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Basic Concepts of
Pathophysiology and
cLS . Pharmacotherapy

Chapter 1 / Plarming Pharmacotherapy
Kenneth W. Witte, PharmD
11 drug prescribing is not based on patient needs and
A all patients* health care needs are not met by prescrib­
ing drugs. Yet, in this time of economic constraint,
hígh risk of medical liability suits, changing health care
services, and high demand by the public for quality health
care, it is imperative that patients receive the most rational
and cost-effective form of therapy. The health care system,
to be effective, must assure that the use of drugs is based on
sound therapeutic judgments and rational decision-making
processes based on the best available knowledge of pharma-
cotherapy.* 1 Melmon and Morrelli2 outlined the prerequisites
for rational drug therapy as having:
1. An accurate diagnosis
2. Knowledge of the pathophysiology of the disease
3. Knowledge of the basic pharmacology and pharmaco- of four processes, as defined in the Oxford Textbook of
kinetics of drugs in normal and diseased people
4. The ability to transfer this knowledge to effective
bedside action
5. Reasonable expectations of these relationships so that
the drug’s effects can be anticipated
6. A plan that reveáis efficacy and toxicity and will set the
course for continued therapy
An Accurate Diagnosis
Problems in making accurate clinical diagnostic decisions
have been expressed in Alvan Feinstein's book Clinical
Judgment.3 The methods used in making appropriate diag-
noses are important parís of the drug prescribing process,
but these are not the purpose of this chapter.
Once the diagnosis is established, the selection of rational
pharmacotherapy cannot be made until there is a thorough
understanding of all other prerequisites. If the diagnosis
remains unknown, the importance of the understanding of
these prerequisites increases even further when a decisión is
made to treat a patient with drugs.
Knowledge of Pathophysiology
Before one can decide on which pharmacotherapy to use in
treating a specific disease, an understanding of the patho­
physiology of the disease is needed, such as the r’elationship
belween the cause and mechanism of the disease, the
resultant structural and functional abnormalities, and the
manifestations of the disease. One of the primary missions of
this book is to impart a detailed understanding of the
pathophysiology of common disease states.
Functional abnormalities of a disease are disturbances in
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the normal performances and actions of cells, tissue, and/or
organs. Structural abnormalities are disturbances of the
normal anatomic and/or biochemical conformaron of the
body. Both types of abnormalities usually result in signs,
symptoms, and laboratory abnormalities, from which the
clinician can make judgments concerning the diagnosis of the
disease. This knowledge is then used in conjunction with the
thorough understanding of the mechanism of action for drugs
in determining how to treat a disease.4
Knowledge of Pharmacology of Drug Therapy
Knowledge of pharmacotherapy involves an understanding
Clinical Pharmacology and Drug Therapy.5 These pro­
cesses, the first three of which are described in detail in
Chapter 3, include:
1. Pharmaceutical process: Is the drug getting into the
patient?
2. Pharmacokinetic process: Is the drug getting to its site
of action?
3. Pharmacodynamic process: Is the drug producing phar-
macologic effects?
4. Therapeutic process: Is the pharmacologic effect being
translated into a therapeutic effect?
The pharmaceutical process is based on the bioavailability
of the drug and patient compliance. Therefore the clinician
must thoroughly understand the factors that affect bioavail­
ability. These factors inelude the physicochemical properties
of the drug, reported bioavailability of producís, formula-
tions and dosage forms, and methods of drug administra-
tion.6 These factors are outlined in Chapter 4, Drug Delivery
and Administraron.
Bioavailability becomes irrelevant if the patient does not
comply with taking the medication. Therefore, in using any
drug, the clinician needs to understand the factors influenc-
ing patient compliance and develop methods that encourage
patients to comply with their drug regimens. Therefore, in
treating a patient with aminophylline one must take into
consideration the percentage of anhydrous theophylline in
the product, the adjustment for equivalent doses of various
salts, the variation of bioavailability between patients and
produets, and the patient’s desire to comply.
The pharmacokinetic process involves the absorption,
distribution, metabolism, and elimination of drugs by the
individual patient. For any drug to work, it must get to the
site of action. The clinician must have a strong understand­
ing of pharmacokinetic principies in order to make a decisión
on selecting the best producís and dosing regimens. These
3
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4 Basic Concepts

principies are discussed in detail in Chaptcr 3, Individualiza- Table 1.1 Patient Variables
tion of Drug Therapy.
The pharmacodynamic process is the molecular and cel- A. Inherent factors
lular pharmacologic action of a drug on cell, tissue, or organ, Age
and the resuitant clinical effects. For example, the-.pharma- Sex
codynamic action of theophylline on a molecular level is that Weight
of a phosphodiesterase inhibitor which blocks the metabo- Race
lism of cyclic AMP. This results in the pharmacologic effect Genetic background
of bronchiolar smooth muscle relaxation.5 Discussions on B. Acquired factors
the pharmacodynamic processes of various drugs are found Education
in respective chapters on the various drugs. Nutritional status
The therapeutic process involves the pharmacologic effect Medical history
of a drug on the pathophysiology of the disease, and how Health status
that results in a beneficial (therapeutic) or detrimental (toxic) Allergies
effect to the patient.5 Immunization status
For example, in using theophylline, the therapeutic effect C. Physiologic variables
is bronchial dilatation, which allows air to flow into the lungs Physiologic and biochemical status of various organ
resulting in better breathing. However, when using too much systems
theophylline, toxic effects such as nausea, vomiting, and Immunologic status
even convulsions may occur. Functional status
D. Disease state variable
Disease states—severity and intensity
Effectiveness of past treatments
Applying Knowledge to Patients Disease states that alter response of a drug or alter
pharmacokinetics of drugs
By increasing knowledge of disease pathophysiology and E. Psychologic variables
understanding the above-mentioned four processes involv- Compliance tendeney
ing the pharmacology of drugs, clinicians can make more Beliefs about therapy
effective pharmacotherapeutic decisions in deciding when a Relationship with health care professional
drug is needed and how effective it will be for a specific Desire for treatment
diagnosis. F. Social and economic factors
However, the clinician will not be effective unless he or Social class
she is able to apply the knowledge to the individual patient. Economic status
The clinician must take into consideration patient variables Relationships
that may influence the choice of therapy. Table.1.1 outlines Use of drugs, alcohol, tobáceo, caffeine
a list of potential patient variables that influence specific Occupation
pharmacotherapy decisions.6 Each item on the list may Home, work, daily environment
influence decisions made on the pharmacotherapeutic plan Data from Reference 6.
and must be part of the considerations when making the
plan. For example, if a patient is a heavy smoker, this factor
has to be taken into consideration when dosing theophylline.
Economic factors have become increasingly important in the first sign of nausea or vomiting (toxic effect). The
formulation of therapeutic plans. These will no doubt affect application of therapeutic effects is key in formulating a
therapeutic decisions for many years to come. pharmacotherapeutic plan and in developing therapeutic
endpoints and goals in treating patients with drugs.

Anticipating Effects
Establishing a Therapeutic Plan

When making pharmacotherapy decisions, the clinician

In making initial pharmacotherapy decisions about a individ­
needs to anticípate measurable effects, which will help
ual patient's drug therapy, the clinician must have a plan
determine whether the drug is effective, is ineffective, or is
that:
causing adversity. These effects may be in the form of
clinical symptoms, pathologic signs, or biochemical changes 1. Determines whether a drug is indicated based on the
in laboratory tests. Thus the clinician should identify the diagnosis
desired therapeutic outcomes and select the therapy that can 2. Selects the most appropriate therapy based on pharma­
best attain them.2 In the example of using theophylline in codynamic and therapeutic processes
treating an asthma attack, the potential therapeutic out­ 3. Selects the most appropriate drug regimen for the
comes may inelude having serum theophylline levels in therapy based on the pharmaceutical and pharmacoki-
therapeutic range, ensuring there is an improvement in signs netic processes
and symptoms of the asthma attack. Or, to recognize toxic 4. Determines how to monitor the therapy based on
effects, the clinician may set an endpoint to lower the dose at anticipated endpoints and outcomes
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Planning Pharmacotherapy 5

Table 1.2 Implementation of Pharmacotherapy Plan

Knowledge needed Thought process Decisión point

Pathophysiology of disease, Investígate patient’s signs, symptoms, laboratory Indication for therapy
physical assessment skills, abnormalities, medical history, present illness;
interviewing skills determine need for therapy
Pharmacotherapy Review pharmacologic effects of drugs; transíate Selection of drug
Pharmacodynamics pharmacologic effects which will provide a
Therapeutics therapeutic effect specific to the patient; evalúate
risks versus benefits; set therapeutic endpoints
Pharmaceutics Determine appropriate product formulation, dosage Selection of drug regimen
Pharmacokinetics form, method of administration, dose, dosing
interval, and duration based on patient parameters
Integration of facts on: Review subjective and objective data collected; Monitoring the therapy
Patient status interpret if therapy is reaching therapeutic
Disease state endpoints, causing toxicity, causing adverse effect
Drug treatment
Laboratory data
Physical assessment
Pathophysiology Evalúate outcome of therapy for effectiveness, Evaluation of therapy
Pharmacotherapy ineffectiveness, adversity
Problem solving
Decisión making

5. Evaiuates results and outcomes of the therapy based on
these measurable endpoints from which further deci-
sions can be made to continué, alter, or discontinué
therapy
Implementation of the Pharmacotherapy Plan
In providing safe, rational, and cost-effective therapy to the
patient, a pharmacotherapeutic plan musí be established.
The knowledge base needed for the different thought
processes used and the decisión points in implementing a
pharmacotherapy plan are outlined in Table 1.2. By using
such a pharmacotherapy plan, a systematic approach must
be used. Once the decisión is made to treat a patient's
problem (diagnosis), the first pharmacotherapeutic decisión
is to determine whether a drug is indicated. This decisión
process should determine the probability of a drug meeting
the therapeutic goal, or endpoint, in treating the problem6
based on the pathophysiology, severity, and/or stage of
problem as denoted by the assessment of the patient. In
making a decisión on whether or not a drug is indicated, the
diagnosis, efficacy of therapy, and risk versus benefit have to
be considered. It must also be decided if the drug is needed
to prevent, cure, or symptomatically treat a problem.
By understanding the decisión of identification or the need
for a drug in a patient, the clinician can avoid and reduce
inappropriate drug use. Overuse and underuse occur when
there is:
1. An inadequacy of the diagnosis that results in:
a. No clinical indication for a drug documented but the
patient receives drug or
b. No drug ordered when there is a documented indica­
tion
2. An inappropriate use of the clinical techniques and labo-
ratory procedures to establish a correct diagnosis
A common example of no clinical indication for a drug for
which the patient receives, a drug occurs with antibiotics.
Antibiotics should only be used when there is an infectious
process or when there are prophylactic conditions requiring
therapy.7 The need for antimicrobial therapy may be consid­
ered inappropriate when neither infectious disease process
ñor the prophylactic condition requiring therapy is present.
There would be no benefit from antimicrobial therapy in if
there is a lack of therapeutic goal to be reached. However, if
there is an infectious process, a therapeutic endpoint of a
no-growth culture could be established and treatment could
be justified.
The second decisión point is the selection of the most
appropriate drug. The most appropriate drug selected should
be therapeutically effective considering the diagnosis, and its
efficacy and safety should facilítate reaching a therapeutic
endpoint. One should review the risks against the benefits of
using a specific drug for a patient by evaluating the potential
for:
Drug-disease contraindicaron
Drug-drug interactions
Drug-laboratory interference
Toxicity
Complications based on patient variables
Hypersensitivity reactions
Predictable adverse effects
Drug-food interactions
By understanding where problems in the selection of drug
therapy commonly occur, inappropriate therapy can be
reduced. When two or more alternative drugs are considered
equally effective, the drug of choice should be based on cost

6 Basic Concepts 4
Table 1.3 Inappropriate Decisions in Regimen Selection
Dose too high or low
Dosing intervals do not give appropriate levels or lead to
noncompliancc " pafameter for determining the effectiveness of therapy,
Failure to discontinué a drug at the proper time
Route of administration does not provide effective serum
levels or is too costly
Dosage form does not provide effective drug levels or
leads to noncompliance
per treatment day, ease of administration, and customary
use in the institution.
Once the choice is narrowed to only one available drug for
the condition, then the drug prescribed should be evaluated
as to proper drug regimen. This is the third decisión point in
the pharmacotherapy plan. The drug regimen is defined as
the (1) dose given per time period (usually 24 hour period),
(2) time interval between doses, (3) duration of therapy, (4)
route and method of administration, and (5) dosage form
(e.g., liquid, salt form) which will best ensure patient com-
pliance.7 The selection of the regimen should take into
consideration patient factors that affect the regimen (exam-
ples are listed in Table 1.1) as well as pharmokinetic factors
(Table 1.3). How and where the drug is dispensed and
administered is also important when considering a drug
regimen. For example, how it is dispensed may depend on
how it is administered. In hospitals, the pharmacy depart-
ment usually dispenses a drug in reády-to-administer form,
and it is delivered on a timely basis in the appropriate
formulation. The nurses’ responsibilities are to administer
the medication to the right patient, at the right time, and by
the right route. Deviation from this process is usually picked
up through quality assurance audits and medication error
reports of the hospital.
In an ambulatory care setting it is usually the pharmacy
that dispenses the medication in a larger supply (such as a
month) to the patient. It then becomes the patient’s respon-
sibility to consume the medication appropriately.
Clinically, a number of factors need to be considered in
the administration of drugs to ensere the safe, efficient, and
cost-effective use of medications. vfhese factors inelude the
appropriate .methods of administration that ensure cost-
efficient use of material, supplies, and labor; the method of
administration that prevents incompatibilities (physical and
chemical), phlebitis, extravasation, fluid overloads, and in-
References
1. Pulliam CC. Therapeutic judgments. Am J Hosp Pharm 1974;31:
385-387.
2. Melmon K.L, Morrelli HF (eds). Clinical Pharmacology Basic
Principies in Therapeutics. New York, Macmillan, 1978, p 3.
3. Feinstein AR. Clinical Judgement. Huntington, NY, Robert E.
Krieger Publishing, 1967.
4. Kent TH (ed). General Pathology A Programmed Text. Boston,
Little, Brown, 1974.
5. Grahame-Smith DG, Aronson JK. Oxford Textbook of Clinical
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teractions with other drugs^nd the method of administra-
tion th.af.ensures accuracy, sterility, and compliance with the
drug regimen.
The four decisión points involve setting the monitoring
incflectivcncss of therapy, or the adversity of therapy.
Monitoring parameters, based on measurable effeets of the
drug (both therapeutic and toxic effeets), involve collecting
and evaluating subjective and objective data about the
patient. Such monitoring parameters should be decided on
before therapy is started and should be implemented at the
appropriate time during therapy.8 For example, objective
data should be measured when the drug has been given for
an appropriate amount of time to have an effect on the
patient. In certain objective measurements, the clinician
must measure against a baseline. All monitoring parameters
should take into consideration the patient variables.
The evaluation of the therapy (the last point) consists of
evaluating the results of the therapy and identifying possible
problems, validating or negating the presence of each prob-
lem, and then taking appropriate action. Such action may
inelude: the continuation of therapy if therapeutic endpoints
are attainable and if treatment^hould continué (for example,
in life-long process of treatinghigh blood pressure); stopping
the therapy if the therapeutic endpoint has been reached and
therefore is no longer needed (such as treating an infection);
switching to another alternative if the therapy is ineffective;
or altering the therapy to correct an undesired or unintended
response. If a serious adverse effect resulted, the drug might
be discontinued and corrective therapy could be instituted.
If therapeutic goals have not been met, or an unintended
event occurred, one might go back through each decisión
point to determine the cause and to make correction.
Summary
Tne clinician, in making pharmacotherapy decisions, must
understand both the pathophysiology of the disease and the
pharmacology of available drugs. The clinician must be able
to apply this knowledge to specific patients before establish-
ing a rational therapeutic plan. Once the therapeutic plan is
implemented, it must be active and ongoing and constantly
evaluated for effectiveness as new data on the patient’s
pro^ress are obtained. By applying these pharmacotherapy
decision-making processes, the clinician gains insight and
new knowledge which allows for more rational pharmaco-
therapeutic decisions for future patients.
Pharmacology and Drug Therapy. Oxford, Oxford University
Press, 1984.
6- Spilker B. Guide to Clinical Interpretation of Data. New York,
Raven Press, 1986.
Kagan BM, Fannin LS, Bondie F. Spotlight on antimicrobial
therapy. JAMA 1973;226:306-310.
8- Kishi DT, Watanabe AS. A systematic approach to drug therapy
for the pharmacist. Am J Hosp Pharm 1974;31:494-497.