Hyponatremia And treatment with tolvaptan - PowerPoint PPT Presentation

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Hyponatremia And treatment with tolvaptan

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UZMA MEHDI, M.D, MS NEPHROLOGY 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. – PowerPoint PPT presentation

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Title: Hyponatremia And treatment with tolvaptan


1
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

3
Hyponatremia
  • Hyoponatremia
  • Approach to the pt.
  • AVP
  • Siadh
  • Treatment strategies of SIADH
  • Non-peptide AVP receptor antagonist
  • Salt Trial
  • Samsca

4
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).

5
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
6
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.

7
Approach to the pt with hyponatremia
  • Decreased serum osmolality --check volume
    status. It could be
  • Hypovolumeic,
  • Hypervolumeic or
  • Euvolumeic.

8
Approach to the patient with Hyponatremia
  • Hypovolumeic Hyponatremia (Dehydartion)
  • Decrease Sodium
  • Decrease water
  • Causes
  • Diarrhea
  • Diuretic use
  • Mineralcorticoid defeciency
  • Osmotic diuresis like mannitol

9
Approach to the patient with Hyponatremia
  • Hypervolumeic Hyponatremia
  • Sodium content unchanged
  • Increase water
  • Causes
  • Heart Failure
  • Cirrhosis
  • Nephrotic syndrome

10
Approach to the patient with Hyponatremia
  • Euvolumeic Hyponatremia
  • Sodium content unchanged
  • Relative increase in water
  • Cause
  • Syndrome of inappropriate diuretic
    hormone
  • (SIADH)

11
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

12
Arginine vasopressin( AVP)
aka Antidiuretic hormone (ADH)
  • Major hormone that controls the water balance
  • Release from pituitary glands
  • Three receptors
  • V1a
  • V1b
  • V2

13
AVP
Increase plasma osmolality
Decrease Intravascular volume
V1a receptors
V2 receptors
Regulate water reabsorption in kidney
Regulate vascular tone
14
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

15
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.

16
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
17
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
18
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

19
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.

20
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

21
Drugs induced Siadh
  • Common drugs
  • SSRIs
  • Ectasy
  • Carbamazepine
  • ddavp

22
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


23
Correcting hyponatremia
  • traditional approach
  • add to the
  • numerator
  • Serum sodium Total body sodium
  • Total
    body water

24
Correcting hyponatremia
  • Current approach
  • Serum sodium Total body sodium
  • Total
    body water
  • Subtract from the
  • the denominator

25
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.

26
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
27
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

28
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

29
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.

30
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)

31
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
32
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
33
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

34
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.

35
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

36
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
-
-
-
-
-
-
37
Results of SALT
38
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.

39
Results of SALT
40
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.

41
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.

42
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.

43
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.

44
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

45
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).

46
Promise of Vasopressin Antagonist
  • Management of hyponatremia
  • Prompt,
  • Reliable and
  • Controlled
  • Permits out pt management
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