Diuretics

Gilbert S 2014
Proximal Tubule
 Proximal Tubule
• Sodium bicarbonate (NaHCO3), sodium chloride
(NaCl), glucose,amino acids, and other organic
solutes are reabsorbed via specific transport
systems in the early proximal tubule(proximal
convoluted tubule, PCT).
• Potassium ions (K+) are reabsorbed via the
paracellular pathway.
• Water is reabsorbed passively, maintaining the
osmolality of proximal tubular fluid at a nearly
constant level
 Proximal Tubule
• Approximately 66% of filtered sodium ions
(Na+), 85% of the NaHCO3, 65% of the K+, 60%
of the water, and virtually all of the filtered
glucose and amino acids are reabsorbed in the
proximal tubule
• Only one group (carbonic anhydrase
inhibitors, which block NaHCO3 reabsorption)
acts predominantly in the PCT.
 Proximal Tubule
• Caffeine is a weak diuretic because it
nonspecifically and weakly blocks adenosine
receptors that participate in the control of
proximal tubule Na+ reabsorption in the
kidney.
• Adenosine receptor antagonists, act mainly in
the PCT and appear to induce a NaCl, rather
than a NaHCO3 diuresis.
 Proximal Tubule
• Sodium bicarbonate reabsorption by the PCT
is initiated by the action of a Na+/H+ exchanger
(NHE3) located in the luminal membrane of
the proximal tubule epithelial cell
• Bicarbonate reabsorption by the proximal
tubule is dependent on carbonic anhydrase.
• This enzyme can be inhibited by
acetazolamide and other carbonic anhydrase
inhibitors
 Proximal Tubule
• Adenosine (released as a result of hypoxia and
ATP consumption), reduces GFR to decrease
energy consumption by the kidney but increases
proximal reabsorption of sodium via stimulation
of NHE3 activity
• Adenosine A1-receptor antagonists significantly
blunt both proximal tubule NHE3 activity and
collecting duct NaCl absorption, and to have
potent vasomotor effects in the renal
microvasculature
 Proximal Tubule
If large amounts of an impermeant solute such
as mannitol (an osmotic diuretic) are present in
the tubular fluid, water reabsorption causes the
concentration of the solute and osmolality of
tubular fluid to rise, eventually preventing
further water reabsorption
 Proximal Tubule
• Organic acid secretory systems are located in the
middle third of the straight part of the proximal tubule
(S2 segment).
• These systems secrete a variety of organic acids (uric
acid, nonsteroidal anti-inflammatory drugs [NSAIDs],
diuretics,antibiotics, etc) into the luminal fluid from the
blood.
• These systems thus help deliver diuretics to the luminal
side of the tubule, where most of them act.
• Organic base secretory systems (creatinine, choline,
etc) are also present, in the early (S1) and middle (S2)
segments of the proximal tubule
 Drugs Acting on Proximal Tubule
1) Carbonic Anhydrase Inhibitor
• The predominant location of this enzyme is
the luminal membrane of the PCT where it
catalyzes the dehydration of H2CO3 to CO2 at
the luminal membrane and rehydration of
CO2 to H2CO3 in the cytoplasm
• Inhibitors blunt NaHCO3 reabsorption and
cause diuresis
 Drugs Acting on Proximal Tubule
• Dosing must be reduced in renal insufficiency
• Name of drugs: Dichlorphenamide &
Methazolamide
• Contraindications: May contribute to
development of hyperammonemia and
hepatic encephalopathy in patients with
cirrhosis
 Drugs Acting on Proximal Tubule
Indication Toxicity
• Glaucoma • Hyperchloremic Metabolic
• Urinary Alkalanization Acidosis
• Metabolic Alkalosis • Renal Stones
• Acute Mountain Sickness • Renal Potassium Wasting
• Drowsiness
• Paresthesias
• Hypersensitivity reactions
• Nervous system toxicity
 Drugs Acting on Proximal Tubule
2) Mannitol
• Indication: Drug abuse or increase in ICP
• Mechanism: Osmotic diuresis
• Side effect: Pulmonary edema, dehydration,
heart failure
• Contraindication: Anuria
 Loop of Henle
• Water is extracted from the descending limb of
this loop by osmotic forces found in the
hypertonic medullary interstitium.
• The thin ascending limb is relatively water-
impermeable but is permeable to some solutes
• Thick ascending limb (TAL) actively reabsorbs
NaCl from the lumen (about 25% of the filtered
sodium)  TAL is a diluting segment since it
reabsorbs salt
 Loop of Henle
• The NaCl transport system in the luminal
membrane of the TAL is a Na+/K+/2Cl–
cotransporter (called NKCC2 or NK2CL)
• Diuretics that work here is also known as loop
diuretics
Loop of Henle
 Loop Diuretics
• Drugs: Furosemide, torsemide, ethacrynic
acid, bumetanide
• NSAIDs can interfere with the actions of loop
diuretics by reducing prostaglandin synthesis
in the kidney
• Contraindications: Allergic reactions,
dangerous if used excessively in hepatic
cirrhosis, borderline renal failure or heart
failure
 Loop Diuretics
Indications Toxicity
• Acute pulmonary edema • Hypokalemic Metabolic
• Other edematous condition Acidosis
• Acute hypercalcemia • Ototoxicity
• Hyperkalemia • Hyperuricemia
• Acute Renal Failure • Hypomagnesemia
• Anion Overdose • Allergic reactions
• Osteoporosis
 Distal Convoluted Tubule
• Only about 10% of the filtered NaCl is
reabsorbed in the distal convoluted tubule
(DCT).
• Like the TAL of Henle’s loop, this segment is
relatively impermeable to water and NaCl
reabsorption further dilutes the tubular fluid.
• The mechanism of NaCl transport in the DCT is
an electrically neutral thiazide sensitive Na+
and Cl– cotransporter (NCC)
 Distal Convoluted Tubule
• the DCT as it does in the TAL, there is no
lumen-positive potential in this segment, and
Ca2+ and Mg2+ are not driven out of the tubular
lumen by electrical forces.
• Instead, Ca2+ is actively reabsorbed by the DCT
epithelial cell via an apical Ca2+ channel and
basolateral Na+/Ca2+ exchanger
• This process is regulated by parathyroid
hormone.
 Thiazide
• Prototypical drug: hydrochlorothiazide (HCTZ)
• Inhibit NaCl reabsorption from the luminal
side of epithelial cells in the DCT by blocking
the NCC
• Thiazides actually enhance calcium
reabsorption
• Contraindications: Hepatic cirrhosis,
borderline renal failure or heart failure
 Thiazide
Indications Toxicity
• Hypertension • Hypokalemic Metabolic
Alkalosis
• Heart Failure • Hyperuricemia
• Nephrolithiasis due to • Impaired carbohydrate
idiopathic hypercalciuria tolerance
• Hyperlipidemia
• Nephrogenic diabetes • Hyponatremia
insipidus • Allergic Reactions
• Weakness
• Fatigability
• Paresthesias
• Impotence
 Collecting Tubule
• The cortical collecting tubule (CCT) is responsible for
only 2–5% of NaCl reabsorption by the kidney
• As the final site of NaCl reabsorption, the collecting
tubule is responsible for tight regulation of body fluid
volume and for determining the final Na+ concentration
of the urine.
• Furthermore, the collecting tubule is a site at which
mineralocorticoids exert a significant influence.
• Lastly, the collecting tubule is the most important site
of K+ secretion by the kidney and the site at which
virtually all diuretic-induced changes in K+ balance
occur.
 Collecting Tubule
• The principal cells are the major sites of Na+, K+, and
water transport and the intercalated cells (α,β) are are
the primary sites of H+ (α cells) or bicarbonate (β cells)
secretion
• The α and β intercalated cells are very similar, except
that the membrane locations of the H+-ATPase and
Cl/HCO3- exchanger are reversed
• Unlike cells in other nephron segments, the principal
cells do not contain co-transport systems for Na+ and
other ions in their apical membranes.
• Principal cell membranes exhibit separate ion channels
for Na+ and K+
 Collecting Tubule
• Since these channels exclude anions, transport
of Na+ or K+ leads to a net movement of
charge across the membrane.
• Because Na+ entry into the principal cell
predominates over K+ secretion, a 10–50 mV
lumen-negative electrical potential develops
• Na+ that enters the principal cell from the
tubular fluid is then transported back to the
blood via the basolateral Na+/K+ ATPase
 Collecting Tubule
• Vasopressin receptors in the vasculature and
CNS are V1 receptors and in kidney V2
receptors
• V2 receptors act via a G protein-coupled,
cAMP-mediated process
 Potassium-Sparing Diuretics
• Antagonize the effects of aldosterone in
collecting tubules
• Inhibition occurs at mineralocorticoid
receptors (spironolactone, eplerenone) or by
inhibition of sodium influx through ion
channels in the luminal membrane (amiloride,
triamterene)
• Contraindications: Severe hyperkalemia, liver
disease
 Potassium-Sparing Diuretics
Indications Toxicity
• Mineralocorticoid excess or • Hyperkalemia
hyperaldosteronism • Hyperchloremic Metabolic
• Hypokalemia Acidosis
• Hepatic ascites • Gynecomastia
• Nehprogenic DI (Amiloride) • Acute Renal Failure
• Kidney Stones (Triamterene)