HYPONATREMIA and its management

1
HYPONATREMIAand its management
2
Hyponatremia

• Definition
• Epidemiology
• Physiology
• Pathophysiology
• Types
• Clinical Manifestations
• Diagnosis
• Treatment

3
Hyponatremia

• Definition
• It is an electrolyte disturbance in which the
  sodium concentration in the plasma is lower than
  normal, specifically below 135 mEq/L.
• Hyponatremia represents a relative excess of
  water in relation to sodium.

4
Hyponatremia

• Epidemiology
• Frequency
• Hyponatremia is the most common electrolyte
  disorder
• Incidence of approximately 1
• Prevalence of approximately 2.5
• Surgical ward, approximately 4.4
• 30 of patients treated in the intensive care
  unit

5
Incidence of Hyponatremia

• Hyponatremia is a common electrolyte disorder
  occurring in up to 15 of hospitalized patients1
• Euvolemic hyponatremia, most often caused by
  SIADH, accounts for about 60 of all types of
  chronic hyponatremia1
• If not treated appropriately, hyponatremia may
  lead to significant morbidity and death2,3

1. Baylis PH. Int J Biochem Cell Biol.
   2003351495-1499.
2. Adrogué HJ. Am J Nephrol. 200525240-249.
3. Huda MSB et al. Postgrad Med J. 200682216-219.

6
Annual Cost of Hyponatremia in the United States

• Prevalence-based cost of illness study, including
  information from databases, published literature,
  and an expert physician panel
• Low and high scenarios were estimated and
  incorporated in a cost of illness model
• Results
• US prevalence for hyponatremia estimated at 3.2
  to 6.1 million persons annually
• Estimated 1 million hospitalizations annually
  with a principal or secondary diagnosis of
  hyponatremia
• 58-67 of patients had a longer length of stay
  due to symptomatic hyponatremia
• Direct costs estimated from 1.6 to 3.6 billion
  annually

Boscoe A et al. Cost Eff Resour Alloc.
200641-11.
7
Hyponatremia

• Epidemiology Cont.
• Mortality/Morbidity
• Acute hyponatremia (developing over 48 h or less)
  are subject to more severe degrees of cerebral
  edema
• sodium level is less than 105 mEq/L, the
  mortality is over 50
• Chronic hyponatremia (developing over more than
  48 h) experience milder degrees of cerebral edema
  
• Brainstem herniation has not been observed in
  patients with chronic hyponatremia

8
Hyponatremia

• Epidemiology Cont.
• Age
• Infants
• fed tap water in an effort to treat symptoms of
  gastroenteritis
• Infants fed dilute formula in attempt to ration
• Elderly patients with diminished sense of thirst,
  especially when physical infirmity limits
  independent access to food and drink

9
Hyponatremia

• Pathophysiology
• Hyponatremia can only occur when some condition
  impairs normal free water excretion
• Acute drop in the serum osmolality
• Neuronal cell swelling occurs due to the water
  shift from the extracellular space to the
  intracellular space
• Swelling of the brain cells elicits 2 responses
  for osmoregulation, as follows
• It inhibits ADH secretion and hypothalamic thirst
  center
• immediate cellular adaptation

10
Hyponatremia

• Types
• Hypovolemic hyponatremia
• Euvolemic hyponatremia
• Hypervolemic hyponatremia
• Redistributive hyponatremia
• Pseudohyponatremia

11
Hypovolemic hyponatremia

• Deficiencies in both TBW and total body Na exist,
  although proportionally more Na than water has
  been lost
• The Na deficit produces hypovolemia

12
Hypovolemic hyponatremia

• Develops as sodium and free water are lost and/or
  replaced by inappropriately hypotonic fluids
• Sodium can be lost through renal or non-renal
  routes

www.grouptrails.com/.../0-Beat-Dehydration.jpg
13
Hypovolemic hyponatremia

• Non-Renal loss
• GI losses
• Vomiting, Diarrhea, fistulas, pancreatitis
• Excessive sweating
• Third spacing of fluids
• Ascites, peritonitis, pancreatitis, and burns
• Cerebral salt-wasting syndrome
• Traumatic brain injury, aneurysmal subarachnoid
  hemorrhage, and intracranial surgery
• Must distinguish from SIADH

www.jupiterimages.com
14
Hypovolemic hyponatremia

• Renal Loss
• Diuretics
• Mineralocorticoid deficiency
• Osmotic diuresis (glucose, urea, mannitol)
• Salt-losing nephropathies (eg, intestitial
  nephritis, medullary cystic disease, partial
  urinary tract obstruction and polycystic kidney
  disease)

15
Euvolemic hyponatremia

• In euvolemic (dilutional) hyponatremia, total
  body Na and thus ECF volume are normal or
  near-normal however, TBW is increased
• In other words, it is increased TBW with
  near-normal total body Na

16
Euvolemic hyponatremia

• Causes
• Primary Polydispia, when water intake overwhelms
  the kidneys ability to excrete water
• Excessive water intake in the presence of
  Addisons disease, hypothyroidism or nonosmotic
  ADH release

17
Euvolemic hyponatremia

• Causes
• Certain drugs like
• Diuretics
• Barbiturates
• Carbamazepine
• Chlorpropamide
• Clofibrate
• Opioids

• Tolbutamide
• Vincristine
• Cyclophosphamide
• NSAIDs
• Oxytocin

18
Euvolemic hyponatremia

• Causes
• SIADH
• Downward resetting of the osmostat
• Pulmonary Disease
• Small cell, pneumonia, TB, sarcoidosis
• Cerebral Diseases
• CVA, Temporal arteritis, meningitis, encephalitis
• Medications
• SSRI, Antipsychotics, Opiates, Depakote, Tegratol

19
Hypervolemic hyponatremia

• Increased total body Na with a relatively greater
  increase in TBW
• Can be renal or non-renal
• Renal
• Acute kidney dysfunction
• Chronic kidney disease
• Nephrotic syndrome
• Non-Renal
• Cirrhosis
• Congestive heart failure

20
Redistributive hyponatremia

• Water shifts from the intracellular to the
  extracellular compartment, with a resultant
  dilution of sodium. The TBW and total body sodium
  are unchanged.
• This condition occurs with hyperglycemia
• Administration of mannitol

21
Hyponatremia

• Pseudohyponatremia
• Spurious hyponatremia or Factitious Hyponatremia
• In this, other substances expand the serum and
  dilute the sodium or a blood constituent leads to
  the creation of asodium-free phase in the blood
  thereby causing the blood plasma volume to be
  overestimated.

22
Hyponatremia

• Clinical Manifestations
• Most patients with a serum sodium concentration
  exceeding 125 mEq/L are asymptomatic
• Patients with acutely developing hyponatremia are
  typically symptomatic at a level of approximately
  120 mEq/L
• Most abnormal findings on physical examination
  are characteristically neurologic in origin
• Patients may exhibit signs of hypovolemia or
  hypervolemia

23
Hyponatremia

• Diagnosis
• CT head, EKG, CXR if symptomatic
• Repeat Na level
• Correct for hyperglycemia
• Laboratory tests provide important initial
  information in the differential diagnosis of
  hyponatremia
• Plasma osmolality
• Urine osmolality
• Urine sodium concentration
• Uric acid level
• FeNa

24
Hyponatremia

• Laboratory tests Cont.
• Plasma osmolality
• normally ranges from 275 to 290 mosmol/kg
• If gt290 mosmol/kg
• Hyperglycemia or administration of mannitol
• If 275 290 mosmol/kg
• hyperlipidemia or hyperproteinemia
• If lt275 mosmol/kg
• Eval volume status

25
Hyponatremia

• Laboratory tests Cont.
• Plasma osmolality lt 275 mosmol/kg
• Increased volume
• CHF, cirrhosis, nephrotic syndrome
• Euvolemic
• SIADH, hypothyroidism, psychogenic polydipsia,
  beer potomania, postoperative states
• Decreased volume
• GI loss, skin, 3rd spacing, diuretics

26
Hyponatremia

• Laboratory tests Cont.
• Urine osmolality
• Normal value is gt 100 mosmol/kg
• Normal to high
• Hyperlipidemia, hyperproteinemia, hyperglycemia,
  SIADH
• lt 100 mosmol/kg
• hypoosmolar hyponatremia
• Excessive sweating
• Burns
• Vomiting
• Diarrhea
• Urinary loss

27
Hyponatremia

• Laboratory tests Cont.
• Urine Sodium
• gt20 mEq/L
• SIADH, diuretics
• lt20 mEq/L
• cirrhosis, nephrosis, congestive heart failure,
  GI loss, skin, 3rd spacing, psychogenic
  polydipsya
• Uric Acid Level
• lt 4 mg/dl consider SIADH
• FeNa
• Help to determine pre-renal from renal causes

28
Diagnostic Algorithm for Hyponatremia
Assessment of volume status

• Hypervolemia
• Total body water ??
• Total body Na ?

• Euvolemia (no edema)
• Total body water ?
• Total body Na ?

• Hypovolemia
• Total body water ?
• Total body Na ??

UNa lt20 mEq/L
UNa gt20 mEq/L
UNa lt20 mEq/L
UNa gt20 mEq/L
UNagt20 mEq/L
Nephrotic syndrome Cirrhosis Cardiac failure
Glucocorticoid deficiency Hypothyroidism Syndrome
of inappropriate ADH secretion -
Drug-induced - Stress
Extrarenal losses Vomiting Diarrhea Third spacing
of fluids Burns Pancreatitis Trauma
Renal losses Diuretic excess Mineralocorticoid
deficiency Salt-losing deficiency Bicarbonaturia
with renal tubal acidosis and metabolic
alkalosis Ketonuria Osmotic diuresis
Acute or chronic renal failure
Legend ? increase ?? greater increase ?
decrease ?? greater decrease ? no change.
Adapted from Kumar S, Berl T. In Atlas of
Diseases of the Kidney. 19991.1-1.22.
29
Hyponatremia

• Treatment
• Four issues must be addressed
• Asyptomatic vs. symptomatic
• acute (within 48 hours)
• chronic (gt48 hours)
• Volume status
• 1st step is to calculate the total body water
• total body water (TBW) 0.6 body weight

30
Hyponatremia

• Treatment Cont.
• Next decide what our desired correction rate
  should be
• Symptomatic
• Immediate increase in serum Na level by 8 to 10
  meq/L in 4 to 6 hours with hypertonic saline is
  recommended
• Acute hyponatremia
• More rapid correction may be possible
• 8 to 10 meq/L in 4 to 8 hours
• Chronic hyponatremia
• slower rates of correction
• 12 meq/L in 24 hours

31
General Principles in the Treatment of Acute
Hyponatremia

• Neurologic consequences can follow both the
  failure to promptly treat as well as the
  excessively rapid rate of correction of
  hyponatremia
• Presence or absence of significant neurologic
  signs and symptoms must guide treatment
• Acuteness or chronicity of hyponatremia impacts
  the rate at which serum Na is corrected
• If drug-induced SIADH, discontinue the drug
• The half-life or offset of effect of the
  offending drug should be taken into consideration
• Frequent monitoring of serum Na is needed

Kumar S, Berl T. In Atlas of Diseases of the
Kidney. 19991.1-1.21 Adrogue HJ, Madias NE. N
Engl J Med. 20003421581-1589.
32
Traditional Treatments for Hyponatremia

• Acute
• Saline infusion
• isotonic
• hypertonic (caution ODS)
• Fluid restriction (slow effect)
• Furosemide NaCl (not in CHF)
• Chronic
• Demeclocycline
• Mineralocorticoids
• Lithium
• Urea

Cawley M. Ann Pharmacother 200741epub DOI
10.1345/aph.1H502
33
Ideal Therapy for Acute Hyponatremia

• Prompt but safe correction of Na in 24 to 48
  hr
• 12 mEq/L in the first 24 hr
• 18 mEq/L in the first 48 hr
• Produces increased water excretion without
  electrolyte excretion (Na and K) - AQUARESIS
• Eliminates or decreases need for fluid
  restriction
• Predictable and reliable action
• Quick onset/offset easily titratable
• No unexpected side effects/toxicities
• No drug/disease interactions
• Cost-effective data available

34
Hyponatremia

• Symptomatic or Acute
• Treatment Cont. - Here comes the Math!!!
• Estimate SNa change on the basis of the amount of
  Na in the infusate
• ?SNa Na Kinf - SNa (TBW 1)
• ?SNa is a change in SNa
• Na Kinf is infusate Na and K concentration in
  1 liter of solution

35
Rx of severe Hyponatremia

• Na deficit 0.6 X BW 120-Na
• Volume of 3 saline required Deficit/500
• To rise sodium 1 meq/L, we need 70cc hypertonic
  saline
• Rate of correction
• Acute (lt48 h) or symptomatic 1-2 meq/L/hr
• Chronic (gt48 h) or asymptomatic 0.5 meq/L/hr
• Do not exceed 12 meq/L rise on the first day

36
Rx of Hyponatremia

• Hypovolemia Isotonic Saline
• Polydipsia Water Restriction
• SIADH Water Restriction
• Furosemide
• Demeclocycline ( toxicity)
• V1 V2 R antagonist (Conivaptan)

37
Rx of Hyponatremia

• When choosing a solution to correct hyponatremia,
  aim for negative free water balance, i.e. the
  calculated osmolality of the urine 2X (UNaUK)
  should be lower than the chosen solutions
  Osmolality.
• IVF osmolality (2 X Na concentration in IVF)
• 3 saline 2 x 513 1026 mOsm/L
• NS 2 x 154 308 mOsm/L
• ½ NS 2 x 75 150
• ¼ NS 2 x 37.5 75

38
NS for Rx of Hyponatremia
A B (SIADH) C
UNa (meq/L) 100 90 80
UK (meq/L) 50 90 50
Calculated UOSM 2xUNaUK 300 360 260
? Na with 1 L NS (Osm300) 0 Desalination phenomenon
Free water balance 0 positive negative
39
Hyponatremia

• IV Fluids
• One liter of Lactated Ringer's Solution contains
• 130 mEq of sodium ion 130 mmol/L
• 109 mEq of chloride ion 109 mmol/L
• 28 mEq of lactate 28 mmol/L
• 4 mEq of potassium ion 4 mmol/L
• 3 mEq of calcium ion 1.5 mmol/L
• One liter of Normal Saline contains
• 154 mEq/L of Na and Cl-
• One liter of 3 saline contains
• 514 mEq/L of Na and Cl-

40
Hyponatremia

• Asymptomatic or Chronic
• SIADH
• Response to isotonic saline is different in the
  SIADH
• In hypovolemia both the sodium and water are
  retained
• Sodium handling is intact in SIADH
• Administered sodium will be excreted in the
  urine, while some of the water may be retained
• possible worsening the hyponatremia

41
Hyponatremia

• Asypmtomatic or Chronic
• SIADH
• Water restriction
• 0.5-1 liter/day
• Salt tablets
• Demeclocycline
• Inhibits the effects of ADH
• Onset of action may require up to one week

42
VASOPRESSIN RECEPTORS
43
Vasopressin Receptor Location Functions (KI
2006)
44
Vasopressin Receptor Antagonists
Tol-vaptan Lixi-Vaptan Sata-vaptan Coni-vaptan
Receptor V2 V2 V2 V1a/V2
Route of administration Oral Oral Oral IV
Urine Volume
UOSM
24 h Na excretion No ? No ? low Dose High Dose No ? No ?
SALT I and SALT II Trials.
45
Vasopressin Receptor Antagonists

• Conivaptan is the only FDA approved one for
• Hyponatremia due to SIADH and CHF
• V1aR antagonist can cause
• Splanchnic vasodilation and variceal bleeding in
  cirrhosis.
• Hypotension and decrease in PCWP
• V1aR blockade can potentially add to the effect
  of beta-adrenergic, RAS, and aldosterone blockade
  in CHF.
• PureV2R antagonists can theoretically be
  deleterious in CHF, as the V1aR remains unblocked
  in face of high ADH level.

46
CONIVAPTAN
47
Conivaptan

• 1,1 Biphenyl-2-carboxamide,N-4-(4,5-dihydro-2-
  methylimidazo4,5-d1benzazepin-6(1H)-yl)carbony
  lphenyl-,monohydrochloride

48
Conivaptan

• Mechanism of action
• Conivaptan inhibits AVP by competitively and
  reversibly binding to selected AVP receptors
  without interacting with the receptorss active
  sites.
• Because of higher affinity for V2, conivaptan is
  predominantly used for its V2-associated
  aquaretic effect.

49
Aquaresis

• Aquaresis is defined as the solute-free excretion
  of water by the kidney
• Because electrolytes represent a major component
  of urine solutes, aquaresis is also
  electrolyte-sparing
• Measured by increases in EWC and is calculated
  from the urine volume and from the plasma and
  urine Na and K
• Typically accompanied by increased urine output
  and reduced urine osmolality
• Distinguished from diuresis (increased urine
  output accompanied by electrolyte excretion)

EWCeffective water clearance. Vaprisol
(conivaptan hydrochloride injection). Prescribing
information. Deerfield, Ill Astellas Pharma US,
Inc. February 2007 Verbalis JG. J Mol
Endocrinol. 2002291-9.
50
Conivaptan

• Only vasopressin receptor antagonist available in
  the U.S.
• Non-selective (V2 V1a) potential for
  splanchnic vasodilatation w/ subsequent
  hypotension or variceal bleeding b/c of V1a
  effects (so not tested in cirrhotics)
• IV formulation only b/c of potent cyt P450 3A4
  inhibition if given orally (so used only for
  inpatients)
• Approved for euvolemic hyponatremia

51
Conivaptan J Clin Endo Metab 2006

• 74 euvolemic (74) or hypervolemic (26) patients
  gt/ 18 years w/ Na 115-130 mEq/l, FBG lt 275mg/dl,
  serum osm lt 290 mosm/kg H20, no volume depletion
• Excluded patients w/ uncontrolled htn or
  arrhythmias, hypotension, untreated thyroid
  abnormalities or adrenal insufficiency, CrCl lt 20
  ml/min, LFTs gt 5x normal, signs of liver disease,
  HIV, those requiring emergent treatment, those on
  meds that cause or treat SIADH
• RCT giving oral conivaptan, 40 or 80mg/d, or
  placebo, given in 2 divided doses x 5 days

52
Conivaptan J Clin Endo Metab 2006

• Fluid intake limited to 2L/24 hrs
• 1 outcome change from baseline in serum Na area
  under the curve
• Statistically significant change from baseline in
  serum Na AUC w/ both doses (achieved in a
  statistically significant shorter amount of time)
• AEs HA, hypotension, nausea, constipation
• Aquaretic effects persisted for at least 6hrs

53
Conivaptan hydrochloride injection

• Conivaptan is indicated for the treatment of
  euvolemic hyponatremia (eg, SIADH, or in the
  setting of hypothyroidism, adrenal insufficiency,
  pulmonary disorders, etc) in hospitalized
  patients
• Conivaptan is also indicated for the treatment of
  hypervolemic hyponatremia in hospitalized
  patients
• Not indicated for the treatment of congestive
  heart failure (effectiveness and safety have not
  been established in these patients)

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
54
Efficacy Endpoints in a Double-Blind Clinical
Trial

• 29 patients receiving 40 mg iv per day (euvolemic
  and hypervolemic)
• Fluid restriction 2 L or less per day
• Primary
• Change in serum Na from baseline during the
  treatment phase, as measured by the serum Na
  AUC (mEqhr/L)
• Secondary
• Time from first dose to a confirmed increase in
  serum Na 4 mEq/L from baseline
• Total time during the treatment phase that serum
  Na was 4 mEq/L above baseline
• Change in serum Na from baseline to end of
  treatment
• Number of patients achieving a confirmed increase
  in serum Na 6 mEq/L or a normal serum Na
  (135 mEq/L)

Astellas Pharma US, Inc. Data on file.
(087-CL-027 Clinical Study Report dated 22 Dec
2003).
55
Change From Baseline in Serum Na
Mean (SE) Change from Baseline in Serum Na
With Vaprisol 40 mg/d
10
VAPRISOL 40 mg/d Placebo
8
6
Change in Serum Na (mEq/L)
4
2
0
2
0
96
8
16
24
32
40
48
56
64
72
80
88
Time (hr)
56
Evidence of Aquaresis

• By day 4, Conivaptan produced a cumulative
  increase in EWC of more than 2900 mL, compared
  with approximately 1800 mL with placebo.

All values at hour 24 of study day. Vaprisol
(conivaptan hydrochloride injection). Prescribing
information. Deerfield, Ill Astellas Pharma US,
Inc. February 2007 Verbalis JG. J Mol
Endocrinol. 2002291-9.
57
Secondary Efficacy Outcomes in Open-Label Study
080
Conivaptan 20 mg/day n37 Conivaptan 20 mg/day n37 Conivaptan 40 mg/day n214
Number () of patients with ?4 mEq/L increase from baseline in serum Na Number () of patients with ?4 mEq/L increase from baseline in serum Na 29 (78) 178 (83)
Median time to ?4 mEq/L increase from baseline in serum Na, hr (95 CI) Median time to ?4 mEq/L increase from baseline in serum Na, hr (95 CI) 23.8 (12.0, 36.0) 24.0 (24.0, 35.8)
MeanSD total time from first dose to ?4 mEq/L increase in serum Na from baseline, hr MeanSD total time from first dose to ?4 mEq/L increase in serum Na from baseline, hr 60.635.2 59.533.2
MeanSD change in serum Na from baseline, mEq/L End of treatment Follow-up day 11 Follow-up day 34 MeanSD change in serum Na from baseline, mEq/L End of treatment Follow-up day 11 Follow-up day 34 9.45.32 7.18.2 11.57.3 8.85.43 8.06.510.76.7
Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
58
Secondary Efficacy Outcomes in Patients With
Hypervolemic Hyponatremia
Placebo n8 Conivaptan 20 mg/day n14 Conivaptan 40 mg/day n66
Number () of patients with ?4 mEq/L increase from baseline in serum Na 1 (12.5) 9 (64.3) 53 (80.3)
Median time to confirmed ?4 mEq/L increase from baseline in serum Na, hr (95 CI) NE 58.5 (NE) 24.1 (23.8, 37.2)
MeanSD from first dose to ?4 mEq/L increase in serum Na from baseline, hr 3.610.3 42.936.2 54.935.6
MeanSD change in serum Na from baseline, mEq/L 0.83.3 7.14.8 7.45.4
Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
59
Safety and Efficacy of Conivaptan in
Hypervolemic Hyponatremia

• 62 of patients had CHF
• IV conivaptan 20, 40, and 80 mg/d
• Time to serum Na gt 4 mEq/L was 24 hr (40 mg)
• Overall change in serum Na 7.4 4.8 mEq/L
• ADEs infusion-site reactions, hypokalemia,
  vomiting, hypotension

Goldsmith S et al ACC 2007
60
Overview of Pharmacokinetics

• Nonlinear pharmacokinetics
• Conivaptans inhibition of its own metabolism
  seems to be the major factor for nonlinearity
• High intersubject variability in clearance (94
  CV)
• Pharmacokinetics in healthy subjects receiving
  20-mg loading dose of conivaptan followed by a
  40-mg/d infusion for 3 days, the mean clearance
  was 15.2 L/hr, and the mean t1/2 was 5 hours
• In patients with hyponatremia receiving 20-mg
  loading dose of conivaptan followed by a 40-mg/d
  infusion for 4 days, the median clearance was
  9.5 L/hr, and the median t1/2 was 8.6 hours

CVcoefficient of variation t1/2terminal
elimination half-life.
Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
61
Distribution, Metabolism, and Excretion

• Conivaptan is extensively bound to human plasma
  proteins (99)
• Cmax 30 mins t1/2 5 hours
• Mass balance study
• 83 of dose was excreted in feces, 12 in urine
• During the first 24 hours after dosing, about 1
  of IV dose was excreted in urine as intact
  conivaptan
• Conivaptan is a substrate and potent inhibitor of
  CYP3A4. The coadministration of conivaptan with
  potent CYP3A4 inhibitors such as ketoconazole,
  itraconazole, clarithromycin, ritonavir, and
  indinavir is contraindicated
• CYP3A4 is the sole isoenzyme responsible for
  metabolism of conivaptan

CYPcytochrome P450. Vaprisol (conivaptan
hydrochloride injection). Prescribing
information. Deerfield, Ill Astellas Pharma US,
Inc. February 2006.
62
Pharmacokinetics in Hepatic and Renal Impairment
and in Geriatric patients

• Use with caution in both populations
• Little data are available

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
63
Precautions Drug Interactions

• Conivaptan is a substrate of CYP3A4, and
  coadministration of conivaptan and CYP3A4
  inhibitors could lead to an increase in
  conivaptan concentration
• Concomitant use of conivaptan and potent CYP3A4
  inhibitors such as ketoconazole, itraconazole,
  clarithromycin, ritonavir, or indinavir is
  contraindicated
• Conivaptan is a potent inhibitor of CYP3A4, and
  conivaptan may increase plasma concentrations of
  coadministered with drugs that are primarily
  metabolized by this isoenzyme

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
64
Preparation Guidelines

• Conivaptan should be diluted only with 5
  Dextrose Injection
• Conivaptan should not be mixed or administered
  with Lactated Ringers Injection or 0.9 Sodium
  Chloride Injection
• Once conivaptan is added to the infusion bag,
  gently invert the bag several times to ensure
  complete mixing
• Compatibility of conivaptan with other drugs has
  not been studied

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
65
Propylene Glycol

• Propylene glycol is an inactive ingredient used
  in the formulation of Vaprisol
• Propylene glycol is an FDA-approved acceptable
  ingredient in food and drug products
• Potency and administration methods vary among
  products
• Maximum potency limits apply

66
Where Does Conivapan Fit?

• No safety issues with the entire vasopressin
  receptor antagonist class
• Infusion-site reactions with infusion
• Do not use in hypovolemic patient
• No data in severe hyponatremia (seizure patient)
• Evolving story in CHF patients
• One dosing approach Administer conivaptan 20 mg
  IV over 30 minutes, check serum Na in 4-6 hours,
  along with urine output, and determine if further
  therapy is needed

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Summary

• Euvolemic and hypervolemic hyponatremia is a
  common electrolyte abnormality
• The neurohormone arginine vasopressin plays a key
  role in salt and water balance
• Treat the primary condition first (i.e.,
  drug-induced, acute heart failure)
• Conivaptan blocks the V2 receptors in the
  collecting ducts of the kidneys, it gets rid of
  what patients have in excessH2O
• The role of conivaptan in the overall management
  of euvolemic and hypervolemic patient with
  hyponatremia is evolving
• Clinical and economic outcomes data are needed