145. GI Drug Absorption, Metabolism, Pharm Review

Question 1

How does pH dependence affect ibuprofen absorption?

Answer 1

most drugs weak acids or bases with ionized/non-ionized forms
Weak acid: protonated = nonionized
Weak base: nonprotonated = nonionized
Nonionized = more lipid soluble = better absorbed

ibuprofen: pKa between stomach acid and small intestine
in acidic enviro (stomach), more protonated = more absorbed
in alkaline enviro (intestine), less protonated = WAY MORE ABSORBED DUE TO WAY HIGHER SURFACE AREA

Question 2

What is bioavailability?
What is included in first pass metabolism?
What drugs have low bioavailability? high F?

Answer 2

F: fraction of administered dose of active/unchanged drug that reaches systemic circulation
1st PM: metabolism by CYPs in intestine wall and liver, and efflux by intestinal epithelium (pgp)

Low F Drugs: morphine, lidocaine, nitroglycerin, propranolol (wide therapeutic window)
High F Drugs: acetaminophen, amoxicillin, codeine (morphine prodrug)

Question 3

What are the effects of RYGB on drug metabolism?

Answer 3

Lower absorptive surface area
Lower first pass metabolism
Faster time to delivery to jejunum

Question 4

How is morphine metabolized?

Answer 4

Glucuronidated
90% inactivated by glucuronidation
10% becomes more potent/activated by glucuronidation

Question 5

What is the equation for hepatic clearance?

Example of high and low extraction drugs?

Answer 5

Cl = Qh x E
E = (Cin - Cout)/Cin (Cin: PV drug, Cout: HV drug)

High Extraction (E>0.7): flow-limited (ex: MORPHINE)
Low Extraction (E<0.03): intrinsically limited by liver clearance and fraction of free drug (Diazepam)

Question 6

What are the effects of cirrhosis on drug metabolism and volume of distribution? How should certain classes of drugs be adjusted?

How is morphine affected by liver?

Answer 6

Decreased metabolic fx = less drug clearance with high extraction ratio, more bioavailability for drugs with high first-pass metabolism
Higher volume of distribution for hydrophilic drugs (ascites)

Dose Adjustment:
High Extraction Ratio: reduce dose (less clearance)
Low Extraction/High Protein Binding: monitor free drug conc. (due to hypoalbuminemia - risk toxic levels)
Hydrophilic drugs: may increase dose (ascites more volume)

Morphine: cirrhosis causes greater bioavailability and greater half-life (low F, high extraction drug)

Question 7

What drugs are in enterohepatic cycle?
What happens with ABx and estradiol use?

What is Gilbert Syndrome?

Answer 7

EH Cycle: drugs biliary excreted - unconjugated by GI lumen - reabsorbed - back to liver
Creates reservoir of 20% total drug in body - can prolong half-life
Ex: Digoxin, Morphine, Estradiol

Abx: less bacteria = impaired recycling = Reduce plasma levels (decrease effectiveness of Birth control!!)

Gilbert Syndrome: mutation in UGT1A1 can’t glucuronidate!!! causing hyperbilirubinemia, episodic jaundice, toxic levels of active metabolites!