Interactions + Pharmacogenetics

Question 1

Define pharmacokinetic drug interaction

Answer 1

Pharmacokinetic drug interactions occur when one drug/substance changes the absorption, distribution, metabolism or excretion of another drug or substance

Question 2

Define pharmacodynamic drug interaction

Answer 2

one drug substance binds or alters the target of another drug substance

Question 3

Define physiological drug interaction

Answer 3

one drug or substance produces the similar or opposite effects of another drug

Question 4

What does it mean when a drug can reversibly bind to CYP450 enzymes?

Answer 4

Reversible interactions of the heme-iron active center or surrounding lipophilic areas (or both)

Inhibition disappears quickly after drug is d/c

EX: fluoroquinolones, azoles

Question 5

What is meant by metabolite intermediate complexation?

Answer 5

CYP450 metabolizes alkylamine drugs to nitrosalkane intermediates which then inhibit the CYP450 enzyme because they have a high affinity for the heme group

Question 6

What is meant by mechanism-based inactivation in the context of CYP450 enzymes?

Answer 6

CYP450 catalytic cycle makes alkene and alkyne metabolites that irreversibly bind (make covalent bonds) to the CYP450 enzyme and inhibit it’s activity

**clinical significance = inhibition persists for much longer after the drug is d/c

Question 7

What does a CYP450 inducer do?

Answer 7

Increases expression of the enzyme

Some drugs induce metabolism of other drugs and sometimes they induce their own metabolism

Question 8

Which class of drugs include metabolic enzymes?

Answer 8

anticonvulsants

Question 9

What is the most common example of a pharmacodynamic drug interaction?

Answer 9

Interaction where someone was administered a GPCR agonist and antagonist at the same time

Question 10

Give an example of a physiological drug interaction

Answer 10

Taking two CNS depressants with two distinct mechanisms of action like a benzodiazepine and an opioid

Question 11

What is the difference between an additive, supra-additive and infra-additive?

Answer 11

Additive → consequence of a drug interaction is the simple sum of the separate effects of each drug

Supra-additive → consequences of drug interaction are much higher than the simple sum of the separate effects of each drug

Infra-additive → consequences of a drug interaction are less than the sum of each drug’s separate effects

Question 12

What are the qualitative variations to drugs?

Answer 12

• unusual or idiosyncratic drug responses
• response that is often dramatic and observed infrequently
• typically unknown cause

Question 13

What are the quantitative variations in individual drug responses?

Answer 13

• same response as usual, just higher or lower
• hyper-reactive or hypo-reactive rather than hypersensitive (means allergic reaction)
• tolerance/tachyphylaxis may affect the quantitative response

Question 14

What is involved in pharmacokinetic vs pharmacological vs physiological variation in drug responses?

Answer 14

Pharmacokinetic → ADME

Pharmacological → changes in drug target, # of targets or levels of endogenous ligand

Physiological → variability in physiological parameter affecting how the body responds to a drug (like diseases)

Question 15

Why is species variability important in drug development?

Answer 15

Different animals have different enzymes that break stuff down so studies on animals may not translate well to humans

Question 16

How is adherence a source of drug response variability?

Answer 16

Could cause different peak concentrations in a day

Question 17

How does disease state contribute to drug response variability?

Answer 17

Different disease states may allow a drug to get into the brain or into “new” compartments (like fluid accumulation in peritoneum) when it wouldn’t normally

Question 18

How is age a factor in drug response variability?

Answer 18

Newborns have little muscle mass for injections, diminished peripheral blood flow,, slower onset of GI secretion, little or no peristalsis → these all effect drug administration and pharmacokinetics

Neonates have higher water % than adults and lower kidney functions

***children are not mini adults, their bodies function differently

Increasing age is associated with increased # of disease states, decrease in organ function and increase in # of medications used → most differences in drug response are due to pharmacokinetic changes

Question 19

How do older adults differ with respect to ADME?

Answer 19

A → little physiological difference but higher rates of use in GI drugs may affect absorption of medicines in this population

D → relative decrease in lean body mass, increase in fat %

M → increased chance of DI, decrease in hepatic clearance

E → decrease in kidney function

Question 20

How is diet a factor in drug response variability?

Answer 20

Fasting or having a full stomach can change drug absorption

Foods can interact with drugs to alter responses

Question 21

Define pharmacogenetics

Answer 21

the study of the genetic basis for variation in drug response

Question 22

Define pharmacogenomics

Answer 22

using tools to survey the genome and assess multigenic determinants of drug response

Question 23

What is the term used to describe “normal” or “typical” metabolizers in the population?

Answer 23

Extensive metabolizers → often the largest group in a given population

Question 24

What is the physiological difference between poor and ultra-rapid metabolizers?

Answer 24

Poor → fewer copies or dysfunctional metabolic enzymes (results in higher peak drug conc over longer periods)

Ultra-rapid → multiple copies of the metabolic gene (results in lower drug conc, may not see therapeutic effect)

***phase 2 metabolic enzymes and drug transporters may contribute to variation in drug response

Question 25

What is the second most common commercial drug metabolizing enzyme?

Answer 25

CYP2D6 → most variable too, >90 distinct alleles identified

Question 26

What is most of the pharmacogenetic variability due to?

Answer 26

changes in drug metabolism

Although there are some others: receptor variability resulting in increased bronchodilation response, receptor variability resulting in increased desensitization

Question 27

What doe you have to consider in order to make predictions about the consequences of a CYP450 polymorphism?

Answer 27

• does the polymorphism result in increased or decreased P450 gene activity?
• Is the parent compound an active drug or a prodrug?
• What is the relative efficacy and toxicity of the parent drug?
• What is the relative efficacy and toxicity of the metabolite?