Pharmacology Ch.

8 outline

Individual variation in drug response

Body weight and composition

– Body size and weight can be significant determinants of drug effects

– Can create more intense effect in small person

Age

– Drug sensitivity varies with age (infants & elderly are esp. sensitive to drugs)
– With infants, their systems haven’t fully developed yet, and they are small
– With the elderly, there is often multiple pathologies and treatment w/ mult
drugs, as well as natural breakdown of organs

Pathophysiology

Abnormal pathophysiology can alter responses to drugs:

– Kidney disease :can reduce drug excretion causing drugs to accumulate in

the body to potentially toxic levels. If renal failure occurs, dosage must be
decreased
– Liver disease: (major site of drug metabolism) if liver ceases to fnc, rates of
metabolism will fall and drug levels will climb. Drug dosages should be
reduced to avoid accumulation of toxic levels. Liver fnc will not affect plasma
levels of drugs that are eliminated largely by nonhepatic mechanisms (renal
excretion)
– Acid-base imbalance: By altering pH partitioning, changes in acid-base status
can alter absorption, distribution, metabolism and excretion of drugs. A drug
will accumulate on the side where pH most favors its ionization. Acidic drugs
will accumulate on the alkaline side, etc.
– Altered electrolyte status: When electrolyte levels become disturbed, multiple
cellular processes become disrupted. Not significant impact usually. (most
important example is digoxing to induce dysthrhythmias when K+ levels are
depressed

Tolerance

Tolerance is a decreased responsiveness to a drug as result of repeated drug

admin.

Pts who are tolerant to a drug require higher dosages to produce effects.
3 categories of drug tolerance:
1 – pharmacodynamic tolerance:familiar type of tolerance associated w/long term
admin of fdrugs such as morphine and heroin. The minimum effective concentration
(MEC) of a drug is abnormally high. Thought to result from adaptive processes that
occur in response to chronic receptor occupation.

2 – 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, causing rates of drug metabolism to
increase. Because of increased metabolism, drug dosage must be increased to
maintain therapeutic drug levels.

3 – tachyphylaxis: a form of tolerane that can be defined as a reduction in drug

responsiveness brought on by repeated dosing over a short time. Occurs quickly.
Not common. (e.g. transdermal nitroglycerin – effects are lost in less than 24 hrs.

Placebo effect

A placebo is a preparation that is devoid of intrinsic pharmacologic activity. So any

response a pt has is based solely on his or her psychological rxn to the idea of
taking a med, and not the med itself.

Primarily used in clinical trials

The Placebo effect is defined as that component of a drug response that is caused
by psychologic factors and not by biochemical or physiologic properties of the drug.

Not all placebo responses are beneficial: can be negative. if a patient believes that
a med is going to be effective then it usually helps promote recovery

It is important to foster positive attitudes w/ placebos

Variability in Absorption

Both rate and extent of drug absorption can vary among patients, so as a result,
both timing and intensity of responses can be changed.

Bioavailability – the ability of a drug to reach the systemic circulation from its site of
administration.
Factors affecting bioavailability include: disintegration time, enteric coating,
sustained release.

Differences occur primarily w/in oral preparations and not w/parenteral prep.

Differences w/in bioavailability are of greatest concern for drugs w/ a narrow

therapeutic range, b/c w/ a relatively small change in drug level, they can produce a
significant change in response.
Other causes of variable absorption
- alterations in gastric pH
-diarrhea
- constipation

Genetics
Pharmacogenetics – the study of how inheritance affects individual drug responses –
an active area of research.

Altered Drug Metabolism

– Most common mechanism by which genetic differences modify drug response

– Either accelerates or retards the metabolism of may drugs
– About 1 in 3500 europeans metabolize succinylcholine very slowly
– See pg. 81 for more
– For drugs w/ a high therapeutic index, altered rates of metabolism may affect
outcome

Altered Drug targets

Genetic varieations can alter the structure of drug receptors and other target
molecules and thereby influence drug responses.

Other ways genetics can influence drug responses

Some individuals have RBCs that are deficient in glucose 6 phosphate

dehydrogenase, puts them @ risk for hemolysis if given aspirin.

Gender

Men and women can respond differently to the same drug.

– Alcohol is metabolized more slowly by women than men

– Opioid analgesics are more effective in women than men
– Quinidine causes greater QT interval prolongation in women than men

Race

2 primary determinants:

– Genetic variations
– Psychosocial factors

Failure to take meds as prescribed

Dosage, age, size, and timing may be altered by medical staff or patient.
Drug interactions

Diet can affect responses to drugs, by affecting the patient’s general health status.
Starvation can reduce protein binding of drugs (by decreasing level of albumin),
increasing levels of free drug and making drug responses more intense. In warfarin,
results could be disasterous!

MAO inhibitors – must avoid tyramine rich foods!