Syndrome of Syndrome of Inappropriate Inappropriate Secretion of Secretion of Antidiuretic Antidiuretic

HormoneHormone(SIADH)(SIADH)Presented byPresented by

Pauline Teo Siew ChinPauline Teo Siew Chin

OutlineOutline IntroductionIntroduction CausesCauses PathophysiologyPathophysiology Signs & SymptomsSigns & Symptoms DiagnosisDiagnosis ManagementManagement ConclusionConclusion ReferencesReferences

IntroductionIntroduction Antidiuretic hormone (ADH): A hormone secreted

by the posterior pituitary

a.k.a vasopressin

stimulated by an increase in plasma osmolality,

hypovolemia Function of ADH:

Increases water reabsorption in distal tubules &

collecting duct of nephron

Concentrates urine

Vasopressor effects

Renal action

Non-renal action

Introduction (con’t)Introduction (con’t) Renal Actions

mediated by V2 receptor

to increase the rate of insertion of water channels into the luminal membrane, thus increasing the permeability to water

Non-Renal Actions

mediated by V1 receptor

causes contraction of smooth muscle, particularly in the CVS

SIADH: A disease of impaired water excretion with accompanying hyponatremia & hypoosmolality caused by excessive secretion of vasopressin

SIADH: “Inappropriate” secretion of vasopressin from either

the posterior pituitary gland or

ectopic sources (eg: small-cell lung cancer) One of the commonest underlying cause for

hyponatremia

Introduction (con’t)Introduction (con’t)

Causes of excessive Causes of excessive vasopressinvasopressin

Neoplasia / Malignancies

Lung (small cell), GIT (stomach, pancreas), Nasopharynx, Lymphoma, Leukemia

Pulmonary Diseases

Bacterial pneumonia, Cystic fibrosis, Tuberculosis, Emphysema, Chronic obstructive pulmonary disease

CNS Injuries / Diseases

Encephalitis, Head injury, Meningitis, Brain tumours or abscess, Haemorrhage or Thrombosis, Subarachnoid hemorrhage

Drugs / Medications

Antipsychotics, TADs, Carbamazepine, Vinblastine, Vincristine, MDMA, Oxytocin, Desmopressin, Chlorpropamide, Tolbutamide

Miscellaneous Idiopathic, Hereditary, Pain, Postoperative, Stress

PathophysiologyPathophysiology The excessive ADH leads to water

reabsorption from renal collecting ducts Patients with SIADH continue to drink

normal amounts of fluids despite low plasma osmolalities due to a downward resetting of their osmotic threshold for thirst

The serum Na+ concentration becomes diluted & falls to abnormal levels

The ensuing volume expansion activates secondary natriuretic mechanisms resulting in Na+ & water loss and the restoration of near euvolemia

Signs & SymptomsSigns & Symptoms Depends on the degree of abnormality in serum Na+

concentration & the rate of fall in serum Na+

Severe symptoms are commonly seen only when the serum Na+ < 120 mmol/L

Slow fall: asymptomatic or non-specific features (eg: lethargy, anorexia, nausea/vomiting, headache, difficulty concentrating)

Rapid fall (rate > 0.5 mmol/L/h) potentially fatal features: confusion, hallucinations, drowsiness, convulsions, coma, respiratory arrest

DiagnosisDiagnosis Can only be diagnosed when there is normal

cardiac, renal, hepatic, adrenal & thyroid function Should be no recent use of diuretics Important features for diagnosis:

Hyponatraemia (serum Na+ < 135 mmol/L)

Decreased plasma osmolality (<275 mOsm/kg)

Increased urine osmolality (>100 mOsm/kg)

Increased urinary Na+ ( > 20mmol/L)

Euvolemic on clinical examination

Supporting features: Supporting features:

Correction of hyponatremia with fluid restriction

Failure of hyponatremia to correct with 0.9% saline

Decreased BUN & serum uric acid levels

Normal serum K+ & bicarbonate levels

Diagnosis (Con’t)Diagnosis (Con’t)

ManagementManagement Dependent upon the degree of hyponatremia &

the presence or absence of symptoms Majority of patients with SIADH do not require

therapy

plasma Na+ stabilizes in the range of 125-132mM

asymptomatic Only initiate treatment when plasma Na+ levels

drop below 120 mmol/L & symptomatic Goal of therapy: to increase plasma osmolality

towards normal

Treatment water restriction salt administration loop diuretics drugs that inhibit renal actions of ADH

(eg: demeclocycline, lithium) increased solute intake vasopressin receptor antagonists

Overly rapid correction in any patient should be avoided because it can lead to an acute decrease in brain cell volume & resulting in osmotic demyelination

Management (con’t)Management (con’t)

(i) Acute development of hyponatremia occurs within 48 hours & rate of decline

in serum sodium concentration exceeds 0.5 mmol/L per hour

Can be fatal & should be treated rapidly Serum Na+ should be corrected by

hypertonic saline (3%) Frusemide may enhance the rise in

serum Na+

Management (con’t)Management (con’t)

Management (con’t)Management (con’t)(ii) Chronic development of hyponatremia Best effects are with treatment of the

underlying cause (eg: withdraw offending drugs, treat neoplasia or infection)

Fluid restriction usually reverses any adverse clinical features and restores the circulating Na+ level & osmolality to normal

Demeclocycline 600 to 1200 mg daily is effective

Vasopressin receptor antagonists showed promising results in the clinical trials

Water RestrictionWater Restriction The mainstay of therapy in asymptomatic

hyponatremia & in chronic SIADH Fluid restriction to 500-1000 ml/day The associated -ve water balance raises

the plasma Na+ concentration towards normal

Salt AdministrationSalt Administration Severe, symptomatic or resistant hyponatremia

often requires the administration of salt Osmolality of the fluid given must exceed that of

the urine in order to elevate the plasma sodium concentration

E.g.: Assume that a SIADH & hyponatremia patient has a urine osmolality that is relatively fixed at 600 mOsm/kg 1L of hypertonic saline (3%) which contains 1026 mOsm (513 each of Na+ & Cl- ) is being administered instead of 1L of isotonic saline (0.9%) which contains 300 mOsm (150 mmol each of Na+ & Cl-)

Overly rapid correction of the serum sodium level should be avoided

To increase Na+ at the rate of 1 mmol/L per hour initially until the serum sodium reaches 120 mmol/L, followed by rate of ≤0.5 mmol/L per hour (maximum 10-12 mmol/L in first 24 hours)

Frusemide increases excretion of free water & can be used in conjunction with hypertonic saline

Salt Administration Salt Administration (con’t)(con’t)

Loop DiureticLoop Diuretic Inhibits reabsorption of sodium & chloride in the

ascending loop of Henle & distal renal tubule

cause increased excretion of water & solutes Lowers the urine osmolality by blocking the

concentrating ability of the kidney Dose for frusemide:

IV: 40mg over 1-2 minutes initially, may increase to 80mg

Oral: 20-80mg/day The effect of hypertonic saline can be enhanced

if given with a loop diuretic

Demeclocycline & Demeclocycline & LithiumLithium

Both act on the collecting tubule cells to diminish its responsiveness to ADH, thereby increase the water excretion

Should be considered only in the rare patient with persistent marked hyponatremia who is unresponsive to or cannot tolerate water restriction

DemeclocyclineDemeclocycline US Brand Name: Declomycin®

Pharmacologic category: Antibiotic (tetracycline derivative)

Indication: susceptible infections, chronic SIADH MOA: inhibits activation of ADH-sensitive adenyl cyclase

in the distal renal tubules & collecting ducts and inhibits the action of ADH in chronic SIADH

Dose for SIADH: Oral = 900-1200 mg/day or 13-15 mg/kg/day divided every 6-8 hours initially, then decrease to 600-900 mg/day

Dosage form: Tablet, as HCl (150 mg, 300 mg) Administer 1 hour before or 2 hours after food or milk

with plenty of fluid Avoid taking antacids before demeclocycline

Demeclocycline Demeclocycline (con’t)(con’t) A/e: pericarditis, nephrogenic diabetes insipidus,

ARF, tinnitus, GI disturbances, tooth discolouration (child < 8 yrs), myasthenic syndrome, rash, increased liver enzymes, hematologic abnormalities

Use of demeclocycline during tooth development may cause permanent discoloration of the teeth & enamel, retardation of skeletal development & bone growth with risk being the greatest for children <4 years & those receiving high doses

Photosensitivity reactions occur frequently Use caution in elderly Should be avoided in hepatic or renal

dysfunction

C/I: Hypersensitivity to demeclocycline, tetracyclines, or other components; children <8 yrs; concomitant use with methoxyflurane; pregnancy

CBC, renal & hepatic function should be monitored

Onset of action: 3-6 days More predictably effective & less toxic than

lithium

Demeclocycline (con’t)Demeclocycline (con’t)

LithiumLithium Is effective only in a minority of patients Is no longer recommended due to the

incidence of gastrointestinal, cardiac, endocrine & CNS side effects

Has a low therapeutic index May induce irreversible renal damage

when used chronically Dose: 900-1200 mg/day

Dietary manipulation is an alternative method to treat persistent SIADH

In normal subjects, the urine volume is primarily determined by water intake via changes in ADH release

However, when ADH levels are relatively fixed, as in the SIADH, the main determinant of the urine output is the rate of solute excretion which is primarily determined by solute intake.

Increased Solute Increased Solute IntakeIntake

Eg: Urine osmolality is 600 mOsm/kg in the SIADH Urine volume will be 1000 mL/day if solute excretion (sodium and potassium salts and urea) is 600 mOsm/day & 1500 mL/day if solute excretion is increased to 900 mOsm/day with a high salt, high protein diet Thus, the elevation in the plasma sodium concentration induced by salt occurs in two stages(i) the direct effect of the ingestion of salt without water, followed by (ii) the excretion of the excess salt with water leading to net negative water balance

Unfortunately, many patients with chronic SIADH have a major underlying illness that limits compliance with increased dietary intake

Increased Solute Intake Increased Solute Intake (con’t)(con’t)

Vasopressin Receptor Vasopressin Receptor Antagonists Antagonists

Selective for the V2 (antidiuretic) receptor or block both the V2 and V1a (vasoconstrictor) receptors

Produce a selective water diuresis without affecting sodium and potassium excretion

RCTs have demonstrated that they raise the plasma sodium concentration in patients with hyponatremia caused by the SIADH, heart failure & cirrhosis

Eg: Conivaptan, tolvaptan, satravaptan Advantages:

predictability of their effect rapid onset of action limited urinary electrolyte excretion

Brand Name: Vaprisol®

Dosage form: IV 5mg/ml in 4ml ampoule MOA: Blocks the V2 and V1a receptors Indication: Treatment of euvolemic hyponatremia

in hospitalized patients C/I: hypersensitivity to the formulation, use in

hypovolemic hyponatremia, concurrent use with strong CYP3A4 inhibitors

A/E: headache, injection side reactions, hypokalemia, vomiting, diarrhea, polyuria, thirst

Effect of conivaptan on free water clearance begins as early as 1-2 hours

ConivaptanConivaptan

Dosage: Adults LD: 20mg infused over 30 mins, followed by continuous infusion of 20mg over 24 hours MD: 20mg/day as continuous infusion over 24 hours, may titrate to maximum 40mg/day. Total duration of therapy not to exceed 4 days

Change infusion site every 24 hours to minimize vascular irritation

Conivaptan (con’t)Conivaptan (con’t)

Tolvaptan: unapproved oral V2 receptor antagonists

RCT showed tolvaptan can raise the serum sodium by 5 mmol/L

Others: satravaptan

Vasopressin Receptor Vasopressin Receptor Antagonists (con’t)Antagonists (con’t)

ConclusionConclusion SIADH: A disease of impaired water excretion with

accompanying hyponatremia & hypoosmolality caused by inappropriate secretion of vasopressin

Dependent upon the degree of hyponatremia & the presence or absence of symptoms

Only initiate treatment when plasma Na+ levels drop below 120mmol/l & symptomatic

Overly rapid correction in any patient should be avoided

Best effects are with treatment of the underlying cause

Treatment: water restriction, salt administration, loop diuretics, demeclocycline, lithium, increased solute intake, vasopressin receptor antagonists

ReferencesReferences British National Formulary September 2006. UK: BMJ

Publishing Group Ltd and RPS Publishing. eMedicine: Syndrome of Inappropriate Antidiuretic Hormone

Secretion. Adapted from www.emedicine.medscape.com Katzung BG 2004. Basic & Clinical Pharmacology. 9 th ed.

Singapore, McGraw-Hill Koda-Kimble MA & Young LY 2001. Applied Therapeutics:

The Clinical Use of Drugs. 7th ed. USA, Lippincott William & Wilkins

Lacy CF et. al. 2006. Drug Information Handbook International. 14th ed. US, Lexi-Comp

Oncology Encyclopedia: Syndrome of Inappropriate Antidiuretic Hormone. Adapted from www.answers.com/library/oncology encyclopedia

Wells BG, Dipiro JL, Schwinghammer TL & Hamilton CW. Pharmacotherapy. 6th ed. USA, McGaw-Hill Companies, Inc

2007 UpToDate® Database

Thank You!Thank You!

• Formed in the supraoptic and paraventricular nuclei of the hypothalamus• Transported to the posterior lobe of the pituitary gland and stored

PathogenesisPathogenesis Severe hyponatremia may also be associated

with K+ loss Since K+ is as osmotically active as Na+, the loss

of K+ contributes to the reductions in the plasma osmolality & Na+ concentration

This K+ is derived from the cells and probably represents part of the volume regulatory response

Cells that increase in size due to water entry in hyponatremia lose K+ and other solutes in an attempt to restore cell volume

Reset OsmostatReset Osmostat Hyponatremia due to a reset osmostat can be found in

about 1/3 of patients & with any of the causes of the SIADH The plasma sodium concentration is normally regulated &

stabilized at a new lower level (125-135 mmol/L) Establishing its presence is important clinically

correcting the hyponatremia is both unnecessary & likely to be ineffective, since raising the plasma osmolality will stimulate both ADH release & thirst

Its presence should be suspected in any patient with apparent SIADH who has mild hyponatremia that is stable over many days despite variations in Na+ and water intake

Diagnosis can be confirmed clinically by observing the response to a water load (10 to 15 ml/kg given orally or intravenously) Normal subjects & those with a reset osmostat should excrete > 80% within 4 hours, while excretion will be impaired in the SIADH

Salt AdministrationSalt Administration E.g.: Assume that a SIADH & hyponatremia patient has a

urine osmolality that is relatively fixed at 600 mOsm/kg If 1L of isotonic saline is given (containing 150 mmol each of Na+ & Cl- or 300 mOsm), all of the NaCl will be excreted (because sodium handling is intact) but in only 500 mL of water (300 mOsm in 500 mL of water = 600 mOsm/kg) The retention of 1/2 of the administered water will lead to a further reduction in the plasma sodium concentration even though the plasma sodium concentration may initially rise because the isotonic saline is hypertonic to the patient. The response is different if hypertonic saline is given. Each liter of 3% saline contains 1026 mOsm (513 each of Na+ & Cl- ). Thus, if 1L of this solution is given, all of the NaCl will again be excreted but now in a larger volume of 1.7L. Thus, after the administration of hypertonic saline, there will be an initial large rise in the plasma sodium concentration and, a smaller effect after the excess sodium has been excreted due to the loss of 700 mL of water.

UreaUrea Osmotic diuretic

Induces diuresis by elevating the osmolarity of glomerular filtrate, thereby hindering tubular reabsorption of waters

Correct hypoosmolality by increasing solute-free water excretion & reducing urinary sodium excretion

Should be considered only in patients with marked hyponatremia that does not respond to other modalities

Generally well tolerated

Common s/e: headache, nausea, and vomiting, syncope, disorientation, dizziness, agitation, mental confusion, nervousness, hypotension, tachycardia, cardiotoxicity resulting in ECG changes, hyperthermia

For rapid correction of hyponatremia in SIADH, urea has been given, in conjunction with sodium chloride supplementation and water restriction, in a dosage of 80 g IV infused over 6 hours (as a 30% solution) or as 2 or 3 30g oral doses administered during a 24-hour period.

Oral: 30g of urea crystals to be dissolved in 10ml of aluminium-magnesium antacid (Maalox®) & 100ml of water. Alternatively, orange juice or other strongly flavored liquids can be used to improve palatability

Urea (con’t)Urea (con’t)