Renal Pharmacology

I. Diuretics
1. CA inhibitors
2. Loop diuretics
3. Thiazide diuretics
4. Potassium sparing
diuretics
5. Osmotic diuretics
II. Agents affecting
renal conservation of
water
1. ADH, analogs and
antagonists

Overview
Table: Major segments of the nephron and their functions

I. Diuretics
1. Carbonic anhydrase (CA) inhibitors
Acetazolamide: is a prototypical CA inhibitor
Pharmacokinetics
• Well absorbed after oral administration
• Onset of action: 30 min → ↑urine pH (HCO3 – diuresis ) is
apparent within 30 minutes
• Duration of action: 12 hrs after a single dose
• Excretion: secretion by the proximal tubule
– Dose reduction in renal insufficiency

CA inhibitors…Cont’d
Pharmacodynamics
• Inhibition of CA activity → ↓HCO3– reabsorption in the
PCT
• The efficacy of acetazolamide decreases significantly with
use over several days.
– reduced HCO3– in the glomerular filtrate
– enhanced NaCl reabsorption (with HCO3– depletion)
• Present major clinical applications are at sites other than the
kidney
– The ciliary body of the eye secretes HCO3– from the
blood into the aqueous humor.
– Formation of CSF by the choroid plexus involves
HCO3– secretion

Proximal tubule…cont’d
Figure 1: Apical membrane Na+/H+ exchange (via NHE3) & bicarbonate
reabsorption in the proximal convoluted tubule cell.

CA inhibitors…Cont’d
Clinical Indications
i. Glaucoma
• Inhibition of CA →↓aqueous humor →↓IOP
• Topically active ones: dorzolamide, brinzolamide
ii. Urinary Alkalinization
• To enhance renal excretion of weak acids ( CA inhibitors
↑urine pH)
iii. Acute Mountain Sickness
• Rapidly progressing pulmonary or cerebral edema can be
life-threatening.
• Acetazolamide: ↓CSF formation and pH of CSF & brain

CA inhibitors…Cont’d
Toxicity
A. Hyperchloremic Metabolic Acidosis
• Acidosis resulting from chronic reduction of body HCO3–
stores by CA inhibitors
B. Renal Stones
• Phosphaturia and hypercalciuria
• Calcium salts are insoluble at alkaline pH → ↑renal stone
formation
C. Renal Potassium Wasting
• Potassium wasting: Na+ reabsorption →↑lumen-negative
electrical potential →↑K+ secretion

CA inhibitors…Cont’d
Contraindications: cirrhosis
• CA inhibitor → alkalinization of the urine →↓excretion of
NH4+ (converted to NH3 & reabsorbed) →
hyperammonemia → hepatic encephalopathy

2. Loop diuretics
• Are the most efficacious diuretic agents currently available
• Prototypical drugs: furosemide & ethacrynic acid
• Other loop diuretics: bumetanide and torsemide
• Loop diuretics selectively inhibit NaCl reabsorption in the
thick ascending LH

Loop diuretics…cont’d
2.1. Furosemide
 Mechanism of action: inhibition of reabsorption of
sodium chloride by blocking Na+/K+/2Cl- symport in the
thick ascending limb of the LH.
Figure 2: Ion transport pathways across the luminal and basolateral membranes
of the thick ascending limb cell.

 They also diminishes the luminal-positive potential due to
recycling of K+ →↑excretion of divalent ions (Mg2+,
Ca2+)
 Uses:
– Hypertension, heart failure, ascites, pulmonary edema
 Adverse effects:
– Dehydration, hyperglycemia, hypokalemia,
hypomagnisemia, hyperuricemia, metabolic alkalosis
– Generally no hypocalcaemia (intestinal absorption of
Ca2+ & reabsorption at the DCT)

Loop diuretics…cont’d
2. 2. Ethacrynic acid
 MOA: inhibition of sulfhydryl-catalyzed enzyme system,
which is responsible for reabsorption of sodium and
chloride in the proximal and distal tubules.
 Uses:
– In patients who are hypersensitive to sulfonamide drugs
such as thiazides and furosemide
– Edema related to heart failure or cirrhosis
 Adverse effects:
– Ototoxicity

3. Thiazides
• Differ from each other in potency & duration of action
• Prototype: hydrochlorothiazide
• Other thiazides: bendroflumethiazide, chlorothiazide,
hydroflumethiazide, etc.
• Thiazide-like diuretics: chlorthalidone, indapamide,
metolazone
Pharmacokinetics
• Administered orally (exception is chlorothiazide →
parenteral)
• Secretion: All thiazides compete for the same secretory
system with uric acid → hyperuricemia

Thiazides…cont’d
MOA:
• Thiazides block Na+/Cl– transporter in the DCT →
inhibition of NaCl reabsorption from the tubular lumine
• Thiazides enhance Ca2+ reabsorption
• ↓IC Na+ by thiazide →↑Na+/Ca2+ exchange in the
basolateral membrane → reabsorption of Ca2+

Thiazides…cont’d
Figure 3: Ion transport across the luminal and basolateral membranes of the DCT cell.

Thiazides…cont’d
Indications
1) Hypertension
2) Heart failure
3) Nephrolithiasis (kidney stones) → hypercalciuria
4) Nephrogenic diabetes insipidus
Toxicity
 Hypokalemic Metabolic Alkalosis
 Hyperuricemia
 Hyponatremia
Contraindications
• Cirrhosis
• Borderline renal failure
• Heart failure

4. Potassium sparing diuretics
• Inhibit Na+ reabsorption (and K+ secretion) at the late distal
and cortical collecting tubules
• MOA:
– Inhibition of aldosterone receptors (spironolactone,
eplerenone) or
– inhibition of Na+ influx through ion channels in the
luminal membrane (amiloride, triamterene) → spare also
K+ (as K+ secretion is coupled with Na+ reabsorption)

Cont’d…
Figure 4: Mechanisms of ions transport and sites of diuretics action in the cells
of the late distal tubule and CCT

Cont’d…
• Spironolactone and eplerenone:
– Are competitive antagonist of aldosterone
– eplerenone has greater selectivity for the
mineralocorticoid /aldosterone receptor than
spironolactone → has considerably fewer adverse effects.
• Amiloride and triamterene:
– are direct inhibitors of Na+ influx
– Triamterene is extensively metabolized in the liver → has
a shorter half-life → warranting more frequent dosing
– Amiloride is not metabolized → less frequent dosing

Cont’d…
Clinical Indications
• As adjunct therapy with thiazides or loop diuretics (wastage
of K+)
• Ascitis
• Heart failure
Toxicity
• Hyperkalemia
• Hyperchloremic metabolic acidosis
• Gynecomastia
• Kidney Stones

Cont’d…
Contraindications
• Oral K+ administration
• Chronic renal insufficiency
• Concomitant use with agents blunting the RAAS
(ARB/ACEI)
– Exacerbates hyperkalemia
• Liver disease → carefully dose adjustment

5. Osmotic diuretics
• Prototype: mannitol
Pharmacokinetics
• Absorption: poorly absorbed by the GI tract
– Must be given parenterally for systemic effect
• Metabolism: not metabolized
• Excretion:filtration→no reabsorption nor secretion
MOA:
• Filtered by the glomerulus but not reabsorbed → ↑osmotic
pressure → ↑water retention & diuresis
• Site of action of osmotic diuretics
– The PCT and descending limb of LH → freely permeable
to water

Osmotic…cont’d
Clinical Indications
 Maintain urine flow in acute renal failure
 Treat acute oligouria
 Reduce intracranial pressure and cerebral edema
 Treat acute glaucoma (↓IOP)
Toxicity
• Extracellular Volume Expansion
• Dehydration
• Hyperkalemia