PharmacodynamicsPharmacodynamics

Dr Rizwan Ashraf

Lecture Objectives Lecture Objectives To understand the basic concepts regarding pharmacodynamics To define agonist and antagonists and other terms in relation to pharmacodynamics To explain the mechanism of drug receptor interaction Define spare receptors To differentitate between different tyes of antagonism

WHAT IS PHARMACODYNAMICS ?

Action of a drug on the body receptor interactions, mechanisms of therapeuticdose-response phenomena, toxic action.

RECEPTOR INTERACTION

A drug will not work unless it is bound

AGREED or NOT AGREED

BOUND WITH WHAT ?

PARTICULAR CONSTITUENTS OF

CELLS & TISSUES IN ORDER TO

PRODUCE AN EFFECT

PROTEINS LIPIDS DNA

RECEPTORS ?

ARE THERE DRUGS THAT ACT WITHOUT ARE THERE DRUGS THAT ACT WITHOUT BEING BOUND TO ANY OF THE TISSUE BEING BOUND TO ANY OF THE TISSUE

CONSTITUENTSCONSTITUENTS

YES OR

NO

YESYES

OSMOTIC DIURETICSOSMOTIC PURGATIVESANTACIDSHEAVY METALS CHELATING AGENTS

BUTBUT

PRINCPLES REMAIN TRUE FOR GREAT MAJORITY

THAT IS _____________________

______________________________.

Most drugs act through Most drugs act through ReceptorsReceptors

Receptors Receptors

Drug ReceptorDrug Receptor

A macromolecular component of a cell with which a drug interacts to

produce a response

Usually a protein

Receptors must be biologically important molecules

Receptors must have structural features that permit drug specificity

Receptors must have a drug-binding site and a biologically active site

Characteristics of ReceptorsCharacteristics of Receptors

          a. specificity a. specificity

          b. selectivity of response b. selectivity of response

          c. sensitivity c. sensitivity

Molecules capable of serving Molecules capable of serving as as

ReceptorsReceptors

Enzymes

Membrane proteins

glycoproteins, lipoproteins)

Nucleic acids

Complex polysaccharides

Many drugs inhibit enzymes

in the patient (ACE inhibitors)

in microbes (sulfas, Penicillins)

in cancer cells (5-FU, 6-MP)

Types of ProteinTypes of Protein Receptors Receptors

Regulatory – mediate the action of endogenous chemicals e.g. hormones,

NT,autocoids

Enzymes – may be inhibited or activated e.g. dihydrofolate reductase

receptor for methotrexate

Transport – e.g. Na+ /K+ ATP’ase for digitalis glycosides

Structural – e.g. tubulin,receptor for colchicine

some drugs bind to:

the genome (cyclophosphamide)

microtubules (vincristine)

Non-receptor Mediated EffectsNon-receptor Mediated Effects Interaction with small molecules

(e.g. binding of heavy metals)

Interaction with enzymes (e.g. sulfonamides, digitalis)

Incorporation into a macromolecule (e.g. some anticancer agents - purine and

pyrimidine analogues)

Nonspecific effects (e.g. membrane perturbation by general anesthetics)

Receptor-independent drug actionsReceptor-independent drug actions Chemically reactive agents

Disinfectants

Alkylating anticancer drugs

Physically active agents

Mannitol

Hydrogen peroxide

Counterfeit biochemical constituents

5-bromouracil

Antagonists tend to up regulate receptors

  Receptor regulationReceptor regulation

    1.1.  HomeostasisHomeostasis     2. Up and down regulation 2. Up and down regulation

    3. Desensitization 3. Desensitization

    4. Tolerance 4. Tolerance

agonists desensitize receptors homologous

(decreased receptor number)

heterologous

(decreased signal transduction

PharmacodynamicsPharmacodynamics

Drug receptor interactionDrug receptor interaction

D + R DR Complex

Drug - Receptor BindingDrug - Receptor Binding

Affinity

Drug Receptor InteractionDrug Receptor Interaction

DR Complex Effect

Theories of the Theories of the relationship between relationship between binding and responsebinding and response

      a. Occupation theorya. Occupation theory

            D + R D + R DR DR RESPONSE RESPONSE:response is proportional to the fraction of occupied :response is proportional to the fraction of occupied  receptors receptors :maximal response occurs when all the receptors are occu:maximal response occurs when all the receptors are occupiedpied

  AriensAriens

response is proportional to the fraction of response is proportional to the fraction of occupied receptors occupied receptors ANDAND the the  intrinsic activity intrinsic activity 

Stephenson Stephenson response is aresponse is a FUNCTION FUNCTION of occupancy  of occupancy maximum response can be produced maximum response can be produced  WITHOUT 100% occupation, WITHOUT 100% occupation, 

i.e. tissues havei.e. tissues have  spare receptorsspare receptors

BIOLOGICAL STIMULUSBIOLOGICAL STIMULUS

PERCENT RECEPTOR OCCUPANCYPERCENT RECEPTOR OCCUPANCY

0%0% 100%100%

BIOLOGICAL RESPONSEBIOLOGICAL RESPONSE RECEPTOR RESERVERECEPTOR RESERVETRETHOLDTRETHOLD

0%0% 100%100%

Max EffectMax EffectThreshold EffectThreshold Effect

Schematic representation of the relationship between threshold, receptor Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological responsereserve, receptor occupancy, biological stimulus and biological response

Receptors are said to be spare

for a given pharmacological response

when the maximal response can be elicited

by an agonist at a concentration that does

not result in occupancy of the full complement

of available receptors

Spare receptors More receptors available than needed

to elicit maximum responseallow maximal response without total receptor occupancy – increase sensitivity of the system

Agonist has to bind only a portion of

receptors for full effect

Some terminologies regarding Some terminologies regarding drug receptor interactiondrug receptor interaction

Affinity

Efficacy

Potency

Ligand

Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug and

receptor

Efficacy: Potential maximum therapeutic response

that a drug can produce.

Potency: Amount of drug needed to produce an

effect.

POTENCY

OR

EFFICACY

Which one is important while selecting a drug for therapy ?

Ligand:

Molecules that binds to a receptor

Classification of Ligands Classification of Ligands

a.a.    agonist agonist

b.  partial agonistb.  partial agonist

c.  antagonist c.  antagonist

pharmacological vs. physiological vs. chemical pharmacological vs. physiological vs. chemical

              pharmacological antagonistspharmacological antagonists

              - - competitive competitive

                       surmountable surmountable

                  - - noncompetitive noncompetitive

AGONIST

AgonistsAgonists Drugs that cause a response Drugs that interact with and activate receptors; They possess both affinity and efficacyTypes Full agonists

An agonist with maximal efficacy (response) has affinity plus intrinsic activity Partial agonists

An agonist with less then maximal efficacy has affinity and less intrinsic activity

Agonists differing in potency and maximum efficacy

Response

Dose

Full agonist

Partial agonist

Agonist Dose Response Curves

[D] (concentration units)

% M

axim

al E

ffec

t

0.01 0.10 1.00 10.00 100.00 1000.000.0

0.2

0.4

0.6

0.8

1.0

Partial agonist

Full Agonist

Partial agonist

PARTIAL AGONISTS - EFFICACYEven though drugs may occupy the same # of receptors, the magnitude

of their effects may differ.

AntagonistsAntagonists Interact with the receptor but do NOT change the receptor

Have affinity but NO efficacy

Block the action of other drugs

Effect only observed in presence of agonist

Types of AntagonistsTypes of Antagonists

Competitive

(Surmountable)decrease apparent

Potency

Noncompetitivedecrease

apparent maximum

efficacy

Competitive AntagonistCompetitive Antagonist

competes with ________for receptor

surmountable with increasing agonist concentration

displaces agonist dose response curve to the ___________(dextral shift)

reduces the apparent affinity of the __________.

Noncompetitive AntagonistNoncompetitive Antagonist

drug binds to receptor and stays boundirreversible – does not let go of receptor

produces slight dextral shift in the agonist DR curve in the low concentration range

but, as more and more receptors are bound (and essentially destroyed),

the agonist drug becomes incapable of eliciting a maximal effect

AGONIST VS ANTAGONIST

What happen when you increase agonist concentration even higher

How do non competitive antagonist affect receptor function

Summary (T or F)

Pharmacodynamics is the study of absorption, distribution, metabolism and elimination of drug. Some drugs can act without binding to a receptor spare receptors allow maximum response without full receptor occupancy Efficacy is the amount of drug needed to produce an effect. Affinity is the attractiveness between 2 drug molecules. Agonist are the drugs that block the response. Partial agonist has affinity and maximum efficacy. Antagonist has efficacy but no affinity. Competitive antagonist decreases potency Non competitive antagonist decreases efficacy