Title: DRUG RECEPTORS AND PHARMACODYNAMICS
1DRUG RECEPTORS AND PHARMACODYNAMICS
2PAUL EHRLICH 1845-1945 Drugs cannot act unless
they are bound to receptors
3PROTEIN 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
4Pharmacodynamics
- 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
5PHARMACODYNAMICS 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 -
6Drug 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
7Levels 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
8Some receptor characteristics
- Ability to recognize specific molecular shapes
- only a limited group of neurochemicals or drugs
can bind to initiate a cellular response
9Endogenous compounds act on their receptors
Neurotransmitter Neuropeptides Hormones Ions
10Best 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
11Some 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)
12PHARMACODYNAMICS 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.
13Agonist
14There 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 -
15An antagonist occupies but does not activate the
drug receptor
16KDk-1/k1
17Types 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)
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20THE 2 STATE MODEL
21BINDING WITH RECEPTORS BONDS
- Ionic bonds
- Hydrogen bonds
- Dispersion forces (Van der Waals)
- Covalent bonds
22BONDS 2
23BONDS 3
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26Reversible antagonists briefly occupy their
receptors
27Inhibition caused by reversible antagonist
overcome by adequate concentration of agonist at
receptor site
Reversible antagonist
Agonist
RESPONSE
28COMPETITIVE INHIBITION
29Irreversible antagonists permanently occupy (bond
covalently) to their receptors
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31NONCOMPETITIVE INHIBITION
32COVALENT BONDS
33Dose-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-or-none)
response
34graded 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
35RELATION BETWEEN DRUG CONCENTRATION AND RESPONSE
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37Dose-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
38drug 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.
39RELATION BETWEEN DRUG CONCENTRATION AND RESPONSE
40RELATION 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
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43quantal dose-response relationship
- The response elicited with each dose of a drug is
described in terms of the cumulative percentage
subjects exhibiting a defined all-or-none effect
and is plotted against the log dose of the drug - (prevention of convulsions, arrhythmia or
death,relief of headache)
44dose-response curves
of population tested
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46QUANTAL DOSE-EFFECT PLOTS
47ED50 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
48Quantal 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.
49Toxic levels
Drug plasma concen-tration
Therapeutic levels
Subtherapeutic levels
50Therapeutic 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)
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52median toxic dose (TD50)
- The dose of drug which produces a specified toxic
effect in 50 of the animal population tested
53therapeutic 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
54RELATION 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
55- 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
56IMATINIB INTERACTION WITH THE BCR-Abl kinase