Lecture 17_Variations in Drug Responses

Question 1

If a normal dose of a drug is prescribed why do some patients show either too much or too little response?

Answer 1

• 1. Compliance: Did patient take drug?
• 2. Bioavailability: If drug was taken properly, was it absorbed properly and delivered to the systemic circulation?
• 3. Pharmacokinetics: Was the drug distributed normally in the body?
• 4. Pharmacodynamics? Did target tissue respond to drug in the expected manner?

Question 2

Why is patient compliance an issue?

Answer 2

• 1. Duration of treatment: There is lowered compliance for drugs that must be taken for a long time.
• 2. Complexity of the dosing regimen (inconvenience): Ameliorated somewhat by marketing of pharmaceutical mixtures (two drugs in one dose) but this results in loss of therapeutic flexibility.
• 3. Patient’s perception of the seriousness of the disease and of the importance and efficacy of treatment.
• 4. Side effects of therapy, if serious, tend to decrease compliance.
• 5. Continuity and ease of contact with physician.

Question 3

Why is noncompliance a serious problem in the treatment of hypertension?

Answer 3

• High blood pressure itself does not cause symptoms but antihypertensives often make patients feel miserable. This decreases drug-taking compliance.
• Compliance was increased by allowing a test group of subjects to measure their own BP readings daily (reinforced with biweekly physician supervision).

Question 4

Important measures to assure compliance in long-term therapies include:

Answer 4

• 1. Simplified dosing schedules
• 2. use of long-acting rather than short-acting drugs
• 3. Minimizing side effects
• 4. Continuous supervision of the patient
• 5. Patient education

Question 5

Factors affecting bioavailability

Answer 5

• 1. GI or liver pathology (eg. diarrhea, biliary obstruction, hypermotility, reduced GI blood flow).
• 2. Formulation of the drug preparation, leading to differences in release of drug into GI fluids.

Question 6

(T/F) Generic drugs are just as good as brand name.

Answer 6

FALSE. Brand names are often (but not always) better formulated than generic drugs, giving more uniform and better bioavailability.

Question 7

Pharmacokinetic reasons for variability to drug response.

Answer 7

• 1. Liver disease may affect metabolism.
• 2. Age (eg., elimination rate of mecillinam is 4 times slower in elderly).
• 3. Smoking

Question 8

(T/F) Pharmacokinetic variation is most evident in early infancy and advanced age, but may also be affected by disease processes at any age.

Answer 8

TRUE.

Question 9

Give an example of a disease process affecting pharmacokinetic variation.

Answer 9

Penicillin, and other antibiotics, do not normally cross the blood brain barrier. However inflammatory processes (eg. meningitis) increase antibiotic permeability, increasing their effectiveness. But… this may also increase the risk for toxicity (high concentrations of penicillin can cause seizures).

Question 10

In adults, drug dosing is generally calculated on the basis of…

Answer 10

…body size and body composition (lean body mass).

Question 11

Most differences in drug doses between men and women are due to…

Answer 11

…different body composition.

Question 12

Obese vs lean with Pm/b drugs.

Answer 12

• Obese person requires smaller dose of low Pm/b drug than lean person of same weight.
• Obese person requires higher dose of high Pm/b drug than skinny person of same weight (fat acts as a drug reservoir).

Question 13

The required dose is proportional to…

Answer 13

…metabolic rate.

Question 14

Metabolic rate is proportional to…

Answer 14

…body surface area (NOT body weight).

Question 15

The required dose is actually more proportional to the metabolic rate, which is in turn closely proportional to body surface area than body weight. Why is this discrepancy important?

Answer 15

It’s not in adults, but it is in babies and small children whose surface area to mass ratio is considerably higher than adults.

Question 16

Young’s Rule

Answer 16

Calculation of children’s dose by age.

Age/(Age+12) = fraction of adult dose.

Question 17

Calculation of children’s dose by body surface area:

Answer 17

(1.5 x weight [in kg]) + 10 = percentage of adult dose to give child.

Question 18

The body surface area calculation method is superior especially with young children. Why is that?

Answer 18

Based on Young’s Rule, a newborn baby would receive 0 percent of adult dose. This is where the formula breaks down (young’s rule doesn’t apply to babies).

Question 19

Pharmacodynamic variations, leading to altered target tissue responses to drugs may be due to…

Answer 19

…genetic abnormalities or to disease processes.
- EX: Hyperthyroidism is frequently associated with an increased number of Beta adrenoceptors and this leads to heart palpitations and anxiety; increased sensitivity to catecholamines results and is treated with Beta-blockers.

Question 20

Sometimes drug interactions will alter pharmacodynamic sensitivity to one or more of the drugs administered. Give an example.

Answer 20

Patients with chronic left ventricular failure are often treated with a diuretic (to reduce edema) and a cardiac glycoside (to increase cardiac muscle contractility). Increased cardiac output by the cardiac glycoside increases renal blood flow, which increases the urinary response to diuretic. This may lead to excessive loss of K+ into urine, and the resulting hypokalemia increases myocardial sensitivity to the cardiac glycoside, increasing the chances for arrhythmia.

Question 21

Tolerance to one drug can also be expressed as…

Answer 21

…cross tolerance to the effects of another.
- EX: CNS depressants (alcohol, benzodiazepines, and other sedatives). Prolonged use of any of these results in an adaptation (tolerance) that occurs to the effects of these drugs.

Question 22

Effects of cross tolerance.

Answer 22

Not only can this lead to decreased responses to the drug that has been taken chronically but it can also lead to decreased responses to other drugs that produce similar effects. For example, alcoholics show significantly decreased responses to general anesthetics, necessitating the administration of higher doses.