PHARMACODYNAMICS

Lourdes T. M. Dominguez, M.D.

University of Santo Tomas
Faculty of Pharmacy
 PHARMACODYNAMICS
  Actions/effects of the drug on the body
  Determines the group in which the drug is
classified and plays a major role in
deciding whether a group is appropriate
therapy for particular symptom or disease
 RECEPTORS
  Specific molecules in a biologic system with which
drugs interact to produce changes in the function
of the system
  Determine the quantitative relations between dose
or concentration of drug and pharmacologic
effects
  Selective in choosing a drug molecule to bind to
avoid constant activation by promiscuous binding
of many different molecules
  Changes its function upon binding in such a way
that the function of the biologic system is altered
in order to have pharmacologic effect
 RECEPTORS
  Selective in ligand-binding characteristics
(respond to proper chemical signals and not to
meaningless ones)
  Mediate the actions of both pharmacologic
agonists and antagonists
  Majority are proteins which provide the
necessary diversity and specificity of shape and
electrical charge
RECEPTOR SITE/RECOGNITION SITE
  Specific binding region of the macromolecule
  High and selective affinity to the drug molecule

 Interaction between the drug and the receptor

is the fundamental event that initiates the action
of the drug
CLASSIFICATION OF RECEPTORS
1. REGULATORY PROTEIN
  Best characterized drug receptors
  Mediates the action of endogenous chemical
signals like neurotransmitters, autacoids and
hormones
  Mediates the effects of the most useful
therapeutic agents
2. ENZYMES
  Inhibited (or less commonly, activated) by
binding a drug
  Eg, dihydrofolate reductase, the receptor for
methotrexate

3. TRANSPORT PROTEINS
  Eg, Na+/K+ ATPase, the membrane receptor for
digitalis

4. STRUCTURAL PROTEINS
  Eg, tubulin, the receptor for colchicine,
an anti-inflammatory drug
 EFFECTORS
  Molecules that translate the drug-receptor
interaction into a change in cellular activity
  Eg, adenyl cyclase
  Some receptors are also effectors
  A single molecule may incorporate both the drug
binding site and the effector mechanism
DRUG CONCENTRATION AND
RESPONSE
 GRADED DOSE-RESPONSE CURVE
  Response of a particular receptor-effector
system is measured against increasing
concentration of a drug
  Graph of the response versus the drug dose
  Sigmoid curve
  Efficacy (Emax) and potency (EC50) are derived
from this curve
  The smaller the EC50, the greater the potency of
the drug
 Emax
  Maximal response that can be produced by a
drug
  All receptors are occupied
  No response even if the dose is increased

EC50
  Concentration of drug that produces 50% of
maximal effect
  Smaller EC50– more potent
 Emax
10
Drug effect

EC50

Drug dose
 Bmax
  Total number of receptor sites
  All receptors have been occupied

KD
  Equilibrium dissociation constant
  Concentration of drug required to bind 50% of
the receptors
  Measure of the affinity of a drug for its binding
site on the receptor
  Smaller KD– greater affinity of drug to receptor
 Bmax
10

Receptor bound
drug
5

KD
Drug dose
 A B C

Agonist effect

0.5
E

Agonist dose
 A B C

Agonist effect 0.5

E

Agonist dose

CURVE A
  Agonist response in the absence of antagonist
 A B C

Agonist effect 0.5

E

Agonist dose

CURVE B
  After treatment with low concentration of antagonist, the
curve is shifted to the right
  Maximal response is preserved because the remaining
available receptors are still in excess
 A B C

Agonist effect 0.5

E

Agonist dose

CURVE C
  Produced after larger concentration of antagonist, the
available receptors are no longer “spare”, sufficient
enough to mediate an undiminished maximal response
 A B C

Agonist effect 0.5

E

Agonist dose

CURVE D and E
  With higher concentrations of antagonist, reduce the
number of available receptors to the point that maximal
response is diminished
  EC50 may approximate the KD that characterizes the
binding affinity of the agonist for the receptor
 COUPLING
  Transduction process between the
occupancy of receptors and production of
specific effect
  Highly efficient coupling can be elicited by
a full agonist and spare receptors
 SPARE RECEPTORS
  Maximal drug response is obtained at less than
maximal occupation of the receptors
  Not qualitatively different from nonspare receptors,
not hidden or unavailable
  Temporal in character, when occupied, they can
be coupled to respond, there is still effect
  Drugs with low binding affinity for receptors will
be able to produce full response even at low
concentration
 SPARE RECEPTORS
  Compare concentration for 50% of maximal effect
(EC50) with concentration for 50% maximal binding
(KD)
  KD > EC50 with spare receptors
  Effect of the drug-receptor interaction may persist
for a longer time than the interaction itself
  Actual number of receptors may exceed the
number of effectors available
 INERT BINDING SITES
  Non-regulatory molecules of the body
  Binding with these molecules will result to no
detectable change in the function of the biologic
system
  Buffers the concentration of the drug
  Bound drugs do not contribute directly to the
concentration gradient that drives diffusion
  Eg, albumin
 AGONIST
  Binds to the receptor and directly or indirectly bring about
an effect
  Full activation of the effector system

PARTIAL AGONIST
  Produces less than the full effect, even when it has
saturated the receptors
  Acts as an inhibitor in the presence of a full agonist

ANTAGONIST
  Binds but do not activate the receptors
  Blocks or competes with agonist
 CLASSIFICATION
1. COMPETITIVE ANTAGONIST
  Competes with agonist receptor
  Binds to the receptor reversibly without
activating the effector system
  Antagonist increases the agonist concentration
needed for a given degree of response
  Concentration-effect curve is shifted to higher
doses (ie, horizontally to the right of the dose
axis)
  Same maximal effect is reached
  Effects are overcomed by adding more agonist
  Increases the median effective dose (ED50)
 Agonist alone

Agonist effect

Agonist + competitive antagonist

Agonist dose
COMPETITIVE ANTAGONIST
2 THERAPEUTIC IMPLICATIONS
(1)  Degree of inhibition produced by the
competitive antagonist depends on the
concentration of antagonist (eg, propranolol)
(2)  Clinical response to a competitive antagonist
depends on the concentration of agonist
that is competing for binding to the receptor
2. IRREVERSIBLE ANTAGONIST
  Binds with the receptor via covalent bonds
  Antagonist’s affinity to the receptor maybe
so high
  Receptor is not available to bind the agonist
  Concentration-effect curve moves downward
  No shift of the curve in the dose axis
  Emax is not reached
  No increase in median effective dose (ED50)
unless there are spare receptors
2. IRREVERSIBLE ANTAGONIST
  Duration of action is relatively independent of its
own rate of elimination
  More dependent on the rate of turnover of
receptors
  Eg, phenoxybenzamine binding with alpha
receptors
 Agonist alone

Agonist effect

Agonist + irreversible antagonist

Agonist dose
3. CHEMICAL ANTAGONISM
  Does not depend on interaction with the
agonist’s receptor
  Drug that interacts directly with the drug being
antagonized to remove it or to prevent it from
reaching its target
  Eg, protamine used to counteract the effect of
heparin making it unavailable for interaction with
proteins involved in the formation of blood
4. PHYSIOLOGIC ANTAGONISM
  Makes use of the regulatory pathway
  Effects that are less specific and less easy to control
  Binds to a different receptor producing an effect opposite
to that produced by the drug it is antagonizing
  Examples
  Glucocorticoids catabolic effects of increase in sugar
is physiologically opposed by insulin
  Histamine causes bronchoconstriction in asthmatic
patients, opposed by bronchodilators like salbutamol
and epinephrine
 SIGNALING MECHANISMS
5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS
(1)  Lipid soluble drug crossing the plasma membrane and
acts on intracellular
receptor (eg, steroids)
(2)  Transmembrane receptor protein-intracellular
enzymatic activity is regulated by a ligand that binds to
the protein’s extracellular domain
(4)  Transmembrane receptor that binds and stimulates a
protein tyrosine kinase (eg, insulin)
(6)  Ligand-gated transmembrane ion channel which
regulates the opening of the ion channel (eg, GABA,
excitatory acetylcholine)
(8)  Transmembrane receptor is coupled with an effector
enzyme by G protein which modulates production of an
intracellular second messenger [eg, cathecolamine
(epinephrine)]
INTRACELLULAR 2ND MESSENGERS
A.  cAMP
  Mediates hormonal responses
  Mobilization of stored energy
breakdown of carbohydrates in the
liver stimulated by cathecolamines
  Conservation of water by the kidneys
mediated by vasopressin
  Calcium homeostasis by parathyroid
hormone
  Heart rate and contraction by beta-
adrenomimetic cathecolamines
B. CALCIUM AND PHOSPHOINOSITIDES
  Bind to receptors linked to G proteins while
others bind to receptor tyrosine kinases
  Crucial step is the stimulation of membrane
enzyme phospholipase C

C. cGMP
  Causes relaxation of vascular smooth muscles
by a kinase-mediated mechanism
  Few signaling roles in a few cell types like the
intestinal mucosa and vascular smooth muscle
cells
 RECEPTOR DESENSITIZATION
  Response gradually diminishes even if the drug
is still there (after reaching an initial high level of
response)
  Reason is not known

STRUCTURE ACTIVITY RELATIONSHIP

  Cells use more than one signaling mechanism
to respond to the drug
 QUANTAL DOSE-RESPONSE CURVE
  Graph of the fraction of a population that shows
a specified response to increasing doses of a
drug
  Minimum dose required to produce a specific
response is determined in each member of
the population
  Sigmoid curve
 ED50
  Median effective dose
  50% of the individuals manifested the desired
therapeutic effect

TD50
  Median toxic dose
  50% of the individuals manifested the toxic
effects

LD50
  Median lethal dose
 THERAPEUTIC INDEX
  Ratio of the TD50 (or LD50 ) to the ED50
determined from the quantal dose-response
curves
  Increased therapeutic index-wide margin of
safety
  Represents an estimate of the safety of the drug
  A very safe drug might be expected to have a
very large toxic dose and a much smaller
effective dose
 Eg, ED50 of 3mg and the LD50 is 150 mg
  Therapeutic index is 50 (150/3)
 THERAPEUTIC WINDOW
  Dosage range between the minimum effective
therapeutic concentration or dose (MEC) and the
minimum toxic concentration or dose (MTC)
  More clinically relevant index of safety
  Eg, Theophylline
  MEC=7-10 mg/L (average of 8 mg/L)
  MTC=15-20 mg/L (average of 18 mg/L)
  Therapeutic window=8-18 mg/L
 MAXIMAL EFFICACY
  Maximal effect (Emax) an agonist can produce if
the dose is taken to very high levels
  Determined mainly by the nature of receptors
and its associated effectors
  Measured with a graded dose-response curve
but not with quantal dose-response curve
 POTENCY
  Amount of drug needed to produce a given effect
  In the graded dose-response curve, the effect
chosen is the 50% of the maximal effect and the
dose is (EC50)
  In the quantal dose-response curve, ED50, TD50,
and LD50 are variables in 50% of the population
 A C

B D

Response

Log concentration

  DRUG B is the most potent

  DRUGS A,C AND D have equal maximal efficacy

and greater maximal efficacy than DRUG B
VARIATION OF RESPONSES IN INDIVIDUALS

1. IDIOSYNCRATIC RESPONSE
  Caused by differences in metabolism (genetic) or
immunologic mechanisms
  Response to the drug is unknown or unusual

2. HYPOREACTIVE RESPONSE
  Intensity of the drug is decreased
  Large dose of the drug is needed to have an effect

3. HYPEREACTIVE RESPONSE
  Intensity of the drug is increased or exaggerated
4. TOLERANCE
  Decreased sensitivity acquired as a result of
exposure to the drug

5. TACHYPHYLAXIS
  Tolerance develops after a few doses
VARIATIONS IN DRUG RESPONSIVENESS
1.  Alteration on the concentration of the drug
that reaches the receptor due to absorption,
distribution and elimination differences
3.  Variation in the concentration of the
endogenous ligands (chemicals produced by
the body that binds to receptors, eg,
cathecolamines)
3. Alterations in number/function of receptors
  DOWN REGULATION
Decrease in # of receptors
  UP REGULATION
Increase in the # of receptors
  OVERSHOOT PHENOMENON/
REBOUND HYPERTENSION
 Drug has been taken for a long time, then
abruptly discontinued
 Eg, propranolol (beta-blocker)
 Gradual decrease of taking the drug by
decreasing/tapering the dose
4. Changes in 2nd messengers
5. Clinical selectivity
  Give the drug that really acts on the disease
  No drug causes a single specific effect only,
they are selective but never specific
  Beneficial and toxic effects may be mediated
by the same receptor-effector mechanism
  D+R DR X (beneficial/toxic)
 WHAT TO DO TO AVOID/CIRCUMVENT TOXIC
EFFECTS
  Give low doses
  Carefully monitor the patient
  Employ ancillary procedures
  Use a safer drug if possible
  Beneficial and toxic effects are mediated
by identical receptors but in different ways
  x (beneficial)
  D+R DR y (toxic)
  HEPARIN
 Low doses for prevention of blood clots
 Very high doses causes internal bleeding
 Monitor PT, PTT and bleeding parameters

  STEROIDS
 Give lowest dose possible
 Give adjunctive drugs
 Anatomic selectivity (lungs-by inhalation)
  ANTIHISTAMINES
H1 receptors – H1 blocker
H2 receptors – H2 blocker

R1 DR1 X (beneficial)
D+
R2 DR2 Y (toxic)