PREPARED BY: MR.JG SAMBAD
MSC.NSG. IKDRC-ITS CON
• Kidney is mainly a regulatory organ; it also has excretory function.
The functional unit of the kidney is nephron. Each kidney contains
about 1 million nephrons, the function of kidney are:
1. Regulatory: Acid-base, fluid and electrolyte balance.
2. Excretory: Excretion of nitrogenous waste products.
3. Hormonal: Activation of vitamin D, production of renin and
MECH ANISM OF URINE FORMATION
it consist of the following steps:
Active tubular secretion
Urine formation begins with glomerular filtration. The volume of
fluid filtered is about 180/L day of which more than 99 % gets
reabsorbed in the renal tubules; urine output is about 1-1.5 L/day.
After filtration, fluid traverses in the renal tubules. The tubular
fluid contains Na+, K+, HCO3-, amino acids, glucose etc.
Proximal convoluted tubule: site-1
• Most of the filtered Na+ is
actively reabsorbed; chloride
is reabsorbed passively along
with sodium. Carbonic
anhydrase plays an important
role in Na+-H+ exchange and
helps in the reabsorption of
HCO3-. Potassium, glucose,
amino acids etc. are also
reabsorbed in the PCT.
Proportionately water also
gets reabsorbed, so tubular
fluid in the PCT remains
Loop of Henle
• The descending
Na+ and urea
• Hence fluid in
the loop become
Thick ascending limb of loop of Henle site-2
• The thick ascending limb is
permeable to water but
highly permeable to Na+
• Active reabsorption of
sodium and chloride occurs
by Na+-K+, 2Cl- Co-
transporter. This is
selectively blocked by loop
• Ca2+ and Mg2+ are also
reabsorbed at this site.
Early distal table site-3
• It is impermeable to
water but sodium and
reabsorbed with the
helps of Na+, Cl-
• This is blocked by
Early distal tubule and collecting duct site-4
• Sodium is actively reabsorbed;
chloride and water diffuse
passively. Exchange of Na+-
K+, H+ ions occur. The Na+-
K+ exchange under the
influence of aldosterone
(aldosterone promote Na+
absorption and K+ depletion).
• Absorption of fluid in the
collecting duct (CD) is under
the influence of ADH. In the
absence of ADH, the CD
becomes impermeable to water
and large amount of dilute urine
is excreted. Normally H+ ions
present in urine convert NH3 to
NH4 which is excreted.
• Diuretics are drug that promote excretion of Na+ and water in urine.
Classification of diuretics
1. Drugs acting at proximal convoluted tubule (PCT) site-1
• Carbonic anhydrase inhibitor: Acetazolamide
2. Drugs acting at thick ascending limb of loop of Henle site-2
• Loop diuretics: furosemide, bumetadine, torsemide, ethacrynic acid.
3. Drugs acting at early distal tubule site-3
• Thiazides: chlorothiazide, hydrochlorothiazide, polythiazide.
• Thiazide related diuretics: chlorthalidone, indapamide, metolazone.
4. Drug acting at late distal tubule and collecting duct site-4
• Aldosterone antagonist: spironolactone and eplerenone.
• Direct inhibitor of Na+ channels: Amiloride and triamterene.
5. Drugs acting on entire nephron (main site of action in loop of Henle)
• Osmotic diuretics: Manito, glycerol, isosorbide.
1) Carbonic Anhydrase Inhibitors
• Mechanism of action:
Both CO2 and H2O diffuse into the tubular cell where H2CO3 is
formed under the influence of carbonic anhydrase. Carbonic acid
dissociates into H+ and HCO3-. The H+ ions exchange with luminal
Na+ . In the lumen the H+ ions combine with HCO3- and form
The H2CO3 dissociates into CO2 and H2O with the help of carbonic
anhydrase, which is present near the brush border. The main site of
action of acetazolamide is proximal tubule.; it also acts in the
collecting duct. Acetazolamide by inhibiting carbonic anhydrase
enzyme, prevents the formation of H+ ions. Na+- H+ exchange is
prevented. Na+ is excreted along with HCO3- in urine.
In the DCT, increase Na+, K+ exchange leads to loss of K+. The net
effect is loss of Na+, K+ and HCO3- in urine resulting in alkaline
Uses of CAI
• Acetazolamide is not used as diuretic because of its low efficacy. It is
used in the following condition:
1. Glaucoma: CAI decrease the intraocular pressure by reducing the
formation of aqueous humor.
2. To alkalinize urine in acidic drug poisoning.
3. Acute mountain sickness: The beneficial effect to decrease the PH
and formation of cerebrospinal fluid.
4. Miscellaneous: as an adjuvant in epilepsy, periodic paralysis,
treatment of metabolic alkalosis resulting from use of diuretics in
congestive heart failure.
Adverse effect of CAI
• Hypersensitivity reaction
• Skin rashes
• Metabolic acidosis
• Renal stone
Contraindication of CAI
• LIVER DISEASE: Hepatic coma may be precipitated in
patient with cirrhosis due to decreased excretion of NH3 in
• COPD: Worsening of metabolic acidosis is seen in patient
with chronic obstructive pulmonary disease.
2) Loop Diuretics (high ceiling diuretics)
• MOA: sites of action is the ascending limb of loop of Henle. Loop
diuretics binds to luminal side of Na+, K+- 2Cl- cotransporter and
block its function. There is an increased excretion of Na+ and Cl- in
urine. The tubular fluid reaching the DCT contains large amount of
Na+. Hence more Na+ exchanges with K+ loss. Furosemide has weak
carbonic anhydrase inhibiting activity hence increase the excretion of
HCO3- and PO34-. They also increase the excretion of Ca2+ and
Mg2+. Loop diuretics are called high-celling diuretics because they
are highly efficacious – have maximal Na+ excreting capacity when
compared to thiazides and potassium sparing diuretics.
• The loop diuretics are rapidly absorbed through the gastrointestinal
tract. Furosemide and bumetadine are administered by oral I.V and
I.M. Routes. Torsemide is given orally. Furosemide has a rapid onset
of action within 2-5 min of I.V; 10-20 min after I.M and 30-40 min
after oral administration. The duration of action of furosemide is short
Therapeutic uses of furosemide
• During the initial stage of renal, hepatic and cardio oedema, loop
diuretics are preferred.
• Intravenous furosemide is used in hypercalcemia as it promotes the
excretion of ca2+ in urine.
• Acute pulmonary oedema- loop diuretics act in the following way
IV furosemide increase PG synthesis increase renal blood flow
increase systemic venous capacitance
results in shift of blood from central pulmonary to systemic vessels,
decrease left ventricular pressure
Produce quick relief from pulmonary oedema
• Loop diuretics may be used in cerebral oedema but IV Manitol is
the preferred drug.
• Hypertension: loop diuretics can be used in hypertensions
associated with CCF/ renal failure and in hypertensive
emergencies. Furosemide is not preferred in uncomplicated
primary hypertension because of short duration of action.
• Loop diuretics can be used in the mild hyperkalemia.
1. Electrolyte disturbances: are the common adverse effects seen
with loop diuretics. They are:
A. Hypokalemia: it is the most important adverse effect. It can
caused fatigue, muscular weakness and cardiac arrhythmia,
especially in patients taking digitalis. It can be treated by K+
B. Hyponatremia: overuse of loop diuretics can cause depletion of
sodium from the body.
C. Hypokalemic metabolic alkalosis: as less K+ is available for
exchange with Na+ in the DCT, more Na+/ H+ exchange takes
place leading to H+ loss, thus causing hypokalemic alkalosis.
D. Hypocalcaemia and hypomagnesaemia: These are due to the
increased urinary excretion of Ca2+ and Mg2+ respectively.
2. The metabolism disturbances include:
Hyperglycemia: This can occur due to decreased insulin secretion.
Hyperuricaemia: these drug decrease the renal excretion of uric acid and
may precipitate attacks of gout.
Hyperlipidemia: they increase plasma triglycerides and LDL cholesterol
3. Ototoxicity: manifest as deafness, vertigo and tinnitus. The
symptoms are usually reversible on stoppage of therapy. The risk of
ototoxicity is increased in patients with renal impairment and in those
receiving other ototoxic drugs like cyclosporine, aminoglycosides
4. Hypersensitivity: skin rashes, eosinophilia, photosensitivity etc. may
3) Thiazide- like diuretics
• Chlorthalidone is a frequently used thiazide like diuretic in
hypertension as it has a long duration of action. Indapamide
and metolazone are more potent, longer acting and produce
fewer adverse effects than thiazides. They are used in
Mechanism of action
• Thiazides inhibits Na+- Cl- symport in early distal tubule and
increase Na+ and Cl- excretion. There is increased delivery of
Na+ to the late distal tubule, hence there is increased exchange
of Na+- K+ which results in K+ loss. Some of thiazide also
have weak carbonic anhydrase inhibitory action and increase
HCO3- loss. Therefore there is a net loss of Na+, K+, Cl-,
Hco3- in urine. Unlike loop diuretics, thiazides decrease Ca2+
• Pharmacokinetics: Thiazide are administered orally. They
have long duration and are excreted in urine.
1. Hypertension: thiazides are used in the treatment of essential
2. Heart failure: thiazides are used for mild to moderate cases of
3. Hypercalcemia: thiazides are used in calcium nephrolithiasis
as they reduce the urinary excretion of calcium.
4. Diabetes insipidus
1. Thiazides cause electrolyte disturbance which include
hypokalemia, Hyponatremia, metabolic alkalosis,
hypomagnesaemia and hypercalcemia.
2. The metabolic disturbances are similar to that of loop
diuretics – hyperglycemia, hyperlipidemia and
3. They may cause impotence, hence thiazides are not the
preferred antihypertensive in young males.
4. Others: skin rashes, photosensitivity, gastrointestinal
disturbances like nausea, vomiting, diarrhea etc. can occur.
4) Potassium Sparing Diuretics
• Spironolactone: it is an aldosterone antagonist. It is a synthetic steroid
and structurally related to aldosterone.
• Aldosterone enters the cell and binds to specific mineral corticoid
receptor (MR) in the cytoplasm of late distal tubule and collecting duct
cells. The hormone receptor complex enters the cell nucleus, where it
induces synthesis of aldosterone induced proteins (AIP). The net effect
of AIP is to retain sodium and excrete potassium.
• Spironolactone competitively blocks the mineral corticoid receptors
and prevents the formation of AIPs. Therefore, spironolactone
promotes Na+ excretion and K+ excretion. Spironolactone is most
effective when circulating aldosterone levels are high. It also increase
• Spironolactone is administered orally, gets partly absorbed and
is highly bound to plasma proteins; extensively metabolized in
liver and forms active metabolite, canrenone, which has long
plasma half- life.
• In edematous condition associated with secondary
hyperaldosteronism. (congestive cardiac failure, hepatic
cirrhosis and nephrotic syndrome).
• Spironolactone is often used with thiazides / loop diuretics to
compensate K+ loss.
• Resistant hypertension due to primary hyperaldosteronism.
• ACE inhibitors × spironolactone
• Eplerenone an aldosterone antagonist is more
selective for mineralocorticoid receptor. Hence
it is less likely to cause Gynacomastia.
5) Osmotic diuretics
• These include Mannitol, glycerol and isosorbide.
Manitol: it is administered intravenously. It is neither metabolized in
the body nor reabsorbed from the renal tubules. It is pharmacologically
inert and is freely filtered at the glomerulus.
Mechanism of action: osmotic diuretics draw water from tissues by
osmotic action. This results in increased excretion of water and
electrolytes. Their site of action is in the loop of Henle and proximal
Mechanism of action
20% Mannitol on IV administration
Increase osmolality of plasma
Shift of Fluid from the ICF to ECF
Expansion of ECF Volume
Increase glomerular filtration rate; Mannitol is freely filtered at the
Increase osmolality of tubular fluid
Inhibit reabsorption of water
The net effect is: Increase in urine volume
- Increased urinary excretion of Na+, K+, Ca2+, Mg2+, HCO3- and
Uses of osmotic diuretics
1. Mannitol is used to prevent acute renal shutdown in shock,
cardiovascular surgery, hemolytic transfusion etc.
2. Mannitol is used to reduce the elevated intracranial tension
(ICT) following head injury or tumor. It draws fluid from the
brain into the circulation by osmotic effect, thus lowering
3. Mannitol 20% (IV), glycerol 50% (oral) and isosorbide (oral)
are used to reduce the elevated IOP in acute congestive
glaucoma. They draw fluid from the eye by osmotic effect, in
to blood – IOP is decreased.
• Too rapid and too much quantity of iv Manitol can cause
marked expansion of ECF volume which can lead to
• Headache, nausea and vomiting may occur.
• Glycerol can cause hyperglycemia.
• Manitol is contraindicated in CCF and pulmonary oedema
because it expands ECF volume by increasing the osmolality
of extracellular compartment and increase the load on heart,
thus aggravating the above condition. Other contraindication
are chronic oedema, anuric renal disease and active
• Vasopressin: it is
nuclei of the
and stored in the
• Desmopresin: it is a selective V2 receptors agonists
and it more potent than vasopressin as an antidiuretic.
It has negligible vasoconstrictor action.
• Lypressin: it act both V1 and V2 receptors. It is less
potent but longer acting than vasopressin. It is
• Telipressin: it is prodrug of vasopressin with
selective V1 action. It is administered intravenously.
• Felypressin: it is mainly used for its vasoconstrictor
(V1) action along with local anesthetics to prolong
their duration of action.
Uses of vasopressin analogues
1. Due to V1 receptor-mediated actions:
- For emergency control of bleeding esophageal varices:
Telipressin is preferred over vasopressin because it is safer. It
control bleeding by constricting of the mesenteric blood
vessels –decrease blood to the portal vessels – reduce pressure
in the varices – stops bleeding.
- vasopressin may be used before abdominal radiography to
expel intestinal gas.
2. Due to V2 receptor- mediated actions:
- Central diabetes insipidus- desmopresin is the drug of choice.
- Heamohopila and von Willebrand's disease- decompression,
administered intravenously, controls bleeding by increasing
factors VIII and von Willebrand's factors.
- Primary nocturnal enuresis: administration of desmopresin at
bedtime reduces nocturnal urine volume.
• Nausea, vomiting, diarrhea, bleaching and abdominal cramps.
• Backache is due to uterine contraction.
• Vasopressin can precipitate an attack of angina by constricting
coronary blood vessels. (V1 mediated). Hence, it is
contraindicated in patients with hypertension and coronary
• Intranasal administration of desmopresin may cause local
irritation and ulceration.
• Fluid retention and Hyponatremia can occur (V1 mediated). It
should not be given to patients with acute renal failure.