Drug Excretion

Question 1

Name three main routes through which drugs leave the body.

Answer 1

Kidney, Lungs, Hepatobiliary system

Question 2

Name “other” routes of drug excretion.

Answer 2

sweat, breast milk, tears, genital secretions, saliva

Question 3

What types of substances are more easily eliminated?

Answer 3

polar substances

Question 4

What happens to soluble drugs on the excretory pathway?

Answer 4

They are metabolised into more polar compounds.

Question 5

Pulmonary excretion is important in the elimination of ____________ (2).

Answer 5

general anesthetics, alcohol

Question 6

Name the components of renal excretion.

Answer 6

(1) glomerular filtration
(2) active tubular secretion
(3) passive tubular reabsorption

Question 7

Briefly discuss some factors that influence the amount of drug in the renal tubular lumen.

Answer 7

(1) Glomerular filtration rate: the rate at which the glomeruli filter blood determines how much drug enters the tubular fluid.
(2) Plasma protein binding: drugs bound to plasma proteins are not filtered by the glomerulus, only the unbound drug passes into the filtrate for excretion.
(3) Active tubular secretion: active carrier mediated tubular secretion may also add drugs to the tubular fluid in the proximal renal tubule.
(4) Conjugated metabolite secretion: conjugated metabolites are secreted by transporters such as p-glycoprotein (P-gp) and multidrug resistance-associated protein type 2 (MRP2) localised in the apical brush-border membrane.

Further notes:
MRPs such as MRP2 and MRP4, are located on the apical side of the tubular cells and are involved in the efflux of drugs and metabolites into the tubular lumen.

Question 8

How else do drugs enter the tubular fluid apart from glomerular filtration?

Answer 8

active carrier-mediated tubular secretion

Question 9

Which transporters are involved in the secretion of conjugated drug metabolites?

Answer 9

💊 P-glycoprotein
💊 MRP2 [multidrug resistance-associated protein 2]

Question 10

Where in the renal tubules does active tubular secretion occur?

Answer 10

proximal convoluted tubules

Question 11

Give some examples of drugs that are actively secreted in the renal tubules.

Answer 11

(1) penicillin [an antibiotic]
(2) methotrexate [a chemotherapy agent and immune system suppressant]
(3) furosemide [a loop diuretic used to treat fluid retention and swelling]
(4) probenecid [used to treat gout]

Question 12

What are OATs and OCTs in relation to drug excretion in the renal tubules?

Answer 12

(1) Organic Anion Transporters (OATs): These transporters, such as OAT1 and OAT3, are located on the basolateral side of the tubular cells. They help in the uptake of organic anions from the blood into the cells.

(2) Organic Cation Transporters (OCTs): OCT2 is a major transporter on the basolateral side that facilitates the uptake of organic cations.

[Diagram 1] [Diagram 2]

Further notes:
💊 There is another group of transporters known as Multidrug and Toxic Compound Extrusion (MATE) Proteins … MATE1 and MATE2-K are located on the apical side and work in conjunction with OCTs to excrete organic cations into the urine.
💊 Breast Cancer Resistance Protein (BCRP): This transporter is also found on the apical side and helps in the efflux of various drugs and xenobiotics.

Question 13

Comment on passive tubular reabsorption in regards to lipophilic and ionized drugs.

Answer 13

💊 Lipophilic drugs can be reabsorbed back into blood circulation and excretion in urine will be low.
💊 Ionized drugs are poorly reabsorbed so urinary excretion will be high.

Question 14

Define clearance.

Answer 14

This refers to the volume of plasma cleared of a drug per unit time.

Question 15

What is the formula for clearance?

Answer 15

[Answer]

Question 16

Explain alkalinization of urine in the treatment of drug overdoses involving weakly acidic drugs like aspirin.

Answer 16

💊 Alkalinization of urine is a medical procedure used to increase the pH of urine, making it more alkaline.
💊 Sodium bicarbonate is typically administered intravenously.
💊 By increasing the pH of the urine, weakly acidic drugs become more ionized. Ionized drugs are less likely to be reabsorbed in the renal tubules and are more readily excreted in the urine. This process enhances the elimination of the drug from the body.

Question 17

Explain acidification of urine in the treatment of overdose with weakly basic drugs.

Answer 17

💊 Ammonium chloride is commonly used to acidify the urine. When administered, it dissociates into ammonium and chloride ions.
💊 The ammonium ion is metabolized in the liver, releasing hydrogen ions, which increase the acidity of the blood and urine.
💊 In an acidic environment, weakly basic drugs become more ionized. Ionized drugs are less likely to be reabsorbed in the renal tubules and are more readily excreted in the urine.

Question 18

What are some physiological changes in the kidneys that occur as people age [and which affect drug excretion]?

Answer 18

(1) Decreased tubular secretion
Tubular secretion is the process by which substances are actively transported from the blood into the renal tubules. In older adults, the efficiency of this process declines due to a reduction in the number and function of renal tubular cells. As a result, drugs and their metabolites are not secreted into the urine as effectively, leading to prolonged drug action and increased risk of toxicity.

(2) Decreased glomerular filtration rate (GFR)
GFR naturally declines with age, typically by about 1mL/min per year after the age of 40.
A lower GFR means that the kidneys are less efficient at clearing drugs from the bloodstream.

Further notes:
Due to the above described changes, higher drug concentrations can lead to increased pharmacological effects and a higher risk of adverse reactions. Therefore, older adults often require lower doses of renally excreted drugs to avoid toxicity.

Question 19

Briefly explain billiary excretion of drugs.

Answer 19

Certain drugs are secreted from the liver into bile by active transporters, then into the duodenum, and hence are passed out with faeces.

Question 20

(a) What is enterohepatic circulation?
(b) Briefly discuss the process and its significance.

Answer 20

(a) Enterohepatic circulation is a process where certain substances, including drugs and their metabolites, are recycled between the liver and the intestines.

(b) Process:
(1) After being metabolized in the liver, drugs or their metabolites are secreted into the bile.
(2) The bile, containing these substances, is released into the small intestine during digestion.
(3) Some of these substances are reabsorbed from the intestine back into the bloodstream.
(4) The reabsorbed substances are transported back to the liver via the portal vein, where they can be secreted into the bile again.

Significance: Enterohepatic circulation can extend the duration of action of certain drugs by repeatedly recycling them through the liver and intestines, thus leading to sustained therapeutic effects or, in some cases, toxicity.

Question 21

Define plasma half-life.

Answer 21

This is the time required for the concentration of a drug in plasma to fall by 1/2 the initial concentration.

Question 22

What factors increase plasma half-life?

Answer 22

(1) Enterohepatic cycling
(2) Decreased metabolism due to liver disease
(3) Decreased clearance due to renal disease or congestive heart failure
(4) High plasma protein binding

Question 23

Define steady state.

Answer 23

This refers to a dynamic equilibrium in which the concentration of a drug in the bloodstream stays constant as a result of its rate of administration being equal to its rate of elimination.

Question 24

Define loading dose.

Answer 24

This is the amount of initial dose of a certain drug required to reach a specific plasma concentration.

Question 25

Define maintenance dose.

Answer 25

Maintenance dose is the dose of a drug that maintains or keeps the drug concentration within the therapeutic range after achieving the desired level with a loading dose [dose required to achieve steady state].