145b - GI Absorption and Metabolism/Pharmacology Review Flashcards
How does the dosing recommendation for high extraction drugs change in patients with cirrhosis?
Reduce dose
- Decreased blood flow = reduced hepatic clearance
- More drug will be floating around for a longer time
(Changes in blood flow do not imapact low extraction drugs; however, hepatic function is also reduced so would need to monitor)
Which statement best explains how gastric bypass surgery (e.g., Roux-en-Y) might interfere with oral
absorption of drugs?
- A less acidic luminal pH may enhance absorption of drugs that are weak acids.
- Bypassing the proximal small intestine may reduce bioavailability for drugs with high first pass metabolism.
- Bypassing the proximal small intestine may enhance bioavailability for drugs that are substrates for p-glycoprotein.
- A more acid luminal pH may enhance absorption of drugs that are weak bases.
c.
Bypassing the proximal small intestine may enhance bioavailability for drugs that are substrates for p-glycoprotein.
After RYGB surgery, a patient reports increased sensitivity to alcohol.
Explain
Time to maximum plasma ethanol concentration is shorter after surgery
(Alcohol is abosrbed more efficiently in the small intestine; it gets here faster due to anatomical change of RYGB surgery)
Which statement best describes clearance of a specific drug in advanced cirrhosis?
- Elimination of digoxin in cirrhosis is enhanced by low hepatic blood flow.
- The bioavailability of oral morphine is enhanced
- Morphine clearance by the liver is impaired because of hypoalbuminemia.
- The bioavailability of oral morphine is lower in cirrhosis.
b. The bioavailability of oral morphine is enhanced
What factors impact the hepatic clearance of low extraction drugs? (2)
- Intrinsic hepatic metabolism
- Protein binding
Which statement explains why co-administration of nilotinib with irinotecan might be dangerous?
- Both drugs may independently suppress bone marrow hematopoiesis.
- Nilotinib induces UDP-glucouronosyltransferease-1 (UGT1A1) which is required for irinotecan activation.
- Nilotinib inhibits UDP-glucouronosyltransferease-1 (UGT1A1) which is required for Phase II metabolism and clearance of irinotecan active metabolites.
- Irinotecan inhibits UDP-glucouronosyltransferease-1 (UGT1A1) which is required for Phase II metabolism and clearance of nilotinib.
c
Nilotinib inhibits UDP-glucouronosyltransferease-1 (UGT1A1) which is required for Phase II metabolism and clearance of irinotecan active metabolites
Where in the GI tract is most ibuprofen absorbed?
Small intestine
- Ibuprofen is an acidic drug (so we would expect it to be absorbed in the stomach bc thats where we find most of the non-ionized form)
- BUT the small intestine has way larger surface area, so even though only 1% of the drug is in its non-ionized form at any given time, most of it is absorbed here ¯_(ツ)_/¯
How does the dosing recommendation for hydrophilic drugs change in patients with cirrhosis?
May need to increase loading dose
- Cirrhosis = increased volume of distribution for hydrophilic drugs
What is the difference between a high extraction and a low extraction drug?
-
High extraction
- The liver is efficient at taking the drug out of the bloodstream
- Extraction is limited by flow
-
Low extraction
- The liver is not efficient at taking the drug out of the bloodstream
- Extraction is limited by intrinsic hepatic clearance
What factor impacts the hepatic clearance of high extraction drugs?
Liver blood flow
(High extraction drug clearance is unaffected by changes in intrinsic hepatic meatbolism or protein binding)
List 3 examples of drugs that undergo extensive enterohepatic recycling
- Digoxin
- Morphine
- Estradiol (oral contraceptive drugs)
Define drug bioavailability
Fraction of an administered dose of unchanged drug that reaches the systemic circulation
If dealing with prodrugs, it’s the amount of active drug that reaches the systemic circulation
What happens in phase 1 and phase 2 of drug metabolism?
- Phase 1
- Inactivates standard drugs
- Activates prodrugs
- Phase 2
- Makes the drug more polar -> facilitates excretion
- Usually glucuronidation
- Makes the drug more polar -> facilitates excretion
Why would a history of episodic unconjugated hyperbilirubinemia be significant when prescribing chemotherapy drugs?
Episodic unconjugated hyperbilirubinemia may be due to Gilbert disease, which results from glucuronosyltransferase deficiency
This enzyme is needed for clearance of chemotherapy drugs
Deficiency -> risk of drug toxicity
What is the henderson-hasselbach equation
(lmao if we have to use this I will be HEATED)
How does increaed protein binding impact the effective concentration of a drug?
Increased protein binding lowers the effective concentration
Drug bound to protein is NOT active
Which of the following pain medications would be safe and effective for a patient with a cirrhotic liver who has an elevated INR and low albumin levels?
- NSAIDs
- Oral morphine
- Subcutaneous morphine
- Oral codeine
- IV fentanyl
c. Subcutaneous morphine
- NSAIDs would work, but risk of bleeding in pts with liver disease (esp if INR is already elevated)
- Oral morphine would work in theory (decreased 1st pass metabolism due to liver disease), but unpredictable
- Oral codeine would be ineffective; not converted to morphine due to liver disease
- IV fentanyl is probably safe, but risky side effect profile; really only used for anesthesia
B - Impaired oral absorption -> lower peak plasma concentration
Weak acids are better absorbed in the [stomach/intestine]
Weak bases are better absorbed in the [stomach/intestine]
Weak acids are better absorbed in the stomach
Weak bases are better absorbed in the intestine
C - Drugs absorbed mainly in the SI will achieve maximum plasma concentrations following an oral dose more rapidly after RYGB
Why?
- The drug will get to the small intestine more quickly due to removal of most of the stomach
- Note: peak plasma concentration may be lower due to decreased absorptive surface area
How doe cirrhosis affect drug metabolism?
- Decreased clearance of high extraction drugs
- Due to decreased blood flow
- Increased bioavailability for drugs with high first pass metabolism
- Decreased bioavailability for prodrugs
How does intestinal bypass surgery affect drug absorption? (5)
-
Decreased peak plasma concentration
- Due to loss of surface area
- Especially affects drugs that are not subject to first pass metabolism (alcohol)
-
Increased bioavailability (due to decreased first pass metabolism)
- Bypassing the proximal small intestine = decreased exposure to CYP3A4, efflux transporters
- Decreased bioavailability of ER formulations
-
Impaired abosrption of weakly acidic drugs, enhanced abosrption of weakly basic drugs
- Due to luminal pH changes
-
More rapid delivery to the jejunum
- Faster time to peak plasma concentration
