This ppt tells us about the topics diuretics and antidiuretics. It also indicates us about their classification, mechanism of action, side effects and many more.

3. Diuretics, also called water pills, are a common treatment for high blood pressure
Diuretics, sometimes called water pills, help rid your body of salt (sodium) and
water. Most of these medicines help your kidneys release more sodium into your
urine. The sodium helps remove water from your blood, decreasing the amount
of fluid flowing through your veins and arteries. This reduces blood pressure.

5. FOR WHAT CONDITIONS ARE DIURETICS USED?
Diuretics are used with other types of medications (adjunctive therapy) in
•edema associated with congestive heart failure (CHF),
•cirrhosis of the liver, and
•corticosteroid and estrogen therapy.
Diuretics also are useful in edema caused by renal dysfunction including
•nephrotic syndrome,
•acute glomerulonephritis, and
•chronic renal failure.
Diuretics are used to lower urinary calcium excretion, making them useful in preventing calcium-containing kidney
stones.
Diuretics are used as the sole therapeutic agents to treat hypertension. Diuretics can also be used in combination with
other antihypertensive drugs to treat more severe forms of hypertension.
Diuretics (specifically the carbonic anhydrase inhibitors) are used as adjunctive treatment of
•chronic simple (open-angle) glaucoma and
•secondary glaucoma
Thiazide diuretics have off–label (non-FDA-approved) uses for osteoporosis in postmenopausal women. They can be
given alone or in combination with calcium or estrogen. Thiazide diuretics also have off-label uses for treating diabetes
insipidus.

7. Loop Diuretics ( HIGH CEILING)
•Mechanism of Action:
• Loop diuretics inhibit the NKCC2 (the luminal Na/K/2Cl co-transporter) in the thick ascending limb of the loop of
Henle.
• Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics, since
loop diuretics inhibit reabsorption of a much greater proportion of filtered sodium than most other diuretic agents. Urinary
output is usually dose dependent and related to the magnitude of fluid accumulation.
• Because loop diuretics produce the most profound diuresis, historically they have been referred to as “high ceiling
diuretics”.
• Loop diuretics are effective in many patients who have significant degrees of renal insufficiency.
•Indications:
• Loop diuretics produce a more potent diuresis & less vasodilation than thiazide diuretics. Therefore they are less
effective in lowering BP than thiazide diuretics.
• Loop diuretics are drugs of choice for patients with severe edema where a potent diuresis is needed, including:
• congestive heart failure, cirrhosis of the liver, and renal disease (e.g. GFR <30 ml/min), including the nephrotic
syndrome.
• Short-term management of ascites due to malignancy, idiopathic edema, and lymphedema.
• Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or the
nephrotic syndrome.
• where a rapid onset of diuresis is desired, e.g., in acute pulmonary edema, or when gastrointestinal absorption is impaired
or oral medication is not practicable.
• by reducing the lumen voltage gradient that drives cation reabsorption in the loop, loop diuretics increase the excretion of
divalent cations (Ca & Mg) & this can be useful in treating disorders causing hypercalcemia

8. CLC-K: Voltage-gated chloride channel & Renal outer medullary potassium channel (ROMK) is an ATP-dependent
potassium channel that transports potassium out of cells.

9. Thiazide diuretics compete for the chloride binding site on the Na/Cl cotransporter that is selectively expressed in
the distal convoluted tubule, inhibiting its ability to transport ions. Inhibition of this cotransporter lowers intracellular
Na, which in turn results in a lowering of intracellular calcium mediated by Na/Ca exchange expressed on the
basolateral membrane. This facilitates the diffusion of calcium through calcium ion channels expressed on the
lumen membrane. The inhibition of Na transport in this segment results in greater delivery of sodium to the
collecting duct, where enhanced Na influx through epithelial Na channels stimulates potassium efflux, which can
result in the development of hypokalemia.
Thiazides must lower blood pressure via some other
mechanism. Plasma and extracellular fluid (ECF)
volumes almost fully recover within 4–6 weeks of thiazide
initiation, yet blood pressure reduction is maintained .
After chronic administration, discontinuation of thiazides
result in a decrease in renin levels and rapid volume
replenishment, although the rise in blood pressure is
much slower
Thiazide Diuretics (MEDIUM EFFICACY)
Common side effects may include:
•dizziness, spinning sensation;
•numbness or tingling;
•diarrhoea, constipation, stomach cramps;
•blurred vision;
•muscle spasm; or
•impotence, sexual problems

10. CLC-K: Voltage-gated chloride channel; TRPV5: Transient receptor potential cation channel subfamily 5 (a calcium
selective channel).

11. Thiazide diuretics drug interactions
Major drug interactions:
•Since thiazides must be secreted into the tubular lumen to inhibit the Na/Cl symporter, their action can be reduced
by drugs such as probenecid which compete for transport into the proximal tubule.
•Hypokalaemia caused by thiazide & loop diuretics can increase the likelihood of potentially fatal polymorphic
ventricular tachycardia (torsade de pointes) if coadministered with other drugs that prolong the QT interval (e.g.
Class III antiarrhythmic, or quinidine-like drugs).
•Alcohol, barbiturates & narcotics may potentiate orthostatic hypotension
•Additive effects occur when combined with other antihypertensive
•Decreased response to pressor amines
•Dosage adjustment of anti diabetic drugs may be necessary.
Using chlorothiazide with other drugs that make you dizzy can worsen this effect. Ask your doctor before using
opioid medication, a sleeping pill, a muscle relaxer, or medicine for anxiety or seizures.
Tell your doctor about all your other medicines, especially:
•other blood pressure medications;
•cholestyramine or colestipol;
•lithium;
•insulin or oral diabetes medicine;
•steroid medicine; or
•NSAIDs (nonsteroidal anti-inflammatory drugs)–aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib,
diclofenac, indomethacin, meloxicam, and others.

12. K-sparing diuretic mechanisms in the Cortical collecting duct. Cells in this region of the nephron absorb Na via luminal
membrane epithelial Na channels (ENaC). Na influx across the luminal membrane leaves lumen-negative potential, which
drives the reabsorption of Cl and efflux of potassium. Cytoplasmic Na is transported across the basolateral cell membrane by
the Na/K ATPase. The gene expression and surface localization of ENaC is modulated by aldosterone, which binds to an
intracellular mineralocorticoid receptor, that increases expression of several genes including those that encode ENaC and the
Na/K ATPase. The collecting duct is the major site of action (in the kidney) of mineralocorticoid receptor antagonists
(spiranolactone & epilerinone), which decrease the expression of ENaC. Direct ENaC inhibitors (amiloride & triamterene)
inhibit Na influx through epithelial Na channels in the luminal membrane.
Potassium Sparing Diuretics(WEAK/ADJUNCTIVE DIURETICS)
INDICATIONS
Used by themselves, potassium-sparing diuretics exert only a mild diuretic effect because the collecting duct reabsorbs only 2-5% of
filtered sodium. They are occasionally used to counteract the potassium-wasting effects of thiazides. They can also potentiate the
effects of other proximally acting diuretics (e.g. loop diuretics).
Hyperaldosteronism-Mineralocorticoid receptor antagonists (spirnololactone & eplerenone) are useful in blunting the symptoms
produced by states of mineralocorticoid excess (hyperaldosteronism) due to primary or secondary causes (including heart failure).
Hypokalemia-For correction of excessive potassium loss.
Treatment of HFrEF-Mineralocorticoid receptor antagonists have been found to preserve cardiac function in the setting of coronary
ischemia, an effect that reduces the rate of progression of systolic heart failure. The RALES trial (1995-98) showed that
spironolactone administration in patients with severe heart failure reduced mortality by 27%, and also reduced the rate of
hospitalization, and improved symptoms. Recent studies indicate that they are of little benefit in patients with diastolic dysfunction.
Drug-resistant Hypertension-Treatment-resistant hypertension is often caused by excessive Na retention. A recent clinical trial
found spironolactone to be superior to non-diuretic add-on drugs at lowering blood pressure.

15. Bicarbonate absorption by the proximal tubule is dependent on the activity of carbonic anhydrase (CA) which
converts bicarbonate (HCO3
-) to CO2 and H2O. CO2 rapidly diffuses across the cell membrane of proximal tubule
cells where it is rehydrated back to H2CO3 by carbonic anhydrase. H2CO3 dissociates to HCO3
- and H+ which are
transported out of the cell on the basolateral side by different transporters. Bicarbonate absorption is therefore
dependent on the activity of carbonic anhydrase. Inhibition of carbonic anhydrase by acetazolamide results in an
increased urinary loss of bicarbonate. This also interferes with the reabsorption of Na and Cl. The basolateral Na/K
ATPase (found in most epithelial cells lining the nephron) maintains a low intracellular Na concentration, which is
necessary for reabsorption of Na, and in the proximal tubule also facilitates the efflux of H+ by the Na/H exchanger
on the luminal side. Increased delivery of Na to the collecting duct results in reabsorption of Na (through epithelial
Na channels) in exchange for increased K efflux, which can cause hypokalemia.
•Carbonic anhydrase inhibitors (e.g. acetazolamide) were one of the first generation of diuretics.
•The loss of bicarbonate produces a metabolic acidosis
•Most of the fluid loss resulting from inhibition of carbonic anhydrase is reclaimed in more distal segments of the
nephron, especially the loop of Henle.
•As a result, the diuretic efficacy of carbonic anhydrase inhibitors is relatively low, and it becomes further
diminished with over several days of treatment due to the development of metabolic acidosis, with an associated
reduction in bicarbonate in the glomerular filtrate.
Carbonic anhydrase(CAse) inhibitor diuretics

17. OSMOTIC DIURETICS
DRUG- Mannitol
MECHANISM
Mannitol is a sugar alcohol that does not cross cell
membranes, and acts as an osmotic diuretic that inhibits
sodium and water reabsorption in the proximal tubule, as
well as the loop of Henle. It produces a greater loss of
water compared to sodium and potassium.
INDICATIONS
Mannitol is not commonly used in patients
with edema, because the initial retention of
mannitol in the circulation can induce
further volume expansion, which can
precipitate the development of pulmonary
edema in patients with heart failure.
Head Injury
By altering Starling forces so that water
leaves cells, mannitol can produce a
beneficial lowering of intracranial
pressure in patients with head injury.
Intracranial pressure typically falls within
60-90 minutes with therapeutic doses (Sam
et al, 2015).
Glaucoma Related Eye Surgery
Mannitol can be used to lower intraocular
pressure before ophthalmic procedures.

18. ARE THERE DIFFERENCES AMONG DIURETICS?
A major difference among diuretics is the level of potency. Potency variation is due to the differences in the sites of
action of diuretics on the kidney structure. h
•Loop diuretics are the most potent diuretics as they increase te elimination of sodium and chloride by primarily
preventing reabsorption of sodium and chloride. The high efficacy of loop diuretics is due to the unique site of action
involving the loop of Henle (a portion of the renal tubule) in the kidneys.
•Thiazide diuretics increase the elimination of sodium and chloride in approximately equivalent amounts. They do
this by inhibiting the reabsorption of sodium and chloride in the distal convoluted tubules in the kidneys.
•In the distal tubule, potassium is excreted into the forming urine coupled with the reabsorption of
sodium. Potassium-sparing diuretics reduce sodium reabsorption at the distal tubule, thus decreasing potassium
secretion. Potassium-sparing diuretics when used alone are rather weak, hence they are used most commonly in
combination therapy with thiazide and loop diuretics.
•Carbonic anhydrase inhibitors work by increasing the excretion of sodium, potassium, bicarbonate, and water
from the renal tubules
•Osmotic diuretics are low-molecular-weight substances that are filtered out of the blood and into the tubules where
they are present in high concentrations. They work by preventing the reabsorption of water, sodium, and chloride.

19. Diuretics are generally safe. Side effects include increased urination and sodium loss.
Diuretics can also affect blood potassium levels. If you take a thiazide diuretic, your potassium level
can drop too low (hypokalemia), which can cause life-threatening problems with your heartbeat. If
you're on a potassium-sparing diuretic, you can have too much potassium in your blood.
Other possible side effects of diuretics include:
•Dizziness
•Headaches
•Dehydration
•Muscle cramps
•Joint disorders (gout)
•Impotence

20. An antidiuretic is a substance that helps to control fluid balance in an animal's body by
reducing urination , opposing diuresis. Its effects are opposite that of a diuretic. The
major endogenous antidiuretics are antidiuretic hormone (ADH; also called vasopressin)
and oxytocin. Both of those are also used exogenously as medications in people whose bodies need
extra help with fluid balance via suppression of diuresis. In addition, there are various other
antidiuretic drugs, some molecularly close to ADH or oxytocin and others not. Antidiuretics reduce
urine volume, particularly in diabetes insipidus (DI), which is one of their main indications.

21. Synthesis and Storage
The synthesis of ADH occurs in the supraoptic and paraventricular nuclei in the hypothalamus. It is then transported
to the posterior pituitary gland via the neurohypophysial capillaries. In the posterior pituitary gland, its synthesis is
completed and it is stored here until it is ready to be secreted into the circulation.
Release
The release of ADH is controlled by several factors. The two most influential factors are changes in plasma osmotic
pressure, and volume status. Other factors that promote the release of ADH include exercise, angiotensin II, and
emotional states such as pain.
ADH release is inhibited by atrial natriuretic peptide (ANP), which is released by stretched atria in response to
increases in blood pressure, as well as alcohol and certain medications.

22. ADH is also called Vasopressin (arginine Vasopressin) produced by the hypothalamus stored in
the posterior pituitary gland is excreted in circulation.
ADH is considered one of the plasma volume regulators, by its ability to concentrate the
urine via its action on the renal distal and collecting tubules by water reabsorption.

23. 2.The osmolarity of the extracellular fluid control ADH
release.
2. Increased osmolarity stimulates the
osmoreceptors in the hypothalamus, which
stimulates the ADH release.
3.The major function of ADH controls:
2. When ADH activity is present, then a small volume
of concentrated urine is excreted.
2. When ADH is absent, then a large volume of
dilute urine is excreted.
3. ADH Maintain water homeostasis.
4. There is water reabsorption by the kidney and
urine concentrated.
5. ADH in sufficient quantity induces generalized
vasoconstriction that leads to an increase in
arterial blood pressure.
6. ADH increases the release of more water
reabsorbed from the distal and collecting tubule; it
increases water reabsorption and leads to
concentrated urine and more water in the blood
circulation.
7. ADH decreased level, less water reabsorbed
(water was allowed to be excreted), leads to dilute
urine and hemoconcentration.

24. ADH release is stimulated by:
1.The increase in serum osmolality.
2.The decrease in intravascular blood volume.
3.Higher secretion at night and with erect posture and exercise.
4.Physical Stress , Surgery & even anxiety.
The most important syndromes associated with ADH are:
1.Diabetes insipidus.
2.Inappropriate ADH syndrome.

25. Increased ADH Level Is Seen In:
1.Hyperfunction of ADH state gives rise to Syndrome of inappropriate antidiuretic hormone secretion (SIADH).
2.There is sustained release of ADH in the absence of a known cause.
3.Central nervous system diseases like tumour's or infection.
4.Pulmonary tuberculosis or pneumonia.
5.Lung cancer (ectopic ADH).
6.Nephrogenic diabetes insipidus due to renal diseases.
7.Myxoedema.
8.Physical stress like pain, trauma.
9.Hypovolemia.
10.Dehydration.
11.Acute and intermittent porphyria.
12.Guillain-Barre syndrome.
Decreased ADH Level Is Seen In:
1.Hypofunction ADH gives rise to a polyuric state.
1. Urine output is more than 2.5 L/day.
2.Nephrogenic diabetes insipidus.
3.Nephrotic syndrome.
4.Water intoxication (psychogenic polydipsia).
5.Surgical ablation of the pituitary gland.
6.Hypervolemia.
7.Decreased serum osmolality.
8.This polyuric state is divided into:
1. Hypothalamic diabetes insipidus.
2. Nephrogenic diabetes insipidus.
3. Psychogenic polydipsia

26. What are antidiuretic hormones used for?
ADH medications may be prescribed to treat different
conditions including:
•Diabetes insipidus
•Von Willebrand’s disease
•Haemophilia A
•Haemorrhage
•Abdominal distension before an x-ray of after surgery
•Enuresis (bedwetting)
•Nocturia (excessive night-time urination) Antidiuretic hormone restrictions
Antidiuretic hormones should not be taken in combination
with certain medications. Certain medications may
enhance the effect of antidiuretic hormones and increase
the risk of water intoxication with hypernatremia. These
medications include:
•Intranasal corticosteroids
•Oral corticosteroids
•Inhaled corticosteroids
•Loop diuretics
•Thiazide diuretics
•Selective serotonin reuptake inhibitors
•Tricyclic antidepressants
•Nonsteroidal anti-inflammatory drugs (NSAIDs)
•Opioid analgesics

27. Common antidiuretic side effects
The most common side effects of antidiuretic hormones include:
•Nausea
•Vomiting
•Diarrhea
•Stomach pain
•Indigestion
•Weakness
•Headache
•Dizziness
•Flushing
•Loss of appetite
More severe but rare side effects of antidiuretic hormones include:
•Low sodium levels
•Mental and mood changes
•Allergic reactions

28. BY;
SARTHAK DAHIYA
50/B/19 (5 SEM.)
THANK YOU