CONIVAPTAN

HYPONATREMIA
The etymology of the word hyponatremia includes the
Greek: hypo, meaning -low, deficient, less than normal.
Latin natrium meaning - sodium (Na+)
Greek hamia meaning -blood.
It is a metabolic condition in which there is not enough sodium (salt) in the
body fluids outside the cells.


Mostrys medical dictionary 8
th
edition 2009
Skorecki K, Ausiello D. Disorders of sodium and water homeostasis. In: Goldman L, Ausiello D, eds.Cecil Medicine.
23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 117.
HYPONATREMIA
DEFINITION
Hyponatremia is defined as a serum sodium concentration of less than
135mEq/L.
The serum sodium concentration in humans is normally between 135 and 144
mEq/L.
Hyponatremia implies a relative excess of total body water to sodium.
Seen in a variety of medical conditions - CHF, liver disease, SIADH, and as a
result of medications (e.g., thiazide diuretics, psychotropic agents, and
chemotherapeutic agents).

Verbalis JG. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007; 120(suppl
11A):S1-S21.
EPIDEMIOLOGY OF HYPONATREMIA
Hyponatremia is the most common electrolyte
abnormality seen in clinical practice.
In fact, over 33% of hospitalized patients
develop the condition.
It is most commonly seen in the elderly, ICU
and post operative patients, and in individuals
with intracranial disorders.
Many cases develop due to too much IV fluid
intake in the hospital setting.
Additionally, this disorder is seen in excessive
endurance aerobic exercise, such as marathon
running. (>13% of marathon runners.)
Hoorn EJ.Nephrol Dial Transplant. 2006 Jan;21(1):70-6.
HYPONATREMIA MORTALITY
The mortality with hyponatremia is dependant on the severity of the
condition.
The risk of death during hospitalization is increased by more than 50% in
patients admitted with hyponatremia compared with normonatremia.
Post operative fatality rates in individuals who develop hyponatremia can be
as much as 11%.
It is important to note that the majority of the fatalities in hyponatremia are a
result of misdiagnosis or lack of diagnosis at the clinical setting.

.
Sushrut Waikar. Am J Med. 2009 September; 122(9): 857865.

Martin RJ. J Neurol Neurosurg Psychiatry. 2004 Sep;75 Suppl 3:iii22-8.
TYPES OF HYPONATREMIA
Classified into one of three main categories:
Euvolemic hyponatremia
Total body water increases, but the
body's sodium content stays the
same.
Hypervolemic hyponatremia
Both sodium and water content in the
body increase, but the water gain is
greater.
Hypovolemic hyponatremia
Water and sodium are both lost from
the body, but the sodium loss is
greater.

Classified as dilutional (Euvolemic or
Hypervolemic), resulting from retained
water, or depletional (Hypovolemic)
resulting from sodium losses in excess of
water.
Dilutional hyponatremia is often
associated with excessive secretion of
arginine vasopressin
Depletional is generally due to renal or
extra renal losses of sodium and water.
Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl
3):S4-S12
WATER AND SODIUM
HOMEOSTASIS
Knoers NVAM.. N Engl J Med. 2005; 352(18):1847-1850.
Total body sodium is primarily extracellular, and any increase results in increased
tonicity, which stimulates the thirst center and arginine vasopressin secretion.
Thirst is stimulated by an increase in osmolality or decrease in extracellular fluid volume
or blood pressure.
Arginine vasopressin then acts on the V2 receptors in the renal tubules, causing increased
water reabsorption.
The opposite occurs with decreased extracellular sodium: a decrease inhibits the thirst
center and arginine vasopressin secretion, resulting in diuresis.
In most cases, hyponatremia results when the elimination of total body water decreases.
Knoers NVAM.. N Engl J Med. 2005; 352(18):1847-1850
Plasma osmolality, a major determinant of total body water homeostasis, is
measured by the number of solute particles present in 1 kg of plasma.
It is calculated in mmol per L by using this formula:
2 [sodium] + [urea] + [glucose]
BODY WATER BALANCE
Role of the kidneys in water balance
SODIUM BALANCE: INTAKE & EXCRETION
Sodium is regulated by aldosterone from the adrenal cortex.
Aldosterone is actually secreted in response to blood pressure, blood volume
and OsM.
More aldosterone: more sodium reabsorption.
Aldosterone target: principal cell (P cell) of the distal tubule & collecting duct.
Vasopressin is synthesized in the
neurosecretory cells of the supraoptic
and paraventricular nuclei of the
hypothalamus and stored in the
posterior pituitary gland.
The neurosecretory cells that arise in
the hypothalamus project to the
posterior pituitary gland, where AVP
is initially stored and then released into
the circulation.
FORMATION OF WATER PORES:
MECHANISM OF VASOPRESSIN ACTION
TYPES OF HYPONATREMIA
Hypervolemic hyponatremia
Euvolemic hyponatremia
Hypovolemic hyponatremia

J R Coll Physicians Edinb 2009; 39:1547
HYPONATRAEMIA- PATHOPHYSIOLOGY
Most total body sodium is extracellular and thus is a primary
determinant of plasma tonicity.
An increase in plasma tonicity stimulates the thirst center to increase
fluid consumption and causes release of Vasopressin (Anti- Diuretic
Hormone)
HYPONATRAEMIA-PATHOPHYSIOLOGY
Vasopressin, also known as antidiuretic hormone, is a peptide
hormone produced by the hypothalamus and transported via axons to
the posterior pituitary & released.
AVP receptor activation causes a decrease in excretion of free water.
The clinical manifestations of hyponatremia are largely due to osmotic
swelling of brain cells, resulting in neurologic and systemic symptoms

R u d o l p h e t a l : H y p o n a t r e m i a : January 2009; p p . 2 3 3 2 , 4 8
HYPOVOLAEMIC HYPONATREMIA
Characterised by clinical and biochemical evidence of dehydration
Best treated by intravenous sodium chloride solution.

Presents with fluid overload
Usually requires
Diuretic therapy
Vasopressin antagonist

Traditionally treated with fluid restriction,
Although the new vasopressin antagonists, the vaptans, show great
potential for future therapy.


J R Coll Physicians Edinb 2009; 39:1547
HYPERVOLAEMIC HYPONATRAEMIA
EUVOLAEMIC HYPONATRAEMIA
VASOPRESSIN RECEPTOR LOCATION &
FUNCTIONS (KI 2006)
Receptor
Newer
Name
Location Function
V1A V1
Vascular smooth muscle cells,
hepatocytes, platelets, uterus,
renal, adrenal and brain cells.
Vasoconstriction, myocardial
hypertrophy, platelet aggregation,
glycogenolysis, uterine contraction.
V1B V3 Anterior pituitary gland Releases ACTH, endorphins.

V2

V2
Basolateral membrane of
collecting ducts of kidney,
vascular endothelium,
vascular smooth muscle cells.
Mediate free water absorption by
mobilizing intracellular vesicles of
aquaporin-2 (AQP2) to the apical
plasma membrane of collecting duct
cells, causing an increase in water
permeability and anti-diuretic effect.
CONIVAPTAN- INTRODUCTION
Only approved VRA for the treatment of hypervolemic and
euvolemic hyponatremia
Vasopressin V2 receptor antagonist
Promote aquaresis, a term used to describe the excretion of
electrolyte-free water without sodium or potassium excretion.
Commonly referred to as vaptans or aquaretics to contrast
their effects with diuretics.

Kidney International (2006) 69, 2124-2130
CONIVAPTAN- MECHANISM OF ACTION
Vasopressin binds to membrane
receptor
Receptors activate c-AMP system
Cell inserts AQP2 water pores into
apical membrane
Water is absorbed by osmosis into
the blood
CONIVAPTAN USES
Euvolemic or hypervolemic hyponatremia
SIADH (euvolemic hyponatremia)
CHF (Hypervolemic hyponatremia )
Cirrhosis (Hypervolemic hyponatremia )
Unapproved uses (under trials)
Nephrogenic DI
Poly Cystic Kidney Disease


Kidney International (2006) 69, 2124-2130
ADVANTAGES OVER CONVENTIONAL THERAPIES
The conventional therapies are
Slow and of low efficiency (fluid restriction, urea,
demeclocycline, lithium),
Unreliable (fluid restriction, demeclocycline, lithium),
Cumbersome (3% NaCl, loop diuretic)

ADVANTAGES OVER CONVENTIONAL
THERAPIES
Treatment Limitations
Fluid restriction

Unreliable, poor patient adherence, takes long time to act
Urea
Hypersensitivity, Unsafe in pregnancy, Azotemia, Liver failure
Can reduce effects of lithium,
Phlebitis, thrombosis.
Demeclocycline
Low potency, nephrotoxic (rarely)
Lithium

Inconsistent results, Lithium toxicity, Anti-anabolic effects,
mainly in cirrhosis and congestive heart failure, Unsafe in
pregnancy.
Diuretics

Hypersensitivity, Hepatic coma, Anuria, Severe electrolyte,
depletion
ADVANTAGES OVER CONVENTIONAL
THERAPIES
Unlike diuretics, Conivaptan does not significantly affect urinary
sodium or potassium excretion
No need for fluid restriction and the correction of hyponatremia can
be achieved comfortably and within a short time
Better efficiency and reliability




CONIVAPTAN: PHARMACOKINETICS
Jalal K Ghali, Conivaptan and its role in the treatment of hyponatremia. Drug Des Devel Ther. 2009; 3: 253268.Published
online 2009 December 29. PMCID: PMC2802125
Parameter Drug
C
max
(at 0.5 h)
619 ng/mL median, healthy males (20 mg loading dose/20
mg/day)
T
max
30 min (end of iv loading dose)
V
d
32L
t

Variable (secondary to nonlinear kinetics)

Protein binding 99%
Metabolism
CYP3A4 (substrate and potent inhibitor); 4 active metabolites
identified with minimal clinical effect
Elimination
Eliminated primarily as metabolites (<1% recovered intact
drug in urine) 83% feces, 12% urine
Mean clearance 15.2 L/h
Bioavailability 44% absorption with oral conivaptan formulation
DOSAGE AND ADMINISTRATION
Conivaptan is for intravenous use only.
Initiate with a loading dose of 20 mg IV administered over 30 minutes.
Follow the loading dose with 20 mg of conivaptan administered in a
continuous intravenous infusion over 24 hours. After the initial day of
treatment, administer conivaptan for an additional 1 to 3 days in a
continuous infusion of 20 mg/day.
If serum sodium is not rising at the desired rate, conivaptan may
be titrated upward to a dose of 40 mg daily, administered in a
continuous intravenous infusion.
The total duration of infusion of conivaptan (after the loading
dose) should not exceed four days.
The maximum daily dose of conivaptan (after the loading dose)
is 40 mg/day.

CONTRAINDICATIONS
Hypovolemic Hyponatremia
Coadministration with Potent CYP3A Inhibitors
Anuric Patients
Known Allergy to Corn or Corn Products



ADVERSE REACTIONS
Most common are -
Infusion site reactions (ISRs)
Headache
Hypotension
Nausea
Constipation and
postural hypotension.
CLINICAL TRIALS
Conivaptan (Vaprisol) is an antagonist of arginine vasopressin receptors V1A
and V2 (10-fold higher affinity to V2 than V1A) that produces a water diuresis,
with electrolyte-sparing effects on the kidney. It is labeled for the treatment of
euvolemic and hypervolemic hyponatremia in hospitalized patients.
Conivaptan causes few serious problems when used in appropriate patients. It
is contraindicated in patients with hypovolemic hyponatremia because it will
cause an increase in free water excretion and may exacerbate the patient's
existing hypovolemic condition.
Some of the most commonly reported adverse reactions are infusion related
(22%), including erythema, phlebitis, and pain at the site of injection; however,
few patients will need to discontinue treatment because of these adverse
effects. Additionally, transient minor hypotension is common with conivaptan
infusion. This adverse reaction is tolerable and is likely the result of water loss.
No other significant hemodynamic effects have been reported. Some patients (9
percent) will develop overly rapid correction of serum sodium levels. There are
no reported cases of neurologic sequelae
Kristine willett, Conivaptan (Vaprisol) for the Treatment of Hyponatremia. American family physician 2008 Oct
15;78(8):984-989
AUTHOR/ REFERENCE STUDY NAME SUMMARY
Goldsmith SR, Gilbertson
DT, Mackedanz SA, Swan SK.
2011 Dec;17(12):982-9. doi:
10.1016/j.cardfail.2011.08.012.
Epub 2011 Oct 6.
Renal effects of conivaptan,
furosemide, and the
combination in patients with
chronic heart failure.
Without adversely affecting important hemodynamic
variables, neurohormones, renal blood flow, or glomerular
filtration rate, Conivaptan significantly augmented both the
diuretic and the natriuretic response to furosemide in patients
with chronic HF
Koren MJ, Hamad A, Klasen
S, Abeyratne A, McNutt
BE, Kalra S. 2011 May
1;68(9):818-27. doi:
10.2146/ajhp100260
Efficacy and safety of 30-minute
infusions of conivaptan in
euvolemic and hypervolemic
hyponatremia.
Conivaptan hydrochloride 20 mg, administered once or twice
daily via 30-minute i.v. infusion, significantly increased SSCs
over 48 hours in patients with euvolemic or hypervolemic
hyponatremia when compared with placebo. Common AEs
were similar to those seen with
continuous Conivaptan infusions.
Kalra S, Efrati S, Arthur
JM, Oliven A, Velez JC, McNutt
BE, Klasen S, Abeyratne A. 2011
Apr 1;68(7):590-8. doi:
10.2146/ajhp100243.
Effect of loading dose and
formulation on safety and
efficacy of conivaptan in
treatment of euvolemic and
hypervolemic hyponatremia.
Intravenous Conivaptan regimens with or without a loading
dose, whether using the ampul or a premixed formulation, had
similar safety, tolerability, and efficacy in patients with
euvolemic or hypervolemic hyponatremia. The pre-mixed
formulation used with a loading dose may be associated with
an increased frequency of overly rapid increase in SSC
compared with the other regimens studied.
Mao ZL, Stalker D, Keirns J. 2009
Jul;31(7):1542-50. doi:
10.1016/j.clinthera.2009.07.011.
Pharmacokinetics
of conivaptan hydrochloride, a
vasopressin V(1A)/V(2)-
receptor antagonist, in patients
with euvolemic or
hypervolemic hyponatremia
and with or without congestive
heart failure from a prospective,
4-day open-label study.
The results of this study suggest that the pharmacokinetics
of conivaptan 20 and 40 mg/d do not differ by volume status
or the presence or absence of congestive heart failure.
AUTHOR/ REFERENCE STUDY NAME SUMMARY
Annane D, Decaux G, Smith N. 2009
Jan;337(1):28-36. doi:
10.1097/MAJ.0b013e31817b8148
Efficacy and safety of oral conivaptan, a
vasopressin-receptor antagonist, evaluated
in a randomized, controlled trial in
patients with euvolemic or hypervolemic
hyponatremia.
Oral conivaptan was effective in increasing
serum [Na] in patients with euvolemic or
hypervolemic hyponatremia and had a
favorable safety profile.
Goldsmith SR, Elkayam U, Haught
WH, Barve A, He W.
Efficacy and safety of the vasopressin
V1A/V2-receptor antagonist conivaptan in
acute decompensated heart failure: a dose-
ranging pilot study.
When added to standard therapy for
ADHF, conivaptan safely improves urine
output. Further study of this compound in
ADHF may be warranted, especially in
view of the limitations of current treatment
for this syndrome.
Verbalis JG, Zeltser D, Smith N, Barve
A, Andoh M. 2008 Jul;69(1):159-68. Epub
2008 Jul 1
Assessment of the efficacy and safety of
intravenous Conivaptan in patients with
euvolaemic hyponatraemia: subgroup
analysis of a randomized, controlled
study.
In hospitalized patients with euvolaemic
hyponatraemia,
i.v. conivaptan significantly increased
serum [Na(+)] promptly and was well
tolerated.
Zeltser D, Rosansky S, van Rensburg
H, Verbalis JG, Smith N. 2007;27(5):447-57.
Epub 2007 Jul 26
Assessment of the efficacy and safety of
intravenous conivaptan in euvolemic and
hypervolemic hyponatremia.
Among patients with euvolemic or
hypervolemic hyponatremia, 4-day
intravenous infusion of conivaptan 40
mg/day significantly increased serum
[Na+] and was well tolerated.
AUTHOR/ REFERENCE STUDY NAME SUMMARY
Galton C, Deem S, Yanez
ND, Souter M, Chesnut R, Dagal
A, Treggiari M. 2011 Jun;14(3):354-
60. doi: 10.1007/s12028-011-9525-8
Open-label randomized trial of the
safety and efficacy of a single
dose conivaptan to raise serum
sodium in patients with traumatic
brain injury.
These data suggest that a single dose conivaptan is safe in
non-hyponatremic patients with severe TBI and may
reduce ICP. Further studies are needed to establish the
effect of conivaptan on clinically relevant endpoints, and its
role in the management of intracranial hypertension.
Naidech AM, Paparello J, Liebling
SM, Bassin SL, Levasseur
K, Alberts MJ, Bernstein RA, Muro
K. 2010 Aug;13(1):57-61. doi:
10.1007/s12028-010-9379-5
Use of Conivaptan (Vaprisol) for
hyponatremic neuro-ICU patients.
Despite an inclusive protocol, most patients were not
candidates for Conivaptan therapy for hyponatremia. The
role of Conivaptan in the Neuro-ICU remains to be defined.
Lasseter KC, Dilzer SC, Smith N.
2007 Mar-Apr;24(2):310-8
Intravenous conivaptan: effects on
the QTc interval and other
electrocardiographic parameters
in healthy volunteers.
No clinically notable changes in ECG parameters were
associated with conivaptan, suggesting that conivaptan did
not affect cardiac repolarization or cardiac conduction.
2006 Jun;91(6Ghali JK, Koren
MJ, Taylor JR, Brooks-Asplund
E, Fan K, Long WA, Smith N.
):2145-52. Epub 2006 Mar 7
Efficacy and safety of
oral conivaptan: a V1A/V2
vasopressin receptor antagonist,
assessed in a randomized,
placebo-controlled trial in patients
with euvolemic or hypervolemic
hyponatremia.
Oral conivaptan (40 and 80 mg/d) was well tolerated and
efficacious in correcting serum [Na(+)] in hyponatremia.