Drugs and the Kidney

Question 1

What’s the kidneys role in eliminating drugs?

Answer 1

Some drugs are excreted unchanged, while most are metabolised by the liver into an inactive compound, which can then be excreted by the kidney:

• Polar drugs are excreted more readily that non-polar drugs
• Non-polar drugs can be reabsorbed

Question 2

Explain the 3 processes that occur for drug excretion

Answer 2

1. Glomerular Filtration:
   • Glomerulus allows drugs small enough to be filtered freely.
   • Drugs can’t be filtered freely when bound to Albumin e.g. Warfarin, to give it a longer half-life, potentially causing toxicity.
2. Active Tubular Secretion:
   • Mainly occurs in the PCT
   • Cation and anion transporters are non-specific and can bind to any anionic/cationic drug.
   • There’s competition between the drugs for the non-specific transporters - will affect the half-life of some drugs.
3. Passive Tubular Reabsorption:
   • Mainly occurs in the PCT and DCT
   • Reabsorption of H2O = ↑filtrate [drug] = ↑concentration gradient for reabsorption.
   • Uncharged/unionised drugs (lipophilic) can cross the lipid membrane, but the charged/ionised drugs (lipophobic) need a transporter.
   • Most drugs are weak acids/bases, so the drug pKa and urinary PH play important roles in their reabsorption as it affects degree of ionisation.

Question 3

What do Diuretics cause?

What are they used to treat?

What are the 2 major groups of Diuretics?

Answer 3

• ↑Urine output, ↑Na and K excretion
• Hypertension, Oedema, Heart/Kidney Failure
• To ↑Electrolyte excretion: Carbonic anhydrase (CA) inhibitors, Loop diuretics, Thiazide diuretics, K-sparing diuretics.

To mainly affect H2O excretion: Water, Ethanol, Osmotic diuretics

Question 4

Describe what happens in the sites that Diuretics act on?

Answer 4

1. Proximal Convoluted Tubule:
   • Affect the active reabsorption of Na+ and the passive movement of Glucose/AA/H2O.
   • Affect the reabsorption of Na+ in exchange for H+ (Na/H exchanger) - needs Carbonic Anhydrase (CA) to produce the H+ ions.
2. Loop of Henle:
   • Affects NaCl transport via the Na/K/2Cl symporter on ascending limb - the thick ascending limb is impermeable to H2O, so blocking the symporter will make the interstitial fluid hypotonic = ↓H2O reabsorption in CD.
3. Distal Convoluted Tubule:
   • Affects reabsorption of Na and Cl via the cotransporter, along with H2O.
   • Affects the aldosterone-stimulated Na+ reabsorption and K+ secretion through ENaC and K channels.
   • Affects the aldosterone-sensitive Na/H exchanger.

Question 5

Give an example of an Osmotic Diuretic

Explain how Osmotic Diuretics affects H2O excretion

What are these drugs used for?

Answer 5

• Mannitol
• Acts on PCT, DCT, CD.
  It’s an inert substance that is freely filtered without any reabsorption. This will cause high concentrations of it in the tubule = ↑Tubular Osmolality = ↓H2O reabsorption - no change in electrolyte excretion.
• • Reducing intracranial and intraocular pressure (doesn’t cross BBB so water has to leave CSF)
  • Prevent acute renal failure: increase tubular flow to prevent drying of nephron
  • Excretion of some types of poisoning

Question 6

Give an example of a CA inhibitor

What is the action of CA inhibitors on the kidney?

What are the other uses of CA inhibitors?

LOOK AT DIAGRAM!

Answer 6

• Acetazolamide
• • CA Inhibition = ↓H+ formation in the PCT cells
  • Loss of HCO3- into lumen - with a loss of H2O
• Treatment of glaucoma - aqueous humour formation is dependent on CA.

Question 7

Give an example of an Loop Diuretic

What is the action of Loop diuretics on the kidney?

What are the other uses of Loop diuretics?

What are some of the side-effects of Loop diuretics?

LOOK AT DIAGRAM!

Answer 7

• Frusemide
• • Very powerful diuretic.
  • Inhibits the Na/K/2Cl symporter on luminal membrane of thick AL. This ↓reabsorption of these electrolytes and increases their excretion - Inhibition = ↓Medullary Interstitial Osmolarity = ↓effects of ADH on CD (↓osmotic drive) = ↑H2O excretion.
• • Chronic heart failure: ↓ECFV = ↓heart congestion.
  • Acute renal failure: drug’s vasodilatory effects ↑renal blood flow.
  • Acute pulmonary oedema: vasodilation = ↓capillary pressure
• Hypokalaemia (huge K+ loss), Metabolic Alkalosis (due to compensatory ↑Na/H exchangers)

Question 8

Give an example of a Thiazide Diuretic

What is the action of Thiazide diuretics on the kidney?

What are the other uses of Thiazide diuretics?

What are some of the side-effects of Thiazide diuretics?

LOOK AT DIAGRAM!

Answer 8

• Bendrofluazide
• • Moderately powerful diuretic.
  • Inhibits the Na/Cl cotransporter on luminal membrane of DCT cells. This ↓H2O reabsorption as a result - compensatory mechanisms in place to increase Na uptake by ↑ENaC and Na/H pump (will ↑↑K and H loss)
• • Hypertension: ↓BV/CO/TPR, Vasodilation
  • Mild heart failure: ↓ECFV.
  • Oedema
• Hypokalaemia (compensation), Metabolic Alkalosis (compensation), Hypercalcemia (↑Na/Ca exchanger), Hypotension

Question 9

What is the action of K-sparing diuretics on the kidney?

Give some examples and their actions

LOOK AT DIAGRAM!

Answer 9

• • Weak diuretic.
  • Act on late DCT and CD.
  • Cause K+ retention in the blood, which counters the high electrolyte loss from the other diuretics.
• • Spironolactone - competitive antagonist of aldosterone at the distal tubule and is used to counter CVS diseases linked with excessive aldosterone production (increases BV too much and overloads the heart).
  • Amiloride - blocks ENaC channels on DCT cells to ↓Na+ reabsorption and K+ loss.
  • Captopril - ACEi = ↓Ang II = ↓Aldosterone secretion.

Question 10

What are drugs that cause kidney damage called?

What are some common examples?

Answer 10

• Nephrotoxic

- NSAIDs, Chemotherapy drugs, Lithium, Cyclosporine etc.