Review: Basic Pharmacology, Drug Discovery, PHARMACOLOGY

Safety and Efficacy

IST
August 21, 2020 1.1
Outline Pharmacodynamics:
I. Pharmacology → What the drug does to the body
A. Branches of Pharmacology → ADME
II. Pharmacodynamics
→ Dose-plasma concentration
A. Pharmacodynamics Principles
1. Drug Receptor interaction
Pharmacodynamics:
a. Receptor
→ What the body/katawan does to the drug
b. Ligand
2. Dose-response relationship → MOA
c. Graded Dose-Response → Plasma concentration effect
Relationship
d. Quantal Dose Response Curve
III. Pharmacokinetics PHARMACODYNAMICS
A. Absorption PHARMACODYNAMICS PRINCIPLES
B. Distribution I. Drug Receptor interaction
C. Metabolism (Biotransformation)
A. RECEPTOR
D. Excretion
E. Elimination o Specific molecule that a drug may interact with that
IV. Drug Discovery plays a regulatory role
A. Drug Screening o Types of receptor:
B. Preclinical Safety and Toxicity Testing ▪ Intracellular receptors
C. Evaluation in Humans ▪ Extracellular receptor target Adhesion receptor
1. Confounding Factors in Clinical Trials target
2. The Food and Drug Administration
▪ Signaling convergence of two drug receptors
3. Clinical Trials: The IND and NDA
LEGEND (antagonistic)
 Previous o Types of transmembrane protein
 Book  Recording Must know ▪ Transmembrane ion channels
Trans
Important Concept
References:
1. Batch 2021 Trans (Finals Reviewer)

PHARMACOLOGY
• Study of drugs or chemical substances that have an
effect on all living organisms

DRUG
• Any substance that brings about a change in biologic
function through its chemical action
• 2 kinds:
o Agonist (activator)
o Antagonist (inhibitor)
• Rational drug design: predict appropriate molecular
structure of drug
▪ Transmembrane G-protein couple receptor
BRANCHES OF PHARMACOLOGY subunit (GPCRS)
• Pharmacodynamics: → Metabotropic receptors
o What the drug does to a body (d for drug) → Uses secondary messengers (cAMP,
• Pharmacokinetics: cGMP, IP3, DAG)
o What the body does to the drug (k for katawan) G- Secondary Actio
• Toxicology: protein messenger n
o Study of the undesirable effects of drugs Gs cAMP Activates Ca2+ channels,
activates adenylyl cyclase
• Medical pharmacology or Pharmacotherapeutics: Gi cAMP Activates K+ channels,
o Rational drug use in the management of disease inhibits adenylyl cyclase
• Pharmacogenomics: Gq IP3 and DAG Activates phospholipase C
o Genetic makeup of a person affects the drug
“HIYANG” ▪ Transmembrane with linked enzymatic domain
→ Biological catalysts (ex. Insulin)

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 PHARMACOLOGY REVIEW: BASIC PHARMACOLOGY, DRUG DISCOVERY, SAFETY AND EFFICACY LECTURE 1.1

B. LIGAND
o Substance that forms a complex with a biomolecule
to serve a biological purpose
o Affinity: ability of a ligand to bind to a receptor
o Intrinsic activity: ability of the ligand to generate
biochemical events leading to effect
o Classification of Ligands:
1. Agonist: Bind to and activate the receptor which
directly or indirectly brings about the effect
→ Types: (see figure below) Figure 2. Competitive antagonism

• Non-competitive Antagonism: bind to either the

active site or an allosteric site of a receptor

Figure 3. Noncompetitive antagonism

a) Full agonist:
→ Produces ALL of the expected effects b. TYPES BASED ON MODE OF ACTION (MOA)
→ Have higher affinity for Ra conformation → favors • Physiologic Antagonism
formation of Ra-D → larger observed effect o 2 ligands acting on DIFFERENT
b) Partial agonist: receptors/proteins producing opposite effects
→ Produces SOME of the expected effects & may be o **For ex., in the Tx of hyperthyroidism,
more or less potent than full agonists adrenergic antagonists are used as
→ Intermediate activity for both Ri and Ra; do not physiologic antagonists to counteract the
evoke as great a response tachycardic effect of excess thyroid hormone
c) Inverse agonist: o **Excess thyroid hormone produces
→ Acts by abrogating this intrinsic (constitutive) tachycardia, at least in part, via up-regulation
activity of the free (unoccupied) receptor of cardiac – adrenoceptors, and blocking -
→ Much higher affinity for Ri → reduces constitutive adrenergic stimulation relieves the
activity and contrasting physiologic results tachycardia
• Pharmacologic Antagonism
o 2 ligands acting in the SAME receptor
producing opposing effects
o E.g. Atropine
• Chemical Antagonism “Inactivation”
o **Ex. Protamine, this basic protein binds to
the acidic heparin and thereby inactivates it

II. Dose-Response Relationship

• The pharmacodynamics of a drug can be quantified by
the relationship between the dose (concentration) of
the drug and the organism’s (patient’s) response to
Figure 1. A model of drug-receptor interaction that drug
• The response to a drug is proportional to the
2. Antagonist – inhibits the action of an agonist but has no concentration of receptors that are bound (occupied)
effect in the absence of the agonist by the drug where:
a. TYPES BASED ON SURMOUNTABILITY o [D] concentration of free drug
• Competitive Antagonism: binds reversibly to the o [DR] concentration of drug-receptor
active site of a receptor complexes
o [R0] concentration of total receptors
o Kd equilibrium dissociation constant or the
drug – receptor interaction

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 PHARMACOLOGY REVIEW: BASIC PHARMACOLOGY, DRUG DISCOVERY, SAFETY AND EFFICACY
TYPES OF DOSE-RESPONSE RELATIONSHIP
GRADED DOSE-RESPONSE RELATIONSHIP
• Describes the effect of various doses of a drug on an
individual
• Linear graph of drug receptor binding or two drugs
with different values of Kd
• Semilogarithmic graphs of the same drug receptor
binding wherein a lower Kd indicates a tighter drug
receptor interaction (higher affinity)
• TWO IMPORTANT PARAMETERS that can be deduced
from graded dose response curve:
o POTENCY - concentration at which the drug elicits
50% of its maximal response (EC50, Km)
o EFFICACY - maximal response produced by the
drug (Emax, Vmax)
QUANTAL DOSE RESPONSE CURVE
• Demonstrate the average effect of a drug, as a function of
its concentration, in a population of individuals
• PARAMETERS:
o Median Effective Dose (ED 50) - dose at which 50%
of subjects exhibit a therapeutic response
o Median Toxic Dose (TD 50) - dose at which 50% of
subjects experience a toxic response or adverse
effect
o Median Lethal Dose (LD 50) - dose at which 50%
of subjects die
o Therapeutic Index - measurement of drug’s
margin of safety
𝑇𝐷 50
𝑻𝒉𝒆𝒓𝒂𝒑𝒆𝒖𝒕𝒊𝒄 𝑰𝒏𝒅𝒆𝒙 (𝑻𝑰) =
𝐸𝐷 50
PHARMACOKINETICS
ABSORPTION
• Passage of the drug from its site of administration into the
blood.
• When it has reached the systemic circulation, the drug is
absorbed.
MECHANISM OF DRUG PASSAGE ACROSS MEMBRANES
PASSIVE DIFFUSION
• Driving force: difference in concentration gradient
• Drug moves from higher to lower concentration
• Utilized by majority of drugs
• Lipid soluble drug easily crosses the lipid bilayer or plasma
membrane
• Water soluble can move easily BUT through a channel or
pore
FACILITATED DIFFUSION
• Carrier-mediated transport process (like active)
• Does not require energy.
• Carrier enhances movement of the drug down an
electrochemical gradient (like passive)
• Larger molecules can pass through the plasma membrane
through the help of carrier proteins.
YAMSON, YAP, YUSI EDITOR: RUTH BELANO
LECTURE 1.1
ACTIVE TRANSPORT
• Requires carrier
• Energy-consuming, fastest
• Moves against a concentration gradient (Uphill)
• Presents with saturability and selectivity
• Competitive inhibition by co-transported compounds
PINOCYTOSIS/ENDOCYTOSIS
• Folding over the part stomach off the cell membrane
• Formation of small vesicle;
• Cell-drinking
• Requires energy
• Used by Griseofulvin and Vitamin ADEK
TYPES OF DOSE-RESPONSE RELATIONSHIP
ORAL CAVITY AND SUBLINGUAL ABSORPTION
• Enter the generic circulation directly.
• Sublingual administration → extensive network of blood
vessels facilitates rapid drug absorption
STOMACH
• With food = much longer in the stomach = longer time to be
absorbed.
• More viscous = increase absorption.
• Lying on the right side increases absorption.
SMALL INTESTINE
• Large surface is because of the villi and microvilli = more
absorption.
• Most absorption occurs in the proximal jejunum.
LARGE INTESTINE
• Smaller absorptive surface area vs. SI.
• Rectum – useful route, for suppository.
• Lower rectum (middle and inferior rectal veins) drain into the
systemic circulation thru the IVC but upper rectum (superior
rectal vein) drains into the portal vein.
MEASUREMENT OF ABSORPTION: BIOAVAILABILITY (F)
• Rate and extent by which a drug reaches systemic
circulation.
• Fraction of unchanged drug that reaches systemic
circulation.
𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒅𝒓𝒖𝒈 𝒓𝒆𝒂𝒄𝒉𝒊𝒏𝒈 𝒕𝒉𝒆 𝒔𝒚𝒔𝒕𝒆𝒎𝒊𝒄 𝒄𝒊𝒓𝒄𝒖𝒍𝒂𝒕𝒊𝒐𝒏
𝑭=
𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒂𝒅𝒎𝒊𝒏𝒊𝒔𝒕𝒆𝒓𝒆𝒅 𝒅𝒓𝒖𝒈
• Lowest to highest (F): Oral → IM → Rectal → IV
• IV: 100% Bioavailability
FACTORS AFFECTING BIOAVAILABILITY
BIOPHARMACEUTICAL FACTORS
• Acidic pH environment + weak acid = lipid soluble
• Alkaline pH environment + weak base = lipid soluble
FIRST PASS ELIMINATION/FIRST PASS METABOLISM
• After intestinal absorption, drugs can be metabolized in the
liver and or excreted into the bile – reduced bioavailability.
• Avoided by sublingual, transdermal and suppository/rectal
preparation.
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DETERMINANTS OF BIOAVAILABILITY CARDIAC OUTPUT AND BLOOD FLOW TO THE TISSUES

PLASMA DATA
• Area under the Curve (AUC) is the most reliable measure
of bioavailability/ overall exposure of drug.
• Directly proportional to the total amount of unchanged drug
that reaches the systemic circulation.
• Highly vascular organs are favored.
PERMEABILITY AND PERFUSION OF MEMBRANES
• Lipophilic drugs are more permeable
• Natural barriers:
o BBB, placental barrier, blood-ocular barrier

URINE DATA DISEASES

• Maximum urinary excretion rate Time • Plasma albumin concentration
• or maximum excretion rate o  in malnutrition, hepatic and renal diseases
• Cumulative amount of drug excreted in the urine • Alpha-1-acid glycoprotein concentration
o  in pregnancy and post MI
PHARMACOLOGIC EFFECT
• Bioequivalence MEASURE OF DISTRIBUTION: VOLUME OF DISTRIBUTION
o Related drugs show comparable bioavailability. (Vd)
o E.g. Generic and branded drugs – same active • Relates the amount of a given drug in the body to the
drugs, different manufacturer but same concentration of the drug in the blood.
bioavailability.
• Therapeutic equivalence
o 2 similar drugs have comparable efficacy and
safety.

DISTRIBUTION
• Process by which a drug reversibly leaves the systemic METABOLISM (BIOTRANSFORMATION)
circulation and enters the interstitial space and/or the cells • Process by which a drug is altered chemically into another
of the tissues. compound called “metabolites” which may be more active
(as in the case of PRODRUGS) or less active than the
• Once in the blood stream, the drug is distributed to the parent drug
different tissues or organs. • Primarily occurs in the liver but also occur in the stomach,
small intestines, plasma, kidney, lung, skin or other tissues.
Table 1. Route of Administration of Drugs • Oral drugs: 80% undergoes first pass metabolism.
Route BA(%) Characteristics
Intravenous (IV) 100 (by def’n) • Most rapid onset 2 PHASES OF BIOTRANSFORMATION
Intramuscular 75 to  100 • Large volumes PHASE 1 REACTIONS
(IM) often feasible • Oxidation, hydrolysis, reduction mediated by
• may be painful cytochrome P450 (drug metabolizing enzymes)
Subcutaneous 75 to  100 • Smaller volumes • Makes the molecules more hydrophilic introducing a
(SC) than IM more polar functional group
• May be painful • If the metabolites are still lipophilic, they still have to
• Slower onset than undergo a conjugation reaction (phase 2)
IV or IM • The more hydrophilic the drug, the more it can be excreted
Oral (PO) 5 to < 100 • Most convenient
• First-pass effect PHASE 2 REACTIONS
may be significant • Glucoronidation, sulfation, glutathione conjugation, n-
Rectal (PR) 30 to < 100 • Less first pass acetylation, methylation
effect than oral • Produce more polar conjugates that can diffuse across the
Transdermal 80 to  100 • Usually very slow membrane that can easily excreted by the kidneys
- Patches absorption used
usually for lack of first - FACTORS AFFECTING DRUG METABOLISM
- Different pass effect
from • Prolonged NON-GENETIC
intradermal duration of action • Age, sex, liver size/function, diet/nutrition, environmental

FACTORS THAT INFLUENCE DRUG DISTRIBUTION GENETIC

• Acetylation – slow and fast acetylators
PLASMA PROTEIN BINDING • Oxidation – poor and extensive
• More protein bound, less distributed. • CYP450 enzymes (e.g. CYP2D6, CYP3A4) are used to
• Less protein bound, more distributed. facilitate drug metabolism

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Table 2: Cytochrome P450 inducers and inhibitors • Rate of loss of gases depends on the rate of respiration and
CYP450 INDUCERS CYP450 INHIBITORS pulmonary blood flow
(PCRABS) (GPACMAN)
Phenytoin Grapefruit juice EXCRETION IN OTHER BODY FLUIDS
Carbamazepine Azole antifungals • Sweat, saliva and milk
Alcohol (chronic) Cimetidine
Barbiturates Macrolides (except DRUG ELIMINATION: KINETIC ORDER
Azithromycin)
St. John’s Wort Amiodarone ZERO ORDER ELIMINATION
Non dihydropyridine CCBs
(Diltiazem, Verapamil) Table 3: 0-order elimination mechanism
• CYP450 inducers: increases rate of excretion of the drug Time after Drug in Amount of Fraction of
(thus lowering drug concentration in the body, producing Drug body (mg) Drug Drug
shorter effects or can decrease drug effects) Administration Eliminated Eliminated
• CYP450 inhibitors: decreases rate of excretion of the drug 0 1000 - -
(thus increasing drug concentration in the body, producing 1 850 150 0.15
longer effects or can lead to toxicity) 2 700 150 0.18
3 550 150 0.21
Enzyme inhibition – increased potential for toxicity
4 400 150 0.27
Enzyme induction – therapeutic failure due to inability to
5 250 150 0.38
achieve drug concentrations
6 100 150 0.60

EXCRETION
• The rate of elimination is constant, but fraction of drug is
• Process by which a drug or its metabolites is eliminated
different
from the body through the kidneys
• Ex: Aspirin, Ethanol, Phenytoin, Fluoxetine, Cisplatin
• Other sites of excretion: biliary system, GIT, skin and lungs
• Clinical implication: Drugs eliminated in the zero order are
(least: breast milk)
SATURABLE. They do not adapt to the needs of the body
• Hydrophilic drugs are absorbed, metabolized and excreted
• Lipophilic drugs are absorbed, metabolized and stored in
FIRST ORDER ELIMINATION
the body

Table 4: 1st – order elimination mechanism

ORGAN EXCRETION
Time after Drug in Amount of Fraction of
Drug body (mg) Drug Drug
RENAL EXCRETION Administration Eliminated Eliminated
• Kidneys – primary organ of removal for most drugs, 0 1000 - -
especially water-soluble and non-volatile drugs 1 850 150 0.15
• Clinical implication: rate of urinary drug excretion will 2 723 127 0.15
depend on the drug’s volume of distribution, its degree of 3 616 109 0.15
protein binding, and the following renal factors: 4 522 92 0.15
o Glomerular filtration rate 5 444 78 0.15
o Tubular fluid pH
6 377 67 0.15
o Extent of back-diffusion of the unionized form
o Extent of active tubular secretion of the compound
• The fraction of drug eliminated is constant, but the amount
o Extent of active tubular reabsorption
of drug eliminated is different
• Clinical implication: Drugs eliminated in the first order are
BILIARY EXCRETION
NON-SATURABLE.
• Plays a major role in excreting heavy metals, anions,
• The higher the concentration, the higher the elimination
cations, and cardiac glycosides
rate. They adapt to the needs of the body to reduce
accumulation of the drug, and thus avoiding toxicity.
ENTEROHEPATIC EXCRETION
• Passive intestinal absorption -> reenters the blood that Table 5: Difference of 0 vs. 1st order
perfuse the intestine -> carried back to the liver Zero Order First Order
Constant Non-uniform
PULMONARY EXCRETION Independent to the amount of Proportional to the amount of
• Any volatile material, irrespective of route of administration, drug drug
may undergo pulmonary excretion Linear curve Curvilinear curve
• Mechanism: simple diffusion across cell membranes Active transport Passive diffusion

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A. Half-life (t ½ )
• Required time to decrease the
concentration of the drug in the plasma by
50%
• Used to determine the frequency of
administration and time to attain steady-
state concentration
• Drug needs about 4-5 half-lives to be
completely eliminated from the body
B. Steady state
• Point where rate of drug availability equals
rate of elimination
• Point of expected maximum drug effect
• Usually attained after 4-5 half-lives
C. Clearance
• Ability of the body to eliminate the drug
completely
• Sum of hepatic metabolism and renal
excretion
• Totality of the individual clearance processes
ELIMINATION
• Collective term for METABOLISM + EXCRETION
• Irreversible removal of the parent drug from the body
• Drug elimination is a 2-step process (metabolism and
excretion)
DRUG DISCOVERY
• Most new drugs or drug products are discovered or
developed through the following approaches:
1) Identification or elucidation of a new drug target
2) Rational design of a new molecule based on an
understanding of biologic mechanisms and drug
receptor structure
3) Screening for biologic activity of large numbers of
natural products, banks of previously discovered
chemical entities, or large libraries of peptides,
nucleic acids, and other organic molecules
4) Chemical modification of a known active molecule,
resulting in a “me-too” analog
• Steps 1 and 2 are often carried out in academic research
laboratories, but the costs of steps 3 and 4 usually ensure
that industry carries them out
DRUG SCREENING
• Involves a variety of assays at the molecular, cellular, organ
system, and whole animal levels to define the
pharmacologic profile
o i.e., activity and selectivity of the drug
YAMSON, YAP, YUSI EDITOR: RUTH BELANO
LECTURE 1.1
• The molecule is studied for a broad array of other actions to
determine the mechanism of action and selectivity of the
drug
o Reveal both expected and unexpected toxic effects
• Whole animal models are generally necessary to determine
the effect of the drug on organ systems and disease models
• Lead compound – the desired result of the screening
procedure (i.e., leading candidate for a successful new drug
PRECLINICAL SAFETY & TOXICITY TESTING
• All drugs are toxic in some individuals at some dose
• Goals of preclinical toxicity
o Identifying potential human toxicities
o Designing tests to further define the toxic
mechanisms
o Predicting the most relevant toxicities to be monitored
in clinical trials
• No effect dose – the maximum dose at which a specified
toxic effect is not seen
• Minimum lethal dose – the smallest dose that is observed
to kill any experimental animal
• Median lethal dose (LD50) – the dose that kills
approximately 50% of the animals
• Limitations of preclinical testing:
1) Toxicity testing is time-consuming
2) Large numbers of animals may be needed to obtain
valid preclinical data
3) Extrapolations of therapeutic index and toxicity data
from animals to humans are reasonable predictive for
many but not for all toxicities
4) Rare adverse effects are unlikely to be detected
EVALUATION IN HUMANS
• A very small fraction of lead compounds reaches clinical
trials and less than one third of the drugs granted INDs
survive clinical trials and reach the marketplace
CONFOUNDING FACTORS IN CLINICAL TRIALS
VARIABLE NATURAL HISTORY OF MOST DISEASES
• A good experimental design takes into account the natural
history of the disease by evaluating a large enough
population of subjects over a sufficient amount of time
• Crossover design – consists of alternating periods of
administration of test drug, placebo and standard
treatment
o Further protection against errors of interpretation
caused by disease fluctuations
o Different subsets of patients receive each possible
sequences of treatment
PRESENCE OF OTHER DISEASES AND RISK FACTORS
• Some diseases alter the pharmacokinetics of drugs
• Other drugs and some food alter the pharmacokinetics of
many drugs
• To avoid this hazard usually involve the crossover
technique and proper selection assignment
• Requires accurate diagnostic tests, medical and
pharmacologic histories and the use of statistically valid
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methods of randomization in assigning subjects to • Pharmacokinetic measurements of absorption, half-life,

particular groups and metabolism

SUBJECT AND OBSERVER BIAS AND OTHER FACTORS PHASE 2

• Placebo response – objective physiologic and
biochemical changes as well as changes in subjective
complaints associated with the disease
• Subject bias effects can be quantitated – and minimized
relative to the response measured during active therapy
o Single-blind design – involves use of placebo,
administered to the same subjects in a crossover
design
• Observer bias can be taken into account by disguising the
identity of the medication being used from both the
subjects and personnel evaluating the subjects’ response
o Double-blind design – a third party holds the code
identifying each medication packet, and the code is
not broken until all the clinical data have been
collected
• Confirmation of compliance to protocols (adherence) is a
necessary element to consider
THE FOOD AND DRUG ADMINISTRATION
• The administrative body that oversees the drug evaluation
process in the USA and grants approval for marketing of
new drug products
• Outside the USA, the regulatory and drug approval and
drug process is generally similar to that in the USA
CLINICAL TRIALS: THE IND AND NDA
• Once a new drug is judged ready to be studied in humans,
a Notice of Claimed Investigational Exemption for a New
Drug (IND) must be filled with the FDA; includes:
1) Information on the composition and source of the
drug
2) Chemical and manufacturing information
3) All data from animal studies
4) Proposed plans for clinical trials
5) The names and credentials of physicians who will
conduct the clinical trials
6) A compilation of the key preclinical data relevant to
study of the drug in humans
• The drug is studied in patients with the target disease to
determine its efficacy (“proof of concept”), and the doses
to be used in any follow-on trials
• Modest number of patients (100-200)
• Single-blind design may be used
• Done in special clinical centers (e.g., university hospitals)
• A broader range of toxicity may be detected
• Have the highest rate of drug failures
• Only 25% of innovative drugs move on to phase 3
PHASE 3
• Large numbers of patients with the target disease—
usually thousands—to further establish and confirm
safety and efficacy
• Designed to minimize errors caused by placebo effects,
variable course of the disease, etc.
• Double-blind and crossover techniques are often used
• Performed in settings similar to those anticipated for the
ultimate use of the drug
• Difficult to design and execute and are usually expensive
• If results meet expectations, application is made for
permission to market
• Marketing approval requires a New Drug Application
(NDA)—or for Biological License Application (BLA)—to the
FDA
PHASE 4
• Once approval to market a drug has been obtained
• This constitutes monitoring the safety of the new drug
under actual conditions of use in large numbers of patients

PHASE 1
• The effects of the drug as a function of dosage are
established in a small number
• 20-100 healthy volunteers
• If the drug is expected to have significant toxicity, volunteer
patients with the disease participate in phase 1
• Determine probable limits of the safe clinical dosage range
Figure 4. The development and testing process required to bring a
• May be nonblind or “open” drug to market in the USA

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SUMMARY
PHARMACODYNAMICS • What the drug does to a body (d for drug)
• Drug Receptor interaction
• Receptor - specific molecule that a drug may interact with that plays a regulatory role
• Types of receptor:
o Intracellular receptors
o Extracellular receptor target Adhesion receptor target
o Signaling convergence of two drug receptors (antagonistic)
• Types of transmembrane protein
o Transmembrane ion channels
o Transmembrane G-protein couple receptor subunit (GPCRS)
o Transmembrane with linked enzymatic domain
• Ligand - Substance that forms a complex with a biomolecule to serve a biological purpose
o Affinity: ability of a ligand to bind to a receptor
o Intrinsic activity: ability of the ligand to generate biochemical events leading to effect
o Classification of Ligands:
▪ Agonist: Bind to and activate the receptor which directly or indirectly brings about
the effect
→ Full agonist: Produces ALL of the expected effects
→ Partial agonist: Produces SOME of the expected effects & may be more or
less potent than full agonists
→ Inverse agonist: Acts by abrogating this intrinsic (constitutive) activity of the
free (unoccupied) receptor
▪ Antagonist: Inhibits the action of an agonist but has no effect in the absence of the
agonist
→ Competitive Antagonism: binds reversibly to the active site of a receptor
→ Non-competitive Antagonism: bind to either the active site or an allosteric
site of a receptor
→ Physiologic Antagonism: 2 ligands acting on DIFFERENT
receptors/proteins producing opposite effects
→ Pharmacologic Antagonism: 2 ligands acting in the SAME receptor
producing opposing effects
→ Chemical Antagonism “Inactivation”
• Dose-Response Relationship
o Graded Dose-Response Relationship: Linear graph of drug receptor binding or two
drugs with different values of Kd
o Quantal Dose Response Curve
▪ Median Effective Dose (ED 50): dose at which 50% of subjects exhibit a
therapeutic response
▪ Median Toxic Dose (TD 50): dose at which 50% of subjects experience a
toxic response or adverse effect
▪ Median Lethal Dose (LD 50): dose at which 50% of subjects die
▪ Therapeutic Index: measurement of drug’s margin of safety

𝑇𝐷 50
𝑻𝒉𝒆𝒓𝒂𝒑𝒆𝒖𝒕𝒊𝒄 𝑰𝒏𝒅𝒆𝒙 (𝑻𝑰) =
𝐸𝐷 50

PHARMACOKINETICS • What the body does to the drug (k for katawan)

• Absorption: Passage of the drug from its site of administration into the blood
▪ Passive Diffusion
▪ Facilitated Diffusion
▪ Active Transport
▪ Pinocytosis/Endocytosis
o Types of Dose-Response Relationship
→ Oral Cavity and Sublingual Absorption: Enter the generic circulation directly;
Sublingual administration → extensive network of blood vessels facilitates rapid
drug absorption
→ Stomach: With food = much longer in the stomach = longer time to be absorbed
→ Small Intestine: Large surface is because of the villi and microvilli = more
absorption
→ Large intestine: Smaller absorptive surface area vs. SI; Rectum – useful route,
for suppository
o Measurement of Absorption: Bioavailability: Rate and extent by which a drug
reaches systemic circulation
o Factors Affecting Bioavailability
→ Biopharmaceutical Factors

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→ First Pass/Elimination/First Pass Metabolism

o Determinants of Bioavailability
→ Plasma Data
→ Urine Data
→ Pharmacologic Effect
• Distribution: Process by which a drug reversibly leaves the systemic circulation and enters
the interstitial space and/or the cells of the tissues
o Factors That Influence Drug Distribution
→ Plasma Protein Binding
→ Cardiac Output and Blood Flow to the Tissues
→ Permeability and Perfusion of Membranes
→ Disease
o Measure of Distribution: Volume of Distribution
• Metabolism: Process by which a drug is altered chemically into another compound called
“metabolites” which may be more active (as in the case of PRODRUGS) or less active than the
parent drug; liver
o 2 Phases
→ Phase 1: Oxidation, hydrolysis, reduction mediated by cytochrome P450 (drug
metabolizing enzymes)
→ Phase 2: Glucoronidation, sulfation, glutathione conjugation, n-acetylation,
methylation
• Excretion: Process by which a drug or its metabolites is eliminated from the body through the
kidneys
o Drug Elimination: Kinetic Order
→ Zero Order Elimination: The rate of elimination is constant, but fraction of drug
is different
→ First Order Elimination: The fraction of drug eliminated is constant, but the
amount of drug eliminated is different
o Half-life: Required time to decrease the concentration of the drug in the plasma by
50%
o Steady state: Point where rate of drug availability equals rate of elimination; point
of expected maximum drug effect
Clearance: Ability of the body to eliminate the drug completely
DRUG DISCOVERY • Drug Screening: Involves a variety of assays at the molecular, cellular, organ system, and
whole animal levels to define the pharmacologic profile
• Preclinical Safety and Toxicity Testing
o No effect dose – the maximum dose at which a specified toxic effect is not seen
o Minimum lethal dose – the smallest dose that is observed to kill any experimental animal
o Median lethal dose (LD50) – the dose that kills approximately 50% of the animals
• Evaluation in Humans
o Confounding Factors in Clinical Trials
→ Viable Natural History of Most Diseases
▪ Crossover design: consists of alternating periods of administration of test
drug, placebo and standard treatment
o Presence of Other Diseases and Risk Factors
o Subject and Observer Bias and Other Factors
→ Placebo response: objective physiologic and biochemical changes as well as
changes in subjective complaints associated with the disease
→ Single-blind design: involves use of placebo, administered to the same subjects
in a crossover design
→ Double-blind design: a third party holds the code identifying each medication
packet, and the code is not broken until all the clinical data have been collected
• Clinical Trials
→ Phase 1: The effects of the drug as a function of dosage are established in a small
number; 20-100 healthy volunteers; nonblind or “open”
→ Phase 2: The drug is studied in patients with the target disease to determine its
efficacy (“proof of concept”), and the doses to be used in any follow-on trials; 100-
200; single-blind design
→ Phase 3: Large numbers of patients with the target disease—usually thousands—
to further establish and confirm safety and efficacy; double-blind and crossover
techniques
→ Phase 4: This constitutes monitoring the safety of the new drug under actual
conditions of use in large numbers of patients

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PRACTICE QUIZ QUESTIONS

Bioavailability is defined as: B) Gout
A) Amount of drug that reaches the systemic circulation C) Hyperkalemia
B) Used to determine the safety and efficacy of generic drugs D) Nephritis
C) The dose or concentration required to bring about 505 of The most common adverse effect of diuretics (except for
the drug’s maximal effect potassium-sparing diuretics) is potassium depletion
D) Measure of drug safety
Which of the following is NOT included in the signs and symptoms
Which anti-anginal drug does NOT cause gingival hyperplasia? of organophosphate poisoning?
A) Nifedipine A) Diarrhea
B) Isosorbide dinitrate B) Tachycardia
C) Diltiazem C) Urination
D) Verapamil D) Miosis
Organophosphate poisoning: DUMBBELLS
Which of the following route of administration has 100% Diarrhea
bioavailability? Urination
A) Transdermal Miosis
B) Rectal Bradycardia
C) Intravenous Bronchoconstriction
D) Oral Emesis
Lacrimation
Route Bioavailability Laxation
Intravenous (IV) 100 Salivation
Intramuscular (IM) 75 to ≤ 100
Which phase involves randomized, double blind, controlled trials?
Subcutaneous (SC) 75 to ≤ 100 A) Phase I
Oral (PO) 5 to < 100 B) Phase II
Rectal (PR) 30 to < 100 C) Phase III
D) Phase IV
Inhalation 5 to < 100
Transdermal 80 to ≤ 100 Which antiarrhythmic drug is used for perioperative thyrotoxic
arrhythmias and supraventricular tachycardia?
The following drugs have narrow therapeutic index except: A) Flecainide
A) Penicillin B) Lidocaine
B) Digoxin C) Procainamide
C) Lithium D) Esmolol
D) Warfarin
Examples of drugs with narrow therapeutic index: Which antihypertensive drug is used in ACE-inhibitor intolerance?
Digoxin, Lithium, Phenytoin, Theophylline, Warfarin A) Minoxidil
B) Losartan
Which of the following beta-blocker has the shortest duration of C) Hydralazine
action? D) Captopril
A) Esmolol Angiotensin receptor-blocking drugs (sartans) are most
B) Timolol commonly used in patients who have had adverse reactions to
C) Atenolol ACE inhibitors
D) Nadolol
Esmolol is rapidly hydrolyzed and has a half-life of approximately Which of the following is not a beta blocker?
10 minutes A) Carvedilol
B) Isoproterenol
Which drug is used for hypertensive emergency and its adverse C) Atenolol
effect is cyanide poisoning? D) Propranolol
A) Amyl nitrate Isoproterenol is a nonselective beta-agonist
B) Methyldopa
C) Prazosin Which drug is used to control blood pressure in
D) Nitroprusside pheochromocytoma?
Nitroprusside is rapidly metabolized by uptake into red blood cells A) Propranolol
with release of nitric oxide and cyanide B) Labetalol
C) Betaxolol
Which hypertensive causes a positive coombs test? D) Timolol
A) Captopril
B) Prazosin Where can you find alpha 2 receptors?
C) Amyl nitrate A) Vascular smooth muscles
D) Methlydopa B) Respiratory smooth muscles
Sometimes makes cross-matching blood for transfusion difficult; C) Nerve terminals
rarely associated with hemolytic anemia, hepatitis and drug fever D) Heart

The following are the adverse effects associated with loop diuretics
EXCEPT:
A) Ototoxicity

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