DIURETICS

by RUTURAJ & ZAID

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URINE FORMATION
INTRODUCTION :-
 Urine formation takes place in kidneys.
 Kidneys are the major organ of urinary system.
 Functional unit of kidney is nephron.

CLINICAL IMPORTANCE OF KIDNEY :-

 Kidney maintains blood pressure
 In treatment of heart failure, renal failure, nephritic syndrome, cirrhosis.
 Renal system has the capability to ulter the above pathological conditions.

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FUNCTIONS OF RENAL SYSTEM :-

 Regulating the blood pressure : by secreation and reabsorption of different

ions
 Regulating blood pressure : by excreation of variable H+ ions & conserving
HCO3- ions
 Maintenance of blood osmolarity : 2 hormones are produced…
Calcitrol – maintains calcitrol homeostatis
Erythropoietin – stimulate formation of blood cells.
 Regulating blood glucose level : by using amino acid of glutamine in
gluconeogenesis.
 Excreation of metabolites and waste products
Ex; Bilirubin, urea, ammonia…

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URINE FORMATION
NEPHRON
 Functional unit of kidney.
 There are around 1 million nephrons in kidney.
 It consists various sections namely;
Renal capsule – having bowmans capsule & glomerulus
Glomerulus – formed by blood vessels.
 It consists Proximal convulated tube, loop of henle,
Collecting duct.
 These sections are responsible for reabsorption and
Secreation of water and various ions.

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 REABSORPTION : movement of water & ions from nephron to blood circulation
 SECREATION : movement of water and ions from blood circulation to nephron

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 GLOMERULUS FILTRATION
 It is the first step in urine formation.
 Here excess fluid and waste products are filtered out of blood into nephron
tubules.

PROXIMAL CONVULATED TUBULES [PCT]

 Na+ gets reabsorbed with glucose
 There is an transporter that uses Na+ for hydrogrn exchange.
 Na+ gets reabsorbed in exchange of K+ by sodium potassium ATPase
pump
 PCT is imp. for acid base balance as H+ ions are secreated and HCO3+
are reabsorbed.
 Other electrlytes such as Ca2+ are also reabsorbed.

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ASCENDING LOOP OF HENLE
 Electrolytes are reabsorbed.
 Here there is a tri-symptomer.
 Where K+, 2Cl-, Na+ are brought back inside cells.
 And then K+, 2Cl- are reabsorbed by anither symptomer.
 Na+ is exchanged for K+ using sodium potassium ATPase pump.

DISTAL CONVULATED TUBULE

 Na+ & Cl- get reabsorbed using symporters
 Cl- has its own channel
 Na+ reabsorbed via sodium potassium ATPase pump
 Mg2+ and Ca2+ reabsorbed via cellular junctions
DISTAL CONVULATED TUBULE & COLLECTING DUCT
 Na+ is reabsorbed with exchang of H+ ion
 Similar to PCT, here also acid-base balance is taking place.
 H+ & HCO3+ ions react & form carbonic acid, and this
carbonic acid undergoes hydrolysis to form water and C02.
 It’s a reversible reaction, catalized by carbonic anhydrase
 Bicarbonate ion is reabsorbed by bicarbonate chloride
exchange.
 Na+ is reabsorbed by K+ exchange controlled by Aldosterone.
 Aldosterone is a hormone secreated by adrenal cortex in
response to low BP.
 Aldosterone conc. : Na+ and water reabsorption
Which causes increase in blood volume, & hence increase in
blood pressure.
COLLECTING DUCT
 The apical surface of cells have special channels called
aquapomins, which allow reabsorption of water.
 Body reabsorps water and increases the osmolality of
urine.
 There will be increase in the solute conc./ ion conc.
 This leads to formation of urine.

CONTENTS OF URINE :-
 95% water, nitrogenous waste, ions, metabolites.
DIURETICS
 These are drugs/agents that are used to increase rate of urine flow & help
body excrete certain salts, especially sodium[Na+].
 They are also known as WATER-PILLS

WHY DIURETICS ?
 They are used to treat edema
 Congestive heart failure
 Renal failure
 Hypertension
 Kidney stones [hypercalciuria]
 Diabetes insipidus
CLASSIFICATION OF DIURETICS
CARBONIC ANHYDRASE INHIBITOR
 These diuretics have low efficacy compared to other diuretics
 Act by inhibiting carbonic anhydrase enzyme present in PCT

MOA :-
 Carbonic anhydrase enzyme function is that it reversibly catalyse the reaction of

 H2CO3 H+ + HCO3
 IN PCT mainly Na+ is reabsorbed, Na+ will combine with liberated HCO3 ion and form sodium
bicarbonate , which is reabsorbed.
 These inhibitor binds the Case enzyme reversibly and inhibits its action & there is no formation of
bicarbonate ions & hence there will be no reabsorption.
SAR
 Case inhibitor should have 2 groups for activity
Heterocyclic sulphonamide group
Meta-disulphamoyl group
 Proto-type carbonic anhydrase inhibitor is Acetazolamide
 Sulphamoyl group is imp. for activity
 Sulphamoyl moiety should be free for binding with Zn2+

of enzyme ACETAZOLAMIDE
 Sulphamoyl substitution gives inactive compound

 The heterocyclic ring should be aromatic in nature

 N- alkylation with methyl group gives methazolamide

 Compund having higher partition coefficient and lower Pka value are
better inhibitor of enzyme
ACETAZOLAMIDE

MOA
 Inhibits the carbanoic anhydrase enzyme reversibly
 Decrease the NA+ reabsorption
 Increase the excretion of NA+,CA2+,HCO3-
 SYNTHESIS OF ACETAZOLAMIDE
 USES :
 Treatment of oedema due to CHF
 Epilepsy
 Glaucoma

ADR :
 Metabolic acidosis
 Drowsiness
 Allergic reactions

METBOLISM :
 Excerted unchanged through through urine
METHAZOLAMIDE

MAO
 More potent than acetazolamide
 Inhibit the action carbonic anhydrase enzyme
 Decrease the reabsorbtion of NA+ AND HCO3- IONS
 USES
 Treatment of oedema due to CHF
 Treat of glaucoma

ADR
 Same as acetazolamide
 DICHLORPHENAMIDE

MAO

 same as acetazolamide

USES
 Treatment of glaucoma
 To treat hyperkalemia

ADR
 rash,drowsiness,nausea,vomiting
 THIAZIDES

 These are most widely used diuretic drugs

 these are sulphonamide derivatives
 are moderately acting diuretics
 also called as ceilling diuertics

 MAO

 act on DCT
 These drugs act by INHIBITING the NA+ and CL-
SYMPORTERS OR COTRANSPORTERS
 INCREASE the ECRETION OF NA+AND CL-
 SAR
 This is the common structure of thiazide diuertics
 parent nucleus is also alled as 1,2,4benzothiadiazide 1,1dioxide
 it contains 2 benzene ring, one benzene is substitution
of sulphur at 1st position and 2 nitrogens at postion 2 and 4
 2nd position : hydrogen at this poisition is more acidic due to presence of neighbouring
electron withdrawing group ie sulphone
 2 position can tolerate the preence of methyl group
 3rd position : substitution at this place with hydrophobic group increse saluertic activity by
1000times and increase lipid solubility
 saturaton of doublebond at postion 3rd and 4th increases activity by 3 to 10 times
 6th position substitution with activating grops such as halogenes is essential for activity
 7th position sulphamoyl group must be free for diuertic activit
 substitution of ethyl group at postions 4th,5th,8th decreases the activity
 sodium salts of thiazides can be used for intravenous administration
 CHLORTHIAZIDE
 Its a proto type thiazide
 6-chloro-2H-1,2,4benzothiadizine7-sulfonamide-1,1dioxide
 MAO
 It inhibits the action of NA+ AND CL- sympoters
 and reduce the reabsorbtion of the above ions
 USES
 to treat odema due to CHF
 To treat renal and hepatic disorders
 to treaat hypertension

METABOLISM
 Eliminatd rapidly by KIDNEY
 ADR
 Stomach pain ,blood in urine or stool, blueing of lips and fingers
synthesis ofchlorthiazide
HYDROCHLOROTHIAZIDE
 6-CHLORO-2,3DIHYDRO-1,2,BENZOTHIADIAZIDINE-7SULPHONAMIDE
 10 times More potent then chlorothiazide

MAO
 same as cholorothiazide

USES
 to treat oedema related to CHF
 renal failure ,hepati failure

ADR
 POSTURAL AHYPOTENSION,DIZZINES,HEADACHE,WEAKNESS
 METBOLISM
 ELIMINATE RAPIDLY BY KIDNEY
HYDROFLUMETHIAZIDE
 3,4DIHUDRO(TIFLOUROMETHY)2H-1,2,4-BENZOTHIAIAZIDINE-7-SLPHONAMIDE-1,1-DIOXIDE
 Potent diuretic

MAO
 SAME AS ABOVE TWO DRUGS
 USES
 TREATE OEDEMA DUE TO CHF
 HEPATIC CIRRHOSIS
 PREMENSTURAL TENSION
 ADR
 NAUSEA, VOMITING,DIARRHEA
 JAUNDICE,PANCRETITIS

METABOLISM
 RAPILY ECRETED BY KIDNEY
 CYCLOTHIAZIDE
 6-CHLORO-3,4-DIHYDRO-3-(-NOR-BROMEN-YL-)-2H-1,2,4-BENZOTHIADIAZINE
-7-SULPHONAMIDE-1,1DIOXIDE

 MAO
same

 USES
used as diuretic and anti hypertensive agent.

 ADR
metabolic alkalosis, irregular electrolyte balance

 METABOLISM
EXCRETED RAPIDLY BY KIDNEY
 #LOOP DIURETICS :-
 They are also called as HIGH CEILING DIURETICS, because they
are highly effective & most potent class of diuretics, in patients with
impaired kidney function.
 Examples of loop diuretic includes FUROSEMIDE, BUMETANIDE,
ETHACRYNIC ACID.

MOA :-
 Its BIOLOGICAL TARGET : “Na-K-Cl” Co-transporter.
 Loop diuretics essentially act on thick ascending limb of
loop of henle in kidneys.
 When introduced, it inhibits/blocks Na-K-Cl Co-transporters,
& reduces reabsorption of Na+ & Cl-
 Along with that, it also inhibit reabsorption of other ions like
Magnesium, potassium, calcium...etc
 This is achieved by competing for Cl- binding site.
 1] FUROSEMIDE

MOA :- same

METABOLISM:-
50% is metabolised in kidneys and rest is excreted UNCHANGED through urine .
Synthesis of furosemide :-
SAR

 In furosemide, position 1 must always be

acidic in nature, therefore carboxylic group
provides optimal diuretic activity.
 For enhanced efficacy, ACTIVATING group
[X] like Cl-, CF3-, aniline, benzyl, etc…can

be used at position 4.
 Presense of sulfamoyl group at position 5 is
prerequisite for optimal high ceiling diuretic
activity.
USES:
 In treatment of edema, associated
with congestive heart failure, liver
cirrhosis, hypertension, etc…
 In treatment of Pulmonary edema.
 To prevent/treat hypercalcemia.
ADR:
 Co-administration of lithium may
lead to severe lithium toxicity.
 Headace, diarrehea, constipation,
nausea etc…
 Ototoxicity.
2] BUMETANIDE

MOA : same

 METABOLISM :-
It is partially metabolized by liver and is excreted through urine.
USES
 In treatment of renal insufficiency.
 For control & management of
acute drug poisoining.
[drug toxicity]
ADR
 Vomiting, headace, nausea, etc…
 May cause temporary hearing loss,
BUT intake of high dose/continuous
usage may lead to permanent
/irreversible hearing loss.
 Can cause muscle cramps or weak
muscles.
3] ETHACRYNIC ACID

 MOA : same

 METABOLISM :-
Metabolised in liver and excreted through urine and stool.
USES
 Treatment of edema, associated
with congestive heart failure, liver
cirrhosis, etc…
 In treatment of hypertension, and
certain type of diabetes.
ADR
 Headace, nausea, dizziness,
diarrhea…etc
 May cause skin rashes and
yellowing of skin & eyes.
 May cause fullness of ears/ringing
of ears/decreased hearing
[ototoxicity]
#POTASSIUM SPARING DIURETICS
 The negative feature of all the other classes of diuretics is that, they induce an
increased renal excreation of potassium, which can potentially cause
HYPOKALEMIA. [ level of K+]
 Potassium sparing diuretics refers to the drugs that cause diuresis effect without
actually causing potassium loss through urine.
 These agents are also known as ‘ANTIKALIURETIC’ agents.
 Drugs present in this classification are namely, TRIAMTERENE, AMILORIDE,
SPIRONOLACTONE…

MOA :-
 It’s mechanism is classified in 2 types :
a. Epithelial sodium channel blockers, Ex:- amiloride, triamterene
b. Aldosterone antagonists, Ex:- spironolactone.
 Potassium sparing diuretics prevent the sodium reabsorption by either binding
with “Epithelial sodium channel blockers[ENaCs]” or “Inhibiting aldosterone
receptor”
1] TRIAMTERENE

 METABOLISM:-
Excreted by the kidneys
 MOA :-
[by epithelial Na+ channel blocking mechanism]
 The drug plugs/acts on the sodium channel from luminal
side[membrane] of the principal cells.
 Once it is plugged, it blocks the electronic entry of 2-3%
of the filtered load of sodium into these cells.
 This reduces lumen-negative trans-epithelial potential
difference, which regulates secretion of K+.
 Therefore the driving force [basic source] for potassium
secretion is either reduced or completely eliminated.
 Therefore excretion of only Na+ takes place through
urine, without actually causing the loss of K+.
USES ADR
 To prevent HYPOKALEMIA.  Hyperkalemia
[especially associated with  Formation of renal stones.
hydrochlorothiazide diuretic]  Nausea, vomiting, headace…etc.
 Treatment of edema associated
with congestive heart failure, liver
cirrhosis, hypertension…etc
2] AMILORIDE

MOA :-
 As same as triamterene.

 METABOLISM :-
Excreted unchanged by kidneys.
USES
 Help prevent body from losing too
much of potassium throught urine.
[hypokalemia]
 To treat hypertension, heart
failure, or edema.
ADR
 Can cause hyperkalemia
 Can cause confusion,dizziness,
fainting, seizures.
 When given in combination with
other diuretic, can cause
dehydration and electrolyte
imbalance.
3] SPIRONOLACTONES

 METABOLISM :-
It is rapidly metabolised and majorly excreted through urine.
 MOA :-
[by aldosterone antagonist mechanism]
 This mechanism requires the presence of endogenous
aldosterone to exert its diuretic effect.
 Normally, Aldosterone regulates the reabsorption of
Na+ in distal convulated tubules and collecting duct.
 So, when Aldosterone antagonist like
SPIRONOLACTONE, antagonizes/blocks the action of
aldosterone at mineralocorticoid receptor, by
competitively inhibiting the action of aldosterone.
 It reduces the reabsorption of Na+ ions.
 This leads to higher levels of K+ in serum, and
promotes/increases Na+ excretion through urine.
 USES ADR
 To treat Hyperaldosteronism  May cause yellowing of skin & eyes.
[ aldosterone levels]  Hyperkalemia
 It is used in treatment blood  Arrhythmia.
pressure, kidney failure...etc
#OSMOTIC DIURETIC
 They are pharmacologically INERT substances, which does not interfere with any chemical
processes, and essentially act by it’s physical property [osmotic pressure]
 They are given intravenously [IV route], and not ORALLY as it might cause diarrhea.
 They increase the osmotic conc. [osmolarity] of blood and renal filtrate.
 Example for osmotic diuretic is MANNITOL.

MOA :-
 In nephron, they act at the portions which are water-permeable in nature,
like proximal convoluted tubules and descending limb of loop of henle.
 By interposing a counterbalancing osmotic force, mannitol prevents normal absorption of
water.
 This results in increase in urine volume.
 Increase in urine volume, decreases contact time between fluid & tubular epithelium, which
reduces the reabsorption of Na+ and water.
MANNITOL

 Mannitol is a naturally occurring sugar alcohol found in variety fruits and

vegetables.
 Manitol is an isomer of sorbitol, only difference in structure of sorbitol and
mannitol is the arrangement of hydroxyl group on second carbon.
METABOLISM :-
It is excreted unchanged through urine.
USES
 Widely used for acute renal failure.
 To reduce intraocular pressure.
 Managing cerebral edema.
 As an antidote in cyanide
poisioning.
ADR
 Excess loss of water and electrolytes can cause;
Dehydration
Hypotension
Which can further lead to nausea,
headace, excessive sweating, vomiting……etc
 Due to rapid increase in intracellular fluid volume, it
may cause congestive heart failure, pulmonary
edema.