DRUG RECEPTORS AND PHARMACODYNAMICS

1
DRUG RECEPTORS AND PHARMACODYNAMICS
2
PAUL EHRLICH 1845-1945 Drugs cannot act unless
they are bound to receptors
3
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

4
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

5
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

6
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

7
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
8
Some receptor characteristics

• Ability to recognize specific molecular shapes
• only a limited group of neurochemicals or drugs
  can bind to initiate a cellular response

9
Endogenous compounds act on their receptors
Neurotransmitter Neuropeptides Hormones Ions
10
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
11
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)

12
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.

13
Agonist
14
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

15
An antagonist occupies but does not activate the
drug receptor
16
KDk-1/k1
17
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)

18
(No Transcript)
19
0
0
20
THE 2 STATE MODEL
21
BINDING WITH RECEPTORS BONDS

• Ionic bonds
• Hydrogen bonds
  
• Dispersion forces (Van der Waals)
• Covalent bonds

22
BONDS 2
23
BONDS 3
24
(No Transcript)
25
(No Transcript)
26
Reversible antagonists briefly occupy their
receptors
27
Inhibition caused by reversible antagonist
overcome by adequate concentration of agonist at
receptor site
Reversible antagonist
Agonist
RESPONSE
28
COMPETITIVE INHIBITION
29
Irreversible antagonists permanently occupy (bond
covalently) to their receptors
30
(No Transcript)
31
NONCOMPETITIVE INHIBITION
32
COVALENT BONDS
33
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-or-none)
  response

34
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

35
RELATION BETWEEN DRUG CONCENTRATION AND RESPONSE
36
(No Transcript)
37
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
38
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.

39
RELATION BETWEEN DRUG CONCENTRATION AND RESPONSE
40
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
41
(No Transcript)
42
(No Transcript)
43
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 all-or-none effect
  and is plotted against the log dose of the drug
• (prevention of convulsions, arrhythmia or
  death,relief of headache)

44
dose-response curves
of population tested
45
(No Transcript)
46
QUANTAL DOSE-EFFECT PLOTS
47
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

48
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.
49
Toxic levels
Drug plasma concen-tration
Therapeutic levels
Subtherapeutic levels
50
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)

51
(No Transcript)
52
median toxic dose (TD50)

• The dose of drug which produces a specified toxic
  effect in 50 of the animal population tested

53
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

54
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

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

56
IMATINIB INTERACTION WITH THE BCR-Abl kinase