2004-2005

2004-2005
Module z
# :
Pharmacodynamics
KusI DesuI
q66-z;z
HSc A1zo
k.desuIususk.cu
2004-2005
Drug Receptors and Pharmacodynamics
(how drugs work on the body)
The action oI a drug on the body,
including receptor interactions, dose-
response phenomena, and mechanisms
oI therapeutic and toxic action.
2004-2005
Pharmacodynamics
how drugs work on the body)
muny drogs inhibit enzgmes
nzymes control a number oI metabolic processes
A very common mode oI action oI many drugs
in the putient {ACI inhibitors)
in microbes {solIus, penicillins)
in cuncer cells {g-IL, 6-MP)
some drogs bind to:
proteins {in putient, or microbes)
the genome {cyclophosphumide)
microtoboles {vincristine)

2004-2005
Pharmacodynamics
most drogs uct {bind) on 7ecepto7s
In or on ceIIs
Iorm LIgIL bonds wILI LIe licnd
exucLIng requIremenLs (sIze, sIupe,
sLereospecIIIcILy)
cun be conists (suIbuLumoI), or
cntconists (proprunoIoI)
receptors huve signol t7onsduction
methods

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Drug Receptor
W A macromolecular component oI a cell
with which a drug interacts to produce
a response
W &sually a protein
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Types of Protein Receptors
. Regulatory change the activity oI
cellular enzymes
. nzymes may be inhibited or
activated
. Transport e.g. Na

/K

ATP`ase
4. Structural these Iorm cell parts
2004-2005
dose response curves
( R( R( eIIect
k

k
-
at equilibrium:
( x R( x k

R( x k
-
so that: R( k

( R( k
-
k

/k
-
aIIinity const.
k-

/k

dissociation
const.k
d
)
the 407 the k
d
the more
549039 the drug
-

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R R Complex
AIIinity measure oI propensity oI a drug to bind
receptor; the attractiveness oI drug and receptor
Covalent bonds are stable and essentially
irreversible
lectrostatic bonds may be strong or weak, but
are usually reversible
Drug - Receptor Binding
AIIinity
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Drug Receptor Interaction
IIicacy or Intrinsic Activity) ability oI a
bound drug to change the receptor in a way
that produces an eIIect; some drugs possess
aIIinity but NOT eIIicacy
R Complex IIect
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0.00 0.25 0.50 0.75 1.00
P
e
r
c
e
n
t

M
a
x
i
m
u
m
0
25
50
75
100
IsoIated MuscIe Contraction
Arithmetic ScaIe
Dose (ug/mI)
here:
drug concentration
R concentration oI drug-receptor complex
- R Iree receptor concentration
rug Free Receptor
rug-receptor Complex
- R)
k

k
-
R
Drug-receptor interaction
2004-2005
Drug-receptor interaction
W At equilibrium:
( x R( x k

R( x k
-
so that: R(

( R( k
-
k
-
/k

dissociation constant k
d
)
2004-2005
What can we learn?
W K
e
k

/k
-
) is called the aIIinity constant
W R is the response; is concentration oI drug
W when R percent eIIect is halI
maximal), or C

) is equal to k
d
or the
reciprocal oI the aIIinity constant
W response is a measure oI eIIicacy
W drugs that have parallel dose-response curves
oIten have the same mechanism oI action
W At equilibrium:
( x R( x k R( x k-
so that: R( k
( R( k-
k-/k dissociation constant kd)
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dose response curves-2
eIIect - R( max * (/(C)
-
occupancy
Concept: spare
receptors
6
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Arithmetic Dose Scale
W Rate oI change is rapid at Iirst and becomes
progressively smaller as the dose is increased
W ventually, increments in dose produce no
Iurther change in eIIect i.e., maximal eIIect Ior
that drug is obtained
W iIIicult to analyze mathematically
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Log Dose Scale
W transIorms hyperbolic curve to a sigmoid
almost a straight line)
W compresses dose scale
W proportionate doses occur at equal
intervals
W straightens line
W easier to analyze mathematically
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Dose (g/kg)
5.28 5.40 5.52 5.64 5.76 5.88 6.00
N
u
m
b
e
r

R
e
s
p
o
n
d
i
n
g
0
10
20
30
EthyI AIcohoI: SIeep
0.I 0.3I 3 I0
0
I0
20
30
40
50
l-lANE
Conliol
Acel/lcholine nuol/l}
/

l
a
l
l

i
n

b
l
o
o
d

i
e
s
s
u
i
e
-2 -I 0 I 2
0
I0
20
30
40
50
l-lANE
Acel/lcholine nuol/l}
Conliol
0.1 0.3 1 3 10
/

l
a
l
l

i
n

b
l
o
o
d

i
e
s
s
u
i
e
Arithmetic vs log scale of dose
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Potency
Relative position oI the dose-eIIect curve along
the dose axis
Has little clinical signiIicance Ior a given
therapeutic eIIect
A more potent oI two drugs is not clinically
superior
Low potency is a disadvantage only iI the dose is
so large that it is awkward to administer
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Analgesia
Dose
hydromorphone
morphine
codeine
aspirin
Relative Potency
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Iy ure LIere spure recepLors?
ullow muximul response ithout
totul receptor occopuncy - increuse
sensitivity oI the system
spure receptors cun bind {und
inte7nolize) extru ligund preventing
un exuggeruted response iI too
moch ligund is present

The receptor theory assumes that all receptors should be occupied to

produce a maximal response. In that case at halI maximal eIIect
Ckd. Sometimes, Iull eIIect is seen at a Iractional receptor
occupation
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onists cnd cntconists
agonist has aIIinity plus intrinsic activity
antagonist has aIIinity but no intrinsic activity
partial agonist has aIIinity and less intrinsic activity
competitive antagonists can be overcome

2004-2005
Agonist Drugs
W drugs that interact with and activate
receptors; they possess both aIIinity and
eIIicacy
W two types
Full an agonist with maximal eIIicacy
Partial an agonist with less then
maximal eIIicacy
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Response
Dose
Full agonist
Partial agonist
Agonist Dose Response Curves
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Antagonist Drug
W Antagonists interact with the receptor
but do NOT change the receptor
W they have aIIinity but NO eIIicacy
W two types
Competitive
Noncompetitive
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Competitive Antagonist
W competes with agonist Ior receptor
W surmountable with increasing agonist
concentration
W displaces agonist dose response curve
to the right dextral shiIt)
W reduces the apparent aIIinity oI the
agonist i.e., increases /Ke
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Noncompetitive Antagonist
W drug binds to receptor and stays bound
W irreversible does not let go oI receptor
W produces slight dextral shiIt in the agonist
R curve in the low concentration range
W this looks like competitive antagonist
W but, as more and more receptors are bound
and essentially destroyed), the agonist drug
becomes incapable oI eliciting a maximal
eIIect
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esensitizction
ugonIsLs Lend Lo desensILIze recepLors
IomoIogous (decreused recepLor
number)
IeLeroIogous (decreused sIgnuI
LrunsducLIon)
unLugonIsLs Lend Lo up reguIuLe
recepLors

2004-2005
dose response curtes-
qucntcl dose response curtes (used in populctions, response is es,no)
Therapeutic index Toxic ose/IIective ose
T/)
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2004-2005
DR Curve. Whole Animal
W raded response measured on a
continuous scale
W "uantal response is an either/or event
relates dose and Irequency oI response in
a population oI individuals
oIten derived Irom Irequency distribution
oI doses required to produce a speciIied
eIIect
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Effectiveness, toxicity, lethality
W - Median IIective ose ; the dose
at which percent oI the population or
sample maniIests a given eIIect; used with
quantal dr curves
W T - Median Toxic ose - dose at
which percent oI the population
maniIests a given toxic eIIect
W L - Median Toxic ose - dose which
kills percent oI the subjects
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Quantification of drug safety
%herapeutic Index
%D50 or LD50
ED50
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dose
Drug A
sleep
death

L
Percent
Responding
2004-2005
dose
Drug B
sleep
death

L
Percent
Responding
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The therapeutic index
The higher the %I the better the drug.
%I`s vary Irom: . some cancer drugs)
to: ~ penicillin)
rugs acting on the same receptor or enzyme system
oIten have the same %I: eg mg oI
hydrochlorothiazide about the same as . mg oI
indapamide)
9
2004-2005
$incl trcnsduction
. enzyme linked
multiple actions)
. ion channel linked
speedy)
. protein linked
ampliIier)
4. nuclear gene) linked
long lasting)
4
2004-2005
1. G protein-linked receptors
Structure:
WSingle
polypeptide
chain threaded
back and Iorth
resulting in
transmembrane
helices
WThere`s a
protein
attached to the
cytoplasmic
side oI the
membrane
Iunctions as a
switch).
2004-2005
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2. Tyrosine-kinase receptors
Structure:
WReceptors exist as individual polypeptides
Wach has an extracellular signal-binding
site
WAn intracellular tail with a number oI
tyrosines and a single helix spanning the
membrane
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. Ion channel
receptors
Structure:
WProtein 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 oI
target cells.
W The signal molecule must be able to pass through
plasma membrane.
xamples:
~Nitric oxide NO)
~Steroid e.g., estradiol, progesterone, testosterone)
and thyroid hormones oI animals).
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B. Second Messengers
WSmall, nonprotein, water-soluble
molecules or ions
WReadily spread throughout the cell by
diIIusion
WTwo most widely used second messengers
are:
. Cycle AMP
. Calcium ions Ca

2004-2005
. Calcium Ions Ca

) and Inositol
Trisphosphate
WCalcium more widely used than cAMP
Wused in neurotransmitters, growth
Iactors, some hormones
WIncreases in Ca

causes many possible

responses:
WMuscle cell contraction
WSecretion oI certain substance
WCell division
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Two beneIits oI a signal-transduction pathway
. Signal ampliIication
. Signal speciIicity
A. Signal ampliIication
WProteins persist in active Iorm long
enough to process numerous molecules
oI substrate
Wach catalytic step activates more
products then in the proceeding steps
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$ummcr
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 k
d
) and intrinsic activity -)
antagonists have aIIinity only
antagonists can be competitive change k
d
) or
non-competitive change -) when mixed with agonists
agonists desensiti:e receptors.
antagonists sensiti:e receptors.