Modulation of clearance by diuretics

Question 1

Describe osmotic diuretics

Answer 1

Mechanism of action of osmotic diuretics
- Mannitol, sorbitol, urea

• Given via infusion (mannitol) with fast action
  ### Rationale of use
• Site of action: proximal tubule (PT) and thick ascending limb (TAL)
• Substances bind water in the tubule, recruiting water from ICF
• Impacts urine concentration and water resorption

Indications and Contraindications; Adverse effects
- Indications (hospital setting - ICU)

• Adverse effects: paracellular transport ↓ causing Mg2+ loss
• Contraindications: heart failure, persisting oliguria/anuria

Question 2

Describe CAH

Answer 2

Mechanism of action of inhibition of CAH
- Actions in various locations

Mechanism of CAH Inhibitors
- Site of action: 1st PT / 2nd CD
- Acetazolamide blocks CAH immediately
- Loss of HCO3- leads to metabolic acidosis
### Rationale of use
### Indications and contraindications; Adverse effects
Clinical Use of CAH Inhibitors

• Indications: open angle glaucoma, edema
• Adverse effects: metabolic acidosis
• Contraindications: acidosis

Question 3

Describe loop diuretics

Answer 3

Mechanism of action of loop diuretics
- Site of action: ascending loop of Henle
- Very potent diuresis with fast action

Mechanism of Loop Diuretics
- Site of action: ascending loop of Henle (TAL)
- Block Na+/K+/2Cl–symporter, leading to significant Na+ reabsorption blockade
- Paracellular diffusion decreases
### Rationale of use
### Indications and contraindications; Adverse effects
- Indications: edema, forced diuresis, impending anuria
- Adverse effects: loss of electrolytes, uric acid excretion changes
- Contraindications: coma hepaticum, anuria

Question 4

Describe thiazides and analogues

Answer 4

Mechanism of action of thiazides and analogues
- Old substance group, competition for Cl–binding site on Na/Cl-symporter

• Good oral absorption, high protein binding

Mechanism of Thiazide Diuretics
- Site of Action: Distal Tubule (DT).
- Competition for Cl–Binding Site: Na/Cl-symporter.
- Excretion of K+ and H+: Due to [Na+] ↑ (Load-dependency of Na+ resorption).
- No TGF Effect: Action after macula.
- Moderate Efficacy: 5% of Na+ load.
- Physiological Impact: Quite “physiological”.
- Weak CAH Inhibition: Some thiazides weakly inhibit CAH.

Rationale of use
### Indications and contraindications; Adverse effects
- Indications:
- Oedemas with good GFR
- Hypertension

• Side Effects:
• Loss of K+
• Retention of uric acid (gout)
• Haemoconcentration (thrombosis, haematocrit)
• Reduced glucose tolerance
• Contraindications:
• Sulphonamide hypersensitivity
• Hypokalemia
• Anuria

Question 5

Describe ENaCis

Answer 5

Mechanism of action of ENaC
- Oral Absorption for Amiloride: 15 - 25%.

• Kinetic Properties: τ1/2 = 21 h (daily dose).
• Action Beyond Kidney: Also in skin, rectum, etc. where ENaC channels are expressed.
• Small Diuretic Effect: Only 2% of Na+ load.

Mechanism of Inhibitors of ENaC

• Site of Action: Distal Tubule (DT) / Collecting Duct (CD).
• Filtered and Secreted in PT: Via organic anion secretion mechanism.
• Blocking Action from Luminal Side: Na+-resorption↓ → small volume loss.
• No Effect on Renal Hemodynamics: After macula densa.
• Amiloride’s Other Effects: High doses can block other transporters.

Rationale of use
### Indications and contraindications; Adverse effects
- Indications:

• Hypertension (in combination with other diuretics).
• Adverse Effects:
• Volume contraction → uric acid reabsorption↑ in proximal tubule.
• Nausea, vomiting, diarrhea.
• Contraindications:
• Hyperkalemia
• Anuria

Question 6

Describe MC receptor antagonists

Answer 6

Mechanism of action of MC receptor antagonists
- Oral Absorption of Spironolactone: 60 - 70%.

• Kinetic Properties: τ1/2 = 1.6 h; metabolized to canrenoate, active with τ1/2 = 10 - 20 h.
• Delayed Effect: Takes a few days, single dose lasts 1 - 3 days.
• Highly Bound to Protein: 90-98%, can interfere with digoxin.
• Small Diuretic Effect: Only 2% of Na+ load, used to lower blood pressure via RAA system

Mechanism of MC Antagonists

• Site of Action: Distal Tubule (DT) / Collecting Duct (CD).
• Basolateral Binding to MC-Receptor: Blocks action.
• AIPs (Aldosterone-Induced Proteins): Involved in gene expression.
• NaCl Transport Dependence: Effect depends on hormonal state and high [hormone].

Rationale of use

Indications and contraindications; Adverse effects
- Indications:

• Hypertension (in combination)
• Hyperaldosteronism
• Diuretic of choice in hepatic cirrhosis
• Adverse Effects:
• Metabolic acidosis
• Interference with steroid biosynthesis (gynecomastia…)
• Contraindications:
• Hyperkalemia
• Hyponatremia
• Anuria