Drug Disposition II

Question 2

Drug metabolism results in: (3)

Answer 2

elimination/renal clearance blood levels effects

Question 3

A member of the cytochrome P450 (CYP) enzyme superfamily High levels in the liver Metabolizes many drugs Genetic polymorphims results in humans with “normal” enzyme activity very low activity (no effect of codeine) very high activity

Answer 3

CYP 2D6 which is a gene

Question 4

Key information needed to predict drug metabolism in your patient (3)

Answer 4

what enzymes metabolize genetic factors that affect enzyme drug activated or inactivated by metabolism

Question 5

What are consequences of biotransformation? (2)

Answer 5

Increased polarity (water solubility), which results in facilitated excretion Pharmacological or toxicological result Inactivation (usually) Activation (sometimes) No effect Metabolite and parent drug may both be active

Question 6

Sites of drug biotransformation (5):

Answer 6

Liver GI Kidney Respiratory tissues: lung, nose Brain, skin, heart

Question 7

Common phases of drug metabolism: (2) Note: don’t necessarily have to go through both phases.

Answer 7

non-conjugative, (non-synthetic ) Oxidations Reductions, Hydrolyses Note: Adds or unmasks functional group Usually inactivates, sometimes activates conjugative (synthetic) Conjugations (covalent coupling of drug to endogenous molecule) Increases polarity Adds bulky moiety Usually inactivating

Question 8

What is this? “microsomal” endoplasmic reticulum mixed-function oxidase uses NADPH and O2 to metabolize drugs

Answer 8

Cytochrome P450s

Question 9

The major human cytochrome P450s involved in clinical drug metabolism: (4)

Answer 9

CYP 3 A 4 2 D 6 1 A 2 2 C

Question 10

Conjugation (Phase II) reactions pathway involves: (2)

Answer 10

Need high-energy cosubstrate

• Activities reduced when low ATP
• Adds polar or ionizable group, increasing water solubility

Question 11

In phase II reactions, what is the most common conjugation reaction? Has many enzymes and conjugates to many functional groups Are often excreted in the bile

Answer 11

glucuronides during glucuronidation

Question 12

KNOW: Other conjugation reactions: (4) GASM

Answer 12

Acetylation Sulfation Methylation Glutathione conjugation

Question 13

Which conjugation reaction’s main purpose is: to protect cells from reactive drugs and metabolites isnot usually a major pathway for drug elimination from the plasma

Answer 13

glutathione conjugation responsible for actetominophen poisoning for example

Question 14

Factors affecting drug metabolism: (2)

Answer 14

Increased therapeutic/ toxic effect due to reduced metabolism neonates, liver disease, genetics, diet, herbal preparations Decreased therapeutic effect due to increased metabolism Gene amplification

Question 15

P450 modifiers in natural products: (2)

Answer 15

grapefruit juice St. John’s Wort

Question 16

In pharmacogenetics, genes can respond to drugs: (2)

Answer 16

monomorphic polymorphic (increased plasma concentration/magnitude of response)

Question 17

Pharmacodynamic polymorphisms in drugs results in alterations in ______ molecules.

Answer 17

target

Question 18

This polymorphism; usually involves alterations in drug metabolizing enzymes more prevalent due to lower selection pressure

Answer 18

pharmacokinetic

Question 19

Detection of pharmacogenetic traits: (2)

Answer 19

Phenotyping Ex.Pharmacokinetics Urinary metabolite ratios Enzyme activities in peripheral blood Can detect all mutant alleles Affected genetic factors, can change with time Genotyping Easily done by sequencing or e.g. gene array chips Does not always reflect phenotype Only detects known mutant alleles

Question 20

Key themes/concepts in pharmacogenetics (2)

Answer 20

Multiple defective alleles/haplotypes Allele distribution can vary substantially in different racial/ethnic groups

Question 21

CYP2D6 polymorphism involves increased response to the following drug classes:

Answer 21

cardiovascular beta blockers tricyclic antidepressents

Question 22

10% of Caucasians 1% of Orientals Large number of mutant (defective) alleles

Answer 22

CYP2D6 polymorphism

Question 23

Pharmacodynamic polymorphisms in non-target genes is:

Answer 23

Malignant Hyperthermia