Download Loop diuretics

Diuretics
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-.
Regulation of Fluid and Electrolytes by the Kidneys
A. Proximal convoluted tubuleNormal 
- 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
Descending 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 Ca2+ 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
Mechanism of action: 
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 .
s
Pharmacodynamics
Inhibition of carbonic anhydrase activity profoundly depresses 85%
of the HCO3- reabsorption in the PCT., and causes significant
HCO3- losses . ,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 HCO3from 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.

Therapeutic uses:
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).
mechanism of action
Mechanism of action .
These drugs inhibit the luminal Na+/K+/2Clco-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 lumen-positive
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.
Clinical Indications
:
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
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 Ca2+ 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 cross-reactivity 
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
mechanism of action
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
toaldesteron.
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 are most useful in states of 
mineralocorticoid excess or hyperaldosteronism (also
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 lifethreatening 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 (angiotensin-converting 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 12 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.

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).
• Conivaptan
• Lixivaptan
• Tolvaptan
ADH Antagonists
• Conivaptan
• Lixivaptan
• Tolvaptan
25-42
Preferred Treatment
© 2012 The McGraw-Hill Companies, Inc. All rights reserved.
THANKS FOR YOUR
ATTENTION !!!