General Principles of Drug Therapy

Integrated Scientific and

Clinical Pharmacology

Pharmacodynamics II
Dose-Response Relationships
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
General Principles of Drug Therapy

 Dose-Response Relationships
 Time-Response Relationships
 Drugs as Agonist
 Drugs as Antagonist
 Signaling and Receptors
 The Future is Now: Biologics

2
General Principles of Drug Therapy

Quantitative Aspects
I. Dose-effect Curve

3
General Principles of Drug Therapy

Example: Action at NMJ

 Repetitive slow stimulation of ulnar nerve causes release

of ACh at thumb NMJs innervated by nerve, resulting in a
reproducible twitch
 Injection of an anticholinergic NMJ blocker (e.g.
pancuronium) results in gradual blockade of
neurotransmission
 As [drug] rises in the tissue, thumb twitch is gradually
blocked

4
General Principles of Drug Therapy

Block of Stimulation-Induced
(ACh-mediated) Thumb-Jerk

% Blockade

drug Blockade develops as drug accumulates

at NMJ and blocks ACh receptors

0 100
Time

5
General Principles of Drug Therapy

Drug-Receptor Interactions Obey Law

Of Mass Action
k1

• At equilibrium, D + R DR.

k2

• k2/k1 = Kd = the equilibrium dissociation constant

for the drug-receptor complex

• Kd gives an idea of the binding affinity of D for R

6
General Principles of Drug Therapy

Concept: Fraction of Receptors

Occupied

 Y = fraction of receptors that are occupied

 RT = total receptor concentration, a property of
the tissue
 [D] is concentration of free (unbound) drug

 Y = [DR]/[RT] = [D]/(Kd + [D])

7
General Principles of Drug Therapy

Receptor Occupancy Theory

Dependency of drug effect on concentration:

*In Classical Receptor Occupancy Theory, the

magnitude of effect is assumed to be directly
proportional to Y:

*Effect = (Maximal Effect) x (Y)

Effect = (Maximal Effect) x ([D]/Kd + [D])

8
General Principles of Drug Therapy

Dose-Effect Curve:

Graded Responses
 Plot of dose (arithmetic scale) vs. effect yields a
curved line (simple rectangular hyperbola)

 Plot using log of the dose yields a sigmoid curve

with a large linear component between about 20%
and 80% of maximal effect
– an intuitively helpful graphical display of drug action

9
General Principles of Drug Therapy

Dose-Effect and Log Dose-Effect

Curves

Effect
Effect

ED50

Dose Log Dose

10
General Principles of Drug Therapy

Deficiencies of Classical Receptor

Occupancy Theory
 Does not allow maximum effect to occur unless all
receptors are occupied

 Cannot relate elicited effect as a function of a

biological stimulus governed by Y

 Thus, does not account for possibility of

amplification between receptor occupancy and
response

11
General Principles of Drug Therapy

Dose-effect Curve:

Quantal Responses
 Graphically expresses frequency that a defined
effect (e.g., blood pressure) occurs in a population
at a given dose

 Can also express cumulative frequency with which

an effect occurs in a population at a given dose and
all lower doses

12
General Principles of Drug Therapy

Normal Distribution Curve

 For all-or-none (quantal) responses

 Shows the variation in minimum (threshold) dose

in individuals in a population

13
General Principles of Drug Therapy

Frequency Distribution for

Quantal (all-or-none) Effects
Number Responding
for the First Time

More sensitive Less sensitive

Dose (mg/kg)

14
General Principles of Drug Therapy

15
General Principles of Drug Therapy

Representative Dose-Effect Curve

Drug-Receptor Interactions:
A typical D-R curve reveals potency, efficacy, and slope

Maximum Effect or Efficacy

Effect

Potency

Log Dose
16
General Principles of Drug Therapy

Drugs are described based on

magnitude of two properties:

1) Affinity for the receptor

 Affinity is related to potency

2) Efficacy once bound to the receptor

 Efficacy refers to maximal effect drug
can elicit

17
General Principles of Drug Therapy

Agonists and Antagonists

• AGONIST - Has affinity for receptor and efficacy
• ANTAGONIST - Has affinity but no efficacy
• Competitive Antagonist
• Noncompetitive Antagonist

• Partial Agonist or Partial Antagonist - Has affinity but

lower efficacy than full agonist.
• Examples of typical curves...next slide
18
General Principles of Drug Therapy

19
General Principles of Drug Therapy

Classes of Dose-Effect Curves

20
General Principles of Drug Therapy

Full Agonists (i.e., equal efficacies) that

Differ In Potency:

A
B C

Compare the ED50s

Drug Concentration (log scale)

21
General Principles of Drug Therapy

Agonists That Differ in Efficacy

A
% Max response

B
C

Log Drug Concentration

22
General Principles of Drug Therapy

23
General Principles of Drug Therapy

Drug properties should be

compared in the same system

24
General Principles of Drug Therapy

Competitive Antagonism Shifts The

Agonist D-R Curve (Potency)

AG alone AG + ANT

Drug Concentration (log scale)

25
General Principles of Drug Therapy

Noncompetitive Antagonism
Decreases Agonist Efficacy

AG alone
% Max response

AG + NC ANT
AG + higher dose NC ANT

Log Drug Concentration

26
General Principles of Drug Therapy

Competitive
antagonism is
Surmountable.
Antagonism:
Noncompetitive
A = Agonist antagonism is NOT
B = Antagonist surmountable: often
due to irreversible
Binding

Allosteric effects
Allosteric: occur when ligand B
binds to a different
site on the receptor
A = Agonist than agonist A
B = Ligand Either antagonism
or potentiation is
possible

27
General Principles of Drug Therapy

Factors Affecting Drug Response

 Resistance: used in context of antimicrobial drugs

 Tolerance: a decrease in drug response during

repeated administration

 Tachyphylaxis: acute development of tolerance

due to rapid repeated admin. of some drugs

28
General Principles of Drug Therapy

Pharmacokinetic Tolerance

 Also called Drug Disposition Tolerance

 Characterized by a decrease in [drug] at its site of

action

 Barbiturates, Alcohol, and many others

29
General Principles of Drug Therapy

Pharmacodynamic Tolerance

 This is due to reduced responsiveness to the drug

at its site of action

 Amphetamine

 Caffeine

 Nicotine

 Morphine, Barbiturates, Alcohol

30
General Principles of Drug Therapy

Drug Safety

Therapeutic Index


31
General Principles of Drug Therapy

Therapeutic and Toxic Effects are

Dose-Related: Ex. Phenobarbital

Sleep Death

ED50 LD50

Dose of Phenobarbital

32
General Principles of Drug Therapy

Therapeutic Index (TI)

TI (preclinical) LD50
ED50

clinical TI TD50
ED50

33
General Principles of Drug Therapy

34
General Principles of Drug Therapy

The End!!!

35