PHARMACOLOGY

- science of drugs

- interactions between living
systems & molecules
introduced from outside
the system

GOAL

- to understand the mechanisms by
which drugs interact with
biologic systems in the
diagnosis & treatment of
disease

Drug

- a natural product, chemical substance,
or pharmaceutical preparation to be used
in the diagnosis or treatment of a disease

- varies in terms of : molecular size
shape
chemical nature
Drug Names :

A. Chemical name - chemical structure of the drug

B. Nonproprietary name - generic name

C. Proprietary name trade name or brand name


Pharmaceutical preparations

- tablets & capsules
- drug solutions and particle suspensions
- skin patches
- aerosols, nasal sprays
- ointments and creams
- suppositories

Branches of Pharmacology
1. Pharmacy - involved in the compounding,
preparation, collection, standardization and
dispensing of the drug.

2. Pharmacognosy recognize the drugs
(description, sources, chemical composition,
nature of doing, etc)
- study of the physical and
chemical properties of the drugs with the
description and identification of their sources
and nature.)

3. Biochemorphology (structure activity relationship or
SAR)
how the chemical structure of the drug is related to
physiological, biological and biochemical effects.

endogenous catecholamines- synthesized in the body (epinephrine,
norepinephrine, dopamine, tyrosine)
synthetic (exogenous) catecholamines- from outside given to the
body (isoproterenol)
ephedrine- mixed-acting symphatomimetic agent; CNS stimulation; not
a catecholamine but its effects on bronchi and other smooth muscles
are quantitatively similar to those of epinephrine
amphetamine- acts indirectly by releasing norepinephrine; also a CNS
stimulant; depresses the appetite by affecting the feeding center in the
lateral hypothalamus
Norepinephrine affects 1, 2 and 1
Epinephrine affects 1, 2, 1 and 2
4. Toxicology study of the harmful effects of drugs and
other chemicals on human, animals and plants

5. Posology deals with the dosage of the drug required to
produce a therapeutic response

6. Molecular Pharmacology studies the mechanism of
action of a drug at enzymatic level (gene therapy;
genetic engineering)

7. Developmental Pharmacology deals w/ drug given to
mother as it affects the fetus during natal, prenatal,
perinatal & neonatal periods.

8. Pharmacogenetics studies the influence of heredity on
the pharmacokinetic and pharmacodynamic response
of the drug.

9. Pharmacogenomics describes the use of genetic information
to guide the choice of drug therapy on an individual basis
discovers which specific gene
variations are associated with a good or poor therapeutic
response to a particular drug

10. Pharmacoepidemiology studies the response in population
at a given time and space of the pharmacologic events,
whether they are adverse or beneficial with the use of
measures of epidemiology

11. Pharmacoeconomics studies the cost effectiveness of
drug treatment

12. Ethnopharmacology deals with the interethnic differences
in response to or metabolism of chemical substances, and
the presence and absence of enzymes in different regions of
the Phil. or of different races.
13. Clinical Pharmacology deals w/ rational development of
drugs, their safe & effective use, and other proper
evaluation of drugs in humans for the prevention,
diagnosis, treatment, alleviation or cure of a disease.
refers to the rational use of
drugs (ESSC crirteria)

Efficacy considers pharmacodynamics, pharmacokinetics,
of the different drug groups; ability of drug to accomplish
what it is intended to do.
Safety side effects, toxicity, frequency and severity
Suitability convenience, compliance, practicality,
contraindications and possible interactions.
Cost
14. Pharmacokinetics movement of the drug in the body and
how the body acts on the drug
fate of drug in the body
involves four processes
Absorption
Distribution
Metabolism (biotransformation)
Excretion

15. Pharmacodynamics biochemical and physiological effects
of drugs and their mechanism of action (includes
enzymatic or molecular level and also toxicological or
adverse effects.)
Pharmacology
Systems pharmacology
Chemotherapy
Molecular
pharmacology
Biochemical
pharmacology
Pharmacokinetics/
Drug metabolism
Neuro-
pharmacology
Gastrointestinal
pharmacology
Cardiovascular
pharmacology
Immuno-
pharmacology
Respiratory
pharmacology
PSYCHOLOGY
Psycho-
pharmacology
CLINICAL
MEDICINE
THERAPEUTICS
Clinical
pharmacology
PHARMACY
Pharmaceutical
Sciences
VETERINARY
MEDICINE
Veterinary
pharmacology
BIOTECHNOLOGY
Biopharmaceuticals
PATHOLOGY
Toxicology
CHEMISTRY
Medical
chemistry
GENETICS
Pharmacogenetics
GENOMICS
Pharmacogenomics
CLINICAL
EPIDEMOLOGY
Pharmacoepidemiology
HEALTH
ECONOMICS
Pharmacoeconomics
Phases of a Clinical Drug Investigation
Phase Purpose
I Establish safety
II Establish efficacy and dose
III Verify efficacy and detect ADRs
IV Obtain additional data following
approval
Phases of Drug Manufacture

I. ANIMAL TESTING (Pre-clinical testing)

- tested in at least 2 rodent & 1 non rodent species
- 1 to 3 yrs. (ave. 18 months)
- here you determine for the:
~ Acute toxicity - observation of animal 7-14 days
using a simple dosage of the drug being tested.
~ Subacute toxicity - 2 weeks to 3 months.
~ Chronic toxicity - 6 months to 2 years.

II. FDA
- 30 days safety review
III. CLINICAL TESTING

Includes humans (healthy adult males)
2-10 yrs (average 5-6 yrs)
the lowest effective dose given to man because humans
can react differently to the drug
pediatric patients not included in the testing because
some drugs can have adverse effects on the
development of the patient.
Short term
Long term (chronic toxicity, reproduction, teratogenicity)

Phase I involves normal healthy adult male
to measure the initial drug safety, biological effects,
metabolism, kinetics
done by the clinical pharmacologist

Phase II involves selected patients, needing the treatment
to measure therapeutic efficacy, dosage range,
metabolism, kinetics
done by clinical pharmacologist

Phase III involves large sample of selected patients
to measure the safety and efficacy
done by clinical investigators

IV. New Drug Application (NDA)
- Review (BFAD)
- Marketing approval

V. Post Marketing Surveillance (PMS)
- to look for chronic effects

Phase IV drug is available commercially
involves patient given the drug treatment
to look for adverse reactions, patterns of drug
utilization, additional indications discovered.
Done by all physicians.
Phases of Product Development
- It takes 12 years on average for an experimental drug to travel from lab to medicine chest. Only five in
5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people
is approved.
Clinical Trials

Preclinical
Testing
File
IND at
FDA
Phase I Phase II Phase III
File NDA
at FDA
FDA Phase IV
Years 3.5 1 2 3 2.5
12
Total
Additional
Post
marketing
testing
required by
FDA
Test
Population
Laboratory
and animal
studies
20 to 80
healthy
volunteers
100 to 300
patient
volunteers
1000 to 3000
patient
volunteers
Review
process /
Approval

Purpose
Assess safety
and biological
activity
Determine
safety and
dosage
Evaluate
effectiveness,
look for side
effects
Verify
effectiveness,
monitor adverse
reactions from
long-term use
Success
Rate
5,000
compounds
evaluated
5 enter trials
1
approved
Placebo I shall please

Used to achieve blindness and subjective bias
Response may involve objective, physiologic and
biochemical changes as well as change in subjects
complaints associated with the disease.
Two types:
1. do not contain pharmacologically active
ingredients (used for negative control)
2. contain some compound with
pharmacological activity different from the test
drug (used for positive control)
FUNDAMENTAL TYPES OF DRUG ACTION

STIMULATION enhances the specialized tissues

DEPRESSION diminished functional activity of specialized
tissues

IRRITATION either stimulate or depress non-specialized
tissues
OTHER DRUG ACTIONS

REPLACEMENT THERAPY- replaces what is sufficient
and deficient

ANTI-INFECTIVE- entails the use of anti-microbial agents

LOCAL- Topically applied, and action is just on the area
itself

SYSTEMIC- produces a systemic effect even if you just
apply it on your on your skin; sprayed or injected
ACTIONS IN RELATION TO SPECIFIC EFFECTS

Cathartic- increases bowel movement

Laxative- for constipated patients

Hypnotic- induces sleep

Diuretic- increases urination

Antacid- has buffering actions; neutralizes HCl

Vasodilator- relaxed vascular smooth muscles (Ca 2+
blocker)
VARIABLES INVOLVED IN DRUG ACTIVITY

Dose of drug administered

Pharmaceutical phase
(bioavailability)
(disintegration and dissolution)

Pharmacokinetic Phase

Pharmacodynamic phase
(drug-cell, drug-receptor, drug-drug interactions;
individual sensitivity; pathological conditions)

Effects
(toxic, therapeutic, subtherapeutic)
PHARMACEUTICAL PHASE involves disintegration of
dosage form (generally water soluble) & dissolution
of active ingredients (lipid soluble)

Bioavailability fraction of unchanged drug
reaching the systemic circulation following
administration by any route

PHARMACODYNAMIC PHASE
Drug-drug interaction simultaneous intake of two
different drugs, one drug may displace another for
its binding site.
another may reduce the
metabolism of the other
Individual sensitivity interpatient variability (for
hyperactive and hypoactive people.
Pathological conditions renal, cardiac, hepatic
dysfunctions, malnutrition
END
Drug formulation - depends on the ff. factors :

A. The barriers that the drug is capable of passing
B. The setting in which the drug will be used
C. The urgency of the medical situation
D. Stability of the drug
E. First Pass Effect
Routes of Drug Administration

A. Enteral - sublingual, oral, rectal
B. Parenteral - IV, IM, SubQ, Intrathecal
C. Transdermal
D. Inhalational
E. Topical
Factors governing choice of route
1. Physical and chemical properties of the drug
(solid/liquid/gas; solubility, stability, pH, irritancy)
2. Site of desired action localized and approachable
or generalized and not approachable.
3. Rate and extent absorption of the drug from different
routes.
4. Effect of the digestive juices and first pass
metabolism on the drug.
5. Rapidity with which the response is desired (routine
treatment or emergency)
6. Accuracy of dosage required (i.v. and inhalational
can provide fine tuning)
7. Condition of the patient (unconscious, vomiting)
Limitations of Oral Route of Administration
Action is slower and thus not suitable for emergencies.
Unpalatable drugs (paraldehyde) are difficult to
administer; drug may be filled in capsules to
circumvent this.
May cause nausea and vomiting (emetine).
Cannot be used for uncooperative/unconscious/vomiting
patient
Certain drugs are not absorbed (streptomycin)
Others are destroyed by digestive juices (penicillin G,
insulin) or in liver (nitroglycerine, testosterone,
lignocaine).
Pharmacokinetic Parameters
1. Absorption
2. Distribution
3. Metabolism
4. Elimination
Pharmacokinetic Variables
1. Half-life
2. Clearance
3. Bioavailability
PHARMACOKINETICS



Factors affecting Pharmacokinetics : rates of drug absorption
distribution
metabolism
elimination


Drug Absorption - passage of a drug from its site of administration into
the circulation

- route of administration
4 Major Mechanisms of Drug Transport across Membranes

A. aqueous diffusion
B. lipid diffusion
C. facilitated diffusion / special carriers
D. pinocytosis / receptor-mediated endocytosis


Effect of pH on absorption of weak acids and bases

weak acids and bases - exist in both ionized and nonionized
forms in the body
- only the uncharged species
( the protonated form for the weak
acid; the unprotonated form for a
weak base ) can diffuse across lipid
membranes pH partition

pH partition weak acids tend to accumulate in compartments of
relatively high pH, weak bases do the reverse
Some important consequences of the pH partition mech.:

1. urinary acidification accelerates excretion of weak bases & retards that of
weak acids, while urinary alkalinization has the opposite effect

2. increasing plasma pH causes weakly acidic drugs to be
extracted from the CNS into the plasma


Factors affecting GI Absorption :

1. GI motility 3. particle size & formulation

2. splanchnic blood flow 4.physicochemical factors
Drug Distribution:
Major Compartments : plasma 5% of B.W.
interstitial fluid 16%
intracellular fluid 35%
transcellular fluid 2%
fat 20%
Volume of Distribution the volume of plasma that
would contain the total body content
of the drug at a concentration equal
to that in the plasma


Dose ( Q ) Ex. : 500 mg
Vd

=
____________ _________
=

100 L

Cp 5 mg / L

V
d
provides an indication of the physiologic distribution
of the drug
small V
d
drugs distribution is restricted to the
plasma & ECF
large V
d
concentrated intracellularly
Factors Affecting Distribution :
1. Organ blood flow
2. Plasma protein binding
3. Molecular size
4. Lipid solubility
Drug Biotransformation to inactivate drugs & other foreign compounds
drug metabolites more water soluble than the parent molecule
prodrugs inactive compounds that are biotransformed to active
metabolites
first-pass effect drugs are converted to inactive metabolites during
their first pass through the liver and have
low bioavailability after oral administration
Phases of drug biotransformation :
A. Phase I ( nonsynthetic ) drugs are oxidized or reduced to a
more polar form
1. oxidative reactions - microsomal cytochrome P450 monooxygenase
- cytoplasmic enzymes
2. hydrolytic reactions - cholinesterases hydrolyze ester & amide drugs
3. reductive reactions - hepatic nitroreductase
B. Phase II ( synthetic ) - drugs are conjugated with acetate,
glucuronate, sulfate or glycine
- most conjugated drug metabolites are
inactive
Kinetics of Metabolism

1. 1
st
order kinetics - rate of drug elimination is proportional to the
plasma drug
a. Elimination Half-life - time required to eliminate half of the amount
of a drug in the body or to reduce the
plasma drug concentration by 50%
b. Drug Clearance - volume of body fluid from which a substance is
removed per unit of time
- liters per hour
elimination rate ( mg/hr )
- CL = ________________________
drug concentration ( mg/L )
2. Zero-order kinetics ( nonlinear or dose-dependent kinetics )
- drugs that saturate routes of elimination disappear
from plasma in a non-concentration dependent
manner
- a constant amount of drug is lost per unit time
- half-life is not constant but depends on the
concentration
- metabolism in the liver involving specific enzymes is
one of the most important factors

total clearance renal clearance + metabolic clearance + all other
clearance
renal clearance renal excretion rate divided by the time plasma
drug concentration

Drug Excretion
Amount of drug excreted = sum of the amounts filtered & secreted
minus the amount reabsorbed
1. renal drug excretion - glomerular filtration
- passive tubular reabsorption
- active tubular secretion
2. biliary excretion & enterohepatic cycling


Pharmacokinetic Variables :
1. volume of distribution 3. half-life
2. clearance 4. biolavailability

Single-Dose Kinetics

1. Plasma drug concentration curve after a single dose of drug
administered, plasma concentration increases as the drug is
absorbed, reaches a peak as absorption is completed &
then declines as the drug is eliminated

2. Bioavailability fraction of the administered dose of the drug that
reaches the systemic circulation in an active form
Continuous & Multiple-Dose Kinetics

1. Drug accumulation & the steady-state principle
When a drug that exhibits first-order pharmacokinetics
is administered continuously or intermittently, the drug will
accumulate until it reaches a plateau or a steady-state plasma
drug concentration.
a. time required to reach the steady-state condition
b. steady-state drug concentration

2. Dosage calculations
a. loading dose V
d
+ desired plasma during concentration
b. maintenance dose drug clearance X average steady-state
plasma drug concentration
Mechanics of Drug Action
A. Nature of Drug Receptors
receptors specific cell molecules to which most drugs interact to
produce their effect
Effects of Coupling :
1. opening or closing of an ion channel
2. activation of biochemical messengers ( 2
nd
messengers )
3. physical inhibition of a normal cellular function
4. turning on of a cellular function
Type of Receptors : hormones & neurotransmitters
enzymes
ion channels &
transporters membrane lipids or
nucleic acids

B. Drug Receptor Interactions :
1. Receptor Binding & Affinity - form H
+
, ionic or hydrophobic bonds with
a receptor site
- form covalent bonds with a
receptor
Affinity - tendency of a drug to combine with its receptor
- strength of binding
Dissociation Constant ( K
D
) - measure of a drugs affinity for a given
receptor


- concentration of a drug required in
solution to achieve 50%
occupancy of its receptors ( molar
concentration )
- the lower the K
D
, the greater is the
drugs affinity for the receptor
2. Signal Transduction receptor binding initiates a cascade of
biochemical events leading to a physiologic
effect ( G protein )

3. Intrinsic Activity - ability of a drug to initiate a cellular effect
( alteration of cell physiology )

Agonists drugs that have both receptor affinity & intrinsic
activity

Antagonists lack intrinsic activity

Type of Agonists : full - maximal response
- increases rate of signal
transduction
partial - submaximal response
inverse - decreases rate of signal
transduction
Types of Antagonists : competitive
noncompetitive
irreversible ( nonequilibrium competitive )
physiological
chemical
C. Functions of Receptors :
1. to propagate regulatory signals from outside to within the effector cell when the
molecular species carrying the signal cannot itself penetrate the cell
membrane
2. to amplify the signal
3. to integrate various extracellular & intracellular regulatory signals
4. to adopt to short term & long term changes in the regulatory milieu & maintain
homeostasis

Dose - Response Relationship
- the relationship between the concentration of a drug at the
receptor site & the magnitude of the response
- response elicited with each dose of a drug is described in terms
of a percentage of the maximal response


Efficacy - maximal response produced by a drug

Potency - expressed in terms of the median effective
dose ( ED
50
), the dose that produces
50% of the maximal response
- determined by the affinity of a drug for its
receptor


2 components of dose response relationships

1. dose-plasma concentration relationship
2. plasma concentration-response relationship


EC
50
( Effective Concentration 50% )
- drug concentration which induces a
specified clinical effect in 50% of the
subjects to which the drug is administered


LD50 ( Median Lethal Dose )
- concentration of a drug whiich induces
death in 50% of the subjects to
which the drug is administered

TI ( Therapeutic Index )
- ratio of LD50 TO ED50
- measures safety of a drug


Margin of Safety
- margin between therapeutic & lethal
doses of a drug


Drug Interactions :

Mechanisms : altered absorption
altered metabolism
plasma protein competition
altered excretion

1. Addition response elicited by the combined
drugs is EQUAL TO the
combined responses of the
Individual drugs
2. Synergism response elicited by combined drugs is
GREATER THAN the combined responses
of the individual drugs
3. Potentiation a drug which has no effect
enhances the effect of a second
drug
4. Antagonism drug inhibits the effect of another
drug
PATIENT PROFILE

Factors to Consider :

age
pregnancy status
smoking & drinking habits
liver or kidney disease
pharmacogenetics
drug interactions
psychosocial factors