Drugs Affecting Kidney Function

Question 1

What are some of the roles of the kidney?

Answer 1

• regulation of water and electrolyte balance
• endocrine functions
• excretion of endogenous waste
• excretion of exogenous compounds (including drugs)

Question 2

What organs are involved with drug elimination?

Answer 2

Combination of metabolism (liver) and Excretion (kidneys)

Question 3

What are some of the Drugs with therapeutic actions on the kidneys?

Answer 3

• Diuretics
• Drugs that affect urine pH (sodium bicarbonate in treatment of aspirin overdose)
• Drugs that alter secretion of organic molecules (probenecid to inhibit secretion of banned substances in sport- usually used for gout traditionally)

Question 4

What are diuretics?

Answer 4

Drugs that increase Na+ and water excretion
- decrease Na+ and Cl- reabsorption
= increased NaCl excretion
= secondary water excretion
It has both an effect locally in the nephron and also distal consequences.

Question 5

What are some different classes of diuretics?

Answer 5

There are different classes of diuretics

• loop diuretics
• thiazide diuretics
• potassium-sparing diuretics
• osmotic diuretics

Question 6

Explain features and mechanisms of loop diuretics?

Answer 6

• the most powerful of diuretic classes - excretion of 15-20% of Na+ in filtrate
• cause ‘torrential’ urine flow
• ie/ frusemide
• The mechanism of action is that it acts on thick acending limb of loop of Henle, thus inhibiting Na+/K+/2Cl- carrier into cells
• inhibition of Na+/K+/2Cl- cotransporter leads to:
  
  • reduction in hypertonicity interstitium
    = reduced osmotic pressure in interstitium
    = reduced water absorption
  • increased Na+ in distal tubule
    = increased osmotic pressure in tubule
    = reduced water absorption

Question 7

What are the pharmacokinetics of loop diuretics?

Answer 7

The pharmacokinetics of loop diuretics are that it is well absorbed from the gut (onset

Question 8

What are some adverse effects of loop diuretics?

Answer 8

Adverse Effects:
- K+ loss from distal tubule
	- ↑ Na+ concentration in dt
		= ↑ Na+ reabsorption
		= ↑ K+ secretion (Na+/K+- ATPase) (normally given with a K+ supplement)
	- hypokalaemia
- H+ excretion
	- metabolic alkalosis
- reduced extracellular fluid volume (in elderly)
	- hypovolaemia and hypotension

Question 9

What are some clinical uses of loop diuretics?

Answer 9

Clinical Uses:

• Salt and water overload in:
  
  • acute pulmonary oedema
  • chronic heart failure
  • ascites (liver cirrhosis)
  • renal failure
• Hypertension (renal impairment)

Question 10

What are some general features of Thiazide Diuretics and what is the mechanism of action?

Answer 10

• moderately powerful class but not as great of an effect as loop diuretics
• ‘true’ thazides (bendrofluzides, hydrochlorothiazide)
• thizaide-like (indapamide)
• Mechanism of Action:
  
  • acts on distal convoluted tubule; inhibiting the Na+/Cl- cotransporter

Question 11

What are the pharmacokinetics of thiazide diuretics?

Answer 11

The pharmacokinetics are that it is orally active and excreted in the urine (tubular section). The maximum effect is at 4-6 hours with an entire duration of 8-12 hours.

Question 12

What are some adverse effects of thiazide diuretics?

Answer 12

Adverse Effects:

• K+ loss from collecting ducts
  
  • as for loop diuretics
  • coadministered with K+ supplement
• ↑ plasma uric acid
  
  • inhibition of tubular secretion of uric acid
  • gout
• these effects are less with indapamide (thiazide-like)

Question 13

What are some clinical uses of thiazide diuretics?

Answer 13

Clinical Uses:

• hypertension
• severe resistant oedema (in combination with a loop diuretic)

Question 14

What are some features of Potassium-Sparing Diuretics and what is the general mechanism of action?

Answer 14

• limited diuretic effect
• used in combination with K+- losing diuretics to prevent K+ loss (ie. in patients with heart failure)
• Examples include spironolactone, triamterene and amiloride (two subclasses)
• Mechanism of Action:
  
  • act on collecting tubule and ducts
  • aldosterone receptor antagonist (spironolactone-aldosterone receptor complex does not bind DNA leading to reduced:
    
    • ↓ activation of Na+ channels
    • ↓ stimulation of Na+ pump synthesis.

Question 15

Give features of Spironolactone.

Answer 15

Spironolactone has the pharmacokinetics of being orally active with a slow onset. THey also have a short half life (10 mins) but the metabolites have a longer half life of 16 hours thus giving the drug a long duration. 
	Adverse Effects: 
	- hyperkalaemia (if used alone)
	- gastrointestinal upset
	Clinical Use:
	- combination with loop or thiazide diuretics
	- heart failure
	- hyperaldosteronism

Question 16

Give features of Triamterene and Amiloride.

Answer 16

Triamterene and Amiloride block the luminal sodium channels in collecting tubules and ducts inhibiting Na+ reabsorption and K+ secretion.
Triamterene pharmacokinetics are that it is well absorbed and have an onset of roughly 2 hours (12-16 hour duration). Amiloride poorly absorbed with a slow onset (but a long duration of 24 hours)

Question 17

What are some features of osmotic diuretics?

Answer 17

• pharmacologically inert (ie/ mannitol)
• filtered but not reabsorbed
• main effect is on the water permeable parts of the nephron (proximal tubule, descending limb of loop, collecting tubules)
• reduce passive water reabsorption
• small reduction only in Na+ reabsorption

Question 18

What are some clinical uses of osmotic diuretics?

Answer 18

Clinical Uses:

• raised:
  
  • intercranial pressure
  • interocular pressure
• prevention of acute renal failure
  
  • GFR so low that all NaCl and water is reabsorbed
  • water retention by osmotic diuretic prevents this
• not for Na+ retention

Question 19

What are some clinical uses of osmotic diuretics?

Answer 19

Clinical Uses:

• raised:
  
  • intercranial pressure
  • interocular pressure
• prevention of acute renal failure
  
  • GFR so low that all NaCl and water is reabsorbed
  • water retention by osmotic diuretic prevents this
• not for Na+ retention

Question 20

What are some adverse effects on the kidney?

Answer 20

• heavy metals
• antibiotics
• antineoplastic agents

Question 21

What are some mechanisms for kidney toxicity?

Answer 21

The kidney is susceptible to toxicity because it receives 25% of blood supply and the substances may be highly concentrated when it reaches the kidney. The kidney is able to carry metabolism of reactive species. It also has contribution from extrarenal events such as volume changes, BP or nervous changes.

The mechanisms for toxicity can be direct or via metabolites:

• reactive oxygen species (cell damage)
• interference with Ca2+ metabolism
• protein/enzyme binding (inhibition of enzyme function or initiation of immune response)

Question 22

Explain the interaction between Heavy Metals and Kidney Toxicity.

Answer 22

• ie. Mercury (inorganic; organic)
  
  • direct toxicity and vasoconstriction
  • binds to thiol groups in proteins (immune glomerulonephritis)
  • damage primarily in proximal tbule (loss of brush border membranes; mitochondrial changes; apoptosis)

Question 23

Explain the interaction between Antibiotics and Renal Toxicity.

Answer 23

• Gentamicin
  
  • treatment of Gram negative infections
  • Causes: proteinuria, reduced GFR, altered concentrating ability
  • Site of action: apical membrane of proximal tubule

cationic drug binds anionic phospholipids
↓
altered generation of PIP2
↓
altered intracellular Ca2+ levels
↓
impaired mitochondrial respiration
↓
cell injury

- toxicity is greater in patients with existing renal disease or if they are taking 	other potentially nephrotoxic drugs
- elimination is renal (nephrotoxicity can impare excretion, vicious cycle)
- need to regularly monitor plasma levels

Question 24

Explain the relationship between Antineoplastics and Renal Toxicity.

Answer 24

• Cisplatin
  
  • cytotoxic anticancer agent
  • treatment of prostate tumours
  • causes dose-limiting nephrotoxicity (proteinuria, increase in blood urea, electrolyte imbalance)
  • mechanism:
    
    • activated inside cells
    • forms highly reactive species
    • binds to nucleophilic cell components (thiols in proteins)
    • in distal tubule and collecting ducts (focal tubular necrosis)