Diuretics are drugs that promote the excretion of sodium and water from the body by acting on the kidney. They work by interfering with sodium transport mechanisms in different segments of the nephron. The main types are loop diuretics which act on the thick ascending limb of the loop of Henle, thiazide diuretics which act on the early distal tubule, and potassium-sparing diuretics which act on the late distal tubule and collecting duct. Diuretics are important drugs used to treat hypertension, heart failure, and edema.

1. DIURETICS
Presented to:
Dr. S.N. Manjula. M.Pharm, Ph.D.
Professor & Head
Department of Pharmacology
JSS College of Pharmacy, Mysuru
Presented by:
Naveen Reddy .P 1st M.Pharm
Department of Pharmacology
JSS College of Pharmacy,
Mysuru
Antihypertensive

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Natriuretic - Increasing renal Sodium excretion
Kaliuretic - Increasing renal Potassium excretion
Calciuretic – Enhanced calcium excretion
Saluretic – Enhanced sodium chloride excretion
Diuretics (WATER PILLS)- Increasing loss of Na+ and water in urine.
TERMINOLOGY

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Kidney
- Weight- 0.5% of total Body, Rk 81-160g Lk 83-176g.
- Cardiac Output- 25% of total (50 times)
Functions ( BASE )
- B alance of Electrolytes, Volume, pH, BP
- A ctivation of Vitamin D
- S ynthesis of Erythropoietin
- E xcretion of Toxins, metabolites
Transport types
- Passive- Simple, channel mediated and facilitated diffusion, solvent drag.
- Active- Primary and Secondary (Symports and Counter transport)
RENAL PHYSIOLOGY

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RENAL PHYSIOLOGY
Filtrate = Plasma – Proteins
Volume of :
- Filtrate - 180 liters
- Urine - 1.5 liters (1%)
Kidneys
- Renal Blood Flow - 1200ml/min
- Renal Plasma Flow - 650 ml/min
- GFR - 120 ml/min
- Reabsorb
• Sodium, Chloride and Bicarbonates > 99%
• Potassium about 85% Renal Physiology

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STRUCTURE AND FUNCTION
Each nephron consists of a :
1. Glomerulus,
2. Proximal Tubule,
3. Loop of Henle,
4. Distal Convoluted Tubule and
5. Collecting Duct

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Proximal Convoluted Tubule: Site-1
• Most of the filtered Na+ is actively
reabsorbed; chloride is reabsorbed
passively along with sodium.
• Carbonic anhydrase plays an
important role in Na+ H+ exchange
and helps in the reabsorption of
HCO3-. Potassium, glucose, amino
acids etc. are also reabsorbed in the
PCT.
• Proportionately water also gets
reabsorbed, so tubular fluid in the
PCT remains isotonic.

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Loop of Henle • The descending limb
is miserable to Na+ and urea and
highly permeable to water. • Hence
fluid in the loop become hypertonic.
Thick Ascending Limb of Loop of
Henle: Site-2
• The thick ascending limb is
permeable to water but highly
permeable to Na+ and Cl-.
• Active reabsorption of sodium and
chloride occurs by Na+-K+, 2Cl-
Co- transporter. This is selectively
blocked by loop diuretics.
• Ca2+ and Mg2+ are also
reabsorbed at this site.

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Early Distal Table: Site-3
• It is impermeable to water but
sodium and chloride are
reabsorbed with the helps of
Na+, Cl- symporter.
• This is blocked by thiazide.

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Early Distal Tubule and Collecting
Duct: Site-4
• Sodium is actively reabsorbed;
chloride and water diffuse passively.
• Exchange of Na+- K+, H+ ions occur.
The Na+- K+ exchange under the
influence of aldosterone (aldosterone
promote Na+ absorption and K+
depletion).
• Absorption of fluid in the collecting
duct (CD) is under the influence of
ADH. In the absence of ADH, the CD
becomes impermeable to water and
large amount of dilute urine is
excreted.
• Normally H+ ions present in urine
convert NH3 to NH4 which is excreted.

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!Diuretics are the drugs which increase the rate of urine formation causing a net loss of Na+ and
water, by interfering with transport mechanism responsible for the reabsorption of solutes from
various segments of the nephron
or
!Diuretics are the drugs that promote the excretion of Na+ and water from the body by an action on
the kidney.
!Very important cardiovascular drugs ▪ Management of chronic heart failure ▪ Anti-hypertensives
(third-line)
!Increase Na+ excretion - NATRIURESIS
• Na+ movement is followed osmotically by water (diuresis)
• Decrease extracellular / plasma volume
– Reduce oedema
– Reduce blood pressure
DIURETICS

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Antihypertensive Drugs
Classification of diuretics
1. Drugs acting at proximal convoluted tubule (PCT) Site-1
- Carbonic anhydrase inhibitor: Acetazolamide
2. Drugs acting at thick ascending limb of loop of Henle Site-2
- Loop diuretics: furosemide, bumetadine, torsemide, ethacrynic acid.
3. Drugs acting at early distal tubule Site-3
- Thiazides: chlorothiazide, hydrochlorothiazide, polythiazide. Benzthiazide.
- Thiazide related diuretics: chlorthalidone, indapamide, metolazone.
4. Drugs acting at late distal tubule and collecting duct Site-4
- Aldosterone antagonist: spironolactone and eplerenone.
- Direct inhibitor of Na+ channels: Amiloride and triamterene.
5. Drugs acting on entire nephron (main site of action in loop of Henle)
- Osmotic diuretics: Manito, glycerol, isosorbide.
CLASSIFICATION

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1) Carbonic Anhydrase Inhibitors
Mechanism of action:
• Both CO2 and H2O diffuse into the tubular cell where H2CO3 is
formed under the influence of carbonic anhydrase.
• Carbonic acid dissociates into H+ and HCO3-.
• The H+ ions exchange with luminal Na+ .
• In the lumen the H+ ions combine with HCO3- and form H2CO3.
• The H2CO3 dissociates into CO2 and H2O with the help of
carbonic anhydrase, which is present near the brush border.
• The main site of action of acetazolamide is proximal tubule. it
also acts in the collecting duct.
• Acetazolamide by inhibiting carbonic anhydrase enzyme, prevents
the formation of H+ ions. Na+ H+ exchange is prevented.
• Na+ is excreted along with HCO3- in urine.
• In the DCT, increase Na+, K+ exchange leads to loss of K+. The
net effect is loss of Na+, K+ and HCO3- in urine resulting in
alkaline urien.
ATZ
(PCT) Site-1

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Uses of CAI • Acetazolamide is not used as diuretic because of its low efficacy.
It is used in the following condition:
1. Glaucoma: CAI decrease the intraocular pressure by reducing the formation of aqueous humor.
2. Acute mountain sickness: The beneficial effect to decrease the PH and formation of
cerebrospinal fluid.
3. To alkalinize urine in acidic drug poisoning.
Adverse effect of CAI • Hypersensitivity reaction • Skin rashes • Fever • Drowsiness • Hypokalemia
• Metabolic acidosis • Headache • Renal stone.
Contraindication of CAI
• LIVER DISEASE: Hepatic coma may be precipitated in patient with cirrhosis due to decreased
excretion of NH3 in alkaline urine.
• COPD: Worsening of metabolic acidosis is seen in patient with chronic obstructive pulmonary
disease
(PCT) Site-1

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2) Loop Diuretics (high ceiling diuretics)
MOA: Sites of action is the ascending limb of loop of
Henle. Loop diuretics binds to luminal side of Na+, K+
2Cl- cotransporter and block its function. There is an
increased excretion of Na+ and Cl- in urine.
•The tubular fluid reaching the DCT contains large
amount of Na+. Hence more Na+ exchanges with K+
loss.
•Furosemide has weak carbonic anhydrase inhibiting
activity hence increase the excretion of HCO3- and
PO34-.
•They also increase the excretion of Ca2+ and Mg2+.
•Loop diuretics are called high-celling diuretics
because they are highly efficacious – have maximal
Na+ excreting capacity when compared to thiazides
and potassium sparing diuretics.
loop of Henle Site-2

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Therapeutic uses of furosemide
• During the initial stage of renal, hepatic and cardio oedema, loop diuretics are preferred.
• Intravenous furosemide, along with isotonic saline is used in hypercalcemia as it promotes the excretion of Ca2+ in
urine.
• Acute pulmonary oedema- loop diuretics Produce quick relief from pulmonary oedema.
• Loop diuretics may be used in cerebral oedema but IV Manitol is the preferred drug.
• Hypertension: loop diuretics can be used in hypertensions associated with CCF/ renal failure and in hypertensive
emergencies.
• Furosemide is not preferred in uncomplicated primary hypertension because of short duration of action.
• Loop diuretics can be used in the mild hyperkalemia.
• Loops block Na+/ K+/ 2Cl- symporter
• Decrease NaCl entry into macula densa tubular cells
- promotes renin release, leading to increased AngII activity
• → Kidney becomes refractory to LDs for some hrs after use
- due to activation of RAAs
loop of Henle Site-2

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Adverse effect
1. Electrolyte disturbances: are the common adverse effects seen with loop diuretics. They are:
A. Hypokalemia: it is the most important adverse effect. It can caused fatigue, muscular weakness and cardiac
arrhythmia, especially in patients taking digitalis. It can be treated by K+ supplementation.
B. Hyponatremia: overuse of loop diuretics can cause depletion of sodium from the body.
C. Hypokalemic metabolic alkalosis: as less K+ is available for exchange with Na+ in the DCT, more Na+/ H+
exchange takes place leading to H+ loss, thus causing hypokalemic alkalosis.
D. Hypocalcaemia and hypomagnesaemia: These are due to the increased urinary excretion of Ca2+ and
Mg2+ respectively.
2. The metabolism disturbances include:
Hyperuricaemia: these drug decrease the renal excretion of uric acid and may precipitate attacks of gout.
Hyperlipidemia: they increase plasma triglycerides and LDL cholesterol levels.
3. Hypersensitivity: skin rashes, eosinophilia, photosensitivity etc. may occur.
Drug interaction
• Furosemide × digoxin (digoxin toxicity)
• Furosemide × aminoglycoside (Ototoxicity)
• Furosemide × NSAIDs (diminish effect of LD)
• Furosemide × lithium (lithium toxicity)
• Furosemide × amiloride (synergistic effect)
loop of Henle Site-2

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3) Thiazide- like diuretics
• Chlorthalidone is a frequently used thiazide like diuretic in hypertension as it has a long duration of
action. Indapamide and metolazone are more potent, longer acting and produce fewer adverse
effects than thiazides.
MOA: Thiazides inhibits Na+ Cl- symport in early distal tubule and increase Na+ and Cl- excretion.
• There is increased delivery of Na+ to the late distal tubule, hence there is increased exchange of
Na+ K+ which results in K+ loss.
• Some of thiazide also have weak carbonic anhydrase inhibitory action and increase HCO3- loss.
• Therefore there is a net loss of Na+, K+, Cl-, Hco3- in urine. Unlike loop diuretics, thiazides
decrease Ca2+ excretion.
• Also used in mild to moderate heart failure
• Thiazides are renally secreted to act on DCT, thiazides are
deemed ineffective in moderate renal impairment (except
metolazone)
DT Site-3

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Pharmacokinetics: Thiazide are administered orally. They have long duration and are excreted in
urine.
Uses: 1. Hypertension: thiazides are used in the treatment of essential hypertension.
2. Heart failure: thiazides are used for mild to moderate cases of heart failure.
3. Hypercalcemia: thiazides are used in calcium nephrolithiasis (Kidney stone) as they reduce the
urinary excretion of calcium.
Adverse effects 1. Thiazides cause electrolyte disturbance which include hypokalemia,
Hyponatremia, metabolic alkalosis, hypomagnesaemia.
2. The metabolic disturbances are similar to that of loop diuretics – hyperglycemia, hyperlipidemia
and hyperuricaemia.
3. They may cause impotence, hence thiazides are not the preferred antihypertensive in young
males.
4. Others: skin rashes, photosensitivity, gastrointestinal disturbances like nausea, vomiting, diarrhea
etc. can occur.
DT Site-3

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Hypokalaemia
Secondary to loop diuretics / thiazides
Due to K+ Loss – kaliuresis leading to hypokalaemia
1. Activation of RAAs → Na+ retention and K+ loss (actions of aldosterone & some via AngII)
via
i. Decrease Na+ in ECF (increased urinary Na+ loss)
ii.Volume depletion, “diuretic hypovolaemia”
iii. Loop diuretics block NaCl entry into macula densa cells
Loops block Na+/ K+/ 2Cl- symporter
2. Increase Na+ delivery to DCT
→ promotes K+ loss (secretion)
Increased renin release →
increase angiotensin II
production & aldosterone
release
Low body fluid
osmolality Low blood
volume Low blood
pressure
Inc Na+ reabsorption and
hence Inc H2O retention
DT Site-3

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Metabolic alkalosis
Secondary to loop diuretics / thiazides
• Increased Na+ delivery to late DCT & CD leads to enhanced Na+ reabsorption which is associated with H+
secretion/ loss
• Also activation of RAAs (with decreased ECF volume) leads to aldosterone activity (Inc H+ secretion)
→ decreased urinary pH
→ increased blood pH (alkalosis)
DT Site-3

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4) Potassium Sparing Diuretics
Aldosterone Antagonist • Spironolactone:
• it is an aldosterone antagonist. It is a synthetic steroid and structurally related to aldosterone.
• Aldosterone enters the cell and binds to specific mineral corticoid receptor (MR) in the cytoplasm
of late distal tubule and collecting duct cells.
• The hormone receptor complex enters the cell nucleus, where it induces synthesis of aldosterone
induced proteins (AIP).
• The net effect of AIP is to retain sodium and excrete potassium.
• Spironolactone competitively blocks the
mineral corticoid receptors and prevents the
formation of AIPs.
• Therefore, spironolactone promotes Na+
excretion and K+ retention.
Amiloride and Triamterene: (Directly Acting)
• Both are directly acting K+ sparing diuretics.
• They directly block the Na+ channels in the
luminal membrane of the cells of the late
DCT and CD.
CT Site-4

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Pharmacokinetics • Spironolactone is administered orally, gets partly absorbed and is highly
bound to plasma proteins; extensively metabolized in liver and forms active metabolite, canrenone,
which has long plasma half- life.
Uses • In edematous condition associated with secondary hyperaldosteronism. (congestive
cardiac failure, hepatic cirrhosis and nephrotic syndrome).
• Spironolactone is often used with thiazides / loop diuretics to compensate K+ loss.
• Resistant hypertension due to primary hyperaldosteronism. (conn’s syndrome)
Drug interaction
• ACE inhibitors × spironolactone
• Eplerenone an aldosterone antagonist is more selective for mineralocorticoid receptor. Hence it
is less likely to cause Gynacomastia.
CT Site-4

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5) Osmotic diuretics
These include Mannitol, glycerol and isosorbide.
Manitol: it is administered intravenously. It is neither metabolized in the body nor reabsorbed from
the renal tubules.
It is pharmacologically inert and is freely filtered at the glomerulus.
20% of mannitol , on i.v administration
Increases in osmolality of plasma
Shift of fluid (osmotic effect) from intracellular
compartment(ICC) to extracellular fluid(ECF)
ECF ICC
Expansion of ECF volume
Increases glomerular filtration rate, mannitol is freely filtered
at the glomerulus
Increases osmolality of tubular fluid
Inhibits reabsorption of water and NaCl
The net effect is the increased urinary excretion of Na+, K+,
Ca+, Mg+, Cl-, HCO3 and PO43
Mechanism of action:
• osmotic diuretics draw water from tissues by
osmotic action.
• This results in increased excretion of water and
electrolytes.
• Their site of action is in the loop of Henle and
proximal tubule.
Renal blood flow
Blood flow to renal medulla
Tonicity in renal medulla
OSMOTIC DIURETICS

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Uses of osmotic diuretics 1. Mannitol is used to prevent acute renal shutdown in shock,
cardiovascular surgery, haemolytic transfusion etc.
2. Mannitol is used to reduce the elevated intracranial tension (ICT) following head injury or tumour. It
draws fluid from the brain into the circulation by osmotic effect, thus lowering ICT.
3. Mannitol 20% (IV), glycerol 50% (oral) and isosorbide (oral) are used to reduce the elevated IOP in
acute congestive glaucoma. They draw fluid from the eye by osmotic effect, in to blood – IOP is
decreased.
Adverse effects • Too rapid and too much quantity of iv Mannitol can cause marked expansion of
ECF volume which can lead to pulmonary oedema.
• Headache, nausea and vomiting may occur.
• Glycerol can cause hyperglycaemia.
Contraindication • Mannitol is contraindicated in CCF and pulmonary oedema because it expands
ECF volume by increasing the osmolality of extracellular compartment and increase the load on heart,
thus aggravating the above condition. Other contraindication are chronic oedema, anuric renal
disease and active intracranial bleeding.
OSMOTIC DIURETICS

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Diuretics Site of action MOA Efficacy
Acetazolamide PCT
Carbonic anhydrase
inhibitor
Low
Loop Diuretics
Thick ascending
limb of loop of
Henle
Inhibit Na+-K+-2Cl-
Cotransport
High
Thiazides Early distal tubule Inhibit Na+-Cl- Symport Medium
K+ sparing
diuretics
DT and CD
Aldosterone antagonists
(Spironolactone)
Directly acting (amiloride
and triamterene)
Low
Mannitol
Loop of Henle and
PCT
Osmotic effect High
Diuretics with their site and mechanism of action
DIURETICS

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Diuretics in practice
• Best taken in the morning
• Patients will experience an increase in urine flow
• May cause postural hypotension, esp. in elderly patients
• Thiazides (and loop diuretics less so) may uncover/worsen diabetes
• Thiazides and loop diuretics may worsen gout
• NSAIDs may reduce the effects of loop diuretics (reduced effects of renal PGs on renal blood flow)
• Patients should be advised to avoid excess salt in the diet
• Electrolytes should be monitored
DIURETICS

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1. Mechanism of action and ADR of Loop Diuretics ?
2. Classify diuretics with specific examples.
3. Explain the role of diuretic as antihypertensive therapy.
4. Define and Classify diuretics. Explain the Pharmacology of Furosemide.
QUESTIONS

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•Pharmacology for medical graduates Third edition by Tara V Shanbhag.
•Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS
•Essentials of Medical Pharmacology [7th Edition] by KD Tripathi
•Rang and Dale 8th Edition By H.P.Rang, J.M. Ritter
REFERENCES
Thank You