Diuretics

Diuretics

An Overview
Diuretics (saluretics) elicit increased
production of urine (diuresis). In the
strict sense, the term is applied to drugs
with a direct renal action. The predominant
action of such agents is to augment
urine excretion by inhibiting the reabsorption
of NaCl and water.
The most important indications for
diuretics are:
Mobilization of edemas: In edema
there is swelling of tissues due to accumulation
of fluid, chiefly in the extracellular
(interstitial) space. When a diuretic
is given, increased renal excretion
of Na+ and H2O causes a reduction in
plasma volume with hemoconcentration.
As a result, plasma protein concentration
rises along with oncotic pressure.
As the latter operates to attract
water, fluid will shift from interstitium
into the capillary bed. The fluid content
of tissues thus falls and the edemas recede.
The decrease in plasma volume
and interstitial volume means a diminution
of the extracellular fluid volume
(EFV). Depending on the condition, use
is made of: thiazides, loop diuretics, aldosterone
antagonists, and osmotic diuretics.
Antihypertensive therapy. Diuretics
have long been used as drugs of first
choice for lowering elevated blood pressure
. Even at low dosage, they
decrease peripheral resistance (without
significantly reducing EFV) and thereby
normalize blood pressure.
Therapy of congestive heart failure.
By lowering peripheral resistance, diuretics
aid the heart in ejecting blood (reduction
in afterload); cardiac
output and exercise tolerance are
increased. Due to the increased excretion
of fluid, EFV and venous return decrease
(reduction in preload).
Symptoms of venous congestion, such
as ankle edema and hepatic enlargement,
subside. The drugs principally
used are thiazides (possibly combined
with K+-sparing diuretics) and loop diuretics.
Prophylaxis of renal failure. In circulatory
failure (shock), e.g., secondary to
massive hemorrhage, renal production
of urine may cease (anuria). By means of
diuretics an attempt is made to maintain
urinary flow. Use of either osmotic
or loop diuretics is indicated.
Massive use of diuretics entails a
hazard of adverse effects : (1) the
decrease in blood volume can lead to
hypotension and collapse; (2) blood viscosity
rises due to the increase in erythro-
and thrombocyte concentration,
bringing an increased risk of intravascular
coagulation or thrombosis.
When depletion of NaCl and water
(EFV reduction) occurs as a result of diuretic
therapy, the body can initiate
counter-regulatory responses,
namely, activation of the renin-angiotensin-
aldosterone system. Because
of the diminished blood volume,
renal blood flow is jeopardized. This
leads to release from the kidneys of the
hormone, renin, which enzymatically
catalyzes the formation of angiotensin I.
Angiotensin I is converted to angiotensin
II by the action of angiotensin-converting
enzyme (ACE). Angiotensin II
stimulates release of aldosterone. The
mineralocorticoid promotes renal reabsorption
of NaCl and water and thus
counteracts the effect of diuretics. ACE
inhibitors augment the effectiveness
of diuretics by preventing this
counter-regulatory response.

NaCl Reabsorption in the Kidney
The smallest functional unit of the kidney
is the nephron. In the glomerular
capillary loops, ultrafiltration of plasma
fluid into Bowman’s capsule (BC) yields
primary urine. In the proximal tubules
(pT), approx. 70% of the ultrafiltrate is
retrieved by isoosmotic reabsorption of
NaCl and water. In the thick portion of
the ascending limb of Henle’s loop (HL),
NaCl is absorbed unaccompanied by
water. This is the prerequisite for the
hairpin countercurrent mechanism that
allows build-up of a very high NaCl concentration
in the renal medulla. In the
distal tubules (dT), NaCl and water are
again jointly reabsorbed. At the end of
the nephron, this process involves an aldosterone-
controlled exchange of Na+
against K+ or H+. In the collecting tubule,
vasopressin (antidiuretic hormone,
ADH) increases the epithelial permeability
for water, which is drawn into
the hyperosmolar milieu of the renal
medulla and thus retained in the body.
As a result, a concentrated urine enters
the renal pelvis.
Na+ transport through the tubular
cells basically occurs in similar fashion
in all segments of the nephron. The
intracellular concentration of Na+ is significantly
below that in primary urine.
This concentration gradient is the driving
force for entry of Na+ into the cytosol
of tubular cells. A carrier mechanism
moves Na+ across the membrane. Energy
liberated during this influx can be
utilized for the coupled outward transport
of another particle against a gradient.
From the cell interior, Na+ is moved
with expenditure of energy (ATP hydrolysis)
by Na+/K+-ATPase into the extracellular
space. The enzyme molecules
are confined to the basolateral parts of
the cell membrane, facing the interstitium;
Na+ can, therefore, not escape back
into tubular fluid.
All diuretics inhibit Na+ reabsorption.
Basically, either the inward or the
outward transport of Na+ can be affected.

Osmotic Diuretics
Agents: mannitol, sorbitol. Site of action:
mainly the proximal tubules. Mode of
action: Since NaCl and H2O are reabsorbed
together in the proximal tubules,
Na+ concentration in the tubular fluid
does not change despite the extensive
reabsorption of Na+ and H2O. Body cells
lack transport mechanisms for polyhydric
alcohols such as mannitol
and sorbitol, which are
thus prevented from penetrating cell
membranes. Therefore, they need to be
given by intravenous infusion. They also
cannot be reabsorbed from the tubular
fluid after glomerular filtration. These
agents bind water osmotically and retain
it in the tubular lumen. When Na
ions are taken up into the tubule cell,
water cannot follow in the usual
amount. The fall in urine Na+ concentration
reduces Na+ reabsorption, in part
because the reduced concentration gradient
towards the interior of tubule cells
means a reduced driving force for Na+
influx. The result of osmotic diuresis is a
large volume of dilute urine.
Indications: prophylaxis of renal
hypovolemic failure, mobilization of
brain edema, and acute glaucoma.

Diuretics of the Sulfonamide Type
These drugs contain the sulfonamide
group -SO2NH2. They are suitable for
oral administration. In addition to being
filtered at the glomerulus, they are subject
to tubular secretion. Their concentration
in urine is higher than in blood.
They act on the luminal membrane of
the tubule cells. Loop diuretics have the
highest efficacy. Thiazides are most frequently
used. Their forerunners, the
carbonic anhydrase inhibitors, are now
restricted to special indications.
Carbonic anhydrase (CAH) inhibitors,
such as acetazolamide and sulthiame,
act predominantly in the proximal
tubules. CAH catalyzes CO2 hydration/
dehydration reactions:
H+ + HCO3
–H2CO3!H20 + CO2.
The enzyme is used in tubule cells
to generate H+, which is secreted into
the tubular fluid in exchange for Na+.
There, H+ captures HCO3
–, leading to formation
of CO2 via the unstable carbonic
acid. Membrane-permeable CO2 is taken
up into the tubule cell and used to regenerate
H+ and HCO3
–. When the enzyme
is inhibited, these reactions are
slowed, so that less Na+, HCO3
– and water
are reabsorbed from the fast-flowing
tubular fluid. Loss of HCO3
– leads to acidosis.
The diuretic effectiveness of CAH
inhibitors decreases with prolonged
use. CAH is also involved in the production
of ocular aqueous humor. Present
indications for drugs in this class include:
acute glaucoma, acute mountain
sickness, and epilepsy. Dorzolamide can
be applied topically to the eye to lower
intraocular pressure in glaucoma.
Loop diuretics include furosemide
(frusemide), piretanide, and bumetanide.
With oral administration, a strong
diuresis occurs within 1 h but persists
for only about 4 h. The effect is rapid, intense,
and brief (high-ceiling diuresis).
The site of action of these agents is the
thick portion of the ascending limb of
Henle’s loop, where they inhibit
Na+/K+/2Cl– cotransport. As a result,
these electrolytes, together with water,
are excreted in larger amounts. Excretion
of Ca2+ and Mg2+ also increases.
Special toxic effects include: (reversible)
hearing loss, enhanced sensitivity to
renotoxic agents. Indications: pulmonary
edema (added advantage of i.v. injection
in left ventricular failure: immediate
dilation of venous capacitance
vessels ! preload reduction); refractoriness
to thiazide diuretics, e.g., in renal
hypovolemic failure with creatinine
clearance reduction (<30 mL/min); prophylaxis
of acute renal hypovolemic
failure; hypercalcemia. Ethacrynic acid
is classed in this group although it is not
a sulfonamide.
Thiazide diuretics (benzothiadiazines)
include hydrochlorothiazide,
benzthiazide, trichlormethiazide, and
cyclothiazide. A long-acting analogue is
chlorthalidone. These drugs affect the
intermediate segment of the distal tubules,
where they inhibit a Na+/Cl– cotransport.
Thus, reabsorption of NaCl
and water is inhibited. Renal excretion
of Ca2+ decreases, that of Mg2+ increases.
Indications are hypertension, cardiac
failure, and mobilization of edema.
Unwanted effects of sulfonamidetype
diuretics: hypokalemia is a consequence
of excessive K+ loss in the terminal
segments of the distal tubules
where increased amounts of Na+ are
available for exchange with K+; hyperglycemia
and glycosuria; hyperuricemia—
increase in serum urate levels
may precipitate gout in predisposed
patients. Sulfonamide diuretics compete
with urate for the tubular organic
anion secretory system.

Potassium-Sparing Diuretics

These agents act in the distal portion of
the distal tubule and the proximal part
of the collecting ducts where Na+ is reabsorbed
in exchange for K+ or H+. Their
diuretic effectiveness is relatively minor.
In contrast to sulfonamide diuretics,
there is no increase in K+ secretion;
rather, there is a risk of hyperkalemia.
These drugs are suitable for oral
administration.
a) Triamterene and amiloride, in addition
to glomerular filtration, undergo
secretion in the proximal tubule. They
act on the luminal membrane of tubule
cells. Both inhibit the entry of Na+,
hence its exchange for K+ and H+. They
are mostly used in combination with
thiazide diuretics, e.g., hydrochlorothiazide,
because the opposing effects on K+
excretion cancel each other, while the
effects on secretion of NaCl complement
each other.
b) Aldosterone antagonists. The
mineralocorticoid aldosterone promotes
the reabsorption of Na+ (Cl– and
H2O follow) in exchange for K+. Its hormonal
effect on protein synthesis leads
to augmentation of the reabsorptive capacity
of tubule cells. Spironolactone, as
well as its metabolite canrenone, are antagonists
at the aldosterone receptor
and attenuate the effect of the hormone.
The diuretic effect of spironolactone develops
fully only with continuous administration
for several days. Two possible
explanations are: (1) the conversion
of spironolactone into and accumulation
of the more slowly eliminated
metabolite canrenone; (2) an inhibition
of aldosterone-stimulated protein synthesis
would become noticeable only if
existing proteins had become nonfunctional
and needed to be replaced by de
novo synthesis. A particular adverse effect
results from interference with gonadal
hormones, as evidenced by the development
of gynecomastia (enlargement
of male breast). Clinical uses include
conditions of increased aldosterone
secretion, e.g., liver cirrhosis with
ascites.
Antidiuretic Hormone (ADH) and
Derivatives (B)
ADH, a nonapeptide, released from the
posterior pituitary gland promotes reabsorption
of water in the kidney. This
response is mediated by vasopressin receptors
of the V2 subtype. ADH enhances
the permeability of collecting duct
epithelium for water (but not for electrolytes).
As a result, water is drawn
from urine into the hyperosmolar interstitium
of the medulla. Nicotine augments
and ethanol decreases
ADH release. At concentrations above
those required for antidiuresis, ADH
stimulates smooth musculature, including
that of blood vessels (“vasopressin”).
The latter response is mediated by
receptors of the V1 subtype. Blood pressure
rises; coronary vasoconstriction
can precipitate angina pectoris. Lypressin
(8-L-lysine vasopressin) acts like
ADH. Other derivatives may display only
one of the two actions.
Desmopressin is used for the therapy
of diabetes insipidus (ADH deficiency),
nocturnal enuresis, thrombasthemia
, and chronic hypotension;
it is given by injection or via
the nasal mucosa (as “snuff”).
Felypressin and ornipressin serve as
adjunctive vasoconstrictors in infiltration
local anesthesia.