Diuretics and antidiuretics explaining mechanism of action, therapeutic indications, adverse effects of the drugs

PPT describes about diuretics & diuretics

1. Diuretics and Antidiuretics

Dr. Rekha

2. Diuretics and Antidiuretics.
• Diuretics are agents that increase renal sodium and water
excretion.
• A diuretic is any drug that elevates the rate of urination and
thus provides a means of forced diuresis.
• Diuretics are drugs that cause a net loss of sodium and
water in the urine.
 A diuretic is an agent that increases urine volume.
• Natriuretic are agents that increase renal excretion of sodium.
• Saluretics are agents that promote renal excretion of sodium
and chloride ions.
• Antidiuretics are drugs that reduce urine volume.

3. Classification of Diuretics.
1] High efficacy diuretics [ Inhibitors of Na
+
- K
+
- 2Cl
-
cotransport ].

a) Sulphamoyl derivatives – Furosemide, Bumetanide,
Torasemide.

2] Medium efficacy diuretics [ Inhibitors of Na
+
- Cl
-
symport ].
a) Benzothiadiazenes ( Thiazides) – Hydrochlorothiazide,
Benzthiazide, Hydroflumethiazide, Clopamide.
b) Thiazide like (related heterocyclic's) – Chlorthalidone,
Metalazone, Xipamide, Indapamide.
3] Weak or adjunctive diuretics.
a) Carbonic anhydrase inhibitors – Acetazolamide.
b) Pottasium sparing diuretics.
i) Aldosterone antagonist – Spironolactone.
ii) Inhibitors of renal epithelial Na channel – Triamterone,
Amiloride.
c) Osmotic diuretics – Mannitol, Isosorbide, Glycerol.
4] Others.
i) ADH antagonists – Conivaptan, Lithium and Demeclocycline.
.

4. • Diuretics can also be classified into the following categories based
on the sites of action along the Nephron:

1] Proximal Convoluted Tubule - Carbonic anhydrase inhibitors and
Osmotic diuretics.
2] Loop of Henle - Loop diuretics, Osmotic diuretics and [ ?
Thiazides].
3] Distal Convoluted tubule - Thiazides, [? Pottasium sparing
diuretics – Aldosterone antagonists and ? Osmotic diuretics].
4] Collecting tubules and collecting duct cells - Potassium
sparing diuretics, Osmotic diuretics and Anti diuretic hormone
antagonists.

5. Overview of urine formation.

150 – 180 litres 99% reabsorbed 1% becomes
filtered urine

6. Nephron and the sites of action of Diuretics.

7. Carbonic Anhydrase inhibitors [ CAI’s ].
Drugs: Acetazolamide, Dichlorphenamide, Methazolamide,
Brinzolamide, Dorzolamide.
• CAI’s are the forerunners of modern diuretics.
• Carbonic anhydrase is present in many Nephron sites,
predominantly in the luminal membrane of the PCT.
• It catalyzes the dehydration of H
2
Co
3
.
• Blocking Carbonic anhydrase its inhibitors block NaHCo
3
reabsorption and cause diuresis.
• The observation that bacteriostatic Sulfonamides caused
alkaline diuresis and hyperchloremic metabolic acidosis led to
their discovery.
• The prototypical CA inhibitor is Acetazolamide.

8. Proximal Convoluted tubule cell.

9. Pharmacokinetics.
• CAI’s are well absorbed after oral administration
• Increase in urine pH due to HCo
3
diuresis is apparent within
30 mins, maximal at 2 hrs, persists upto 12hrs after a single
dose.
• Excretion of the drug is by secretion in PCT
•Dose reduction in renal insufficiency is necessary.
Pharmacodynamics.
• 85% of the HCo
3
reabsorptive capacity of the superficial PCT
is inhibited.
• Overall 45% inhibition of whole kidney HCO
3
reabsorption is
seen.
• CAI’s - HCo
3
loss and hyperchloremic metabolic acidosis.

10. • Reduced HCo
3
in glomerular filtrate and HCo
3
depletion leads
to increased NaCl reabsorption in the remainder of the
nephron.
• This results in decreased diuretic efficacy of Acetazolamide
when used over several days.
• Presently clinical application of CAI involve CA dependant
HCo
3
and fluid transport at sites other than kidney – ciliary
body and choroid plexus [opposite direction to PCT i.e.
removal from blood.]
Clinical Indications.
A] Glaucoma.
• CAI reduce aqueous humor formation and decrease IOP.
• Most common clinical indication for CAI’s.
• Topical forms available.

11. B] Urinary alkalinization.
• Renal excretion of cystine [cystinuria] and other weak acids
can be enhanced by increasing urinary pH.
• CAI effect lasts 2-3 days.
• Prolonged therapy requires HCo
3
administration.
C] Metabolic acidosis.
• Respiratory acidosis and excessive diuretic use in severe HF.
• Corrects alkalosis and provides small additional diuresis to
correct volume overload.
D] Acute mountain sickness.
• Rapid ascent to above 3000m.
• Life threatening pulmonary and cerebral edema.
• Decrease CSF formation and pH and increase ventilation.
E] Others – epilepsy, hypokalemic periodic paralysis and
severe hyperphosphatemia.

12. Toxicity.
• Hyperchloremic metabolic acidosis.
• Renal stones.
• Renal Pottasium wasting.
• Drowsiness and Parasthesias.
• Hypersensitivty reactions.
• Nervous system toxicity.
Contraindications.
• Cirrhosis – decrease in NH
4
excretion can lead to
hyperammonemia and hepatic encephalopathy.

13. Illustration of diuretic action and substances reabsorbed
in the Loop of Henle.
Substances reabsorbed in the LOH
1) Water – descending limb.
2) NaCl – about 25% filtered sodium
3) Magnesium.
4) Calcium. Divalent Cations
5) Pottasium.
• Salt reabsorption in this segment
dilutes the tubular fluid and this is
called the “ diluting segment ”.
• Medullary portions of the TAL
contribute to medullary hypertonicity.

14. Loop Diuretics.
Drugs. Furosemide, Ethacrynic acid, Bumetanide, Torsemide.
[Organic mercurial diuretics – no longer used].
• Loop diuretics selectively inhibit NaCl reabsorption in the loop.
• The large NaCl absorptive capacity of the segment and the
fact that drug action is not limited by the development of
acidosis, makes them the most efficacious diuretics available.
• The prototypical drugs of this class are Furosemide
[sulfonamide derivative] and Ethacrynic acid [Phenoxyacetic
acid derivative].
Pharmacokinetics.
• Loop diuretics are rapidly absorbed.
• They are eliminated by the kidney by glomerular filtration and
tubular secretion.

15. • Absorption of oral Torsemide is rapid (1hr) and almost as
complete as with IV. Duration of action is 4-6hrs.
• Absorption of oral Furosemide is 2-3 hrs. Duration of action is
also 2-3 hrs.
• Half life depends on renal function.
• Since they act on the luminal side of the tubule their diuretic
activity correlates with their secretion by the PCT.
• Agents that compete for weak acid secretion in the PCT like
NSAID’s and Probenecid can reduce their secretion by PCT
when co administered.
Pharmacodynamics.
• Loop diuretics inhibit NKCC2, the luminal Na/K/2Cl
transporter in Henles loop.

16. Medullary thick ascending limb - Loop of Henle.

17. • They thereby reduce reabsorption of NaCl and diminish the
lumen positive potential that comes from K
+
recycling.
• Reducing this potential results in the increased excretion of
Magnesium and Calcium.
• Prolonged use can cause hypomagnesemia.
• Vitamin D induced intestinal absorption of Calcium and active
reabsorption of calcium in the DCT generally prevent
hypocalcemia.
• Combinations of loop diuretics and saline infusions are useful

in treating hypercalcemia.
• NSAID’s can blunt activity of COX , reduce PG synthesis and
interfere with loop diuretic activity – significant in Nephrotic
syndrome and Hepatic Cirrhosis.
• Furosemide increases renal blood flow.
• Furosemide and Ethacrynic acid are useful in Heart failure.

18. Clinical Indications.
A] Edematous States.
• They are used in edematous states such as peripheral edema

or acute pulmonary edema as a result of cardiac, renal or
vascular diseases that reduce blood flow to the kidney.
• Sensing of insufficient efficient arterial blood volume leads to
salt and water retention and edema formation.
• Judicious use of diuretics along with careful monitoring of the
patients hemodynamic status and understanding of the
underlying illness is essential.
• HCD’s are preferred in heart failure.
• HCD’s are drugs of choice for Nephrotic and resistant edema.
• Massive doses are used in renal failure.
• HCD’s decrease the need for dialysis in impending acute
renal failure.

19. B] Hypertension.
• HCD’s are indicated only in the presence of renal insufficiency, CHF,
resistant cases or hypertensive emergencies.
C] Anemia.
• Along with blood transfusions to prevent vascular overload.
D] Hypercalcemia.
• HCD’s increase calcium excretion and urine flow.
• Help reduce serum calcium level.
• Excess salt that is lost must be replaced.
E] Hyperkalemia.
• Mild hyperkalemia – significantly enhances urinary excretion of
Pottasium.
• Enhanced by coadminstration of NaCl and water.
F] Anion Overdose. – No longer used.
G] Acute renal Failure.
• Increase rate of urine flow and K
+
excretion. Do not shorten
duration of renal failure.

20. Toxicity.
• Hypokalemic metabolic alkalosis.
• Ototoxicity.
• Hyperuricemia.
• Hypomagnesemia.
• Allergic and other reaction.

Contraindications.
• Furosemide, Bumetanide and Torsemide display allergic
cross reactivity in patients sensitive to sulfonamides.
• Overzealous use is dangerous in Hepatic cirrhosis,
borderline renal failure and heart failure.

21. Illustration of diuretic action and substances reabsorbed
and secreted in the Distal Convoluted tubule cell.
Substances reabsorbed in DCT:
1)4-8% of filtered Na and Cl.
2)Calcium reabsorption under
PTH hormone control.
•This segment is relatively
impermeable to water and
NaCl reabsorption further
dilutes the tubular fluid.

22. Thiazide Diuretics.
Drugs. Hydrochlorothiazide, Bendroflumethiazide, Chlorothiazide,
Benzthiazide, Hydroflumethiazide, Clopamide, Chlorthalidone, Metalazone,
Xipamide, Indapamide.
• Thiazides emerged from efforts to synthesize more potent CAI’s.
• It later became clear that they inhibit NaCl transport
predominantly in DCT.
• Thiazides have an unsubstituted sulfonamide group.
• The prototypical thiazide is Hydrochlorothiazide.
Pharmacokinetics.
• All Thiazides can be administered orally but there are
differences in their metabolism.
• Chlorothiazide is the parent of the group and is not very lipid
soluble and has to be given in relatively large doses.
• It is the only thiazide available for parenteral administration.

23. • Chlorthalidone is slowly absorbed and has a longer duration of action.
• Indapamide though primarily excreted by biliary system has enough of its
active form excreted by kidney to exert its effect.
• All Thiazides are secreted by the organic acid secretory systems in the
PCT and compete with uric acid secretion and result in elevated uric acid
levels.
Pharmacodynamics.
• Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells
in DCT by blocking Na/Cl transporter NCC.
• They also enhance Calcium reabsorption in contrast to HCD’s.
• This has been attributed to combination of PCT and DCT effects by
thiazides.
• In PCT - Thiazide induced volume depletion leads to enhanced Na and
passive Ca reabsorption. In the DCT lowering of Na entry by blocking
NCC enhances Na / Ca exchange in the basolateral membrane and
increases overall Ca reabsorption.
• They can unmask hypercalcemia due to other causes.

24. • Useful in the treatment of kidney stones caused by hypercalciurea.
• They are partly dependent on renal PG production for their actions and
therefore NSAID’s can blunt their effects.
Distal Convoluted tubule cell.

25. Clinical indications.
A] Edema.
• Thiazides can be used for mild to moderate cases, for maintenance
therapy.
• Act best in cardiac edema, less effective in renal or hepatic edema and
powerless in the presence of renal failure.
• Development of secondary hyperaldosteronism in cirrhotics leads to
development of refractoriness to thiazides.
B] Hypertension.
• Thiazides and related diuretics especially Chlorthalidone are one of the
first line drugs.
C] Diabetes insipidus.
• They reduce urine volume.
D] Hypercalciuria with recurrent stones in the kidney.
• Act by reducing calcium excretion.

26. Toxicity.
• Hypokalemic metabolic alkalosis and hyperuricemia.
• Impaired carbohydrate tolerance due to decreased
pancreatic release of insulin and diminished tissue
utilization of glucose.
• Hyperlipidemia.
• Hyponatremia.
• Allergic reactions.
• Other toxicities – Weakness, fatigability, paresthesias
and impotence.
Contraindications.
• Excessive use is dangerous in patients with hepatic
cirrhosis, borderline renal failure or heart failure.

27. Interactions of HCD’s and Thiazides.
1] Thiazides and HCD’s potentiate all other anti hypertensives.
2] Hypokalemia induced:
i)Enhances digitalis toxicity,
ii)Increases polymorphic ventricular tachycardia due to quinidine and other
antiarrhytmics,
iii)Potentiates competitive NM blockers and reduces sulfonylurea action.
3] HCD’s and AG antibiotics produce additive ototoxicity and
nephrotoxicity.
4] When given with cotrimoxazole has caused higher incidence of
thrombocytopenia.
5] Diuretic and antihypertensive actions of Thiazides and HCD’s are
reduced by NSAID’s.
6] Probenecid competitively inhibits secretion.
7] Diuretics diminish uricosuric action of Probenecid.
8] Serum Lithium level rises due to enhanced reabsorption of Lithium
and Na in the PCT, when diuretic therapy is instituted.

28. Illustration of diuretic action and substances reabsorbed
in the Collecting tubule and collecting duct cells.

Substances reabsorbed in the
Collecting tubule:
1)2-5% of NaCl,
2)Water reabsorption under ADH control.

Substances secreted in the collecting
tubule:
1)Pottasium ions, Coupled to Na
2)Hydrogen ions. Reabsorption.

29. Potassium sparing diuretics.
Drugs. Spironolactone, Eplerenone, Amiloride, Triamterene.
• Prevent K+ secretion by antagonizing the effects of
aldosterone at the late distal and cortical collecting tubules.
• Inhibition may be :
i) Direct pharmacologic antagonism of minerelocorticoid
receptor – Spironolactone, Eplerenone.
ii) Inhibition of sodium influx through ion channels in the
luminal membrane – Amiloride, Triamterene.

Pharmacokinetics.
• Spironolactone is a synthetic steroid that acts as a competitive

antagonist to Aldosterone.
• Spironolactone has a relatively slow onset of action (several
days).It is inactivated in the liver.
• Its analog Eplerenone is much more selective for the Minerelo
corticoid receptor.

30. • It is also less active on androgen and progesterone receptors

and therefore has fewer adverse effects.
• Triamterene is metabolized in the liver and excreted by the
kidney. It has a short half life and must be given repeatedly.
Pharmacodynamics.
• Pottasium sparing diuretics reduce sodium absorption in the
collecting tubules and ducts.
• Aldosterone regulates Na absorption and K secretion and
therefore its antagonists interfere with this process.
• Similar effects are also seen with H+ handling and partly
explains the metabolic acidosis seen with aldosterone
antagonists.
• Since aldosterone antagonists depend on PG’s for their
actions NSAID’s can blunt their action.

31. Collecting tubule and collecting duct cells.

32. Clinical indications.
A] States of minerelocorticoid excess or hyperaldosteronism.
• due to either primary hypersecretion or secondary
hyperaldosteronism.
• K sparing diuretics blunt the K wasting that occurs.
B] Reduce progression of albuminuria in diabetics.
• Low doses of eplerenone (25-50 mg / day) interferes with
fibrotic and inflammatory effects of aldosterone.
C] Myocardial infarction.
• Eplerenone has been found to reduce myocardial perfusion
defects after MI.
D] Edema
• More useful in cirrhotic and nephrotic edema.
E] To counteract K loss due to thiazide and loop diuretics.
F] Hypertension – as adjuvant to prevent hypokalemia.

33. Toxicity.
• Hyperkalemia.
• Hyperchloremic metabolic acidosis.
• Gynecomastia.
• Acute renal failure, Kidney stones.
Contraindications.
• Oral K administration should be discontinued to prevent
hyperkalemia.
• Should be avoided in patients with chronic renal insufficiency.
• Concomitant use with agents like β blockers or ACE inhibitors
which blunt the effects of RAS can cause hyperkalemia.
• Dosing adjustment in patients of liver disease for Triamterene
and spironolactone.
• Strong CYP3A4 inhibitors ( ketoconazole, itraconazole) markedly increase

blood levels of eplerenone.

34. Osmotic diuretics.
Drugs. Mannitol, Isosorbide, Glycerol.
• These agents are active in the PCT, LOH, DCT and CTCD
cells.
• The PCT and DL of LOH are freely permeable to water.
• Osmotically active agents that are filtered by the glomerulus
but not reabsorbed causes water to retained in these
segments and promotes a water diuresis.
• Such agents are used to reduce ICP and promote prompt
removal of renal toxins.
• The prototypic osmotic diuretic is mannitol.
Pharmacokinetics.
• Poorly absorbed by the GI tract and when administered orally
causes osmotic diarrhea.
• Given parenterally for systemic effect.

35. • Mannitol is not metabolized and is excreted by glomerular
filtration within 30-60 mins, without any tubular reabsorption
and secretion.
• Osmotic diuretics have their major effect in the PCT and
DL of LOH.
• They oppose the action of ADH in the Collecting tubule.
• The presence of nonreabsorbable solutes prevent the
absorption of water by interposing a countervailing osmotic
force.
• The result of which is an increase in urine volume.
• The increase in urine flow rate decreases the contact time
between fluid and tubular epithelium.
• Therefore sodium as well as water reabsorption is reduced.
• The resulting natriuresis is of lesser magnitude than water
diuresis resulting in excessive water loss and hypernatremia.

36. Clinical indications.
1] Increase of urine volume.
• used to increase water excretion in preference to sodium
excretion.
• To maintain GFR and urine flow in impending acute renal
failure e.g. shock, severe trauma, cardiac surgery, hemolytic
reactions:500 – 1000 ml of solution may be infused over 24 h.
• Some oliguric patients do not respond to osmotic diuretics
therefore a test dose of mannitol 12.5 g IV should be given
before starting a continuous infusion.
2] Reduction of intracranial and intraocular pressure.
• Osmotic diuretics alter starlings forces so that water leaves
cells and reduces intracellular volume.
• This effect is used to reduce intracranial pressure in
neurologic conditions and intraocular pressure before surgery.

37. Isosorbide and Glycerol.
• These are orally active osmotic diuretics which may be
used to reduce intraocular or intracranial tension.
• Intravenous Glycerol can cause hemolysis.
Toxicity.
• Extracellular volume expansion.
• Dehydration, Hyperkalemia, Hypernatremia.
• Hyponatremia , Headache.
• Nausea, vomiting and hypersensitivity reactions.
Contraindications.
• Acute tubular necrosis, anuria.
• Pulmonary edema.
• Acute left ventricular failure, CHF.
• Cerebral hemorrhage.

38. ADH hormone antagonists.
Drugs. Conivaptan, Lixivaptan, Tolvaptan, Lithium and
Democlocycline.
• Medical conditions like CHF and SIADH secretion cause
water retention as a result of ADH excess.
• These conditions can result in dangerous hyponatremia.
• Several non peptide ADH receptor antagonists (Vaptans) have
been studied with encouraging results.
• Conivaptan exhibits activity against both V1a and V2
receptors, is currently available for IV administration and has
been approved for use.
• Lixivaptan and Tolvaptan are selectively active against V2
receptor are orally administered and are expected to receive
FDA approval soon.
• Lithium and Democlocycline are no longer used.

39. Water Transport in the collecting duct cells.
• AQP 1 – PCT cells

40. Pharmacokinetics.
• Conivaptan has ½ life of 5 - 10 hours.
Pharmacodynamics.
• ADH antagonists inhibit the effects of ADH in the collecting
tubule.
• Conivaptan is a pharmacologic antagonist at V1a and V2
receptor.
Clinical indications.
A] SIADH secretion.
• ADH antagonists are used to treat the syndrome when water
restriction has failed to correct the abnormality.
• Lithium carbonate has been used but results are not
predictable.
• Democlocycline in dosages of 600 – 1200 mg / day yields a
predictable result and is less toxic.

41. B] Other causes of elevated ADH.
• ADH is elevated in diminished effective circulating blood
volume as in CHF.
• Conivaptan is useful because blockade of V1a receptors by
this drug leads to decreased peripheral vascular resistance
and increased cardiac output.
Toxicity.
1] Nephrogenic Diabetes insipidus.
• Serum Na needs to be monitored.
• If Lithium is being used NDI can be treated with thiazide
diuretic or amiloride.
2] Renal failure.
• Lithium – ARF and chronic interstitial nephritis.
• Democlocycline – ARF.

42. Antidiuretics.
• These drugs are used to reduce urine volume especially
in Diabetes insipidus which is their primary indication.
• Antidiuretics can be classified as follows:
1] Antidiuretic hormone [ ADH ] and its analogues.
• Vasopressin, Desmopressin, Lypressin, Terlipressin.
2] Diuretics.
• Thiazides, Amiloride, High ceiling diuretics.
3] Miscellaneous drugs use to treat Diabetes insipidus.
• Chlorpropamide, Carbamazepine.

43. Diabetes Insipidus.
• Diabetes insipidus is a disorder resulting from deficiency of
anti-diuretic hormone [ADH] or its action and is characterized
by the passage of copious amounts of dilute urine.
• There are 2 types of Diabetes Insipidus:
i) Neurogenic or Central or Pituitary origin diabetes insipidus –
Deficient production of ADH.
ii) Nephrogenic Diabetes insipidus – inadequate responsiveness
to ADH.
• It must be differentiated from other polyuric states such as
primary polydipsia and osmotic diuresis.
• Symptoms of DI include – polyuria, polydipsia, thirst, Nocturia,
hypernatremic dehydration, anorexia, constipation, hyperthermia
and lack of sweating.

44. ADH [ Vasopressin ] Receptors.

• ADH receptors are G protein coupled cell membrane receptors.
• Two subtypes V1 and V2 have been identified, cloned and characterized.
Receptors Selective Agonist
1. V
1a
receptor [ vascular & other
smooth muscles, platelets,
liver.]
[ Phe
2
, Ile
2
, Orn
8
] AVP
2. V
1b
receptor [ localized to
anterior pituitary.]
Deamino [D-3 ( pyridyl )-Ala
2
]
AVP
3. V
2
receptor [ CD cells in
kidney and blood vessels.]
Desmopressin ( dDAVP )
Receptors Selective Antagonist
1. V
1a
receptor d ( CH
2
)
5
[Tyr (Me
2
) ] AVP
2. V
1b
receptor dp [ Tyr ( me
2
) AVP
3. V
2 receptor d ( CH
2 )
5 [ D – Ile
2
, Ile
2
, Ala –
NH
2
9
] AVP

45. Antidiuretic Hormone and its analogues.
• Mammalian ADH is “8-arginine-vasopressin [AVP]”.
• “8-lysine-vasopressin” – [Lypressin] found in swine, synthetic.
• ADH is a non peptide secreted along with Oxytocin by the
Neurohypophysis.
• It is synthesized in the hypothalamic nerve cell bodies
[supraoptic and paraventricular], as a large precursor peptide
along with its binding protein ‘neurophysin’.
• It is transported down the axons to the nerve endings in the
median eminence and ‘Pars nervosa’.
• Osmoreceptors present in the hypothalamus and volume
receptors present in the left atrium, ventricles and pulmonary
veins primarily regulate the rate of ADH release governed by
body hydration.

46. • Impulses form baroreceptors and higher centre's also affect
synthesis and release.
• The two main physiological stimuli for ADH release are rise in

plasma osmolarity and contraction of e.c.f volume.
ADH Secretion.

47. • Antidiuretic hormone is produced by the hypothalamus of
the brain.
• ADH works on collecting ducts of
kidney nephrons.
• ADH will cause the pores of the
collecting duct to dilate and thus
allow water to move faster.
• Water will leave the collecting
duct because the interstitial
fluid around the collecting duct
is hypertonic.
• ADH prevents the body from
losing too much water.

48. Actions of Antidiuretic hormone [ ADH ].
1) Kidney
• ADH acts on CD cells to increase their water permeability. Maximum
osmolarity of urine that can be obtained is 4 times higher than plasma.
• Graded effect at lower concentration of ADH i.e. urine volume closely
balances fluid intake.
Mechanism of Action.
V2 receptor activation Aqueous channels
inserted into
apical membrane
Increases intracellular cAMP
Rate of endocytosis and
Activation of cAMP dependant degradation of WCV’s
decreased
protein kinase A
Water permeability of CD cells
increased
Phosphorylation of relevant proteins
Continued V2 stimulation
upregulates
Exocytosis of aquaporin 2 WCV’s AQ-2 synthesis through cAMP
response
element of gene coding AQ-2.

49. 2) On Blood Vessels.
• AVP is also called vasopressin because it constricts
blood vessels through V1 receptors and raises BP.
• The concentration required for this effect is much higher
than for maximal antidiuresis.
• The cutaneous, mesenteric, skeletal muscle, fat depot,
thyroid, and coronary beds are particularly constricted.
• Prolonged exposure to AVP causes vascular smooth muscle
hypertrophy.
• Its role in CHF, hemorrhage and hypotensive states is being
researched.
• AVP also has V2 mediated vasodialatory action which can be
unmasked when administered with a V1 antagonist.

50. 3) GIT.
• Increased peristalsis in gut especially the large bowel – evacuation and
expulsion of gases may occur.
4) Viscera.
• Contraction of visceral smooth muscles.
5) Uterus.
• contraction due to AVP acting on oxytocin receptors.
6) CNS.
• Exogenously administered AVP cannot penetrate BBB.
• Recognized as a peptide neurotransmitter in many areas
of brain and spinal cord.
• May be involved in regulation of temperature, circulation,
ACTH release and in learning of tasks.
7) Others.
• Induces platelet aggregation and hepatic glycogenolysis.

51. • Releases coagulation factor VIII and vWF from vascular
endothelium through V2 action.
Pharmacokinetics.
• Inactive orally and destroyed by trypsin.
• Can be administered parenterally or intra nasally.
• Peptide chain of AVP is rapidly cleaved in many organs like
liver and kidney.
• Plasma t1/2 ranges from 25 mins. to 3-4 hrs [ aqueous AVP].

Vasopressin analogues.
Lypressin.
• It is 8 – Lysine Vasopressin.
• Less potent than AVP. Acts on both V1 and V2 receptors.
• Longer duration of action – 4 to 6 hours. Used for V1 actions.

52. Terlipressin.
• Synthetic prodrug of vasopressin.
• Used for bleeding esophageal varices.
• Produces less adverse effects than Lypressin.

Desmopressin [ dDAVP ].
• It is a synthetic peptide and a selective V2 antagonist.
• Has 12 times more potent antidiuretic activity than AVP and
negligible vasoconstrictor activity.
• It is longer acting than AVP, owing to slow enzymatic
degradation. Its t1/2 is 1 - 2 hours. Duration of action is 8 -12
hours.
• Preparation of choice for all V2 receptor mediated actions.
• Debate over preference and convenience of route of administration.

53. • Intranasal route has a bioavailability of 10 – 20 % and is
preferred.
• Oral route has bioavailability of 1-2% i.e. 10 to 15 times of
intranasal dose has to be used. Most patients find it more
convenient.
• Oral route produces systemic effects without nasal side
effects.
Uses of ADH and its analogues.
1] V2 receptor actions – [ Desmopressin is the DOC ].
A] Diabetes insipidus.
• DI of pituitary origin [ Neurogenic Diabetes insipidus ] is the
most important indication for vasopressin.
• It is ineffective in Nephrogenic DI since kidney is
unresponsive to ADH.

54. • Dose of Desmopressin is individualized by measuring 24 hour
urine volume.
• For differentiating DI, Desmopressin in a dose of 2 µg IM is
used now rather than aqueous vasopressin.
B] Bedwetting in children and nocturia in adults.
• Intranasal or oral Desmopressin at bedtime.
• Fluid intake is reduced 1 hour before and 8 hours after the
dose to avoid fluid retention.
• Periodical monitoring of BP and body weight is required to
check for fluid overload.
• Drug is withdrawn for 1 week every 3 months for
reassessment.
C] Renal concentration test.
• 5 – 10 units i.m. of aqueous vasopressin or 2 µg of desmo -
-pressin causes maximum urinary concentration.

55. D] Haemophilia and von Willebrand’s disease.
• AVP can check bleeding by releasing coagulation factor VIII and vWF.
• Desmopressin is preferred in a dose of 3 µg / kg diluted in 50 ml of saline
and infused i.v. over 30 minutes.
2] V1 receptor actions.
A] Bleeding oesophageal varices.
• Vasopressin / Terlipressin can stop bleeding by constricting mesenteric
blood vessels and reducing blood flow through the liver to the varices,
allowing clot formation.
• Terlipressin stops bleeding in 80% of cases and has been shown to
improve survival and has replaced vasopressin due to fewer adverse
effects and greater convenience in use.
B] Before abdominal radiography.
• AVP / Lypressin have been occasionally used to drive out gases before
abdominal radiography.

56. Adverse effects.
• Because of V2 selectivity Desmopressin produces fewer
adverse effects than Vasopressin, Lypressin or Terlipressin.
• Transient flushing and headache are frequent.
• Nasal irritation, congestion, rhinitis, ulceration and epistaxis
can occur on local application.
• Systemic side effects include belching, nausea, abdominal
cramps, Pallor, urge to defecate, backache in females.
• Fluid retention and hyponatremia may develop.
• Urticaria and allergy.
• AVP can cause constriction of coronary vessels and lead to
bradycardia, increased cardiac afterload and precipitate
angina.
• Contraindicated in patients with IHD, HT, chronic nephritis and
psychogenic polydipsia.

57. Diuretics.
Drugs - Thiazides, Amiloride, High ceiling diuretics.
• Thiazide diuretics exert a paradoxical effect in Diabetes insipidus.
• They reduce urine volume in Pituitary as well as Renal DI.
• Their efficacy is however low and urine cannot become hypertonic as can

with AVP in Neurogenic DI.
• Hydrochlorothiazide 25-50 mg TDS or a longer acting agent is used. Less
effective than AVP but more convenient and cheap for Pituitary origin DI.
• Reduce Polyuria to some extent.
• Potassium supplements are needed.
• High ceiling diuretics are also effective but are less desirable
due to their short and brisk action.
• Amiloride is the DOC for Lithium induced Nephrogenic DI.
• Amiloride can be combined with Thiazide and Indomethacin in
the treatment of Nephrogenic DI.

58. •
Possible Explanations.
1] Thiazides induce a state of sustained electrolyte
depletion
Glomerular filtrate is more completely reabsorbed in
PCT
Reduced salt reabsorption in cortical diluting segment
Smaller volume of less diluted urine is presented to
CTCD cells and passed out
2] Thiazides reduce Glomerular filtration rate
Reduced fluid load on tubules

59. Miscellaneous drugs used to treat Diabetes Insipidus.
Chlorpropamide.
• It is a long acting oral hypoglycemic drug.
• It reduces urine volume in DI of Pituitary origin.
• It sensitizes the kidney to ADH action and therefore its efficacy
depends on small amounts of the circulating ADH.
• Nearly 50% of patients with partial Neurogenic DI respond well.
• A thiazide may be added to augment the response.
• Hypoglycemia in DI limits its usefulness.
• Dose used: 125 – 500 mg / day.
Carbamazepine.
• It is an antiepileptic which reduces urine volume in DI of
Pituitary origin.
• High doses and adverse effects limit its value in the treatment
of DI.

60. References.
1] Basic and Clinical Pharmacology, 11
th
edition by Bertram G.
Katzung.
2] Essentials of medical Pharmacology, 6
th
edition by K.D.
Tripathi.
3] Diabetes insipidus by Dr. Abdelaziz Elamin, Sultan Qaboos
University, Muscat.
4] Fluid Balance - Robert Harris, ppt 2009.
5] Diuretics by William B. Jeffries, Ph.D.
6] ADH ppt. by Benjamin Cummins.

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