CHAPTER 5 PHARMACODYNAMICS

Pharmacodynamics – study of the biochemical and physiologic effects of drugs and

the molecular mechanisms by
which those effects are produced
- study of what drugs do to the body and how they do it

I. DOSE RESPONSE RELATIONSHIPS

- relationship between the size of an administered dose and the intensity
of the response produced
- determine the minimum amount of drug we can use, the maximum
response a drug can elicit, and how
much we need to increase the dosage to produce the desired
increase in response

A. BASIC FEATURES OF THE DOSE RESPONSE RELATIONSHIP

- as dosage is increased, the response becomes progressively larger
- because drug responses are graded, therapeutic effects can be adjusted
to fit the needs of each
patient (raise or lower the dosage until a response of the desired
intensity)
- if drug responses were all-or-nothing instead of graded, drugs could
produce only one intensity of
response
- if response were too strong or too weak for a particular patient,
there would be nothing we
could do to adjust its intensity to better suit the patient

1. Phase I – occurs at low doses

- the curve is flat during this phase because doses are too low to
elicit a measurable response

2. Phase II – an increase in dose elicits a corresponding increase in the

response
- during this phase the dose response relationship is graded

3. Phase III – as the dose is raised higher, we eventually reach a point where
an increase in dose is
unable to elicit a further increase in response and the curve flattens
out

B. MAXIMAL EFFICACY AND RELATIVE POTENCY

1. Maximal Efficacy – largest effect that a drug can produce

- indicated by the height of the dose-response curve
- a drug with very high maximal efficacy is not always more
desirable than a drug with lower
efficacy
 2. Relative Potency – potency refers to the amount of drug we must give to
elicit an effect
- a potent drug is one that produces its effects at low doses
- potency is rarely an important characteristic of a drug
- can be important if a drug is so lacking in potency that doses
become inconveniently large
(which is rare)
- potency of a drug implies nothing about its maximal efficacy –
potency and efficacy are
completely independent qualities
- refers only to the dosage needed to produce effects – never to the
maximal effects a drug can
produce

endogenous – produced by the body naturally

- relating to or produced by metabolic synthesis in the body

II. DRUG RECEPTOR INTERACTIONS

A. INTRODUCTION TO DRUG RECEPTORS

- only way drugs can produce their effects is by interacting with other
chemicals
- receptors are the special “chemicals” in the body that drugs interact with
to produce effects

receptors – any functional macromolecule in a cell to which a drug

binds to produce its effects
- generally reserved for what is arguably the most important
group of macromolecules
through which drugs act: the body’s own receptors for
hormones,
neurotransmitters, and other regulatory molecules

- general equation for the interaction between drugs and their receptors
D + R ↔ D-R COMPLEX → RESPONSE (D = drug and
R = receptor)

- binding of a drug to its receptor is usually reversible

- receptors are activated (turned “ON”) by interaction with other
molecules, regulated by
endogenous compounds and then mimics or blocks the
actions of endogenous
regulatory molecules
- the drug will either increase or decrease the rate of the physiologic
activity normally controlled
by the receptor

Receptor Binding Effects:

 - drugs can mimic the action of endogenous NE and thereby increase
cardiac output
OR
- drugs can block the action of endogenous NE and thereby prevent
stimulation of the heart by
an autonomic neurons

Properties of Receptors and Drug-Receptor Interactions:

- receptors through which drugs act are normal points of control of
physiologic processes
- under physiologic conditions, receptor function is regulated by
molecules supplied by the body
- all that drugs can do at receptors is mimic or block the action of
the body’s own regulatory
molecules
- because drug action is limited to mimicking or blocking the body’s
own regulatory molecules,
drugs cannot give cells new functions – rather, drugs can only
alter the rate of pre-
existing processes (cannot make the body do anything that it
is not already capable of
doing)

B. THEORIES OF DRUG RECEPTOR INTERACTION

- help explain dose-response relationships and the ability of drugs to mimic
or block the actions of
endogenous regulatory molecules

1. Simple Occupancy Theory

- assumes that all drugs acting at a particular receptor are identical
with respect to the ability to
bind to the receptor and the ability to influence receptor function
once binding has taken place
- the intensity of the response to a drug is proportional to the
number of receptors
occupied by that drug
- a maximal response will occur when ALL available receptors
have been occupied
- there is nothing in this theory to explain why one drug should be
more potent than another, nor
can this theory explain how one drug can have higher maximal
efficacy than another

2. Modified Occupancy Theory

- intensity of the response to a drug is still related to the number of
receptors occupied
- intensity is also related to the ability of the drug to activate
receptors once binding has
occurred
 Independent Qualities of drugs:
a. affinity – the strength of the attraction between a drug and its
receptor
- drugs with high affinity can bind to receptor when
present in low
concentrations, therefore, are effective in low
doses
- very potent
- drugs with low affinity must be present in high
concentrations to bind to their
receptors
- not very potent
- ex. of carbon monoxide

b. intrinsic activity – the ability of a drug to activate the

receptor following binding and is
reflected in its maximal efficacy
- drugs with high intrinsic activity cause intense receptor
activation and have
high maximal efficacy (able to cause intense
responses)
- drugs with low intrinsic activity cause only slight
activation and have low
maximal efficacy

- two drugs can occupy the same number of receptors but produce
effects of different intensity;
the drug with the greater intrinsic activity will produce the
more intense response

E. AGONISTS, ANTAGONISTS, AND PARTIAL AGONISTS

1. Agonists – drugs that mimic the body’s own regulatory molecules

- molecules that activate receptors
- neurotransmitters, hormones, and all other endogenous regulators
of receptor functions
- as agonists, drugs simply bind to receptors and mimic the actions
of the body’s own regulatory
molecules
- in terms of modified occupancy theory, these drugs have both
affinity and high intrinsic
activity
affinity allows the agonist to bind to receptors
intrinsic activity allows the bound agonist to “activate”
or “turn on” receptor
function
- agonists do not necessarily make physiologic processes go faster;
receptor activation can also
 slow down a particular process

2. Antagonists – drugs that block the actions of endogenous regulators

- produce their effects by preventing receptor activation by
endogenous regulatory molecules
and drugs (agonists)
- employed most commonly in the treatment of overdose
- have virtually no effects on their own on receptor function
- in terms of modified occupancy theory, these drugs have affinity
for a receptor but with no
intrinsic activity
- response is determined by how much agonist is present (if there is
no agonist present,
administration of an antagonist will have no observable effect)

Classes:
a. Noncompetitive (Insurmountable) Antagonists – bind
irreversibly to receptors and
inhibition of these agents cannot be overcome – no
matter how much
agonist may be available
-irreversibility does not mean effects last forever; effects
wear off as the
receptors to which they are bound are replaced
(life cycle)
- effect of binding is equivalent to reducing the total
number of receptors
available for activation by an agonist
- intensity of response is proportional to the total number
of receptors occupied
- reduce the maximal response that an agonist can elicit
- if sufficient antagonist is present, agonist effects will be
blocked completely
- rarely used therapeutically

b. Competitive (Surmountable) Antagonists – bind reversibly

to receptors and the
inhibition they cause is surmountable
- produce receptor blockade by competing with agonists
for receptor binding
- if competitive antagonist and an agonist have equal
affinity for a particular
receptor, the receptor will be occupied by
whichever agent is present
in the highest concentration

3. Partial Agonists – also mimic the actions of endogenous regulatory

molecules, but they produce
 responses of intermediate intensity (moderate intrinsic
activity)
- maximal effect that a partial agonist can produce is lower than that
of a full agonist
- can act as antagonists as well as agonists

F. REGULATION OF RECEPTOR SENSITIVITY

- in response to continuous activation or continuous inhibition, the number
of receptors on the cell
surface can change, as can their sensitivity to agonist molecules
(drugs and endogenous
ligands)

desensitized / refractory / down regulation - when the receptors of a

cell are continually exposed to
an agonist, the cell usually becomes less responsive
- responsible mechanisms include destruction of receptors by the
cell and modification of
receptors such that they respond less fully

hypersensitive / supersensitive – when the receptors of a cell are

continually exposed to antagonists,
the cell usually becomes more responsive
- responsible mechanisms include synthesis of more receptors

IV. INTERPATIENT VARIABILITY IN DRUG RESPONSES

- in order to promote the therapeutic objective, you must be alert to
interpatient variation in drug
responses
- it is not possible to predict exactly how an individual patient will respond
to medication
- each patient must be evaluated to determine his or her actual response
to treatment

A. ED50
- an abbreviation for average effective dose
- the dose that is required to produce a defined therapeutic response in
50% of the population
- can be considered a “standard” dose and is frequently the dose
selected for initial treatment
- after evaluating the response to the “standard” dose, adjustments can be
made for subsequent doses
B. CLINICAL IMPLICATIONS OF INTERPATIENT VARIABILITY
1. The initial dose of a drug is necessarily an approximation. Subsequent
doses must be “fine tuned”
based on the patient’s response.
- administer the medication as prescribed and evaluate the response
- dosage adjustments can then be made as needed
 - if the physician’s order calls for a dose that differs from the
recommended dose by a large
amount, that order should be challenged

2. When given an average effective dose (ED50) some patients will be

undertreated, whereas others will
have received more drug than they need.
- when therapy is initiated with a dose equivalent to the ED50 it is
especially important to
evaluate the patient’s response
- patients who fail to respond may need an increase in dosage
- signs of toxicity will need a dosage reduction

3. Since drug responses are not completely predictable, you must look at the
patient (and not the
reference books) to determine if too much or too little medication
has been administered
- doses should be adjusted based on the patient’s response and not
just on the basis of what
some reference says is supposed to work
- an average dose may be effective for some patients, ineffective for
others, and toxic for still
others

4. Because of variability in responses, nurses, patients, and other concerned

individuals must evaluate
actual responses and be prepared to inform the prescribing
physician about these responses so
that proper adjustments in dosage can be made

V. THERAPEUTIC INDEX
- a measure of a drug’s safety
- determined using laboratory animals
- ratio of a drug’s LD50 to its ED50

LD50 – average lethal dose

- dose that is lethal to 50% of the animals treated

- large therapeutic index indicates that a drug is relatively safe

LD50 is much larger than the therapeutic dose
- small therapeutic index indicates that a drug is relatively unsafe
LD50 is not much larger than the therapeutic dose

- if a drug is to be truly safe, the highest dose required to produce

therapeutic effects must be
substantially lower than the lowest dose capable of causing death