WEEK 1: Drugs and the kidney

Question 1

Describe THE ROLE OF THE KIDNEY IN DRUG
HANDLING

Answer 1

1. Free drug enters the glomerular filtrate
2. There is active secretion of the drug in the proximal convoluted tubule
3. There is passive reabsorption of lipid soluble and unionized drug in the distal tubule and the collecting duct.
4. The lipid insoluble and ionized drug is then excreted in urine.

Question 2

What is glomerular filtration of drug?

What is the normal GFR in a standard patient?

Answer 2

Blood in the afferent arteriole contains both the bound and unbound form of the drug.

The unbound form of the drug can flow from the glomerulus into the Bowman’s capsule.

 Normally proteins do not appear in urine

 Normal glomerular filtration rate is
about 100ml/minute (standard
patient)

Question 3

Name a drug that inhibits the excretion of penicillin.

Name a drug that inhibits the excretion of metformin.

Answer 3

Probenecid inhibits the excretion of penicillin. Cimetidine inhibits the excretion of metformin.

Question 4

Most of the drugs exist as weak acids or weak bases  They dissociate in solution to give ionized and non-ionized forms  The ionized form is trapped in the filtrate and excreted in urine.  Weak acids are excreted more in alkaline urine.

What can be used to alkalinize urine to enhance excretion of acidic drugs such as aspirin?

What can be used to acidify urine?

Answer 4

Urine is alkalinized with sodium bicarbonate to enhance excretion of acidic drugs such as aspirin.

Ammonium chloride, vitamin C NSAIDS,methionine and Uracil.

Question 5

Describe how the drugs listed can result in the matched problems.

Glomerular filtration rate alteration (NSAIDS)
Crystal nephropathy (Acyclovir)
Tubular cell toxicity (Aminoglycosides)
Interstitial nephritis (Antibiotics and NSAIDS)

Answer 5

1. Glomerular Filtration Rate (GFR) Alteration (NSAIDs - Nonsteroidal Anti-Inflammatory Drugs):

Mechanism: NSAIDs work by inhibiting enzymes called cyclooxygenases (COX-1 and COX-2), which are involved in the synthesis of prostaglandins. Prostaglandins play a role in regulating blood flow to the kidneys by dilating blood vessels in the glomerulus.

Effect: Inhibition of prostaglandin synthesis can lead to constriction of the blood vessels in the kidneys, reducing renal blood flow and potentially causing a decrease in GFR. This effect is particularly significant in individuals with pre-existing conditions like chronic kidney disease or volume depletion.

2.Crystal Nephropathy (Acyclovir):

Mechanism: Acyclovir is an antiviral medication used to treat herpes virus infections. In some cases, especially when high doses are administered rapidly, acyclovir can crystallize in the renal tubules.

Effect: Crystallization of acyclovir in the renal tubules can lead to crystal nephropathy, causing obstruction and damage to the tubular cells. This can result in acute kidney injury, and it is more likely to occur in individuals with dehydration or impaired renal function.

Tubular Cell Toxicity (Aminoglycosides):

Mechanism: Aminoglycosides, such as gentamicin and amikacin, are antibiotics that are effective against a wide range of bacteria. They are taken up by renal tubular cells, where they can exert toxic effects.

Effect: Aminoglycosides can cause direct toxicity to renal tubular cells, leading to acute tubular necrosis. This damage can result in impaired tubular function, reduced urine concentration ability, and, in severe cases, acute kidney injury.

Interstitial Nephritis (Antibiotics and NSAIDs):

Mechanism: Certain antibiotics, such as penicillins and cephalosporins, and NSAIDs can cause an immune-mediated inflammatory reaction in the renal interstitium, known as interstitial nephritis.

Effect: In interstitial nephritis, inflammation occurs in the spaces between the kidney tubules. This can lead to impaired renal function, decreased urine concentration, and, in some cases, acute kidney injury. The onset of symptoms may include fever, rash, eosinophilia, and elevated serum creatinine.

Question 6

State the net effect of diuretics.

State the indications for diuretics.

Describe how they generally work

State the main 5 types of diuretics

Answer 6

Increase volume of urine
excreted
* Edematous states (heart, renal,
liver failure)
* Non-edematous states
(Hypertension, nephrolithiasis…)

• Most inhibit specific ion transporters in the nephron, decrease reabsorption of sodium and draw water into the lumen.
• Thiazide, Loop, Potassium sparring, Carbonic anhydrase inhibitors, osmotic

Question 7

Hydrochlorothiazide
 Distal convoluted tubule

 Inhibit the sodium-chloride cotransporter.
(Diuresis, Hyponatremia)
 Enhance the sodium-calcium exchange in the basolateral membrane.
(Hypercalcemia)

 Stimulates the aldosterone-sensitive Na/K exchanger (Hypokalemia)
 Increased urine pH

Name the described class of diuretic.

Answer 7

Thiazide diuretic

Question 8

 Furosemide, Ethacrynic acid

The most powerful diuretics

 Ascending Loop of Henle

 Inhibit the sodium-potassium-chloride.
cotransporter
 Decrease reabsorption of sodium, potassium, calcium, magnesium and chloride ions.

 Hypovolemia, Hyperuricemia, Ototoxicity

Name the diuretic.

Answer 8

Loop diuretic

Question 9

 Collecting tubule.
 Spironolactone and eplerenone
(aldosterone receptor antagonists)
 Amiloride and triamterene
(Sodium channel inhibitors)

 Combination with thiazides or loops to maintain potassium balance.

 Hyperkalemia (Avoid ACEI, ARB and BB)

 Spironolactone (Anti-androgen
effects)

Name the class of diuretic.

Answer 9

Potassium sparing diuretic

Question 10

Acetazolamide
 Proximal tubule

 Cause net loss of both sodium and bicarbonate ions
 Hypokalemia  Treatment of drug overdose (weak acids), metabolic alkalosis

 Treatment of glaucoma and intracranial hypertension

Name the class of diuretic.

Answer 10

Carbonic anhydrase inhibitor

Question 11

Describe the MOA of osmotic diuretics.

Answer 11

Filtered Load:
Osmotic diuretics are freely filtered by the glomerulus during the process of glomerular filtration in the kidneys. They enter the renal tubules along with the filtrate.

Limited Reabsorption:
As the filtrate moves through the proximal tubule and other segments of the nephron, osmotic diuretics are poorly reabsorbed. This results in a higher concentration of the diuretic within the tubular fluid.

Osmotic Gradient:
Osmotic diuretics, being osmotically active substances, create an osmotic gradient in the renal tubules. This gradient prevents the reabsorption of water from the tubular fluid back into the bloodstream.

Reduced Water Reabsorption:
The osmotic gradient established by the presence of osmotic diuretics prevents the normal reabsorption of water in the renal tubules. As a result, more water stays in the tubular fluid.

Increased Urine Output:
The inability to reabsorb water effectively leads to an increased volume of tubular fluid. This excess fluid is eventually excreted as urine. The diuretic effect is primarily due to the increased excretion of water, along with the accompanying electrolytes (sodium, chloride, etc.), leading to an overall increase in urine output.