Download Diuretic agents Diuretic A "diuretic" is an agent that increases urine

Diuretic agents
Diuretic
A "diuretic" is an agent that increases urine volume, while a "natriuretic"
causes an increase in renal sodium excretion. Because natriuretics almost
always also increase water excretion, they are usually called diuretics.
Renal Tubule Transport Mechanisms:
Approximately 16 to 20 percent of the blood plasma entering the
kidneys is filtered from the glomerular capillaries into the Bowman's
capsule. The filtrate, although normally free of proteins and blood cells,
does contain most low-molecular-weight plasma components in
approximately the same concentrations as are found in the plasma. These
include glucose, sodium bicarbonate, amino acids, and other organic
solutes as well as electrolytes, such as Na+, K+, and Cl-.
Normal Regulation of Fluid and Electrolytes by the Kidneys
A- In Proximal Tubule.
Approximately 66% of total sodium ions (Na +), 85% of the filtered
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.
Sodium bicarbonate reabsorption is initiated by the action of Na +\H+
exchange, allow the Na+ to enter the cell from tubular lumen in one for
one exchange with a proton usually H+ from inside the cells. Proton
secreted in the lumen combine with bicarbonate to form carbonic acid
(H2CO3), H2CO3 is dehydrated in order to be transported into CO2
+H2O which cross the membranes, and this reaction is catalyzed by
carbonic anhydrase enzyme (CA).
B- LOOP OF HENLE.
The proximal tubule empties into the thin descending limb of
Henle's loop. Water is extracted from the descending limb of this
loop by osmotic forces found in the hypertonic medullary
interstitium.
And not participate in salt reabsorption .As the
DLOH freely permeabile to water and not to solutes until it
reaches benet of LOH ( maxim. Concentrated urine ).
The thick ascending
The thick ascending limb (TAL) of the loop of Henle actively
reabsorbs NaCl from the lumen (about 25% of the filtered sodium),
The thick ascending limb is nearly impermeable to water. Salt
reabsorption in the TAL therefore dilutes the tubular fluid, and it is called
a "diluting segment."
The NaCl transport system in the luminal membrane of the TAL is a
Na+/K+/2Cl- cotransporter . This transporter is selectively blocked by
diuretic agents known as "loop" diuretics.
C- Distal convulated tubule
Only about 10% of the filtered NaCl is reabsorbed in the distal
convoluted tubule (DCT). This segment is relatively impermeable to
water , and NaCl reabsorption further dilutes the tubular fluid. This Na +
and Cl- cotransport is blocked by Thiazide-diuretics.
Ca2+ is actively reabsorbed by the DCT epithelial cell via an apical Ca 2+
channel and basolateral Na+/Ca2+ exchanger. This process is regulated by
parathyroid hormone.
D- Convoluting Collecting tubule (CCT):(( Na+ exchange for K+,
H+)
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 . The collecting tubule is responsible for only 2-5% of
NaCl reabsorption by the kidney. As it is 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. Reabsorption of Na+ via the epithelial Na channel (ENaC) and its
coupled secretion of K+ is regulated by aldosterone.
CARBONIC ANHYDRASE INHIBITORS (Acetazolamide )
Carbonic anhydrase is present in many nephron sites, but the
predominant location of this enzyme is the luminal membrane of the PCT
where it catalyzes the dehydration of H2CO3. By blocking carbonic
anhydrase, the exchange of Na+ to H+ will be decreased and result in
mild diuresis ,in addition NaHCO3 is retained in the lumin with elevation
of urinary PH. The loss of HCO3 and retained of H+ result in metabolic
acidosis .
Pharmacodynamics
Inhibition of carbonic anhydrase activity profoundly depresses
85% of the HCO3- reabsorption in the PCT, and causes significant HCO3losses . The fact that HCO3- depletion leads to enhanced NaCl
reabsorption by the remainder of the nephron, the diuretic efficacy of
acetazolamide decreases significantly with use over several days and
hyperchloremic
metabolic
acidosis
occur.
At present, the major clinical applications of acetazolamide involve
carbonic anhydrase-dependent HCO3- and fluid transport at sites other
than the kidney. The ciliary body of the eye secretes HCO 3- from the
blood into the aqueous humor. Likewise, formation of cerebrospinal fluid
by the choroid plexus involves HCO3- secretion, they are similarly
inhibited by carbonic anhydrase inhibitors.
Pharmacokinetics
The carbonic anhydrase inhibitors are well absorbed after oral
administration. An increase in urine pH from the HCO 3- diuresis is
apparent within 30 minutes, maximal at 2 hours, and persists for 12 hours
after a single dose. Excretion of the drug is by secretion in the proximal
tubule segment. Therefore, dosing must be reduced in renal insufficiency.
Clinical Indications :
A.Glaucoma : The most common use of acetazolamide is to reduce the
elevated intraocular pressure of open-angle glaucoma. Acetazolamide
decreases the production of aqueous humor, probably by blocking
carbonic anhydrase in the ciliary body of the eye. It is useful in the
chronic treatment of glaucoma but should not be used for an acute attack;
pilocarpine is preferred for an acute attack because of its immediate
action..
B.Urinary alkalinization
C. Metabolic alkalosis .
D. Acute mountain sickness.
Side effects
A- Hyperchloremic metabolic acidosis
B. Renal stones .
Phosphaturia and hypercalciuria occur during the bicarbonaturic
response to inhibitors of carbonic anhydrase. Calcium salts are relatively
insoluble at alkaline pH, which means that the potential for renal stone
formation from these salts is enhanced.
C. Renal potassium wasting .
Potassium wasting can occur because Na+ presented to the collecting
tubule is partially reabsorbed and thus enhancing K+ secretion.
D. Other toxicities.
Drowsiness and paresthesias are common following large doses of
acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients
with renal failure, leading to nervous system toxicity. Hypersensitivity
reactions (fever, rashes, bone marrow suppression, and interstitial
nephritis) may also occur.
LOOP DIURETICS. (furosemide
bumetanide and torsemide and
ethacrynic acid).
Due to the large NaCl absorptive capacity of this segment , loop
diuretics are among the most efficacious diuretic agents available.
Mechanism of action .
These drugs inhibit the luminal Na+/K+/2Cl- co-transporter in the thick
ascending limb of Henle's loop. By inhibiting this transporter, the loop
diuretics reduce the reabsorption of NaCl and also diminish the lumenpositive potential that comes from K+ recycling . This positive potential
normally drives divalent cation reabsorption in the loop and by reducing
this potential, loop diuretics cause an increase in Mg2+ and Ca2+
excretion. Prolonged use can cause significant hypomagnesemia in some
patients. Since the ALOH responsible for reabsorption of 25-30% of
filterd Nacl, and the downstream sites cannot able to compensate for this
increased Na+ load, the loop diuretics are the most efficacious agents .
In addition to their diuretic activity, loop agents have direct effects on
blood flow through several vascular beds by inducing the synthesis of
prostaglandins, both furosemide and ethacrynic acid have also been
shown to reduce pulmonary congestion and left ventricular filling
pressures in heart failure before a measurable increase in urinary output
occurs.
Pharmacokinetics
The loop diuretics are rapidly absorbed. They are eliminated by the
kidney by glomerular filtration and tubular secretion. Absorption of oral
torsemide is more rapid (1 hour) than that of furosemide (2-3 hours) and
is nearly as complete as with intravenous administration. The duration of
effect for furosemide is usually 2-3 hours and that of torsemide is 4-6
hours. Half-life depends on renal function.
:
The most important indications : Acute pulmonary edema, other
edematous conditions, hyperkalemia, acute renal failure, and anion
overdose(toxic ingestions of bromide, fluoride, and iodide, which are
reabsorbed in the thick ascending limb).
Side effects.
A. hypokalemic metabolic alkalosis .
By inhibiting salt reabsorption in the TAL, loop diuretics increase Na
delivery to the collecting duct. Increased delivery leads to increased
secretion of K+ and H+ by the duct, causing hypokalemic metabolic
alkalosis .This toxicity is a function of the magnitude of the diuresis and
can be reversed by K+ replacement and correction of hypovolemia.
B. Ototoxicity.
Loop diuretics occasionally cause dose-related hearing loss that is usually
reversible. It is most common in patients receiving other ototoxic agents
such as aminoglycoside antibiotics.
C. Hyperuricemia.
Loop diuretics compete with uric acid secretion in the proximal tubule. .
D.Hypomagnesmia .
E.Allergic reaction
Except for ethacrynic acid, the loop diuretics are sulfonamides. Therefore
skin rash, eosinophilia and, less often, interstitial nephritis are occasional
side effects of these drugs. This toxicity usually resolves rapidly after
drug withdrawal. Loop diuretics can cause sever dehydration .
THIAZIDES
The thiazide diuretics are the most widely used of the diuretics drugs,
thiazides inhibit NaCl transport predominantly in the DCT by different
mechanisms. The prototypical thiazide is hydrochlorothiazide.
Pharmacokinetics:
All of the thiazides can be administered orally. All of the thiazides
are secreted by the organic acid secretory system in the proximal tubule
and compete with the secretion of uric acid by that system. As a result,
thiazide use may blunt uric acid secretion and elevate serum uric acid
level.
Pharmacodynamics
Thiazides inhibit NaCl reabsorption from the luminal side of
epithelial cells in the DCT by blocking the Na +/Cl- transporter , as aresult
these drugs increase the concentration of Na ana Cl- in the tubular fluid .
The increased Na+ in the filtrate arriving in distal tubule , more K- will
also exchange for Na+, thus prolonged use of thiazide result in continous
loss of K+ from the body . In contrast to the situation in the TAL, where
loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca 2+
reabsorption. Thiazides are useful in the treatment of kidney stones
caused by hypercalciuria.
The action of thiazides depends in part on renal prostaglandin production,
therefore with continues use there is a continuous hypotensive effect
resulting from reduced pvr caused by relaxation of arteriolar smooth
muscles.
The actions of thiazides can also be inhibited by NSAIDs under certain
conditions.
Clinical Indications :
The major indications for thiazide diuretics are (1) hypertension, (2) heart
failure, (3) nephrolithiasis due to idiopathic hypercalciuria, and (4)
nephrogenic diabetes insipidus, because thiazide have ability to produce
hyperosmollar urine
Side effects
A.hypokalemia.
B- Hyponatremia.
C- Hypercalcemia
D- Hyperuricemia. Compete with uric acid secretion.
E-Hyperglycemia may occur in patients who are overtly diabetic or who
have even mildly abnormal glucose tolerance tests. The effect is due to
both impaired pancreatic release of insulin and diminished tissue
utilization of glucose.
F.Hyperlipidemia :Thiazides cause a 5-15% increase in total serum
cholesterol and low-density lipoproteins (LDL). These levels may return
toward baseline after prolonged use.
G. Allergic reaction The thiazides are sulfonamides and share crossreactivity with other members of this chemical group. Photosensitivity or
generalized dermatitis occurs rarely.
F. Other toxicities.Weakness, fatigability, and paresthesias similar to
those of carbonic anhydrase inhibitors may occur. Impotence has been
reported but is probably related to volume depletion. Volume depletion
can cause orthostatic hypotension
POTASSIUM-SPARING DIURETICS.
These diuretics prevent K+ secretion by antagonizing the effects of
aldosterone at the late distal and cortical collecting tubules. Inhibition
may occur by direct pharmacologic antagonism of mineralocorticoid
receptors (spironolactone) or by inhibition of Na+ influx through ion
channels in the luminal membrane (amiloride, triamterene).
Pharmacokinetics:
Overall, spironolactone has a rather slow onset of action, requiring
several
days
before
full
therapeutic
effect
is
achieved.
Amiloride and triamterene are direct inhibitors of Na + influx in the CCT.
Triamterene is metabolized in the liver, and excreted by the kidney, it has
a shorter half-life and must be given more frequently than amiloride .
Pharmacodynamics
Potassium-sparing diuretics reduce Na+ absorption in the
collecting tubules and ducts. Na+ absorption (and K+ secretion) at this site
is regulated by aldosterone, as described above. Spironolactone binds to
aldosterone receptors and act as competitive antagonist to aldesteron.
Amiloride and triamterene do not block the aldosterone receptor
but instead directly inhibits Na+ reabsorption in CCT. Since K+ secretion
is coupled with Na+ entry in this segment, these agents are also effective
potassium-sparing diuretics. Similar effects are observed with respect to
H+ handling by the intercalated cells of the collecting tubule, in part
explaining the metabolic acidosis seen with aldosterone antagonists).
Clinical Indications .
Potassium-sparing diuretics
mineralocorticoid
excess
or
are most
useful in
hyperaldosteronism
states
(also
of
called
aldosteronism), due either to primary hypersecretion (Conn's syndrome,
ectopic adrenocorticotropic hormone production) or to secondary
hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic
syndrome, or other conditions associated with diminished
effective
intravascular
volume).
Toxicity
A.Hyperkalemia Unlike other diuretics, K+-sparing diuretics can
cause mild, moderate, or even life-threatening hyperkalemia . The risk of
this complication is greatly increased by renal disease (in which maximal
K+ excretion may be reduced) or by the use of other drugs that reduce
renin (beta- blockers, NSAIDs) or angiotensin II activity (angiotensinconverting enzyme inhibitors, angiotensin receptor inhibitors
B. metabolic acidosis ; By inhibiting H+ secretion in parallel with K+
secretion.
C.Gyencomastia
: Gynecomastia, impotence, and benign prostatic
hyperplasia have all been reported with spironolactone.
D. Acute renal failure .The combination of triamterene with
indomethacin has been reported to cause acute renal failure. This has not
been reported with other K+-sparing diuretics.
E. Kidney stones; Triamterene is only slightly soluble and may
precipitate in the urine, causing kidney stones.
Osmotic Diuretics (Manitol).
The proximal tubule and descending limb of Henle's loop are freely
permeable to water . Any osmotically active agent that is filtered by the
glomerulus but not reabsorbed such as mannitol and urea cause water to
be retained in these segments.
If the substance that is filtered
subsequently undergoes little or no reabsorption, then the filtered
substance will cause an increase in urinary output and promotes a water
diuresis.
Pharmacokinetics
Osmotic diuretics are poorly absorbed, which means that they must
be given parenterally. If administered orally, mannitol causes osmotic
diarrhea. Mannitol is not metabolized and is excreted by glomerular
filtration within 30-60 minutes, without any important tubular
reabsorption or secretion.
Pharmacodynamics
Osmotic diuretics have their major effect in the proximal tubule
and the descending limb of Henle's loop. The presence of a
nonreabsorbable solute such as mannitol prevents the normal absorption
of water by interposing a countervailing osmotic force. As a result, urine
volume increases. The increase in urine flow rate decreases the contact
time between fluid and the tubular epithelium, thus reducing Na+ as well
as water reabsorption. The resulting natriuresis is of lesser magnitude
than the water diuresis, leading eventually to excessive water loss and
hypernatremia.
Clinical Indications
A.To increase urine.
Osmotic diuretics are used to increase water excretion in preference
to sodium excretion. This effect can be useful when avid Na + retention
limits the response to conventional agents. It can be used to maintain
urine volume and to prevent anuria that might otherwise result from
presentation of large pigment loads to the kidney (eg, from hemolysis or
rhabdomyolysis).
B. Reduction of intracranial and intraoculal pressure.
Osmotic diuretics alter Starling forces so that water leaves cells and
reduces intracellular volume. This effect is used to reduce intracranial
pressure in neurologic conditions and to reduce intraocular pressure
before ophthalmologic procedures. A dose of 1-2 g/kg mannitol is
administered intravenously.
Toxicity.
A. Extracellular volume expansion
Mannitol is rapidly distributed in the extracellular compartment and
extracts water from cells. Prior to the diuresis, this leads to expansion of
the extracellular volume and hyponatremia. This effect can complicate
heart failure and may produce florid pulmonary edema. Headache,
nausea, and vomiting are commonly observed in patients treated with
osmotic
diuretics.
B. Dehydration, Hyperkalemia,and hypernatremia .
Excessive use of mannitol without adequate water replacement can
ultimately lead to severe dehydration, free water losses, and
hypernatremia. As water is extracted from cells, intracellular K +
concentration rises, leading to hyperkalemia.
6- ADH Antagonists
ADH regulates water balance in the body (controlled
in the
hypothalamus , excreted by the posterior pituitary, controls
aquaporins)
• ADH antagonists block the ADH receptors in the kidneys.
Inhibition of ADH receptors causes excretion of free water without
electrolyte loss (aquaresis).