Transcript Pharmacodynamics

2004-2005
Module 2
#1
Pharmacodynamics
Kash Desai
966-2723
HSc A120
[email protected]
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Drug Receptors and Pharmacodynamics
(how drugs work on the body)
The action of a drug on the body,
including receptor interactions, doseresponse phenomena, and mechanisms
of therapeutic and toxic action.
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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)
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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
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Drug Receptor
• A macromolecular component of a cell
with which a drug interacts to produce
a response
• Usually a protein
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Types of Protein Receptors
1. Regulatory – change the activity of
cellular enzymes
2. Enzymes – may be inhibited or
activated
3. Transport – e.g. Na+ /K+ ATP’ase
4. Structural – these form cell parts
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dose response curves

k1
[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]
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k-1
the lower the kd the more
potent the drug
Drug - Receptor Binding
D+R
DR Complex
Affinity
Affinity – measure of propensity of a drug to bind
receptor; the attractiveness of drug and receptor
– Covalent bonds are stable and essentially
irreversible
– Electrostatic bonds may be strong or weak, but
are usually reversible
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Drug Receptor Interaction
DR Complex
Effect
Efficacy (or Intrinsic Activity) – ability of a
bound drug to change the receptor in a way
that produces an effect; some drugs possess
affinity but NOT efficacy
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Isolated Muscle Contraction
Drug-receptor interaction
Arithmetic Scale
100
Percent Maximum
Drug + Free Receptor
75
D
(100 - DR)
k1
k-1
Drug-receptor Complex
DR
50
Where:
25
D = drug concentration
DR=
0
concentration
0.00
0.25 of
drug-receptor
complex
0.50
0.75
1.00
Dose (ug/ml)
100
DR
=
free
receptor
concentration
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Drug-receptor interaction
• 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)
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• 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)
• Ke (k1/k-1) is called the affinity constant
• DR is the response; D is concentration of drug
• when DR = 50 percent (effect is half
maximal), D (or EC50) is equal to kd or the
reciprocal of the affinity constant
• response is a measure of efficacy
• drugs that have parallel dose-response curves
often have the same mechanism of action
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dose response curves-2
effect =  [DR] = Emax * [D]/([D]+EC50)
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% occupancy

Concept: spare
receptors
Arithmetic Dose Scale
• Rate of change is rapid at first and becomes
progressively smaller as the dose is increased
• Eventually, increments in dose produce no
further change in effect i.e., maximal effect for
that drug is obtained
• Difficult to analyze mathematically
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Log Dose Scale
• transforms hyperbolic curve to a sigmoid
(almost a straight line)
• compresses dose scale
• proportionate doses occur at equal
intervals
• straightens line
• easier to analyze mathematically
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Ethyl
Alcohol:
Arithmetic
vs log Sleep
scale of dose
30
20
10
0
0.1
0.31
% fall in blood pressure
40
Number Responding
% fall in blood
pressure
50
30
20
Control
L-NAME
10
3
50
40
30
20
10
0
-2
10
Acetylcholine nmol/kg
0
5.28
5.40
-1
0
1
2
0.1 0.3
1
3
10
Acetylcholine nmol/kg
5.52
5.64
5.76
Dose (g/kg)
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Control
L-NAME
5.88
6.00
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
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Relative Potency
hydromorphone
morphine
codeine
Analgesia
aspirin
Dose
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Why are there spare receptors?
 allow maximal response without
total receptor occupancy – 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
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occupation
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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
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Agonist Drugs
• drugs that interact with and activate
receptors; they possess both affinity and
efficacy
• two types
– Full – an agonist with maximal efficacy
– Partial – an agonist with less then
maximal efficacy
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Agonist Dose Response Curves
Full agonist
Partial agonist
Response
Dose
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Antagonist Drug
• Antagonists interact with the receptor
but do NOT change the receptor
• they have affinity but NO efficacy
• two types
– Competitive
– Noncompetitive
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Competitive Antagonist
• competes with agonist for receptor
• surmountable with increasing agonist
concentration
• displaces agonist dose response curve
to the right (dextral shift)
• reduces the apparent affinity of the
agonist i.e., increases 1/Ke
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Noncompetitive Antagonist
• drug binds to receptor and stays bound
• irreversible – does not let go of receptor
• produces slight dextral shift in the agonist
DR curve in the low concentration range
• this looks like competitive antagonist
• but, as more and more receptors are bound
(and essentially destroyed), the agonist drug
becomes incapable of eliciting a maximal
effect
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Desensitization
 agonists tend to desensitize receptors
 homologous (decreased receptor
number)
 heterologous (decreased signal
transduction)
 antagonists tend to up regulate
receptors
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dose response curves-3
quantal dose response curves (used in populations, response is yes/no)
Therapeutic index =Toxic Dose50/Effective Dose50
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(TD50/ED50)
DR Curve: Whole Animal
• Graded – response measured on a
continuous scale
• Quantal – response is an either/or event
– relates dose and frequency of response in
a population of individuals
– often derived from frequency distribution
of doses required to produce a specified
effect
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Effectiveness, toxicity, lethality
• 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
• TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect
• LD50 - Median Toxic Dose 50 - dose which
kills 50 percent of the subjects
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Quantification of drug safety
Therapeutic Index =
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TD50 or LD50
ED50
Drug A
100
sleep
death
Percent
50
Responding
0
ED50
LD50
dose
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Drug B
100
Percent
Responding
sleep
death
50
0
ED50
dose
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LD50
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The therapeutic index
 The higher the TI the better the drug.
 TI’s 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)
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Signal transduction
1.
enzyme linked
(multiple actions)
2.
ion channel linked
(speedy)
3. G protein linked
(amplifier)
4. nuclear (gene) linked
(long lasting)
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1.
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G protein-linked receptors
Structure:
•Single
polypeptide
chain threaded
back and forth
resulting in 7
transmembrane
å helices
•There’s a G
protein
attached to the
cytoplasmic
side of the
membrane
(functions as a
switch).
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2.
Tyrosine-kinase receptors
Structure:
•Receptors exist as individual polypeptides
•Each has an extracellular signal-binding
site
•An intracellular tail with a number of
tyrosines and a single å helix spanning the
membrane
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3.
Ion channel
receptors
Structure:
•Protein pores
in the plasma
membrane
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Intracellular receptors
Not all signal receptors are located on the plasma membrane.
Some are proteins located in the cytoplasm or nucleus of
target cells.
•
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).
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B.
Second Messengers
•Small, nonprotein, water-soluble
molecules or ions
•Readily spread throughout the cell by
diffusion
•Two most widely used second messengers
are:
1. Cycle AMP
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2. Calcium ions Ca2+
2.
Calcium Ions (Ca2+) and Inositol
Trisphosphate
•Calcium more widely used than cAMP
•used in neurotransmitters, growth
factors, some hormones
•Increases in Ca2+ causes many possible
responses:
•Muscle cell contraction
•Secretion of certain substance
•Cell division
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Two benefits of a signal-transduction pathway
A.
1.
Signal amplification
2.
Signal specificity
Signal amplification
•Proteins persist in active form long
enough to process numerous molecules
of substrate
•Each catalytic step activates more
products then in the proceeding steps
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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 ()
 antagonists have affinity only
 antagonists can be competitive (change kd) or
 non-competitive (change ) when mixed with agonists
 agonists desensitize receptors.
 antagonists sensitize receptors.
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