CHAPTER 8 INDIVIDUAL VARIATION IN DRUG RESPONSES

I. Body Weight and Composition

- the absence of adjustments in dosage, body size can be a significant
determinant of drug effects
- response to a drug is determined in large part by the concentration of the
drug at its sites of action
- the higher the concentration, the more intense the response
- when adjusting dosage to account for body weight, the clinician may
base the adjustment on body
surface area rather than on weight per se
- surface area determinations account not only for the patient’s
weight but also for how fat or
lean the patient may be
- dosage adjustments based on body surface area provide a more
precise means of controlling
drug responses than do adjustments based on weight alone

II. Age
- infants and elderly are especially sensitive to drugs
- the very young have heightened drug sensitivity as a result of
organ immaturity
- the elderly have a heightened drug sensitivity due to organ
degeneration
- the elderly also have an increased severity of illness, the presence
of multiple pathologies,
and treatment with multiple drugs

III. Gender
- for most drugs, we don’t know much about gender-related differences
because, until recently,
essentially all drug research was done in men
- clinicians must keep in mind that the information currently available may
fail to accurately predict
responses in female patients

IV. Pathophysiology
- abnormal physiology (someone that is sick) can alter responses to drugs

A. KIDNEY DISEASE
- can reduce drug excretion, causing drugs to accumulate in the body,
possibly to toxic levels

B. LIVER DISEASE
- can cause drugs to accumulate
- if the liver ceases to function, rates of metabolism will fall and drug levels
will climb
 - applies only to those drugs that are eliminated primarily by the liver
- liver dysfunction will not affect plasma levels of drugs that are eliminated
largely by nonhepatic
mechanisms

V. Tolerance
- decreased responsiveness to a drug as a result of repeated drug
administration

A. PHARMACODYNAMIC TOLERANCE
- refers to the familiar type of tolerance associated with long-term
administration of drugs such as
morphine and heroin
- requires increased drug levels to produce effects that could formerly be
elicited at lower drug levels
- MEC of a drug is abnormally high
- thought to result from adaptive processes that occur in response to
chronic receptor occupation

B. METABOLIC TOLERANCE
- tolerance resulting from accelerated drug metabolism
- brought about by the ability of certain drugs (e.g., barbiturates) to induce
synthesis of hepatic drug-
metabolizing enzymes, thereby causing rates of drug metabolism to
increase
- because of increased metabolism, dosage must be increased to maintain
therapeutic drug levels

C. TACHYPHYLAXIS
- form of tolerance that is a reduction in drug responsiveness brought on
by repeated dosing over a
short time
- occurs quickly
- not a common mechanism of drug tolerance
- ex. Transdermal nitroglycerin – using a transdermal patch, effects are lost
in less than 24 hours

VI. Placebo Effect

- patient’s beliefs affect the response to drugs
- preparation that is devoid of intrinsic pharmacologic activity
- any response that a patient may have to a placebo is based solely on
his/her psychologic reaction to
the idea of taking a medication and not any direct physiologic or
biochemical action of the
placebo itself
- primary use of the placebo is as a control preparation during clinical trials
- fostering a positive attitude may help promote beneficial effects
 - also important, is that members of the team be consistent with one
another

VII. VARIABILITY IN ABSORPTION

- both the rate and extent of the drug absorption can vary
- both the timing and intensity of responses can be changed
- differences in manufacturing are a major cause of variability in drug
absorption
- other causes include the presence or absence of food, diarrhea or
constipation, and differences in
gastric emptying time

A. BIOAVAILABILITY
- ability of a drug to reach the systemic circulation from its site of
administration
- such factors as tablet disintegration time, enteric coatings, and
sustained-release formulations can
alter bioavailability, and can thereby make drug responses variable
- occur primarily with oral preparations and not with parenteral
preparations
- differences in bioavailability are of greatest concern for drugs with a
narrow therapeutic range
- narrow range calls -- a relatively small change in the drug level can
produce a significant
change in response
- a small decline in drug level may cause therapeutic failure,
whereas a small increase in drug
level may cause toxicity

VIII. Failure to Take Medicine as Prescribed

- medications are not always administered as prescribed:
dosage size and timing may be altered
doses may be omitted or extra doses may be taken
- common explanation for variability in the response to a prescribed dose
is failure to take medications
as prescribed

Factors affecting this failure:

- patient compliance (adherence) – cooperative and accurate
participation in one’s own therapy
- manual dexterity, visual acuity, intellectual capacity,
psychological state, attitude
toward drugs, ability to pay for medication, and appropriate
diet all apply