents
(C) Mutagenesis in bacteria
(D) Teratogenesis in any mammalian species
(E) Teratogenesis in primates
Which of the following would probably not be included in an optimal
phase 3 clinical trial of a new analgesic drug for mild pain?
(A) A negative control (placebo)
(B) A positive control (current standard analgesic therapy)
(C) Double-blind protocol (in which neither the patient nor immediate
observers of the patient know which agent is active)
(D) A group of 1000–5000 subjects with a clinical condition requiring
analgesia
(E) Prior submission of an NDA (new drug application) to the FDA
The “dominant lethal” test involves the treatment of a male adult
animal with a chemical before mating; the pregnant female is later
examined for fetal death and abnormalities. The dominant lethal test
therefore is a test of
(A) Teratogenicity
(B) (B) Mutagenicity
(C) Carcinogenicity
(D) Sperm viability