Metabolism and Excretion Flashcards
What is drug metabolism?
drugs undergo a chemical structure transformation through enzyme catalysis (after administration to pt)
Describe drug metabolizing enzymes
1) They have endogenous (already within human) substrates
2) They play a role in normal metabolism
Where does drug metabolism occur?
Primary site: Liver
Secondary: lungs (30%), intestines (6%), kidney (8%), skin (1%), placenta (5%)
Also bacteria have enzymes capable of this
By which pathways do these chemical transformations occur? – during drug metabolism
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
What is the general concept for pharmacological consequences of drug metabolism?
Drug metabolism is a detoxifying process
Lipid-soluble compounds converted to water soluble to be readily excreted
What is the most common pharmacological consequence of drug metabolism?
Metabolism:
Active drug –> inactive or less active compound
What three other metabolic outcomes?
1) Active drug –> more active compound
2) Inactive compound (prodrug) –> active ingredient (designed)
3) Active drug –> toxic metabolite (rare.. e.g. acetaminophen)
What is a Phase I reaction?
Inserts/unmasks a functional group that makes the compound more water-soluble
Compound is now ready to undergo a Phase II reaction
What 3 types of reactions are involved in Phase I?
1) Oxidation (P-450 dependent or not)
2) Reduction (azo, nitro, carbonyl)
3) Hydrolysis
Which enzymes are involved in Phase I?
1) CYP450 (includes NADPH, flavoprotein,O2)
2) Reductase
3) Esterases or amidases
Do genetic polymorphisms affect Phase I?
YES!
Ex: CYP2D6/CYP2C19: Amplichip test available for detection
CYP2C9: Warfarin metabolizing enzyme
VKORC1: Warfarin target enzyme (vit K reductase)
General development patterns of activity with respect to age in Phase I?
YES.
Decreases with age in 1/3 of patients
Can Phase I reactions be inhibited or induced?
Yes and yes
Significant!
Relative ease of saturability at high drug substrate levels in Phase I? (think of the enzymes involved)
Minimal
What is a Phase II reaction?
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
What general type of reaction is involved in Phase II? What are the 4 subsets?
Conjugation reaction
1) Glucuronidation
2) N-acetylation
3) Glutathione conjugation
4) Sulfate conjugation
Which enzymes are involved in Phase II?
Transferases!
E.g. UDP glucuronyl transferase, N-acetyltransferase
Do genetic polymorphisms affect Phase II reactions?
Yes (fewer than Phase I)
General development patterns of activity with respect to age in Phase II?
Variable but less than Phase II
Can Phase II reactions be inhibited or induced?
It’s possible, but less so than Phase I1
Relative ease of saturability at high drug substrate levels in Phase II? (think of the enzymes involved)
Substantial: limited supply of reactants especially UDP glucuronyl transferase
More easily saturable than Phase I
What is induction?
Increased drug metabolizing activity (increased clearance) via stimulation of CYP450 system
Requires 48-72 hours to see effect (slow compared to inhibition)
What are the therapeutic consequences of induction?
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)
What is inhibition?
Decrease clearance of drug by preventing drug metabolism
Phase I enzymes are more prone than Phase II
What are the mechanisms of inhibition?
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
What are the therapeutic consequences of inhibition?
Metabolic inhibition can occur when sufficient hepatic concentration is reached (w/in hours)
Inhibition can decrease clearance of an inhibited drug —> increased toxicity
Examples of inducers
1) Cigarette/weed smoke
2) Air pollutants
3) Industrial chemicals
4) Ethanol
5) Rifampin
6) DDT
Examples of inhibitors
1) Erythromycin
2) Grapefruit juice
3) SSRIs
Describe the general characteristics of kidney excretion
Loss of chemically unchanged drug from body –> kidneys are most important for excretion especially for water-soluble and non-volatile compounds
What is kidney filtration with respect to drug excretion?
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)
What is kidney secretion with respect to drug excretion?
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
What is tubular reabsorption with respect to drug excretion?
Two types: passive and active
What is passive reabsorption?
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
What is active reabsorption?
Important for endogenous compounds (e.g. glucose and AAs)
Most drugs reduce this active transport
How does pH affect diffusion during reabsorption?
Diffusion of weak acid/base depend on urine pH
Compound will become ionized or not depending on pH (remember charged molecules can’t diffuse)
What is enterohepatic recycling?
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
What are the therapeutic consequences of enterohepatic recirculation of drugs?
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
Describe the factors influencing drug passage from plasma to breast milk
Most drugs do cross (unchanged) into breast milk but at LOW levels —> infant plasma levels are lower than therapeutic levels
How do you prevent infant exposure from drug passage in breast milk?
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
How do you choose which medications for a breatfeeding mother?
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
Other factors to remember about breast milk and drug selection
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)
