Pharmacology of Diuretics Flashcards
Na+-K+-2Cl- Symport Inhibitors (also called Loop diuretics/High ceiling diuretics)
chemically diverse
drugs: Furosemide and bumetanide contain a sulfonamide moiety. Ethacrynic acid is a
phenoxyacetic acid derivative and torsemide is a sulfonylurea
Na+-K+-2Cl- Symporter Location
luminal membrane of the TAL in Henle’s Loop (thats why Loop Diuretics)
Why do diuretics acting on PT have lower efficacy compared to loop diuretics?
Even though the PT normally reabsorbs 65% of filtered Na+, diuretics acting exclusively in the PT have low efficacy because the TAL has a large reabsorptive capacity and reabsorbs most of the rejectate from the PT. In contrast, Na+K+-2Cl symport inhibitors are highly efficacious.
What factors effect the efficacy of inhibitors of Na+-K+-2Cl- symport?
(1) 25% of the filtered Na+
normally is reabsorbed by the TAL, and
(2) nephron segments distal to the TAL do not possess the reabsorptive capacity to rescue the flood of rejectate from the TAL.
How does the Na+K+2Cl- symporter work?
This symporter uses the energy of the Na+electrochemical gradient for “uphill” transport of K+ and Cl- into the cell, while K+ channels in the luminal membrane (referred to as ROMK) provide a conductive pathway for the apical recycling of K+, and basolateral Cl- channels (called CLC-Kb) provide a mechanism for basolateral exit of Cl-
attenuate Ca2+ and Mg2+ reabsorption in the
TAL by abolishing the transepithelial potential difference
luminal membranes of TAL epithelial cells are hyperpolarized because they have many channels for K+. On the other hand, the basolateral membrane has many channels for Cl-, so the
basolateral transmembrane potential is less negative i.e., conductance for Cl- depolarizes the
basolateral membrane. As a result of hyperpolarization of the luminal membrane and
depolarization of the basolateral membrane, a transepithelial potential difference of 10 mV
exists with the lumen positive with respect to the interstitial space. The lumen-positive potential
provides an important driving force for the paracellular flux of Na+, Ca2+, and Mg2+ into the
interstitial space.
What is Bartter’s Syndrome and its causes?
inherited hypokalemic alkalosis with
salt wasting and hypotension
mutations in genes coding for Na+-K+-2Cl- symporter, apical K+ channel, basolateral Cl- channel, or Cl- channel subunit Barttin
Na+-Cl- Symport Inhibitors (also called Thiazide diuretics/Thiazide-like diuretics)
Inhibitors of the Na+-Cl- symport are sulfonamides, and because the first inhibitors of Na+-Clsymport were 1,2,4-benzothiazide-1,1-dioxides, this class of diuretics became know as thiazide diuretics.
drugs available: chlorothiazide, hydrochlorothiazide, metolazone, and chlorthalidone.
What is the current model of electrolyte transport by the Na+Cl- symporter?
transport is powered by a Na+ pump in the basolateral membrane. Energy in the electrochemical gradient for Na+ is harnessed by the Na+-Cl- symporter in the luminal membrane
and moves Cl- into the epithelial cell against its electrochemical gradient. Cl- then exits the basolateral membrane passively via a Cl- channel.
What is Gitelman’s
Mutations in the Na+-Cl- symporter cause a form of inherited hypokalemic alkalosis
What are the Na+ Channel Inhibitors (also called K sparing diuretics)?
Triamterene and amiloride are the only two drugs of this class in clinical use. Amiloride is a pyrazinoylguanidine derivative, and triamterene is a pteridine. Thus, both drugs are organic bases and are transported by the organic base secretory mechanism in PT.
evidence indicates that amiloride blocks epithelial Na+ channels in the luminal membrane of principal cells in the late distal tubule and CD. The amiloride-sensitive Na+channel (called ENaC) consists of three subunits.
What are the K+ sparing drugs?
Triamterene and amiloride cause small increases in NaCl excretion and usually are employed for their antikaliuretic actions to offset the effects of other diuretics that increase K+ excretion.Consequently, triamterene and amiloride, along with spironolactone, are often classified as potassium-sparing diuretics.
Describe the locations of the Na+ channels in the nephron
principal cells in the late distal tubule and CD have epithelial Na+ channels in their luminal membranes that provide a conductive pathway for Na+ entry into the cell down the electrochemical gradient created by the basolateral Na+ pump. The higher permeability of the luminal membrane for Na+ depolarizes the luminal membrane but not the basolateral membrane, creating a lumen-negative transepithelial potential difference (PD). This transepithelial voltage provides an important driving force for the secretion of K+ into the lumen via K+ channels (ROMK) in the luminal membrane.
What are Type A intercalated cells?
They are cells in the CD that mediate H+ secretion into the tubular lumen. Tubular acidification is driven by a luminal H+-ATPase (proton pump), and this pump is aided by partial depolarization of the luminal membrane.
What is Liddle’s syndrome
an autosomal dominant form of low-renin, volume expanded hypertension that is due to mutations
in the or subunits, leading to increased basal ENaC activity
Mineralocorticoid Receptors (MR) Antagonists (also called K-sparing diuretics/ Alsoterone antagonists)
Mineralocorticoids cause salt and water retention and increase K+ and H+ excretion by binding
to specific MRs.
drugs: spironolactone (1 17-spironolactone) and eplerenone
