pharmacodynamics

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Chapter 5
Pharmacodynamics

2
Pharmacodynamics
 The study of the biochemical and physiologic
effects of drugs and the molecular
mechanisms by which those effects are
produced
 The study of what drugs do to the body and
how they do it

3
Therapeutic Objective
 To accomplish the therapeutic objective,
nurses must have a basic understanding of
pharmacodynamics
 Educating patients about their medications
 Making PRN decisions
 Evaluating patients for drug responses (both
beneficial and harmful)
 Collaborating with physicians about drug therapy

4
Pharmacodynamics
 Dose-response relationships
 Drug-receptor interactions
 Drug responses that do not involve receptors
 Interpatient variability in drug responses
 The therapeutic index

5
Dose-Response Relationships
 Relationship between the size of an
administered dose and the intensity of the
response produced
 Determines
 The minimum amount of drug we can use
 The maximum response a drug can elicit
 How much we need to increase the dosage to
produce the desired increase in response

6
Dose-Response Relationships
 As the dosage increases, the response
becomes progressively larger.
 Tailor treatment by increased/decreased
dosage until desired intensity of response is
achieved.
 Three phases occur (see Figure 5-1).

7
Fig. 5-1. Basic components of the dose-response curve.
A, A dose-response curve with dose plotted on a linear scale. B, The same dose-response
relationship shown in A but with the dose plotted on a logarithmic scale. Note the three
phases of the dose-response curve: Phase 1, The curve is relatively flat; doses are too low to
elicit a significant response. Phase 2, The curve climbs upward as bigger doses elicit a
corresponding increase in response. Phase 3, The curve levels off; bigger doses are unable
to elicit a further increase in response. (Phase 1 is not indicated in A because very low doses
cannot be shown on a linear scale.)

8
Maximal Efficacy and
Relative Potency
 These two characteristic properties of drugs
are revealed in dose-response curves.
 Maximal efficacy
 The largest effect that a drug can produce
(height of the curve; see Fig. 5-2A)
 Match the intensity of the response with the
patient’s need.
 Very high maximal efficacy is not always more
desirable. Don’t hunt squirrels with a cannon.

9
Fig. 5-2. Dose-response curves demonstrating efficacy and potency.
A, Efficacy, or “maximal efficacy,” is an index of the maximal response a drug can produce. The
efficacy of a drug is indicated by the height of its dose-response curve. In this example,
meperidine has greater efficacy than pentazocine. Efficacy is an important quality in a drug.
B, Potency is an index of how much drug must be administered to elicit a desired response.
In this example, achieving pain relief with meperidine requires higher doses than with morphine.
We would say that morphine is more potent than meperidine. Note that, if administered in
sufficiently high doses, meperidine can produce just as much pain relief as morphine. Potency is
usually not an important quality in a drug.

10
Maximal Efficacy and
Relative Potency
 Relative potency
 The amount of drug we must give to elicit an effect
(see Fig. 5-2B)
 Rarely an important characteristic of the drug
 Can be important if lack of potency forces
inconveniently large doses
 Implies nothing about maximal efficacy – refers to
dosage needed to produce effects

11
Drug-Receptor Interactions
 Drugs
 Chemicals that produce effects by interacting with
other chemicals
 Receptors
 Special chemicals in the body that most drugs
interact with to produce effects

12
Receptor
 A receptor is any functional macromolecule in
a cell to which a drug binds to produce its
effects.
 Technically, receptors can include enzymes,
ribosomes, tubulin, etc.
 The term receptor is generally reserved for
the body’s own receptors for
 Hormones, neurotransmitters, and other
regulatory molecules

13
Receptor Binding
 Binding of a drug to its receptor is usually
reversible.
 Receptor activity is regulated by endogenous
compounds.
 When a drug binds to a receptor, it will mimic
or block the action of the endogenous
regulatory molecules and increase or
decrease the rate of physiologic activity
normally controlled by that receptor.

14
Fig. 5-3. Interaction of drugs with receptors for norepinephrine.
Under physiologic conditions, cardiac output can be increased by the binding of
norepinephrine (NE) to receptors (R) on the heart. Norepinephrine is supplied to
these receptors by nerves. These same receptors can be acted on by drugs,
which can mimic the actions of endogenous NE (and thereby increase
cardiac output) or block the actions of endogenous NE (and thereby reduce
cardiac output).

15
Important Properties of
Receptors
 Receptors are normal points of control of
physiologic processes.
 Under physiologic conditions, receptor
function is regulated by molecules supplied
by the body.
 Drugs can only mimic or block the body’s own
regulatory molecules.
 Drugs cannot give cells new functions.

16
Important Properties of
Receptors
 Drugs produce their therapeutic effects by
helping the body use its preexisting
capabilities.
 In theory, it should be possible to synthesize
drugs that can alter the rate of any biologic
process for which receptors exist.

17
Four Primary Receptor Families
 Cell membrane–embedded enzymes
 Ligand-gated ion channels
 G protein–coupled receptor systems
 Transcription factors

18
Fig. 5-4. The four primary receptor families.
1, Cell membrane–embedded enzyme. 2, Ligand-gated ion channel. 3, G protein–coupled
receptor system (G = G protein). 4, Transcription factor. (See text for details.)

19
Receptors and Selectivity of
Drug Action
 The more selective a drug is, the fewer side
effects it will produce.
 Receptors make selectivity possible.
 Each type of receptor participates in the
regulation of just a few processes.

20
Receptors and Selectivity of
Drug Action
 Lock and key mechanism
 Does not guarantee safety
 Body has receptors for each:
 Neurotransmitter
 Hormone
 All other molecules in the body used to regulate
physiologic processes

21
Fig. 5-5. Interaction of acetylcholine with its receptor.
A, Three-dimensional model of the acetylcholine molecule. B, Binding of acetylcholine to its
receptor. Note how the shape of acetylcholine closely matches the shape of the receptor.
Note also how the positive charges on acetylcholine align with the negative sites on the receptor.

22
Theories of
Drug-Receptor Interaction
 Simple occupancy theory
 Modified occupancy theory
 Affinity
• Strength of the attraction
 Intrinsic activity
• Ability of the drug to activate a receptor upon binding

23
Fig. 5-6. Model of simple occupancy theory.
The simple occupancy theory states that the intensity
of response to a drug is proportional to the number of
receptors occupied; maximal response is reached with
100% receptor occupancy. Because the hypothetical
cell in this figure has only four receptors, maximal
response is achieved when all four receptors are
occupied. (Please note: Real cells have thousands
of receptors.)

24
Drug-Receptor Interactions
 Agonists, antagonists, and partial agonists
 Agonists
 Antagonists
 Noncompetitive vs. competitive antagonists
 Partial agonists

25
Agonists
 Agonists are molecules that activate
receptors.
 Endogenous regulators are considered
agonists.
 Agonists have both affinity and high intrinsic
activity.
 Dobutamine mimics norepinephrine at
cardiac receptors.
 Agonists can make processes go “faster” or
“slower.”

26
Antagonists
 Produce their effects by preventing receptor
activation by endogenous regulatory
molecules and drugs
 Affinity but no intrinsic activity
 No effects of their own on receptor function

27
Antagonists
 Do not cause receptor activation but cause
pharmacologic effects by preventing the
activation of receptors by agonists
 If there is no agonist present, an antagonist
will have no observable effect.

28
Noncompetitive vs.
Competitive Antagonists
 Noncompetitive antagonists
 Bind irreversibly to receptors
 Reduce the maximal response that an agonist can
elicit (fewer available receptors)
 Impact not permanent (cells are constantly
breaking down “old” receptors and synthesizing
new ones)

29
Noncompetitive vs.
Competitive Antagonists
 Competitive antagonists
 Compete with agonists for receptor binding
 Bind reversibly to receptors
 Equal affinity: receptor occupied by whichever
agent is present in the highest concentration

30
Fig. 5-7. Dose-response curves in the presence of competitive and noncompetitive
antagonists.
A, Effect of a noncompetitive antagonist on the dose-response curve of an agonist.
Note that noncompetitive antagonists decrease the maximal response achievable with an
agonist. B, Effect of a competitive antagonist on the dose-response curve of an agonist.
Note that the maximal response achievable with the agonist is not reduced. Competitive
antagonists simply increase the amount of agonist required to produce any given intensity of
response.

31
Partial Agonists
 These are agonists that have only moderate
intrinsic activity.
 The maximal effect that a partial agonist can
produce is less than that of a full agonist.
 Can act as antagonists as well as agonists

32
Regulation of Receptor
Sensitivity
 Receptors are dynamic cell components.
 Number of receptors on cell surface and
sensitivity to agonists can change in
response to
 Continuous activation
 Continuous inhibition

33
Regulation of Receptor
Sensitivity
 Continuous exposure to agonist
 Desensitized or refractory
• Down-regulation
 Continuous exposure to an antagonist
 Hypersensitive

34
Drug Responses That Do Not
Involve Receptors
 Simple physical or chemical interactions with
other small molecules
 Examples of receptorless drugs
 Antacids, antiseptics, saline laxatives, chelating
agents

35
Interpatient Variability in
Drug Responses
 The dose required to produce a therapeutic
response can vary substantially among
patients.
 Measurement of interpatient variability
(see Fig. 5-8)
 The ED50

36
Fig. 5-8. Interpatient variation in drug responses.
A, Data from tests of a hypothetical acid suppressant in 100 patients. The goal of the study is to
determine the dosage required by each patient to elevate gastric pH to 5. Note the wide
variability in doses needed to produce the target response for the 100 subjects. B, Frequency
distribution curve for the data in A. The dose at the middle of the curve is termed the ED50—the
dose that will produce a predefined intensity of response in 50% of the population.

37
Interpatient Variability in
Drug Responses
 Clinical implications of interpatient variability
 The initial dose of a drug is necessarily an
approximation.
 Subsequent doses must be “fine tuned” based on
the patient’s response.
 ED50 in a patient may need to be increased or
decreased after the patient response is evaluated.

38
Therapeutic Index
 Measure of a drug’s safety
 Ratio of the drug’s LD50 (average lethal dose
to 50% of the animals treated) to its ED50
 The larger/higher the therapeutic index, the
safer the drug.
 The smaller/lower the therapeutic index, the
less safe the drug.

39
Fig. 5-9. The therapeutic index.
A, Frequency distribution curves indicating the ED50 and LD50 for drug “X.” Because its LD50 is much greater
than its ED50, drug X is relatively safe. B, Frequency distribution curves indicating the ED50 and LD50 for drug
“Y.” Because its LD50 is very close to its ED50, drug “Y” is not very safe. Also note the overlap between the
effective-dose curve and the lethal-dose curve.

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