SM_145b: GI Absorption and Metabolism / Pharmacology Review

Question 1

____ is the main criterion for choosing the route of administration

Answer 1

Bioavailability is the main criterion for choosing the route of administration

Question 2

____, ____, and ____ are best routes for administration of drugs

Answer 2

Intravenous, intraosseous, and endotracheal are best routes for administration of drugs

Question 3

Most drugs in clinical use are ____ and ____

Answer 3

Most drugs in clinical use are weak acids and bases

• Exist in ionized and non-ionized forms
• Non-ionized form is more lipid soluble -> preferentially penetrates lipid membranes

Question 4

Proportion of ionized to non-ionized forms of a drug can be determinated by the ____

Answer 4

Proportion of ionized to non-ionized forms of a drug can be determinated by the Henderson-Hasselbach equation

pH = pKa + log ([conjugate base] / [acid])

Question 5

Most ibuprofen is in the ____ form in the stomach

Answer 5

Most ibuprofen is in the protonated form in the stomach

Question 6

pH differences across the gastric cell membrane lead to ____

Answer 6

pH differences across the gastric cell membrane lead to ion trapping

Question 7

Uncharged form of ibuprofen is near 100% in the ____ and 1% in the ____

Answer 7

Uncharged form of ibuprofen is near 100% in the stomach and 1% in the small intestine in the intestine

• Surface area of intestines is several thousand times larger than that of the stomach
• Large surface of the small intestines accounts for increased drug absorption
• Longer transit times: <1 hr in stomach and >3 hr in small intestine also contributes

Ibuprofen largely absorbed from intestine

Question 8

____ is the fraction of an administered dose of unchanged drug that reaches the systemic circulation

Answer 8

Bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation

• Metabolism in either the intestinal wall or liver before the drug can reach the systemic circulation reduces bioavailability

Question 9

First pass metabolism via CYPs occurs in the ____ and ____

Answer 9

First pass metabolism via CYPs occurs in the small intestine and liver

Question 10

Describe drugs with high bioavailability

Answer 10

Drugs with high bioavailability

• Acetaminophen
• Amoxicillin
• Codeine
• Diazepam
• Metronidazole
• Trimethoprim
• Warfarin

Question 11

Describe drugs with low bioavailability

Answer 11

Drugs with low bioavailability due to first pass metabolism

• Morphine
• Demerol
• Lidocaine
• Nitroglycerin
• Propranolol

Question 12

Phase I of drug metabolism requires ____, while phase II involves ____

Answer 12

Phase I of drug metabolism requires CYP450 enzymes, while phase II involves conjugation pathways

Question 13

Phase I metabolism most commonly involves ____, while phase II metabolism is most commonly ____

Answer 13

Phase I metabolism most commonly involves CYP3A4/5, while phase II metabolism is most commonly glucuronidation

Question 14

Morphine-3-glucuronide is ____, while morphine-6-glucuronide is ____

Answer 14

Morphine-3-glucuronide is inactive, while morphine-6-glucuronide is active

Question 15

Cl_h = ____ x ____

Answer 15

Cl_h = Q_h x E

Hepatic clearance = hepatic blood flow x extraction ratio

Question 16

E = ____ x (____ - ____)

Answer 16

E = Q_h x (C_in - C_out)

• E is extraction ratio
• Q_h is hepatic blood flow
• C_in is concentration of drug in portal vein
• C_out is concentration of drug in hepatic vein

Question 17

High extraction drugs (E > 0.7) are ____

Answer 17

High extraction drugs (E > 0.7) are flow limited

Question 18

Low extraction drugs (E < 0.03) are ____

Answer 18

Low extraction drugs (E < 0.03) are limited by intrinsic hepatic clearance and fraction of free drug (unbound to protein)

Question 19

Protein binding to drugs ____ and ____

Answer 19

Protein binding to drugs lowers the effective concentration and slows the distribution to extravascular sites

• Greater binding: less available free active drug, longer half-life because less metabolized and eliminated

Question 20

Describe parameters of drugs by extraction

Answer 20

Parameters of drugs by extraction

Question 21

Cirrhosis ____ drug metabolism and ____ volume of distribution for hydrophilic drugs

Answer 21

Cirrhosis decreases drug metabolism and increases volume of distribution for hydrophilic drugs

• Decreased drug metabolism: decreased clearance for drugs with high extraction ratios, increased bioavailability for drugs with high first-pass metabolism

Question 22

____ bioavailability is higher and half-life is longer in advanced cirrhosis

Answer 22

Morphine bioavailability is higher and half-life is longer in advanced cirrhosis

• Lower dose and longer inter-dose interval are recommended
• Avoid combining with other sedatives

Question 23

Describe biliary drug excretion

Answer 23

Biliary drug excretion

• Transfer of drug or metabolites from plasma to the bile through the hepatocytes
• Drugs handled by biliary excretion are eliminated in feces
• Drugs may be excreted into bile either in native form or after metabolism into more polar conjugates
• Bile is released in the gut lumen, from which the native drug can be reabsorbed (enterohepatic cycle)
• Conjugated drug can be liberated by intestinal bacteria and also reabsorbed

Question 24

Drugs travel from the ____ to the ____, undergo metabolism, and then enter ____ pockets

Answer 24

Drugs travel from the portal vein to the hepatocytes, undergo metabolism, and then enter bile pockets

Question 25

In the enterohepatic cycle, drugs ____ in the liver to form ____ are secreted into the ____

Answer 25

In the enterohepatic cycle, drugs conjugated in the liver to form glucuronides are secreted into the bile

• Can be cleaved by bacterial B-glucuronidases in the colon to liberate the drug molecule, which is then reabsorbed
• Create a reservoir of 20% of total drug in the body -> can prolong drug half-life
• Examples of recycled drugs: digoxin, morphine, estradiol

Question 26

Antibiotic treatment can impair recycling of and reduce plasma levels of ____

Answer 26

Antibiotic treatment can impair recycling of and reduce plasma levels of oral contraceptives

Question 27

Gilbert syndrome is a common genetic disorder of bilirubin conjugation resulting in ____ and ____

Answer 27

Gilbert syndrome is a common genetic disorder of bilirubin conjugation resulting in unconjugated hyperbilirubinemia and episodic jaundice

• Autosomal recessive
• Mutations in glucuronosyltransferase (UGT1A1)
• 80% reduced enzyme activity
• More severe allelic disorder: Crigler-Najjar syndrome

Question 28

Irinotecan is a ____ that is activated by ____

Answer 28

Irinotecan is a pro-drug that is activated by carboxyesterases

• SN-38 is a cytotoxic topoisomerase I inhibitor
• SN-38 is responsible for dose-limiting toxicity