Renal Handling of Drugs

Question 1

What is renal excretion of a drug?

Answer 1

the neat result of glomerular filtration, active tubular secretion and tubular reabsorption

• Few drugs may undergo renal metabolism
  (e. g. insulin).

Question 2

What 2 important factors govern the filtration process from the blood into the Bowman’s capsule?

Answer 2

1. Molecular size e.g. heparin
2. Plasma-protein binding
   
   • results in poor excretion

Question 3

Function of drug filtration?

Answer 3

Can determine mechanism of elimination of some drugs

e.g. aminoglycosides, vancomycin, fluconazole, flucytosine

Question 4

How do majority of drugs enter the kidney tubule?

Answer 4

tubule secretion

Question 5

Describe tubule secretion of drugs and how therapeutic effects of drugs can be prolonged ?

Answer 5

1. Drugs are carried against a favourable chemical gradient from the capillary network into the tubule
   - active process
2. Prolonging therapeutic effect, agents can be administered that block tubule secretion to slow the excretion of the drug
   use of probenecid

Question 6

Describe the 2 carrier systems of tubule drug secretion?

Answer 6

1. basic carriers which transport basic drugs
   e. g. amiloride, dopamine, histamine
2. acidic carriers for acidic drugs
   e. g. frusemide, penicillin, indomethacin

Question 7

Inhibition of drug tubular secretion may?

Answer 7

1. Reduce drug renal clearance
2. Prolong drug-half life
   
   • might cause undesired accumulation
3. Allow spacing of the doses

Question 8

What is resorption?

Answer 8

is referred to as passive diffusion since the process does not require energy
- This flow occurs because water is resorbed from the kidney tubules by diffusion
- majority of water that initially enters the
nephron is resorbed back into the blood as a means of conserving body fluid
- as this movement occurs, some drugs are transported along with it

Question 9

What is drug clearance?

Answer 9

The rate of elimination of substances from the blood

- its a function of time

Question 10

Drug clearance depends on what properties?

Answer 10

1. blood flow
2. molecule plasma concentration
3. glomerular filtration
4. tubular secretion
5. tubular reabsorption

Question 11

What is the function of drug clearance rates?

Answer 11

helps in determining the right dosage
- some have a high clearance, they are
eliminated from the blood rapidly by the
kidneys, such as the diuretic frusemide
- Others have a low clearance due to
inefficient excretion-low maintenance doses required

Question 12

What causes a decrease in renal drug clearance?

Answer 12

1. Impairment of renal function, due to disease
2. competition between drugs or endogenous substances for the tubular secretion transporter sites (renal drug interactions)

Question 13

What is renal excretion?

Answer 13

Irreversible transfer of drug or drug metabolites from the plasma into the urine

Question 14

Factors that influence renal excretion include?

Answer 14

1. plasma drug concentration,
2. plasma protein binding
3. renal function

Question 15

What can increase renal excretion of drugs?

Answer 15

an increase of urine flow diminishes the time available for tubular reabsorption and therefore, can increase renal excretion of drugs

Question 16

Which nephron function accounts for most drug excretion?

Answer 16

Renal filtration

Question 17

Which substances are reabsorbed?

Answer 17

Water and most electrolytes are passively and actively reabsorbed from the renal tubules back into the circulation

Question 18

Which substances can not be reabsorbed?

Answer 18

Polar compounds, such as drug metabolites, cannot diffuse back into the circulation and are excreted unless a specific transport mechanism exists for their reabsorption
eg, as for glucose, ascorbic acid, and B vitamins

Question 19

What happens to renal drug excretion with age?

Answer 19

decreases

- at age of 80, clearance is typically reduced to half of what it was at age of 30

Question 20

Describe the principles that govern the renal handling of drugs?

Answer 20

principles of transmembrane passage
1. Drugs bound to plasma proteins remain in the circulation
- only unbound drug is contained in the
glomerular filtrate
2. Un-ionized forms of drugs and their
metabolites tend to be reabsorbed readily from tubular fluids

Question 21

Drugs are transferred from the plasma into the urine by?

Answer 21

1. Glomerular filtration

2. Active tubular secretion - predominant in the proximal tubule

Question 22

Describe how glomerular filtration transfers drugs from plasma to urine?

Answer 22

Unbound drug molecules of less than 20’000 Da are filtered through the glomerulus with the primary urine.

Question 23

Describe how active tubular secretion transfers drugs from plasma to urine?

Answer 23

Several transportors are responsible
1. the P-glycoproteins (PGps)
2. the multidrug resistance-associated proteins (MRPs)
3. the organic anion transporters (OATs)
4. the organic cation transporters (OCTs), etc.
- These transporters are not highly specific and
may become saturated at high drug concentrations

Question 24

Following intoxication what can used to increase the renal excretion of certain drugs and toxins?

Answer 24

1. forced diuresis

2. urine pH control

Question 25

What is the relationship between urine pH and drug excretion?

Answer 25

Urine pH has a great influence on drug excretion

1. quickly or slowly
2. in some clinical situations it is manipulated to control the excretion of certain drugs from the body

Question 26

Describe how urine pH affects drug excretion?

Answer 26

Most drugs are either weak acids or weak bases
1. In alkaline urine, acidic drugs are more
readily ionised and in acidic urine, alkaline
drugs are more readily ionised
2. Ionised substances are more soluble in
water so dissolve in the body fluids and
more readily for excreted

Question 27

Describe the use of urine pH control in drug poisoning?

Answer 27

altering urine pH to increase excretion
acidification and alkalinisation
e.g. In aspirin poisoning/overdosage
- making the urine more alkaline with
sodium bicarbonate increases ionisation
of the salicylic acid (aspirin metabolite)
and increases excretion from the body

Question 28

What happens when there is a difference in pH between two compartments separated by a membrane?

Answer 28

weak acids will accumulate in a basic compartment and weak bases will accumulate in an acidic compartment

Question 29

What is ion trapping?

Answer 29

Drugs in an unionised form diffuse across cellular membranes

• drug excretion via different systems
• acidic vs basic

Question 30

What is the difference between renal clearance and renal excretion?

Answer 30

renal clearance - reflects the excretion of drug into the urine by the kidneys
renal excretion - the neat result of glomerular filtration, active tubular secretion and tubular reabsorption

Question 31

Describe the drug interactions at the level of tubular secretion?

Question 32

What problems arise from reduced renal function?

Answer 32

1. Reduced renal excretion of a drug or its metabolites may cause toxicity
2. Sensitivity to some drugs is increased even if elimination is unimpaired
3. Many side effects are tolerated poorly by patients with renal impairment
4. Some drugs are not effective when renal function is reduced
   - dose reduction or the use of alternative drug

Question 33

What problems arise from renal impairment?

Answer 33

1. Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g. absorption, drug distribution, non-renal clearance [metabolism])
2. Drug dosing errors are common in patients with renal impairment and can cause adverse effects and poor outcomes
   - Dosages of drugs cleared renally should be adjusted according to creatinine clearance and eGFR