Hyponatremia And treatment with tolvaptan

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Hyponatremia And treatment with tolvaptan

• UZMA MEHDI, M.D, MS
• NEPHROLOGY

2
Case

• Patient presentation in ER
• 68-year-old female smoker
• Malaise
• Poor appetite
• Mild neurologic symptoms
• Physical Exam
• 130/75 mmHg, 88, no orthostatic changes.
• Lab results
• serum Na 124, K 3.2, Cl 94, Hco3
  26 Bun 16, Creatinine 0.6
• Posm249, Uosm415 UNa 48, uric
  acid 1.8,
• Normal thyroid function test and am
  cortisol level.
• Diagnostic imaging
• CT scan showed right lung nodule
• Diagnosis
• Hyponatremia
• SIADH secondary to lung mass

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Hyponatremia

• Hyoponatremia
• Approach to the pt.
• AVP
• Siadh
• Treatment strategies of SIADH
• Non-peptide AVP receptor antagonist
• Salt Trial
• Samsca

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Hyponatremia

• Hyponatremia defines as serum sodium
  concentration lt135meq/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.
• (Arief at al 1976 Terian et al 1994 Borroni et
  al 2000 Lee et al 2000, Bennani et al 2003
  Goldberg et al 2004 Ruf et la 2005).

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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
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Approach to the patient with Hyponatremia

• Check serum osmolality.
• increased or decreased.
• Increased osmolality-----
• ---mannitol, glyceine or hyperglycemia
• ---movement of water from ICF to ECF
  compartment. It causes translocational
  hyponatremia.
• Decreased osmolality can be due to other causes.

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Approach to the pt with hyponatremia

• Decreased serum osmolality --check volume
  status. It could be
• Hypovolumeic,
• Hypervolumeic or
• Euvolumeic.

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Approach to the patient with Hyponatremia

• Hypovolumeic Hyponatremia (Dehydartion)
• Decrease Sodium
• Decrease water
• Causes
• Diarrhea
• Diuretic use
• Mineralcorticoid defeciency
• Osmotic diuresis like mannitol

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Approach to the patient with Hyponatremia

• Hypervolumeic Hyponatremia
• Sodium content unchanged
• Increase water
• Causes
• Heart Failure
• Cirrhosis
• Nephrotic syndrome

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Approach to the patient with Hyponatremia

• Euvolumeic Hyponatremia
• Sodium content unchanged
• Relative increase in water
• Cause
• Syndrome of inappropriate diuretic
  hormone
• (SIADH)

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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

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Arginine vasopressin( AVP)
aka Antidiuretic hormone (ADH)

• Major hormone that controls the water balance
• Release from pituitary glands
• Three receptors
• V1a
• V1b
• V2

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

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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.

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Collecting duct Cell
Luminal surface
Basolateral surface
Aquaporin 3
Recycling vesicles for AQP-2
ADH
Without ADH collecting duct is impermeable to
water.
V2 repceptors fpr ADH
Aquaporin 4
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Collecting duct cell
Luminal surface
Basolateral surface
Aquaporin 3
AQP-2
V2 repceptors for ADH
In Presence of ADH collecting duct is permeable
to water.
ADH
Aquaporin 4
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SIADH

• Inappropriate release of ADH causes siadh.
• It is diagnosed by checking
• Serum sodium lt135
• Serum osmolality lt280
• Urine osmolality gt100
• Urine sodium gt30
• also low serum uric acid lt4.0

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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.

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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

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Drugs induced Siadh

• Common drugs
• SSRIs
• Ectasy
• Carbamazepine
• ddavp

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Clinical manifestation of siadh

• Acute (lt48 hours)
• Stupor/coma
• Convulsions
  Treatment with
• Respiratory arrest 3 NaCl
• Chronic (gt48 hours)
• Headache
• Irritability
  Treat with medicines
• Nausea vomiting like
  Vaptans
• Confusion Disorientation
• Gait disturbance

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Correcting hyponatremia

• traditional approach
• add to the
• numerator
• Serum sodium Total body sodium
• Total
  body water

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Correcting hyponatremia

• Current approach
• Serum sodium Total body sodium
• Total
  body water
• Subtract from the
• the denominator

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Treatment strategies for Acute hyponatremic
emergencies

• 3 NaCl 100ml bolus for severe symptoms.
• 3 NaCl_at_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.

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Treatment strategies for chronic hyponatremia
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
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Rate of correction

• Acute symptomatic
• 4 to 6 mEq/L in first 4 hours
• Target lt12 mEq/L in first 24 hours.
• Chronic
• Target correction at lt8 mEq/L in first
  24 hours
• Goal not to exceed
• 12 mEq/L in first 24 hr
• 18 mEq/L in first 48 hr

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Importance of appropriate serum sodium
correction

• Too-rapid correction of hyponatremia (e.g., gt12
  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

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The ideal therapy

• Water excretion without electrolyte excretion
• (Na and K) Aquresis.
• Prompt but safe correction in 24-48 hours
• lt12mEq/L in first 24 hr
• lt 18mEq/L in first 48 hr
• Eliminates fluid restriction.
• Predictable and reliable action
• Sustained effect and titratable
• No unexpected side effects/toxicities.

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Non-peptide AVP receptor antagonist (Vaptans)

• Aquaretic nonpeptide arginine vasopressin
  receptor (AVPR) antagonists are safe and
  effective hyponatremia therapies.
• Varbalis,JG at al, Hyponatremia treatment gui
  delines 2007, Am J of Med, 2007 Nov120(11 Suppl
  1)S1-21
• Vaptans lead to aquaresis, an electrolyte-sparing
  excretion of free water, that results in the
  correction of serum sodium concentration.
• Vasopressin antagonists in treatment of
  hyponatremia Olszewski,W Pol Arch MED Wewn,
  2007 Aug117(8)

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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
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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
Not available in United states
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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 lt135 without neurological symptoms.
• R.W.Schrier et al Tolvaptan,a selective
  oral vasopressin v2 receptor antagonist, for
  hyponatremia. New Eng JM, vol 355, no 20.Nov
  16,2006

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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.

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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

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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
-
-
-
-
-
-
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Results of SALT
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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.

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Results of SALT
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SALT Trial

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

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Results of SALT

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

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Results of SALT

• Significant effect on fluid balance
• With SAMSCA, urine output is greater than
  fluid intake, which results in a net negative
  fluid balance.

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Samsca

• SAMSCA is indicated for the treatment of
  clinically significant hypervolemic and euvolemic
  hyponatremia (serum sodium lt125 mEq/L ) in heart
  failure, cirrhosis, and SIADH.
• It is available in 15mg, 30mg and 60mg tablets.

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Samsca

• SAMSCA 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

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Samsca

• SAMSCA 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., gt12
  mEq/L/24 hours) can cause serious neurologic
  sequel, including osmotic demyelination syndrome
  (ODS).

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Promise of Vasopressin Antagonist

• Management of hyponatremia
• Prompt,
• Reliable and
• Controlled
• Permits out pt management