pharmacodynamics Flashcards
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
pharmacodynamics
Specific molecules in a biologic system with
which drugs interact to produce changes in
the function of the system
RECEPTORS
Determine the quantitative relations between
dose or concentration of drug and
pharmacologic effects
RECEPTORS
Selective in choosing a drug molecule to bind
to avoid constant activation by promiscuous
binding of many different molecules
RECEPTORS
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
RECEPTORS
Majority are proteins which provide the
necessary diversity and specificity of
shape and electrical charge
RECEPTORS
Specific binding region of the macromolecule
High and selective affinity to the drug molecule
RECEPTOR SITE/RECOGNITION SITE
is the fundamental event that initiates the action
of the drug
Interaction between the drug and the receptor
CLASSIFICATION OF RECEPTORS
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
REGULATORY PROTEIN
CLASSIFICATION OF RECEPTORS
Inhibited (or less commonly, activated) by
binding a drug
Eg, dihydrofolate reductase, the receptor for
methotrexate
ENZYMES
CLASSIFICATION OF RECEPTORS
Eg, Na+/K+ ATPase, the membrane receptor
for digitali
TRANSPORT PROTEINS
CLASSIFICATION OF RECEPTORS
Eg, tubulin, the receptor for colchicine,
an anti-inflammatory drug
STRUCTURAL PROTEINS
Molecules that translate the drug-receptor
interaction into a change in cellular activity
Eg, adenyl cyclase
EFFECTORS
Response of a particular receptor-effector system is measured against increasing concentration of a drug Graph of the response versus the drug dose
GRADED DOSE-RESPONSE CURVE
Sigmoid curve Efficacy (Emax) and potency (EC50) are derived from this curve The smaller the EC 50, the greater the potency of the drug
GRADED DOSE-RESPONSE CURVE
Maximal response that can be produced
by a drug
All receptors are occupied
No response even if the dose is increased
Emax
Concentration of drug that produces
50% of maximal effect
Smaller EC
50–more potent
EC50
Total number of receptor sites
All receptors have been occupied
Bmax
Equilibrium dissociation constant
Concentration of drug required to
bind 50% of the receptors
KD
Measure of the affinity of a drug
for its binding site on the receptor
KD
Smaller KD
–greater affinity of drug to receptor
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
COUPLING
Maximal drug response is obtained at less
than maximal occupation of the receptors
Not qualitatively different from nonspare
receptors, not hidden or unavailable
SPARE RECEPTORS
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
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
SPARE RECEPTORS
Non-regulatory molecules of the body
Binding with these molecules will result
to no detectable change in the function
of the biologic system
INERT BINDING SITES
Buffers the concentration of the drug Bound drugs do not contribute directly to the concentration gradient that drives diffusion Eg, albumin
INERT BINDING SITES
Binds to the receptor and directly or
indirectly bring about an effect
Full activation of the effector system
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
PARTIAL AGONIST
Binds but do not activate the receptors
Blocks or competes with agonist
ANTAGONIST
CLASSIFICATION
Competes with agonist receptor
Binds to the receptor reversibly without
activating the effector system
COMPETITIVE ANTAGONIST
CLASSIFICATION
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
COMPETITIVE ANTAGONIST
CLASSIFICATION
Effects are overcomed by adding more agonist
Increases the median effective dose
ED50
COMPETITIVE ANTAGONIST
2 THERAPEUTIC IMPLICATIONS
produced by the competitive antagonist depends on the
(1) Degree of inhibition
2 THERAPEUTIC IMPLICATIONS
concentration of antagonist (eg, propranolol)
depends on the concentration of agonist that
is competing for binding to the receptor
(2) Clinical response to a competitive antagonist
CLASSIFICATION
Binds with the receptor via covalent bonds
Antagonist’s affinity to the receptor maybe so high
Receptor is not available to bind the agonist
IRREVERSIBLE ANTAGONIST
CLASSIFICATION
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
IRREVERSIBLE ANTAGONIST
CLASSIFICATION
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
IRREVERSIBLE ANTAGONIST
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
CHEMICAL ANTAGONISM
Eg, protamine used to counteract the
effect of heparin making it unavailable
for interaction with proteins involved in
the formation of blood
CHEMICAL 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
PHYSIOLOGIC ANTAGONISM
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
crossing the plasma membrane and acts on intracellular
receptor (eg, steroids)
(1) Lipid soluble drug
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
intracellular enzymatic activity is
regulated by a ligand that binds to
the protein’s extracellular domain
(2) Transmembrane receptor protein
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
that binds and stimulates a protein tyrosine
kinase (eg, insulin)
(3) Transmembrane receptor
5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS which regulates the opening of the ion channel (eg, GABA, excitatory acetylcholine)
(4) Ligand-gated transmembrane ion
channel
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
is coupled with an effector enzyme by G protein
which modulates production of an intracellular second messenger
[eg, cathecolamine (epinephrine)]
(5) Transmembrane receptor
INTRACELLULAR 2ND MESSENGERS
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
A. cAMP
INTRACELLULAR 2ND MESSENGERS
Bind to receptors linked to G proteins while others bind to receptor tyrosine kinases
B. CALCIUM AND PHOSPHOINOSITIDES
INTRACELLULAR 2ND MESSENGERS
Crucial step is the stimulation of membrane enzyme phospholipase C
B. CALCIUM AND PHOSPHOINOSITIDES
INTRACELLULAR 2ND MESSENGERS
Few signaling roles in a few cell types like the intestinal mucosa and vascular smooth muscle cells
C. cGMP
INTRACELLULAR 2ND MESSENGERS
Causes relaxation of vascular smooth
muscles by a kinase-mediated mechanism
C. cGMP
Response gradually diminishes even if the
drug is still there (after reaching an initial
high level of response)
Reason is not known
RECEPTOR DESENSITIZATION
STRUCTURE ACTIVITY RELATIONSHIP
Cells use more than one signaling mechanism
to respond to the drug
Graph of the fraction of a population that
shows a specified response to increasing
doses of a drug
QUANTAL DOSE-RESPONSE CURVE
Minimum dose required to produce a specific
response is determined in each member of
the population
Sigmoid curve
QUANTAL DOSE-RESPONSE CURVE
Median effective dose
50% of the individuals manifested
the desired therapeutic effect
ED50
Median toxic dose
50% of the individuals manifested the toxic effects
TD50
Median lethal dose
LD50
Ratio of the TD
50 (or LD50 ) to the ED50 determined from the quantal dose-response curves
Increased therapeutic index-wide margin of
safety
THERAPEUTIC INDEX
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 INDEX
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
THERAPEUTIC WINDOW
normal value MEC
7-10 mg/L (average of 8 mg/L)
normal value Therapeutic window
8-18 mg/L
normal value MTC
15-20 mg/L (average of 18 mg/L)
ex of therapeutic window
theophylline
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
MAXIMAL EFFICACY
Measured with a graded dose-response
curve but not with quantal dose-response
curve
MAXIMAL EFFICACY
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)
POTENCY
In the quantal dose-response curve, ED50,
TD50, and LD50 are variables in 50% of the
population
POTENCY
VARIATION OF RESPONSES IN INDIVIDUALS
Caused by differences in metabolism (genetic)
or immunologic mechanisms
Response to the drug is unknown or unusual
IDIOSYNCRATIC RESPONSE
VARIATION OF RESPONSES IN INDIVIDUALS
Intensity of the drug is decreased
Large dose of the drug is needed to have
an effect
HYPOREACTIVE RESPONSE
VARIATION OF RESPONSES IN INDIVIDUALS
Intensity of the drug is increased or exaggerated
HYPEREACTIVE RESPONSE
VARIATION OF RESPONSES IN INDIVIDUALS
Decreased sensitivity acquired as a result of
exposure to the drug
TOLERANCE
VARIATION OF RESPONSES IN INDIVIDUALS
Tolerance develops after a few doses
TACHYPHYLAXIS
VARIATIONS IN DRUG RESPONSIVENESS
that reaches the receptor due to absorption,
distribution and elimination differences
- Alteration on the concentration of the drugq
- Variation in the concentration of the endogenous
- Alterations in number/function of receptors
- Changes in 2nd messengers
- Clinical selectivity
VARIATIONS IN DRUG RESPONSIVENESS
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
OVERSHOOT PHENOMENON/
REBOUND HYPERTENSION
VARIATIONS IN DRUG RESPONSIVENESS
3. Alterations in number/function of receptors
Decrease in # of receptors
DOWN REGULATION
VARIATIONS IN DRUG RESPONSIVENESS
3. Alterations in number/function of receptors
Increase in the # of receptors
UP REGULATION
WHAT TO DO TO AVOID/CIRCUMVENT
TOXIC EFFECTS
Give low doses
Carefully monitor the patient
Employ ancillary procedures
VARIATIONS IN DRUG RESPONSIVENESS
Beneficial and toxic effects may be mediated
by the same receptor-effector mechanism
D + R DR X (beneficial/toxic)
- Clinical selectivity
WHAT TO DO TO AVOID/CIRCUMVENT
TOXIC EFFECTS
Use a safer drug if possible
Beneficial and toxic effects are mediated
by identical receptors but in different ways
Low doses for prevention of blood clots
Very high doses causes internal bleeding
Monitor PT, PTT and bleeding parameters
HEPARIN
Give lowest dose possible Give adjunctive drugs Anatomic selectivity (lungs-by inhalation)
STEROIDS
