9/30/2022

DIURETICS
How do they work?
WHAT DO THEY DO?
When do I use them?
How do I use them?

Dr. Abu Syed Md. Mosaddek

Prof. Of Pharmacology

00 1 00 2

00 3 00 4

Thiazides

• Most widely used diuretic.

• Sulfonamide derivative.

00 5 00 6

00 1
 9/30/2022

Mechanism of Action
Thiazide diuretics mainly act in the proximal part of
distal convoluted tubule.

•Thiazides freely filtered and secreted in proximal

tubule.
•Bind to the electroneutral NaCl cotransporter.
• Impair Na+ and Cl- reabsorption.
•Decreased excretion of Ca++ and uric acid.

00 7 00 8

Whole Body Effects of Thiazides:

• Increased urinary excretion of
•Increased K+ and Mg++ Excretion. Na+
Cl-
K+
•So, these drugs cause increase the concentration Water
of Na+, and Cl- in the tubular fluid which is HCO3- (dependent on
excreted out along with iso-osmotic amount of structure)
• Reduced ECF volume
water. • Reduce blood pressure (lower CO)
• Reduced GFR
• Besides, they have mild vasodilator effect due to decrease sensitivity of NA to
arteriole and also direct action on vascular smooth muscle.

00 9 00 10

Pharmacokinetics: Diabetes Insipidus:

• Oral administration - absorption poor Thiazides:
• Diuresis within one hour Decrease plasma volume.
• T1/2 for chlorothiazide is 1.5 hours, chlorthalidone is 44 hours ↓
Decrease GFR
Therapeutic Uses:
↓
• Edema due to CHF
Increase Na+ and H2o re-absorption in PCT
• Essential hypertension (mild to moderate)
• Diabetes insipidus ↓
• Hypercalciuria Decrease delivery of Na+ and H20 to DCT.
• To prevent recurrent stone formation in idiopathic hypercalciuria. ↓
So, used in DI.

00 11 00 12

00 2
 9/30/2022

DM:
Thiazides do not used in DM because— Thiazide: Use in Hypercalciuria and recurrent Ca2+ Calculi:
• Decrease insulin secretion due to K+ depletion. • Thiazides promote distal tubular Ca2+ reabsorption
• Decrease peripheral utilization of glucose. • Prevent “excess” excretion which could form stones in the ducts of the kidney
• Increase lipid level.
• Destroy β-cells of pancreas.

00 13 00 14

Thiazide Toxicity:
• Hypokalemic alkalosis due to:
Increased availability of Na+ for exchange at distal convoluted tubule and
collecting duct
↓
Stimulates Na+ exchange with K+ and H+ increasing their excretion.

00 15 00 16

• Volume contraction induced aldosterone release Impaired carbohydrate tolerance –

• Hyperuricemia: Hyperglycemia and glycosuria due to --
Competes with secretion of uric acid in PCT. • Diminished insulin secretion due to K+ depletion.
↓ • Decrease peripheral utilization of glucose
Inhibits the secretion of it. • Destroys beta cells of pancreas.
↓ • Elevated plasma lipids → 5 – 15% increase in serum cholesterol and increase
Increases serum uric acid. LDL.
Or • Hypersensitivity – skin rash, dermatitis and necrotizing vasculitis.
Enhances transport in the proximal tubule
↓
Increases uric acid re-absorption

00 17 00 18

00 3
 9/30/2022

Loop diuretics
• These drugs have their major action on thick part of ascending limb of loop of
Henle.
• These drugs are also called high ceiling diuretics.
Management of hypokalamia: Available Loop Diuretics:
1. Administration of green nut water, banana. • Furosemide (prototype)
2. Kcl solution / tablet. • Bumetanide
3. Combination with K+ sparing diuretics. • Torsemide
• Ethacrynic acid

00 19 00 20

• Enter proximal tubule via organic acid transporter.

Mechanism of Action • Inhibit the Na+-K+-2Cl- co-transport system in the luminal membrane of the
thick ascending limb of loop of Henle.
↓
Reduce the re-absorption of Nacl
↓
Excretion of Na+ and Cl- along with iso-osmotic amount of water and increase
excretion of K+.
• Decrease excretion of uric acid.

00 21 00 22

Other actions of frusemide: 2. Increases renal blood flow due to prostaglandin

1. Induces renal prostaglandin synthesis ↓
↓ Causes redistribution of blood flow within renal cortex.
Participates in the renal actions of these drugs. ↓
3. Increase systemic venous capacitance
↓
NSAIDs inhibit prostaglandin synthesis in kidney Decrease left ventricular filling pressure.
↓ ↓
Interfere with diuretic action of these drugs. So used in pulmonary congestion and CCF.

00 23 00 24

00 4
 9/30/2022

Pharmacological Effects of Loop Diuretics:

[Link] of diluting ability:

Increased Na+, Cl- and K+ excretion.

[Link] electrostatic driving force in CCD:

Increased K+ and H+ excretion

00 25 00 26

Pharmacokinetics:
• Rapid oral absorption Therapeutic Uses:
• Bioavailability ranges from 65-100% • Severe hypertension
• Rapid onset of action • Edema of cardiac, hepatic or renal origin
• Extensively bound to plasma proteins • Acute pulmonary edema – (parenteral route)
• Secreted by proximal tubule organic acid transporter. • Chronic renal failure
• Hypertension complicated by renal impairment.
• Symptomatic hypercalcemia-- combined with isotonic Nacl solution.

00 27 00 28

Loop Diuretic Toxicity: Drug Interactions:

• Hypokalemic metabolic alkalosis due to increase renal secretion of K+ and H+. • Displacement of plasma protein binding of anticoagulants→ bleeding.
• Magnesium and calcium depletion • Li+ clearance is decreased
• Chronic dilutional hyponatremia • Additive toxicity with other ototoxic drugs
• Hyperuricemia – increase uric acid re-absorption. • With Propranolol (↑ level of later), amphotericin B (↑ nephrotoxicity)
• Ototoxicity • Inhibitors of organic acid transport (probenecid) and decreased diuretic action
• Hypovolemia leading to hypotension and severe dehydration. • With NSAIDs → decreased diuretic action due to inhibition of PG synthesis.
• Reduced GFR, circulatory collapse,
• Allergic reactions – skin rash, eosinophilia and interstitial nephritis.

00 29 00 30

00 5
 9/30/2022

Potassium sparing diuretics Mechanism of action

• These drugs act in the distal convoluted tubule (late part)

• Inhibit Na+ re-absorption, K+ secretion and H+ secretion.
• Used primarily when aldosterone is present in excess.

• Spironolactone: has extensive first pass effect and limited diuretic action.

00 31 00 32

Spironolactone and eplerenone:

• They are synthetic aldosterone antagonists.
Decrease H+ secretion and also decrease uric acid excretion.
• They competitively block the binding of aldosterone to its cytoplasmic receptor.

• The Na+ is transported by epithelial sodium channel which is aldosterone Net effect:
dependent. Increases the excretion of Na+, Cl- and H20 and decreases K+, H+ secretion.

• So, inhibition of the Na+ retaining action of aldosterone and concomitant

decrease in its K+ secreting stimulation.

00 33 00 34

Pharmacokinetics:
In late part of DCT and early part of CT: • 70% absorption in GI tract
• Sodium ions are exchanged for potassium and hydrogen. • Extensive first pass effect in liver and enterohepatic circulation
• Extensively bound to plasma proteins
• Only 5% of filtered Na+ is reabsorbed here. • 100% metabolites in urine
• Active metabolite: canrenone (active)

00 35 00 36

00 6
 9/30/2022

Toxicity:
• Hyperkalemia - avoid excessive K+ supplementation when
Therapeutic Uses:
patient is on spironolactone
• Hypertension alone or in combination with thiazides.
• Cirrhosis of liver. • Androgen like effects due to its steroid structure and have
• Secondary hyper-aldosteronism caused by cirrhosis of liver.
affinity toward progesterone and androgen receptors.
• Prevent K+ loss caused by other diuretics Gynecomastia, impotence in male
Menstrual irregularities in female
• Metabolic acidosis due to H+ and K+ sparing effect.
• GI disturbances
• Lethargy and mental confusion.

00 37 00 38

Triamterene and Amiloride : Mechanism of Action:

• Has limited diuretic efficacy. • Blockade of luminal Na+ channel in the principal cells of the CCD
• Non-steroid in structure • Amiloride: blocks the Na/H exchanger in intercalated cells
• Not aldosterone antagonists. • Blockade of the electrogenic entry of sodium causes a drop in apical membrane
• Do not block aldosterone receptor. potential (less negative), which is the driving force for K+ secretion
• Directly interfere with Na+ entry through the epithelial Na+ channels in the
apical membrane of the collecting tubule.
• These agents are also effective K+ sparing agents.

00 39 00 40

Pharmacokinetics:

Triamterene Amiloride
• 50% absorption of oral dose • 50% absorption of oral dose
• 60% bound to plasma proteins • not metabolized, excreted in urine unchanged
• Extensive hepatic metabolism with active metabolites • Secreted by proximal tubular cation transporters
• Secreted by proximal tubule via organic cation transporters

00 41 00 42

00 7
 9/30/2022

Toxicity:
• Hyperkalemia. Avoid K+ supplementation
• Nausea, vomiting, leg cramps, dizziness, nephrolithiasis
(triamterene)
• Nausea, vomiting, diarrhea, headache
Therapeutic uses:
(amiloride)
Eliminate K+ wasting effects of other diuretics in:
• Edema
• Hypertension

00 43 00 44

Drug interaction: Acetazolamide

• Do not use in combination with spironolactone since the potassium sparing
effect is greater than additive • It is a sulfonamide without antibacterial activity.
• Its main action is to inhibit carbonic anhydrase (CA) enzyme in the proximal
• Caution with ACE inhibitors→ hyperkalemia. tubular cells.
• Due to less efficacy, it is much less used as diuretic.
• It produces 5% diuresis i.e. 5% Na+ will not be reabsorbed from tubule.

00 45 00 46

Carbonic anhydrase is a normal component of proximal tubular cell.

Mechanism of Action
Normally:
Secreted H+ combined with filtered HCo-3
↓
Form H2Co3.
+↓CA
Converted into water and Co2.
↓
Co2 is reabsorbed.

00 47 00 48

00 8
 9/30/2022

A. In side of cell: Acetazolamide inhibits CA. Carbonic anhydrase inhibitors are the self limiting diuretic
↓ because:
H+ is not be available for Na+ exchange The loss of HCo3-
↓
Leads to excretion of sodium along with water. ↓
Causes metabolic acidosis
B. In lumen: Acetazolamide inhibits CA. ↓
↓ H+ will be secreted more.
HCo3- can not be converted H2Co3
↓
↓
More Na+ will be reabsorbed with iso-
Then Co2 and H20 osmotic amount of water.
↓ ↓
So HCo3- remains poorly diffusible form Diuretic effect of acetazolamide is inhibited.
↓
↓
Excreted in large amount
↓ • Bicarbonate wasting limits the diuretic efficacy of the drug
Cause alkaline urine. to 2-3 days.
00 49 00 50

Therapeutic Uses:
• Urinary alkalization – To make uric acid crystal more excreted.
• Metabolic alkalosis – To reduce body HCo3- stores.
• Glaucoma: acetazolamide, dorzalamide – Decrease aqueous humor formation.
Preoperatively in acute angle glaucoma to lower IOP before surgery.
• Acute mountain sickness – CA Inhibitor Toxicity:
weakness, dizziness. • Hyperchloremic metabolic acidosis
• Nephrolithiasis: renal stones – increased phosphate excretion and
hypercalciuria occurs due to HCo3- responses to CA inhibitor.
• Potassium wasting-- hypokalemia

00 51 00 52

Mechanism of Action:
Osmotic diuretics Inhibition of Water Diffusion
• Free filtration in osmotically active concentration
• Proximal tubule
• Thin limb of the loop of Henle
Osmotic Diuretic Characteristics: • Osmotic pressure of non-reabsorbable solute
• Freely filterable ↓
• Little or no tubular reabsorption Prevents water reabsorption
• Inert or non-reactive ↓
• Resistant to degradation Increase urine volume

00 53 00 54

00 9
 9/30/2022

Therapeutic Uses:
• Drug poisoning
Osmotic Diuretics in Current Use:
• Cerebral oedema
• Mannitol (prototype)
• Raised intraocular pressure
• Urea
• Acute oliguric renal failure (prophylaxis of acute renal failure)
• Glycerine
• Isosorbide

00 55 00 56

Mechanism:
• The proximal tubule and descending limb of loop of Henle are freely permeable
to water.
• As osmotic agent in those parts Toxicity of Osmotic Diuretics:
↓ • Increased extracellular fluid volume
Is not reabsorbed • Hypersensitivity reactions
↓ • Glycerine metabolism can lead to hyperglycemia and glycosuria
Causes water to be retained in these segments • Headache, nausea and vomiting
↓
Promotes a water diuresis.

00 57 00 58

Mannitol: Indication of diuretics:

It is a forced diuretic. 1. Oedema due to cardiac, renal and hepatic diseases (associated with Na+
overload).
When injected i/v, it is not metabolized and is rapidly filtered by the glomeruli. 2. Acute pulmonary oedema following M.I. (with out Na+ overload)
3. Hypertension.
Being not absorbable, it exerts osmotic effect which interfere back diffusion of 4. Hypercalcemia.
water and reabsorption of Na+. 5. Idiopathic hypercalciuria.
6. Diabetes insipidus.

00 59 00 60

00 10