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DIURETICS
Functions of the kidneys
Maintain internal environment by regulating
composition of extracellular compartment
• Volume
• Acid-base balance
• Osmotic pressure
• Electrolyte concentration
• Excretion of metabolites
and toxic substances
Anatomy of the Nephron
Renal process involved in the production of urine:
1) Glomerular filtration
2) Renal tubular secretion
3) Renal tubular reabsorption
Glomerular filtration
Tubular secretion
PCT organic acid secretory transport system
PCT organic base secretory transport system
Renal tubular sodium reabsorption
Renal handling of water and substances
Average Values for Several Substances
Handled by Filtration and Reabsorption
Substance
Water, L
Sodium, g
Glucose, g
Urea, g
Amount
Filtered
per Day
180
630
180
56
Amount
Excreted
1.8
3.2
0
28
%
Reabsorbed
99.0
99.5
100
50
Renal handling of water and substances
Average Values for Several Substances
Handled by Filtration and Reabsorption
Substance
Water, L
Sodium, g
Glucose, g
Urea, g
Amount
Filtered
per Day
180
630
180
56
Amount
Excreted
1.8
3.2
0
28
%
Reabsorbed
99.0
99.5
100
50
Total Body Sodium Balance:
Input = Output
Renal excretion of sodium
The goal of diuretic therapy is to increase
the net excretion of water by the kidneys by :
• interfering with the renal tubular reabsorption
of sodium and subsequently water
• antagonizing the hydroosmotic effect of
vasopressin (antidiuretic hormone)
Transport pathways across tubular cells
PROXIMAL TUBULES
Proximal Tubular Diuretics
Osmotic Diuretics
• Mannitol
• Urea
• Glycerin
• Isosorbide
“Mannitol”
Sodium, glucose and bicarbonate reabsorption
in the proximal convoluted tubule
Mannitol
Therapeutic Uses:
1.
2.
3.
4.
Acute renal failure (i.e., maintain urine flow)
Reduce cerebrospinal fluid volume and pressure
Glaucoma
Facilitate urinary excretion of toxic substances
Adverse Effects:
1. Extracellular expansion and subsequent adverse effects in
patients with congestive heart failure and pulmonary edema
Proximal Tubular Diuretics
Carbonic Anhydrase Inhibitors
• Acetazolamide
Proximal Convoluted Tubule
Basolateral
Apical
Na+
Na+
HCO3-
K+
H+
H+
HCO3-
H2CO3
CA
CO2 + H2O
CA
CO2 + H2O
ATP
Action of Acetazolamide
Apical
Basolateral
Na+
Na+
K+
H+
HCO3-
H+
ATP
HCO3-
H2CO3
CA
CO2 + H2O
Acetazolamide
Urine [H+, NH4+, Cl-]
Urine [HCO3-]
Urine [Na+, K+], pH, H2O
CA
CO2 + H2O
Plasma [HCO3-]
Acetazolamide
Therapeutic Uses:
1. Open angle glaucoma (chronic simple) –
decreases formation of aqueous humor
2. Create an alkaline urine to facilitate urinary excretion of acidic drugs
3. Metabolic alkalosis
4. High altitude sickness
Adverse Effects:
1. Metabolic acidosis
Loop of Henle
Loop Diuretics
• Furosemide
• Bumetanide
• Torsemide
• Ethacrynic acid
Electrolyte transport pathways in the TALH
Urine:
[Na+, K+, Cl-,
Ca+, Mg+, H+,
NH4+], H2O
pH
No Δ [HCO3-]
Therapeutic Uses:
1.
2.
3.
4.
Loop Diuretics
Removal of edema (e.g., pulmonary edema) and ascites
Hypertension
Symptomatic hypercalcemia
Dilutional hyponatremia during SIADH (i.e., state of high ADH)
Adverse Effects:
1.
2.
3.
4.
5.
6.
7.
Volume depletion and circulatory contraction
Diuretic-induced hyponatremia
Diuretic-induced metabolic alkalosis (aka, contraction alkalosis)
Hypokalemia
Ototoxicity
Activation of RAS
Drug interactions:
a) Anticoagulants (Warfarin)
b) Aminoglycosides
c) Cardiac glycosides
d) Drugs that utilize the proximal tubule
organic acid secretory pathway
(e.g. probenecid, penicillin, salicylates, etc.)
Early
Distal Convoluted Tubule
Thiazide and Thiazide-like Diuretics
• Hydrochlorothiazide
• Chlorothiazide
• Chlorothalidone
• Metolazone
Sodium and chloride reabsorption in the
early distal convoluted tubule
Urine:
[Na+, K+, Cl-,
~HCO3-],
pH, H2O
[Ca+, H+,
NH4+]
pH
Thiazide and Thiazide-like Diuretics
Therapeutic Uses:
1.
2.
3.
4.
Hypertension
Hypocalcemia
Removal of edema and ascites
Nephrogenic diabetes insipidus
Adverse Effects:
1.
2.
3.
4.
5.
6.
7.
Volume depletion and circulatory contraction
Hypokalemia
Activation of RAS
Aggravate hyperglycemia
Increase plasma cholesterol and triglycerides
Increase plasma uric acid
Drug interactions:
a) Cardiac glycosides
b) Drugs that utilize the organic acid
secretory pathway (eg. penicillin)
Late
Distal Convoluted Tubule
and Collecting Duct
Late Distal Tubule Diuretics
(aka, potassium-sparing diuretics)
Epithelial Na Channel (ENaC) Antagonists
• Amiloride
• Triamterene
Aldosterone Receptor Antagonists
• Spironolactone
Sodium - Potassium exchange in the
late distal convoluted tubule
Urine:
[Na+, Cl-,
HCO3-],
pH, H2O
[K+, H+,
NH4+]
Spironolactone
Potassium-Sparing Diuretics
Therapeutic Uses:
1.
2.
3.
4.
Hypertension
Hypokalemia
Refractory edema and ascites
Primary aldosteronism
Adverse Effects:
1. Hyperkalemia
Antidiuretic Hormone
(vasopressin) and water transport
in the collecting ducts
AVP-dependent water permeability in the distal nephron
Vasopressin – mediated water reabsorption
Collecting Duct Diuretics
Vasopressin antagonists (Aquaretics)
• Conivaptan
• ~ Demeclocycline and Lithium
Therapeutic Uses:
1. Hyponatremia
(e.g., as in SIADH)
Collecting Duct Antidiuretics
Synthetic Vasopressin agonists
• Desmopressin (DDAVP)
Therapeutic Uses:
1. Central diabetes insipidus
Nephrogenic diabetes insipidus
Therapeutic treatment:
- Thiazide diuretic
- NSAIDs
Other Drugs with Diuretic Activity
1. Methylxanthines (eg. theophylline and caffeine)
2. Dopamine, dobutamine, cardiac glycosides
3. Alcohol (ethanol)
4. Water