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M.T. Piascik PHA 824 November 11, 2008. PHARMACODYNAMICS. Learning Objectives. The definition of a drug The different types of receptors at which drugs can act The concept of affinity and those factors that cause a drug to bind to a receptor The concept of intrinsic activity

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pharmacodynamics

M.T. Piascik

PHA 824

November 11, 2008

PHARMACODYNAMICS

learning objectives
Learning Objectives
  • The definition of a drug
  • The different types of receptors at which drugs can act
  • The concept of affinity and those factors that cause a drug to bind to a receptor
  • The concept of intrinsic activity
  • The difference between full and partial agonists
  • The definitions of potency and efficacy
  • The definition of ED50
learning objectives cont
Learning Objectives (cont.)
  • The concept of spare receptors
  • The information regarding drugs that can be obtained from the log-dose response curve
  • The properties of a competitive antagonist and how it differs from an irreversible receptor agonist
  • The definition of LD50
  • The concept of a therapeutic index and how it is calculated
true or false a correct definition of a drug is
True or False?A correct definition of a drug is --
  • A chemical substance that interacts with a receptor to produce a beneficial therapeutic effect.
  • Answer—FALSE!!
  • Correct definition: A drug is a chemical substance that interacts with a receptor to produce a physiologic effect– regardless whether the effect is beneficial.
drug properties
Drug Properties
  • Drug binding to a receptor is mediated by the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor.
  • Agonists activate cellular signaling pathways to alter physiologic activity.
  • Antagonists bind to the receptor but cannot initiate a change in cellular function. Occupation of the receptor without activation results in blockade of the actions of agonists.
receptor
Receptor
  • Any cellular macromolecule to which a neurotransmitter or drug binds to initiate its effects. The endogenous function of a receptor is to participate in neurotransmission or physiologic regulation.
factors governing drug action11
FACTORS GOVERNING DRUG ACTION
  • Affinity is a measure of the tightness with which a drug binds to the receptor.
  • Intrinsicactivity is a measure of the ability of an agonist that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity.
understanding the concept of affinity
UNDERSTANDING THE CONCEPT OF AFFINITY
  • Affinity describes the strength of binding to receptors.

2) k1 describes the rate at which a drug associates with the receptor while k-1 describes the ease at which a drug dissociates from its receptor.

understanding the concept of affinity14
UNDERSTANDING THE CONCEPT OF AFFINITY

Affinity = k 1 /k -1 = __[DR]___

[D] [R]

The term most often used to represent affinity is the equilibrium dissociation constant or KD

KD = k -1/k 1 = ___[D] [R]___

[DR]

After appropriate mathematical substitution, it can be stated that;

Amount bound to receptor = [D]

[D]+KD

  • This equation states that the amount of drug bound to the receptor is dependent on the drug concentration and Kd.
understanding the concept of affinity15
UNDERSTANDING THE CONCEPT OF AFFINITY

Making the assumption that an effect of a drug is dependent on the number of receptors occupied, it can be stated that at binding equilibrium, the drug effect would be also be constant.

Affinity describes the strength of binding to receptors, Drugs that bind with great avidity to the receptors are said to have high affinity. The term most often used to represent affinity is the equilibrium dissociation constant or its abbreviation KD. The description of the strength of binding of drugs to receptors is very important in pharmacology. KD values are often used to compare the potency of different drugs as well as in the characterization of receptors.

The units of the equilibrium dissociation are in concentration, for 1 x 10-8M or 10 nanomolar. There is an inverse relationship between the KD and affinity. The smaller the KD, the higher the affinity.

an illustration of the relationship of affinity and drug binding
AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Make the following simple calculations and graphical representations.

an illustration of the relationship of affinity and drug binding17
AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Amount bound to receptor = [D]

[D]+KD

Terazosin has an equilibrium dissociation constant of 1.0 nM.

Calculate the percentage of receptors occupied at each Terazosin concentration

Terazosin % Receptors

Occupied

0.5 nM

1.0 nM

4.0 nM

10.0 nM

an illustration of the relationship of affinity and drug binding18

= ???

0.5

0.5 + 1.0

AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Terazosin at 0.5 nM:

an illustration of the relationship of affinity and drug binding19

1.0

1.0 + 1.0

= 33% Receptor Occupancy

0.5

0.5 + 1.0

= 50% Receptor Occupancy

AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Terazosin at 0.5 nM:

At 1.0 nM :

an illustration of the relationship of affinity and drug binding20

4.0

1.0

4.0 + 1.0

= 80% Receptor Occupancy

1.0 + 1.0

= 33% Receptor Occupancy

0.5

0.5 + 1.0

= 50% Receptor Occupancy

AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Terazosin at 0.5 nM:

At 1.0 nM :

At 4.0 nM :

an illustration of the relationship of affinity and drug binding21

4.0

10.0

1.0

10.0 + 1.0

4.0 + 1.0

= 90% Receptor Occupancy

= 80% Receptor Occupancy

1.0 + 1.0

= 33% Receptor Occupancy

0.5

0.5 + 1.0

= 50% Receptor Occupancy

AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Terazosin at 0.5 nM:

At 1.0 nM :

At 4.0 nM :

At 10.0 nM :

an illustration of the relationship of affinity and drug binding22
AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Amount bound to receptor = [D]

[D]+KD

Epinephrine has an equilibrium dissociation constant of 100 nM.

Calculate the percentage of receptors occupied at each epinephrine concentration:

Epinephrine % Receptors

Occupied

50.0 nM

100.0 nM

400.0 nM

1000 nM

an illustration of the relationship of affinity and drug binding23

= ???

50.0

50.0 + 100.0

AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Epinephrine at 50.0 nM:

an illustration of the relationship of affinity and drug binding24

400.0

1000.0

100.0

1000.0 + 100.0

400.0 + 100.0

= 90% Receptor Occupancy

= 80% Receptor Occupancy

100.0 + 100.0

= 33% Receptor Occupancy

50.0

50 + 100

= 50% Receptor Occupancy

AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

At 50.0 nM:

At 100.0 nM :

At 400.0 nM :

At 1000.0 nM :

an illustration of the relationship of affinity and drug binding25
AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Amount bound to receptor = [D]

[D]+KD

Terazosin at: Epinephrine at: % Receptors Occupied

0.5 nM 50 nM 33 %

1.0 nM 100 nM 50 %

4.0 nM 400 nM 80 %

10.0 nM 1000nM 90 %

50% OF RECEPTORS WILL BE OCCUPIED WHEN A DRUG

IS GIVEN AT A CONCENTRATION EQUAL TO ITS KD

an illustration of the relationship of affinity and drug binding26
AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

Now plot the relationship between concentration and receptor occupancy.

an illustration of the relationship of affinity and drug binding27
AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

50% OF RECEPTORS WILL BE OCCUPIED WHEN A DRUG

IS GIVEN AT A CONCENTRATION EQUAL TO ITS KD

understanding the concept of intrinsic activity
UNDERSTANDING THE CONCEPT OF INTRINSIC ACTIVITY

AN ILLUSTRATION OF INTRINSIC ACTIVITY

maximal drug responses and spare receptors
MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS

1) As the concentration of a drug in a human organ system increases, the response of that system would be expected to increase until a maximal response is obtained.

2) The relationship between the number of receptors occupied and the physiologic response is complex.

maximal drug responses and spare receptors31
MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS
  • In many human physiological systems, not all receptors must be occupied by drug to achieve a maximal response.
  • A certain number of receptors are “spare.”
maximal drug responses and spare receptors32
MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS

The amplification of cellular signaling

pathways is responsible for the

nonlinear relationship between

receptor occupancy and response.

dose response curves
DOSE-RESPONSE CURVES

1)Dose-response relationships are a common way to portray data in both basic and clinical science.

2)To present the data, the concentration of the drug is plotted on the x-axis and the effect would be presented on the y-axis. A plot of drug concentration ([D]) versus effect (E/Emax in the graphs) is a rectangular hyperbola.

3)Most often, the log of the drug concentration is plotted versus the effect. A plot of the log of [D] versus Effect is a sigmoid curve.

dose response curves34
DOSE-RESPONSE CURVES

The dose at which 50% of the maximal effect is observed is referred to as the ED50

potency
Potency

1) Potency refers to the concentration of a drug required to produce a given physiologic effect. Drugs with high receptor affinity will exhibit greater potency than those with lower affinity.

potency36
Potency

Norepinephrine (NE) has a higher affinity for a receptor than does phenylephrine(PE).

The ED50 for norepinephrine is 100 nM while the ED50 for phenylephrine is 35,000 nM.

Norepinephrine would be said to have greater potency than phenylephine.

efficacy
Efficacy

1) Efficacy is often used to describe the maximal level of response a drug can produce.

efficacy38
Efficacy

Norepinephrine would have a greater efficacy than methoxamine which in turn would have a greater efficacy than clonidine.

additional concepts regarding partial agonists
ADDITIONAL CONCEPTS REGARDING PARTIAL AGONISTS
  • Partial agonists can block the actions of full agonists.
  • To achieve a maximal effect, partial agonists must occupy all receptors to produce a maximal effect.
  • If a full agonist is given in the presence of a receptor saturating dose of a partial agonist, the full agonist cannot access the receptor and hence its actions will be blocked
antagonists
ANTAGONISTS
  • Antagonists that bind in a reversible manner are referred to as competitive antagonists.
  • Agonists, if given in high concentrations, can displace the antagonist from the receptor
antagonists42

[D]

[

[DR]

[DR]

+

+

[R]

[R]

+

+

[AR]

[AR]

[A]

[A]

ANTAGONISTS
  • The antagonist [A] and agonist [D] are competing for the same limited number of receptors [R].
antagonists43
ANTAGONISTS

Amount of agonist bound to the receptor = [D]

In the presence of an antagonist [D]+Kd(1+[A]/Ka)

  • Examine the effect of terazosin (Ka= 1.0 nM) on the occupancy of the alpha1-adrenergic receptor by epinephrine ( = KD 100 nM).
  • Epinephrine % Receptors %Receptors % Receptors

Occupied Occupied Occupied

(Teraz = 0) (Teraz = 1nM) (Teraz = 10 nM)

  • 50.0 nM 33
  • 100.0 nM 50
  • 400.0 nM 80
  • 1000.0 nM 90
antagonists44
ANTAGONISTS

Amount of agonist bound to the receptor = [D]

In the presence of an antagonist [D]+Kd(1+[A]/Ka)

Amt Epi bound at 50 nM in the presence = 50 nM

of 1 nM terazosin 50 nM+ 100 nM(1+1 nM/1nM)

  • Epinephrine % Receptors %Receptors % Receptors

Occupied Occupied Occupied

(Teraz = 0) (Teraz = 1nM) (Teraz = 10 nM)

  • 50.0 nM 33 20
  • 100.0 nM 50
  • 400.0 nM 80
  • 1000.0 nM 90
antagonists45
ANTAGONISTS

Amount of agonist bound to the receptor = [D]

In the presence of an antagonist [D]+Kd(1+[A]/Ka)

Amt Epi bound at 50 nM in the presence = 50 nM

of 1 nM terazosin 50 nM+ 100 nM(1+1 nM/1nM)

  • Epinephrine % Receptors %Receptors % Receptors

Occupied Occupied Occupied

(Teraz = 0) (Teraz = 1nM) (Teraz = 10 nM)

  • 50.0 nM 33 20 4
  • 100.0 nM 50 33 8
  • 400.0 nM 80 66 26
  • 1000.0 nM 90 83 47
antagonists46
ANTAGONISTS

PE alone

competitive antagonists
COMPETITIVE ANTAGONISTS

1) Reversible binding to the receptor.

2) The blockade can be overcome by increasing the agonist concentration.

3) The maximal response of the agonist is not decreased.

4) The agonist dose-response curve in the presence of a competitive antagonist is displaced to the right, parallel to the curve in the absence of agonist.

irreversible receptor antagonists
Irreversible Receptor Antagonists

1) Irreversible receptor antagonists are chemically reactive compounds. These ligands first bind to the receptor. Following this binding step, the ligand then reacts with the functional groups of the receptor

applications to therapeutics
APPLICATIONS TO THERAPEUTICS
  • Few drugs interact with one and only one receptor.
  • Such a drug would be said to be specific.
  • Most drugs interact with more than one receptor class and thus have the capability to produce distinctly different pharmacologic effects. Some of these effects could be beneficial, some could be toxic. Such a drug would be said to be selective.
applications to therapeutics51
APPLICATIONS TO THERAPEUTICS
  • Assume a drug can interact with two receptor systems with the following characteristics;
  • Receptor System # 1:

KD= 0.40, effect- lowering of systemic arterial blood pressure.

  • Receptor System # 2:

KD = 40.0, effect- lethal ventricular arrhythmias.

the therapeutic index
The Therapeutic Index
  • The Therapeutic Index is the ratio of the ED50 of a drug to produce a lethal effect to the ED50 to produce a therapeutic effect.
  • The dose required to produce death in 50% of a population is referred to as the LD50.
the therapeutic index54
The Therapeutic Index

The ED50 for the beneficial effect of blood pressure lowering is 0.4 nM while the LD50 is 40 nM. Therefore, the therapeutic index will be:

TI = LD50 ED 50

TI = 40.0 nM

0.4 nM

TI = 100

factors governing drug action60

Drug in receptor micro-environment

Drug binds to receptor

Receptor activation of cell signaling

Physiologic response

Drug administration

Drug absorption

Drug distribution to receptor sites

PHARMACOKINETIC

PHARMACODYNAMIC

FACTORS GOVERNING DRUG ACTION