Module 2: Individual Variation in Drug Response

Question 1

Individual Variation

Answer 1

Sources of individual variation:
1. Physiologic

2. Pathophysiologic
3. Genetic variables
4. Exogenous issues

**Drug therapy needs to be pt-specific because of these individual variations

Question 2

Individual Variation #1: Physiologic

Answer 2

Sources of physiologic factors:
1. Body weight/composition

2. Age — can lead to organ immaturity in young pts (especially in premature neonates), or organ dysfunction in older pts
3. Tolerance — decreased responsiveness to a drug (i.e. opioids) as a result of repeated drug admin. (due to changes in receptor expression)
4. Placebo effect — a preparation that has no intrinsic pharmacologic property (often used in RCT); it is the component of drug response that is caused by the psychological factor of taking the drug, not by the biochemical or physical properties of the drug
5. Sex — i.e. Alcohol tends to be metabolized more slowly in female pts

**Race is a social construct; it is not a biological or physiologic factor, therefore, it does not provide an accurate picture of human biologic variation

Question 3

Individual Variation #2: Pathophysiologic

Answer 3

The effects of the body from a specific disease or disorder, and that subsequent effect on PK or PD

Sources of pathophysiologic factors:
1. Kidney, liver disease — reduced drug excretion (kidneys) and metabolism (liver) which can lead to drug accumulation and potential toxicity, increasing the drug’s half-life and subsequently requiring dose alteration

2. Diarrhea/constipation disorders
3. Electrolyte disturbance (rare) — a drug (i.e. Digoxin) that uses electrolytes as part of their MOA can lead to either toxicity or therapeutic failure if there is electrolyte imbalance

Question 4

Individual Variation #3: Genetic variables

Answer 4

Sources of genetic variables:
1. Alterations in drug metabolism (PK) — enzymes and proteins that are coded by DNA may be overabundant or lacking (and thus break down meds. too quickly, inhibiting a desired therapeutic response OR have difficulty metabolizing meds., leading to extreme toxicity)

2. Alteration in drug targets (PD) — lacking receptors; i.e. Herceptin is a drug used to treat breast CA, and only works against tumors that express HER2 (thus gene testing is required prior to admin.); HER2 is a protein that elicits tumor growth, and is over-expressed in about 25% of pts with breast CA
3. Alterations in response to drugs (immune response or PD) — a pt’s immune system may be hypersensitive because of their genetic code; i.e. A pt with certain genes and genotypes that is admin. an antiepileptic drug may be more likely have extreme allergic reactions

Question 5

Individual Variation #4: Exogenous issues

Answer 5

Sources of exogenous issues:
1. DDIs or DFIs

2. Diet — anything that leads to changes in levels of protein (i.e. malnourishment) can, in theory, affect the way the body responds to drug therapy
3. Adherence issues — failure to take a med. as prescribed

Question 6

General Measures to Minimize Individual Variation

Answer 6

Measures to minimize individual variation:
1. Obtain a thorough drug history that includes OTC and CAM meds.

2. Consider PK and PD changes due to age and/or functional state
3. Monitor the pt’s clinical response and plasma drug levels (when applicable)
4. Use the simplest drug regimen possible
5. Monitor for DDIs
6. Periodically review the need for continued drug therapy

Question 7

Pediatric Pts

Answer 7

Pediatric factors to consider:
1. Ongoing growth and development

2. Two-third of drugs are not tested on children
3. More sensitive to drugs than other pt populations
4. Show greater individual variation
5. Sensitivity due mainly to organ immaturity — i.e. The hemostatic (blood clotting) system is not mature until a pt is an adolescent
6. Increased risk for ADRs

Question 8

Pediatric Pts: Age Groups

Answer 8

Neonates and infants are at the highest risk for individual variation

Pediatric age groups:
1. Neonates (0-4 weeks old)

2. Infants (5-52 weeks old)
3. Children (1-12 yrs. old)
4. Adolescents (12-16 yrs. old)

Question 9

Neonates and Infants

Answer 9

Sources of increased sensitivity due to immature state of PK processes:
1. Absorption

2. Permeable BBB — drugs pass more freely into the brain compared to older pts
3. Limited protein binding of drugs
4. Decreased hepatic metabolism — the liver’s capacity to metabolize drugs increases rapidly at 1 mo. of age (matures at 1 yr. of age)
5. Decreased renal excretion — for at least a week postnatal, there is low renal blood flow and GFR (matures at 1 yr. of age)
6. Prolonged and irregular gastric emptying time (matures at 8 mos.)
7. IM absorption — First few days postnatal: Slow, erratic, and delayed (there is low blood flow to the muscles); Early infancy: IM absorption rate surpasses neonates and adults
8. Rapid transdermal absorption in infants — the epidermis of infants tends to be very thin, and blood flow to the skin is much greater than adults

Question 10

Children (>1 yr. old)

Answer 10

Most PK parameters and drug sensitivity similar to adult pts

Faster drug metabolism than adults until 2 yrs. of age; followed by gradual, then sharp decline at puberty (adolescence)

Dosage may be higher or time between doses may be shorter — i.e. Vancomycin is admin. q12h to most adult pts (unless they have significant renal dysfunction); it is admin. q6h to peds. pts because it is cleared rapidly

Question 11

Dosage Determination

Answer 11

Dosing is based on weight (kg) = Below 12 yrs. old OR below 40 kg

Initial dose is, at best, an approximation; subsequent dosing usually need to be adjusted

Question 12

Pediatric-Specific ADRs

Answer 12

Children are vulnerable to unique AEs related to organ immaturity and ongoing growth and development

Age-related AEs:
1. Growth suppression due to glucocorticoids

2. Discoloration of developing teeth due to tetracyclines
3. Kernicterus: a disorder due to severe jaundice of the newborn in which bilirubin deposits in the brain — Sulfonamides displace bilirubin from serum albumin sites; bilirubin is able to cross the BBB and deposit in brain tissue, causing brain damage, cerebral palsy, hearing loss, vision problems, and other neurologic problems (thus it is never used in infants <1-3 mos. old)

Question 13

Measures to Reduce ADRs in Pediatric Pts

Answer 13

Preventative measures to reduce ADRs in pediatric pts:
1. Provide verbal and written instructions

2. Describe how to handle spills and spitting up of dose
3. Ways to avoid multiple dosing of child (i.e. use admin. chart)
4. Select most appropriate dosage form and schedule
5. Suggest mixing med. with juice/food when allowed to improve palatability
6. Provide measuring device (metric units)
7. Spend time teaching/observing parents’ admin. skill

Question 14

Geriatric Pts

Answer 14

Geriatric factors to consider:
1. Multiple and severe illnesses — severity of illness, multiple pathologies

2. Multidrug therapy — excessive prescribing
3. Poor adherence
4. Altered PK — most sensitive to drugs than younger adults, and with greater PK variation

Question 15

Physiologic Changes in Older Adults

Answer 15

PK changes:
1. Absorption — increased gastric pH (basic), decreased absorptive surface area, decreased splanchnic blood flow, and decreased GI motility and gastric emptying

2. Distribution — increased body fat, decreased lean body mass, decreased total body water, decreased serum albumin, and decreased CO
3. Metabolism — decreased hepatic blood flow, mass, and enzyme activity
4. Excretion — decreased renal blood flow, decreased GFR, decreased tubular secretion, and decreased number of nephrons

Question 16

PD Changes in Geriatric Pts

Answer 16

Alterations in receptor properties may underlie altered sensitivity to some drugs, causing:
1. More intense effects — i.e. CNS depressants

2. Less effective drugs, even in the same concentrations — i.e. Beta blockers, due to a reduction in number of beta receptors

Question 17

Measures to Reduce ADRs in Geriatric Pts

Answer 17

Preventative measures to reduce ADRs in geriatric pts:
1. Simplify the regiment

2. Provide clear and concise verbal and written instructions
3. Choose appropriate dosage form
4. Request pharmacy label containers using large print, easy to open
5. Suggest use of calendar and pill box
6. Verify the pt has access to pharmacy and can afford the med.
7. Enlist help of family/friends
8. Encourage the pt to dispose of discontinued meds.
9. Avoid drugs on the Beers criteria list
10. Monitor for AEs, DDIs, and DFIs

Question 18

Beer’s Criteria List

Answer 18

Lists meds. that cause ADRs in older adults due to their pharmacologic properties and the physiologic changes of aging

Helps inform clinical decision-making concerning med. prescription for older adults, ultimately improving safety and quality of care