Download DRUG RECEPTORS AND PHARMACODYNAMICS

DRUG RECEPTORS AND
PHARMACODYNAMICS
PAUL EHRLICH 1845-1945
Drugs cannot act unless they are bound to receptors
PROTEIN TARGETS FOR DRUG
BINDING
4 main kinds of regulatory protein are
commonly involved as primary drug
targets
• Receptors
• Enzymes methotrexate-dihydrofolate reductase
• Carrier molecules (transporters) (SSRI,
TCA)
• Ion channels local anesthetics-voltage sensitive
Na channel
Pharmacodynamics
Is what the drug does to the body.
Interaction of drugs with cellular proteins,
such as receptors or enzymes, to control
changes in physiological function of particular
organs.
• Drug-Receptor Interactions
– Binding
• Dose-Response
– Effect
• Signal Transduction
– Mechanism of action, Pathways
PHARMACODYNAMICS 2
• Receptors largely determine the quantitative
relations between dose or concentration of
drug and pharmacologic effects
• Receptors are responsible for selectivity of
drug action, the molecular size, shape and
electrical charge of a drug determine its
binding characteristics
• Receptors mediate the actions of both
pharmacologic agonists and antagonists
Drug receptor
• A protein macromolecule produced
by the body that was designed by
nature to interact with an
endogenous molecule (ligand), but
which will also interact with a drug
molecule, if it has the correct
chemical structure
Levels of protein
structure
Primary→ sequence of aa
that make up the pp
chain
Secondary →interaction
of + charged H atoms
with – charges O atoms
on C from the same
polypeptide chain
Tertiary → interaction
of aa that are relatively
far apart on the protein
backbone
Quaternary → binding
interaction among 2 or
more independent
protein subunits
Some receptor characteristics…
 Ability to recognize specific molecular shapes:
only a limited group of neurochemicals or drugs can
bind to initiate a cellular response
Endogenous compounds act on their receptors
Neurotransmitter
Neuropeptides
Hormones
Ions
Best fit -- highest
affinity
Some fit; no
cellular effect;
block receptor
preventing its
activation by drug
or neurochemical
or hormone
The ability of a drug to activate a receptor and
generate a cellular response is its efficacy
Some receptor characteristics…
 Binding of ligand is only temporary
 Ligand binding produces physical changes in protein
conformation, initiating intracellular changes that
ultimately generates behavioral effects.
 Receptors have a life cycle (as other proteins do).
Receptors can be modified in numbers (long-term
regulation) and in sensitivity.
– Receptors can up-regulate: increase in numbers (chronic
absence of agonist)
– Down-regulate: decrease in numbers (chronic presence of
agonist)
PHARMACODYNAMICS
AGONISTS & ANTAGONISTS
• Receptors mediate the actions of both
pharmacologic agonists and antagonists.
Some drugs and many natural ligands such as
hormones and neurotransmitters activate the
receptor to signal as a direct result of binding
to it. Agonists (Full agonists, Partial agonists,
Inverse agonists)
Antagonists bind to receptors but do not
activate generation of a signal, they interfere
with the ability of an agonist to activate the
receptor.
Agonist
There are 3 types of agonist...
• Full agonist: Produces the maximal
responce
• Partial agonist (agonist-antagonist or
mixed agonist-antagonist): produces the
submaximal responce
*In the presence of full agonist, a partial
agonist will act like an antagonist because it
prevents the full agonist to bind the receptor
An antagonist occupies but does not
activate the drug receptor
KD=k-1/k+1
Types of drug antagonism
• chemical antagonism (interaction in solution)
• pharmacokinetic antagonism (one drug
affecting the absorption, metabolism or
excretion of the other)
• competitive antagonism (both drugs binding to
the same receptors); the antagonism may be
reversible or irreversible
• interruption of receptor-effector linkage
• physiological antagonism (two agents
producing opposing physiological effects)
0
0
THE 2 STATE MODEL
BINDING WITH RECEPTORS
BONDS
•
•
•
•
Ionic bonds
Hydrogen bonds
Dispersion forces (Van der Waals)
Covalent bonds
+++
++
+
++++
BONDS 2
BONDS 3
Reversible antagonists briefly
occupy their receptors
Inhibition caused by reversible antagonist overcome by
adequate concentration of agonist at receptor site
Reversible
antagonist
Agonist
RESPONSE
COMPETITIVE INHIBITION
Irreversible antagonists permanently
occupy (bond covalently) to their
receptors
NONCOMPETITIVE INHIBITION
COVALENT BONDS
Dose-response relationships
• The
relationship
between
the
concentration of drug at the receptor
site and the magnitude of the response
is called the dose-response relationship
• Depending on the purpose of the the
studies,
this
relatioship
can
be
described in terms of a graded
(continous) response or a quantal (all-ornone) response
graded dose-response relationship
• In this relationship; percentage of a
maximal response is plotted against the
log dose of the drug
• Illustrates the relatioship between drug
dose, receptor occupancy and the
magnitude of the resulting physiologic
effect
• It follows from receptor theory that the
maximal response to a drug occurs when
all receptors that can be occupied by
that drug
RELATION BETWEEN DRUG
CONCENTRATION AND RESPONSE
Dose-response (dose-effect) curve
Half maximal response
indicates that 50% of the
reseptors are occupied
Maximal response
indicates that, all
receptors are
occupied by drug
EC 50
Median effective dose
drug efficacy
• The ability of a drug to elicit a maximal
response
– Also called intrinsic activity of a drug
Therapeutic efficacy, or effectiveness, is the capacity
of a drug to produce an effect and refers to the
maximum such effect. For example, if drug A can
produce a therapeutic effect that cannot be obtained
with drug B, however much of drug B is given, then
drug A has the higher therapeutic efficacy. Differences
in therapeutic efficacy are of great clinical importance.
RELATION BETWEEN DRUG
CONCENTRATION AND RESPONSE
RELATION BETWEEN DRUG
CONCENTRATION AND RESPONSE
A agonist response
in the absence of an
antagonist
B low concentration
antagonist
C larger
concentration of
antagonist
D and E spare
receptors have been
used up
quantal dose-response relationship
• The response elicited with each dose of a
drug is described in terms of the cumulative
percentage subjects exhibiting a defined allor-none effect and is plotted against the log
dose of the drug
• (prevention of convulsions, arrhythmia or
death,relief of headache)
% of population
tested
dose-response curves
QUANTAL DOSE-EFFECT PLOTS
ED50: median effective dose
• ED50 (median effective dose):
– The dose of a drug that produces a
specified, desired effect in 50% of
the animal population tested
Quantal dose-response relationships. The dose-response curves for a
therapeutic effect (sleep) and a toxic effect (death) of a drug are compared.
The ratio of the LD50 to the ED50 is the therapeutic index. The ratio of the
LD1 to the ED99 is the certain safety factor. ED = effective dose; and
LD = lethal dose.
Drug
plasma
concentration
Toxic levels
Therapeutic levels
Subtherapeutic levels
Therapeutic index (TI)
TI = TD 50
ED50
The ratio of the dose producing a
specified toxic effect in 50% of
the test population (TD50) to the
dose producing a specified desired
effect in 50% of the test
population (ED50)
median toxic dose (TD50)
• The dose of drug which produces a
specified toxic effect in 50% of
the animal population tested
therapeutic index (TI)
• Also may be defined as:
LD50
ED50
Where LD50 is the median lethal dose –
the dose of the drug that is lethal to
50% of the animal population tested
RELATION BETWEEN DRUG
CONCENTRATION AND RESPONSE
E = Emax X C
C + EC50
E is the effect observed at concentration C,
Emax is the maximal response that can be
produced by the drug
EC50 is the concentration of the drug that produces
50% of maximal effect
B = Bmax X C
C + KD
Bmax total concentration of receptor sites
KD the equilibrium dissociation constant, conc of
free drug at which half-maximal binding is
observed
IMATINIB INTERACTION WITH
THE BCR-Abl kinase