Module 5: Excretion Flashcards
Define drug excretion:
- List 4 organs that do so
Is the removal of parent drug and drug metabolites from the body
1) Kidney
2) Bile
3) Lung
4) Breast milk
What accounts for the majority of drug excretion?
The kidney
What is the function of the kidney in relation to drug excretion?
- What happens if function is impaired?
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.
Describe what happens to drug excretion in N-stage kidney disease:
- PT’s require dialysis
- Drug elimination is almost negligible
- Drug does therefore must be reduced
What is the basic structural and functional unit of the kidney?
The nephron
What does the nephron do?
1) Regulates water, electrolyte and drug excretion.
2) Controls blood volume, blood pressure, blood pH and solute (including drug) excretion
What are the three factors that affect renal drug excretion?
1) Glomerular Filtration
1) Tubular Secretion
2) Tubular Reabsorption
What occurs at the glomerulus during filtration?
- What does hydrostatic pressure do?
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
Glomerular filtration rate is…
~ 120 ml/min/1.73 m2 or about 20% of total renal plasma flow.
What affects glomerular filtration?
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
What occurs at tubular secretion?
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.
Drug secretion in the kidney primarily occurs by…
Two transport systems, one for weak acids and one for weak bases.
What occurs during tubular reabsorption?
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
What is the effect of age on renal function?
- Newborns
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
How does billiard drug excretion occur?
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.
What are characteristics of drugs eliminated in the bile?
1) larger molecular weight > 300 Da
2) have both polar and lipophilic groups (amphipathic molecules)
3) are glucuronidated.
In the bile, what is enterohepatic recycling?
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)
Drugs eliminated by pulmonary excretion are usually…
- Examples?
gaseous and/or highly volatile
- the best examples are general anesthetics
Is pulmonary drug excretion is not heavily reliant on drug metabolism?
No
What factors affect pulmonary drug excretion? (3)
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
Why is drug excretion important for mothers?
> 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
Drugs excreted in breast milk usually have:
1) Low protein binding
2) Low molecular weight
3) High lipophilicity
What is the drug transporter that transports drugs into breast milk?
The drug transporter breast cancer resistance protein (BCRP) transports drugs into breast milk.
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?
Consultation with a pediatrician is suggested to help guide dosing.
Breast milk has a high/lower pH and higher/lower lipid content than plasma?
Breast milk has a lower pH and higher lipid content than plasma.
What other routes (3) of drug excretion is there?
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.
