1. Diuretics From Diuresis to Clinical Use
Prof Dr Mahmoud Khattab

2. DIURETICS What are Diuretics? How & Where they work? Osmotic Diuretics
Carbonic Anhydrase Inhibitors
Thiazide Diuretics
Loop Diuretics
K+-sparing Diuretics
M Khattab 2008

3. DIURETICS
Diuretics work to effectively increase sodium and water excretion (increasing urine volume)
In turn they decrease extra-cellular fluid (ECF) and effective circulating volume
Diuretics interfere with the normal sodium handling by the kidney. How is Na+ handled by kidneys?
Target molecules for diuretics are specific renal tubular membrane transport proteins
Adequate quantities of the diuretic drug must be delivered to its site of action. HOW?
M Khattab 2008

4. Sodium Excretion Regulation
Nephron Segment
Filtered Na+ reabsorbed
Na+ Transporter
Hormone
Proximal CT
60-70%
Na+- H+ antiporter
Angiotensin II
Loop of Henle
20-30%
Na+-K+-2Cl- symporter
Distal CT
5-10%
Na+-Cl- symporter
Cortical Collecting T
1-3%
Epithelial Na+ channel
Aldosterone
Medullary Collecting
ANP
M Khattab 2008

5. Osmotic Diuretics They do not inhibit a specific transport protein
They are pharmacologically inert & filtered by GF
NOT reabsorbed creating an increased intra-luminal osmotic pressure inhibiting water/solute re-absorption
The main tubular sites of action are the PCT and the thick descending limb of Henle loop (freely permeable to water)
Osmotic diuretics produce only mild natriuresis
M Khattab 2008

6. Mannitol/Urea (IV), Isosorbide/Glycerin (Local & Oral)
Osmotic Diuretics
Therapeutic Uses
Mannitol/Urea (IV), Isosorbide/Glycerin (Local & Oral)
Acutely raised intracranial pressure, e.g. after head trauma
Acute attacks of glaucoma
Plasma osmolarity is increased by solutes that does not penetrate into the brain or the eye
This results in extraction of water from the two sites but implies no diuretic effect
M Khattab 2008

7. Osmotic Diuretics
Acute renal failure to restore glomerular filtration rate that is aggressively diminished
Drug overdose or poisoning
Adverse Effects
Hypokalemia
Acute increase in intravascular volume
M Khattab 2008

8. Carbonic Anhydrase Inhibitors
Acetazolamise & Dichlorphenamide
Site of action?
Mechanism of action?
CA inhibition→ ↑luminal PCT H+→↓ bicarbonate reabsrobtion → ↓ Na+ /H+ transporter activity
Only mild natriuresis (1-3%)
Increased bicarbonate in urine
M Khattab 2008

9. Carbonic Anhydrase Inhibitors
Therapeutic Uses
Glaucoma: CA transports Na+/bicarbonate with water (osmosis) to anterior chamber
CA inhibition lowers aqueous humor formation
Urine alkalinization to trap acidic substances dissolved in urine (e.g., uric acid, Hb, cysteine)
Acute mountain sickness
Enhancing bicarbonate excretion in chronic respiratory acidosis (chronic respiratory obstructive diseases with CO2 retention)
Epilepsy
M Khattab 2008

10. Carbonic Anhydrase Inhibitors
Adverse Effects
Hypokalemia
Metabolic acidosis
Allergic effects
Acute renal failure caused by nephrolithiasis, where acetazolamide may crystallize during chronic use (does not occur with methazolamide)
M Khattab 2008

11. Thiazide Diuretics Site & mechanism of action:
Early distal renal tubule
Block Na+/Cl- symporter
Efficacy: Moderate 5% natriuresis
Limits the excretion of electrolyte-free water (urine dilution)
Reduction of Ca2+ excretion:
↑ Ca2+ reabsrobtn by DCT
↓ECF→ enhance passive Na+/ Ca2+ re-absrobtion by PCT
Luminal
membrane
Basolateral
membrane
Hydrochlorthiazide, chlorthalidone, metolazone, indapamide
M Khattab 2008

12. Thiazide Diuretics Therapeutic Uses Treatment of hypertension
Treatment of mild heart failure
Mild edema
Diabetes inspidus
Calcium nephrolithisis
Idiopathic recurrent nephrolithisis with or without hypercalciuria can be prevented by thiazide diuretics
M Khattab 2008

13. Thiazide Diuretics Side Effects
Hypokalemia & Metabolic alkalosis
Hyperuricemia
Hyperglycemia & glucose intolerance related to:
Hypokalemia-induced decrease of insulin release
Intravascular V↓→ sympathetic stimulation
Increased plasma cholesterol, VLDL cholesterol, and TG (high doses)
Hyponatremia in elderly HTN patients, mild renal failure (Intravascular V↓→ increased ADH→ water moves to ECF → decreased Na+ concentration
Occasionally sustained hypercalcemia, GIT intolerance, pancreatitis, allergic manifestations
M Khattab 2008

14. LOOP DIURETICS (HIGH-CEILING DIURETICS)
Frusemide, Bumetanide, Ethacrynic acid, Torasemide
Site of action: thick ascending limb of Hele’s loop
Loop diuretics inhibit Na+-K+-2C1- symporter at the apical membrane
M Khattab 2008

15. LOOP DIURETICS Pharmacological Actions
They decrease the re-absorption of Na+, K+ & Cl- → increases their urinary elimination
Increased urinary elimination of Ca2+ /Mg2+, the ascending loop is important site for Ca2+ handling
They may enhance glomerular blood flow & filtration (prostaglandins–dependent)
Loop diuretics are the most potent diuretics “high ceiling” increasing sodium excretion up to 25-30% of the filtered load. Why?
They impair free water clearance (ability to dilute urine)
M Khattab 2008

16. LOOP DIURETICS Pharmacokinetics
They reach the lumen by glomerular filtration & tubular secretion
They have good bioavailability, peak plasma level after 30 min of oral intake
Loop diuretics have fast onset of few minutes
They have short duration - <6 hours after oral administration & < two hours after parenteral administration
Torasemide has the longest duration
M Khattab 2008

17. LOOP DIURETICS Therapeutic Uses
Treatment of CHF:
lower peripheral edema (↓preload)
ameliorating pulmonary edema (dyspnea, orthopnea, cough) especially acute cases
standard formulation (not SR), are preferred because of potency & fast onset
Treatment of arterial hypertension
Sustained release preparations of longer duration of action & gradual BP lowering effect can be used
M Khattab 2008

18. LOOP DIURETICS Therapeutic Uses
Acute pulmonary edema
Renal failure
Hepatic cirrhosis with ascites
Treatment of hypercalcemia as those occuring with hyperparathyroidism & malignancy
M Khattab 2008

19. LOOP DIURETICS Side Effects
Hypokalemia, that might be associated with muscle weakness & cardiac dysrhythmias
Increased Na+ to collecting tubules increases its exchange with K+
↑Na+ loss & ↓ECF→ renin- aldosterone release
Metabolic alkalosis, related to hypokalemia
Occasional glucose intolerance in pred-diabetic patients
Hyperuricemia (gout attacks) is frequent because of increased PCT solute re-absorption
M Khattab 2008

20. LOOP DIURETICS Side Effects
Ototoxicity: Rapid IV injection of large doses of loop diuretics produced transient deafness
Ethacrynic permanent deafness was reported
Loop diuretic ototoxicity is magnified by concurrent administration of other ototoxic drugs
Hyponatremia is much less frequent than is with thiazide diuretics
NSAIDs blunt natriuresis
Large doses, in low GFR patients, increase serum creatinine (↓ BP & ↓ GFR)
M Khattab 2008

21. Loop versus Thiazide Diuretics D-R Relationship
Thiazide diuretics have almost flat D-R curve
Loop diuretics have steep D-R curve with higher efficacy
How does this affect
drug selection in HTN
& CHF?
M Khattab 2008

22. Potassium-Sparing Diuretics Aldosterane Antagonists
Spironolactone is a competitive antagonist for aldosterone on its intracellular receptors
Binding of aldosterone with
the receptors initiates DNA
transcription, initiating transcription of specific proteins resulting in:
early increase in the number of sodium channels
late increase in the number of Na+-K+-ATPase molecules
Mild diuresis 1-3% -- --
Spironolactone (Aldosterane Antagonist)
M Khattab 2008

23. Potassium-Sparing Diuretics Triametrene & Amiloride (Na+-channel Blockers)
They inhibit Na+ re-absorption & K+ secretion
They block the entry of sodium via the Na+ selective channels in the apical membrane of the principal cells
With decreased Na+ entry, there is decreased Na+ extrusion across the basolateral membrane by the Na+-K+-ATPase
M Khattab 2008

24. Potassium-Sparing Diuretics Pharmacokinetics & Adverse Effects
They have good oral bioavailability
Spironlactone is metabolized into the active metabolite canrenone with t1/2 of 18 hours
Traimetrene & amiloride durations are 9 & 24 hours respectively
Adverse Effects:
Hypokalemia, especially when combined with ACEIs, ARBs, NSAIDs
Spironolactone caused peppermint unpleasant after-taste & nausea/vomiting
Spironolactone steroidal structure is related to gynecomastia in men
Impotence & menstrual irregularities
M Khattab 2008

25. Hemodynamic Mechanism of Antihypertensive Effect of Diuretics
M Khattab 2008

26. Molecular Mechanism of Antihypertensive Effect of Diuretics
M Khattab 2008

27. Therapeutic Applications of Diuretics
Treatment of hypertension:
Thiazide diuretic proved to be equivalent safety & efficacy to new agents (ALLHAT study),
Can be used in combination with new agents & beta-blockers at low-dose (fewer side effects)
In presence of renal failure, loop diuretic is used
Edema States (↑ECF Na+/water retention):
Thiazide diuretic is used in mild edema with normal renal function
Loop diuretics are used in cases with impaired renal function
M Khattab 2008

28. Therapeutic Applications of Diuretics
Congestive Heart failure
Diuretics lower peripheral & pulmonary edema
Thiazides may be used in only mild cases with well-preserved renal function
Loop diuretics are much preferred in more severe cases especially when GF is lowered
In cases of life-threatening acute pulmonary edema, high-dose furosemide is given IV
It promptly & powerfully decreasing edema + venodilation (↓preload)
High-dose furosemide may be life-saving
M Khattab 2008

29. Therapeutic Applications of Diuretics
Congestive Heart failure (Continue):
Diuretic therapy may cause ↓GFR (↑serum creatinine) in cases of severe fall in preload & CO
Spironolactone, aldosterone R antagonist, proved to improve survival in severe CHF
It is added to ACEI+diuretic+β-bloker
Risk of hyperkalemia must be avoided
Aldosterone is implicated in myocardial fibrosis
M Khattab 2008

30. Therapeutic Applications of Diuretics Renal Diseases
1ry Na+/fluid retention as glomerulonephritis, acute/chronic renal failure & diabetic nephropathy
2ry Na+/fluid retention in nephrotic syndrome
Thiazides are used till GFR ≥ mL/min
Loop diuretic are used below given values, with increasing the dose with as GFR goes down
Hepatic Cirrhosis with Ascites
Spironolactone is of choice, loop diuretic may be added if diuresis was insufficient
Rapid powerful diuresis→ ↓plasma volume & renal hypo-perfusion → irreversible renal failure (hepatorenal syndrome)
M Khattab 2008

31. Therapeutic Applications of Diuretics Diabetes Inspidus
Rarely occuring metabolic (lack of ADH) or nephrogenic (ADH-insensitive collecting ducts)
Large volume(>10 L/day) of dilute urine
Thiazide diuretics effectively reduce urine volume
They cause both natriuresis & water diuresis → intra-vscular volume decreases → PCT & DCT re-absorptive capacity increases
M Khattab 2008

32. Diuretic Resistance
Failure of usual doses of loop diuretics in CHF, nephrotic syndrome, & chronic renal disease
Reduced delivery of diuretic molecules to the site of action
Chronic suppression of Na+ rebsorption in ascending Henle’s loop → structrural/functional changes in DCT & collecting ducts →↑ absorptive capacity of late segment of the nephron
The combination of a loop & a thiazide diuretic is usually very effective in resistant edema cases
M Khattab 2008