Metabolism and Excretion

Question 1

What is drug metabolism?

Answer 1

drugs undergo a chemical structure transformation through enzyme catalysis (after administration to pt)

Question 2

Describe drug metabolizing enzymes

Answer 2

1) They have endogenous (already within human) substrates

2) They play a role in normal metabolism

Question 3

Where does drug metabolism occur?

Answer 3

Primary site: Liver

Secondary: lungs (30%), intestines (6%), kidney (8%), skin (1%), placenta (5%)

Also bacteria have enzymes capable of this

Question 4

By which pathways do these chemical transformations occur? – during drug metabolism

Answer 4

Most frequent: oxidation

Also:
1) reactions catalyzed by membrane-bound enzymes of SER (CYP450 enzymes!) that sirrr takes a sip!

2) some by soluble enzymes in cytosol

Question 5

What is the general concept for pharmacological consequences of drug metabolism?

Answer 5

Drug metabolism is a detoxifying process

Lipid-soluble compounds converted to water soluble to be readily excreted

Question 6

What is the most common pharmacological consequence of drug metabolism?

Answer 6

Metabolism:

Active drug –> inactive or less active compound

Question 7

What three other metabolic outcomes?

Answer 7

1) Active drug –> more active compound
2) Inactive compound (prodrug) –> active ingredient (designed)
3) Active drug –> toxic metabolite (rare.. e.g. acetaminophen)

Question 8

What is a Phase I reaction?

Answer 8

Inserts/unmasks a functional group that makes the compound more water-soluble

Compound is now ready to undergo a Phase II reaction

Question 9

What 3 types of reactions are involved in Phase I?

Answer 9

1) Oxidation (P-450 dependent or not)
2) Reduction (azo, nitro, carbonyl)
3) Hydrolysis

Question 10

Which enzymes are involved in Phase I?

Answer 10

1) CYP450 (includes NADPH, flavoprotein,O2)
2) Reductase
3) Esterases or amidases

Question 11

Do genetic polymorphisms affect Phase I?

Answer 11

YES!

Ex: CYP2D6/CYP2C19: Amplichip test available for detection

CYP2C9: Warfarin metabolizing enzyme

VKORC1: Warfarin target enzyme (vit K reductase)

Question 12

General development patterns of activity with respect to age in Phase I?

Answer 12

YES.

Decreases with age in 1/3 of patients

Question 13

Can Phase I reactions be inhibited or induced?

Answer 13

Yes and yes

Significant!

Question 14

Relative ease of saturability at high drug substrate levels in Phase I? (think of the enzymes involved)

Answer 14

Minimal

Question 15

What is a Phase II reaction?

Answer 15

when an endogenous substrate combines with a pre-existing/metabolically inserted functional group

—> then forms a highly polar (water soluble) conjugate that is excreted via urine

Question 16

What general type of reaction is involved in Phase II? What are the 4 subsets?

Answer 16

Conjugation reaction

1) Glucuronidation
2) N-acetylation
3) Glutathione conjugation
4) Sulfate conjugation

Question 17

Which enzymes are involved in Phase II?

Answer 17

Transferases!

E.g. UDP glucuronyl transferase, N-acetyltransferase

Question 18

Do genetic polymorphisms affect Phase II reactions?

Answer 18

Yes (fewer than Phase I)

Question 19

General development patterns of activity with respect to age in Phase II?

Answer 19

Variable but less than Phase II

Question 20

Can Phase II reactions be inhibited or induced?

Answer 20

It’s possible, but less so than Phase I1

Question 21

Relative ease of saturability at high drug substrate levels in Phase II? (think of the enzymes involved)

Answer 21

Substantial: limited supply of reactants especially UDP glucuronyl transferase

More easily saturable than Phase I

Question 22

What is induction?

Answer 22

Increased drug metabolizing activity (increased clearance) via stimulation of CYP450 system

Requires 48-72 hours to see effect (slow compared to inhibition)

Question 23

What are the therapeutic consequences of induction?

Answer 23

Maximal effects in 7-10 days

Induction by 1 agent may increase clearance of another drug –> reduced therapeutic effect (increased elimination) or increased toxicity (toxic metabolite)

Question 24

What is inhibition?

Answer 24

Decrease clearance of drug by preventing drug metabolism

Phase I enzymes are more prone than Phase II

Question 25

What are the mechanisms of inhibition?

Answer 25

1) can inhibit enzyme synthesis
2) inhibitor acts as a substrate competing for an enzyme
3) inhibitor can also inhibit w/o being a substrate

Question 26

What are the therapeutic consequences of inhibition?

Answer 26

Metabolic inhibition can occur when sufficient hepatic concentration is reached (w/in hours)

Inhibition can decrease clearance of an inhibited drug —> increased toxicity

Question 27

Examples of inducers

Answer 27

1) Cigarette/weed smoke
2) Air pollutants
3) Industrial chemicals
4) Ethanol
5) Rifampin
6) DDT

Question 28

Examples of inhibitors

Answer 28

1) Erythromycin
2) Grapefruit juice
3) SSRIs

Question 29

Describe the general characteristics of kidney excretion

Answer 29

Loss of chemically unchanged drug from body –> kidneys are most important for excretion especially for water-soluble and non-volatile compounds

Question 30

What is kidney filtration with respect to drug excretion?

Answer 30

Think glomeruli! 120mL/min; all drugs smaller than albumin will be filtered (MW: 69K)

Only free drug filtered (not protein bound)

Drugs cleared this route have half life of 1-4 hours (high protein binding can extend this though)

Question 31

What is kidney secretion with respect to drug excretion?

Answer 31

Active tubule secretion: drugs transported from blood to urine (120-600ml/min)

Occurs with drugs that are stronger acids and bases in prox tubule

Reversible protein-binding does NOT greatly affect secretion rate

Question 32

What is tubular reabsorption with respect to drug excretion?

Answer 32

Two types: passive and active

Question 33

What is passive reabsorption?

Answer 33

Occurs with lipid soluble molecules in the proximal and distal tubules

As water is reabsorbed, lumen to blood back-diffusion is favored because drug is concentrated in luminal fluid

Question 34

What is active reabsorption?

Answer 34

Important for endogenous compounds (e.g. glucose and AAs)

Most drugs reduce this active transport

Question 35

How does pH affect diffusion during reabsorption?

Answer 35

Diffusion of weak acid/base depend on urine pH

Compound will become ionized or not depending on pH (remember charged molecules can’t diffuse)

Question 36

What is enterohepatic recycling?

Answer 36

Drug metabolizes in liver and secreted into bile —> stored in gallbladder —> delivered to intestine via bile duct —> hydrolyzed by bacterial enzymes back to parent drug (more lipid soluble) —> reabsorbed from gut

Question 37

What are the therapeutic consequences of enterohepatic recirculation of drugs?

Answer 37

1) reduces elimination of drug —> prolongs t1/2 and duration of action in body
2) some drugs have reservoir of recirculating drug –> accounts for 20% of total drug present
3) Antibiotics reducing gut flora can decrease enterohypatic recycling and plasma drug levels … think drug-drug interaction

Question 38

Describe the factors influencing drug passage from plasma to breast milk

Answer 38

Most drugs do cross (unchanged) into breast milk but at LOW levels —> infant plasma levels are lower than therapeutic levels

Question 39

How do you prevent infant exposure from drug passage in breast milk?

Answer 39

Desynchronize breastfeeding and peak milk/[drug]

1) breastfeed at end of dosing interval/administer drug after nursing
2) administer dose prior to infant’s longest sleep time
3) fat (and thus drug) content of milk: increases during feeding time

Question 40

How do you choose which medications for a breatfeeding mother?

Answer 40

1) select drugs with little-no passage to milk
2) drugs with rapid clearance
3) lipid soluble compounds = increased milk concentration
4) high protein binding = decreased milk concentration

Question 41

Other factors to remember about breast milk and drug selection

Answer 41

1) Milk is MORE acidic than plasma (5.6 vs 7.4) —> accumulates basic compounds by ion trapping
2) Never use drugs contraindicated by AAP
3) Some drugs affect milk production/secretion/ejection (think prolactin/oxytocin)