Pharmacodynamics

Husnul Khotimah
Pharmacodynamics
Pharmacodynamics deals with the study of the
biochemical and physiological effects of drugs
and their mechanisms of action.
A thorough analysis of drug action can
provide the basis for both the rational
therapeutic use of a drug and the design of
new and superior therapeutic agents.
 PRESCRIBED DOSE (R/)
Px compliance

ADMINISTERED DOSE
PK Factors :
A D M E Physiological
CONSENTRATION AT Pathological
LOCUS OF ACTION Genetics
PD Factors : Age
receptor Interaction
functional state

EFFECT / Px RESPONSE

side effect
therapeutic toxic
Mechanisms of Drug Action
The effects of most drugs result from their
interaction with macromolecular components of
the organism
These interactions initiate the biochemical and
physiological changes that are characteristic of
the response to the drug.
The term receptor denotes the component of the
organism with which the chemical agent is
presumed to interact.
Mechanisms of drug action
◦ Non-specific drug action
general anaesthetics, osmotic diuretics,
antacids
◦ Alter transport systems
Ca antagonists, local anaesthetics, cardiac
glycosides
◦ Alter enzyme function
COX inhibitors, MAO inhibitors, AChE
inhibitors
◦ Act on receptors
Synaptic transmitter substances, hormones
 Langley (1905) “Receptive substance”
Nicotin Electrical stimulation
(-) CURARE

Skeletal muscle Skeletal muscle

contraction contraction

Ehrlich (1913) specificity of the chemical

structure

receptor structure

“corpora non agunt nisi fixata”

Drug Receptor

A macromolecular component of
a cell with which a drug
interacts to produce a response
Usually a protein

2004-2005
Transmembrane Receptor
Characteristics of Drug-Receptor
Interactions
Chemical Bond: covalent, ionic, hydrogen,
hydrophobic, and Van der Waals.
Competitive, agonist-antagonist
Specific and Selective
Structure-activity relationships
Transduction mechanisms
Drug – Receptor Interaction
 4 Type Receptors →
Signaling Mechanisms

= drug

 
Out  

In G

X Y
P gene
 Signal transduction

1. enzyme linked
(multiple actions)

2. ion channel linked

(speedy)

3. G protein linked
(amplifier)
4. nuclear (gene) linked
(long lasting)

2004-2005
1. G protein-linked receptors Structure:
•Single polypeptide
chain threaded back
and forth resulting in
7 transmembrane å
helices
•There’s a G protein
attached to the
cytoplasmic side of
the membrane
(functions as a
switch).
2. Tyrosine-kinase receptors
Structure:
•Receptors exist as individual polypeptides
•Each has an extracellular signal-binding
site
•An intracellular tail with a number of
tyrosines and a single å helix spanning the
membrane
2004-2005
 3. Ion channel
receptors
Structure: Protein pores in
the plasma membrane

2004-2005
Intracellular receptors

Not all signal receptors are located on the plasma membrane.

Some are proteins located in the cytoplasm or nucleus of
target cells.
• The signal molecule must be able to pass through
plasma membrane.

Examples:
~Nitric oxide (NO)
~Steroid (e.g., estradiol, progesterone, testosterone)
and thyroid hormones of animals).
▪ B. Second Messengers
▪ Small, nonprotein, water-soluble molecules
or ions
▪ Readily spread throughout the cell by
diffusion
▪ Two most widely used second messengers
are:
▪ 1. Cycle AMP
▪ 2. Calcium ions Ca2+
2. Calcium Ions (Ca2+) and Inositol Trisphosphate
•Calcium more widely used than cAMP
•used in neurotransmitters, growth factors, some
hormones
•Increases in Ca2+ causes many possible responses:
•Muscle cell contraction
•Secretion of certain substance
•Cell division
Two benefits of a signal-transduction pathway
1. Signal amplification
2. Signal specificity

A. Signal amplification
•Proteins persist in active form long enough to
process numerous molecules of substrate
•Each catalytic step activates more products
then in the proceeding steps
Foundational Concepts
Addictive Effect
◦ An effect in which two substances or actions used in
combination produce a total effect the same as the
sum of the individual effects
Synergistic Effect
◦ The use of two or more drugs that produce a greater
effect of one drug used alone
◦ Ex. NSAID added to codeine for pain relief
Antagonistic Effect
◦ The use of a second drug reduces the effect of
another drug
◦ The second drug has an antagonistic effect
◦ A second drug may bind to the same receptor as the
first drug, thus preventing the agonist response
 Agonist Dose Response Curve

Full agonist
Partial agonist
Response

Dose
Placebo Effect
◦ Either a therapeutic or adverse response that cannot
be attributed to the pharmacological effect of the
drug
◦ Contains no active ingredient
◦ 35% of the population responds to a placebo effect
●Responses include relief of fever, headache, anxiety,
nausea, & pain
●Effect is not imaginary
 The Major Effectors and Intracellular
Second Messengers in GPCR Systems

Effector 2nd messenger

➢adenylyl cyclase ➢cyclic AMP (cAMP)

✓phospholipase C ✓calcium, DAG, and
phosphoinositide
(IP3)
Pharmacodynamic Principles
Addictive Effect
◦ An effect in which two
substances or actions used in
combination produce a total
effect the same as the sum of
the individual effects
Synergistic Effect
◦ The use of two or more drugs
that produce a greater effect
of one drug used alone
◦ Ex. NSAID added to codeine
for pain relief

Foundational Concepts
Pharmacodynamic Principles
Antagonistic Effect
◦ The use of a second drug
reduces the effect of
another drug
◦ The second drug has an
antagonistic effect
◦ A second drug may bind to
the same receptor as the
first drug, thus preventing
the agonist response

Foundational concepts
Pharmacodynamic Principles
Placebo Effect
◦ Either a therapeutic or
adverse response that cannot
be attributed to the
pharmacological effect of the
drug
◦ Contains no active ingredient
◦ 35% of the population
responds to a placebo effect
● Responses include relief of
fever, headache, anxiety,
nausea, & pain
● Effect is not imaginary

Is the placebo effect an ethical

Foundational concepts patient treatment in AT?
Pharmacodynamic Principles
If a patient is convinced
that pain relief is
imminent upon
administration of an
analgesic, a placebo
effect may bring
greater relief than what
would be expected
from the drug alone

Can a placebo be used as a

Foundational concepts diabetic treatment?
Pharmacodynamic Principles
Tolerance
◦ A diminished response to a
drug as a result of
continued use
◦ Not all drugs produce
tolerance
◦ When tolerance is developed
for one drug in a category, a
cross tolerance may
developed for another drug
in the same category

Foundational concepts
Pharmacodynamic Principles
2 major mechanisms
that cause
pharmacological
tolerance
◦ Enzyme Induction
● The liver produces more
drug-metabolizing
enzymes
◦ Receptor Effects
● Responsiveness of the
receptors decreased

Foundational concepts Enzyme or receptor?

Pharmacodynamic Principles
As the concentration of
the drug increases,
more molecules will
occupy more receptors,
which then produces a
greater response
This is known as the
Does-Response
Principle

Dose-response
relationship
Pharmacodynamic Principles
Potency
◦ The dose of a drug
required to produce a
particular effect relative to
the dose of another drug
that acts by a similar
mechanism to produce the
same effect
◦ Caffeine vs Amphetamines

Caffeine or
Single dose amphetamines?
Pharmacodynamic Principles
When multiple doses of a
drug are administered,
blood concentration
increases beyond that of a
single dose
The body absorbs what it
can and metabolizes or
excretes the excess
The “leveling off” of the
drug is the steady state

Multiple dose & Steady State

Pharmacodynamic Principles
Maintenance Dose
◦ A dose administered at a
regular dosing interval on a
repetitive basis
Loading Dose
◦ One or more doses that are
higher than the maintenance
dose & administered at the
beginning of therapy
◦ Achieves the desirable
concentration quicker

Maintenance & loading

Pharmacodynamic Principles
Measure blood
concentration of the
drug
The range between the
low and high desired
concentration is
referred to as
therapeutic range or
therapeutic window

Therapeutic drug
monitoring
Pharmacodynamic Principles
Refers to the extent to
which the patient is
taking the medication as
prescribed
Reasons for patient non-
compliance
◦ High cost
◦ Forgetting to take meds
◦ Inconvenience
◦ Poor patient education

Patient compliance
Pharmacodynamic Principles
The liver and kidney
remove most drugs
from the body
Disease, drug toxicity,
& aging process may
necessitate dosage
adjustment

Liver & kidney function Human liver

Pharmacodynamic Principles
Receptor Antagonist
◦ 2 drugs have an affinity
for the same receptor
◦ One drug displaces the
other and diminishes the
response
◦ Agonist vs Antogonist

Types of drug interactions

Pharmacodynamic Principles
Enzyme Induction
◦ When a drug increases the
metabolizing enzymes for
another drug
Enzyme Inhibition
◦ 2 drugs bind on the same
metabolizing enzyme
◦ One drug inhibits the
enzyme for the other

Types of drug interaction

Pharmacodynamic Principles
Physiologic Antagonism
◦ 2 drugs given concurrently
oppose each other
◦ Neither drug effects the
mechanism of action

Types of drug interactions

Pharmacodynamic Principles
Physiologic Agonists
◦ 2 or more drugs used
concurrently result in an
increase in physiologic
effects
◦ The drugs do not have the
same mechanism of action

Types of drug interactions

Pharmacodynamic Principles
Absorption Effects
◦ The use of one drug
inhibits the absorption of
another when given
concurrently
Excretion Effects
◦ One drug increases or
decreases the excretion of
another

Types of drug interactions

Pharmacodynamic Principles
Side Effects
◦ Unintended effect based
on the pharmacologic
action of the drug
Allergic Reactions
◦ Exaggerated immune
response to a certain drug
Organ Cytotoxic Effects
◦ Adverse effects on organs

Adverse drug reactions

Pharmacodynamic Principles
Idiosyncratic Reactions
◦ Reaction that is particular to
an individual or defined
group of people
Drug-drug Interactions
◦ Interaction of 2 or more
drugs that result in a
disadvantage to a patient
Drug-food Interactions
◦ Interaction of a drug with
food that results in an
adverse patient reaction

Adverse drug reactions

Pharmacodynamic Principles
Drug-herb Interactions
◦ Interaction of a drug with
herbal products that results
in an adverse patient
reaction
Drug Use During
Pregnancy
◦ Most drugs cross the
placenta
◦ Thus, posing an adverse
reaction to the child

Adverse drug reactions