CLASSIFICATION OF DIURETIC

Classification DRUGS Brand Name

Mechanism of action

THIAZIDES AND RELATED (Chlorothiazide) 3 Steps

SULFONAMIDE Hydrochlorothiazide 1. They are secreted in the proximal convoluted
DIURETICS Clopamide Indapamide tubules (like the loop diuretics; OAT1  OAT4,
Chlorthalidone MRP4)
2. Travel along the nephron down to the distal
convoluted tubule (DCT; the site of action)
3. Inhibit Na+ Clsymporter in the luminal membrane
of DCT cells (by binding to its Cl- -binding site)
(Mutation of Na+ Clsymporter: Gitelman’s
syndrome, a form of inherited hypokalemic
alkalosis.)
 Na+ , Clreabsorption
 Mg2+ , Ca2+ reabsorption
 K + , H+ secretion in the DCT ( hypokalemia,
alkalosis, hypercalcemia hypomagnesemia)
LOOP DIURETICS Furosemide 3 Steps
Bumetanide 1. They are secreted by the proximal convoluted
Torasemide tubule via the basolateral OAT1  luminal OAT4
Ethacrynic acid and MRP4 – see Appendix 4.
2. Travel along the nephron to the thick ascending
limb of the loop of Henle
3. Bind to and inhibit the Na+ K + 2Clsymporter in
the luminal membrane of the tubular cells  The
diuretic effect correlates with the urinary
excretion rather than with the blood levels of
these drugs
 Na+ , Clreabsorption
 Ca2+ , Mg2+ reabsorption
 K + , H+ secretion in the DCT ( hypokalemia,
alkalosis, hypocalcemia hypomagnesemia)
OSMOTIC DIURETICS Mannitol 1. After getting into the bloodstream and then into the
Urea extracellular water space, osmotic diuretics increase the
Glycerin osmolarity of the plasma and the extracellular (EC) water
Isosorbide  osmotically extract water from the intracellular space
 expand the extracellular fluid volume
  the renal blood flow, i. e.:
  the glomerular blood flow   GFR
  the blood flow in vasa recta
 NaCl in the interstitium of the medulla (carried
there by Na+K + 2Clsymporter of the ascending limb of the
loop of Henle) is washed out
  the medullary tonicity created by the
ascending limb of the loop of Henle
  water reabsorption from the leaky
descending limb of the loop of Henle
 DIURESIS
2. After being filtered in the glomeruli without being
 reabsorbed in the renal tubules, osmotic diuretics
 the osmolarity of the tubular fluid
  the reabsorption of water from the "leaky"
segments of the tubular system, i.e.
 from the proximal convoluted tubule, i.e.:
 from the descending limb of the loop of Henle
 from the collecting duct
 DIURESIS
Osmotic diuretics are
- primarily diuretics:  water excretion
- secondarily saluretics:  salt excretion due to:
- dilution of tubular fluid (  salt
reabsorption) - faster tubular fluid flow ( 
salt reabsorption)
CARBONIC ANHYDRASE Acetazolamide Acetazolamide avidly binds to and potently inhibits
INHIBITORS Brinzolamide* carbonic anhydrase (CA), a Zn-containing enzyme (IC ~10
Dichlorphenamide* nM). Renal CA is largely in the proximal tubular cells, both
Methazolamide* in the luminal membrane (facing the lumen) and the
cytoplasm.
 Na+ –H + exchange
 NaHCO3 reabsorption  alkaline urine
  H + secretion  systemic acidosis
Na+ CHANNEL Amiloride 3 Steps
ANTAGONISTS Triamterene 1. Amiloride and triamterene, as organic cations, are
secreted by the organic cation secretory
mechanism into the proximal convoluted tubules
(OCT2  MATE; see Appendix 4).
2. They travel along the nephron to the collecting
duct (the site of action).
3. They block Na+ channels in the apical membrane
of the principal cells in the collecting duct. These
Na+ channels are called epithelial Na+ channels;
they are different from the voltage-gated Na+
channels that are present in the plasma
membrane of excitable cells.
 Na+ reabsorption
 K + , H+ secretion in the CD ( hyperkalemia, acidosis)
ALDOSTERONE Spironolactone The effects of aldosterone (the most potent
ANTAGONISTS (MRA) Canrenoate mineralocorticoid produced by the suprarenal gland):
Eplerenone 1. The renal effects of aldosterone – physiological
effects:
 It acts on i.c. mineralocorticoid receptors (MR)
in the principal cells of the distal convoluted
tubule (DCT) and the collecting duct (CD)
 It increases the expression of:
- the Na+ channels  in the luminal
membrane of principal cells
- the Na+K +ATPase  in the basolateral
membrane of principal cells.
 Effects:
- Primary:  Na+ reabsorption from the DCT and
the CD (via Na+ channel  Na+K +ATPase) -
 Secondary:  lumen-negative transepithelial
potential difference, which promotes:
- K + secretion (via K+ channels in principal cells)
- H + secretion (via H+ -ATPase in type A
intercalated cells).
2. The cardiovascular effects of aldosterone –
pathophysiological effects:
 Activation of the RAAS (which occurs in congestive
heart failure and cardiac infarct, for example) causes
several adverse cardiovascular effects. These include high
blood pressure, cardiac and vascular remodeling (i.e.
hypertrophy and fibrosis), renal injury with magnesium
loss, baroreceptor sensitization, ventricular arrhythmias,
and increased mortality in patients with heart failure. It
has been assumed that angiotensin II causes these
negative outcomes of RAAS activation.
 However, aldosterone also plays a role. MR is also
found in cardiomyocytes, the vascular smooth muscle cells
and macrophages. Through MR in these cells, aldosterone
(or the much less active but much more abundant cortisol)
induces expression of genes whose products (e.g. BMP,
ALP, collagene) contribute to cardiovascular hypertrophy
and remodeling, and in turn, to the adverse clinical
consequences of RAAS activation (e.g. heart failure,
hypertension, arrythmias, renal impairment).
 Na+ reabsorption
 K + , H+ secretion in the CD ( hyperkalemia, acidosis)