Module 5: Excretion

Question 1

Define drug excretion:

- List 4 organs that do so

Answer 1

Is the removal of parent drug and drug metabolites from the body

1) Kidney
2) Bile
3) Lung
4) Breast milk

Question 2

What accounts for the majority of drug excretion?

Answer 2

The kidney

Question 3

What is the function of the kidney in relation to drug excretion?
- What happens if function is impaired?

Answer 3

Healthy kidneys serve to limit the duration and intensity of drug effects.
- Decreased kidney function prolongs the duration of action and intensity of drug effects.

Question 4

Describe what happens to drug excretion in N-stage kidney disease:

Answer 4

• PT’s require dialysis
• Drug elimination is almost negligible
• Drug does therefore must be reduced

Question 5

What is the basic structural and functional unit of the kidney?

Answer 5

The nephron

Question 6

What does the nephron do?

Answer 6

1) Regulates water, electrolyte and drug excretion.

2) Controls blood volume, blood pressure, blood pH and solute (including drug) excretion

Question 7

What are the three factors that affect renal drug excretion?

Answer 7

1) Glomerular Filtration
1) Tubular Secretion
2) Tubular Reabsorption

Question 8

What occurs at the glomerulus during filtration?

- What does hydrostatic pressure do?

Answer 8

Drugs enter the kidney from the renal artery in afferent arterial
- Hydrostatic pressure within glomerular capillaries forces low molecular weight drugs into the renal tubules

Question 9

Glomerular filtration rate is…

Answer 9

~ 120 ml/min/1.73 m2 or about 20% of total renal plasma flow.

Question 10

What affects glomerular filtration?

Answer 10

SIZE

• Only non-protein bound (i.e. free) drugs are filtered at the glomerulus
• Lipid solubility and pH do not affect glomerular filtration of drugs

Question 11

What occurs at tubular secretion?

Answer 11

Drugs not filtered by the glomerulus leave the glomerulus by the efferent arteriole.

• The efferent arterioles divide to form capillaries that surround the proximal tubule.
• Drugs can be secreted from the blood surrounding the tubules into the lumen of the proximal tubule
• Secretion is a rapid capacity process.

Question 12

Drug secretion in the kidney primarily occurs by…

Answer 12

Two transport systems, one for weak acids and one for weak bases.

Question 13

What occurs during tubular reabsorption?

Answer 13

As drugs move toward the distal tubule, their concentration increases.

• This is primarily due to the actions of the loop of henle which functions to concentrate tubular solutes.
• Once in the distal tubule the drug concentration often exceeds the concentration in the blood that immediately surrounds the distal tubule.
• If the drug is uncharged or lipid soluble, it’s able to leave the tubule and be reabsorbed back into the blood

Question 14

What is the effect of age on renal function?

- Newborns

Answer 14

Newborns

• Kidney function is low, meaning filtration rate is low
• Drugs excreted slowly
• 40mL/min/1.73m^2
• By 2y, reaches that of a health adult

Adults
- 120mL/min/1.73m^2

Overall

• As we age, renal function decreases
• If renal function is decreased, renal drug excretion is decreased

Question 15

How does billiard drug excretion occur?

Answer 15

Transporters on the canalicular membrane of hepatocytes transport drugs and metabolites from the liver into the bile.

1) P-glycoprotein transports a variety of amphipathic drugs into bile; and
2) MRP2 transports glucuronidated metabolites into bile.

Drugs released into the bile are ultimately released into the intestine during digestive processes.
- Drugs released into the intestine may be excreted into the feces or undergo enterohepatic recycling.

Question 16

What are characteristics of drugs eliminated in the bile?

Answer 16

1) larger molecular weight > 300 Da
2) have both polar and lipophilic groups (amphipathic molecules)
3) are glucuronidated.

Question 17

In the bile, what is enterohepatic recycling?

Answer 17

Drugs and drug conjugates excreted in the bile enter the intestinal lumen and stored in the gallbladder, and released back into the intestine

• Intestinal bacteria can cleave conjugate metabolites leaving the original drug
• The original drug may be reabsorbed in the intestine to re-enter the body (i.e. enterohepatic recycling)

Question 18

Drugs eliminated by pulmonary excretion are usually…

- Examples?

Answer 18

gaseous and/or highly volatile

- the best examples are general anesthetics

Question 19

Is pulmonary drug excretion is not heavily reliant on drug metabolism?

Answer 19

No

Question 20

What factors affect pulmonary drug excretion? (3)

Answer 20

1) Rate of Respiration
2) Cardiac Output
3) Solubility of Drug in blood:
- High drug blood solubility à low pulmonary excretion
- Low blood drug solubility à high pulmonary excretion

Question 21

Why is drug excretion important for mothers?

Answer 21

> 90% of women take at least one drug in the first week post-partum.
- Drug excretion in breast milk is important because breast-fed infants may be inadvertently exposed to drugs

Question 22

Drugs excreted in breast milk usually have:

Answer 22

1) Low protein binding
2) Low molecular weight
3) High lipophilicity

Question 23

What is the drug transporter that transports drugs into breast milk?

Answer 23

The drug transporter breast cancer resistance protein (BCRP) transports drugs into breast milk.

Question 24

It is important to note that while drug exposure via breast milk is an important concern, only relatively few drugs pose a clinically relevant risk to infants
- Who should mothers consult?

Answer 24

Consultation with a pediatrician is suggested to help guide dosing.

Question 25

Breast milk has a high/lower pH and higher/lower lipid content than plasma?

Answer 25

Breast milk has a lower pH and higher lipid content than plasma.

Question 26

What other routes (3) of drug excretion is there?

Answer 26

1) Hair – Drugs may be excreted into hair follicles.
- Drugs can be measured in hair to determine how long a person has been exposed.
- This is especially useful in forensics; Hair grows ~ 1 cm/month.

2) Saliva – drug excreted in saliva is usually swallowed and then subject to either intestinal absorption or fecal excretion.
3) Sweat – Drugs excreted in sweat are mostly washed away although a minor amount of dermal reabsorption may occur.