Pharmacodynamics/Toxicodynamics

Elizabeth Kampira PhD

What is
Pharmacodynamics
Effect of the drug on the biochemical and
physiological function of the body.
The mechanisms of drug action and the
relationship between drug concentration and
effect.
LR
L +R
where L=ligand (drug), R=receptor
(attachment site)

Toxicodynamics
Is the study of toxic actions of xenobiotic substances on
living systems.
It is concerned with processes and changes that occur
to the drug at the target tissue, including metabolism
and binding that results in an adverse effect.
These effects are result of the interaction of the
biologically effective dose of the ultimate (active)
form of the toxicant with molecular target
Simply, TD is concerned with what the toxicant do to the
body

harmacodynamics/Toxicodynamic

Dosage
Exposure

Plasma Site of
Conc.
action

Toxicokinetics

Toxic
Effects

Toxicodynamics

Molecular Targets
Concept

The toxic action of a chemical is a consequence of

physical/chemical interaction of the active tha
the
form of
chemical
a molecul targe withi th livin t
with
ar
t
n
e g
organism

Molecula Target Concep

r
s
t

Examples of Molecular
Targets

Proteins
Arylhydrocarbon(Ah) receptor
Dioxin
HemoglobinCO
LipidsCarbon
tetrachloride
DNAAflatoxin

Toxicodynamics

Why concerned with what the drug does to the body

FDA Approved and Unapproved Uses

Interactions with Other Drugs
Adverse Effects and Contraindications

Why concerned with what the

drug does to the body

AIDS EVALUATION OF MEDICAL LITERATURE:

Better assessment of new modalities for using drugs
Better assessment of new indications for drugs
Better assessment of new concerns regarding risk-benefit

Why concerned with what the

does to the body
AIDS PATIENT-DOCTOR RELATIONSHIP:
The patient has more respect for and trust
in a therapist who can convey to the
patient how the drug is affecting the
patients body.
A patient who understands his/her therapy
is more inclined to become an active
participant in the management of the
patients disease.

Why concerned with what

the drug does to the body
PEACE OF MIND!
Knowledge of how a drug works increases the
therapists
confidence that the drug is being used
appropriately.

HOW DO DRUGS WORK?

Most work by interacting with endogenous proteins:

Some antagonize, block or inhibit

endogenous proteins

Some activate endogenous proteins

A few have unconventional mechanisms of
action

HOW DO DRUGS ANTAGONIZE, BLOCK OR

INHIBIT ENDOGENOUS PROTEINS?

ntagonists of Cell Surface Receptors

ntagonists of Nuclear Receptors

nzyme Inhibitors

on Channel Blockers

ransport Inhibitors

hibitors of Signal Transduction Proteins

Toxicodynamics
Determines the no. of receptors that can
interact with toxicants
Binding
Interaction
Induction of toxic effects

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.

Macromolecular nature of drug

receptors
Regulatory proteins
Enzymes
Transport proteins
Structural proteins
The ability to bind to a receptor is mediated by the
chemical structure of the drug that allows it to Interact
with complementary surfaces on the receptor

RECEPTOR:
A macromolecular component of the organism that
binds the drug and initiates its effect.

Cell surface receptor

A receptor that is embedded in the cell membrane and
functions to receive chemical information from the
extracellular compartment and to transmit that information
to the intracellular compartment
In most cases, the chemical nature of the receptor site
remains obscure.

HOW DO DRUGS WORK BY ANTAGONIZING

CELL SURFACE RECEPTORS?
Cell surface receptors exist to transmit chemical
signals from the
outside to the inside of the cell.

Some compounds bind to cell surface receptors, yet

do not
activate the receptors to trigger a response.
When cell surface receptors bind the molecule, the
endogenous
chemical cannot bind to the receptor and cannot
trigger a
response.

HOW DO DRUGS WORK BY ANTAGONIZING

CELL SURFACE RECEPTORS?
Extracellular
Compartment

Bound Endogenous
Activator (Agonist) of Receptor

Displaced Endogenous
Activator (Agonist) of
Receptor

Extracellular
Compartment
Bound Antagonist
of Receptor (Drug)

Cell Membrane
Active Cell Surface Receptor

Intracellular
Compartment

Cellular Response

Intracellular
Compartment

Inactive Cell Surface

Receptor Upon being Bound

HOW DO DRUGS WORK BY ANTAGONIZING

CELL SURFACE RECEPTORS?
Displaced Endogenous Activator
(Agonist) of Receptor

Extracellular
Compartment

Bound Antagonist
of Receptor

Cell Membrane

IntracellularActive Receptor
Compartment

Inactive Receptor

Allosteric Inhibitor

Are they clinically useful?

Angiotensin Receptor
Blockers
(ARBs) for high blood
pressure,
heart failure, chronic
renal insufficiency
(losartan [Cozaar];
valsartan [Diovan])

HOW DO DRUGS ANTAGONIZE, BLOCK OR

INHIBIT ENDOGENOUS PROTEINS?

Antagonists of Cell Surface Receptors

Antagonists of Nuclear Receptors

Enzyme Inhibitors
Ion Channel Blockers
Transport Inhibitors
Inhibitors of Signal Transduction Proteins

HOW DO DRUGS WORK BY ANTAGONIZING

NUCLEAR RECEPTORS?
Bound
Antagonist
of Receptor
(Drug)

Displaced
Endogenous
Activator
(Agonist) of
Nuclear
Receptor

Inactive
Nuclear
Receptor
In Cytosolic
Compartmen
t

DNA

Nucleus

Intracellular
Inactive Nuclear Receptor
Compartment
In Nuclear Compartment

Estrogen Receptor Antagonists for the prevention and treatment of breast

cancer (tamoxifen [Nolvadex])

HOW DO DRUGS ANTAGONIZE, BLOCK OR

INHIBIT ENDOGENOUS PROTEINS?

Antagonists of Cell Surface Receptors

Antagonists of Nuclear Receptors

Enzyme Inhibitors
Ion Channel Blockers
Transport Inhibitors
Inhibitors of Signal Transduction Proteins

HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate

Product

Cellular Function
Inactive Enzyme

Substrate
Bound Enzyme
Inhibitor (Drug)

Enzymes catalyze
the biosynthesis of
products from
substrates.
Some drugs bind to
enzymes and inhibit
enzymatic activity.
Loss of product due
to enzyme inhibition
mediates the
effects of enzyme
inhibitors.

e.g Cyclooxygenase Inhibitors for pain

relief,
particularly due to arthritis (aspirin;

HOW DO DRUGS ANTAGONIZE, BLOCK OR

INHIBIT ENDOGENOUS PROTEINS?

Antagonists of Cell Surface Receptors

Antagonists of Nuclear Receptors

Enzyme Inhibitors
Ion Channel Blockers
Transport Inhibitors
Inhibitors of Signal Transduction Proteins

ARE DRUGS THAT BLOCK ION

CHANNELS CLINICALLY USEFUL?

Some important
examples:
Calcium Channel Blockers (CCBs) for angina and
high blood pressure (amlodipine [Norvasc];
diltiazem [Cardizem])
Sodium Channel Blockers to suppress cardiac
arrhythmias
(lidocaine [Xylocaine]; amiodarone [Cordarone])

ARE DRUGS THAT INHIBIT TRANSPORTERS

CLINICALLY USEFUL?
Some important examples:
Selective Serotonin Reuptake Inhibitors (SSRIs) for the
treatment of depression (fluoxetine [Prozac];
fluvoxamine [Luvox])
Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in
renal epithelial cells to increase urine and sodium
output for the treatment of edema (furosemide
[Lasix]; bumetanide [Bumex])

ARE DRUGS THAT INHIBIT SIGNAL

TRANSDUCTION PROTEINS
CLINICALLY USEFUL?
Some important examples:
Tyrosine Kinase Inhibitors for chronic
myelocytic
leukemia (imatinib [Gleevec])
Type 5 Phosphodiesterase Inhibitors for
erectile
dysfunction (sildenafil [Viagra])
This is a major focus of drug development

HOW DO DRUGS WORK BY ACTIVATING

ENDOGENOUS PROTEINS?

gonists of Cell Surface Receptors

. alpha-agonists, morphine agonists)

gonists of Nuclear Receptors

. HRT for menopause, steroids for inflammation)

nzyme Activators

. nitroglycerine (guanylyl cyclase), pralidoxime )

on Channel Openers

. minoxidil (K) and alprazolam (Cl))

HOW DO CHEMICALS WORK BY ACTIVATING

CELL SURFACE RECEPTORS?
KEY CONCEPTS:
Cell surface receptors exist to transmit chemical
signals from
the outside to the inside of the cell.
Some chemicals bind to cell surface receptors and
trigger a response.
Chemicals in this group are called receptor
agonists.
Some agonists are actually the endogenous
chemical signal,

HOW DO CHEMICALS WORK BY

UNCONVENTIONAL MECHANISMS OF ACTION?
Disrupting of Structural Proteins
e.g. vinca alkaloids for cancer, colchicine for gout

Being Enzymes
e.g. streptokinase for thrombolysis

Covalently Linking to Macromolecules

e.g. cyclophosphamide for cancer

Reacting Chemically with Small Molecules

e.g. antacids for increased acidity

Binding Free Molecules or Atoms

e.g. drugs for heavy metal poisoning, infliximab (anti-TNF)

HOW DO DRUGS WORK BY

UNCONVENTIONAL
MECHANISMS OF ACTION (Continued)?

Being Nutrients
e.g. vitamins, minerals

Exerting Actions Due to Physical Properties

e.g. mannitol (osmotic diuretic), laxatives

Working Via an Antisense Action

e.g. fomivirsen for CMV retininitis in AIDS

Being Antigens
e.g. vaccines

Having Unknown Mechanisms of Action

e.g. general anesthetics

Characteristics of Drug-Receptor
Interactions
Chemical Bond: ionic, hydrogen,
hydrophobic, Van der Waals, and
covalent.
Saturable
Competitive
Specific and Selective
Structure-activity relationships
Transduction mechanisms

Receptor Transduction Mechanisms

Neurotransmitter and peptide signaling requires
receptormediated responses to affect the target
cell.
Ion channel linked receptors e.g. Ach nicotinic
(Na+) and GABA (Cl-)
Second messenger generation, adenylate
cyclase stimulation or inhibition - cAMP,
guanylate cyclase - cGMP, phospholipase C IP3, DAG
Some receptors are themselves protein kinases
Intracellular receptors (e.g. corticosteroids,
thyroid hormone)

Quantitative aspects of
drug-receptor interaction
Drug-Receptor Interactions Obey
the Law Of Mass Action
At
equilibrium
By law of mass
action:

k1

D R DR effect
k2

[ D ].[ R ].k1 [ DR ].k 2

Therefore:

k2
[ D ].[ R ]
KD
k1
[ DR ]
K1 rate constant for combination
K2 rate constant for dissociation
KD equilibrium dissociation constant

Occupancy Theory
Single-occupancy theory
The intensity of the bodys response to the drug
is directly related to the number of receptors
occupied by the drug.
The maximum response occurs when all of the
receptors have drug molecules attached.
Modified occupancy theory
Different drugs have different strengths of attractions,
or affinity, for receptor sites.
Once a drug is attached to a receptor, it has different
abilities to stimulate the receptor

OCCUPATION THEORY OF DRUG-RECEPTOR

INTERACTIONS
If RT = total # of receptors, then
RT = [R] + [DR]
Replace [R] by (RT -[DR]) and rearrange:

DR complex

D+
R

EFFECT

Fractional occupancy = DR
RT
DR
R+
DR
But from KD
= KD DR
D

[DR]
RT

[D]

= Max. effect
Kd + [DR]

effect

[DR]
=
Max. effect RT

[D]

When [D] = KD
[DR] = 0.5
RT

=
Kd + [D]

1.00

[DR]/Rt

0.75

[ DR ]
[ D]

Rt
K D [ D]

0.50

0.25

0.00

KD

10

[D]

Notice how the drug effect reaches a plateau or maximum.

This is because there are a finite number of receptors.

15

20

Dose-Response
Concept

The magnitude of the toxic effect will be a

function of the
is related to
concentration of the active form
concentration of altered molecular targets, which in turn
toxicant(
biologically
the
of the effective at th sit wher th
molecul
target ar locate
dose)
e e e
e
ar
s
e d.

12

% Bound

Receptor Binding

Kd

Concentration of Ligand
The log-dose response curve is dependent on the affinity of the ligand for the receptor and its intrinsic
activity. Affinity determines the position of the dose-response curve on the X-axis, while intrinsic activity
affects the magnitude of the response.
The dose-response relationship (from C.D. Klaassen, Casarett and Doulls
Toxicology, 5th ed., New York: McGraw-Hill, 1996).

mpounds Have Different Affinities for the Same Recep

1.00

Kd=0.5
Kd=1

[DR]/RT

0.75

kd=5

0.50

0.25

0.00
0.01

0.10

[D]

1.00

10.00

(concentration units)

100.00

Types of Receptor Antagonists

Competitive

Noncompetitive

PARTIAL AGONISTS - EFFICACY

Even though drugs may occupy the same # of receptors, the
magnitude of their effects may differ.
Full Agonist

% Maximal Effect

1.0
Partial agonist

0.8
0.6

Partial agonist

0.4
0.2
0.0
0.01

0.10

1.00

[D]

10.00

100.00

(concentration units)

1000.00

Receptor Sensitivity
Changes in receptor sensitivity
Receptors are not static.
Continual stimulation from an agonist
usually makes the drug less effective.
Continual blockage from an antagonist
usually makes the drug more likely to react.
Nonreceptor responses
Drugs exert their effect by reacting physically
or chemically with other molecules in the
body

HOW TO EXPLAIN EFFICACY?

Drug (D)

Ri

DRi

The relative affinity

of the drug to either
conformation will
determine the effect of
the drug

Ra

Factors Governing Drug Action

1. Affinity
A measure of the tightness
that a drug binds to the
receptor.

DRa

CONFORMATIONAL SELECTION

2.Intrinsic activity.
Is a measure of the ability of a
drug once bound to the
receptor to generate an effect
activating stimulus and
producing a change
in cellular activity.

Spare Receptors

Receptor Regulation
Sensitization or Up-regulation
1. Prolonged/continuous use of receptor
blocker
2. Inhibition of synthesis or release of
hormone/neurotransmitter Denervation
Desensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of
agonist
Homologous vs. Heterologous

ED50

GRADED DOSERESPONSE CURVE

ED50

Cumulative
Frequency
Distribution

QUANTAL DOSERESPONSE CURVE

Frequency
Distribution

Morphine

Aspirin

THERAPEUTIC INDEX AN INDEX OF SAFETY

TheTherapeutic Index (TI)is used
to compare the therapeutically
effective dose to the toxic dose

Hypnosi
s

Death

Therapeutic index
The use of theED50andLD50doses to
derive theTI may be misleading as to safety,
depending on the slope of the dose-response
curves for therapeutic and lethal effects.
To overcome this deficiency, toxicologists
often use another term to denote the safety
of a drug the Margin of Safety (MOS).
TheMOSis usually calculated as the ratio
of the dose that is just within the lethal range
(LD01) to the dose that is 99% effective (ED99).
The MOS = LD01/ED99. A physician must use
caution in prescribing a drug in which the MOS is
less than 1.

ED99A
ED50A
LD1A

LD1
Margin of Safety =
ED99

Causes of Variability in Drug

Response
Those related to the biological system
1. Body weight and size
2. Age and Sex
3. Genetics - pharmacogenetics
4. Condition of health
5. Placebo effect

Causes of Variability in Drug

Response
Those related to the conditions of
administration
1. Dose, formulation, route of
administration.
2. Resulting from repeated administration
of drug:
drug resistance; drug tolerance-tachyphylaxis;
drug allergy

3. Drug interactions:
chemical or physical;
GI absorption;
protein binding/distribution;
metabolism (stimulation/inhibition);
excretion (pH/transport processes);