Pharmacodynamics

Pharmacodynamics

Collected and Prepared By

S.Bohlooli, PhD

Bound Free Free Bound

LOCUS OF ACTION

“RECEPTORS”TISSUE

RESERVOIRS

SYSTEMIC CIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATION

Molecular pharmacology :

Molecular pharmacology is concerned with studies of basic mechanisms of drug actions on biological systems.

The idea that drugs act upon specific sites (receptive substance) began with John New Port Langley (1852-1926) of Cambridge.

However the word ‘receptor’ is given by Paul Ehrlich (1854- 19 15).

The receptor concept which forms a key note in the development of molecular pharmacology became firmly established by the quantitative work of Alfred Joseph Clark (1885-1941), a professor of pharmacology at Kings College London.

Receptor (key element)

In addition to its usefulness for explaining biology, the receptor concept has important practical consequence for The development of drugs Arriving at therapeutic decisions in clinical

practice.

Receptors:

Largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects

Are responsible for selectivity of drug action

Mediate the actions of pharmacologic antagonists

Macromolecular nature of drug receptors

Regulatory proteins

Enzymes

Transport proteins

Structural proteins

Quantitative aspects of drug-receptor interaction

Drug-Receptor Interactions Obey the Law Of Mass Action

effectDRRDk

k

1

2

2].[1].].[[ kDRkRD By law of mass action:

At equilibrium

][

]].[[

1

2

DR

RDK

k

kD

Therefore:

Total number of receptors: Rt = [R] + [DR]

][

]].[[

DR

RDKD

[R] = Rt – [DR]

][

]].[[].[

][

])[].([

DR

DRDRD

DR

DRRDK ttD

After rearrangement:

][

].[][

DK

RDDR

D

t

][

][][

DK

D

R

DR

Dt

KD

When [D] = KD

[DR] RT

= 0.5

[D]

[DR

]/R

t

0 5 10 15 200.00

0.25

0.50

0.75

1.00

][

][][

DK

D

R

DR

Dt

Receptor Binding

The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).

% B

oun

d

Concentration of Ligand

KD

Relation between drug dose & clinical response

1. Affinity for the receptor. Affinity is related to potency.

2. Efficacy once bound to the receptor. Efficacy refers to the maximal effect the drug can elicit.

Drugs are described based on the magnitude of two properties:

AGONISTAGONIST - Has affinity for receptor and efficacy. - Has affinity for receptor and efficacy.

ANTAGONISTANTAGONIST - Has affinity but no efficacy. - Has affinity but no efficacy.

Competitive AntagonistCompetitive Antagonist Noncompetitive AntagonistNoncompetitive Antagonist

Partial AgonistPartial Agonist or Partial Antagonist or Partial Antagonist – – Has affinity but Has affinity but lowerlower efficacy than full agonist. efficacy than full agonist.

Agonists and Antagonists

Receptor ligand types

Full Agonists (i.e., equal efficacies) that Differ In Potency:

Drug Concentration (log scale)Drug Concentration (log scale)

% M

ax R

esp

onse

% M

ax R

esp

onse

AABB CC

Compare the EC50s

Agonists That Differ in Efficacy

AA

BB

CC

Log Drug ConcentrationLog Drug Concentration

% M

ax r

esp

on

se%

Max

res

po

nse

Full and partial agonist occupancy and response relationship

0.0

50

100

0.01 0.1 1.0 10.0

Res

pons

e(%

)

Response(full agonist) Occupancy

(both)

Response(partial Agonist)

Concentration (umol/l)

Inverse agonist

Inverse agonist can exist where an appreciable level of activation may exist even when no ligand is present For example: receptors for benzodiazepines, cannabinoidsand dopamine

Under such condition it may be possible for a ligand to reduce the level of activation. such drugs are known as inverse agonist

Competitive Antagonism Shifts The Agonist D-R Curve (Potency)

Drug Concentration (log Drug Concentration (log scale)scale)

% M

ax R

esp

onse

% M

ax R

esp

onse AG + ANTAG + ANTAG aloneAG alone

EC50EC50

Noncompetitive Antagonism Decreases Agonist Efficacy

Log Drug ConcentrationLog Drug Concentration

% M

ax r

esp

on

se%

Max

res

po

nse

AG aloneAG alone

AG + NC ANTAG + NC ANT

AG + higher doseAG + higher doseNC ANTNC ANT

Receptors are said to be ‘spare’ for a given pharmacologicalresponse when the maximal response can be elicited by anagonist at a concentration that not result in occupancy of thefull complement of available receptors

Spare receptor

Emax

Log Concentration

Res

pone

s(%

) Agonist alone

Agonist with noncompetitive antagonist in

presence of spare receptor

Agonist with noncompetitive antagonist in absence of

spare receptor

R R’

LR LR’

L L EffectNo effect

Possible mechanism for the partial agonist phenomenon.

Agonist like to bind to receptor in R’ state and shifts the equilibrium toward more LR’ and makes effect

Antagonist like to bind to receptor in R and R” state without any preference and makes no shifts in net equilibrium

Partial agonist has a little more affinity for receptor in R’ states than R state and makes partial effect

Inverse agonist has more affinity to receptor in R state and shifts the equilibrium toward more LR and make negative response than resting state.

Desensitization and Tachyphylaxis

DesensitizationToleranceRefractorinessDrug resistance

Changes in receptor

Loss of receptor

Exhaustion of mediators

Increased metabolic degradation

Physiological adaptation

Active extrusion of drug from cells

How?

Drug Antagonism

Pharmacologic

Chemical

Pharmacokinetic

Physiologic

Dimercaprol & heavy metals

Propranolol & norepinephrine

Phenobarbital & warfarine

Epinephrine & histamine

Signaling mechanism &

drug action

Type of receptors

Ligand gated ion channels

G protein coupled receptors

Ligand-Regulated Transmembrane Enzymes

Including Receptor Tyrosine Kinases

Cytokine Receptors

Intracellular receptors

-amino butyric acid (GABA) Glycine Aspartate Glutamate Acethylcholine Serotonin

Ligand gated ion channel (iontropic receptors)

R

Ligand gated ion channel (iontropic receptors)

ions

Hyper polarizationor

depolarization

Cellular effects

Adernocorticotropic hormone Acetylcholine Angiotensin Catecholamines Chrionic gonadotropin Follicle stimulating hormone Glucagon Histamine Luteinizing Hormone Seretonin Vasopressin

G protein coupled receptors

R

+E

G G- + -

Ions

Second messengersChange inexcitability

Ca2+ release Protein phosphorylation

other

Cell effects

G protein coupled receptors

Ligand -regulated transmembrane enzyme including receptor tyrosine kinases Insulin Epidermal growth factor (EGF) Platelet-derived growth factor (PDGF) Arterial natriuretic factor (ANF) Transforming growth factor (TGF- )

Cytokine receptors Growth hormone Erythropoietin Interferones

Kinase linked receptors

R/E

Protein phosphorylation

Gene transcription

Protein synthesis

Cellular effects

Kinase linked receptors

R

Nucleus

Gene transcription

Protein synthesis

Cellular effects

Nuclear receptors

Well Established Second Messengers

Cyclic Adenosine Monophosphate (cAMP) Calcium and Phosphoinositides Cyclic Guanosine Monophosphate (cGMP)

Good Luck