Syndrome of

Inappropriate Secretion of
Antidiuretic Hormone
(SIADH)

Presented by
Pauline Teo Siew Chin
 Outline
 Introduction
 Causes
 Pathophysiology
 Signs & Symptoms
 Diagnosis
 Management
 Conclusion
 References
 Introduction
 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 Renal action
 Concentrates urine
 Vasopressor effects Non-renal action
 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
 Introduction (con’t)
 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
 Causes of excessive vasopressin
Neoplasia / Lung (small cell), GIT (stomach, pancreas),
Malignancies Nasopharynx, Lymphoma, Leukemia

Bacterial pneumonia, Cystic fibrosis, Tuberculosis,

Pulmonary
Emphysema, Chronic obstructive pulmonary
Diseases disease
Encephalitis, Head injury, Meningitis, Brain
CNS Injuries /
tumours or abscess, Haemorrhage or Thrombosis,
Diseases Subarachnoid hemorrhage
Antipsychotics, TADs, Carbamazepine,
Drugs /
Vinblastine, Vincristine, MDMA, Oxytocin,
Medications Desmopressin, Chlorpropamide, Tolbutamide

Miscellaneous Idiopathic, Hereditary, Pain, Postoperative, Stress

 Pathophysiology
 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 & 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
 Diagnosis
 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
 Diagnosis (Con’t)
 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
 Management
 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
 Management (con’t)
 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)
(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)
(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 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 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-)
 Salt Administration (con’t)
 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
 Loop 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 & Lithium
 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
 Demeclocycline
 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 (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
 Demeclocycline (con’t)
 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
 Lithium
 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
 Increased Solute Intake
 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 Intake (con’t)
 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
 Vasopressin Receptor 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
 Conivaptan
 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
 Conivaptan (con’t)
 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
 Vasopressin Receptor Antagonists
(con’t)
 Tolvaptan: unapproved oral V2 receptor
antagonists
 RCT showed tolvaptan can raise the
serum sodium by 5 mmol/L
 Others: satravaptan
 Conclusion
 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
 References
 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!
• Formed in the supraoptic
and paraventricular nuclei
of the hypothalamus
• Transported to the
posterior lobe of the
pituitary gland and stored
 Pathogenesis
 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 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 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.
 Urea
 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
 Urea (con’t)
 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