Diuretics & anti diuretics

DIURETICS &
ANTI-DIURETICS AGENT
By:- Dr. Manish Pal Singh,
Associate Professor
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AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA

General Physiology of Urine Formation
❑ The main function of kidneys to maintain a homeostasis balance of
electrolytes and water.
❑ Urine formation starts from glomerular filtration (g.f.).
❑ Normally 180 L of fluid everyday filtered; but more than 99% of the g.f. is
reabsorbed in the tubules , only about 1.5L urine is produced in 24 hr.
❑ The diuretics mainly inhibit the reabsorption at tubular side.
2
Source*-http%3A%2F%2Fpathwaymedicine.org%2Furine-formation-mechanisms

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➢Each kidney contains approximately one million nephrons and is
capable of forming urine independently.
The nephrons are composed of glomerulus, proximal tubule, loop of
henle, distal tubule.
Loop of Henle
Source*-https%3A%2F%2Fwww.unmc.edu%2Felearning%2Fegallery%2Fthe-main-processes-of-the-nephron

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Mechanism of Tubular Reabsorption
➢ It’s an energy dependent transmembrane pumps as well as channels in between
the loose fitting cells of proximal tubule (PT).
➢ All Na+ that enters through cells via Na+K+ATPase-energised Na+-K+
antiporter.
5Source*- l=https%3A%2F%2Fcourses.lumenlearning.com%2Fsuny-
ap2%2Fchapter%2Ftubular-reabsorption-

Stages of Tubular Reabsorption
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Site-4
(Distal Tubule {DT})
Site-3
(Cortical diluting
segment of
loop)
Site-2
(Loop of
Henle)
Site-1
(PT)

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Heart
• Pumping action of heart control renal blood flow.
• Relative dimensions of glomerular vessels.
RAS
• Distal Tubular reabsorption of Na+ & Secretion of K+/H+
• AT-II- effect on intracellular beds & Na+/H2O reabsorption.
Prostaglandins &
Atrial natriuretic
factors (ANP)
• PG’s- direct renin release & inhibits the action of antidiuretic
hormone (ADH)
• Atrial natriuretic peptide produced by atrium & inducing ‘Natriuresis’
in response to salt & water overload.
Regulation of Renal Function (GFR)

DIURETICS
❑ These are drugs which cause a net loss of Na+ & water in urine.
❑ They are popularly used in the management of hypertension as their used in
edema.
“Diuretics (“water pills”) are the drugs which increase the urine out put
(or) urine volume” .
Natriuresis- “Any drug when introduce into the body
increases the out put of sodium
ie., loss of sodium in urine”.
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The first oral diuretics ‘Chlorthiazide’
(1957)- Thiazide diuretics

9Source*- https%3A%2F%2Fwww.ctdt.co.in

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Source*- https%3A%2F%2Fslideplayer.com

High Ceiling (Loop) Diuretics:- {Frusemide}
➢ These agents produce a peak diuresis much greater than observed with
other commonly used diuretics.
➢ They act by inhibiting the luminal Na/K/2Cl symporter.
➢ It has broader dose response curve.
➢ It is more convenient for i.v. use.
➢ Its maximal natriuretic effect is much greater than that of other classes.
➢ The onset of action- i.v. (2-5 min); oral (20-40 min) & i.m (10-20 min).
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Mechanism Of Action
✓ Loop diuretics (ferusemide) primarily target on ‘Site-II’ (thick AscLH).
✓ Where it is inhibit Na+-K+-2Cl- co transport.
✓ Its minor action component of action on PT.
✓ K+- excretion increase due to- high Na+ load reaching DT.
12
Source*-
https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3D5k5btYZTKhQ&psig

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➢It causes changes in
renal & systemic
hemodynamics.
➢It can causes increases
Ca++ excretion as well as
Mg++ excretion
➢Molecular action of it
can bind with Cl- binding
site of cotransporter pump
protein to inhibit its
transport function.
Source*- http%3A%2F%2Ftmedweb.tulane.edu%2Fpharmwiki%2Fdoku.php%2Floop_diuretics

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Indications:-
➢Edema- in cardiac; hepatic or renal.
➢Highly preferred in CHF
➢Acute pulmonary edema (LVF); following MI
➢Cerebral edema
➢Hypertension
➢Hypercalcaemia
Source*- https://encrypted-tbn0.gstatic.com/images?

Thiazide Diuretics
❑ These drugs compete for the chloride binding site of the sodium/chloride
symporter and inhibit the re-absorption of sodium &chloride.
❑ These are medium efficacy diuretics with primary ‘Site-III’ (in the cortical
diluting segment or the early DT).
❑ As a result these drugs increase the concentration of Na and Cl in the tubular
fluid and increase its excretion.
❑ Reduce blood volume decrease G.F.R
❑ Decrease B.P. in hypertensives.
❑ Thiazide reduce urine volume in both pituitary origin as well as renal DI
(diabetic insipidus) by an unknown mechanism.
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➢They bind to specific receptors
located on the luminal
membrane.
➢It can cause increased amount
of Na+ is presented to distal
nephron; urinary K+- excretion is
increased in parallel to the
natriuretic response.
Source*- https%3A%2F%2Fwww.memorangapp.com

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ADR’s:-
•Potassium depletion
•Hyperuricemia
•Hypercalcemia and hypomagnesemia
•Nausea, vomiting ,diarrhea
•Ortho static hypotension
•Inhibition of insulin secretion
Indications:-
✓DI- they reduce urine volume
✓Hypercalciuria
✓Edema
✓Reduces the intra ocular pressure- used in treatment of Glaucoma.
Source*- https%3A%2F%2Fwww.indiamart.com%2Fproddetail%2Fhydrochlorothiazide-ip-25mg-21465357162.html

Comparison Between
Loop Diuretics
➢ They inhibit Na/K/2Cl symporter.
➢ Acts at thick ascending loop of
henle.
➢ These are Ca+ wasting drugs.
➢ They cause heavy diuresis.
➢ Para thyroid hormone
independent Ca absorption.
➢ It can reabsorb 25% to 30% of
Na.
Thiazide Diuretics
➢ They act by inhibiting Na/Cl
symporter.
➢ Acts at distal convoluted tubule.
➢ These are Ca+ retaining drugs.
➢ They cause mild diuresis.
➢ Para thyroid hormone dependent Ca
absorption.
➢ It can reabsorb 8% of Na.
18

Carbonic Anhydrase (CAse) Inhibitors
(Acetazolamide):
➢ CAse- is an enzyme which catalyses the reversible reaction H2O + CO2-------
H2CO3.
➢ Transport in H+- ion secretion from tubule side, help to Na+ Reabsorption
in tubular cells.
➢ Acetazolamide is a sulfonamide derivative which is a non competitive
reversible inhibitor of “carbonic anhydrase enzyme”.
➢ Resulting slowing of hydration of CO2 - decreased availability of H+ to
exchange with luminal Na+ through the Na+-H+ antiporter.
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CAs - enzyme is responsible for
catalytic reversible hydration of
carbon dioxide and dehydration of
carbonic acid.
The net effect is inhibition of
HCO3- (with Na+) reabsoprtion in
PT--- prompt but mild alkaline
diuresis ensues.
Source*- https%3A%2F%2Fwww.youtube.com

➢ ADR’s:-
➢ Hypokalemia
➢ Acidosis
➢ Drowsiness
➢ Renal calculi.
➢ Nausea, loss of hearing, loss of appetite.
➢ Uses:- (Self limiting used as diuretics)
➢ Glaucoma
➢ To alkaline urine- for urinary tract infection or to promote excretion of certain acidic
drugs.
➢ Epilepsy- in absence seizures
➢ Acute mountain sickness
➢ DIAMOX; IOPAR; SYNOMAX- (Brands)
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Potassium Sparing Diuretics
(Spironolactone):{Aldosterone Antagonist}
➢ These are either aldosterone antagonist or directly inhibit Na+ channels in
DT & CD cells to indirectly converse K+.
➢ They act by inhibiting sodium reabsoprtion in the late distal tubule and thus
indirectly spare potassium excretion.
➢ Spironolactone is a steroid ,chemically related to the mineralocorticoid
aldosterone.
➢ Aldosterone, by binding to its receptor- {Aldosterone induced proteins-
(AIPs)} in the cytoplasm increases expression &function of Na channel
and sodium pump {K+ secretion}.
22

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➢Competitive and reversible inhibition
of the aldeosterone present in the
cytoplasm of principal cells(located in
late DCT and cortical CT).
➢Formation of inactive
spironoloactone- receptor complex
which cannot get traslocated into the
nucleus to bind to DNA.
➢Failure to produce “aldosterone-
induced proteins” which normally
promote Na+ reabsoprtion via ENac
and as a result of which K+ secretion
via K+ channel is facillated.
➢Decreased Na+ reabsorption and
decreased K+ secretion.
Source*- https%3A%2F%2Fhealthjade.net%2Fpotassium-sparing-
diuretics

ADR’s:-
▪ Gynaecomastia and impotence in male; hirsutism
▪ breast discomfort and menstrual irregularities in female.
▪ GI upset –can cause peptic ulcer.
▪ Hyperkalemia.
Uses:-
▪ Fluid retention of hyperaldosteronism
▪ Resistant HTN (used only as adjuvant to thiazide to prevent hypokalemia).
▪ To counteract K+ loss due to thiazide and loop diuretics
▪ Hypokalemia and hypomagnesemia
▪ Heart failure
24

Osmotic Diuretics
(Mannitol):
➢ Osmotic diuretics act on proximal tubule and also at loop of henle .where
they prevent water reabsoprtion by increasing osmolality of tubular fluid.
➢ Mannitol is a nonelectrolyte of low molecular weight; freely filtered at the
glomerulus & undergoes limited reabsorption ; therefore excellently suited
to be used as osmotic diuretic.
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increase
urine volume
flow rate
Decrease contact time between
fluid and tubular epithelium
Decrease Na+ reabsorption

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Uses:-
▪Increased intracranial or intraocular tension(acute
congestive
▪glaucoma,head injury,storke,etc.)
▪To maintain g.f.r. and urine flow in impending acute
renal Failure
▪To counteract low osmolarity of plasma/e.c.f.due
to rapid Haemodialysis.
ADR’s:-
▪ It is contraindicated in acute tubular necrosis
▪ Anuria
▪ Pulmonary edema
▪ Acute LVF
▪ CHF
▪ Cerebral haemorrhage
Source*- htpp/:OsmoseIt%2Fposts%2Fwhat-are-some-side-effects-of-osmotic-diuretics-
share-your-answers-in-the-commen

Anti-Diuretics
➢ Antidiuretics ( inhibit the water excretion without affecting salt excretion)
are drugs that reduce urine volume, particularly in diabetes insipidus(DI).
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Anti-Diuretics
Miscellaneous:-
Indomethacin;
Chlorpropamide
ADH
(Vasopressin)
Thiazide
diuretics

ADH {Anti-diuretics hormone}:
➢ ANTIDIURETIC HORMONE (ADH) is secreted by the posterior pituitary
gland.
➢ It’s a nonpeptide secreted along with ‘Oxytocin’.
➢ The rate of ADH release governed by body hydration.
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ADH- release
Contraction of e.c.f.
volume
Rise in plasma
osmolarity

ADH-Receptors:
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• Located on vascular & other smooth muscles, platelets etc.
• Follow IP3/DAG- Ca+ release- ACTH release, vasoconstriction
etc.V1
• Located primarily on the CD cells in the kidney
• Regulate their water permeability- CAMP production
• Its more sensitive to ADH than V1-receptors.V2
ADH-receptors- ‘G-protein coupled’- receptors

MAO- ADH (Kidney cells):
➢ ADH enhances water reabsorption by acting on the collecting duct.
➢ ADH activates the V2 receptors present on the cell membrane of the
collecting duct and increases the water permeability of these cells.
➢ ADH causes vasoconstriction and raises BP mediated by V1receptors.
➢ Vasopressin is given parentally as injection of SC,IM,IV.
➢ When ADH is absent, CD cells remain impermeable to water--- dilute urine
(produced by the diluting segments) is passed as such.
➢ Activation of V2- receptor by ADH– increased CAMP dependent protien
kinase A- which promote “aquaporin-2” water channel containing vesicles.
30

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➢The water permeability of
CD cells is increased in
proportion to the population of
aquaporin-2 channels in the
apical membrane at any given
time.
➢While V1- receptors
activation constricts vasa recta
to diminish blood flow to inner
medulla which will help in
maintaining high osmolarity in
this region and thus
contributing to antidiuresis .
Source*- https%3A%2F%2Fwww.qsstudy.com

Vasopressin Analogues:-
❑ Lypressin:- {20 IU, 10 IU-IM or SC or 20 IU diluted in 100-200 ml of dextrose
solution and infused IV in 10-20 min}.
❑ Terlipressin:- {2mg, repeat 1-2 mg every 4-6hr}
❑ Desmopressin:- {IV or SC; 2-4Ug/day}
ARTONI, AGRA, UP, INDIA 32
Uses:-
✓Diabetes insipidus of pituitary origin desmopressin is the
preparation used.
✓It should be used lifelong.
✓Bleeding esophageal varices-ADH constricts mesenteric
blood vessels (v1receptors ) and may help.
✓Before abdomonal radiography-expels gases from the
bowel.
✓Hemophilia and von willebrand’s disease- ADH may
release factor VIII and prevent bleeding. Source*- https%3A%2F%2F1.bp.blogspot.com

ADR’s& Contraindication of ADH- Analogues
▪ When used intranasally ADH can cause nasal irritation, allergy, rhinitis and
atrophy of nasal mucosa's.
▪ Other effects include nausea, abdominal cramps and backache (due to
constriction of the uterus).
▪ Patient suffering from vascular disease, especially disease of coronary arteries.
▪ V2- selectively desmopressin produces fewer adverse effects than vasopressin,
lypressin or terlipressin.
▪ Its contraindicated in patients with ischemic heart disease.
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Miscellaneous Anti-Diuretics:
Chlorpropamide--- has a long duration of action oral hypoglycemic, found to
reduce urine volume in DI of pituitary origin
➢ But not in renal DI is sensitize the kidney to ADH action its efficacy depends on
small amount of the circulating home one.
➢ It is not active when ADH is totally absent.
➢ It also directly prone salt reabsorption in the ascending limb C-may contribute to its
antidiuretic action.
Carbamazepine--- is an antiepileptic anticonvulsant, drug which, reduces urine
volume in DI of pituitary origin.
➢ It has been shown to stimulate ADH secretion. However it is not valuable in the
treatment of DI.
➢ Contraindications- Abnormalities in liver function
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