DIURETICS ---

 Drugs that increase volume of urine flow.

 Effects the ion transport in the nephron
 Principle sites of actions are the tubules
 Because the mechanism for reabsorption of salt and water differ in all 4 segments of
the tubules,diuretics also have different mechanism of action
 Most diuretics act from the luminal side of the membrane and must be present in
the urine
 They are filtered at the glomerulus and also secreted by the weak acid secretory
carrier in the PCT
 An exeption is aldosterone receptor antagonist group that enter the tubule from
basolateral side

FIVE MAJOR CLASSES OF DIURETICS ARE –

1. Carbonic anhydrase inhibtors
2. Loop diuretics
3. Thiazide diuretics
4. Osmotic diuretics
5. Potassium sparing diuretics

PROXIMAL CONVULATED TUBULES –

1. Isosmotic absorption of amino acid ,glucose and numerous cations
2. Also for sodium chloride and sodium bicarbonate
3. Responsible for 60-70 percent of sodium reabsorption
4. No drug till date directly acts on Nacl absorption here
5. Mechanism of absorption of bicarbonate –
 Bicarb is converted to CO2 via carbonic anhydrase
 Than bicarb is regenerated again in the tubular cells
6. Sodium is exchanged for the hydrogen ion generated transported into interstial
space by sodium potassium pump
CARBONIC ANHYDRASE INHIBTORS –
- Present on lumen of PCT
- Indirectly inhibits absorption of NaCl
- As it inhibits production of hydrogen ion due to inhibition of enzyme
PROTOTYPE AND MECHANISM OF ACTION –
- Acetazolamide
- It is sulfonamide derivative
- Inhibits carbonic anhydrase in the brush border and the cytoplasm
- Carbonic anhydrase is aslo found in other tissues and plays anse important role in
secretion of CSF and aqueous humor
- this drug inhibits carbonic anhydrase in all tissues of the body
EFFECTS –
 bicarb diuresis is the major effect
 as a result … metabolic acidosis
 lots of potassium ion is secreted that leads to potassium wasting
  secretion of bicarb in CSF and aqueous humor is reduced
 in the eye , it is usefull to reduce interocular pressure
 in the CNS ,acidosis results in hyperventilation
CLINICAL USES –
- in treatment of severe glaucoma
- must be administered orally or parenterally
- can be used to prevent acute mountain sickness
TOXICOSIS –
- drowsiness and parasthesias are repoted after oral dose
- cross- allergenicity between this and other sulfonamide derivatives
- alkalinasation of urine by this drug may cause precipitation of calcium salts and
formation of renal stones
- patients with hepatic impairment often excrete large quantities of ammonia in urine
in form of ammonium ions ,,,, if given this drug alkalination of urine pevent
coversion of ammonia to ammonium ions
- this can lead to hepatic encephalopathy

THICK ASCENDING LOOP OF HENLE –

- pumps sodium , potassium and chloride out of the lumen into interstium of kidney
- reabsorption is facilitated by carriers
- these carriers are target of loop diuretics
- responsible for 20-30percent of sodium reabsorption

LOOP DIURECTICS—
- Furosemide is the prototype drug
- “Furosemide, bumetanide, and torsemide are sulfonamide derivatives.”
- Ethacrynic acid is a phenoxyacetic acid derivative
- Loop diuretics inhibit the cotransport of sodium, potassium, and chloride
- The loop diuretics are relatively short-acting

EFFECTS –
- produces a massive sodium chloride diuresis
- blood volume may be significantly reduced.
- The diluting ability of the nephron is reduced
  −
- Inhibition of the Na /K /2Cl transporter also results in loss of the lumen-
positive potential, which reduces reabsorp- tion of divalent cations as well.
- Ethacrynic acid is a moderately effective uricosuric drug if blood volume is
maintained.
- Loop diuretics also reduce pulmonary vascular pressures
- Prostaglandins are important in maintaining glomerular filtra- tion.
- When synthesis of prostaglandins is inhibited, for example, by nonsteroidal
anti-inflammatory drugs, the efficacy of most diuretics decreases.

CLINICAL USE AND TOXICITIES –

- major application of loop diuretics is in the treatment of edematous states
- sometimes used in hypertension
- less common but important application is in the treatment of severe
 hypercalcemia.
- diuresis without volume replacement results in hemoconcentration
- Loop diuretics usually induce hypokalemic metabolic alkalosis
- loop diuretics can cause hypovolemia and cardiovascular complications.
- Ototoxicity is an important toxic effect of the loop agents.

DISTAL CONVOLUTED TUBULE (DCT)

- segment actively pumps sodium and chloride out of the lumen of the nephron
- This cotransporter is the target of the thiazide diuretics.
- Amiloride and triamterene act by blocking the epithelial sodium channels in
the same portion of the nephron

EFFECT—

 cause an increase in sodium clearance and a decrease in potassium

 hydrogen ion excretion and therefore qualify as potassium-sparing diuretics.

THIAZIDE ---

A. PROTOTYPE AND MECHANISM OF ACTION—

- Hydrochlorothiazide, the prototypical agent, and all the other members of
this group are sulfonamide derivatives.
- The major action of thiazides is to inhibit sodium chloride transport in the
early segment of the distal con- voluted tubule
- Thiazides are active by the oral route and have a duration of action of 6–12 h,

EFFECTS –

- thiazides produce moderate but sustained sodium and chloride diuresis.

- Hypokalemic metabolic alkalosis may occur
- Because they act in a diluting segment of the nephron, thiazides may reduce
the excretion of water and cause dilutional hyponatremia.
- Thiazides also reduce blood pressure
- the maximal pressure-lowering effect occurs at doses lower than the maximal
diuretic doses

CLINICAL USE AND TOXICITIES—

- The major application of thiazides is in hypertension,

- Chronic therapy of edematous conditions such as mild heart failure is another
application
- the cortical collect- ing tubules compensate by reabsorbing sodium and
excreting potassium.
- Diabetic patients may have significant hyperglyce- mia.
- Serum uric acid and lipid levels are also increased in some persons.

CORTICAL COLLECTING TUBULE (CCT)—

 - The final segment of the nephron is the last tubular site of sodium reabsorption
and is controlled by aldosterone
- The reabsorption of sodium occurs via channels (ENaC, not a transporter) and
is accompanied by loss of potassium or hydrogen ions.
- The collecting tubule is thus the primary site of acidification of the urine and
the last site of potassium excretion

POTTASIUM SPARING DIURETICS –

PROTOTYPES AND MECHANISM OF ACTION –

- Spironolactone and eplerenone are steroid derivatives and act as

pharmacologic antagonists of aldosterone in the collecting tubules.
- combining with and blocking the intracellular aldosterone receptor, these drugs
reduce the expression of genes that code for sodium ion channels
- Amiloride and triamterene act by blocking the inhibitors and angiotensin
receptor blockers [ARBs])

EFFECTS—

- cause an increase in sodium clearance

- a decrease in potassium nd hydrogen ion excretion
- may cause hyperkale- mic metabolic acidosis

CLINICAL USE AND TOXICITIES---

- Potassium wasting caused by chronic therapy

- Aldosteronism is an important indication for spironolactone.
- Aldosteronism is also a feature of heart failure
- The most important toxic effect of potassium-sparing diuretics is hyperkalemia.
- These drugs should never be given with potassium supplements.
- Spironolactone can cause endocrine abnormalities, including gynecomastia and
antiandrogenic effects.

OSMOTIC DIURETICS—

A.PROTOTYPE AND MECHANISM OF ACTION—

- Mannitol, the prototypical osmotic diuretic, is given intravenously.

- Other drugs often classified with mannitol , include glycerin, isosorbide and
urea.
- The major location for this action is the proximal convoluted tubule.

EFFECTS –

- The volume of urine is increased.

 - Sodium excre- tion is usually increased
- Mannitol can also reduce brain volume and intracranial pressure by osmotically
extracting water from the tissue into the blood.
- A similar effect occurs in the eye.

CLINICAL USE AND TOXICITY –

- are used to maintain high urine flow

- are useful in reducing intraocular pressure in acute glaucoma and intracranial
pressure in neurologic conditions.
- Removal of water from the intracellular compartment may cause hyponatremia
and pulmonary edema

ANTIDIURETIC HORMONES AGONIST AND ANTAGONIST ---

A.PROTOTYPES AND MECHANISM OF ACTION

- Antidiuretic hormone (ADH) and desmopressin are proto- typical ADH

agonists.
- parenteral route
- Conivaptan and tolvaptan are ADH antagonists.
- Demeclocycline was previously used for this purpose
- Lithium also has ADH-antagonist effects but is never used for this purpose.
- ADH facilitates water reabsorption from the collecting tubule by activation of
V2 receptors, which stimulate adenylyl cyclase via Gs.
- The increased cyclic adenosine monophosphate (cAMP) causes the insertion of
additional aquaporin AQP2 water channels into the luminal membrane in this
part of the tubule
- Conivaptan is an ADH inhibitor at V1a and V2 receptors.
- Tolvaptan is a more selective V2 blocker
- Demeclocycline and lithium inhibit the action of ADH at some point distal to
the generation of cAMP

EFFECTS AND CLINICAL USES –

AGONISTS –

- ADH and desmopressin reduce urine volume and increase its concentration.
- ADH and desmopressin are use- ful in pituitary diabetes insipidus.
- are of no value in the nephrogenic form of the disease
- These therapies reduce blood volume, a very strong stimulus to proximal
tubular reabsorption.

ANTAGONIST –

- ADH antagonists oppose the actions of ADH and other naturally occurring
 peptides that act on the same V2 receptor
- syndrome of inappropriate ADH secretion (SIADH) can be treated with
demeclocycline and conivaptan.

TOXICITY –

- In the presence of ADH or desmopressin, a large water load may cause

dangerous hyponatremia.
- Large doses of either peptide may cause hypertension in some persons.
- Conivaptan and tolvaptan may cause demyelination with serious neurologic
consequences if hyponatremia is corrected too rapidly.