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Diuretics

The term diuretics is applied to


the agent that act directly on
the kidney which elicit "diuresis
( in urine volume) by promoting the
renal excretion of Na+ "natriuresis
( sodium excretion in the kidney) &
the excreted Na+ is followed
osmotically by water
Therefore plasma volume
1st lec.

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Therefore the predominant


action of such agents is to
enhancement of the urine
excretion by inhibiting the
reabsorption of Na+ (natriuretic)
&thus H2O

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The effects of diuretics are predictable from


a knowledge the function of the segment
of the nephron in which they act

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Renal transport mechanisms &


diuretic drug groups:
1- Proximal convoluted Tubule (PCT)
The major site for NaCl & NaHCO3 reabsorption
Active secretion & re-absorption of weak
acids &weak bases also occurs in the PCT
PCT is responsible for ~60-70% of the
total re-absorption of Na+

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60% of the filtered H2O is passively


reabsorbed the target of osmotic
diuretics action
85% of the filtered NaHCO3 are
reabsorbed through the action of
carbonic anhydrase enzyme
the target of carbonic anhydrase
inhibitor diuretics action
(Carbonic anhydrase enzyme the
enzyme required for the HCO3reabsorption process)
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2- Descending limb of the loop of Henle


No solute re-absorption take place in this segment
Water is passively re-absorbed in which osmotic
diuretics can partly exert their action
3 -Thick ascending limb of loop of Henle
(TAL)
This segment pumps Na/K+/2Cl- out of the lumen
of the kidney
It is also a major site of Ca++ & Mg++ reabsorption
The loop of Henle is the major site for salt
re-absorption
This region is impermeable to water, resulting in
dilution
of the luminal
fluid
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Dr. Hala Zaqout

Thus the thick ascending limb of the loop


of Henle (TAL) is sometimes referred to as
diluting segment
Re-absorption of Na+, K+ & Cl- are all
accomplished by a single carrier Na+/
K+/ 2Cl co-transporter which is the
target of the loop diuretics action

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4- Distal Convoluted Tubule (DCT)


This segment actively re-absorb Na+ & Clout of the lumen of the nephron via the
carrier Na+/ Cl
co-transporter which is the target of
Thiazide diuretics action
Ca++ re-absorption&excretion in this
segment is regulated under the control
of parathyroid hormone (PTH)

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5- Cortical collecting Tubule (CCT) & Duct


It is the last tubular site for the Na+ reabsorption controlled by Aldosterone
hormone
Therefore it determines the final
concentration of Na+ in the urine
Aldosterone hormone its secretion is
stimulated by renin-angiotensinII
mechanism (RAAS)
It acts at receptors in the collecting duct
resulting in:
- Na+ re-absorption &
- 9 K+ wasting Prepared by Dr. Hala Zaqout

Aldosterone-receptor which is the target


of
Aldosterone antagonist diuretics
action
In the collecting ducts , the re-absorption
of Na+
also occurs via Na+ channels (not a
transporter) & is accompanied
proportionally by ~ an equivalent loss of
the K+ excreted in the urine
Na+ channels are the target of
potassium-sparing diuretics action
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Reabsorption of water occurs in the


collecting tubule under the control of antidiuretic hormone (ADH, vasopressin)

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Classification of diuretics:

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Diuretics classified in various way


depending on their:
1-Structure

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2- Site of action of diuretics:


Diuretics can be subdivided according to
the segment of nephron in which they
work
- Proximal tubule: as Carbonic anhydrase
inhibitors, Osmotic diuretics
- Loop of Henle: as Loop diuretics
- Early distal tubule: as Thiazide diuretics
-Late distal tubule & collecting duct:
as Aldosterone antagonist & renal
epithelial Na+ channel inhibitors
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3- Efficiency/potency: diuretic effects on


the excretion of electrolytes & water
(high efficacy, moderate efficacy & low
efficacy diuretics)
1- Weak diuretics:
-Carbonic anhydrase inhibitors
-Potassium-sparing diuretics
2- Moderately potent:
-Thiazide & Thiazide-like diuretics
3- Potent /high ceiling/loop diuretics
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4- Mechanism of action:
Each agent have MOA:
1- Osmotic diuretics: As Mannitol (IV
infusion)
2- Inhibitors of Na+/K+/2Cl- cotransporter:
known as loop diuretics /high ceiling/ high
efficacy diuretics : As Furosemide is the most
commonly used drug in this group
3- Inhibitors of Na+/Cl- co-transporter:
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a- 21Thiazide diuretics:
As Hydrochlorothiazide

b- Thiazide-like diuretics: As Metolazone,


Indapamide
are chemically different but
pharmacologically
similar to Thiazide diuretics
4- Inhibitors of renal Na+ channels:
known as K+ sparing diuretics
As Amiloride & Triamterene
5- Mineralocorticoid-receptor antagonist :
known as Aldosterone antagonists
As Spironolactone
6- Carbonic anhydrase inhibitors:
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As Acetazolamide

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Therapeutic uses of diuretics:

- Diuretics traditionally/extensively used in the


treatment of cardiovascular diseases
(CVD) as:
Hypertension (non-edematous state) & as
an adjunct-therapy to extracellular/ plasma
volume
oedema (edematous state) in diseases
such as congestive heart failure (CHF)
- Renal failure & liver cirrhosis
- To intraocular pressure (IOP) or intracranial
pressure (ICP)

- To
correct pathological
or drug-induced plasma
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electrolyte imbalances

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1- Osmotic diuretics: ( e.g Mannitol IV infusion)


Mannitol is pharmacologically inert & being freely
filtered at Bowmans capsule by the glomerulus
& not reabsorbed
Note:
Glucose is not used
clinically as a diuretic but frequently causes
osmotic diuresis (glycosuria) in patients with
hyperglycemia
Glycerin is metabolized & can cause
hyperglycemia
Urea may cause thrombosis
or pain if extravasation occurs & it should not
be administered to patients with impaired liver
function because of the risk of elevation of
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blood
ammonia levels

MOA:

Osmotic diuretics effect depend on the


development of osmotic pressure cause
H2O to be retained mostly/ more specific in the
proximal convoluted tubule & partially in the
descending limb of loop of Henle segments
As a result passive reabsorption of
H2O & promotes H2O diuresis
As a result urine
osmolarity, leading to volume of the
urine
Therefore osmotic diuretics prevent passive
re-absorption of H2O, so carry a large
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volume of dilute urine

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:Therapeutic uses of osmotic diuretic


1- Reduction of intracranial pressure (ICP)
&intraocular pressure (IOP):
-In acute
congestive attacks glaucoma (treatment for
short-term reduction of IOP both
preoperatively & postoperatively in patients
who require ocular surgery
In the cerebral oedema before & after neurosurgery

As a result osmotic diuretics osmotic


pressure of plasma extract the fluid /H2O
from the eye & brain intraocular pressure
(IOP)&
intracranial
pressure (ICP)
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Osmotic diuretics are contraindicated


!!!in active intracranial hemorrhage
If bleeding is occurring into the brain
then the Mannitol will be directly added
to the brain & will raise the osmotic
pressure in the brain lead to water
being added to the brain which is the
opposite of what the Mannitol is being
given for

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2- Prophylactic administration to maintain


urine volume
to prevent anuria in acute oliguric renal
failure secondary to trauma, or shock, or
drug toxicities , or might otherwise result
from presentation of large pigment loads to
the kidney (e.g hemolysis or
rhabdomyolysis )
(but contraindicated in established renal
failure/ anuria)
3- Acute poisonings: dilution of urine by
urinary flow to maintain kidney function
following acute toxic ingestion of
nephrotoxic
substances
that capable of
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producing acute renal failure (ARF)

Use of Mannitol in the treatment of dialysis


disequilibrium syndrome!!!
A- By hemodialysis too rapid removal of
solutes from the extracellular fluid (ECF)
results in the osmolality of ECF consequently,
water moves from the extracellular
compartment into the intracellular
compartment causing hypotension & CNS
symptoms Osmotic diuretics the osmolality
of the ECF compartment thereby shift water
back into the extracellular compartment
Side effects:
- Extracellular fluid volume or expansion( EFV)
& subsequent adverse effects in patients with
congestive heart failure (CHF) &acute
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Dr. Hala
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pulmonary
edema
byso
contraindicated

2- Loop diuretics: (e.g Furosemide,


Ethacrynic acid, Torsemide &
Bumetanide)

Have highest degree of efficacy , most


potent diuretics, high ceiling diuretics
(which have a very powerful diuretic
effect)
Q-Whats the meaning of high ceiling
diuretics!!!
A- In Loop diuretics doses
diuretic responses but Thiazides
diuretics are low ceiling diuretics
because the maximal response is
reached at a relatively low dosage
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MOA:
Act by inhibition of Na+/K+/ 2Clcotransporter in the Thick Ascending Limb
of loop of Henle (TAL) profound in
the urinary excretion of Na+,Cl-

& also inhibit the re-absorption of


divalent cations causes loss of Ca++ &
Mg++
Note:
Mutations in the Na+-K+-2Cl symporter
causes a form of inherited hypokalemic
alkalosis called Bartter syndrome (with
salt wasting & hypotension)

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~ 65% of furosemide is excreted unchanged


in urine & the remainder is conjugated to
glucuronic acid in the kidney, thus in
patients with renal disease but not liver
disease the elimination T1/2 of furosemide
is prolonged
In contrast Bumetanide & Torsemide
have significant hepatic metabolism
the elimination
T1/2 of these
loop
diuretics are prolonged by
liver but not renal disease
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Therapeutic uses :
1-Oedema associated with chronic
congestive heart failure (CHF) to
minimize venous &pulmonary congestion
or hepatic disease as edema & ascites
of liver cirrhosis or renal disease as
edema of nephrotic syndrome
edema in CHF

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edema in nephrotic syndrome

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edema in hepatic cirrhosis:


1- Diseased liver synthesis of protein
mainly albumin colloidal osmotic
pressure (low osmolarity) of the blood
2- Diseased liver failure of aldosterone
metabolism
fluid retention is also promoted by
levels of circulating aldosterone due to
blood volume secondary
hyperaldosteronism

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hydrostatic pressure due to portal- 3


HTN
4- Lymphatic obstruction fluids escape
from the portal vascular system
&accumulate/collect in the abdomen
(ascites)

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2- Hypertension (complicated
edematous conditions)
Thiazide diuretics are usually preferred in
the treatment of uncomplicated primary
hypertension (HTN)Why!!! the
relative potency & short elimination T1/2
of loop diuretics render them less useful
for uncomplicated hypertension (HTN)
than Thiazide-type diuretics

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3- Acute pulmonary oedema: (emergency


situation)
Loop diuretics particularly IV
furosemide (DOC) in acute pulmonary edema
of HF because of their rapid onset of
action&intense diuresis particularly when given
IV
Loop diuretics systemic venous capacitance,
thereby left ventricular filling pressure
this effect which may be mediated by release
of renal prostaglandins (vasodilating effect
appears immediately & is faster than the
diuretic effect
As 46a result vessel
dilatation
&

blood
volume
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venous return preload

Loop diuretics PG synthesis


induce expression of COX-2 which
participates in the synthesis of
prostaglandins (PGE2) from arachidonic
acid

4- Acute hypercalcaemia : in disorders


that cause hypercalcemia
Ca ++ excretion can be usefully
enhanced by treatment with loop
diuretics + saline infusions
5- In patients with a drug-overdose or toxic
ingestions of bromide, fluoride & iodide,
which are reabsorbed in the TAL loop
diuretics + saline solution are useful &
can be used to induce a forced diuresis to
facilitate more rapid renal elimination of
the offending drug
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6- In patients with acute renal failure (ARF)


receive a trial dose of a loop diuretic in an
attempt to convert oliguric ARF to non-oliguric
ARF but not in established RF / anuria
Note:
Loop diuretics are act promptly even in
low/poor renal function (Crcl < 30-50
ml/min)
But Thiazide diuretics are ineffective in
people with low/poor renal function (Crcl <
30-50ml/min)
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Drug-drug interactions:
- Loop diuretics+ Anticoagulants!!!
- Loop diuretics + Digoxin!!!
digitalis-induced arrhythmias
- Loop diuretics + Lithium!!! Li
toxicity by Li excretion/ eliminatioin

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-Furosemide + Probenecid !!!


Probenecid in the secretion of loop
diuretics may result from simultaneous
administration of Probenecid which
compete for weak acid transport system
in the proximal tubule
- Loop diuretics + NSAIDs!!! NSAIDs
inhibit the vasodilator PG synthesis
promote Na+ & H2O retention on chronic
use ,so the renal response to loop
diuretics diuretic response is blunted

Side effects of loop diuretics :

furosemide in patients with


sulfa allergy!!!

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1- Fluid & electrolyte imbalance:


a-Hyponatremia: volume depletion may
cause hypotension,circulatory collapse &
thromboembolism
b-Hypomagnesemia & hypokalemia :
may precipitate cardiac arrhythmia
particularly in patients receiving Digoxin
c-Hypocalcaemia

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2- Ototoxicity: occurs most frequently


with rapid IV administration , higher
doses only in the inner ear can result
from impaired/ alterations in the
electrolyte composition of endolymph
may contribute to drug-induced
ototoxicity
Ethacrynic acid is the most ototoxic of
the loop diuretics, simultaneous use with
Aminoglycosides
their ototoxic effect
(drug-drug interaction)
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3- Metabolic side effects:


a- Hyperuricemia: it is due to uric acid
secretion due to competition with loop diuretics
for tubular secretion precipitates gout
b- Hyperglycemia: (rarely) on the long-term
treatment interfere with the glycemic control in
diabetic patient
- c- Plasma lipid profile: LDL & HDL level in
the plasma
Loop diuretics in pregnant patients!!!
diuretics can deplete maternal intravascular
volume
Generally diuretics should be avoided in
pregnancy
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& breastfeeding

3- Thiazide & thiazide-like diuretics:


Thiazide (e.g Bendroflumethiazide)
Thiazide -like (e.g Metolazone, Indapamide)

Thiazide diuretics are moderately powerful


& actively excreted into the early Distal
Convoluted Tubule (DCT)
MOA:
Inhibit Na+ & Cl- re-absorption in the early
DCT by inhibiting Na+/ Cl co-transporter
Excretion of Ca++ ion in the urine
/enhance the reabsorption of Ca++
ion by Na+/Ca++ exchange
Excretion of K+ & Mg++ by
Na+/K+ exchange
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Note:
Mutations in the Na+-Cl symporter causes
a form of inherited hypokalemic
alkalosis called Gitelman syndrome

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Therapeutic use:
1- Hypertension (essential HTN)

2- Heart failure( a symptomatic mild to moderate


HF )
3- Hypercalciuria (idiopathic) : prevent excess
Ca+2 excretion to form renal stones (Ca++ oxalate
type) Thiazides in Ca++ nephrolithiasis !!!
Thiazides in hyperparathyroid patients!!!
4- Nephrogenic diabetes insipidus (DI)!!!
Thiazides act paradoxically probably due to ECF
volume which cause a compensatory
reabsorption of Na+ & H2O in PCT
Also Thiazides may sensitivity of the collecting
tubules to ADH urine volume in patients with
DI

Side effects of Thiazide diuretic:


- Thiazide in patients with Sulfa
allergy!!!
- Thiazides in pregnancy!!! relative
contraindications because of the
risk of blood volume & can cross the
placental barrier with the risk of
neonatal jaundice

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1- Orthostatic hypotension
(Hypovolemia) & Hyponatremia
2-Hypokalemia
3- Hypercalcemia : due to: -direct Ca++
reabsorption in DCT & -reabsorption
in PCT
4- Hyperuricaemia : precipitate gout
5- Hyperglycaemia (reversible) on long-term
treatment due to insulin release, precipitate
type II diabetes mellitus or worsen glucose
control in DM (this is less pronounced with
Indapamide)
6- Elevated plasma lipids:
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hyperchlesterolemia & hyper triglyceridemia

4- Carbonic Anhydrase Inhibitors (CAI):


As Acetazolamide ,Dorzolamide,
Brinzolamide,
Sulfanilamide derivative
Weak diuretics & have limited use
as diuretics CAI is classified as
a diuretic, but its important clinical
effects are related to its effect on
acid-base balance & on intraocular
fluid formation caused metabolic
acidosis & alkaline urine (urine PH)
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CA is present at various sites throughout


the nephron (extrarenal tissues), but is
mainly found on the luminal membrane of
proximal tubule cells
Proximal tubule is the major site of action
of CAI
CA enzyme also is involved in secretion of
titratable acid in the collecting duct
system therefore, the collecting duct
system is a secondary site of action for
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CAI

MOA:
Inhibition of CA enzyme is associated with
a rapid
in urinary HCO3 excretion to ~35% of
filtered load
This, along with inhibition of titratable acid
&NH4+ secretion in the collecting-duct
system, results in an in urinary pH to~
8 & development of a metabolic acidosis

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Therapeutic use:
1- Glaucoma: used in the chronic treatment
of open-angle glaucoma
Carbonic anhydrase in the ciliary processes
of the eye mediates the formation of large
amounts of HCO3 in aqueous humor
inhibition of carbonic anhydrase this
results in in the amount of HCO3secreted in the aqueous humor, so the
rate of formation of aqueous humor
consequently IOP
Topically agents are available as Dorzolamide
which IOP without producing renal or
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2- prophylaxis in acute mountain


sickness /high-altitude sickness:
The drug forces the kidneys to excrete
bicarbonate
by the amount
of bicarbonate excreted in the urine
the blood becomes more acidic, so
acidifying the blood
stimulates ventilation which the
amount of O2 in the blood
symptoms of mountain sickness
Acetazolamide starting a few days
before going to the higher altitude

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Side effects:
1- Rapid tolerance: they are called selflimiting diuretics!!! their diuretic effect
in 2-4 days!!!
2- Hyperchloremic metabolic acidosis
occurs because of reduction in HCO 3 stores
3- hypokalemia
4- Acetazolamide is sulfonamide derivatives
Sulphonamide- like allergic reactions: blood
dyscriasia , crystalluria & renal damage
(Contraindicated in patients with sulfa allergies)
5- Renal stone, precipitation of Ca2+,PO4 salts
in the alkaline urine
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Contraindication:
-CAI induced alkalinization of the urine &
urinary excretion of ammonia (NH +4)
diversion of ammonia of renal origin from
urine into the systemic circulation a
process that may induce or worsen
hepatic encephalopathy
(contraindicated in patients with
hepatic cirrhosis)
Worsening of metabolic or respiratory acidosis (contraindicated in patients
with hyperchloremic acidosis or
severe COPD)
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Acetazolamide in epilepsy!!!

5- Aldosterone antagonist
(Spironolactone, Eplerenone) & K+
sparing diuretics( Amiloride,
Triamterene)
These drugs should not be used by
pregnant women or women who are
breastfeeding because of possible growth
retardation(placental circulation) &
milk production

5- Aldosterone-antagonist
(Spironolactone) &
K+ sparing
diuretics( Amiloride)
Aldosterone: is secreted from the adrenal
cortex & plays an important role in the
control of renal Na+ excretion &
extracellular electrolyte balance
Under conditions of :
Plasma Na+ concentration & / or
Sympathetic nervous system stimulation

quantities of renin released by the kidney


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into
systemic circulation
RAAS

The net results of actions of Aldosterone are:


1- Na+ retention
2- K+ excretion &
3- Stimulate H+ secretion mild systemic alkalosis
A- Aldosterone-antagonist:
Spironolactone is a very weak diuretic
MOA:
Antagonize the Aldosterone action competitively
by:
- Inhibit Na+ re-absorption in the late distal tubule
& collecting duct , so Na+ excretion &
- Block Na+/K+ exchange , so the loss of K+ &
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H+

Mineralocorticoid-Receptor (MR) that binds


aldosterone as well as cortisol &deoxycorticosterone
The clinical efficacy of MR-antagonists is a
function of endogenous aldosterone levels
the higher the endogenous aldosterone level
the greater the effects of MR-antagonists on
the urinary excretion

Eplerenone is a more specific blocker of (MR) &


it has very little/low affinity for the androgen &
progesterone receptors (<1% & <0.1%,
respectively) compared with Spironolactone

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Therapeutic uses :
Spironolactone is particularly useful in the
treatment of :
-Resistant HTN due to primary
hyperaldosteronism
&
-Refractory edema associated with
secondary aldosteronism

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- Primary hyperaldosteronism (Conns


syndrome) associated with adrenal adenoma or
bilateral adrenal hyperplasia
- Secondary hyperaldosteronism associated
with cardiac failure, hepatic cirrhosis, severe
ascites, nephrotic syndrome
- Congestive heart failure: Spirinolactone
added to standard therapy prevents cardiac
remodeling morbidity , mortality
&ventricular arrhythmias in advanced CHF
(Stage III - Stage IV CHF)
- In conjunction (add-on) with K+ wasting
diuretics
these agents are useful concurrently/adjunct
with
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Loop & Thiazide diuretics

Side effects:
1- Hyperkalemia: particularly in patients of renal
failure (monitor plasma K+)
2- Steroid-like side effects: as
gynecomastia , impotence hirsutism, menstrual
irregularities , deepening of voice the
explanation for this is :
Spironolactone has some affinity toward
progesterone & androgen-receptors can
stimulate steroid-receptors that influence the
synthesis of sex hormones
3- Spironolactone also may induce diarrhea,
gastritis, gastric bleeding&peptic ulcers
(contraindicated)
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4- CNS side effects: as confusion

B- K+ sparing diuretics :
Weak diuretics, act directly by blocking the
Na+ channels in the luminal membrane in
the late distal tubules & collecting ducts ,
so inhibit Na+ reabsorption & K+
secretion K+ & H+ retention
MOA:

Are independent on Aldosterone the drugs


do not act upon the renin-angiotensinaldosterone system (RAAS), but the net
effect upon urinary composition is similar
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Therapeutic use:
1- Oedema & HTN : primary use of these
drugs as adjunct with Loop diuretic or
Thiazide diuretic
/ prevent diureticinduced hypokalemia
2- Lithium-induced nephrogenic diabetes
insipidus!!! Amiloride blocks Lithium
reabsorption from the collecting tubules
Side effects:
- Hyperkalemia
Amiloride in patients with RF!!!
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Q- Amiloride aerosol inhalaion in


cystic fibrosis!!!
A- By/inhibiting
Na+ absorption from the surface of airway
epithelial cells hydration of respiratory
secretion improves mucociliary clearance
Q- Amiloride in Liddles syndrome!!!
Liddle syndrome is an autosomal dominant
mutations in the or subunits of ENaC
leading to basal ENaC activity of renal
Epithelial
So Na Channels (ENaC) are inappropriately
activated form of low-renin, volumeexpanded HTN

~ 5% of people of African origin


polymorphism in the subunit of - ENaC
Amiloride is particularly effective in
BP in patients with HTN who carry this
polymorphism
As a result Liddle syndrome can be
treated effectively with Na+-channel
inhibitors

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