Drugs & the Kidney

Question 1

Which drugs commonly affect kidney function?

Answer 1

• Diuretics: Sodium reabsorption blockers.
• ACE-I/ARBs: Efferent arteriole vasodilation → ↓ glomerular pressure.
• NSAIDs: ↓Prostaglandins → ↓ auto-regulation, interstitial nephritis.
• Tenofovir: AKI, Fanconi syndrome.

Question 2

Renal effects of ACE inhibitors, ARBs, and NSAIDs

Answer 2

• ACE-I and ARBs: selective vasodilatation of efferent glomerular arteriole, reducing glomerular hypertension. Should be prescribed with caution in CKD due hyperkalaemia risk, though use is not contraindicated.
• NSAIDs: decrease renal prostaglandin production, thereby limiting the capacity for glomerular auto-regulation. They are also important causes of both acute and chronic interstitial nephritis [N.B. selective COX-2 inhibitors have not been found to be safer]

Question 3

Renal effects of diuretics and tenofovir

Answer 3

• Diuretics: all diuretics block sodium absorption at one site along the nephron (see Table 16.9)
• Tenofovir: nucleotide analogue - an effective component of anti-HIV treatment but can cause AKI and the proximal tubular Fanconi syndrome

Question 4

Classes of diuretics

Answer 4

• Loop: furosemide, bumetanide
• Thiazide: bendroflumethiazide, hydrochlorothiazide, metolazone, indapamide
• Potassium-sparing: amiloride, triamterene
• Mineralocorticoid antagonists: spironolactone, eplenerone
• Carbonic anhydrase inhibitors: acetazolamide

Question 5

Loop diuretics mode of action and clinical use:-
- Furosemide: Derived from “fur-“ (a reference to furan, part of its chemical structure) and “-semide” (from sulfonamide, indicating the presence of a sulfonamide group in its structure).
- Bumetanide: “Bume-“ refers to its butyl-methyl substitution, and “-tanide” echoes the sulphonamide group.
- Link: Both names highlight their structural similarity and the sulphonamide moiety, crucial for their action in blocking the sodium-potassium-chloride co-transporter in the loop of Henle

Answer 5

Block type 2 Na+ K+ 2Cl– (NKCC2) transporter in thick ascending limb of loop of Henle (responsible for reabsorption of ~25% of filtered Na+) (see Figure 16.1C).
Volume overload: more potent natriuretics than thiazides. Limited use in hypertension (unless also volume overloaded). 2+ Also cause Ca loss.

Question 6

Thiazide diuretics mode of action and clinical use:-
- Thiazide: Derived from “thia-“ (sulphur-containing) and “azide” (nitrogen-containing), referring to their chemical structure with a sulfur-nitrogen ring.
- Bendroflumethiazide: “Ben-“ (benzene group), “drof-“ (dihydro), “flu-“ (fluorine substitution), and “methiazide” (a thiazide core structure).
- Hydrochlorothiazide: Indicates the addition of chlorine and hydrogen to the thiazide base.
- Metolazone: “Meto-“ (methyl group), “-lazone” (a chemical suffix denoting its quinazoline structure).
- Indapamide: Contains “-amide” (an amide group) and “ind-“ (indoline ring structure).
- Link: The term “thiazide” is a core identifier of their sulfur-nitrogen ring, pivotal for their function in the distal convoluted tubule.

Answer 6

Block Na+ Cl– cotransporter in apical membrane of DCT tubular cells (responsible for ~5–7% of Na+ reabsorption) (see Figure 16.1D).
E ffective in hypertension. Can be useful adjuncts to loop diuretics to aid diuresis.

Question 7

Potassium-sparing diuretics mode of action and clinical use:-
- Amiloride: “Ami-“ (amino group), “-lo-“ (linked to an open lactam ring), and “-ride” (suffix for chemical compounds).
- Triamterene: “Tri-“ (three) and “-amterene” (indicating three amine groups in its structure).
- Link: Both names highlight chemical groups responsible for their selective inhibition of sodium channels in the collecting duct, which conserves potassium.

Answer 7

Block epithelial
Na+ channel (ENaC) in late DCT and collecting duct (see Figure 16.1D).
Mitigate ↓K+ seen with other diuretics.

Question 8

Mineralocorticoid antagonist mode of action and clinical use:-
- Spironolactone: “Spir-“ (spiral, indicating a lactone ring structure) and “-olactone” (a lactone group, crucial for binding to the aldosterone receptor).
- Eplerenone: “Epler-“ (epoxide group in its structure) and “-enone” (a ketone group).
- Link: Names emphasize the structural groups (lactone, epoxide) that enable antagonism of mineralocorticoid receptors.

Answer 8

Block mineralocorticoid receptor in collecting duct (also heart, vasculature, brain)
Evidence base in treatment of heart failure. Useful adjunct in treatment of hypertension. Mitigate ↓K+ seen with other diuretics.

Question 9

Carbonic anhydrase inhibitor mode of action and clinical use:-
- Acetazolamide: “Acet-“ (acetyl group), “azo-“ (nitrogen group), and “-lamide” (amide group).
- Link: Reflects the chemical groups required for inhibiting carbonic anhydrase in the proximal tubule.

Answer 9

Block luminal carbonic anhydrase in proximal tubule, inhibit reabsorption of filtered HCO3– (see Figures 16.2 and 16.3)
Little eff icacy as a diuretic: limited use. Prophylaxis and treatment of altitude sickness.

Question 10

Diuretics - side effects

Answer 10

• Loop: ↓K+. Metabolic alkalosis.
• Thiazide: ↓K+. ↑urate. Impaired glucose tolerance. ↑Ca2+.
• Potassium-sparing: ↑K+.
• Mineralocorticoid antagonists: ↑K+.
• Carbonic anhydrase inhibitors: Metabolic acidosis. Worsening hypercapnia in those with lung disease.