Hyponatremia is defined as a serum sodium concentration below 135 mEq/L. It is commonly seen in hospitalized patients and those with conditions like heart failure, cirrhosis, and SIADH. Treatment involves correcting the underlying cause and raising the serum sodium level, but too rapid of a correction can cause serious neurological complications. Tolvaptan is a vasopressin receptor antagonist that promotes water excretion without electrolyte loss, allowing for a safe correction of hyponatremia within 24-48 hours. Clinical trials demonstrated its ability to significantly increase serum sodium levels compared to placebo.

1. Hyponatremia

2. Hyponatremia
•Approach to the pt.
•AVP
•Siadh
•Treatment strategies of SIADH
•Non-peptide AVP receptor antagonist
•Salt Trial
•Tolvaptan

3. Hyponatremia
• Hyponatremia defines as serum sodium concentration <135meq/L.
• Most frequent electrolyte abnormality in the hospitalized pt.
• Essentially common in critical care units. In addition to being a
potentially life-threatening condition, hyponatremia is an
independent predictor of death among intensive care unit and
geriatric patients and those with heart failure, and cirrhosis.

4. Hyponatremia
• Changes in serum sodium concentration results from derangements
in water balance.
• Low serum sodium concentration denotes a relative deficit of
sodium and /or a relative excess of water.
• As seen in the formula, hyponatremia may result from either a
decrease in the numerator or an increase in the denominator.
Serum sodium = total body sodium
total body water

5. Approach to the patient with Hyponatremia
Check serum osmolality.
increased or decreased.
Increased osmolality-----
---mannitol, glycine or hyperglycemia
---movement of water from ICF to ECF compartment.
It causes trans locational hyponatremia.
Decreased osmolality can be due to other causes.

6. Approach to the pt with hyponatremia
• Decreased serum osmolality --check volume status. It could be:
Hypovolumeic,
Hypervolumeic or
Euvolumeic.

7. Approach to the patient with Hyponatremia
Hypovolumeic Hyponatremia (Dehydartion)
Decrease Sodium
Decrease water
Causes
Diarrhea
Diuretic use
Mineralcorticoid defeciency
Osmotic diuresis like mannitol

8. Approach to the patient with Hyponatremia
Hypervolumeic Hyponatremia
Sodium content unchanged
Increase water
Causes
Heart Failure
Cirrhosis
Nephrotic syndrome

9. Approach to the patient with Hyponatremia
•Euvolumeic Hyponatremia
Sodium content unchanged
Relative increase in water
•Cause
Syndrome of inappropriate diuretic hormone
(SIADH)

10. Approach to the patient with Hyponatremia
Hyponatremia with decreases serum osmolality
ECF volume ECF volume ECF volume
decreased normal (euvolumic) increased (edema)
Renal Extrarenal SIADH CHF
Diuretics GI losses Cirrhosis
Nephrotic syndrome
Urine Na Urine Na Urine Na Urine Na
TB Na
TB water
TB Na
TB water
TB Na
TB water

11. Arginine vasopressin( AVP)
aka
Antidiuretic hormone (ADH)
•Major hormone that controls the water balance
•Release from pituitary glands
•Three receptors
V1a
V1b
V2

12. AVP
Increase
plasma
osmolality
Decrease
Intravascular
volume
V1a
receptors
V2
receptors
Regulate
vascular tone
Regulate water
reabsorption in
kidney

13. Vasopressin receptors
V1A receptors
• smooth muscle cells of blood vessels
• vasoconstrictive action
V1B receptors
• anterior pituitary
• Regulate pituitary ACTH secretion
V2 Receptors
• collecting duct cells
• antidiuretic effects of vasopressin

14. Vasopressin Action
• After binding of AVP to V2 receptors --- c-Amp is formed---
increased expression of AQP2 and AQP3 – insertion into cell
membrane.
• Increase driving force for water reabsorption.
• Increased water flow in collecting duct.

15. Collecting duct Cell
Luminal surface Basolateral surface
Aquaporin 3
Aquaporin 4
V2 repceptors fpr ADH
Recycling
vesicles for
AQP-2 ADH
Without ADH
collecting
duct is
impermeable
to water.

16. Collecting duct cell
Luminal surface
Basolateral surface
Aquaporin 3
Aquaporin 4
V2 repceptors for ADH
AQP-2
ADH
In Presence
of ADH
collecting
duct is
permeable
to water.

17. SIADH
• Inappropriate release of ADH causes siadh.
• It is diagnosed by checking :
Serum sodium <135
Serum osmolality <280
Urine osmolality >100
Urine sodium >30
also low serum uric acid <4.0

18. Causes of SIADH
Central nervous system;
meningitis, brain abcess,
stroke, acute psycosis
Pulmonary
pneumonia, lung abcess,
tuberculosis
Endocrine
Addison's disease, hypothyroidisim ,
hypopituitarism
Neoplastic
pancreatic or lung cancers.

19. Drugs induced SIADH
Increased ADH ADH potentiation
Anti-depressant carbamazepine
anti-psycotics chlopropamide
carbamazepine cyclophosphamide
platinum alkaloids Nsaids
alkylating agents ADH like activity
interferon vasopressin
levimasole ddavp
oxytocin

20. Drugs induced Siadh
•Common drugs
SSRI’s
Ectasy
Carbamazepine
ddavp

21. Clinical manifestation of siadh
Acute: (<48 hours)
Stupor/coma
Convulsions Treatment with
Respiratory arrest 3% NaCl
Chronic; (>48 hours)
Headache
Irritability Treat with medicines
Nausea & vomiting like Vaptans
Confusion & Disorientation
Gait disturbance

22. Correcting hyponatremia
• Traditional approach;
add to the
numerator
Serum sodium = Total body sodium
Total body water

23. Correcting hyponatremia
• Current approach;
Serum sodium = Total body sodium
Total body water
Subtract from the
the denominator

24. Treatment strategies for Acute
Hyponatremic Emergencies
• 3% NaCl: 100ml bolus for severe symptoms.
• 3% NaCl@1 to 2ml/kg/hr for 2 to 4 hours plus furosemide.
• Goal: correction by 4 to 6 mEq/L in first few hours.
• Monitor closely to avoid excessive correction.

25. Treatment Mechanism Advantages Limitations
Fluid restriction
(0.5- 1 liter/day)
Water intake Effective,
inexpensive
Poor compliance
Demeclocycline
(600-1200mg/d)
Inhibits action of
adh
Easily available 3-4 days for
onset,
nephrotoxicity
Urea
(30mg/d)
Osmotic diuresis Decreased risk Poor palatability,
Avoid in ckd
Lithium
(up to 900mg/d)
Inhibits action of
adh
Easily available Slow onset,
toxicity
Treatment strategies for Acute
Hyponatremic Emergencies

26. Rate of correction
Acute symptomatic :
4 to 6 mEq/L in first 4 hours
Target <12 mEq/L in first 24 hours.
Chronic:
Target correction at <8 mEq/L in first 24 hours
Goal not to exceed;
12 mEq/L in first 24 hr
18 mEq/L in first 48 hr

27. Importance of appropriate serum sodium
correction
Too-rapid correction of hyponatremia (e.g., >12
mEq/L/24 hours) can cause osmotic demyelination
syndrome (ODS) resulting in:
dysarthria, dysphagia,
seizures, coma and death
spastic quadriparesis.
Risk factors for ODS:
severe malnutrition,
alcoholism,
advanced liver disease

28. The Ideal therapy
Water excretion without electrolyte excretion
(Na+ and K+) Aquresis.
Prompt but safe correction in 24-48 hours;
<12mEq/L in first 24 hr
< 18mEq/L in first 48 hr
Eliminates fluid restriction.
Predictable and reliable action
Sustained effect and titratable
No unexpected side effects/toxicities.

29. Non-peptide AVP receptor antagonist
(Vaptans)
Aquaretic nonpeptide arginine vasopressin receptor
(AVPR) antagonists are safe and effective
hyponatremia therapies.
Vaptans lead to aquaresis, an electrolyte-sparing
excretion of free water, that results in the correction of
serum sodium concentration.

30. Non-peptide AVP receptor antagonist
tolvaptan lixivaptan satavaptan conivaptan
Receptor V2 V2 V2 V1a/V2
Route of administration
oral oral oral IV
Urine volume
Urine osmolality
Na excretion/
24 hours
Low dose
High Dose

31. SALT Trial
Multicenter randomized, placebo-controlled, double-blind phase 3 studies
(Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2) [SALT-1
and SALT-2]
225 pts with hyponatremia due to SIADH, cirrhosis or CHF vs 223 controls.
Serum Na <135 without neurological symptoms.

32. SALT Trial
•Pt were randomly assigned to placebo vs 15mg of
tolvaptan
•Dose of tolvaptan was increased to 30mg and then to
60mg if necessary.
Primary end points;
•Change in serum sodium from baseline to day 4 and
day 30.
•Serum sodium a week after discontinuation of drug.

33. SALT Trial
Significant increase in as early as 8 hours :
7% of tolvaptan-treated patients had an increase in serum
sodium greater than 8 mEq/L
vs 1% of placebo-treated patients
Results consistent among patients with heart failure,
cirrhosis, and SIADH
The average rates of serum sodium correction during the
treatment initiation (first 24 hours) were
3.83 mEq/L for SAMSCA (15 mg) and
0.30 mEq/L for placebo

34. SALT Trial
Serum Sodium Tolavaptan Placebo
Baseline 128.5 ± 4.5 128.7 ± 4.1
Day 4 133.9 ± 4.8 129.7 ± 4.9
Day 30 135.7 ± 5.0 131.0 ± 6.2

35. Results of SALT

36. Results of SALT
•In the SALT trials on Day 4, SAMSCA increased
serum sodium concentration by 4.8 mEq/L vs
0.2 mEq/L for placebo.
•On Day 30, SAMSCA increased serum sodium
concentration by 7.4 mEq/L vs 1.5 mEq/L for
placebo.

37. Results of SALT

38. SALT Trial
• None of the patients in these studies had evidence of osmotic
demyelination syndrome (ODS) or related neurologic sequel.
• In patients receiving Tolvaptan who develop too-rapid rise in serum
sodium, discontinue or interruption of treatment with SAMSCA and
administration of hypotonic fluid was considered.

39. Results of SALT
•Reduced need for fluid restriction
Fluid restriction during the first 24 hours of therapy
with Tolvaptan may increase the likelihood of overly
rapid correction of serum sodium and should be
avoided.

40. Results of SALT
•Significant effect on fluid balance
With Tolvaptan, urine output is greater than fluid intake,
which results in a net negative fluid balance.

41. Tolvaptan
•Tolvaptan is indicated for the treatment of clinically
significant hypervolemic and euvolemic
hyponatremia (serum sodium <125 mEq/L ) in
heart failure, cirrhosis, and SIADH.
•It is available in 15mg, 30mg and 60mg tablets.

42. Tolvaptan
Tolvaptan is contraindicated in the following conditions:
• Urgent need to raise serum sodium acutely
• Inability of the patient to sense or appropriately respond to thirst
• Hypovolemic hyponatremia
• Concomitant use of strong CYP 3A inhibitors
• Anuric patients

43. Tolvaptan
•Tolvaptan should be initiated and re-initiated in
patients only in a hospital where serum sodium can be
monitored closely.
•Too rapid correction of serum sodium (e.g., >12
mEq/L/24 hours) can cause serious neurologic sequel,
including osmotic demyelination syndrome (ODS).

44. Vasopressin Antagonist
• Management of hyponatremia
Prompt,
Reliable and
Controlled
Permits out pt management