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Pharmacology of Renal System

Components of renal system

Kidneys
Ureters
Urinary bladder
Urethra

Components of nepheron

Renal corpuscle

a)
b)

Bowmans capsule
Glomerulus

Renal tubule

PCT
Loop of henle
Thin descending loop of Henle
Thick ascending loop of Henle
DCT
Collecting duct

Renal transport mechanisms:


Proximal convoluted tubule 60-70%
Thick portion of ascending limb of the loop of
Henle. 25%
Distal convoluted tubule 5-10%
Cortical collecting tubule 5% (Aldosterone and
ADH)

Functions of Renal System

Excretion of waste products


Maintenance of acid-base balance
Regulation of systemic blood
pressure

Process of urine formation

Glomerular filtration
Tubular secretion
Tubular re-absorption

Diuretic Drugs
These are drugs which increase the rate of
urine flow and sodium excretion and are used
to adjust the volume and/or composition of
body fluids in a variety of clinical situations,
including:
Hypertension, heart failure, renal failure, and
liver cirrhosis

How could urine output be increased ?


Glomerular filtration Vs Tubular reabsorption
(the most important clinically)

Purpose of Using Diuretics

To induce diuresis
To facilitate the flow of fluid in edema (udder
edema, cerebral edema, glaucoma)
Hypertension
Hyperaldosteronism
Congestive heart failure (CHF)

Brisket edema

Udder edema

Glaucoma
Cerebral edema

Hypertension

1. Carbonic anhydrase inhibitors


Acetazolamide
Site of action: PCT
Mode of action: Inhibition of CA enzyme
Effects:

Prevents the reabsorption of water, carbon


dioxide and bicarbonte
Partial inhibition of sodium reabsorption
Enhanced flow of alkaline urine

Mode of action of Acetozolamide


In the lumen H+ react with HCO3- to form H2CO3
H2CO3 rapidly decomposes to Co2 & H2O by CA

Acetozolamide

CO2 is lipophilic & rapidly diffuses across the luminal membrane


into epethelial cells where it reacts with H2O to form H2CO3 by CA
H2CO3 spontaneously ionizes to H & HCO (in the cell)
+

resulting in complete abolition


of NaHCO3 reabsorption

blood volume BP

HCO3- transported across basolateral membrane in exchange


for Na+ through Na+-HCO3-symporter
Net effect is transport of NaHCO3 from the tubular lumen
to interstitial space followed by movement of H2O
i.e. blood volume BP

Acetozolamide

Na+-H+ antiporter

Na+-HCO3- symporter

Na+

Na+

H+

H+

HCO3-

H2CO3
CA

CO2 + H2O

Lumen

Na

Na+

HCO3-

CA inhibitor

HCO3-

H2CO3
CA

CO2+ H2O

Blood

Clinical uses:
Hydrocephalus (cerebral edema)
Glaucoma
To enhance urination
Adverse effect:
Systemic acidosis (due to reduced level of
bicarbonate in the plasma)

2. Osmotic diuretics
Glycerol
Mannitol
Site of action: Thin descending loop of Henle
Mode of action:

Increase the osmolarity of tubular fluid


Help to draw more water from
intracellular and interstitial environments
causing enhanced flow of urine

Glycerol can be given orally however


sometimes it can cause vomiting
Mannitol is unable to get absorbed after oral
administration
Activation of rennin angiotensin
aldosterone system terminates their diuretic
action

3. Loop diuretics
Frusemide/Furosemide (Lasix)
Ethacrynic acid
Site of action: Thick ascending loop of Henle
Mode of action: Block the action of Na+/K+/2Cl
symport system

Considered as most potent diuretics

Mode of action of Loop diuretics


Loop diuretics
Absorbed from GIT and go to site of action
Acts on the ascending loop of Henle

Inhibit Na+-K+-2Cl- symport


Reduced NaCl reabsorption
Diuresis blood volume BP

Loop diuretics
(Furosemide, Bumetanide, Ethacranic acid)

Na+-K+-2Cl- symport

Na+ pump (Na+-K+ ATPase)

Loop diuretics

Na+
K+

Cl-

Na+
K+

Cl-

K+

K+
ATPase

Na+
Cl-

K+ Channel

Lumen

Cl- Channel

Blood

Effects:
Diuresis
Natriuresis
Kaliuresis
Adverse effects:
Ototoxicity
Nephrotoxicity
Hypokalemia

4. Thiazide diuretics
Chlorothiazide
Hydrochlorothiazide
Site of action: DCT
Mode of action: Block Na+/Cl- symport system
Effects:
Diuresis
Natriuresis
Commonly used to treat udder edema

Mode of action of Thiazide diuretics


Thiazide
Go to site of action by
Glomerular filtration & Tubular secretion
Acts on luminal membrane of distal collecting tubule
at distal tubule
Na+-Cl- symport mechanism
Na+ reabsorption
Na+ excretion and diuresis blood volume BP

Thiazide diuretics

Na -Cl symporter
+

K+ Channel

Na+ pump
(Na+-K+ ATPase)

Thiazide

Na+

Na+
Cl-

Na+

K+

K+ Channel

Lumen

K+
ATPase

ClK+

K+

Cl-

Cl- Channel

Blood

Thiazide diuretics
Adverse effects

Hyperuricemia ( serum uric acid)

Hypercalcemia

Hyperglycemia

Contraindications:

Gout

Diabetes mellitus

5. Potassium sparing diuretics


Triamterone
Amiloride
Site of action: Collecting duct
Mode of action: Block Na+/K+ antiport
system
Effects:
Diuresis
Natriuresis
Potassium retention

Primarily used to treat cerebral edema


These drugs can cause hyperkalemia so
they are contraindication in patients taking
potassium supplements
Triamterone can cause megaloblastic
anemia

6. Aldosterone receptor antagonists


Spironolactone
Site of action: Collecting duct
Mode of action: Interference with reninangiotensin-aldosterone system
Effects:
Reduce the reabsorption of water and sodium
Cause diuresis and natriuresis
Reduce the osmolarity and osmolality of blood

Mode of action of Aldosterone receptor antagonists


Aldosterone (AL)
Aldosterone penetrates the cell from interstitial side and
binds with mineralocorticoid receptor (MR)

Spironolactone binds to MR
& prevent AL action

MR -receptor complex translocates to the nucleus & binds to


specific sequences of DNA and promote mRNA synthesis
Na+ excretion and diuresis
blood volume BP

mRNA then directs synthesis of aldosterone induced proteins (AIPs)

The AIPs activate Na+ Channel, translocate Na+ channel to luminal


membrane, increase Na+ channel and Na+-K+ ATPase and ATP formation
from mitochondria

Na+ reabsorption and excretion of K+ and H+ blood volume BP

Spironolactone
(Aldosterone receptor antagonist)

MR

Spironolactone

mRNA

Nucleus

Amiloride

AL

MR-AL

Na+-K+ ATPase

AIP

Na+ Channel

Na+
K+
Lumen

Na+

Na+
K

ATPase

K+

Blood

Spironolactone is also used for the


treatment of hyperaldosteronism

Adverse effects:
Impairment of the receptor occupancy of
testosterone and progesterone
Can cause sexual dysfunction in case of
overdosage or prolonged use