hyponatremia in siadh: role of the vaptans

Hyponatremia in SIADH:Role of the Vaptans

Mary Joana CoPharm.D Candidate 2011

Western UniversityCOH Medicine Rotation Student

Case: R.M.66 yo Male, diagnosed with AML in ‘09

s/p Allo-HSCT MUD (day 0 -7/1/10)Complications: GI GVHD Stage III Tacrolimus 1.5mg BID Sirolimus 4mg Once Daily Prednisone 30mg Once Daily Budesonide 3mg TID

Allergy: Cefazolin/Ceftazidime – Rash

PMH:CAD (s/p 1 stent placement 2001)DM type 2 (2001)Hypertension Lisinopril 5mg Daily Prazosin 1mg DailyHyperlipidemia Simvastatin 40mg Daily

FH1 sister with cervical CA & hepatitis

SH:1 ppd x 40 yr, quit 2000Limited alcohol useNo history of Illicit drug useMarried, good family support wife at bedside

Micafungin 50mg Once DailyAcyclovir 400mg BIDBactrim DS 800/160mg 1 tab BID on Sat/Sun

Supportive Care:Lasix 40 mg Daily x 2 daysZolpidem 10mg QHS prn insomniaLorazepam 1mg q6hr prn nauseaFamotidine 20mg BIDMagnesium + Protein 1 tab BID

Chief Complaint

CC: Diarrhea, Low Serum Na w/ TPN (Lomotil 2.5mg prn diarrhea)

7/16 7/17 7/18 7/19 7/20 7/21 7/22 7/23 7/24 7/25 7/26 7/27 7/28 7/29 138 133 131 131 127 126 128 129 130 131 132 132 130 131Na:

Diarrhea Episode: intermittently, started on

16th ~1600 ml 20th ~1800ml loose stool

17th ~1500 ml loose stool 21st no diarrhea

18th started solu-medrol

Is having a low Na an urgent matter? What are the various causes of

having this electrolyte abnormality? Does RM require immediate

treatment? If so, what are the options

available to him?

Low Sodium Levels

HYPONATREMIA Total body Na deficit (Na <135mEq/L)

From renal/extra renal loss exceeding intake Common in hospitalized patients ~15-30%

Setting also allows for diagnosis Clinical complication of wide pathophysiology

Associated with many underlying disease states Multiple etiologies Differing pathophysiologic mechanisms Results in confusion in management

Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21.

Why is Na important? Osmotic Equilibrium

Osmolality: 280-295 mOsm/Kg H20 85-95% Na is extracellular Cell function relies on maintenance of body fluid tonicity

Present as disorders of water balance: Altered Na and Water content: Regulation of volume and osmolality Alterations in Na levels manifest as:

ECF volume depletion Hypotension Tachycardia

ECF volume overload Peripheral edema Pulmonary Edema

Water balance regulated through ADH (AVP; vasopressin) Hypothalamus: Thirst Control Center

Washington Manual of Therapeutics

Palmer, Biff F., John R. Gates, and Malcolm Lader. "Causes and Management of Hyponatremia." The Annals of Pharmacotherapy 37 (2003): 1694-701.

http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=10935&searchStr=hyponatremia

Isotonic Hyponatremia: Hyperproteinemia Hyperlipidemia



Hypertonic Hyponatremia: Hyperglycemia (Translational Hyponatremia)

Corrected Na=Na + 0.016 x (Glu-100) Mannitol, sorbitol, glycerol, maltose Radiocontrast dye agents

http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=10935&searchStr=hyponatremiaWashington Manual of Therapeutics

Hypotonic Hyponatremia Volume status dependent

Hypovolemic, Hypervolemic, Euvolemic, Washington Manual of Therapeutics


Other etiologies

Iatrogenic: Pharmacologic Agents:

Via stimulation of AVP release: Nicotine, carbamazepine, antidepressants, narcotics,

antipsychotics, antineoplastics Potentiation of antidiuretic action:

Chlorpropramide, methylxanthines, NSAIDs Vasopressin analogs:

Oxytocin, desmopressin acetate (dDAVP)

Exogenous sources of free water: Maintenance IVF TPN


Symptoms

Symptoms related to degree of Na insufficiency:ACUTE:121-130 mEq/L

Nausea, malaise, headache, lethargy, muscle cramps, disorientation, restlessness

<120 mEq/L Obtundation, seizures, respiratory arrest,

coma, deathCHRONIC: (developed over days)Usually Asymptomatic / Non-Specific

Nausea, fatigue, gait disturbance, forgetfulness, muscle cramps confusion, lethargy

Palmer, Biff F., John R. Gates, and Malcolm Lader. "Causes and Management of Hyponatremia." The Annals of Pharmacotherapy 37 (2003): 1694-701.

Back to our case…

Mr. RM: CNS: Asymptomatic Serum Na: levels were lowest on 7/21: 126mEq/L Serum Osmolality: (278-295 mOsm/Kg): 287 mOsm/Kg H2O = “isotonic

hyponatremia” Protein levels: Low protein levels (5.5-5.7) Lipid Levels: TG high: (7/19) 212 (7/26) 277

Hyperglycemia: Glucose levels:

7/16 7/17 7/18 7/19 7/20 7/21 7/22 7/23 7/24 7/25 7/26 7/27 7/28 7/29 Na: 138 133 131 131 127 126 128 129 130 131 132 132 130 131Glu: 206 184 180 248 201 260 172 123 147 127 203 114 151 152Corrected Na: 128 128 129TG 212 277

… Acute fluid loss:

Diarrhea: stool volume Diuretics: Lasix 40mg IV daily X 2

Iatrogenic: IVF: TPN: Pharmacological Agents:

Lisinopril Hypothyroidism:

TSH (0.35-5.5 mIU/L): 0.897 Adrenal Insufficiency:

Cortisol: 9.2 @ 1215h(@0800h: 6-23 ug/dL)(@2000h: 0-9 ug/dL)

Possible SIADH due to GVHD….

SIADH Fluid Balance:

Water Intake, Renal Function (reabsorption; secretion), ADH ADH (anti-diuretic hormone)/AVP (arginine vasopressin)

Anterior hypothalamus Responsible for retention of solute-free water

Affected by: Increased POsm = Increased AVP = Water retention Decreased BP = Increased AVP = Water retention

In SIADH: Decreased Posm = Inappropriate AVP secretion = Water

retention/Hyponatremia “Inappropriate secretion of ADH” What happens to the electrolytes when there is increased

ADH?

Sherlock, Mark, and Chris J. Thompson. "The Syndrome of Inappropriate Antidiuretic Hormone: Current and Future Management Options." European Journal of Endocrinology 162 (2010): S13-18.

SIADHDiagnostic Criteria for SIADH:

A) Essential:Plasma Osmolality <270 mOsmol/Kg H2OUrine Osmolality >100mOsmol/Kg H2OEuvolemiaUrinary Sodium >40 mmol/L, with normal salt and water intakeExcluding Hypothyroidism & Glucocorticoid deficiency

B) Supplemental:Abnormal Water Load TestElevated plasma AVP levels

Compare to RM:Plasma Osmolality (278-295 mOsm/Kg): 287 mOsm/KgUrine Osmolality (250-1200 mOsm/Kg): 711 mOsm/KgDetermined to be clinically euvolemic per PEUrine Na: 159 mmol/L

Excluded Hypothyroidism & Glucocorticoid DeficiencyOther:

History of GVHD due to Inflammation

Sherlock, Mark, and Chris J. Thompson. "The Syndrome of Inappropriate Antidiuretic Hormone: Current and Future Management Options." European Journal of Endocrinology 162 (2010): S13-18.

RM

Hyperglycemia Hypertriglyceridemia Acute Fluid Loss Exogenous Water Sources Possible SIADH

…..We’ve ID’d possible causes, what do we do now???

Treatment Options

ID cause & remove it! Fluid Restriction Saline Infusions

Normal Saline Hypertonic Saline

Diuretic Therapy Aquaretic Therapy

Conivaptan Tolvaptan

Other Agents Lithium Demeclocycline Urea

RM7/16 7/17 7/18 7/19 7/20 7/21 7/22 7/23 7/24 7/25 7/26 7/27 7/28 7/29

Na: 138 133 131 131 127 126 128 129 130 131 132 132 130 131Glu: 206 184 180 248 201 260 172 123 147 127 203 114 151 152Corrected Na: 128 128 129

TPN w/ Insulin & Na repletionFluid

Restriction <1L/day

Lasix 40mg IV

Fluid Restriction (Free Water) 7/22: <1L/day

Lasix 40mg QD x 2 days 7/21 7/22

Na repletion: 7/20 7/21 7/22 7/23 Na Phosphate 25 25 25 25 Na Acetate 85 85 85

85 Na Chloride 85 85 105

105

Hyperglycemia: Insulin in TPN:

58u/L 64u/L (7/20-7/23) +Lispro 5u SC AC/QHS +SSI

Treatment ACUTE vs. CHRONIC

Affects management of treatment Low Na=cells can swell or extrude solutes Capacity of “adaptation”-brain may extrude solutes

Acute Hyponatremia = Cerebral Edema= Brain Herniation Goal/Recommendation: Increase Na not to exceed 10-12 mmol/L over

24h or <18 mmol/l over 48h Methods:

ID source remove cause Mild-moderate symptoms:

No further Intervention needed Severe symptoms:

Hypertonic (3%) Saline 3% NaCl Careful infusion rates due to risk of Central Pontine

Myelinolysis Requires monitoring ~q2hr

<12mEq/L change over 24hr, serial Chem 7Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia Treatment Guidelines

2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21.

Treatment

Chronic Hyponatremia = Brain Adaptation Rate of correction is important Brain adapts and may

extrude solutes Brain is vulnerable to injury if Na is rapidly corrected

due to this compensation…Brain can “shrink” due to inability to recapture lost solutes

“Central Pontine Myelinolysis” / “Osmotic Demyelenation”

Most important in the brain due to the confines of the skull Dysarthria, dysphagia, seizures, altered mental status,

quadriparesis, hypotension 1-3 days after correction of serum sodium

<12mEq/L change over 24hr, serial Chem 7

Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia Treatment Guidelines


Treatment Chronic Hyponatremia cont..

Hypovolemic: Normal Saline- Restores tissue perfusion

Euvolemic/Hypervolemic Na & H20 restriction Loop diuretic w/ Salt tablets – Loops also loose electrolytes! Vasopressin Receptor Antagonist

Other Demeclocycline

Cause Nephrogenic Diabetes Insipidus Onset 2-5 days Profound Polyuria Hypernatremia Nephrotoxicity, photosensitivity, skin rash

Urea Long-term treatment may be effective (5 years) Animal model showed benefit

Lithium Downregulates vasopressin-stimulates aquaporin-2 expression Unpredictable efficacy Cause Nephrogenic Diabetes Insipidus

Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia Treatment Guidelines


Vaptan Therapy

Class of drugs affecting AVP, thus play an important role in circulatory & water homeostsis 3 receptor sub-types:

V1a vascular smooth musclevasoconstriction/cardiac hypertrophy

V1blimbic systemstimulates ACTH & endorphins

V2renal collecting duct systemresorption of free water

Conivaptan (Vaprisol)

"Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia."

Zeltser, David, Steven Rosansky, Hannes Van Rensburg, Joseph G. Verbalis, and Neila Smith. "Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia." American Journal of Nephrology 27 (2007): 447-57

Astellas IV formulation, v1/v2 receptor antagonist FDA approval in 2004

Treatment of Euvolemic/Hypervolemic Hyponatremia Multi-center, double-blind, placebo controlled, randomly assigned (4days)

Conivaptan 30min LD (20mg diluted to 100ml D5W) infusion 96hr CIV days 1-4 (diluted to 250ml)

40mg/day 80 mg/day

Placebo 100ml D5W as LD 250 ml D5W Important Exclusion Criteria:

Hypovolemic hyponatremia Cardiac problems: SBP <85mmHg, orthostatic hypotension, uncontrolled HTN or

tachyarrhythmia needing pacemaker Hyponatremia requiring immediate treatment Medications interacting with CYP4503A4 Other medications: AVP, oxytocin, desmopressin, lithium, urea, demeclocycline

Co-intervention: instructed to maintain 24hr Na intake, calorie consumption, caffeine intake, and had limited daily fluid intake <2L/day (excluding food)

Modified ITT Similar Baseline Characteristics across study groups, Mean baseline Na: ~124

mEq/L

Conivaptan (Vaprisol)"Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

Zeltser, David, Steven Rosansky, Hannes Van Rensburg, Joseph G. Verbalis, and Neila Smith. "Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia." American Journal of Nephrology 27 (2007): 447-57

Time to increase >/= 4mEq/L : Conivaptan 40mg/day: 24 hours Conivaptan 80mg/day: 10 hours PBO: no increase within 4 day infusion

Change in serum Na from baseline to end of treatment Conivaptan 40mg/day: 6.3 mEq/L Conivaptan 80mg/day: 9.4 mEq/L PBO: 0.8 mEq/L

Patients with increase in Na >/=6mEq/L or Na >/=135 mEq/L Conivaptan 40mg/day: 69% (6.3) Conivaptan 80mg/day: 88.5% (23) PBO: 20.7% (6)

Change in serum Na from Baseline to 6-9days post treatment : Conivaptan 40mg/day: 8.1mEq/L (n=13) Conivaptan 80mg/day: 4.7 mEq/L (n=26) PBO: 5.2 mEq/L (n=17)


Discontinuation was mainly due to Infusion site reactions

Other ADRs: hypotension, postural hypotension, pyrexia, hyperkalemia, infusion site thrombosis


Baseline characteristics were matched

ADRs due to drug were evaluated and recorded

Able to monitor patients levels often, setting was inpatient

Fluid restriction carried out & recorded violations:

Conivaptan 80mg/day: 54%

Conivaptan 40mg/day: 38%

PBO: 21% Endpoints used were

useful Baseline Na levels were

~124mEq/L

1/3 of patients were hypervolemic and were infused with D5W

Length of treatment was only 4 days

Follow-up was done for only 6-9days post treatment

Outcomes were not assessed by symptoms

Baseline symptoms not recorded, if any

Drop-out rate was high Target Na levels not

specified Did not address long term

benefit of correctiong hyponatremia


Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia

Schrier, Robert G., Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank Czerwiec, and Cesare Orlandi. "Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia." New England Journal of Medicine 355 (2006): 2099-112.

Tolvaptan (Samsca)

Otsuka Pharmaceutical Orally active V2RA selectively excretes electrolyte-free water FDA approval in 2009

Treatment of Euvolemic/Hypervolemic Hyponatremia Prospective, multi-center, randomized centrally, double-blind, placebo controlled Conducted 2 trials to assess reproducibility (SALT-1 & SALT-2)

Tolvaptan 15mg tab 1 tab PO Daily x 30 days OR PBO Important Patient Population Criteria:

Inclusion Etiologies: CHF, cirrhosis or SIADH

Exclusion Criteria: Other etiologies Hypovolemic hyponatremia Other cardiac diseases (post-MI, SVT, SBP<90) Serum Na <120 mmol/L w/ neurological impairment Poor prognosis not tolerating fluid shifts: short-term survival

Similar Baseline Characteristics across study groups (except height in SALT-2), Mean baseline Na: ~128 mEq/L

Co-Administration/Co-intervention: Fluid restriction was not mandatory; treatment with other agents were not allowed (demeclocycline, lithium, urea)

Dose adjustments were made at the discretion of the investigator at Day 4 Drug was administered until day 30, final assessments done at day 37


Tolvaptan (Samsca) "Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia."


Values were statistically significant Increases in Na were greater in Tolvaptan group than PBO in both trials and in both

stratifications at Day 4 and much more at Day 30 Increases were more rapid (by day 4) and greater (marked hyponatremia)


Tolvaptan patients reached normal Na levels on day 4 and 30 more than PBO

Day 4: SALT-1 (40% vs 13%) SALT-2 (55% vs11%) Day 30: SALT-1 (53% vs 25%) SALT-2 (58% vs25%)

Less “marked” hyponatremia Day 4: SALT-1 (13% vs 49%) SALT-2 (10% vs 40%) Day 30: SALT-1 (7% vs 35%) SALT-2 (15% vs 32%) not sig

SF-12 scores Showed difference in “mental component summary” in “marked

hyponatremia” patients, but not overall Vitality, social functioning, calmness, sadness

No difference in physical component summary OTHER:

Day 37 analysis: Na concentrations showed no difference between each arm



ADR Most common: Thirst (14%;5%); Dry mouth (13%;4%) Incidence: Tolvaptan: 171 patients PBO: 176, not all ADRs were deemed to be related

to study drug weakness, nausea, constipation, peripheral edema, ascites, diarrhea, fatigue,

vomiting Tolvaptan:

8 patients withdrew due to ADR Rash, dysguesia, nocturia, urinary frequency, exanthema, muscle weakness, hypernatremia

PBO: 8 patients withdrew due to ADR

Rash, ARF, increased SCr, decreased Na, aggravated hyponatremia, vomiting Completed Follow-up @ 7-days & 30-days:

Tolvaptan: N=171 (76%) PBO: N=154 (69%)

Study Withdrawal: Total: N= 123

Tolvaptan: 54 (24%) PBO: 69 (31%)



Reproducible results SALT-1 SALT-2

Baseline characteristics were matched

Endpoints were measured at Day 4 & 30

ADRs due to drug were evaluated and recorded


OP setting primarily: No mandated fluid restriction, but

co-intervention possible No mandated change in patients

medication regimen (diuretic use) if for primary disease

CHF patients Other etiologies excluded No severe Hyponatremia w/

Neurological ADRs were allowed Serum Na baseline ~128 mmol/L Outcomes were assessed via AUC, not

by symptoms Baseline symptoms not recorded, if any Subjective safety assessments Drop-out rate was high Target Na levels not specified Did not state Na levels of 4 patients who

exceeded target levels Did not address long term benefit of

hyponatremia

Conivaptan VS Tolvaptan“The Vaptans” Conivaptan Tolvaptan

Convenience

MOA

IV

non-selective

PO

selective

Efficacy/Onset Mean Increases:

40 mg/day: 6.3mEq/L

80 mg/day: 9.4 mEq/L

Lost effect at end of tx

As early as 10 hr in the 80mg arm, increase >=4mEq/L

Mean increases

~6.2 mEq/L (end of 30 day treatment)

Lost effect at end of tx

At day 4,~4mEq/L increase was achieved

Safety Infusion site reactions, phlebitis, cardiac effects

Limited to v2 antagonism

Rash

DDI Strong CYP3A4 Inhibitor/substrate

P-glycoprotein Substrate

Tolvaptan VS Fluid Restriction Vasopressin V2 Receptor Blockade with Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia

prospective, multicenter, randomized, active-controlled, open-label trial N=28 patients (euvolemic/hypervolemic hyponatremia) with Na <135 mmol/L

Inclusion Criteria: age 18 years, serum sodium 135 mmol/L for 2 consecutive days, and normovolemia or signs of fluid overload

Exclusion Criteria: acute coronary ischemic events 60 days after randomization, a history of sustained ventricular tachycardia or ventricular fibrillation, or serum creatinine 2.8 mg/dl.

Arms: Tolvaptan 10mg/day60mg/day x ~27days (n=17) Fluid restriction 1200ml/day + PBO x ~27days (n=11)

Follow-up: 65 days Endpoints:

Primary: Normalization of Serum Na: Na >135 mmol/L or >=10% increase in baseline

Secondary: urine osmolality, urine volume, urine sodium concentration, body weight, total fluid intake, free-water clearance, and thirst score.

Thirst score: via visual analog scale Safety: adverse events, vital signs, laboratory tests, electrocardiograms, and the

rate of sodium correction.

Gheorghiade, Mihai, Stephen G. Goulieb, James Udelson, Marvin Konstam, Frank Czerwiec, John Ouyang, and Cesare Orlandi. "Vasopressin V2 Receptor Blockade with Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia." American Journal of Cardiology 97 (2006): 1064-067.

Results: (p 0.0065) Increase in Serum Na by:

5.7 +/- 3.2 mmol/L in the tolvaptan group and 1.0 +/- 4.7 mmol/L in the fluid restriction group

ADR: No differences in serum potassium, blood pressure, or heart

rate were observed between treatment groups. No differences in thirst score or adverse events requiring drug discontinuation were observed between treatment groups.

Drop out rates were high Therapy completion:

6/17 Tolvaptan vs 2/28 PBO At 14 days, patients can withdraw if no benefit has been seen Used LOCF method

Tolvaptan VS Fluid Restriction Vasopressin V2 Receptor Blockade with Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia

What happens next?

…data are limited in comparing effectiveness/toxicities of the vasopressin antagonists with other therapeutic options for hyponatremia

Chronic Hyponatremia Mild hyponatremia is associated with reversible

attention deficit and gait instability which can cause a high rate of falls & admissions for bone fractures

Studies only go as far as 30 days What is the role in acute setting?

Limited data to show that it is effective in acute situations

RM

What else can we do for Mr. RM

Na levels are still low after interventions, although seems like it is trending up (8/3) = 133mEq/L

Hypertriglyceridemia may need to be adressed Continue to treat Hyperglycemia V2RA: May be beneficial if RM presents with Na levels that

have been continually low for consecutive days

QUESTIONS?

hyponatremia in siadh: role of the vaptans

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