1. DIURETICS

2. • Diuresis: increased urine flow
• Diuretics: substances which elicit diuresis
• In the kidney, water reabsorption dependent
primarily on Na+ reabsorption
• Thus a diuretic is an agent which inhibits tubular Na+
reabsorption (along with Cl-, HCO3-) resulting in
increased excretion of these ions

5. Classification of diuretics
A)
According to the site of Action:
1) Site –I ( Proximal convoluted tubule) acting drugs :
–
Osmotic diuretics: mannitol, isosorbide , urea
–
Carbonic anhydrase inhibitors : acetazolamide , methazolamide ,
dichlorphenamide
–
Xanthene drugs : aminophylline , theophylline , theobromide , caffeine
2) Site-II (Ascending limb of loop of Henle) acting drugs:
–
Furosemide , bumetanide, ethacrynic acid , mefruside, piretanide
3) Site –III ( Distal convoluted tubule )acting drugs :
–
Thiazides: chlorothiazide, hydrochlorthiazide, benzthiazide ,
hydroflumethiazide , clopamide
–
Thiazide like( related heterocyclics ) : cholrthalidone , metolazone ,
Xipamide , Indapamide
–
Mercurials: mercaptomerin, mersibid, mercurophyll, mersalyl
4) Site –IV ( Collecting Duct) :
–
K+ sparing diuretics : spironolactone , triamterene , amiloride

6. B) According to potency:
1) High ceiling(efficacy)
diuretics (loop
diuretics)
–
–
–
–
–
Furosemide
Bumetanide
Piretanide
Ethacrynic acid
Mefruside
2) Moderate efficacy
diuretics ( thiazides )
– Hydrochlorthiazide
– Bendroflumethiazide
3) Low efficacy diuretics
a) Osmotic diuretics :
b) Potassium sparing
c) Carbonic anhydrase
inhibitors
d) Xanthene groups

7. Proximal Convoluted tubule
• 66% of total sodium ions
(Na+, but 85% of the
filtered NaHCO3), 65% of
the K+, 60% of the water,
and virtually all of the
filtered glucose and
amino acids are
reabsorbed.
• Specific transport
• Passive transport
• Paracellular pathways

8. Carbonic anhydrase inhibitor:
Acetazolamide
• Pharmacokinetics
– The carbonic anhydrase inhibitors are well
absorbed after oral administration. An increase in
urine pH from the HCO3– diuresis is apparent
within 30 minutes, maximal at 2 hours, and
persists for 12 hours after a single dose. Excretion
of the drug is by secretion in the proximal tubule
S2 segment. Therefore, dosing must be reduced in
renal insufficiency

9. • Mechanism
– By inhibiting the action of carbonic anhydrase ,
inhibits reabsorption of sodium
– Blocks NaHCO3 reabsorption causing bicarbonate
diuresis
– Metabolic acidosis

10. Clinical Indications
•
•
•
•
•
•
Glaucoma
Urinary alkalinization.
Metabolic alkalosis
Acute mountain sickness
Premenstrual oedema
Other uses:
– adjuvants in the treatment of epilepsy, in some forms of
hypokalemic periodic paralysis, and to increase urinary
phosphate excretion during severe hyperphosphatemia.

11. Toxicity
• HYPERCHLOREMIC METABOLIC ACIDOSIS
• RENAL STONES
– Phosphaturia and hypercalciuria occur during the bicarbonaturic response to
inhibitors of carbonic anhydrase.
• RENAL POTASSIUM WASTING
– Potassium wasting can occur because Na+ presented to the collecting tubule is
partially reabsorbed, increasing the lumen-negative electrical potential in that
segment and enhancing K+ secretion. This effect can be counteracted by
simultaneous administration of potassium chloride.
• OTHER TOXICITIES
– Drowsiness and paresthesias are common following large doses of
acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with
renal failure, leading to nervous system toxicity. Hypersensitivity reactions
(fever, rashes, bone marrow suppression, and interstitial nephritis) may also
occur.

12. Mannitol
• Sugar alcohol
• Characters :
–
–
–
–
–
Freely filtered
No absorption
Pharmacologically inert
IV administration
Entire tubule
• Indications :
– Glaucoma
– Cerebral oedema
– Prevention of acute
renal failure
– Before neurosurgery to
reduce CSF and
intraocular pressure
– Oliguric states (
rhabdomyolysis)

13. • Contraindications :
– Anuria (risk of cardiac
failure )
– Marked pulmonary
congestion
– Prevention of acute
renal failure
– Intracranial hemorrhage
• Adverse effects :
– Transeint expansion of
ECF volume
– Hyponatremia
– Headche , nausea ,
vomiting

14. Loop of henle
• action of the transporter
contributes to excess K+
accumulation within the
cell. Back diffusion of this
K+ into the tubular lumen
causes a lumen-positive
electrical potential that
provides the driving force
for reabsorption of
cations—including
magnesium and
calcium—via the
paracellular pathway

15. Loop diuretics
• Pharmacokinetics
– rapidly absorbed.
– eliminated by the kidney by glomerular filtration and tubular
secretion.
– Absorption of oral torsemide is more rapid (1 hour) than that of
furosemide (2–3 hours) and is nearly as complete as with
intravenous administration.
– The duration of effect for furosemide is usually 2–3 hours and
that of torsemide is 4–6 hours.
– Half-life depends on renal function.
– Reduction in the secretion of loop diuretics may result from
simultaneous administration of agents such as NSAIDs or
probenecid, which compete for weak acid secretion in the
proximal tubule.

16. Characters :
– Very potent
– Can act in severe renal and heart failure where
other diuretics fail
– Rapid onset

17. Mechanism:
– inhibit NKCC2, the luminal Na+/K+/2Cl– transporter
in the thick ascending limb of Henle's loop
– Decrease intracellular K, back diffusion, positive
potential, increase diuresis
– induce synthesis of renal prostaglandins
– increase renal blood flow
– Massive dose inhibits carbonic anhydrase

18. Indications
•
•
•
•
•
•
•
•
•
Acute pulmonary oedema
Moderate hypertension
Left ventricular failure
Congestive heart failure
Oedema due to liver cirrhosis
Oliguric phase of acute renal failure
Hypercalcemia
Hyperkalemia
anion overdose (treating toxic ingestions of bromide,
fluoride, and iodide, which are reabsorbed in the thick
ascending limb)

19. Toxicity
•
•
•
•
•
•
•
•
•
•
Hypokalemic metabolic alkalosis
Ototoxicity
Nephrotoxicity
Myalgia
Hyperuricemia
Hypomagnesemia
Hypovolemia
severe dehydration. Hyponatremia
Hypovolemic hypotension
Allergic & other reactions
– Except for ethacrynic acid, the loop diuretics are sulfonamides.
Therefore skin rash, eosinophilia and, less often, interstitial nephritis
are occasional side effects of these drugs. This toxicity usually resolves
rapidly after drug withdrawal. Allergic reactions are much less
common with ethacrynic acid.
– Cross allergenicity with thiazides, sulfonamides

20. Contraindication
• hepatic cirrhosis, borderline renal failure, or
heart failure
• Gout
• Anuric renal failure
• Pregnancy
Drug Interactions :
– Digoxin
– Aminoglycosides
– Cephalosporins
– Warfarin

22. Distal convoluted tubule
• K+ does not recycle across the
apical membrane of the DCT
as it does in the TAL, there is
no lumen-positive potential in
this segment, and Ca2+ and
Mg2+ are not driven out of the
tubular lumen by electrical
forces. Instead, Ca2+ is actively
reabsorbed by the DCT
epithelial cell via an apical Ca2+
channel and basolateral
Na+/Ca2+ exchanger (Figure
15–4). This process is
regulated by parathyroid
hormone.

23. Thiazides
• Pharmacokinetics
– All of the thiazides can be administered orally
– Chlorothiazide, the parent of the group, is not very
lipid-soluble and must be given in relatively large
doses. It is the only thiazide available for parenteral
administration.
– Chlorthalidone is slowly absorbed and has a longer
duration of action.
– Although indapamide is excreted primarily by the
biliary system, enough of the active form is cleared by
the kidney to exert its diuretic effect in the DCT

24. Pharmacodynamics
• Thiazides inhibit NaCl reabsorption from the
luminal side of epithelial cells in the DCT by
blocking the Na+/Cl– transporter (NCC).
• ATP dependent K channel openers
• Enhance Calcium reabsorption by two ways :
– In the proximal tubule, thiazide-induced volume
depletion leads to enhanced Na+ and passive Ca2+
reabsorption.
– In the DCT, lowering of intracellular Na+ by thiazideinduced blockade of Na+ entry enhances Na+/Ca2+
exchange in the basolateral membrane and increases
overall reabsorption of Ca2+

25. Indications
(1) hypertension,
(2) heart failure,
(3) nephrolithiasis due to idiopathic
hypercalciuria, and
(4) nephrogenic diabetes insipidus.

26. Toxicity
•
•
HYPOKALEMIC METABOLIC ALKALOSIS AND HYPERURICEMIA
IMPAIRED CARBOHYDRATE TOLERANCE
– Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly
abnormal glucose tolerance tests. The effect is due to both impaired pancreatic release of
insulin and diminished tissue utilization of glucose. Hyperglycemia may be partially reversible
with correction of hypokalemia.
•
HYPERLIPIDEMIA
– Thiazides cause a 5–15% increase in total serum cholesterol and low-density lipoproteins
(LDL). These levels may return toward baseline after prolonged use.
•
HYPONATREMIA
– It is due to a combination of hypovolemia-induced elevation of ADH, reduction in the diluting
capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the
drug or limiting water intake.
•
ALLERGIC REACTIONS
– The thiazides are sulfonamides and share cross-reactivity with other members of this chemical
group. Photosensitivity or generalized dermatitis occurs rarely. hemolytic anemia,
thrombocytopenia, and acute necrotizing pancreatitis.
•
OTHER TOXICITIES
– Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase inhibitors may
occur. Impotence has been reported but is probably related to volume depletion

27. Collecting tubule
• The principal cells are the
major sites of Na+, K+, and
water transport and the
intercalated cells are the
primary sites of H+
secretion
• principal cells do not
contain cotransport
systems for Na+ and other
ions in their apical
membranes

28. Potassium sparing diuretics :
spironolactone
• Aldosterone antagonist
• Steroid chemically related to mineralocorticoid aldosterone
Mechanism of ALDOSTERONE ACTION
• By combining with aldosterone receptor , promotes gene
mediated mRNA synthesis, induces the formation of
aldosterone induced proteins which promote Na+
reabsorption by :
– Activating sodium channel
– Translocating sodium channels from cytosolic site to luminal
membrane and Na/K ATPase to basolateral membrane
– Increase ATP production by mitochondria
Spironolactone competitively inhibits the formation of aldosterone
induced proteins (AIPs) and blocks all the action of aldosterone
in the principal cell of the collecting duct.

29. • Pharmacokinetics :
– High oral bioavailability
– Highly bound to plasma proteins
– Completely metabolised in liver , converted to
active metabolites –canrenone .
– Undergoes some enterohepatic circulation

30. • Indications
– Edema
– Hyperaldosteronic states
– Adjunct to other
diuretics
– Antiandrogenic to treat
women with hirsuitism
or significant acne
– Congestive heart failure
– Hypertension
• Adverse effects
– Hyperkalemia
– Acidosis
– Antiandrogen ( male
gynecomastia)
– Drowsiness
– Confusion
– Abdominal upset
– Impotence
– Menstrual irregularities
– Peptic ulcer

31. Renal epithelial sodium channel
blockers
• Amiloride , triamterene
Bind to the sodium channel from the luminal side and
block it, reducing the lumen negative transepithelial
potential difference responsible for K+ And H+
secretion and indirectly inhibit K excretion.
Triamterene is metabolized in the liver, but renal
excretion is a major route of elimination for the active
form and the metabolites.
triamterene has a shorter half-life and must be given
more frequently than amiloride (which is not
metabolized).

32. Triamterene:
• Bioavailability :30-70%
• Protein binding: 67%
• Metabolism: conjugated to hydroxytriamterene
• Half-life: 1-2 hours, active metabolite 3 hours
• Excretion: renal <50%, 21% unchanged
Amiloride:
Bioavailability: Readily absorbed
Metabolism: none
Half-life :6 to 9 hours
Excretion :unchanged in urine