3. Drug Receptors and Pharmacodynamics
(how drugs work on the body)
The action of a drug on the body,
including receptor interactions, dose-
response phenomena, and mechanisms
of therapeutic and toxic action.
2004-2005
4. 2
Pharmacodynamics
(how drugs work on the body)
๏ many drugs inhibit enzymes
Enzymes control a number of metabolic processes
A very common mode of action of many drugs
๏ in the patient (ACE inhibitors)
๏ in microbes (sulfas, penicillins)
๏ in cancer cells (5-FU, 6-MP)
๏ some drugs bind to:
๏ proteins (in patient, or microbes)
๏ the genome (cyclophosphamide)
๏ microtubules (vincristine)
2004-2005
5. 3
Pharmacodynamics
๏ most drugs act (bind) on receptors
๏ in or on cells
๏ form tight bonds with the ligand
๏ exacting requirements (size, shape,
stereospecificity)
๏ can be agonists (salbutamol), or
antagonists (propranolol)
๏ receptors have signal transduction
methods
2004-2005
6. Drug Receptor
โข A macromolecular component of a cell
with which a drug interacts to produce
a response
โข Usually a protein
2004-2005
7. Types of Protein Receptors
โข Regulatory โ change the activity of
cellular enzymes
โข Enzymes โ may be inhibited or
activated
โข Transport โ e.g. Na+ /K+ ATPโase
โข Structural โ these form cell parts
2004-2005
8. 5
dose response curves
k1 ฮฑ
[D] + [R] [DR] effect
k -1
at equilibrium: k1/k-1 = affinity const.
[D] x [R] x k1 = [DR] x k-1 k-1/k1 = dissociation
const.(kd)
so that: [DR] = k1
[D] [R] k-1 the lower the kd the
more potent the drug
2004-2005
9. Drug - Receptor Binding
D+R DR Complex
Affinity
Affinity โ measure of propensity of a drug to bind
receptor; the attractiveness of drug and receptor
โ Covalent bonds are stable and essentially
irreversible
โ Electrostatic bonds may be strong or weak, but
are usually reversible
2004-2005
10. Drug Receptor Interaction
DR Complex Effect
Efficacy (or Intrinsic Activity) โ ability of a
bound drug to change the receptor in a way
that produces an effect; some drugs possess
affinity but NOT efficacy
2004-2005
11. Drug-receptor interaction
k1
Drug + Free Receptor Drug-receptor Complex
D (100 - DR) k-1 DR
Where:
D = drug concentration
DR= concentration of drug-receptor complex
100 - DR = free receptor concentration
2004-2005
12. Drug-receptor interaction
โข At equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
k-1/k1 = dissociation constant (kd)
2004-2005
13. โข At equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
What can we learn?
k-1/k1 = dissociation constant (kd)
โข Ke (k1/k-1) is called the affinity constant
โข DR is the response; D is concentration of drug
โข when DR = 50 percent (effect is half
maximal), D (or EC50) is equal to kd or the
reciprocal of the affinity constant
โข response is a measure of efficacy
โข drugs that have parallel dose-response curves
often have the same mechanism of action
2004-2005
15. Arithmetic Dose Scale
โข Rate of change is rapid at first and becomes
progressively smaller as the dose is increased
โข Eventually, increments in dose produce no
further change in effect i.e., maximal effect for
that drug is obtained
โข Difficult to analyze mathematically
2004-2005
16. Log Dose Scale
โข transforms hyperbolic curve to a sigmoid
(almost a straight line)
โข compresses dose scale
โข proportionate doses occur at equal
intervals
โข straightens line
โข easier to analyze mathematically
2004-2005
17. Arithmetic vs log scale of dose
% fall in blood pressure
50
50
40
% fall in blood
40
pressure
30
30
20 Control 20
Control
L-NAME
10 10 L-NAME
0 0
0.1
0.31 3 10 -2 -1 0 1 2
Acetylcholine nmol/kg 0.1 0.3 1 3 10
Acetylcholine nmol/kg
2004-2005
18. Potency
๏Relative position of the dose-effect curve along
the dose axis
๏Has little clinical significance for a given
therapeutic effect
๏A more potent of two drugs is not clinically
superior
๏Low potency is a disadvantage only if the dose
is so large that it is awkward to administer
2004-2005
20. 7
Why are there spare receptors?
๏ allow maximal response without
total receptor occupancy โ increase
sensitivity of the system
๏ spare receptors can bind (and
internalize) extra ligand preventing
an exaggerated response if too
much ligand is present
The receptor theory assumes that all receptors should be occupied to
produce a maximal response. In that case at half maximal effect
EC50=kd. Sometimes, full effect is seen at a fractional receptor
2004-2005
occupation
21. 10
Agonists and antagonists
๏ agonist has affinity plus intrinsic activity
๏ antagonist has affinity but no intrinsic activity
๏ partial agonist has affinity and less intrinsic activity
๏ competitive antagonists can be overcome
2004-2005
22. Agonist Drugs
โข drugs that interact with and activate
receptors; they possess both affinity and
efficacy
โข two types
โ Full โ an agonist with maximal efficacy
โ Partial โ an agonist with less then
maximal efficacy
2004-2005
24. Antagonist Drug
โข Antagonists interact with the receptor
but do NOT change the receptor
โข they have affinity but NO efficacy
โข two types
โ Competitive
โ Noncompetitive
2004-2005
25. Competitive Antagonist
โข competes with agonist for receptor
โข surmountable with increasing agonist
concentration
โข displaces agonist dose response curve
to the right (dextral shift)
โข reduces the apparent affinity of the
agonist i.e., increases 1/Ke
2004-2005
26. Noncompetitive Antagonist
โข drug binds to receptor and stays bound
โข irreversible โ does not let go of receptor
โข produces slight dextral shift in the agonist
DR curve in the low concentration range
โข this looks like competitive antagonist
โข but, as more and more receptors are bound
(and essentially destroyed), the agonist drug
becomes incapable of eliciting a maximal
effect
2004-2005
27. 11
Desensitization
๏ agonists tend to desensitize receptors
๏ homologous (decreased receptor
number)
๏ heterologous (decreased signal
transduction)
๏ antagonists tend to up regulate
receptors
2004-2005
28. 8
dose response curves-3
quantal dose response curves (used in populations, response is yes/no)
Therapeutic index =Toxic Dose50/Effective Dose50
2004-2005
(TD50/ED50)
29. DR Curve: Whole Animal
โข Graded โ response measured on a
continuous scale
โข Quantal โ response is an either/or event
โ relates dose and frequency of response in
a population of individuals
โ often derived from frequency distribution
of doses required to produce a specified
effect
2004-2005
30. Effectiveness, toxicity, lethality
โข ED50 - Median Effective Dose 50; the dose
at which 50 percent of the population or
sample manifests a given effect; used with
quantal dr curves
โข TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect
โข LD50 - Median Toxic Dose 50 - dose which
kills 50 percent of the subjects
2004-2005
32. Drug A
100 sleep
death
Percent 50
Responding
0
ED50 LD50
dose
2004-2005
33. Drug B
100 sleep
death
Percent 50
Responding
0
ED50 LD50
dose
2004-2005
34. 9
The therapeutic index
๏ The higher the TI the better the drug.
๏ TIโs vary from: 1.0 (some cancer drugs)
to: >1000 (penicillin)
๏ Drugs acting on the same receptor or enzyme system
often have the same TI: (eg 50 mg of
hydrochlorothiazide about the same as 2.5 mg of
indapamide)
2004-2005
35. 4
Signal transduction
1. enzyme linked
(multiple actions)
1. ion channel linked
(speedy)
1. G protein linked
(amplifier)
1. nuclear (gene) linked
(long lasting)
2004-2005
36. Structure:
1. G protein-linked receptors
โขSingle
polypeptide
chain threaded
back and forth
resulting in 7
transmembrane
รฅ helices
โขThereโs a G
protein
attached to the
cytoplasmic
side of the
membrane
(functions as a
2004-2005
switch).
38. 2. Tyrosine-kinase receptors
Structure:
โขReceptors exist as individual polypeptides
โขEach has an extracellular signal-binding
site
โขAn intracellular tail with a number of
tyrosines and a single รฅ helix spanning the
membrane
2004-2005
40. 3. Ion channel
receptors
Structure:
โขProtein pores
in the plasma
membrane
2004-2005
41. Intracellular receptors
Not all signal receptors are located on the plasma membrane.
Some are proteins located in the cytoplasm or nucleus of
target cells.
โข The signal molecule must be able to pass through
plasma membrane.
Examples:
~Nitric oxide (NO)
~Steroid (e.g., estradiol, progesterone, testosterone)
and thyroid hormones of animals).
2004-2005
42. B. Second Messengers
โขSmall, nonprotein, water-soluble
molecules or ions
โขReadily spread throughout the cell by
diffusion
โขTwo most widely used second messengers
are:
1. Cycle AMP
2004-2005
2. Calcium ions Ca2+
43. 2. Calcium Ions (Ca2+) and Inositol
Trisphosphate
โขCalcium more widely used than cAMP
โขused in neurotransmitters, growth
factors, some hormones
โขIncreases in Ca2+ causes many possible
responses:
โขMuscle cell contraction
โขSecretion of certain substance
โขCell division
2004-2005
44. Two benefits of a signal-transduction pathway
1. Signal amplification
2. Signal specificity
A. Signal amplification
โขProteins persist in active form long
enough to process numerous molecules
of substrate
โขEach catalytic step activates more
products then in the proceeding steps
2004-2005
46. 12
Summary
๏ most drugs act through receptors
๏ there are 4 common signal transduction methods
๏ the interaction between drug and receptor can be described
mathematically and graphically
๏ agonists have both affinity (kd) and intrinsic activity (ฮฑ)
๏ antagonists have affinity only
๏ antagonists can be competitive (change kd) or
๏ non-competitive (change ฮฑ) when mixed with agonists
๏ agonists desensitize receptors.
๏ antagonists sensitize receptors.
2004-2005
