DRUG ACTION & PHARMACODYNAMIC

M. Imad Damaj, Ph.D.Associate Professor

Pharmacology and ToxicologySmith 652B, 828-1676, mdamaj@hsc.vcu.edu

Life History of A Drug

Non-SpecificMechanims

Drug-Receptor Interaction

Drug-Receptor Interaction

kk11

kk22

Drug (D)Drug (D)

Receptor (R)Receptor (R)

EffectEffect

DrugDrug--Receptor Receptor ComplexComplex

LigandLigand--binding binding domain domain

EffectorEffectordomaindomain

D + RD + RKKdd == kk22/k/k11

AffinityAffinityDRDR

EfficacyEfficacy

Drug-Receptor Interaction

Affinity – Measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor

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

Simple Occupancy Theory

RECEPTOR THEORY

MASS ACTION LAW

R + D DR effectk1k2

k3

25%

50%

75%

100%

Simple Occupancy Theory

Simple occupancy theorySimple occupancy theory: “ Intensity of response to a drug is proportional to the number of receptors occupied by that drug”

Maximal response occurs when all available receptors have been occupiedThis theory is not able to explain why one drug is more potent than another if they bind to the same receptor and both bind maximally to all receptors? (Example: Demerol vs Talwin)

Drug receptor interactions may involve Drug receptor interactions may involve many different types of chemical many different types of chemical bonds, some irreversible but usually bonds, some irreversible but usually weak nonweak non--covalent interactions that are covalent interactions that are reversible:reversible:

Covalent: almost irreversibleCovalent: almost irreversibleElectrostatic: Van Electrostatic: Van derder WaalsWaals and and

HydrogenHydrogenIonic: opposite chargesIonic: opposite charges

Drug-Receptor Bonds

Structure-Activity RelationshipAffinity & efficacy are determined by Affinity & efficacy are determined by

chemical structurechemical structure

Stringent RelationshipStringent Relationship

Drug-Receptor Interaction: Receptor Specificity

How can a drug interact with one receptor type and not others ?

Selectivity does not guarantee safety!

Structure-Activity RelationshipExploitation of SAR could lead to new Exploitation of SAR could lead to new

drug designdrug designStructural modification of Librium leads to the generation of other tranquilizers

Theories of Drug-Receptor Interaction

What are receptors?Traditional model was a rigid one:

“Lock and Key”– Lock Receptor surface– Key Drug or Ligand

Receptor

Drug

Theories of Drug-Receptor Interaction

Receptors fluid, flexible surfaces or pocketsCan change 3-D structure as ligand docksOccupy small portion or surface of a macromoleculeLigand - Receptor docking structure changes

Inactive Active

Modified Occupancy TheoryModified Occupancy Theorya. Affinity bindinga. Affinity binding- strength of the attraction between drug and receptor. The > affinity the > potency: Drugs with low affinity require higher concentrations to bind to receptorb. Intrinsic activityIntrinsic activity- ability of a drug to activate its receptor. High intrinsic activity relates to high maximal efficacy

Theories of Drug-Receptor Interaction

Receptor Theory: Agonists & AntagonistsAgonist: Molecules that activate receptors - a drug with affinity and efficacyAntagonist: Molecules that prevent receptor activation by endogenous regulatory molecules and drugs - a drug that has affinity but not efficacy

Inactive Active

AgonistAntagonist

Agonist Antagonist

Receptor Receptor

ActivatedReceptor

InactiveReceptor

Drug (D)

Ri

DRi DRa

Ra

CONFORMATIONAL SELECTION

HOW TO EXPLAIN EFFICACY?

The relative affinityOf the drug to either conformation will determine the effect of the drug

SPARE RECEPTORS

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 occupation Spare receptors

Allow maximal response without total receptor occupancy – increase sensitivity of the system

The number of receptors may exceed the number of effector-molecules available

Receptor remains activated after agonist departs: more than one receptor is activated

Drugs & Signal Transduction Mechanisms

Receptor-effector coupling: Transduction process between receptor occupancy and

drug response

Main Receptor Classes

1. G protein-Coupled Receptors Structure:

Single polypeptide chain threaded back and forth resulting in 7 transmembraneα-helices

There’s a G protein attached to the cytoplasmicside of the membrane (functions as a switch).

2. Ion Channel Receptors

Structure:Protein pores in

the plasma membrane

3. 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 α-helix spanning the membrane

4. Intracellular Receptors

Nuclear proteins

Consist a DNA-binding domain attached to a ligand-binding and transcriptional control domains

Effects are produced as a result of increased protein sysnthesis - slow onset

Second Messengers & Signal Transduction

Second Messengers & Signal Transduction

DOSE-RESPONSE RELATIONSHIPS

To determine the quantitative relation

between drug concentration and

response

DOSE EFFECT RELATIONSHIP

Dose-Response Curve

Type of Dose-Response Curves

GradedGraded

QuantalQuantal

•• Measured in a single biologic unitMeasured in a single biologic unit

•• Continuous scale (Continuous scale (↑↑dose dose →→ ↑↑effect)effect)

•• Relates dose to intensity of effectRelates dose to intensity of effect

•• Population studiesPopulation studies

•• AllAll--oror--none pharmacologic effectnone pharmacologic effect

•• Relates dose to frequency of effectRelates dose to frequency of effect

Types of Dose-Response Curves: Graded

Graded:Dose related to magnitude

on a graded scale

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PDE PDE InhibitionInhibition

RelaxationRelaxation

% ControlControl

TheophyllineTheophylline [µM][µM]

Types of Dose-Response Curves: QuantalDose related to % of subjects showing a

specified “all-or-non” response

DoseDose

# of

# of

S ubj

ects

S ubj

ects

0

10

20

30

40

50

1 3 5 7 9 11 13 150

10

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1 3 5 7 9 11 13 15

DoseDose

Cum

ulat

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% o

f C

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of

Subj

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Subj

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Characteristics of A Dose-Response Curve

Variability

POTENCY• Amount of a drug needed to produce a given effect• Determined mainly by the affinity of the receptor for the drug• Potency affects drug dosage• Relatively unimportant in clinical use of drugs• Are more potent drugs superior therapeutic agents?• Expressed as EC50 (µM) or ED50 (mg/kg)

• Graded= 50% of the maximal effect• Quantal = 50% population studied (LD50, TD50)

Potency: Graded Responses

ED50 or EC50 = Dose needed to produce 50% of the maximal effect.

% of% ofMaximalMaximal

EffectEffect

[Drug][Drug]

ECEC5050

Potency: Quantal Responses

0

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100 10000

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% % Achieving Achieving Complete Complete AnalgesiaAnalgesia

Total Total LidocaineLidocaine Dose (mg)Dose (mg)FerranteFerrante et al. et al. AnesthAnesth AnalgAnalg 82:9182:91--7, 19967, 1996

EDED5050 = 400 mg= 400 mg

EDED9090 = 490 mg= 490 mg

Potency: Quantal Responses

EFFICACY

• The maximal effect that can be produced by a drug

• Determined mainly by the properties of the drug and its receptor-effector system

• Important clinical measure

• Partial agonist have lower maximal efficacy than full agonists

Dose-Response Curves and Efficacy

Dose-Response Curves Showing Efficacy & Potency

SLOPE

The shape of the curve describe drug binding to receptors

Indicator of useful dosage range (steepness of the curve)

The slope have more theoretical than practical use

Slopes of Dose-Response Curves

VARIABILITY

Curves usually represent the mean response of a sample of population

Effect may vary considerably

“Start Low, Go Slow”

Expressed as 95% Confidence limits

Confidence Limits of Dose-Response Curves

Value of Dose-Response Curves

⇒ Determining if a drug produces a certain desired effect

⇒ Determining potency or dose required in producing effect

⇒ Comparing one drug with others:1. Efficacy

2. Potency

3. Safety

Comparing Dose-Response Curves

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% of % of Maximal Maximal

EffectEffect

[Drug][Drug]

Drug ADrug A

Drug CDrug C

Drug BDrug B

Relative Safety of A Drug

Dose-response curves help estimating the safety of a drug

Therapeutic Index: TI= LD50/ED50 * LD50= the median lethal dose of a drug in animals* Statement on selectivity of desired effects vs toxic

More general concept: The Median Toxic Dose (TD50)

* No drug produce a single effect: example of Codeine* Severity of the disease* Concentration vs dose

Therapeutic Index

Examples of TI

Substance safety margin

Alcohol 1:4 - 1:10

Aspirin 1:50

Caffeine 1:100

Marijuana 1:400-1:1800

Certain Safety FactorProblems with TI: o Comparison of the mid-points of DRCo Overlap of DRC

Determination of Certain Safety Factor:o Compare the extremes of the DRCo Important concept: used to determine a Therapeutic

Windowo 99% and 1% are not absolutes

Certain Safety Factor = LD1ED99

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Therapeutic and Toxic Effects

DoseDose

% % RespondingResponding

TherapeuticTherapeuticToxicToxic

EDED9999TDTD11EDED5050

TDTD5050

Drug Interaction & Dose-Response Curves

EffectEffect

Log [Drug]Log [Drug]

AgonistAgonist

Partial agonistPartial agonist

AntagonistAntagonist

Inverse AgonistInverse Agonist

Receptors, Agonists & AntagonistsA) Competitive Antagonists

Receptors, Agonists & Antagonists

A) Non-Competitive Antagonists

Antagonist Effects on Dose-Response Curves

A) Competitive Antagonists

Acetylcholine (µg/ml)

Antagonist Effects on Dose-Response Curves

A) Competitive Antagonists

Antagonist Effects on Dose-Response Curves

C) Non-Competitive Antagonists

Antagonist Effects on Dose-Response Curves

C) Non-Competitive Antagonists100

50

00.6 4.8 38.4

[Epinephrine] (µM)

Perc

enta

ge M

axim

um C

ontr

actio

n

Epinephrine

Epinephrine+ 2 x 10-7 Dibenamine

Epinephrine+ 4 x 10-7 Dibenamine

Non-Competitive Antagonist Effects on Dose-Response Curves

Thank you for your attention