DIURETICS NOTES BY NEETHU.I.S

1. DIURETICS
NEETHU. I.S
ASSISTANT PROFESSOR
EZHUTHACHAN COLLEGE OF PHARMACEUTICAL SCIENCES
TRIVANDRUM

2. DIURETICS
Diuretics (natriuretics) are drugs which cause a net loss of Na+ and water in urine.
Classification
1. High ceiling(Inhibitors of Na+K+2Cl- cotransport)
Furosemide
Bumetanide
Torasemide
2. Medium efficacy( Inhibitors of Na+ Cl- symport)
Benzothiadiazines
Hydrochlorthiazide
Hydroflumethiazide
Benzthiazide
Thiazide like
Chlorthalidone
Metolazone
Xipamide
Indapamide
Clopamide

3. 3. Weak/ adjunctive diuretics
A. Carbonic anhydrase inhibitors
Acetazolamide
B. Potassium sparing diuretics
1.Aldosterone antagonist
Spironolactone
Eplerenone
2. Renal epithelial Na + channel inhibitors
Amiloride
Triamterene
C. Osmotic diuretics
Mannitol
Isosorbide
Glycerol

4. HIGH CEILING DIURETICS
Thick ascending limb of
loop of Henle (site 2)

5. The major site of action is the thick ascending limb of loop of henle
(TAL),therefore, called loop diuretics.
Drug binds to the luminal side of Na+-k+-2cl- cotransporter and block its
function.
Inhibits the reabsorption of Na,K+,Cl- ions by inhibiting Na+-k+-2cl-
cotransporter ,also inhibits the reabsorption of Mg2+ & ca2+
There is increased excretion of Na and cl- in urine
Loop diuretics called high ceiling diuretics because they are
highly efficacious –have maximal Na+ excreting capacity when
compared to Thiazide and potassium sparing diuretics.

6. Uses of high ceiling diuretics
1. Edema :edema due to cardiac, hepatic or renal problems can be treated. The high ceiling diuretics
are preferred in CHF for rapid mobilization of edema fluid
2. Acute pulmonary edema (acute LVF, following MI): Intravenous administration of furosemide or its
congeners produces prompt relief.
3. Cerebral edema Mainly osmotic diuretics are primarily used to lower intracranial pressure by
withdrawing water, furosemide may be combined to improve efficacy
4. Hypertension High ceiling diuretics are indicated in hypertension only in the presence of renal
insufficiency, heart failure and in hypertensive emergencies.
5. Anaemia: Furosemide may be infused along with blood transfusion, to prevent volume overload in
severely anaemic patients.
6. Hypercalcaemia of malignancy: augments Ca2+ excretion and prevents volume overload

7. Bumetanide
It is similar to furosemide in all respects, but is 40 times more potent.
Effective in some cases not responding to furosemide, and may be tolerated by patients allergic to
furosemide
Preferred for oral use in CHF
Torsemide
2-3 times more potent than frusemide
Used in edema and hypertension

8. ADR
ELECTROLYTE IMBALANCES
Hypokalemia,hyponatremia,hypocalcemia,hypomagnesemia
Metabolic disturbances
Hyperglycemia,hyperurecemia,hyperlipidemia
Hypersensitivity
Ototoxicity

9. Thiazide and related diuretics
THIAZIDE AND RELATED DIURETICS (Inhibitors of Na+-Cl¯ symport)
Thiazides are medium efficacy diuretics
Primary site of action is in the early DT (Site III).
Inhibit Na+ –Cl¯ symport at the luminal membrane
There is net loss of Na,k,cl,Hco3- in urine.unlike loop diuretics thiazide decrease ca2+ excretion
Absorbed orally long DOA and excreted in urine
ADR
Electrolyte disturbances
Hypokalemia,hyponatremia,hypomagnesemia,hypocalcemia,metabolic disturbances like Frusemide.
Impotence
Skin rashes,nausea,vomiting,diarrhoea etc
Site 3- drugs acting on cortical
diluting segment

11. USES
1. Edema Thiazides may be used for mild to moderate cases.
2. Hypertension Thiazides and related diuretics, especially chlorthalidone and indapamide are one of
the first line drugs
3. Diabetes insipidus(increase the concentration of urine)
4. Hypercalciuria

12. Complications of high ceiling and thiazide type diuretic therapy
1. Hypokalaemia This is the most significant problem’.
The usual manifestations are weakness, fatigue, muscle cramps; cardiac arrhythmias are the serious
complications.
Hypokalaemia can be prevented and treated by:(a) High dietary K+ intake or
(b) Supplements of KCl (24–72 mEq/day) or
(c) Concurrent use of K+ sparing diuretics
2. Acute saline depletion Over use of diuretics, particularly high ceiling ones, may cause dehydration
and marked fall in BP, especially on standing up

13. 3. GIT and CNS disturbances Nausea, vomiting and diarrhoea may occur
with any diuretic. Headache, giddiness, weakness, paresthesias, impotence
are occasional complaints with thiazides as well as loop diuretics.
4. Hearing loss This occurs only with high ceiling diuretics but it is
infrequent. The risk increases when these drugs are used in the presence of
renal insufficiency.
5. Allergic manifestations Rashes, photosensitivity occur, especially in
patients hypersensitive to sulfonamides. Blood dyscrasias are rare; any
diuretic may be causative
6. Hyperuricaemia Long-term use of higher dose thiazides in hypertension
causes rise in the blood urate level.
7. Hyperglycaemia and dyslipidemia

14. 8.. Magnesium depletion It may develop after prolonged use of thiazides or loop
diuretics, and may increase the risk of ventricular arrhythmias
9.. Thiazides have aggravated renal insufficiency, probably by reducing g.f.r.

15. WEAK ADJUNCTIVE DIURETICS
1. CARBONIC ANHYDRASE INHIBITORS
Carbonic anhydrase (CAse) is an enzyme which catalyses the reversible
reaction
H2 O + CO2 →← H2 CO3 .
Carbonic acid dissociates into H2 CO3 →← H+ + HCO3 ¯ .
Carbonic anhydrase thus functions in CO2 and HCO3 ¯
transport and in H+ ion secretion.
The enzyme is present in renal tubular cell (especially PT) gastric mucosa,
exocrine pancreas, ciliary body of eye, brain and RBC.
DRUGS ACTING ON PCT Site 1

16. The main site of action is PCT and in collecting duct
Acetazolamide prevent CA enzyme prevent the formation of H+. Thus
Na+-H+ Exchange is prevented. Na+ is excreted along with HCO3- in
urine.
Net effect is loss of Na+,K+,Hco3-
Adverse effects
Acidosis, hypokalaemia, drowsiness, paresthesias, fatigue,
abdominal
discomfort.
Hypersensitivity reactions—fever, rashes.
Bone marrow depression is rare

17. 1. Glaucoma: as adjuvant to other ocular hypotensives .
2. To alkalinise urine: for urinary tract infection or to promote
excretion of certain acidic drugs.
3. Epilepsy: as adjuvant in absence seizures
4. Mountain sickness

18. POTASSIUM SPARING DIURETICS
Aldosterone antagonists and renal epithelial Na+ channel inhibitors indirectly conserve
K+ while inducing mild natriuresis, and are called ‘potassium sparing diuretics’.
Normally aldosterone increase sodium reabsorption and
potassium excretion
Aldosterone antagonist
Spironolactone
It is a steroid, chemically related to the mineralocorticoid aldosterone
Drugs acting on DCT

19. Aldosterone (Aldo) penetrates the cell from the interstitial side and combines with
the mineralocorticoid receptor (MR).
The complex translocates to the nucleus—promotes gene mediated mRNA
synthesis.
The mRNA then directs synthesis of aldosterone induced proteins (AIPs).
The AIPs include Na+K+ ATPase and renal epithelial (amiloride sensitive)
Na+ channels.
The AIPs activate these Na+ channels and, translocate them from cytosolic site
to luminal membrane. They also translocate Na+K+ATPase to the basolateral
membrane
AIPs increase ATP production by mitochondria as well. All these changes
promote Na+ reabsorption .
Spironolactone acts from the interstitial side of the tubular cell, combines
with MR and inhibits the formation of AIPs to act as a competitive
antagonist and opposes aldosterone action ie it inhibit the reabsorption of
Na and excretion of K ions

21. Use
Spironolactone is a weak diuretic and is used mostly in combination with
other more efficacious diuretics.
1. To counteract K+ loss due to thiazide and loop diuretics.
2. Edema: Spironolactone is more useful in cirrhotic and nephrotic edema
(salt n water retension) in which aldosterone levels are generally high. It
potentiates thiazides and loop diuretics and is frequently added to them in the
treatment of ascites (fluid in abdomen) due to cirrhosis of liver.
3. Hypertension: Spironolactone is used to augment a thiazide diuretic in the
treatment of resistant hypertension. It also serves to prevent thiazide-induced
hypokalaemia.
4. Heart failure: As additional drug to conventional therapy in moderate to
severe CHF; it serves to retard disease progression and lower mortality
5. Primary hyperaldosteronism (Conn’s syndrome).

22. Renal epithelial Na+ channel inhibitors Triamterene and amiloride
Their most important effect is to decrease K+ excretion.
Mechanism of action
The luminal membrane of late DT and CD cells expresses a distinct ‘renal
epithelial’ or ‘amiloride sensitive’ Na+ channel through which Na+ enters the
cell
This Na+ entry partially depolarizes the luminal membrane and promotes
secretion of K+ through K+ channels.
Amiloride and triamterene block the luminal Na+ channels and
indirectly inhibit K+ excretion
Thus, amiloride conserves both K+ and H+ while marginally increasing Na+
excretion.

23. Both triamterene and amiloride are used with a thiazide type or a high
ceiling diuretic to prevent hypokalaemia and slightly augment the natriuretic
response
Risk of hyperkalaemia is the most important adverse effect of amiloride and
triamterene.
These drugs should not be given to patients with renal insufficiency or those
taking K+ supplements because dangerous hyperkalaemia may develop.
Usual side effects are nausea, diarrhoea and headache.
Amiloride blocks entry of Li+ through Na+ channels in the CD cells and
mitigates diabetes insipidus induced by lithium
Uses
Edema
HRT

24. Drugs acting on entire nephron
Osmotic diuretics
TUBULAR FLUID
Mannitol is freely filtered at
the glomerulus

25. ADR
Head ache
Nausea
Vomiting
Hyperglycemia

26. Uses Mannitol is never used for the treatment of chronic edema
or as a natriuretic. Its indications are:
1. Increased intracranial or intraocular tension (acute congestive
glaucoma,head injury, stroke, etc.): by osmotic action it
encourages movement of water from brain parenchyma, CSF
and aqueous humour.
2. To maintain g.f.r. and urine flow in acute renal failure, e.g. in
shock, severe trauma, cardiac surgery, haemolytic reactions.
3. To counteract low osmolality of plasma and e.c.f. due to rapid
haemodialysis or peritoneal dialysis

27. Classification based on site of action
1. Drugs acting at PCT (site 1)
Carbonic anhydrase inhibitors
Acetazolamide, dorzolamide, brinzolamide
2. Drugs acting at thick ascending limb of loop of Henle(site 2)
Furosemide
Bumetanide
Torasemide

28. 3. Drugs acting at cortical diluting segment (site 3)
Benzothiadiazines
Hydrochlorthiazide
Hydroflumethiazide
Benzthiazide
Thiazide like
Chlorthalidone
Metolazone
Xipamide
Indapamide
Clopamide

29. 4. Drugs acting at distal convoluted tubule
Aldosterone antagonist
Spironolactone
Eplerenone
Renal epithelial Na + channel inhibitors
Amiloride
Triamterene
5. Drugs acting on entire nephron
Osmotic diuretics
Mannitol
Isosorbide
Glycerol