CPPS 306 Diuretics II

For thizide and thiazie-like diuretics, there are more than 11 types, but what is the prototype

Hydrochlorothiazide

What are the general characteristics of thiazide and thiazide like diuretics

Inhibit Na-Cl symporter

Cause reabsorption of calcium

Evoke direct vasodilation

Thiazide ad Thiazide like diuretics inhibit Na-Cl symporter, expand on this in terms of where, and what does it have a secondary inhibitory effect on

It inhibits NaCl transport in the distal convoluted tubule (DCT) of the nephron

• Has secondary inhibitory effect on the Na-Cl symporter of the proximal tubule

Thiazide diuretics increase Ca reabsorption in the distal convoluted tubule, what conditions is this effect useful for

Hyper-calciuria

Nephro-lithiasis

Where is the Na-Cl symporter located in the nephron?

In the luminal membrane (apical) of epithelial cells in the DCT

What are the effects of thiazide on renal hemodynamics

Increase K + uric acid excretion

Chronically administered thiazide reduce Ca excretion

Why are thiazides only moderately efficacious in facilitating excretion of Na and Cl

Because 90% of the filteres Na is reabsorbed before reaching the DCT of the nephron

What thiazide effect enhances HCO3 and phosphate excretion

Some thiazides are week inhibitors of carbonic anhydrase

What do thiazides DONT have an effect on

Renal blood flow

Tubuloglomerular feedback (TGF)

What are the theraputic uses of thiazides

• Acute glomerulunephritis

• Chronic renal failure

• Edema with congestive heart failure

• Hypertensoin

• Hepatic cirrhosis

• Nephrotic syndrome

• Nephrogenic diabetes insipidues

• Reduce urinary excretion of Ca

Give examplesof K sparing diuretics and what do these inhibit

Triam-terene + A-milo-ride

• Inhibits renal epithelial Na channels

What do Triamteren and amiloride cause a small increase in and what are they usually used for

Small increase in NaCl excretion

• Usually used for their anti-kaliuretic effects to relieve diuretics that increase K excretion

Eevated permeability of the luminal membrane to Na⁺ depolarizes the luminal membrane but not the basolateral membrane. What does this generate?

A lumen-negative transepithelial potential differences, which drives K secretion into the tubular lumen through K channels

Mechanism of action for amiloride and traimterene:

They suppres the _____ channels in the _____ _____ of the principal cells of the late ____ ____ and ____ ____

supress the epithelial Na+ channels in the luminal membrane of the principal cells of the late distal tubule and collecting duct

Why are K sparing diuretics rarely used for edema or hypertension

Because they only evoke MILD natriuresis effect

Since K sparring only induce mild natriuresis effects, what combination of drugs increase their diuretic and anti-hypertensive response

K sparring + thiazides or loop diuretics

What does aerosolized amiloride improve

Muco-ciliary clearance in patients with cystc firborsis

What drug is useful for lithium-induced nephrogenic diabetes insipidus

Amiloride BECAUSE it blocks Li transport to the cells of the collecting tubules

Which type of diuretic drug class antagonizes mineralocorticoid receptors

K sparring diuretics

• Spironolactone

• Eplrerenone

Activation of mineralcorticoids in the nephron leads to what changes

increased:

• Na reabsorption

• Water retention

• K excretion

What do epithelial cells in the late distal tubule and collecting duct of the nephron containing mineralcorticoid receptors have a high affinity for

Aldosterone

What is the intracellular mechanism of action of aldosterone in renal epithelial cells

Aldosterone binds to MR → this coomplex moves to the nucleus → regualts transcription of genes → production of aldosterone induced proetins (AIPs)

Whatis the effect of aldosterone induced proteins (AIPs) on Na trasnport in renal epithelial cells

AIPs:

• increase Na conductance in the luminal membrane

• increase Na/K ATPase activity in basolateral membrane

Enhancing Na/Cl REABSORPTION

How does aldosterone increase K and H secretion in the nephrone

Increased Na reabsorption creates a lumen-negative transepithelial potential, which drives secretion of K and H into the tubular lumen.

Which diuretics is the only diuretics that DO NOT require access to the tubular lumen to induce diuresis

MR antagonist

What are the effects of MR antagonists on renal hemodynamics and tubuloglomerular feedback (TGF)

little to NO effect

Spirnolactone has some affinity for progesterone and andorgen receptors, so what does this lead to

Induce side effects like

• Menstrual irregularities

• Impotence and gynecomastia

What is gynecomastia and which K sparing diuretic casues this

Enlarged titties in males

• Spirnolactone

What drug combination is used o treat edema and hypertension

Sipronolactone + Thiazide OR loop diuretics

Which drug is used to treat primary hyperaldosteronism? and what is hyperaldosteronism

Spironolactone

Hyperaldosteronism (Conn’s syndrome) = disorder where adrenal glands make excessive adlosterone

Which diuretic drug i sused to treat patients with liver cirrhosis + heart failure

Spironolactone

• multidrug therapy with spironolactone