Diuretics

the detail study of diuretics which include their drugs, use,classification of diuretics, side effect, mechanism of action, metabolism, synthesis etc. this all things are cover in this presentation.

1. Diuretics
Ravish Yadav

2. Anatomy and Physiology of Renal
system
►Remember the nephron is the most important part of the
kidney that regulates fluid and electrolytes.
► Urine formation:
1.Glomerular filtration rate = 180L/day
2.Tubular re-absorption (around 98%)
3.Tubular secretion

3. ►How could urine output be increased ?
↑Glomerular filtration Vs ↓Tubular reabsorption
(the most important clinically)
oIf you increase the glomerular filtration increase
tubular reabsorption (so you cant use glomerular
filtration)
►Purpose of Using Diuretics
1. To maintain urine volume ( e.g.: renal failure)
2. To mobilize edema fluid (e.g.: heart failure, liver
failure, nephrotic syndrome)
3. To control high blood pressure.

4. ►Percentage of reabsorption in each segment:
•Proximal convoluted tubule 60-70%
•Thick portion of ascending limb of the loop of Henle. 25%
•Distal convoluted tubule 5-10%
•Cortical collecting tubule 5% (Aldosterone and ADH)

5. Physiology of tubular reabsorption
The filtrate
here is
isotonic
The filtrate here
is hypertonic

8. Classificationof Diuretics
►The best way to classify diuretics is to look for their Site of
action in the nephron
Site 1 Diuretics that inhibit transport in the Proximal
Convoluted Tubule ( Osmotic diuretics, Carbonic
Anhydrase Inhibitors)
Site 2 Diureticsthat inhibit transport in the Medullary
Ascending Limb of the Loop of Henle ( Loop diuretics) or
High ceiling Diuretics
Site 3 Diureticsthat inhibit transport in the Distal Convoluted
Tubule( Thiazides : Indapamide , Metolazone)
Site 4 Diuretics Diuretics that inhibit transport in the Cortical
Collecting Tubule (Potassium sparing diuretics)

11. A. Diuretics that inhibit transport in the
Convoluted Proximal Tubule
1. Osmotic Diuretics (e.g.: Mannitol)
MOA: They are hydrophilic compounds that are easily filtered
through the glomerulus with little re-absorption and thus
increase urinary output via osmosis.
PK:Given parentrally. If given orally it will cause osmotic diarrhea.
IUPAC: (2R,3R,4R,5R)-
Hexane-1,2,3,4,5,6-hexol

12. ISOSORBIDE
IUPAC: (3S,3aR,6R,6aR)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-diol

13. 2.Carbonic Anhydrase Inhibitors(Acetazolamide(Oral) ;
Dorzolamide (Ocular) ; Brinzolamide (Ocular)
Mechanism of actionSimply inhibit reabsorption of sodium and
bicarbonate.
It prevents the
reabsorption of
HCO
3and Na
•Inhibition of HCO
3 reabsorption metabolic acidosis.
•HCO
3depletion enhance reabsorption of Na and Cl hyperchloremea.
•Reabsorption of Na ↑ negative charge inside the lumen ↑K secretion

14. ACETAZOLAMIDE
IUPAC: N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide

16. •Weak diuretic : because depletion of HCO
3enhance reabsorption of Na and Cl
•In glaucoma :
The ciliary process absorbs HCO
3 from the blood.
↑HCO
3↑aqueous humor.
Carbonic anhydrase inhibitors prevent absorption of HCO
3from the blood.
•Urinary alkalinization : to increase renal excretion of weak acids e.g.cystin and uric acid.
•In metabolic alkalosis.
•Epilepsy : because acidosis results in ↓seizures.
•Acute mountain sickness (Altitude sickness).
•Benign intracranial hyper tension.
Dorzolamde and brinzolamide are mixed with βblockers
(Timolol) to treat glaucoma (as topical drops)

17. ►Side Effects of Acetazolamide:
Sedation and drowsiness; Hypersensitivity reaction (because it
contains sulfur) Acidosis (because of decreased absorption of HCO
3)
; Renal stone (because of alkaline urine); Hyperchloremia,
hyponatremia and hypokalemia

18. METHAZOLAMIDE
IUPAC: N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2-ylidene)acetamide
A carbonic anhydrase inhibitor that is used as a diuretic and in the
treatment of glaucoma

19. BRINZOLAMIDE
IUPAC: (4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-3,4-
dihydrothieno[3,2-e]thiazine-6-sulfonamide

20. ETHOXZOLAMIDE
IUPAC: 6-ethoxy-1,3-benzothiazole-2-sulfonamide
Ethoxzolamide is a carbonic anhydrase inhibitor used as diuretic and
in glaucoma. It may cause hypokalemia

21. SITE I
DRUGS

22. B. Diuretics Acting on the Thick Ascending Loop
of Henle(loop diuretics) High ceiling (most efficacious)
►e.g. Furosemide (Lasix
R
), Torsemide, Bumetanide
(Bumex
R
), Ethacrynic acid.
1)Mechanism of Action: Simply inhibit the coupled
Na/K/2Cl cotransporter in the loop of Henle. Also,
they have potent pulmonary vasodilating effects (via
prostaglandins).
2)They eliminate more water than Na.
3)They induce the synthesis of prostaglandins in kidney
and NSAIDs interfere with this action.
They are the best diuretics for 2 reasons:
1-they act on thick ascending limb which has large capacity of reabsorption.
2-action of these drugs is not limited by acidosis

24. In loop diuretics and
thiazides :
The body senses the loss of
Na in the tubule.
This lead to compensatory
mechanism (the body will try
to reabsorb Na as much as
possible)
So the body will
increase synthesis of
aldosterone leading to
:
1-increase Na
absorption
2-hypokalemia
3-alkalosis

25. 2.Side effects:.
Ototoxicity; Hypokalemicmetabolic alkalosis; hypocalcemiaand
hypomagnesemia; hypochloremia; Hypovolemia; hyperuricemia
(the drugs are secreted in proximal convoluted tubule so they
compete with uric acid’s secretion) hypersensitivity
reactions(contain sulfur)
3.Therapeutic Uses
a) Edema (in heart failure, liver cirrhosis, nephrotic syndrome)
b) Acute renal failure
c) Hyperkalemia
d) Hypercalcemia

26. Dosage of loop diuretics:
Furosemide 20-80 mg
Torsemide 2.5-20 mg
Bumetanide 0.5-2.0 mg
Loop
diuretics
Furosemide:
Taken orally or i.v
If taken orally only 50 % is
absorbed
Torsemide:
Taken orally.
Better absorption
Fast onset of action
↑t
1/2
Bumetanide(Bumex®)
Taken orally
40 times potent than
furosemide.
Fast onset
Short duration of action

28. FUROSEMIDE/FRUSEMIDE
Furosemide is a benzoic-sulfonamide-furan. It is a diuretic with
fast onset and short duration that is used for EDEMA and
chronic Renal insufficiency.
IUPAC: 4-chloro-2-(furan-2-ylmethylamino)-5-
sulfamoylbenzoic acid

29. O
NH
2 2,4-Dichloro 5 sulfamoyl benzoic acid
Furosemide
2,4-Dichloro benzoic acid

30. AZOSEMIDE
IUPAC: 2-chloro-5-(2H-tetrazol-5-yl)-4-(thiophen-2-
ylmethylamino) benzenesulfonamide
Azosemideis a monosulfamyl belonging to the class of High
Ceiling loop diuretics.
Azosemideinhibitssodiumandchloridereabsorption
throughout the thick ascending limb of the loop of Henle.

31. BUMETANIDE (Phenoxybenzoic acid der.)
Bumetanideis a Loop Diuretic. The physiologic effect
ofbumetanideis by means of Increased Diuresis at Loop of
Henle.
IUPAC: 3-(Aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid

32. ETHACRYNIC ACID (Phenoxyacetic acid der.)
It inhibits symport of sodium, potassium, and chloride primarily in the
ascending limb of Henle, but also in the proximal and distal tubules. This
pharmacological action results in excretion of these ions, increased urinary
output, and reduction in extracellular fluid. This compound has been
classified as a loop or high ceiling diuretic.
IUPAC: 2-[2,3-dichloro-4-(2-methylidenebutanoyl) phenoxy]acetic acid

33. C. Diuretics that Inhibit Transport in the Distal
Convoluted Tubule (e.g.: Thiazidesand
Thiazide-like (Indapamide; Metolazone)
►Pharmacodynamics:
Mechanism of action: Inhibit Na
+
via inhibition of Na
+
/Cl
-
cotransporter.
They have natriuretic action.
►Side Effects: No ototoxicity; hypercalcemia due to ↑PTH,
more hyponatremia; hyperglycemia (due to both impaired
pancreatic release of insulin and diminished utilization of
glucose) hyperlipidemia and hyperurecemia ; hypokalemic
metabloic alkalosis.

36. ►Clinical uses:
Hypertension Drug of Choice (Hydrochlorthiazide; Indapamide
(Natrilex
R
)
Refractory Edema (doesn’t respond well to ordinary treatment)
together with the Loop diuretics (Metolazone).
Nephrolithiasis (Renal stone) due to idiopathic hypercalciuria
Hypocalcemia.
Nephrogenic Diabetes Insipidus. (it decreases flow of urine 
more reabsorption)

37. CHLORTHIAZIDE
IUPAC: 6-chloro-7-Sulfamoyl-2H-1,2,4-benzothiadiazine 1,1-dioxide

39. HYDROCHLORTHIAZIDE
IUPAC: 6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-
sulfonamide

40. BENZTHIAZIDE
IUPAC: 3-((Benzylthio)methyl)-6-chloro-7-sulfamoyl-2H-
benzo-1,2,4-thiadiazine 1,1-dioxide

41. METHYCLOTHIAZIDE
Methyclothiazide is a thiazide diuretic with properties similar to
those of hydrochlorothiazide.
IUPAC: 6-chloro-3-(chloromethyl)-2-methyl-1,1-dioxo-3,4-
dihydro-1,2,4-benzothiadiazine-7-sulfonamide

42. TRICHLORMETHIAZIDE
Trichlormethiazide is a thiazide diuretic with
properties similar to those of hydrochlorothiazide
IUPAC: 6-chloro-3-(dichloromethyl)-1,1-dioxo-3,4-dihydro-2H-
1,2,4-benzothiadiazine-7-sulfonamide

43. CHLORTHALIDONE
A benzenesulfonamide-phthalimidine that tautomerizes to a
benzophenones form.
It is considered a thiazide-like diuretic.
IUPAC: 1-keto-3-(3'-Sulfamyl-4'-chlorophenyl)-3-hydroxyisoindoline

44. METOLAZONE
A quinazoline-sulfonamide that is considered a thiazide-like
diuretic which is long-acting so useful in chronic renal failure. It
also tends to lower blood pressure and increase potassium loss.
IUPAC: 7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2-
dihydroquinazoline-6-sulfonamide.

45. QUINETHIZONE
Quinethazoneis a thiazide diuretic used to treat hypertension.
Common side effects include dizziness, dry mouth, nausea, and
lowpotassium levels.
IUPAC: 7-chloro-2-ethyl-4-oxo-2,3-dihydro-1H-quinazoline-6-
sulfonamide

46. INDAPAMIDE
A benzamide-sulfonamide-indole. It is called a thiazide-like
diuretic but structure is different enough (lacking the thiazo-
ring) so it is not clear that the mechanism is comparable.
IUPAC: 4-chloro-N-(2-methyl-2,3-dihydro-1H-indol-1-yl)-3-
sulfamoylbenzamide

47. D. Diuretics that inhibit transport in the Cortical Collecting Tubule (e.g.
potassium sparing diuretics).
Classification of Potassium Sparing Diuretics:
A)Direct antagonist of mineralocorticoidreceptors
(Aldosterone Antagonists e.g spironolactone
(Aldactone
R
) or
B) Indirect via inhibition of Na
+
influx in the luminal
membrane (e.g. Amiloride, Triametrene)

48. Spironolactone (Aldactone
R
)
►Synthetic steroid acts as a competitive antagonist of aldosterone
with a slow onset of action.
►Mechanism of action:Aldosterone cause ↑K
and H
+
secretion and ↑Na reabsorption.
►The action of spironolactone is the opposite

49. Clinical Uses of K
+
sparing Diuretics:
•In states of primary aldosteronism (e.g. Conn’s syndrome, ectopic ACTH production)
of secondary aldosteronism (e.g. heart failure, hepatic cirrhosis, nephrotic syndrome)
•To overcome the hypokalemic action of diuretics
•Hirsutism (the condensation and elongation of female facial hair) because it is an
antiandrogenic drug.

50. Side effects:
►Hyperkalemia(some times it’s useful other wise it’s a side
effect).
►Hyperchloremic(it has nothing to do with Cl) metabolic
acidosis
►Antiandrogniceffects (e.g. gynecomastia: breast
enlargement in males, impotence) by spironolactone.
►Triametrenecauses kidney stones.
►Diuretics Combination preparations
these are anti-hypertensive drugs:
Dyazide
R
= Triametrene50 mg + Hydrochlorothiazide HCT 25 mg
Aldactazide
R
= Spironolactone 25 mg + HCT 25 mg
Moduretic
R
= Amiloride5 mg + HCT 50 mg
►Note : HCT to decrease hypertension and K sparing diuretics
to overcome the hypokalemiceffect of HCT
►Contraindications: Oral K administration and using of ACE inhibitors

51. SPIRONOLACTONE
Spironolactone is a synthetic 17-lactone steroid which is a renal competitive
aldosterone antagonist in a class of pharmaceuticals called potassium-sparing
diuretics.
It is used mainly in the treatment of refractory edema in patients with
congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects
on the endocrine system are utilized in the treatments of hirsutism and acne
but they can lead to adverse effects.
IUPAC: S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-3,5'-
dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-
cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethanethioate

52. EPLERENONE
Eplerenoneis a selectivealdosteronereceptor antagonist.Eplerenonebinds to the
mineralocorticoid receptor and blocks the binding ofaldosterone, thereby
decreasingsodiumresorption and subsequently increasingwateroutflow. This
leads to a decrease in blood pressure.Eplerenoneis used in the treatment of
hypertension and congestive heart failure.
IUPAC: methyl (1'R,2R,2'S,9'R,10'R,11'S,15'S,17'R)-2',15'-dimethyl-5,5'-dioxo-18'-
oxaspiro[oxolane-2,14'-pentacyclo[8.8.0.0¹,¹⁷.0²,⁷.0¹¹,¹⁵]octadecan]-6'-ene-9'-
carboxylate

53. TRIAMTERENE
Triamtereneis apteridinederivative withpotassium-sparing diuretic
property.Triamtereneblocks thesodium-potassiumexchange pump (Na-K-
ATPase) in the luminal membrane of principal cells in the late distal tubule,
cortical collecting tubule and collecting duct in the kidney. This reversible
inhibition of the electrogenicsodiumtransport decreases the lumen-negative
transepithelial potential difference and thus reduces the driving force for K+
movement into the tubular lumen resulting in the inhibition
ofsodiumreabsorption in exchange for K+ and H+.
IUPAC: 6-phenylpteridine-2,4,7-triamine

54. AMILORIDE
IUPAC: 3,5-Diamino-N-carbamimidoyl-6-chloropyrazine-2-
carboxamide
A pyrazine compound inhibiting sodium reabsorption through sodium
channels in renal epithelial cells. This inhibition creates a negative potential
in the luminal membranes of principal cells, located in the distal convoluted
tubule and collecting duct. Negative potential reduces secretion of
potassium and hydrogen ions. Amiloride is used in conjunction with
diuretics to spare potassium loss.