rational use of drugs
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WHAT IS THE RELATIONSHIP BETWEEN AMOUNT OF DRUG IN THE BODY AND THE EFFECT OF
THE DRUG?
WHY BE CONCERNED ABOUT DOSE-EFFECT RELATIONSHIPS?
• Predict the effects of changing the dose.
• Reveal the necessary trade-offs between efficacy and adverse effects.
• Facilitate comparisons of alternative medicationsfor the same indication.
• Enhance understanding of how best to use receptor blockers.
DOSE-EFFECT RELATIONSHIPS:
WHAT DETERMINES THE DOSE-EFFECT RELATIONSHIP?
DOSE OFDRUG
[DRUG] ATTARGET SITE
[DRUG-RECEPTOR COMPLEX]
RESPONSE
The Dose-Response Causal Chain
WHAT IS THE RELATIONSHIPBETWEEN DOSE OF DRUG AND
[DRUG] AT TARGET SITE ?
DOSE OFDRUG
[DRUG] ATTARGET SITE
DOSE
[DRUG]As a rough approximation, the relationship
between dose of drug and [drug] ismore-or-less linear at a specified time after drug administration.
Linear
WHAT IS THE RELATIONSHIPBETWEEN [DRUG-RECEPTOR COMPLEX]
AND RESPONSE?
CONCENTRATION OFDRUG-RECEPTOR
COMPLEX
RESPONSE
[DRUG-RECEPTOR]
RESPONSEAs a rough approximation, the relationship
between concentration of drug-receptorcomplex and response to the drug is
more-or-less linear.
Linear
WHAT IS THE RELATIONSHIPBETWEEN [DRUG] AT TARGE SITE
AND [DRUG-RECEPTOR COMPLEX]?
The relationship between [Drug] at target site and [Drug-Receptor Complex]
is not linear!
Non-Linear[DRUG] AT
TARGET SITE[DRUG-RECEPTOR COMPLEX]
DOSE OFDRUG
[DRUG] ATTARGET SITE
In the causal chain between dose of drug and response, the dominant non-linear step is the formation of the drug-receptor complex.
Therefore, it is this step that mainly determines the shape of the dose-effect and the concentration-effect
relationships!!
CONCENTRATION OFDRUG-RECEPTOR
COMPLEX
RESPONSE
Linear LinearNon-Linear
WHAT DETERMINES THE DOSE-EFFECT RELATIONSHIP?
WHAT IS THE RELATIONSHIP BETWEEN[DRUG] AND [DRUG-RECEPTOR]?
[R] [R-D][D]+
By Law of Mass Action: [R]free x [D]free/[R-D] = KD (Equation #1)
(Where KD is the equilibrium dissociation constant)
By Conservation of Mass: [R]free + [R-D] = [R]total (Equation #2)
Rearranging equation #2 gives: [R]free = [R]total - [R-D] (Equation #3)
WHAT IS THE RELATIONSHIP BETWEEN[DRUG] AND [DRUG-RECEPTOR]?
[R] [R-D][D]+
Substitution of equation #3 into equation #1 gives: ([R]total - [R-D]) x [D]free/[R-D] = KD (Equation #4)
Rearranging equation #4 gives: [R-D] = ([R]total x [D]free)/([D]free + KD) (Equation #5)
WHAT IS THE RELATIONSHIP BETWEEN[DRUG] AND [DRUG-RECEPTOR]?
[R] [R-D][D]+
Note that equation #5 gives explicit relationship between [R-D],the dependent variable, and [D]free, the independent variable:
[R-D] =[R]total x [D]free
[D]free + KD
WHAT IS THE RELATIONSHIP BETWEEN[DRUG] AND [DRUG-RECEPTOR]?
Log [D]free versus [R-D] [D]free versus [R-D]
Graphs were computer generated using equation #5 with [R]total = 100 and KD = 10
0 250 500 750 1000 12500
50
100
150
[DRUG]free
[D-R]
0.01 0.1 1 10 100 1000 100000
50
100
150
[DRUG]free
[D-R]
y-axis is [R-D] y-axis is [R-D]
WHAT IS THE RELATIONSHIP BETWEEN[DRUG] AND [DRUG-RECEPTOR]?
[R] [R-D][D]+
A plot of [D]free versus [R-D] is hyperbolic
A plot of log [D]free versus [R-D] is sigmoidal
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
If we assume that the response is proportional to [R-D], then:
Response = m x [R-D] (Equation #6)
Maximal Response = m x [R-D]maximal = m x [R]total (Equation #7)
and
(where m is the proportionality constant)
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Substitution of equations #6 and #7 into equation #5 givesequation #8:
Response =Maximal Response x [D]free
[D]free + KD
Log [D]free versus Response[D]free versus Response
Graphs were computer generated using equation #8 with maximal response = 100 and KD = 10
0.01 0.1 1 10 100 1000 100000
50
100
150
[DRUG]free
Response
0 250 500 750 1000 12500
50
100
150
[DRUG]free
Response
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
y-axis is Response y-axis is Response
[R] [R-D][D]+
A plot of [D]free versus response is hyperbolic
A plot of log [D]free versus response is sigmoidal
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response
[D]freeLet:
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response =Maximal Response x [D]free
[D]free + KD
Response = Maximal Response x KD
2KD
=1/2 Maximal
Response
We Know That:
Substituting KD for [D]free:
Response
KD=
Simplifying:
[D]free
Let:
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response =Maximal Response x [D]free
[D]free + KD
=1/2 Maximal
Response
We Know That:
Substituting ½ Maximal Response
For Response
Response
KD=Simplifying:
1/2 Maximal Response
= Maximal Response x [D]free
[D]free + KD
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
0.01 0.1 1 10 100 1000 100000
50
100
150
[DRUG]free
Response
[D]free = KDResponse = 1/2 Maximal Response
The [drug] which causes 1/2 maximal responseis called the EC50 and corresponds
to the KD if there is a linear relationship between [D-R] and response.
EC50
Maximal Response 1/2 Maximal Response
y-axis is Response
(Equivalence #9)
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response =Maximal Response x [D]free
[D]free + EC50
Since EC50 corresponds to KD, can substitute EC50 for KD in equation #8 to give equation #10:
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response =Maximal Response x [D]free
[D]free + EC50
Empirically, it has been found that equation #10 (above) describes theconcentration-effect relationship for many drugs, evenwhen the assumption of linearity between [R-D] and
response does not hold.
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response =Maximal Response x [D]free
[D]free + EC50
When the assumption of linearity does not hold, the EC50 no longer approximates the KD. For example, the EC50 will be
much smaller than the KD when “spare receptors” are present.
A tissue is said to express “spare receptors” when only a small fraction of the receptor population must be occupied by drug to
give a maximal response.
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response =Maximal Response x [D]free
[D]free + EC50
The term “potency” refers to the EC50 of a drug. The lower the EC50,the greater the potency. A low KD and a high number of
spare receptors increases the potency of a drug.
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Response =Maximal Response x [D]free
[D]free + EC50
The term “efficacy” refers to the maximal response of a drug. The greaterthe maximal response, the greater the efficacy. The more effectively
a drug engages signal-transduction systems in a cell per unit receptor occupied, the greater is the efficacy of that drug.
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Maximal Response To Agonist A
Drugs that activate a given type of receptor may or may not do so equally,i.e., the maximal response elicited by a given drug may be
the same as, less than or more than another drugin the same pharmacological class.
Maximal ResponseTo Agonist B
=, <, or >
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Agonist A is “Best in Class”, i.e., no other agonist induces a greater maximal effect.
The “Best in Class” is called a “full agonist”, and any drugthat generates a maximal response equal to the “Best in Class” is
also referred to as a “full agonist.”
Maximal Response to Agonist A = Maximal Response
to Agonist B
Assume:
Assume:
Both Agonist A and agonist B are “full agonists.”
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Concentration of Agonist
Agonist A Agonist B
Agonist A and agonist Bare both full agonists.However, agonist A is
more potent than agonist B.
y-axis is Response
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Agonist A is “Best in Class”, i.e., no other agonist induces a greater maximal effect.
In this case agonist B is a “partial agonist.”
Maximal Response to Agonist A > Maximal Response
to Agonist B
Assume:
Assume:
Any drug that generates a maximal response less than that elicited by the “Best in Class” is referred to as a
“partial agonist.”
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Concentration of Agonist
Full Agonist A Partial Agonist B
y-axis is Response
WHAT IS THE CONCENTRATION-EFFECT (RESPONSE)
RELATIONSHIP?
Agonist A is a full agonist andagonist B is a partial agonist.
However, agonist A and agonist B have equal
potency.
WHAT IS THE DOSE-EFFECT (RESPONSE)
RELATIONSHIP?
[Drug]free = dose/volume (Equation #11)
EC50 = ED50/volume (Equation #12)
and
(where dose is the amount of the drug in the body at some time after drug administration)
(where volume is the apparent volume in which the drug is dispersed)
(where ED50 is the dose of drug that generates an EC50)
WHAT IS THE DOSE-EFFECT (RESPONSE)
RELATIONSHIP?
Substitution of equations #11 and #12 into equation # 10 givesequation #13:
Response =Maximal Response x Dose
Dose + ED50
Log Dose versus ResponseDose versus Response
Graphs were computer generated using equation #13 with maximal response = 100 and ED50 = 10
WHAT IS THE DOSE-EFFECT (RESPONSE)
RELATIONSHIP?
0 250 500 750 1000 12500
50
100
150
Dose
Response
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
y-axis is Response y-axis is Response
[R] [R-D][D]+
A plot of DOSE versus response is hyperbolic
A plot of log DOSE versus response is sigmoidal
WHAT IS THE DOSE-EFFECT (RESPONSE)
RELATIONSHIP?
Response
DOSE
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
WHAT IS THE DOSE-EFFECT (RESPONSE)
RELATIONSHIP?
Dose = ED50Response = 1/2 Maximal Response
The dose which causes 1/2 maximal response iscalled the ED50. Although the ED50 is affected
by the KD and EC50 it is greatly influencedby the apparent volume in which
the drug is distributed.
ED50
Maximal Response 1/2 Maximal Response
ED50 is never equal to EC50 or KD!
y-axis is Response
WHAT IS THE EFFECT OF DRUGS THAT BLOCK DRUG-RECEPTOR INTERACTIONS OR THAT
INHIBIT SIGNAL TRANSDUCTIONMECHANISMS ON THE DOSE-
RESPONSE CURVE?
[R] [R-D][D]+ Response
BLOCKING DRUG
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Concentration of Agonist
- Drug Antagonist + Drug Antagonist
SURMOUNTABLE ANTAGONIST
y-axis is Response
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
CHARACTERISTICS OF SURMOUNTABLE ANTAGONIST:
• Produces parallel shift in concentration-response curve of agonist
• Full effect of agonist can be restored by increasing concentration of agonist
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
MOST COMMON MECHANISM OF SURMOUNTABLE ANTAGONISM:
• Competitive interaction between agonist (potency and efficacy) and antagonist (potency but no or little efficacy)
at binding site on receptor
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
Population of Inactive Receptors
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
Add an excess of high potency agonist molecules
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
Allow system to reach equilibrium
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
Add some antagonist molecules
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
Allow system to reach new equilibrium
Response =Maximal Response x [D]free
[D]free + apparent KDagonist
Where apparent KDagonist = (1 + [Antagonist]/KDantagonist) x actual KDagonist
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
It can be shown mathematically that the net effect of a competitive antagonist is to increase the apparent KD, or said differently
to decrease the apparent potency of the agonist.
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Concentration of Agonist
Agonist Alone Agonist + Competitive Antagonist
Note apparent shift inEC50 for the agonist.
y-axis is Response
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Concentration of Agonist
- Drug Antagonist + Drug Antagonist
INSURMOUNTABLE ANTAGONIST
y-axis is Response
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
CHARACTERISTICS OF INSURMOUNTABLE ANTAGONIST:
• Produces non-parallel shift in concentration-response curve of agonist
• Full effect of agonist cannot be restored by increasing concentration of agonist
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
MOST COMMON MECHANISMS OF INSURMOUNTABLE ANTAGONISM:
• Competitive but irreversible binding of antagonist to binding site on receptor
• Allosteric modulation of receptor by antagonist so as to attenuate coupling of receptor to signal transduction
• Blockade of signal transduction “downstream” of receptor
WHAT IS THE EFFECT OF BLOCKINGDRUGS ON CONCENTRATION-RESPONSE CURVES?
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Concentration of Agonist0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Concentration of Agonist
SURMOUNTABLE ANTAGONISM
INSURMOUNTABLE ANTAGONISM
PHENOMENON
MECHANISMReversible Competitive Interaction
Irreversible Competitive InteractionIf spare receptors & right dose & time
Blockade of Signal TransductionIf spare receptors & right dose
Allosteric ModulationIf just the right type
We represent the effect of a drug in an INDIVIDUAL as a concentration- or dose-response curve in which the
GRADED effects of the drug are related to concentrations or doses of the drug.
WE HAVE BEEN DISCUSSING CONCENTRATION-AND DOSE-RESPONSE CURVES WITHIN AN INDIVIDUAL.
HOW ARE THESE RELATIONSHIPS EXPRESSEDIN A PATIENT POPULATION?
We represent the effect of a drug in a POPULATION as a concentration- or dose-response curve in which the
QUANTAL effect of the drug is related to concentrations or doses of the drug.
A QUANTAL effect is an effect that is either present or absent(e.g., alive vs. dead, asleep vs. awake, response = or > x vs. response < x).
WHAT IS A QUANTAL CONCENTRATION- OR DOSE-RESPONSE CURVE?
A QUANTAL concentration- or dose-response curve is a plotof concentration or dose versus % of patients in the
population who exhibit the quantal response at the given concentration or dose.
WHAT IS A QUANTAL CONCENTRATION- OR DOSE-RESPONSE CURVE?
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
Log Dose or Concentration of Agonist
% of Individuals Responding At
or Below IndicatedDose or Concentration ED50 or EC50
Note: If quantal response happens to be death, ED50 is called LD50.
WHAT IS A QUANTAL CONCENTRATION- OR DOSE-RESPONSE CURVE?
Although both GRADED and QUANTAL relationships have ED50s and EC50s, these parameter are NOT
the same for GRADED and QUANTAL relationships!
GRADED Relationships:ED50s and EC50s indicate doses and concentrations thatcause 1/2 maximal response in a given INDIVIDUAL.
QUANTAL Relationships:ED50s and EC50s indicate doses and concentrations that
cause 1/2 of the POPULATION to respond.
WHAT ARE THE IMPORTANT CLINICALIMPLICATIONS OF WHAT
WE HAVE LEARNED?
Since the log dose-response curve is sigmoidal, increasing the dose of a drug when the response is submaximal
will enhance the therapeutic effect.
Since the log dose-response curve is sigmoidal, increasing the dose of a drug when the response is maximal
will not improve the therapeutic effectbut may subject the patient to toxicity.
WHAT ARE THE IMPORTANT CLINICALIMPLICATIONS OF WHAT
WE HAVE LEARNED?
The log dose-response curve is sigmoidal, regardless of whether the “response” is therapeutic or toxic.
The safety of a drug can be assessed by examining the log dose-response curves for therapeutic versus toxic effects.
The more separation between the therapeutic log dose-response curves and the toxic log dose-response
curves, the safer the drug.
WHAT ARE THE IMPORTANT CLINICALIMPLICATIONS OF WHAT
WE HAVE LEARNED?
A drug with low potency and high efficacy may be better thana drug with low efficacy and high potency.
Potency is a determinant of how much of the drug must be given toobtain a “ceiling” effect.
Efficacy refers to magnitude of the “ceiling” effect.
WHAT ARE THE IMPORTANT CLINICALIMPLICATIONS OF WHAT
WE HAVE LEARNED?
If an antagonist is being employed to block the effect of an agonist, it is important to know whether the antagonist is of the
surmountable or insurmountable type.
Dose of surmountable antagonist must be increasedif amount of agonist (endogenous or exogenous) in
the patient increases.
Dose of insurmountable antagonist usually does not need upwardadjustment as amount of agonist in body increases.
WHAT ARE THE IMPORTANT CLINICALIMPLICATIONS OF WHAT
WE HAVE LEARNED?
GRADED DOSE/CONCENTRATION RELATIONSHIPShelp to understand how changing dose of drug will effect
the degree of response of an individual patient.
QUANTAL DOSE/CONCENTRATION RELATIONSHIPShelp to understand how changing dose of drug will effect
the % of your patients who will experiencea defined response.
Now you know!!
WHAT IS THE RELATIONSHIP BETWEEN AMOUNT OF DRUG IN THE BODY AND THE EFFECT OF
THE DRUG?
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