L45: Diuretics + ACE Inhibitors

Question 1

Effects of Diuretic agents

Answer 1

↑ fluid excretion

1. Oedematous state
   - e.g. heart failure
   - ↓ peripheral / pulmonary oedema without significant ↓ blood volume
   - excessive diuresis may ↓ blood volume —> ↓ organ perfusion
2. Non-oedematous state
   - ↓ hypertension

Question 2

Loop diuretics (Furosemide, Ethacrynic acid)

Answer 2

Mechanism:
Inhibit NKCC of thick ascending LoH
1. ↓ reabsorption of Na —> ↓ reabsorption of water in CD
2. ↑ excretion of K
- ∵ ↑ distal tubular Na stimulate Aldosterone-sensitive Na pump to ↑ Na reabsorption in exchange for K + H
- and ∵ ↑RAAS triggering by ↓ blood volume
—> ↑ H+ excretion (via H/K-ATPase)
3. ↓ reabsorption of Mg + Ca

Use:

1. Oedema
   - oedematous status due to retention of Na
   - ↓ left ventricular filling pressure —> ↑ venous capacitance —> ↓ venous and pulmonary congestion
2. Hypertension
   - limited use because short half life —> post-diuretic Na reabsorption

Adverse effects:

• Hyponatremia —> extracellular fluid depletion —> hypotension, reduced GFR
• Hypokalaemia —> arrhythmia (solved by ↓ Na intake, K supplementation)
• Metabolic alkalosis —> compromise cardiac function (K replacement)
• Hypomagnesemia —> arrhythmia
• Hyperuricemia (due to hypovolemia —> ↑ reabsorption of uric acid)
• Hyperglycemia
• Hyperlipidemia
• Ototoxicity (due to ethacrynic acid, reversible)
• Sulfonamide-related allergic reaction

Resistance:

• Reduction in renal blood flow (↓ delivery of diuretics to kidneys, too much substrate accumulate at organic acid transporter at proximal tubule)
• Drug interaction (↑ NKCC expression by NSAID, compete for organic acid transport system)
• Increased proximal tubular Na reabsorption (hepatic cirrhosis)

Question 3

Thiazide diuretics (Hydrochlorothiazide, Chlorthalidone)

Answer 3

Mechanism:
Inhibit Na/Cl cotranporter in Distal tubule
—> ↓ NaCl reabsorption
—> ↑ Ca reabsorption

Uses:

1. Odema
   - not as effective since most Na has been reabsorbed in LoH
2. Hypertension
   - efficacious
   - inexpensive
   - longer acting with safe profile —> once daily, well tolerated, few CI
   - synergistic with other antihypertensive
   - long term use associated with vasodilation effect

Adverse effects:

• Hyponaetremia
• Hypokalaemia
• Metabolic alkalosis
• Hypomagnesemia
• Hyperuricemia
• • Hypercalcaemia
• Hyperglycaemia (due to reduced insulin, hyperpolarisation of pancreatic beta cells, reversed by treating hypokalaemia)
• Hyperlipidaemia
• Sulfonamide-related allergic reactions

Question 4

Potassium-sparing diuretic (Amiloride, Spironolactone, Eplerenone)

Answer 4

Amiloride: inhibit epithelial Na channel in Collecting duct (???過左distal tubule, 不trigger RAAS system —> not excrete K)
Spironolactone, eplerenone: Aldosterone antagonist

—> Inhibit Na+ reabsorption but also ↓ K excretion

Use:

• mild natriuresis effect —> combined with other diuretics
• ↓ K secretion by other diuretics

Adverse effects:

• Hyperkalaemia —> arrhythmia (cautious with ACE inhibitor, ARB, renin inhibitor)
• Acidosis —> inhibit excretion of H —> compromise cardiac function
• Gynecomastia, impotence (Spironolactone only: antagonist for androgen and progesterone receptor)

Question 5

Diuretic efficacy and combination therapy

Answer 5

Loop > thiazide > K-sparing

Combination:

1. Loop + thiazide (synergistic, though not recommended for outpatient because hypokalaemia)
2. K-sparing + Loop/thiazide (prevent hypokalaemia)

Question 6

Inhibitors of RAAS system (ACE inhibitor and ARB)

Answer 6

1. ACE inhibitors (Captopril, Lisinopril, Enalapril)
   - ↓ formation of AT2
   —> ↓ vasoconstriction (hypertension)
   —> ↓ fluid retention (oedema)
   —> ↓ ventricular remodelling (heart failure)
   - ↓ metabolism of bradykinin —> vasodilation
2. ARB (losartan, valsartan)
   - antagonist of type I angiotensin receptor
   - same effect as ACE inhibitor (except bradykinin)

Use:

1. Hypertension
2. Oedema
3. Heart failure

Adverse effects:

• Hypotension
• Acute renal failure
• • Hyperkalaemia (antagonise aldosterone effect)
• CI in Pregnancy
• • dry cough, angiooedema (ACE inhibitor only due to bradykinin)

Question 7

Advantage and Disadvantage of ARB and ACE inhibitor

Answer 7

Advantage of ARB:
1. More complete blockade of RAAS system (since AT2 can be formed through ACE-independent pathway)

2. Do not affect type II angiotensin receptor —> vasodilation, bradykinin release

Disadvantage of ACE inhibitor and ARB:
- Disrupt negative feedback of AT2 on renin release
—> ↑ renin release from JG cell
—> limit effectiveness

Question 8

Renin inhibitor

Answer 8

↓ activity of renin
—> ↓ RAAS effect (same as ACE inhibitor and ARB)

Adverse effect:

• Acute renal failure
• Hyperkalaemia
• CI in Pregnancy

Question 9

Potential problem with ACE inhibtor, ARB and renin inhibitor

Answer 9

Alternative mechanism for aldosterone production (aldosterone escape)
—> e.g. ↑K / Adrenocorticotrophic hormone (ACTH) can trigger aldosterone release
—> limit effectiveness of angiotensin inhibitors