Far Eastern University

Institute of Nursing

MODULE 7: Drug Action: Pharmacodynamic Phase

I. INTRODUCTION:

Pharmacodynamics (sometimes described as what a drug does to the body) is the

study of the biochemical, physiologic, and molecular effects of drugs on the body and
involves receptor binding (including receptor sensitivity), postreceptor effects,
and chemical interactions. Pharmacodynamics, with pharmacokinetics help explain
the relationship between the dose and response, i.e., the drug's effects. The
pharmacologic response depends on the drug binding to its target. The concentration
of the drug at the receptor site influences the drug’s effect. In the pharmacodynamic
phase a biologic or physiologic response results. This module will also briefly discuss
Pharmacogenetics, Tolerance & Tachyphylaxis, and placebo Effect.

II. OBJECTIVES

Upon completion of this module, the student is expected to:

1. Differentiate the three phases of drug action.
2. Explain the meaning of pharmacodynamics, dose response, maximal efficacy,
receptors, and nonreceptors in drug action.
3. Define the terms protein-bound drugs, half-life, therapeutic index, therapeutic
drug range, side effects, adverse reaction, and drug toxicity.
4. Check drugs for half-life, percentage of protein-binding effect, therapeutic range,
and side effects in a drug reference book.
5. Describe the nursing implications of pharmacodynamics.
6. Explain the three effects associated with pharmacodynamic interactions.
7. Discuss drug interaction and give examples

III. DISCUSSION

Pharmacodynamic Phase

Pharmacodynamics is the study of the way drugs affect the body. Drug
response can cause a primary or secondary physiologic effect or both. The
Primary effect is desirable, and the secondary effect may be desirable or
undesirable. An example of a drug with a primary and secondary effect is
diphenhydramine Benadryl), an antihistamine. The primary effect of
diphenhydramine is to treat the symptoms of allergy, and the secondary effect
is a central nervous system depression that causes drowsiness. The secondary
effect is undesirable when the patient drives a car. But at bedtime it could be
desirable because it causes mild sedation and helps induce sleep.

Formative Assessment (to be submitted): Think of a way to explain the

pharmacodynamics phase to a 70-year-old male and write it as a narrative on
a one-page bond paper. To be submitted as scheduled.

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1.1. Dose Response and Maximal Efficacy

Dose response is the relationship between the minimal versus the

maximal amount of drug dose needed to produce the desired drug
response. Drug dose is usually adjusted to achieve the desired
response.

All drugs have maximum drug effect (maximal efficacy) but is different
for every drug. For example, morphine and tramadol hydrochloride are
both pain relievers. The maximum efficacy of morphine is greater than
the maximum efficacy of tramadol hydrochloride regardless of how
much tramadol is given. The pain relief with the use of tramadol
hydrochloride is not as great as it is with morphine.

1.2. Onset, Peak, and Duration of Acton

One important aspect of pharmacodynamics is knowing the drug’s

onset, peak, and duration of action. Onset of action is the time it takes
to reach minimum effective concentration (MEC) after a drug is
administered. Peak action occurs when the drug reaches its highest
blood or plasma concentration. Duration of action is the length of time
the drug has pharmacologic effect. The figure below illustrates the
areas in which onset, peak and duration of action occurs.

Some drug produce effects in minutes, but others may take hours or
days. A time-response curve evaluates three parameters of drug action:
the onset of drug action, peak action, and duration of action.

It is necessary to understand time-response in relationship to drug

administration. If the drug plasma or serum level decrease below
threshold or MEC, adequate drug dosing is not achieved; too high a
drug level above the maximum toxic concentration (MTC) can result in
toxicity.

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1.3. Receptor Theory

Drugs act through receptors by binding to the receptor to produce

(initiate) a response or to block (prevent) a response. The activity of
many drugs is determined by the ability of the drug to bind to a specific
receptor. The better the drug fits at the receptor site the more
biologically active the drug is. It is similar to the fit of the right key in a
lock.

Most receptors, which are proteins in nature, are found in cell

membranes. Drug binding-sites are primarily on proteins,
glycoproteins, proteolipids, and enzymes. There four receptor families:
a. Kinase-linked receptor
b. Ligand-gated ion channels
c. G protein-coupled receptor system
d. Nuclear receptors

The ligand-binding domain is the site on the receptor at which

drugs bind.

1.3.1. Kinase-linked receptors

• The ligand-binding domain for drug binding is at the cell
surface
• Drug activates enzymes inside the cells, response is initiated
• Responses to activation of these receptors occur in seconds.
• Insulin is a good example of an endogenous ligand that acts
through this type of receptor.
1.3.2. Ligand-gated ion-channels
• Channel spans the cell membrane
• Channel opens, allowing the flow of ions into and out of the
cells
• Ions are primarily sodium and calcium
1.3.3. G protein-coupled receptors
3 components:
• The receptor
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 • The G protein that binds with guanosine triphosphate (GTP)
• The effector (either enzyme or ion channel)
1.3.4. Nuclear receptors
• Found in the cell nucleus and not on the surface of the cell
membrane
• Activation of receptors through the transcription factors are
prolonged. With the first three receptor groups, activation of the
receptors is rapid.

The figure illustrates the:

1. Kinase-linked receptors
2. Ligand-gated ion-channels
• When an endogenous ligand or agonist drug binds the receptor,
the channel opens, allowing ions to flow inward or outward.

• The direction of flow is determined by the concentration gradient of

the ion across the membrane.
• Responses to activation of a ligand-gated ion channel are
extremely fast, usually occurring in milliseconds.
• Several neurotransmitters, including acetylcholine and gamma-
aminobutyric acid (GABA), act through this type of receptor.
3. G protein-coupled receptors systems work as follows:
• Binding of an endogenous ligand or agonist drug activates the
receptor, which in turn activates G protein, which in turn activates
the effector.
• Responses to activation of this type of system develop rapidly.

• Numerous endogenous ligands—including NE, serotonin,

histamine, and many peptide hormones—act through G protein–
coupled receptor systems
4. Nuclear receptors

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1.4. Agonist and Antagonist

An agonist is a drug that binds to a receptor and produces a functional

response. Examples include morphine (μ-opioid receptor) and clonidine (α2-
adrenoceptor).

Antagonists are drugs that block a cellular response by attaching to the

receptors without activating them

Above figure illustrates how an agonist (blue capsule in the 2nd column) binds
to a receptor site to produce an enhanced cellular activity or response. Let us
take salbutamol as an example. Salbutamol is a short-acting, selective beta2-
adrenergic receptor agonist widely used as a bronchodilator to manage
asthma and other chronic obstructive airway diseases. When salbutamol binds
to the receptor site like in the 2nd column, beta receptors in the body, both beta-
1 and beta-2 are stimulated resulting in relaxation of the bronchial muscles,
dilating the airways (bronchial tubes) of the lung.

While an antagonist drug (illustrated in the 3rd column) binds to a receptor site
to block cellular activity. An example drug is amlodipine. Amlodipine is a
calcium channel blocker and is commonly used in the treatment of high blood
pressure and angina. It inhibits the influx of calcium ions into both vascular
smooth muscle and cardiac muscle resulting in reduction in peripheral vascular
resistance, causing a decrease in blood pressure.

Nonspecific Drug Effect

Many agonists and antagonists lack specific and selective effects. A
receptor produces a variety of physiologic responses depending on
where in the body the body the receptor is located.

Cholinergic receptors are located in the bladder, heart, blood vessels,

stomach, bronchi, and eyes. A drug that stimulates or blocks the

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 cholinergic receptors affects all anatomic sites of location i.e. the
bladder, heart, blood vessels, stomach, bronchi, and eyes. Drugs that
affect various sites are nonspecific drugs. An example of a drug with
non-specificity is bethanecol (Urecholine). It is given for post-operative
urinary retention to increase bladder contraction (and facilitate
urination). However, given bethanecol’s nonspecificity, it also results to
decreased heart rate, decreased blood pressure, increased gastric acid
secretion, and constriction of the bronchioles and the pupils of the eyes.
These other effects may be either desirable or harmful. Drugs that
evoke a variety of responses throughout the body have a nonspecific
response.

Nonselective Drug Effect

Drugs may also act at different receptors. Drugs that affect various
receptors are nonselective drugs or have properties of nonselectivity.
Chlorpromazine (Thorazine) acts on the norepinephrine, dopamine,
acetylcholine, and histamine receptors, and a variety of responses
result from actions at these receptor sites.

In the illustration below, epinephrine acts on the alpha1, beta1, and beta2
receptors. It is expected that a patient given epinephrine would have
elevated heart rate, elevated BP, and dilated bronchioles as a result of
its nonselectivity.

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Categories of Drug Action

There are four categories of drug action:

1. Stimulation or depression – rate of cell activity or secretion is
increased in drug action that stimulates. In drug action that depresses,
cell activity or function of a specific organ is reduced.
2. Replacement – replacement drugs such as insulin replace essential
body compounds.
3. Inhibition or killing of organisms – drugs that inhibit or kill
organisms interfere with bacterial cell growth (e.g. penicillin exerts its
bactericidal effects by blocking the synthesis of the bacterial cell wall).
4. Irritation – drugs also can act by the mechanism of irritation (e.g.,
laxatives irritate the inner wall of the colon, thus increasing peristalsis
and defecation.)

Therapeutic Index (TI)

The safety of a drug is a major concern. The therapeutic index
estimates the margin of safety of a drug through the use of a ratio that
measures the effective or therapeutic dose (ED) in 50% of people and
the lethal dose (LD) in 50% of people or animals. The closer the ratio is
to 1, the greater the danger of toxicity.

Formula: TI = LD50 / ED50

Drugs with a low therapeutic index have a narrow margin of safety.

Drug dose might need adjustment, and plasma (serum) drug levels

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 need to be monitored because of the small safety range between the
ED and the LD.

Drugs with a high therapeutic index have a wide margin of safety,

which have less danger of producing toxic effects. Plasma (serum)
drug levels do not need to be monitored routinely for drugs with high
TI.

Therapeutic Range (Therapeutic Window)

The therapeutic range (therapeutic window) of a drug concentration in
plasma is the level of drug between the minimum effective
concentration in the plasma for obtaining desired drug action and the
minimum toxic concentration (the toxic effect.).

If the therapeutic range is narrow, such as for digoxin (0.5 to 1 ng/ml),

the plasma drug level should be monitored periodically to avoid drug
toxicity. Monitoring the therapeutic range is not necessary if the drug
is not considered as highly toxic. When the therapeutic range is given,
it includes both protein-bound and unbound portions of the drug.

Peak and Trough Drug Levels

Peak drug level indicates the rate of absorption of the drug, and
trough drug levels indicate the rate of elimination of the drug. Peak
and trough levels are requested for drugs that have a narrow
therapeutic index and are considered toxic, such as the
aminoglycosides antibiotics. If either the peak and trough level is too
high, toxicity can occur. If the peak is too low, no therapeutic effect
is achieved. Peak drug level is the highest plasma concentration of
drug at a specific time. Peak drug level indicates the rate of absorption.
If the drug is given orally, the peak time might be 1 to 3 hours after drug
administration. If the drug is given IV, the peak time might occur in 10
minutes. If a peak drug level is ordered, a blood sample should be
drawn at the proposed time, according to the route of
administration.

The trough drug level is the lowest plasma concentration of a drug,

and it measures the rate at the drug is eliminated. Trough levels are
drawn immediately before the next dose of drug is given,
regardless of the route of administration.

Loading Dose

When immediate drug response is desired, a large initial dose,

known as the loading dose of the drug, is administered to achieve
a rapid minimum effective concentration in plasma. After a large
initial dose, a prescribed dosage per day is ordered. Digoxin (Digitek,
Lanoxicaps, Lanoxin), a digitalis preparation requires a loading dose
when first prescribed. Digitalization is the process by which the
minimum effective concentration level for digoxin is achieved in the
plasma within a short time.

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Pharmacodynamic Interactions

Additive drug effect. When two drugs with similar action are administered, the
drug interaction is called additive drug effect and is the sum of the effects of
the two drugs. Additive effects can be desirable or undesirable. For example,
a desirable drug effect occurs when a diuretic and a beta blocker are
administered for the treatment of hypertension. In combination, these two drugs
use different mechanisms to have a more pronounced blood pressure-lowering
effect. As another example, aspirin and codeine are two analgesics that work
by different mechanisms but can be given together for increased pain relief.
An example of undesirable additive effect is that from two vasodilators:
hydralazine (Apresoline) prescribed for hypertension and nitroglycerin
prescribed for angina. Th result could be severe hypotensive response.
Another example is the interaction of aspirin and alcohol. Aspirin is directly
irritating to the stomach, causes platelet dysfunction, and inhibits
prostaglandin-mediated mucus production of the gastric mucosa, which
protects the underlying issues of the stomach. Alcohol disrupts the gastric
mucosal barrier and suppresses platelet production. Both aspirin and alcohol
can prolong bleeding time and, when taken together, may result in gastric
bleeding.

Synergistic Drug Effect or Potentiation

When two or more drugs are given together, one drug can potentiate or have
a synergistic effect on another. In other words, the clinical effect is substantially
greater than the combined effect of the two. An example of this is the
combination of meperidine (Demerol), a narcotic analgesic, and promethazine
(Phenergan), an antihistamine. One of the major side effects of promethazine
is sedation. When used with meperidine in post-surgery patients, promethazine
potentiates or enhances the drowsiness effect of meperidine. Less meperidine
is required when it is combined with promethazine, which can be desirable. An
example of undesirable effect occurs when alcohol and a sedative-hypnotic
drug, such as chlordiazepoxide (Librium) or diazepam (Valium) are combined.
The resultant effect of this example is increased central nervous system (CNS)
depression.
Antagonistic Drug Effect
When two drugs have opposite effects, or antagonistic effects, are
administered together, each drug cancels the effect of the other. In other words,
the actions of both drugs are nullified. An example of antagonistic effect occurs
when the adrenergic beta stimulant isoproterenol (Isuprel) and the adrenergic
beta blocker propranolol (Inderal) are given together. Neither drug delivers the
expected therapeutic effect.
There are some situations that the antagonistic drug effect is desirable. In
morphine overdose, naloxone s given as an antagonists (antidote) to block the
narcotic response. This is a beneficial interaction of an antagonist.
The use of two prescription drug can have and additive, synergistic,
antagonistic, or no effect. This is especially true of warfarin. When taken with

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another drug, the effects of the second drug can increase, decrease, or have
no effect on the anticoagulant.

Side effects, Adverse Reactions, and Toxic Effects

Side effects are physiologic effects not related to desired drug effects.
All drugs have desirable or undesirable side effects. Even with a correct
drug dosage, side effects can occur and are predicted. Side effects
result mostly from drugs that lack specificity, such as bethanecol
(Urecholine). The terms side effects and adverse reactions are
sometimes used interchangeably but they are different. Some side
effects are expected as part of drug therapy. The occurrence of these
undesirable side effects is not a reason to discontinue drug therapy.

Adverse reactions are more severe than side effects. They are a range
of untoward effects (unintended and occurring at normal doses) of
drugs that cause mild to severe side effects, including anaphylaxis
(cardiovascular collapse). Adverse reactions are always undesirable.
Adverse effects must always be reported and documented because
they represent variances from planned therapy.

Toxic Effects

Toxic effects or toxicity of a drug can be identified by monitoring the

plasma (serum) therapeutic range of the drug. However for drugs that
have wide therapeutic index, therapeutic ranges are seldom given. For
drugs with a narrow therapeutic index such as aminoglycoside
antibiotics and anticonvulsants, therapeutic ranges are closely
monitored. When the drug level exceeds the therapeutic range, toxic
effects are likely to occur from overdosing or drug accumulation.

Pharmacogenetics

Pharmacogenetics is the scientific discipline studying how the effect of

a drug action varies from a predicted drug response because of genetic
factors or hereditary influence. Because people have different genetic
makeup, they do not always respond identically to a drug dosage or
planned therapy. Genetic factors can alter metabolism of the drug in
converting its chemical form to an inert metabolite, thus, the drug action
can be enhanced or diminished. Some persons are less or more
sensitive to drugs and their drug actions because of genetic factors. For
example, African Americans do not respond as well as Caucasians to
some classes of antihypertensive medications, such as ACE inhibitors.

Tolerance and Tachyphylaxis

Tolerance refers to a decreased responsiveness over the course of
therapy. In contrast, tachyphylaxis is the rapid decrease in response
to a drug. In essence, tachyphylaxisis an “acute tolerance.” Drug
categories that can cause tachyphylaxis include narcotics, barbiturates,
laxatives, and psychotropic agents. If the nurse does not recognize the
development of tolerance, the patient’s request for more pain
medication might be mistaken as drug-seeking behavior associated

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 with addiction. Prevention of tachyphylaxis should always be a part of
the therapeutic regimen.

Placebo Effect
A placebo effect is a psychologic benefit from a compound that may not
have the chemical structure of a drug effect. This is mostly used in
clinical drug studies where a group of subjects receive a placebo to
compare with a new drug or treatment.

SUMMARY OF FORMATIVE ASSESSMENTS FOR MODULE 7:

• Think of a way to explain the pharmacodynamics phase to a 70-year-old male
and write it as a narrative on a one-page bond paper. To be submitted as
scheduled.

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