Drugs Affecting Renal

Function:

12-Nov-16 1
Main function of kidneys is
• The excretion of waste products such as
urea, uric acid and creatinine.
• Also play an important role in acid-base
balance and regulation of salt and
electrolyte content and volume of
extracellular fluid.
• Production and release of different
hormones play a vital role in controlling
BP and red blood cell production.

12-Nov-16 2
 Diuretics:
• Drugs that increase the amount of urine
produced by kidneys. OR
• Agents that promote a net loss of sodium
ions, and accompanying Cl- and HCO3
ions and water from body resulting in an
increase in flow of urine formation.

12-Nov-16 3
 In vet. practice, diuretics are used to
increase urine flow when there is fluid
retention and oedema in case of heart
failure, hepatic disease, cerebral oedema etc.

Also used to induce urine flow in renal

failure to create forced excretion of poisons
or drugs in overdose, and to reduce systemic
BP.

12-Nov-16 4
• Most diuretics increase urine volume by
reducing the efficiency of sodium
resorbing processes and thereby
increasing the obligatory water loss.
• They alter not only the excretion of Na++
but also renal transport of other cations
like K, H, Ca and Mg, anions like Cl,
HCO3 and H2PO4 and uric acid.
12-Nov-16 5
12-Nov-16 6
 An Overview of Diuretics:
• In strict sense, the term is applied to
drugs with a direct renal action.
• Predominant action of such agents is to
augment urine excretion by inhibiting
the reabsorption of NaCl and water

12-Nov-16 7
 Indications of diuretics:
• Mobilization of edema: In edema there
is swelling of tissues owing to
accumulation of fluid, chiefly in the
extracellular (interstitial) space. When a
diuretic is given, increased renal
excretion of Na++ and water causes a
reduction in plasma volume with
hemoconcentration.
12-Nov-16 8
• Antihypertensive therapy: Diuretics
have been used as drugs of first choice
for lowering elevated blood pressure.
• Even at low dosage, they decrease
peripheral resistance and thereby
normalize blood pressure.

12-Nov-16 9
• Therapy of congestive heart failure: By
lowering peripheral resistance, diuretics
aid the heart in ejecting blood.

• Prophylaxis of renal failure: In shock

(circulatory failure), secondary to
massive haemorrhage, renal production
of urine may cease (anuria). Diuretics
maintain urine flow

12-Nov-16 10
 Classification:
Depending upon
• their major site of action
• mechanism of action
• chemical structure
• potency
• alteration of urinary pH
12-Nov-16 11
 According to Potency:
• I. High Efficacy diuretics

• 1. High ceiling diuretics/Loop diuretics:

Furosemide

• 2. Mercurial diuretics: Mersalyl

12-Nov-16 12
• II. Moderate efficacy diuretics:

• 1. Thiazide diuretics: Chlorothiazide,

hydrochlorothiazide etc.

• 2. Thiazide-like diuretics: Chlortalidone,

clopamide etc.

12-Nov-16 13
 III. Low efficacy or adjunctive
diuretics:
• 1. Osmotic diuretics: Mannitol, sorbitol
etc.

• 2. Carbonic anhydrase inhibitors:

Acetazolamide

12-Nov-16 14
• 3. Potassium sparing diuretics:
• a. Inhibitors of renal epithelial Na+
channels: Triamterene

• b. Aldosterone receptor antagonists:

Spironolactone

12-Nov-16 15
 IV. Miscellaneous Diuretics:
• 1. Acidifying or alkalinising salts:
• a. Acidifying salts: Ammonium chloride
and sodium chloride
• b. Alkalinising salts: Potassium acetate
and potassium citrate
• 2. Methylxanthines/Xanthine diuretics:
Aminophylline and theophylline

12-Nov-16 16
 High ceiling diuretics/Loop
diuretics:
• Most potent group of diuretics
• Frusemide: structurally related to
sulphonamides so also called sulphonamide
loop diuretic.
• They inhibit sodium and chloride
reabsorption in nephrons producing rapid
diuretic effect by inhibiting Na, K and Cl
symporter.
12-Nov-16 17
• The sodium-chloride symporter (also
known as Na+-Cl− cotransporter) is
a cotransporter in the kidney which has
the function of
• reabsorbing sodium and chloride ions
from the tubular fluid into the cells of
the distal convoluted tubule of the nephron.

12-Nov-16 18
• Due to blockade of Na, K and Cl
symporter, frusemide causes a profound
increase in urinary excretion of Na and
Cl.
• Frusemide increases renal excretion of
Na, K, Cl, Ca, Mg, H, Ammonium and
Bicarbonate.

12-Nov-16 19
 Clinical Use:
• Frusemide is used for its diuretic activity
in all species.
• Used in cardiovascular and pulmonary
oedema, hepatic and renal dysfunction,
hydrothorax, ascites and non-specific
oedema.
• During sporting event these diuretics are
banned with other drugs.
12-Nov-16 20
 Mercurials:
• Used for many years where a prompt
and potent diuresis was indicated.
• In acidic pH, these drugs liberate
mercuric ion that combines with –SH
group of enzymes associated with
transport system in kidney tubule.

12-Nov-16 21
• These drugs depress mainly the
reabsorption of Na and Cl with less effect
on K and HCO3.

12-Nov-16 22
 Thiazides diuretics:
• Thiazides are sulphonamide derivatives
and are related in structure to the
carbonic anhydrase inhibitors.
• They inhibit Na+-Cl cotransport and
have significantly greater diuretic
activity.
• Most of them are derived from
benzothiadiazine so called thiazide
diuretics.
12-Nov-16 23
• Thiazide diuretics act mainly in distal
tubule to decrease the reabsorption of
Na+ by inhibition of Na+- Cl co-
transporters.
• Also have a secondary effect in proximal
tubule.
• They don’t cause significant alteration
in acid-base balance.
12-Nov-16 24
 Thiazide like diuretics:
• Recently discovered group of
sulphonamide diuretic drugs
• Pharmacological properties similar to
thiazide diuretic.
• Primary target of all non-thiazide
diuretics is the distal convoluted tubule,
where they inhibit the sodium-chloride
symporter.
12-Nov-16 25
 Osmotic diuretics
• Pharmacologically inert substances,
freely filtered at the glomerulus but not
significantly reabsorbed from tubules.
• Administered in large doses to increase
the osmolality of plasma and tubular
fluid.

12-Nov-16 26
 MoA:
• Appear to limit tubular reabsorption of
water and electrolyte in a variety of
ways.
• a. Inhibit passive reabsorption of water
in those segments of nephron which are
freely permeable to water i-e proximal
tubule, descending limb of loop of Henle
and also distal tubule.
12-Nov-16 27
• b. They extract water from intracellular
compartments and expand extracellular
fluid volume.
• This decreases blood tonicity, increases
renal blood flow and glomerular
filtration rate and reduces renin and
aldosterone secretion.

12-Nov-16 28
• c. The increase in renal medullary blood
flow removes excess of Na+, Cl- and
urea from renal medulla
• d. Also inhibit transport processes in
thick ascending limb of loop of Henle by
an unknown mechanism.

12-Nov-16 29
 Osmotic diuretics:
• Mannitol: Pharmacologically inert.
Its presence in renal tubule prevents
reabsorption of water by osmotic action.
It increase urine volume and excretion of all
cations and anions.

12-Nov-16 30
• In general, it increases urinary excretion
of Na, K, Ca, Mg, Cl, HCO3 and
phosphate
• Like other osmotic diuretics, mannitol
may increase renal blood flow and
glomerular filtration

12-Nov-16 31
 Treatment:
• Mannitol toxicity may be treated by
correcting electrolyte and fluid
imbalance.
• Haemodialysis is effective in clearing
mannitol.

12-Nov-16 32
 Carbonic anhydrase (CA)
inhibitors:
• They block the carbonic anhydrase
enzyme that catalyses the first part of
reversible reaction in which CO2 and
water are converted to carbonic acid
and vice-versa.
• Thus they function on CO2 and HCO3
transport and in H+ ion secretion.

12-Nov-16 33
• They block the functioning of CA
enzyme predominantly at proximal
convoluted tubule, reducing the number
of hydrogen ions available for Na+-H+
exchange.

12-Nov-16 34
 Potassium sparing diuretics:
• Interfere with sodium reabsorption at the
distal segments of nephron and promote
sodium excretion without potassium loss.
• these diuretics are mild diuretics and are
usually used in conjunction with loop or
thiazide diuretics.

12-Nov-16 35
 Methylxanthines/ Xanthine
derivatives:
• Long been used as weak diuretics.
• They act by increasing the renal blood
flow by cardiac stimulation and increase
in glomerular filtration rate.
• They also act directly by inhibiting
reabsorption of Na+ and water in
proximal convoluted tubule.

12-Nov-16 36
 Drugs affecting urinary pH :
• The kidneys control acid-base balance
by excreting either acidic or basic urine.
• Unlike blood, the pH of urine can range
from 4.5 to 8.0 depending on the acid-
base status of extracellular fluid.

12-Nov-16 37
• Changes in urine pH are therapeutically
achieved by use of either urinary
acidifier or alkalizer.

12-Nov-16 38
 Urinary Acidifiers:
• Cause acidification of urine
• They enhance excretion of basic
substances by increasing their ionisation
in the filtrate that diminishes their
passive reabsorption across the tubular
wall.

12-Nov-16 39
• Ammonium chloride, ascorbic acid,
sodium acid phosphate, methionine,
sodium chloride, ethylenediamine
dihydro-chloride and ammonium
sulphate are clinically used to acidify the
urine.

12-Nov-16 40
Acidifying or alkalinising salts/
Saline diuretics:
• Some salts used primarily for
acidification of urine also provide a
diuretic effect and are known as saline
diuretics.
• Rarely used clinically for their diuretic
effect.

12-Nov-16 41
• Ammonium Chloride: Acidifying salt
that possesses some diuretic effect. It has
limited and short term effect. It causes
metabolic acidosis which is an adverse
effect.

• Sodium Chloride: Used in the control of

urolithiasis in veterinary medicine.

12-Nov-16 42
 Alkalinising Salt:
• Potassium citrate and Potassium
acetate: In the past they are used as
diuretics. They are potentially
dangerous and mostly used to change
the pH of urine, rather than as diuretics.

12-Nov-16 43
 Urinary Alkalinizers:
• Cause alkalinisation of the urine.
• They increase the antibacterial activity
of some antimicrobials like
aminoglycosides, erythromycin and
fluoroquinolones.
• They increase the solubility of
sulphonamides so decrease chances of
crystalluria and kidney damage.
12-Nov-16 44
• Alkalinisation of urine decreases
formation of uric acid and stones.
• Sodium bicarbonate and sodium citrate
are commonly used urinary alkalizers.

12-Nov-16 45
12-Nov-16 46
12-Nov-16 47