Download Advanced Pharmacology-I (PHR5001) Introduction to Pharmacology

Advanced Pharmacology-I
(PHR5001)
Introduction to Pharmacology
Dr. M G Azam
Asstt. Professor
Dept. of Pharmacy, NSU
Pharmacology
The word pharmacology comes from the
Greek word for drug, pharmakon (means “an
active principle”). Pharmacology is “knowledge
about drugs”.
It is the study of what biologically active
compounds do in the body, and how the body
reacts to them.
Drug & Body
• A drug is anything that affects the way an organism
works. For now we only consider drugs which are used to
cure a disease.
• A disease is anything which affects the proper functioning
of the body. It can be an infection, a genetic disorder, or
the result of environmental conditions such as
malnourishment, poisoning, or stress.
• Engineers often find it easy to see the body as a factory.
• Most of the work in our body is done by proteins. The
body contains thousands of different kinds of proteins.
The construction of each is determined by the DNA in the
nucleus of each cell. DNA may be thought of as long
strings of instructions which code for how each protein is
too be built.
Pharmacology
• Pharmacology is the science of drugs, which
deals with the detailed study of source,
– chemical nature,
– route of administration,
– absorption,
– distribution,
– metabolism,
– excretion,
– pharmacological effects and
– side effects of the drugs.
Pharmacology: Its Scope
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Three important and interrelated areas:
Pharmacokinetics
Pharmacodynamics
Pharmacogenetics
Pharmacokinetics
Pharmacokinetics is what the body does to the drug.
The magnitude of the pharmacological effect of a drug depends
on its concentration at the site of action :
•Absorption
•Distribution
•Metabolism
•Elimination
e.g. Pharmacokinetics of Paracetamol :
-rapidly & almost completely absorbed, orally attaining peak blood
levels at 30-60 min;
- 25%bound to plasma proteins, widely & uniformly distributed in the
body;
- extensively metabolized in the liver, primarily by glucuronide & sulfate
conjugation into inactive metabolites which are excreted in urine;
- has a plasma half life 2-3 hours .
Pharmacodynamics
Pharmacodynamics is what the drug does to the body.
It is the interaction of drugs with cellular proteins such as
receptors or enzymes to control changes in physiological
function of particular organs. It covers :
•Drug-Receptor Interactions
•Dose-Response study
•Signal Transduction : Mechanism of action, Pathways
e.g. Pharmacodynamics of Paracetamol :
-Paracetamol inhibits prostaglandin synthesis in the CNS.
- It has less effect on COX in peripheral tissues which accounts for its
weak anti-inflammatory activity.
Pharmacodynamics
Pharmacodynamics includes interaction between the
drug and target cells or tissues and the body’s
response to that interaction.
:
A) Effects of the drug: both beneficial &
harmful effects
• What does a drug do in the body?
B) Mechanism of actions of the drug
• How does a drug act in the body?
Pharmacogenetics
Area of pharmacology concerned with unusual responses
to drugs caused by genetic differences between
individuals.
Responses that are not found in the general population but
due to an inherited trait that produces a diminished or enhanced
response to a drug.
An individual's response to a drug depends on the complex interplay
between environmental factors and genetic factors. Variation in drug
response therefore may be explained by variation in environmental
and genetic factors, alone or in combination.
Differences in Enzyme Activity – Most common drug metabolizing
enzyme family Cytochrome P450 (CYP) includes >30 isoforms
Therapeutics
Therapeutics deals with  Use of drugs in living body for therapeutic
purpose
 Therapeutics is the extension of the knowledge
gained from medical pharmacology to the rational
use of drugs (RUD) in the treatment of disease
The goal of therapeutics is to achieve a desired
beneficial effect with minimal adverse effects
Pharmacotherapeutics
• It deals with the practical application of drugs in
the treatment and prevention of disease.
• The way we use drugs to prevent and treat
diseases
• Vaccines prevent disease
– Are the most cost-effective, most important medical
development of the 20th century
• Other drugs treat disease
Basic principles of drug therapy provide a conceptual
framework for deploying drugs with maximal efficacy while
minimizing the risk of adverse effects.
Drug Actions – Drug Interactions
• Desired effect: Effect of drug in the body that was intended
• Side effect: Additional effect on the body by the drug that was
not part of the goal for that medication
• Adverse reaction: One in which the body reacts to a drug in an
unexpected way that may endanger a patient’s health and
safety
• Contraindication: Any special symptom or circumstance that
indicates that the use of a particular drug or procedure is
dangerous, not advised, or has not been proven safe for
administration
• Local effect: Response to a medication that is confined to a
specific part of the body
• Systemic effect: Generalized or widespread response to a drug
by the body because it is absorbed into the bloodstream
Some other definitions
 Effects (therapeutic effects)
“The desired results of administration of a medication”
"Therapeutic Window" /"Therapeutic Concentration Range" is the range of
concentration over which the probability for therapeutic success is very
high at only limited toxicity.
 Indications
“The reasons for administering a medication or performing a treatment”
 Pharmacologic Profile: A description of all of the pharmacologic
effects of a drug (e.g., effects on blood pressure, respiration, renal
function, endocrine function, the central nervous system, etc.).
 Receptor:
“A specific protein in either the plasma membrane or interior of a target
cell with which the drug combines”
Concept of Drug-Receptor Interactions
Therapeutic and toxic effects of drugs result from their
interactions with molecules in the patient. Most drugs act by
associating with specific macromolecules in ways that alter the
macromolecules' biochemical or biophysical activities
The receptor concept has important practical consequences for the
development of drugs and for arriving at therapeutic decisions in
clinical practice.
1. Receptors largely determine the quantitative relations between dose
or concentration of drug and pharmacologic effects.
2. Receptors are responsible for selectivity of drug action.
3. Receptors mediate the actions of both pharmacologic agonists and
antagonists
Agonists: Drugs that interact with a receptor to produce a biologic
response are termed AGONISTS. An agonist has affinity for the
receptor and efficacy.
An ANTAGONIST is a drug that binds to a specific receptor, but the
drug-receptor interaction does not lead to a biologic response. An
antagonist has affinity for the receptor but
low or zero efficacy
For Example,
Half -Life (T ½)
• Half-life of a drug means the time in which the
concentration or effects of the drug decline by one
• The time needed for a drug's level in the blood stream
to go down to one half its beginning level.
In the simplest case, the body may be considered as a
single compartment of a size equal to the volume of
distribution (Vd). The time course of drug in the body will
depend on both the volume of distribution and the
clearance
Half-life
Peak serum
concentration
Drug
serum
Concen
tration
(mcg)
½ peak
Time of Maximum
Drug concentration
Time
Dose-Response Curve
1. Sub-effective dose
2. Ceiling effect, or
maximal effect
3. Threshold effect
and threshold dose
4. The plot shows a
graded response dose-dependent
effect
Potency & Efficacy
Potency is related to the size of the dose
necessary to produce a certain effect. It is
determined in part by the affinity of the receptor
for the drug.
Efficacy (or intrinsic activity) is related to the
maximal effect obtained by the drug (i.e., when all
receptors are bound to drug)
ED50 is the dose required to cause a therapeutic effect
(positive response) in 50% of a population
TD50 or LD50 is the dose required to produce a toxic effect
(or death in animal studies) in 50% of the studied population.
For every drug
there is a doseresponse curve
for effectiveness
and a doseresponse curve
for toxicity
Therapeutic Index is an indication of safety.
The larger the ratio the safer the drug.
Narrow therapeutic index drugs
Warfarin
Lithium
Digoxin
Phenytoin
Gentamycin
Amphotericin B
5-fluorouracil
AZT (zidovudine)
Key Pharmacokinetic Parameters
Parameter
(unit)
F*
(%)
AUCp
(uM.hr)
CL*p
(L/hr/kg)
T1/2
(hr)
Vd*
(L/kg)
Description
Measure of:
Influenced by:
Bioavailability
Fraction of dose
available in systemic
circulation
Absorption and
elimination (gut and
liver during first pass)
Area under the
plasma concentration
vs. time curve
Systemic exposure;
Important determinant
for efficacy and safety
Both F and CLp
AUCoral = F x Dose
CLp
Plasma clearance
Rate of drug elimination
Metabolic/excretion
rate, plasma protein
binding, blood flow
Elimination half-life
Time to reduce plasma
concentration by 50%;
Important determinant
of dosing frequency
Both CL and Vd
T1/2  Vd/CLp
Volume of
distribution
Drug distribution to
tissues
Plasma and tissue
binding
* Need Intravenous dosing
Drug Development Process
• Discovery and formulation: Synthesis of a potential new drug molecule and
an understanding of its interaction (mechanism) with the appropriate biologic targets.
Repeated application of this approach leads to compounds with increased potency and
selectivity
• Preclinical evaluation: Relevant biologic effects, drug metabolism, and
pharmacokinetic profiles and particularly an assessment of the relative safety of
the drug must be characterized in animals before human drug trials can be started.
• Clinical evaluation -Phases I-IV: With regulatory approval, human
testing can then go forward in three phases before the drug can be considered for
approval for general use.
• Post-marketing surveillance: A fourth phase of data gathering and
safety monitoring is becoming increasingly important.
The development and testing process required to
bring a drug to market