Pharmacodynamic

Lecturer : Tirta Darmawan Susanto, dr., MKes

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 Pharmacodynamics

Objectives :
1.Definition of pharmacodynamics
2.Molecular mechanism mediating drug
action.
3.Definition of Receptor
4.Drugs and receptors interaction
5.Second Messenger system
6.Dose effect relationship
7.Factors Modifying Drug Responses
 Definition

Pharmacodynamics the actions of the

drug on the body mechanism of action
and therapeutic and toxic effects
Pharmacodynamics interaction of drug
molecules with biological target receptor
bind and interact to exert effect.
Basic for rational therapy and invent new
drugs
MOLECULAR MECHANISMS MEDIATING
DRUG ACTION
MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

There are many intervening steps between

drug binding or receptor activation and the
ultimate tissue response.
Drug intermediaries to relay (transduce)
the drug signal the cellular
communication (second messenger
signaling) and effector systems response
There are many different types of molecular
targets mediating drug responses
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

Drug Targets
A.Receptors
molecular entities that evolved specifically
to bind certain substances cellular
communication (e.g., -adrenergic
receptors).
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

B. General Sites
not have specifically evolved as
communication mechanisms may or may
not adhere to all pharmacodynamic
principles discussed earlier (e.g., intrinsic
activity) can act as receptors for drug
action.
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

B. General Sites
Examples of general sites mediating drug
action include the following:
Components in key signaling or metabolic
pathways
Ion channels or transporters found in the
cell membrane
Intracellular or extracellular enzymes
Structural components
C. Unidentified Targets
Finally, the molecular targets for some drugs
have not been completely elucidated yet.
example the target for inhaled general
anesthetics
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

Receptor Coupling and Transduction

Mechanisms
Transduction conversion of the information
contained in the drug molecule (e.g., size,
shape) into a signal that can be recognized
and acted on by the cell ultimate biologic
response.
Transduction greatly amplify the signal
only few drugs to generate response.
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

Extracellular Transduction Mechanisms

A number of dugs act outside of the cell
affect cellular function.
They act via
a. Extracellular Enzymes alter the activity
of extracellular enzymes.
b. Direct interaction with endogenous
molecules to affect their ability to reach
their sites of action.
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

Transmembrane Transduction
Mechanisms
Receptors or other targets embedded in the
plasma membrane
a. G proteincoupled receptors (GPCRs)
seven transmembrane pass receptors, a
large class of receptors that mediate the
majority of endogenous transmitter and
hormone driven responses
MOLECULAR MECHANISMS MEDIATING
DRUG ACTION
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

b. Receptor-coupled enzymes bypass the G

protein coupling mechanism link directly
to cellular communication cascades.
The receptor is directly coupled to kinase
enzymatic activity within the cell.
MOLECULAR MECHANISMS MEDIATING
DRUG ACTION
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

C. Transmembrane ion channels allow the

passage of ions from one side of a
membrane to another open, closed, or
inactive state, which represent different
conformations of the channel protein.
MOLECULAR MECHANISMS MEDIATING
DRUG ACTION
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

Intracellular Transduction Mechanisms

Drugs bind to their primary site of action after
being transported or diffusing into the
intracellular space of the cell.
Once inside the cell these receptors may be
coupled to a number of transduction
mechanisms
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

Intracellular Transduction Mechanisms

a. Intracellular Receptors
Lipophilic drugs passively cross the cell
membrane do not require cell membrane
receptors.
One target for these drugs is an intracellular
receptor that activates transcriptional
pathways ligand gated transcriptional
regulation.
 MOLECULAR MECHANISMS MEDIATING
DRUG ACTION

Intracellular Transduction Mechanisms

b. Intracellular Enzymes
Some drugs directly target intracellular
enzymes, such as phosphodiesterase (PDE),
that control second messenger pathways.
c. Structural Mechanisms
Drugs can also target structural components
of cells (e.g., the cytoskeleton or
microtubules) to affect their function
MOLECULAR MECHANISMS MEDIATING
DRUG ACTION
 Receptor

Receptor Cell surface or intracellular

regulatory proteins endogenous chemical
signals such as neurotransmitters and
hormones adrenoreceptors, steroid
receptors, acetylcholine receptors.
Receptor
 Receptor

Receptors
determine the quantitative relationship
between drug dose and pharmacologic
effect
responsible for the selectivity of drug action
mediate the actions of pharmacologic
agonists and antagonists
 Receptor

Drugs bind to other, nonregulatory

molecules in the body without producing a
discernible effect inert binding sites
buffering the concentration of a drug
bound drug does not contribute directly to
the concentration gradient that drives
diffusion
Eg. Albumin and orosomucoid (1-acid
glycoprotein)
 Drug and Receptor Interaction

Drugs bind to receptors variety of

chemical bonds very strong covalent
bonds (which usually result in irreversible
action), weaker electrostatic bonds (eg,
between a cation and an anion), and much
weaker interactions (eg, hydrogen van der
Waals, and hydrophobic bonds).
Drug interaction with molecular targets
initiating event in a multistep process
ultimately alters tissue function
 Drug and Receptor Interaction

2 basic concept
Drugs accelerate the physiologic processes
Drugs do not create new functions, only
modulate the functions
If drug-receptor binding results in activation of
the receptor (similar with endogenous
chemical) agonist;
if inhibition results (have no intrinsic
activity) antagonist
Drug and Receptor Interaction
 Drug and Receptor Interaction

Quantitation of the effects of drug-receptor

binding as a function of dose yields dose
response curves
Drug and Receptor Interaction
 Drug and Receptor Interaction

Law of mass action

The combination of drug (also called
ligand) and receptor depends on the
concentrations of each
The amount of drug-receptor complex
formed determines the magnitude of the
response
A minimum number of drug receptor
complexes must be formed for a response
to be initiated (threshold)
 Drug and Receptor Interaction

Law of mass action

As drug concentration increases, the
number of drug-receptor complexes
increases and drug effect increases
A point will be reached at which all
receptors are bound to drug, and therefore
no further drug-receptor complexes can be
formed and the response does not increase
any further (saturation)
 Drug and Receptor Interaction

Drug+Receptor DrugReceptor Complex

Effect
Although the amount of drug receptor-
complex formed is proportional to the
concentrations of drug and receptor, this
relationship is not linear but is in fact
parabolic
Drug and Receptor Interaction
 Drug and Receptor Interaction

This relationship should be familiar to you.

These curves are Michaelis-Menten curves
or rectangular hyperbolae (Biochemistry -
Enzyme kinetics)
 Drug and Receptor Interaction

We use dose-response curves to:

1)determine a drug's potency and efficacy in
order to compare its effects with other
drugs (agonists) producing the same
response
2)determine how safe a drug is to use
Drug and Receptor Interaction
Drug and Receptor Interaction
 Drug and Receptor Interaction

Efficacy maximum effect (Effectmax) of a

drug.
Potency comparative measure different
doses of two drugs needed to produce the
same effect
 Drug and Receptor Interaction

Factors Affecting Drug-Target Interactions

Two basic properties of the drug-receptor
interaction contribute importantly to drug
responses
the ability of the drug to bind to its receptor
control the strength, duration, and type of
the drug-receptor interactionaffinity
the ability of the drug to alter the activity of
its receptor agonist, antagonist, partial
agonist, inverse agonist
 Drug and Receptor Interaction

Collectively these factors dictate the strength

with which the drug forms a complex with its
receptor affinity:
Size and shape of the drug molecule
Types, number, and spatial arrangement of
drug binding sites (stereochemistry)
 Drug and Receptor Interaction

Cont.dictate the strength with which the drug

forms a complex with its receptor affinity:
Intermolecular forces between drug and
binding sites
a. Van der Waals forces = weak bonds and
transient reversible effects
b. Hydrogen bonds = intermediate bonds and
transient reversible effects
c. Covalent bonds = strong bonds and long-
lasting or irreversible effects
 Drug and Receptor Interaction

A measure of the relative ease with which the

association and dissociation reactions occur
equilibrium dissociation constant (KD).
Drugs with high affinity a small value for KD,
and vice versa
KD the concentration of drug needed to bind
50% of the total receptor population
Lower KDlower concentrations to achieve
sufficient receptor occupancy exert an effect
Drug and Receptor Interaction
 Drug and Receptor Interaction

Agonists (sometimes called full agonists

maximum activation of the receptor and
elicit a maximum response from the tissue
intrinsic activity of 1.
Antagonists bind but produce no
activation of the receptor and therefore
block responses from the tissue intrinsic
activity of 0.
 Drug and Receptor Interaction

Antagonism inhibition of stimulation by

endogenous ligands
Chemical (Physical) Antagonists
Physiologic (Functional) Antagonists
Pharmacokinetic Antagonists
Pharmacologic Antagonists
Drug and Receptor Interaction
 Drug and Receptor Interaction

Partial agonistsintrinsic activity between 0

and 1 weaker activation of the receptor
than full agonists or the endogenous ligand
partial activation of the receptor and its
downstream signaling events.
The clinical effect of a partial agonist
depend on its intrinsic activity and the
concentration of the endogenous ligand
 Drug and Receptor Interaction

Partial agonists
If concentrations of the endogenous ligand are
really low, will increase receptor
activation, a weak agonist.
If concentrations of endogenous ligand are
high, compete for receptors a weaker
activation of the receptor than endogenous
ligand less cumulative receptor
activation. inhibition weak antagonist
 Drug and Receptor Interaction

Inverse Agonist inhibit evident with

receptors that exhibit baseline (ongoing or
constitutive) activity in the absence of
agonist binding.
 Drug and Receptor Interaction

Inverse Agonist
One example is in cancer chemotherapy
mutations of the epidermal growth factor
receptor receptor to be active in the
absence of epidermal growth factor
antagonist would be of no benefit
inverse agonists would suppress receptor
activation reduce the growth signaling via
this pathway.
 Drug and Receptor Interaction

Selectivity of Drug Responses

The cell will respond only to the spectrum of
drugs that exhibit affinity for the receptors
expressed by the cell.
The greater the extent to which a drug
molecule exhibits high affinity for only one
receptor the more selective will be the
drugs actions lower potential for side
effects.
 Drug and Receptor Interaction

Selectivity of Drug Responses

The higher the affinity and efficacy the
smaller the amount of drug necessary the
lower the potential for nonselective actions.
 Second Messenger System

Transduction or coupling mechanism

linked to the final effector system via an
intermediate cell signaling (second
messenger) system.
It is not possible to discuss the intricacies of
all second messenger systems linked to
clinically relevant drug action.
Second Messenger System
 Second Messenger System

a. Cyclic Adenosine Monophosphate Pathway

b. Cyclic Guanosine Monophosphate
c. Phospholipase C, Inositol 1,4,5
Trisphosphate (IP3), Diacylglycerol (DAG)
help in understanding drug interactions.
Nitrates and PDE5 inhibitors Concurrent
use of these two drugs excessive levels
of cGMP excessive vasodilation
dangerous reductions in blood pressure
 Dose Effect relationship

Quantifying Drug-Target Interactions:

Dose-Response Relationships
There are two basic types of dose-response
curvesgraded and quantal each
provides useful information for therapeutic
decisions.
 Dose Effect relationship

A. Graded Dose-Response Curves

 Dose Effect relationship

B. Quantal Dose-Response Curves

 Factors Modifying Drug Responses

There is considerable variability in

responsiveness to drugs among individuals.
Drug responsiveness may also vary in the
same patient over time or with disease
progression.
 Factors Modifying Drug Responses

a. Changes in the amount of drug at the

intended molecular target
Polymorphisms in drug absorption,
distribution, or metabolism are major
causes of interindividual variability.
Prolonged drug administration can alter
these variables.
Disease processes can alter drug
absorption, distribution, and metabolism.
 Factors Modifying Drug Responses

b. Changes in the drug receptor itself

Different patients express differing numbers
or composition of receptors (receptor
polymorphisms), leading to differences in
affinity or efficacy of the drugs they bind.
Chronic drug administration, disease, or age
can alter drug receptor numbers and
function.
 Factors Modifying Drug Responses

c. Changes in coupling or signaling

mechanisms
Activation of signaling pathways can result
in feedback modification of the receptor or
upstream signaling molecules to decrease
their effectiveness.
 Addendum

Tachyphylaxis or desensitization
relatively rapid (minutes, hours) changes
in drug responsiveness caused by repeated
drug administration.
Tolerance reductions in responsiveness
that occur over a longer time frame (days or
longer) caused by prolonged drug
administration.
 Addendum

Homologous desensitization or
tolerance specific to one receptor type or
drug class.
Heterologous desensitization or
tolerance affects many receptor types or
drugs.
 Summary

Pharmacodynamics is what the drugs do to

the body.
It involve drug targets (receptor, enzymes,
structural), and second messenger.
Second messenger amplify the signal from
drugs
Many conditions can modify the drug
responses
 References

Katzung BG, Masters SB, Trevor AJ. Basic

Clinical Pharmacology 12th edition. 2012.
Lange McGraw Hill.
Goodman and Gillmans. The Pharmacological
Basis of Theurapetic 11th Edition.
American Society for Experimental
Therapeutics:
http://aspet.org/pharmacology_resources/#
Databases
. Chapter 1 : Basic Principles of
Pharmacodynamics.