Disorders of the

Neurohypophysis
Diabetes Insipidus
Idiopathic Central DI
• Approximately 30 to 50 percent of cases of CDI are
idiopathic

• Associated with destruction of the hormone-secreting cells

in the hypothalamic nuclei.

• It has been suggested that an autoimmune process is

involved in many, if not most, patients
Idiopathic Central DI
• Insight into the mechanism of autoimmunity in some
individuals was provided by a longitudinal study
evaluating the presence of cytoplasmic antibodies
directed against vasopressin cells (Ab-positive) in patients
with endocrine autoimmune diseases but initially without
CDI
• Among almost 900 such patients, 9 found to be Ab-positive and
139 Ab-negative controls were prospectively followed. At four
years, none of the controls developed CDI.
• By comparison, four of the nine Ab-positive patients had partial CDI
at study entry and, among the remaining five patients, three
developed partial DI and one developed complete CDI.
Idiopathic Central DI
• This autoimmune process is characterized by lymphocytic
inflammation of the pituitary stalk and posterior pituitary
that resolves after destruction of the target neurons.

• MRI early in the course often reveals thickening or

enlargement of these structures.
Idiopathic Central DI
• The incidence of such antibodies in those with CDI, their
association with other autoimmune diseases, and their
correlation with radiologic features was evaluated in a study of
150 patients with central DI that was performed by the same
Italian group
• The disease was idiopathic in 43 percent, familial in 4 percent,
granulomatous in 8 percent, and secondary to cranial trauma, tumor, or
surgery in 45 percent.
• Antibodies to vasopressin cells were found in about one-third of the
patients with idiopathic disease and approximately one-quarter of
patients with nonidiopathic disease.
• Antibody positivity was independently associated with age less than 30
years at disease onset in those with idiopathic disease, a history of
autoimmune disease, or pituitary stalk thickening.
• Autoimmune CDI was highly probable in young patients with a history of
autoimmune disease and pituitary stalk thickening.
Idiopathic Central DI
• Thickening of the pituitary stalk is a nonspecific finding,
since some patients with this finding later develop a
germinoma or histiocytosis
• In children, progressive thickening of the stalk as determined by
serial MRIs is strongly suggestive of a germinoma.

• Anterior pituitary hormone deficiency, with decreased

release of growth hormone, thyroid stimulating hormone,
and adrenocorticotropic hormone , also may be present or
develop in patients with idiopathic CDI
Idiopathic Central DI
• However, some patients who develop an anterior pituitary
endocrinopathy years after the diagnosis of CDI may have
a pituitary or suprasellar tumor, suggesting that the initial
abnormality was due to an occult pathologic process.

• As an example, in one study of 16 patients first diagnosed

with idiopathic CDI, the detection of evolving gonadotropin
deficiency in three individuals resulted in the diagnosis of
pituitary or suprasellar germinomas 20, 6, and 3 years
after the initial presentation
• These data, if confirmed, suggest that such patients should
undergo regular endocrine follow-up.
Neurosurgery or trauma
• CDI can be induced by neurosurgery (usually
transsphenoidal) or trauma to the hypothalamus and
posterior pituitary
• The incidence of CDI in these patients varies with the
extent of injury, ranging from 10 to 20 percent after
transsphenoidal removal of an adenoma limited to the
sella to as high as 60 to 80 percent after removal of very
large tumors.
• A much lower rate of postoperative CDI has been reported
with minimally invasive endoscopic pituitary surgery (2.7
percent permanent and 13.6 percent transient)
Neurosurgery or trauma
• A serum sodium higher than 145 meq/L within the first five
days postoperatively had a high predictive value for
permanent DI development.

• In contrast, patients with a serum sodium less than

145 meq/L in the first five days postoperatively will rarely,
if ever, develop permanent DI, thereby validating short
postoperative inpatient stays with minimal risk of
readmission for DI management
Neurosurgery or trauma
• Craniopharyngioma has been associated with CDI both
before surgery and particularly after surgery
• A somewhat different response has been detected after
transfrontal surgery for a craniopharyngioma.
• In this setting, the polyuria appears to result in at least some
patients from the release of an ADH precursor from the
hypothalamus that competes for but does not activate ADH V2
receptors
• These patients initially have high serum immunoreactive ADH
concentrations, but their ADH has little or no biological activity and
they have diminished response to exogenous hormone
replacement.
• Thus, they behave as if they have nephrogenic DI (NDI), although
the polyuria is typically transient.
Neurosurgery or trauma
• Severe damage to the hypothalamus or tract by
neurosurgery or trauma often results in a
typical triphasic response
• Initial polyuric phase, beginning within 24 hours and lasting 4 to 5
days;
• Reflects inhibition of ADH release due to hypothalamic dysfunction
• Antidiuretic Phase: on days 6 to 11
• Stored hormone is slowly released from the degenerating posterior
pituitary.
• During this stage, excessive water intake can lead to hyponatremia
because of a transient syndrome of inappropriate ADH secretion
• Permanent DI may then ensue after the posterior pituitary stores
are depleted.
• Most cases are not permanent
Neurosurgery or trauma
• A study of 1571 patients with pituitary adenomas of all
types who underwent transsphenoidal surgery at the
same center provides insight into the relative frequency of
these different responses
• Among these patients, 30 percent had microadenomas and 70
percent macroadenomas.
• The key findings were:
• 31%- immediate postoperative polyuria
• 17%- polyuria on day three, and
• 6%- polyuria on day seven.
• Of these patients, 24 percent received one or more doses of ADH.
Neurosurgery or trauma
• Ctd
• After three months, only 0.9 percent were still receiving ADH or had
polyuria.
• 3.4 percent of patients had transient polyuria and then transient
hyponatremia.
• 1.1 percent had the triphasic pattern of polyuria, hyponatremia, and then
polyuria.
• 5.2 percent had only transient hyponatremia, either within one to three
days or five to ten days after surgery.
Neurosurgery or trauma
• Despite the relatively high frequency of CDI in patients
undergoing neurosurgery, most cases of polyuria in this
setting are not due to CDI
• More common causes are excretion of excess fluid administered
during surgery and/or an osmotic diuresis induced by mannitol or
glucocorticoids (which cause hyperglycemia and glucosuria) given
in an attempt to reduce cerebral edema.
• These conditions can be differentiated from CDI by measuring the
urine osmolality and the response to water restriction and the
administration of ADH.
Neurosurgery or trauma
• CDI after neurosurgery rarely occurs in combination with
cerebral salt-wasting.

• Depending upon the balance of the ensuing water and

solute (NaCl) diuresis, hyponatremia, normonatremia, or
hypernatremia may be present
Approach to DI
• Figure 404-4
• Simplified approach to the differential diagnosis
• of diabetes insipidus. When symptoms suggest diabetes insipidus
• (DI), the syndrome should be differentiated from a genitourinary (GU)
• abnormality by measuring the 24-h urine volume and osmolarity on
• unrestricted fluid intake. If DI is confirmed, basal plasma arginine vasopressin
• (AVP) should be measured on unrestricted fluid intake. If AVP is
• normal or elevated (>1 pg/mL), the patient probably has nephrogenic
• DI. However, if plasma AVP is low or undetectable, the patient has either
• pituitary DI or primary polydipsia. In that case, magnetic resonance
• imaging (MRI) of the brain can be performed to differentiate between
• these two conditions by determining whether or not the normal posterior
• pituitary bright spot is visible on T1-weighted midsagittal images.
• In addition, the MRI anatomy of the pituitary hypothalamic area can
• be examined to look for evidence of pathology that sometimes causes
• pituitary DI or the dipsogenic form of primary polydipsia. MRI is not reliable
• for differential diagnosis unless nephrogenic DI has been excluded
• because the bright spot is also absent, small, or faint in this condition.
Management of Nephrogenic DI
• The urine output in patients with nephrogenic DI can be
lowered with
1. A low salt, low protein diet,
2. Diuretics, and
3. Nonsteroidal antiinflammatory drugs (NSAIDs).
Management of Nephrogenic DI
• In infants, early recognition is of immediate clinical
significance because treatment can avert the physical and
mental retardation that results from repeated episodes of
dehydration and hypernatremia.

• In adults, the decision to undertake treatment must be

based upon the individual patient's intolerance of the
polyuria and polydipsia since, in almost all patients, the
thirst mechanism is sufficient to maintain the plasma
sodium in the high-normal range
Management of Nephrogenic DI
• Decreased dietary solute
• When the urine osmolality is fixed, as in nephrogenic DI, the urine
output is determined by solute excretion.
• Suppose that the maximum urine osmolality is 150 mosmol/kg.
• In this setting, the daily urine volume will be 5 liters if solute
excretion is in the normal range at 750mosmol/day, but only 3 liters
if solute excretion is lowered to 450 mosmol/day by dietary
modification.
• These observations provide the rationale for the use of a low salt,
low protein diet to diminish the urine output in nephrogenic DI
Management of Nephrogenic DI
• Decreased dietary solute
• The reduction in urine output will be directly proportional to the
decrease in solute intake and excretion

• Restriction of salt intake to ≤100 meq/day (2.3 g sodium) and

protein intake to ≤1.0 g/kg may be reasonable goals, but such diets
are not easy to achieve and maintain.

• Furthermore, protein restriction in infants and young children may

be harmful and is not advised.
Management of Nephrogenic DI
• Decreased dietary solute
• Although most children with nephrogenic DI are underweight and
relatively short during the first years of life, their height and weight
become progressively normal during school-age years

• These growth observations could be related in part to limited

caloric intake and decreased dietary solute during the first years of
life.
Management of Nephrogenic DI
• Diuretics
• Thiazide diuretics in combination with a low solute diet can
diminish the degree of polyuria in patients with nephrogenic DI

• The potassium-sparing diuretic amiloride also may be helpful, both

by its additive effect with the thiazide diuretic and, with reversible
lithium -induced disease, by possibly allowing lithium to be
continued.

• A thiazide diuretic (such as hydrochlorothiazide, 25 mg once or

twice daily) acts by inducing mild volume depletion.
• As little as a 1 to 1.5 kg weight loss can reduce the urine output by more
than 50 percent (eg, from 10 L/day to below 3.5 L/day in a study of
patients with nephrogenic DI on a severely sodium-restricted diet
[9 meq/day])
Management of Nephrogenic DI
• Diuretics
• This effect is presumably mediated by a hypovolemia-induced
increase in proximal sodium and water reabsorption, thereby
diminishing water delivery to the ADH-sensitive sites in the
collecting tubules and reducing the urine output.

• Diuretic therapy can lead to a variety of usually mild electrolyte

complications.

• The initial natriuresis and therefore the later antipolyuric response

can be enhanced by combination therapy with amiloride (or other
potassium-sparing diuretic)
• This regimen has an additional benefit, since amiloride partially blocks
the potassium wasting induced by the thiazide
Management of Nephrogenic DI
• Diuretics
• Amiloride may be particularly beneficial in patients with reversible
lithium nephrotoxicity, given its site and mechanism of action

• If amiloride is used, a small contraction of extracellular fluid volume

may ensue, and it may be necessary to decrease the dose of
lithium chronically administered and to measure plasma
concentrations at frequent intervals until a new steady state is
achieved.
Management of Nephrogenic DI
• Diuretics
• This drug (Amiloride) closes the sodium channels in the luminal
membrane of the collecting tubule cells
• These channels constitute the mechanism by which filtered lithium
normally enters these cells and then interferes with their response to
ADH
• The permeability for lithium of the epithelial sodium channel (ENaC) is
1.5- to twofold higher than that for sodium
• Whereas sodium is extruded from the interior of the cell to the blood
compartment by the sodium pump (Na-K-ATPase) located at the
basolateral membrane, lithium is a poor substrate for the sodium pump.
• As a consequence, toxic intracellular levels could build up quickly in all
cells expressing ENaC at their plasma membrane and exposed to
therapeutic concentrations of lithium (0.6 to 1.2 mmol/L)
• Glycogen synthase kinase 3 (GSK-3 beta) is inhibited by lithium and is
probably the common molecular target for the primary and secondary
toxic effects of lithium
Management of Nephrogenic DI
• Diuretics
• A loop diuretic, although also capable of inducing mild volume
depletion, is not as likely to lower the urine output in nephrogenic
DI.

• These agents decrease sodium chloride reabsorption in the

medullary thick ascending limb of the loop of Henle, thereby
decreasing the accumulation of NaCl in the medullary interstitium
that is essential for the production of a concentrated urine.

• Thus, a loop diuretic induces relative ADH resistance, an effect that

is counterproductive in nephrogenic DI
Management of Nephrogenic DI
• Nonsteroidal Antiinflammatory Drugs
• The efficacy of NSAIDs in this setting is dependent upon inhibition
of renal prostaglandin synthesis.

• In normal subjects, prostaglandins antagonize the action of ADH

and NSAIDs increase concentrating ability
• If, for example, normal subjects are given a submaximal dose of ADH,
the ensuing rise in urine osmolality can be increased by more than
200 mosmol/kg if the patient has been pretreated with a NSAID

• The net effect in patients with DI may be a 25 to 50 percent

reduction in urine output, a response that is partially additive to that
of a thiazide diuretic
Management of Nephrogenic DI
• NSAIDs
• This approach is particularly beneficial in patients with polyuria due
to complex congenital polyuric-polydipsic Bartter-like syndromes, in
whom prostaglandins appear to be pathogenetically important.

• Not all NSAIDs are equally effective in a given patient; as an

example, indomethacin appears to have a greater effect than
ibuprofen

• A variety of complications may ensue with long-term use of

NSAIDs.
Management of Nephrogenic DI
• Exogenous ADH
• Most patients with non-hereditary nephrogenic DI have partial
rather than complete resistance to ADH.

• It is therefore possible that attaining supraphysiologic hormone

levels will increase the renal effect of ADH to a clinically important
degree.

• In some patients with nephrogenic DI, exogenous ADH has been

found to increase the urine osmolality by 40 to 45 percent, an effect
that would be expected to produce a similar decline in urine volume
Management of Nephrogenic DI
• Exogenous ADH
• Thus, desmopressin (dDAVP) may be tried in patients who have
persistent symptomatic polyuria after implementation of the above
regimen.

• One case report of a patient with lithium -induced nephrogenic DI

suggested that benefit may be more likely if desmopressin is
combined with a NSAID
Management of Nephrogenic DI
• Experimental Approaches
• Most patients with congenital X-linked nephrogenic DI have
defective V2 vasopressin receptors that are unable to properly fold
intracellularly and, as a consequence, do not transfer to the cell
surface where the receptors could respond to circulating
vasopressin.

• Several new approaches to treatment of this disorder are being

investigated: V2 receptor chaperones and V2 receptor bypass
Management of Nephrogenic DI
• Experimental Approaches
• V2 receptor chaperones — In in vitro systems, the administration of selective,
cell permeable nonpeptide V2 and V1a
• receptor antagonists were able to rescue mutant V2 receptors, presumably
acting intracellularly to promote proper folding and maturation [ 28,29 ]. This
resulted in the expression of functional cell surface V2 receptors, suggesting that
such a therapeutic approach may be effective in patients.
• In a pilot study, a nonpeptide V1a receptor antagonist was administered to five
men with nephrogenic DI (each with one of three identified mutations in the
AVPR2 gene that codes for the V2 receptor) [ 29 ]. This resulted in an increase in
urine osmolality from a mean of 100 to 150 mosmol/kg, and reductions in urine
volume from 12 to 8 L/day and in water intake from 11 to 7 L/day. Nonpeptide V2
agonists have also been demonstrated experimentally to rescue misfolded
AVPR2 mutations responsible for X-linked nephrogenic DI [ 30,31 ].
• Most mutations in aquaporin-2 (the vasopressin-sensitive water channel) that are
associated with nephrogenic DI result in proteins being retained in the
intracellular space [ 32 ]. Research to find chaperone-like molecules to help
direct these proteins to the cell surface is ongoing [ 33 ].
Experimental approaches
• Experimental Approaches
• V2 receptor bypass — The antidiuretic activity of the V2 receptor is
mediated by the activation of a G protein signaling cascade that
leads to increased intracellular cyclic AMP and the trafficking of
aquaporin-2 to the cell membrane. The collecting duct also
expresses two prostaglandin E2 receptors (EP2 and EP4) that,
similar to the V2 receptor signalling cascade, can increase
intracellular cyclic AMP; prostaglandin E2 signalling through these
receptors increases the apical membrane abundance and
phosphorylation of aquaporin-2 [ 34 ].
• Thus, stimulation of prostaglandin E2 receptors EP2 and EP4 may
be a way of bypassing the need for V2 receptor signalling. In a
mouse model of X-linked nephrogenic DI, for example, ONO-AE1-
329, a selective agonist of the EP4 prostaglandin E2 receptor in the
collecting tubule cells, increased urine osmolality from 150 to
500 mosmol/kg H2O
Hypodipsic Hypernatremia
• Each line depicts schematically the relationship of plasma arginine vasopressin
(AVP) to plasma osmolarity during water loading and/or infusion of 3% saline in a
patient with either AH (open symbols) or SIAD (closed symbols).
• The shaded area indicates the normal range of the relationship.
• The horizontal broken line indicates the plasma AVP level below which the hormone
is undetectable and urinary concentration usually does not occur.
• Lines P and T represent patients with a selective deficiency in the osmoregulation of
thirst and AVP that is either partial or total
• In the latter, plasma AVP does not change
• in response to increases or decreases in plasma osmolarity but remains
• within a range sufficient to concentrate the urine even if overhydration
• produces hypotonic hyponatremia. In contrast, if the osmoregulatory
• deficiency is partial ( ), rehydration of the patient suppresses plasma
• AVP to levels that result in urinary dilution and polyuria before plasma
• osmolarity and sodium are reduced to normal. Lines a –d represent
• different defects in the osmoregulation of plasma AVP observed in
• patients with SIADH or SIAD
• In a ( ), plasma AVP is markedly elevated and fluctuates widely
without relation to changes in plasma osmolarity, indicating
complete loss of osmoregulation
• In b ( ), plasma AVP remains fixed at a slightly elevated level
until plasma osmolarity reaches the normal range, at which
point it begins to rise appropriately, indicating a selective
defect in the inhibitory component of the osmoregulatory
mechanism.
• In c ( ), plasma AVP rises in close correlation with plasma
osmolarity before the latter reaches the normal range,
indicating downward resetting of the osmostat.
• In d ( ), plasma AVP appears to be osmoregulated normally,
suggesting that the inappropriate antidiuresis is caused by
some other abnormality.
Hypodipsic Hyponatremia- Measures after initial
Rx
• Once the patient has been rehydrated, an MRI of the brain
and tests of anterior pituitary function should be performed to
look for the cause and collateral defects in other hypothalamic
functions.

• A long-term management plan to prevent or minimize

recurrence of the fluid and electrolyte imbalance also should
be developed. This should include
• A practical method to regulate fluid intake in accordance with variations
in water balance as indicated by changes in body weight or serum
sodium determined by home monitoring analyzers.
• Prescribing a constant fluid intake is ineffective and potentially
dangerous because it does not take into account the large, uncontrolled
variations in insensible loss that inevitably result from changes in
ambient temperature and physical activity
 Hyponatremia 2 to
o

Inappropriate Antidiuresis
Inappropriate Antidiuresis
• What is the mechanism of hyponatremia in cortisol
deficiency?

• Hyponatremia and hyperkalemia are the two major

electrolyte abnormalities of primary adrenal insufficiency.
Hyponatremia is mediated by increased release of
antidiuretic hormone (ADH) which results in water
retention and a reduction in the plasma sodium
concentration

• Both cortisol and aldosterone deficiency contribute to this

problem:
ADH with Cortisol deficiency
• The hypersecretion of ADH seen in cortisol deficiency
1. Reductions in systemic blood pressure and cardiac output
induced (via an unknown mechanism) by the lack of cortisol.
2. Cortisol deficiency results in increased hypothalamic secretion of
corticotropin releasing hormone (CRH), an ADH secretagogue
• May be a more important mechanism
• Cortisol feeds back negatively on CRH and ACTH, an inhibitory effect
that is removed with adrenal insufficiency
3. Cortisol appears to directly suppress ADH secretion
ADH with Aldosteron deficiency
• The hypersecretion of ADH induced by aldosterone
deficiency is caused by renal salt wasting with resultant
volume depletion.

• Hypovolemia increases ADH levels by reducing the

osmotic threshold for ADH release from the hypothalamus
and by increasing the magnitude of ADH release for a
given change in plasma osmolality
Inappropriate Antidiuresis- Etiology
• In SIADH, the inappropriate secretion of AVP can have
many different causes.
• They include
1. Ectopic production of AVP by lung cancer or other neoplasms
• The ectopic forms result from abnormal expression of the AVP-NPII
gene by primary or metastatic malignancies.
2. Eutopic release induced by various diseases or drugs
• The eutopic forms occur most often in patients with acute infections or
strokes but have also been associated with many other neurologic
diseases and injuries.
• The mechanisms by which these diseases interfere with osmotic
suppression of AVP are not known.
3. Exogenous administration of AVP, DDAVP, or large doses of
oxytocin
Management of Hyponatremia
• Differs depending on the type and the severity and
duration of symptoms.

• Acute symptomatic SIADH, the aim should be to raise

plasma osmolarity and/or plasma sodium at a rate
approximating 1% an hour until they reach levels of about
270 mosmol/L or 130 meq/L, respectively.

• This can be accomplished in either of two ways. (see next

slide)
Acute Hyponatremia ctd
1. Infusion of hypertonic (3%) saline at a rate of about 0.05
mL/kg body weight per minute.
• This treatment also has the advantage of correcting the sodium
deficiency that is partly responsible for the hyponatremia and often
produces a solute diuresis that serves to remove some of the
excess water.
2. The other treatment is to reduce body water by giving
an AVP receptor-2 antagonist (vaptan) to block the
antidiuretic effect of AVP and increase urine output
• One of the vaptans, a combined V2/V1a antagonist (Conivaptan),
has been approved for short-term, in-hospital IV treatment of
SIADH, and others are in various stages of development.
Acute Hyponatremia ctd
• With either approach, fluid intake should be restricted to
less than urine output, and serum sodium should be
checked at least once every 2h to ensure it is not raised
too fast or too far.

• Doing so may result in central pontine myelinolysis, an

acute, potentially fatal neurologic syndrome characterized
by quadriparesis, ataxia, and abnormal extraocular
movements.
Chronic Hyponatremia- Euvolemic
• Chronic and/or minimally symptomatic SIADH
• The hyponatremia can and should be corrected more gradually.
• This can be achieved by restricting total fluid intake to less than the
sum of urinary and insensible losses.
• Because the water derived from food (300–700 mL/d) usually
approximates basal insensible losses in adults, the aim should be
to reduce total discretionary intake (all liquids) to approximately
500 mL less than urinary output.
• Adherence to this regimen is often problematic and, even if
achieved, usually reduces body water and increases serum sodium
by only about 1–2% per day.
Chronic Hyponatremia- Euvolemic
• Chronic and/or minimally symptomatic SIADH ctd
• Hence, additional approaches are usually desirable if not
necessary.
• The best approach for treatment of chronic SIADH is the
administration of an oral vaptan, tolvaptan, a selective V2
antagonist that also increases urinary water excretion by blocking
the antidiuretic effect of AVP.
• Some restriction of fluid intake may also be necessary to achieve
satisfactory control of the hyponatremia.
• It is approved for treatment of nonemergent SIADH with initial
inhospital dosing.
Chronic Hyponatremia- Euvolemic
• Chronic and/or minimally symptomatic SIADH ctd
• Other approaches include
• Demeclocycline, 150–300 mg PO tid or qid, or
• Fludrocortisone, 0.05–0.2 mg PO bid.

• Demeclocycline
• The effect of the demeclocycline manifests in 7–14 days and is due to
induction of a reversible form of nephrogenic DI.

• Potential side effects include phototoxicity and azotemia

Chronic Hyponatremia- Euvolemic
• Chronic and/or minimally symptomatic SIADH ctd
• Fludrocortisone
• Effect also requires 1–2 weeks
• Partly due to increased retention of sodium and possibly inhibition of
thirst.
• It also increases urinary potassium excretion, which may require
replacement through dietary adjustments or supplements and may
induce hypertension, occasionally necessitating discontinuation of the
treatment.
Chronic Hyponatremia- Euvolemic
• For euvolemic hyponatremia caused by protracted nausea
and vomiting or isolated glucocorticoid deficiency (type
III), all abnormalities can be corrected quickly and
completely by giving
• An antiemetic or
• Stress doses of hydrocortisone (for glucocorticoid deficiency).

• As with other treatments, care must be taken to ensure

that serum sodium does not rise too quickly or too far.
Chronic Hyponatremia- Euvolemic
• SIAD due to an activating mutation of the V2 receptor, the
V2 antagonists usually do not block the antidiuresis or
raise plasma osmolarity/sodium.
• In that condition, use of an osmotic diuretic such as urea is
reported to be effective in preventing or correcting hyponatremia.

• However, some vaptans may be effective in patients with a different

type of activating mutation so the response to this therapy may be
neither predictable nor diagnostic
Chronic Hyponatremia- Hypervolemic
• Fluid restriction is also appropriate and somewhat
effective if it can be maintained.
• However infusion of hypertonic saline is contraindicated
because it further increases total body sodium and edema
and may precipitate cardiovascular decompensation.
• However, as in SIADH, the V2 receptor antagonists are
also safe and effective in the treatment of hypervolemic
hyponatremia caused by congestive heart failure.
• Tolvaptan is approved by the FDA for this indication with the caveat
that treatment should be initiated or reinitiated in hospital.
• Its use should also be limited to 30 days at a time because of
reports that longer periods may be associated with abnormal liver
chemistries.
Chronic Hyponatremia- Hypovolemic
• The defect in AVP secretion and water balance usually
can be corrected easily and quickly by stopping the loss of
sodium and water and/or replacing the deficits by mouth
or IV infusion of normal or hypertonic saline.
• As with the treatment of other forms of hyponatremia, care must be
taken to ensure that plasma sodium does not increase too rapidly
or too far.

• Fluid restriction and administration of AVP antagonists are

contraindicated in type II hyponatremia because they
would only aggravate the underlying volume depletion and
could result in hemodynamic collapse.
Thank You!