Lecture 04 - Pharmacokinetics and Pharmacodynamics

Question 1

What are the four categories that effect metabolism of drugs

Answer 1

• host factors (diet and disease states)
• influence of genetics
• enzyme induction
  -inhibition of CYP enzymes

Question 2

What is pharmacogenetics

Answer 2

the study of genetically determining variation in drug metabolism

Question 3

What is pharmacogenomics

Answer 3

the customization of dosing to match a patients specific genetic profile

Question 4

What are polymorphisms

Answer 4

mutations that occur inn at least 1% of the population

Question 5

What do polymorphisms result in

Answer 5

decreased activity, increased activity, no activity, no change in activity

Question 6

What is an extensive metabolizer

Answer 6

a person who metabolizes a probe drug at a rate similar to that of most of the population

Question 7

What is a poor metabolizer

Answer 7

a person who metabolizes a probe drug at a rate slower than most of the population

Question 8

What is the therapeutic consequence of being a poor metabolizer

Answer 8

lack of response due to inability to convert pro drug to its active form or may result in high levels of parent drug causing toxic side effects

Question 9

What is an ultra-rapid metabolizer

Answer 9

a person who metabolizes a drug more rapidly than most of the population due to the presence of multiple copies of the CYP2D6 gene

Question 10

What is the therapeutic consequence of being an ultra-rapid metabolizer

Answer 10

these people fail to respond to conventional doses of drugs

Question 11

How do we determine what kind of metabolizer someone is

Answer 11

genotyping (predict optimal dose using genetic info) or phenotyping (predict dose using drug ratio in urine)

Question 12

What is CYP2D6

Answer 12

accounts for 1-5% of total CYP, expressed in liver intestines kidney and brain, metabolizes 30% of drugs currently used

Question 13

What are some common substrates of CYP2D6

Answer 13

codeine, fluoxetine, amitriptyline, paroxetine

Question 14

What is CYP2C9*1

Answer 14

the wildtype

Question 15

What is CYP2C9*2

Answer 15

a mutation of A to C at position 144, results in reduced metabolism of warfarin

Question 16

What is CYP2C9*3

Answer 16

a mutation of I to L at position 259, results in reduced metabolism of warfarin

Question 17

How does warfarin get effected by CYP2C9

Answer 17

if person has the poor metabolizer mutation they need a lower dose otherwise the S-isomer will build up and not be metabolized which can be dangerous

Question 18

What does enzyme induction do

Answer 18

can increase CYP enzyme expression by increase synthesis, decrease degradation, or activate pre-existing components of the metabolic system

Question 19

How does ethanol interact with acetaminophen

Answer 19

it induces CYP2E1 which increases metabolism of acetaminophen to NAPQI

Question 20

What is the double whammy with alcohol abuse and acetaminophen

Answer 20

often alcoholics are malnourished resulting in low glutathione stores

Question 21

What types of inhibitors are there from drugs to the CYP enzymes

Answer 21

competitive inhibition for active site between substrates, competitive inhibition of active site (non substrate), metabolic activation forming inhibitory products

Question 22

What does inhibition do

Answer 22

drug isn’t converted to active form which causes a decreased concentration below the therapeutic level

Question 23

What does induction do

Answer 23

the drug is metabolized at a higher rate causing an increased concentration and more risk of toxic side effects

Question 24

How can polymorphisms in NAT-2 gene effect drug metabolism

Answer 24

slow acetylators are unable to acetylate a range of drugs

Question 25

How can polymorphisms in NAT-2 gene modulate risk of cancer

Answer 25

it acetylates aromatic amines found in tobacco smoke and charred foods that can induce cancers

Question 26

What is cyclosproine

Answer 26

a first line immunosuppressant that has revolutionized the field of organ transplants and reduced acute rejection rates

Question 27

Where is cyclosporine found

Answer 27

a cyclic peptide of 11 amino acids from the fungus tolypocladium inflatum

Question 28

How does cyclosporine work

Answer 28

it inhibits calcineurin through cyclophilin to block NDAT-mediated transcription of IL-2

Question 29

What is sirolimus

Answer 29

used in place of and in combination with cyclosporine or tacrolimus

Question 30

How does sirolimus work

Answer 30

binds FKBP12 and the complex inhibits mTOR and blocks signalling downstream of IL-2 which inhibits IL-2-mediated activation of T and B cells

Question 31

What is the first line immunosuppressant drug used in the IS

Answer 31

tacrolimus

Question 32

How does tacrolimus work

Answer 32

it is a clacineurin inhibitor 100x more potent than cyclosporine

Question 33

What factors effect appropriate dosing for transplants

Answer 33

organ type, kidney function, diet, time after transplant, protein binding, metabolism, route of administration, drug formulation