PHARMACOLOGY LECTURE NOTE

BY

LINUS V.E.

FACTORS MODIFYING DRUG ACTION

A multitude of host (patient), drug and environmental factors influence drug response. A
basic understanding of these factors can guide the choice of appropriate medication (drug)
and the individual dose for each patient. Variations in response to similar dose of a drug
between different patients and even the same patient on varying occasions do occur.
However, the range of variability maybe marked or limited depending on the
pharmacokinetic and pharmacodynamic characteristics of the drug. Drugs mostly disposed
by metabolism are most affected while drugs excreted by the kidneys are least affected. All
factors affecting the processes of absorption and biotransformation may influence the
outcomes of drug actions. Factors modifying the actions of drugs are explained below;

1. Patient’s Compliance

2. Medication Error

3. Pathological Factors

4. Tolerance

5. Physiological Variables

6. Genetic Factors

7. Drug Related Factors

8. Environmental Factors & Time Of Administration

1. Patient’s Compliance

This is also known as adherence, concordance or therapeutic alliance. Patient’s

compliances defined as the extent to which a patient follows a drug regimen prescribed by
a healthcare professional/ medical practitioner e.g. doctor, pharmacist, e.t.c. The
assumption that when a healthcare professional tells a patient what to do and the patient
carefully follows it is unrealistic. This is as a result of several habits, beliefs, values or the
lifestyle of the patient (i.e. patient’s quality of life belief) may differ from the professional’s
therapeutic goals. For effective results to be seen, a patient must be willing to carefully
follow the therapeutic regimen of the healthcare practitioner. Non compliance may be
intentional or accidental and these inconsistencies may result in decreased therapeutic
results. Patient compliance is a very important factor that modifies the rate of drug action
and as such when there is increased patient compliance there will be increased or
maximum therapeutic effect of the drug and when there is reduced patient compliance (i.e.
non compliance) to a therapeutic regimen, there will be inconsistent or nonexistent
response to therapeutic regimen.

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Several variables that may influence compliance behavior in certain patients and several
suggestions on how to improve compliance in order to achieve therapeutic goals have been
cited. For certain forms of treatment, patient may be required to come to the hospital in
which case certain things like work might be a problem. Age also poses as a challenge for
instance; compliance tends to be more of a problem in pediatric practice because it
requires the active participation of both the child and the parents involved. The parents
must be well informed about the drug including the directions to follow and the child in
turn must be willing to comply and not spill the medicine. Also, elderly patients may also
have problems in following prescriptions meticulously. This is because elderly patient’s
capacity to understand and remember their medication as well as their ability to carry out
the task may not be completely ascertained. The route of administration of a drug may also
affect compliance as well as dosing schedule. To improve compliance;

1. Practical dosage forms are important and as a result, many tablets are now sugar
coated making them easier to take and a larger number of drug manufactured for
children are in form of elixirs or suspensions which may be obtained in a variety of
different flavor hence increasing compliance in children.
2. Precise, clear instructions with most important information should be given to the
patient.
3. Solutions should be sought for when the patient has physical or sensory disabilities
e.g. the use of large type on labels and written materials.
4. Support and assistance should be sought for from caregivers or family members of
the patient involved.

2. Medication Error

Medication errors are errors that occur as a result of mistakes or failure to complete ones’
medication as prescribed by a prescriber, pharmacist or doctor. Medication errors usually
results in adverse events which may include death. Medication errors may occur as a result
of errors in prescription therefore, by examining aspects of prescription writing that can
cause errors and by modifying prescription habits accordingly, the probability that a
patient will receive the right / correct prescription can be increased by the physician.
Medication errors can also be reduced by being sensitive to the common problems that can
occur with medication orders and communicating with the patient’s physician or
pharmacist or other healthcare professionals. Good practice in preparation of medication
orders in both institutional and outpatient setting is summarized as follows;

All drug orders should be clearly written using metric measurements of weight and
volume.

1. Patient’s weight and age should be included on prescription when appropriate so

that dosage can be checked.
2. Drug names should not be abbreviated; abbreviations may lead to
misinterpretation.
3. Directions for drug administration should be clearly written in English

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 4. Good handwriting goes a long way to prevent medication errors as poor
handwriting is a well known and preventable cause of dispensing/ medication
errors. Thus, both physicians and other healthcare professionals share in the
responsibility for preventing adverse events by writing prescriptions clearly.
5. The patient’s diagnosis should be provided on the prescription orders. This is the
single most important measure to prevent medication errors based on sound alike
or look alike drug names. For example; an order for administration of morphine
sulfate must not be abbreviated as ‘MS’ as this may result in administration of
Magnesium sulfate.

In addition, the therapeutic purpose and the patient diagnosis should be included to
prevent medication/ dispensing error. Medication error goes a long way to affect the
actions of a drug. Errors in medication are a very important factor that can modify the
action of a drug as the absence of medication error will increase the action of the drug
while presence of medication error will decrease/ prevent drug action.

3. Pathological Factors

In addition to the factors discussed earlier, pathological states may modify the actions of
drugs. Not only drugs modify disease processes, several diseases can also influence drug
disposition and drug action. These diseases include; gastrointestinal disease, liver diseases,
renal diseases, thyroid disease, congestive heart failure.

a. Gastro Intestinal Diseases

Gastrointestinal diseases can alter the absorption of drugs administered orally and
these changes can either increase or decrease drug action. Gastric stasis occurring
during migraine attack retards absorption of ingested drugs.

b. Liver Disease
This affects/influence drug disposition. In liver diseases, prolong duration of
action occurs because of increased half life. Plasma protein binding for some
drugs is increased by leading to adverse effects. Impaired liver microsomal
enzymes may lead to toxic levels o drugs like diazepam and theophylline.
c. Renal Disease
This markedly affects the pharmacokinetic of many drugs as well as alters the
effects of some drugs. The clearance of drugs that are primarily excreted
unchanged is reduced Examples of such drugs includes aminoglycosides,
digoxin. Kidney disease results in abnormality in the Glomerular filtration rate
(GFR), tubular function, leading to abnormal effect of drugs.
d. Congestive heart failure: it can alter drug kinetics by;
 Decreasing drug absorption from the g.i.t. due to mucosal edema and splanchnic
vasoconstriction e.g. a reduction in procainamide and hydrochlorothiazide
absorption.
 Retarding drug elimination as a result of decreased perfusion and congestion of the
liver, reduced Glomerular filtration rate and increased tubular reabsorption; dosing

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 rate of drugs may need reduction, as for lidocaine, theophylline.

4. Tolerance

This is the resistance to the normal therapeutic dose of a drug, hence producing a lesser
response to the normal therapeutic dose. This also refers to the requirement of a higher
dose of a drug to produce a given response. It usually occurs with most drugs of abuse. Loss
of therapeutic efficacy which is a form of tolerance often called “refractoriness”. Drug
tolerance may be natural or acquired.

Natural or innate tolerance: In this case, the individual or specie is inherently less
sensitive to the drug e.g. rabbits are tolerant to atropine. Some individuals are hypo
responders to certain drugs e.g. to β adrenergic blockers or alcohol.

Acquired tolerance: this form of tolerance occurs by repeated use of a drug in an

individual who was initially responsive. This is because the body is capable of developing
tolerance to most drugs. Acquired tolerance is readily recognized in the case of CNS
depressants e.g. alcohol. Continuous presence of the drug in the body usually increases the
development of tolerance. However, significant tolerance does not develop in drugs like
atropine, cocaine, sodium nitroprusside, etc. not all actions of drug results in tolerance,
consequently therapeutic index of a drug may increase or decrease with prolonged use of
the drug. For example; tolerance develops to the sedative action of Chlorpromazine but not
its antipsychotic action.

Cross Tolerance: this is the development of tolerance to pharmacologically related drugs

for example; alcoholics are relatively tolerant to Barbiturates and general anesthetics.
Cross tolerance may be complete or partial. Complete cross tolerance exists are very close
e.g. complete tolerance occurs between morphine and pethidine. Partial cross tolerance
occurs when two drugs are not closely related. E.g. partial cross tolerance exists between
morphine and barbiturates. In cross tolerance, an individual is tolerant to drugs that have
similar chemical structure. Hence, most drugs that resemble each other in their chemical
structure is said to show cross tolerance.

5. Physiological Variables

Certain physiological factors modify the effects or actions of drugs. These include; age, sex,
plasma protein binding, body weight, food, allergy, species and race, e.t.c.

Age: the adult dose is for people between 18 and 60 years of age. The tissues of infants and
children are sensitive to large number of drugs. Children under 12 years require a fraction
of the adult dose because:

1. Drug metabolizing enzyme system is inefficient in them.

2. Their barriers are not fully developed, thus are more sensitive to CNS stimulants. All
parts of the body are affected by the drug.
3. Infants have an immature renal tubular system. After one year of age, elimination by

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 kidneys is increased.
4. Hepatic metabolizing capacity is also under developed.
5. Gastric acid secretions are not adequate.

The dose for a child is calculated from the adult dose up to 8 years of age. The average adult
dose is for an individual of medium built. Geriatric age group (> 60 yrs) requires special
consideration because physiological changes that occur with age are kept in mind such as:
reduced body weight, reduced body, reduced intestinal motility & mesenteric blood flow,
reduced renal and hepatic functions and altered mental functions. Elderly patients often
require lesser doses than adults because they are prone to suffer from adverse drug
reactions. If liquid preparations are available, they should be preferred as they are
convenient for absorption.

Sex: females have smaller body size and require smaller doses. The subjective effects of
drugs may differ in females because of their mental makeup. Certain drugs act differently in
males and females. For example; Gynaecomastia is a side effect of Ketoconazole that can
occur only in men but not in women, androgens are unacceptable in women and estrogens
are unacceptable to men. In women, consideration must be given to menstruation,
pregnancy and lactation. Drugs given during pregnancy can affect the fetus and also, there
are marked and progressive physiological changes that occur during pregnancy, especially
in the third trimester and this can affect/ alter drug disposition. During pregnancy

1. Gastrointestinal motility is reduced hence there is delayed absorption of orally

administered drug.
2. Plasma and extracellular fluid volume expands.
3. Renal blood flow increases markedly hence, polar drugs are eliminated faster.
4. Induction of hepatic microsomal enzymes thus, drugs are metabolized faster.

During lactation, certain drugs may be excreted through breast milk and this may affect the
infant e.g. some purgatives, chloramphenicol.

Body size: body size influences the concentration of the drug attained at the site of action.
The average adult dose is normally associated with individuals of medium built. In the case
of individuals that are exceptionally lean or obese and for children, dose may be calculated
on the basis of body weight (BW);

Individual dose BW (kg) average adult dose

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The dose for these patients may also be calculated using the body surface area. It has been
argued that the body surface area (BSA) is more accurate than the BW as a basis for dose
calculation because the BSA encompasses; the total body water, extracellular fluid volume
and metabolic activity.

Individual dose BSA (m2)

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 1.7

Or using the Dubois formula the BSA can be calculated;

BSA (m2) 0.425Height (m2)0.725

Body size affects immensely the action of a drug as it may cause either an increase in the
action of the drug or a resultant decrease in the action of the drug.

Food: drugs are better absorbed on an empty stomach. However, most drugs are usually
taken with food as a result of their tendency to cause gastric irritation. Food affects the
outcome or the resultant effect/ action of the drug.

Allergy: this is the abnormal response of a drug resulting from antigen-antibody reaction,
leading to the liberation/ release of histamine and histamine-like substances resulting in
reactions like skin rashes, decreased blood pressure, e.t.c. this also modifies drug action
since certain reactions that are originally related to that of the is manifested.

Plasma protein binding: drug molecules may bind to plasma proteins (usually albumin).
Bound drugs are pharmacologically inactive; hence only the free unbound drug acts on
target sites in tissues to produce biological response and be available to the processes of
elimination. Decreased plasma proteins (i.e. hypoalbuminemia) may alter the level of free
drugs available for biological response and elimination. Certain conditions like
malnutrition causes decreased amino acids thus, decreased proteins leading to decreased
binding sites for drug which can modify the action of drugs.

Species and race: this also another important physiological factor that influences drug
actions. There are many examples of differences in responsiveness to drugs among
different species for instance; the responsiveness of a rabbit to atropine (it is resistant to
atropine) is different from that of other species like rat and mice. These differences are
important while extrapolating results from experimental animals to man. In humans, some
racial differences have been observed. For example; Blacks require a higher dose of
atropine and ephedrine to dilate their pupil while Mongols require lower doses of atropine
and ephedrine to dilate their pupil.

6. Genetic Factors

Genetic abnormalities influence the dose of a drug and the response to drugs. Genetics
affects the drug response at two levels: at the level of receptors and the level drug
metabolizing enzyme; thus, interfering with certain functions such as rate of plasma drug
clearance. Pharmacogenetics is the study of the relationship between genetic factors and
drug response. It also encompasses pharmacogenomics, which applies tools for surveying
the entire genome to assess mutagenic determinants of drug response. Technical advances
in genomics permit genotype-to-phenotype analysis in which genomic polymorphisms are
exploited to assess whether a particular genomic variability translates into phenotypic
variability of drug response. Polymorphism is a variation in the DNA sequence that is

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present at an allele frequency of 1% or greater in a population.

Idiosyncrasy: is the abnormal response/ drug reaction that occurs due to genetic disorder.
It is the unpredictable response seen on first dose of drug on hereditary basis. This may be
due to: oxidation, acetylation, succinylcholine apnea (succinyl CoA) and glucose 6-
phosphate dehydrogenase deficiency.

7. Drug Related Factors

Route of administration: drugs are usually administered via various routes and the route
of administration of a drug may greatly influence/ modify the actions of those drugs. The
route of administration of a drug determines the bioavailability of the drug and by
extension the therapeutic effects/ response that will be produced by that drug. Some drugs
are incompletely absorbed following oral administration, however given intravenously,
their dose have to be reduced since the bioavailability of the drug will be increased. It
governs the speed and intensity of drug response.

Dosage form of the drug: the preparation of a drug goes a long way to modify the actions
of a drug. Drugs in solid forms disintegrate slowly and as a result, it usually takes a longer
period of time for the therapeutic effects of the drug to be manifested. However, drugs that
are in liquid form have a more rapid onset of action than those in the solid form since it
disintegrates faster than those in the solid form. Hence, dosage form of a drug should be
put into consideration during prescription as it goes a long to either increase/ decrease the
actions of a drug.

Rate of elimination of drug: any drug will cumulate in the body if the rate of
administration is more than the rate of elimination. However, slowly eliminated drugs are
particularly liable to cause cumulative toxicity e.g. prolonged use of chloroquine causes
retinal damage.

Drug interactions: frequently, the effect of one drug is either reduced or enhanced in the
presence of another drug. There are two types of interactions of drugs: pharmacodynamic
interactions and pharmacokinetic interactions.

Pharmacodynamic interactions involve a direct conflict between the effects of drugs.

This results in the effect of one of the two drugs being enhanced (synergism) or reduced
(antagonism). For example:

 Co administration of monoamine oxidase inhibitors (MAOIs) and ephedrine results

in the enhancement of the effect of ephedrine (synergism).
 Propranolol, a β-adrenoceptor antagonist given for angina and hypertension, will
reduce the effect of salbutamol, a β2-adrenoceptor agonist given for the treatment of
asthma (antagonism).

Pharmacokinetic interactions occur when two or more drugs interact in such a way that
the effect of one drug interferes with the pharmacokinetic properties/ processes of the

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other drug hence resulting in the alteration of the effects of the other drug(s).For example:

 If administered with diuretics, non-steroidal anti-inflammatory drugs (NSAIDs) will

reduce the anti hypertensive of diuretics.
 Enzyme induction, which occurs as a result of administration of certain drugs, can
affect the metabolism of other drugs served by that enzyme. E.g. alcohol (an enzyme
inducer) increases the metabolism of other drugs like cyclosporine hence, modifying
the action of the drug.
 Enzyme inhibition, which occurs as a result of co administration of an enzyme
inhibitor with another drug, results in the enhancement of the actions of that drug
due to reduced metabolism. E.g. co administration of cimentidine (an enzyme
inhibitor) with many drugs like phenytoin results in enhancement of the effects/
actions of the other drug since cimentidine inhibits the metabolism of phenytoin.

Synergism is the facilitation of pharmacological response by concomitant use of two drugs.

When two or more drugs are administered simultaneously in such a way that their
combined effect is greater than that elicited by either drug alone, synergism is said to have
occurred. The total pharmacological effect will be more than the sum of their individual
effects and as such, the action is more than the normal therapeutic effect of the drug. E.g.
The interaction between cimentidine and phenytoin.

Drug antagonism occurs when two drugs interact in such a way that the combined effect
produced is lesser than that produced by either of the drugs alone. In antagonism, the total
effect produced is less than the sum of their individual effects; hence the resulting
pharmacological effect is less than the normal therapeutic effect of the drug. E.g. Interaction

between propranolol and salbutamol.

8. Environmental Factors & Time Of Administration

Several environmental factors affect drug responses. Exposure to certain chemicals like
insecticides, carcinogens, tobacco smoke and consumption of charcoal broiled meat are
well known to induce metabolism. The subjective effects of a drug may be markedly
influenced by the setup in which it is taken. The effects of certain drugs are best seen at
certain periods/ time. For example, hypnotics/ sedatives act better at night in a quiet
familiar surrounding and smaller doses are required to produce this effect unlike when it is
taken during the day, thus the time of administration of a drug may also modify the actions
of the drug.

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