ADH (Antidiuretic Hormone) - Everything You Need to Know

1. What IS ADH?

Think of it as your body's "water saver" - its main job is to stop you from losing too much water in your urine.

• Katzung's Basic and Clinical Pharmacology, 16th Ed.

2. Where is it Made and Stored?

3. What Triggers its Release?

A. High Blood Osmolality (most important)

• Osmolality = how concentrated your blood is (basically how much sodium/solutes are dissolved)
• Normal blood osmolality = ~285-290 mOsm/L
• When you're dehydrated or eat salty food, osmolality rises
• Osmoreceptors in the hypothalamus detect this and signal ADH release

B. Low Blood Volume / Low Blood Pressure

• When you lose blood or fluids (e.g., hemorrhage, vomiting), baroreceptors in the aorta/carotid detect the drop
• They signal the hypothalamus to release ADH
• This is a stronger emergency signal - even small drops in BP cause big ADH surges

Other stimuli that INCREASE ADH:

• Nausea/vomiting
• Pain, stress, surgery
• Hypoxia (low oxygen)
• Certain drugs (morphine, nicotine, carbamazepine, SSRIs)

Things that DECREASE ADH:

• Alcohol (this is why alcohol makes you urinate a lot)
• Atrial natriuretic peptide (ANP)
• Low osmolality (drinking lots of water)

4. How Does ADH Work? (Mechanism of Action)

V2 Receptors (kidney - main effect)

1. ADH binds to the V2 receptor on the blood-side of the collecting duct cell
2. V2 is a G-protein coupled receptor - activates Gs protein → adenylyl cyclase → cAMP
3. cAMP triggers protein kinase A
4. This causes vesicles carrying pre-formed water channels (Aquaporin-2, AQP2) to fuse with the apical (urine-side) membrane
5. Water rushes from the dilute urine in the tubule, through AQP2, across the cell, and out through AQP3/AQP4 on the blood side
6. Result: concentrated urine, water retained in blood

• Katzung's Basic and Clinical Pharmacology, 16th Ed.

V1 Receptors (blood vessels - secondary effect)

• Found on vascular smooth muscle
• Activation causes vasoconstriction (raises blood pressure)
• Coupled to Gq → phospholipase C (different pathway)
• This is why ADH is also called "vasopressin"

Extra V2-like Receptors (outside kidney)

• Stimulate release of von Willebrand factor and Factor VIII from endothelial cells
• This is why desmopressin (synthetic ADH) is used to treat bleeding disorders like hemophilia A and von Willebrand disease

5. What Happens in the Kidney? (Simplified)

• Costanzo Physiology, 7th Ed.

6. ADH and Urea

7. Clinical Disorders of ADH

A. Diabetes Insipidus (DI) - Too Little ADH Effect

• Polyuria (large urine output, up to 10-20 L/day)
• Polydipsia (extreme thirst)
• Hypernatremia (high blood sodium, concentrated blood)
• Dilute urine (low urine osmolality)

• Central DI: DDAVP (desmopressin) - synthetic ADH analog, intranasal/oral/SC
• Nephrogenic DI: low-salt diet, thiazide diuretics (paradoxically reduce urine output), demeclocycline is not used here

B. SIADH - Too Much ADH (Syndrome of Inappropriate ADH Secretion)

• CNS disorders (meningitis, stroke, brain tumors)
• Pulmonary disease (TB, pneumonia, small cell lung cancer)
• Drugs: carbamazepine, SSRIs, NSAIDs, antipsychotics, morphine
• Post-surgical stress

• Water is retained (dilutes the blood)
• Hyponatremia (low blood sodium) - this is the hallmark
• Concentrated urine (paradoxically, even though patient is "waterlogged")

• Fluid restriction (first line)
• Demeclocycline (blocks ADH action on kidneys)
• Vaptans (conivaptan, tolvaptan) - V2 receptor antagonists that block ADH's kidney effect and cause free-water excretion ("aquaresis")

8. Drugs That Target ADH

ADH Analogs (Agonists)

ADH Antagonists (Vaptans)

Vaptans cause aquaresis - excretion of free water without sodium loss. They raise serum sodium in SIADH/heart failure/cirrhosis.

• Katzung's Basic and Clinical Pharmacology, 16th Ed.

9. Quick Reference: ADH Summary Table

10. Memory Aid

• V1 = Vessels (vasoconstriction, Gq pathway)
• V2 = Volume/water (kidney water reabsorption, cAMP pathway)

• DI: Dry blood, dilute urine (too little ADH effect)
• SIADH: Dilute blood, concentrated urine (too much ADH effect)

Diabetes Insipidus (DI) and SIADH - Detailed Guide

PART 1: DIABETES INSIPIDUS (DI)

The Core Concept

Simple analogy: Think of the collecting duct as a tap. ADH normally closes the tap (retains water). In DI, the tap is always wide open - water pours out endlessly.

Types of DI

1. Central (Neurogenic) DI

• Brain tumors (craniopharyngioma, pituitary adenoma, metastases)
• Head trauma
• Neurosurgery (especially pituitary surgery)
• Subarachnoid hemorrhage / intracranial hemorrhage
• Meningitis / encephalitis
• Sarcoidosis, histiocytosis X (infiltrative)
• Congenital (rare)

1. Phase 1 (DI): Immediately post-op - damaged neurons can't release ADH → polyuria
2. Phase 2 (SIADH): Days later - dying neurons dump stored ADH → water retention, hyponatremia
3. Phase 3 (DI again): If enough neurons die, ADH is permanently deficient → polyuria returns

2. Nephrogenic DI

• AVPR2 gene mutations (>90% of congenital cases) - X-linked recessive, affects males predominantly, prevalence ~4 per million males
• AQP2 gene mutations (<10% of congenital cases) - can be autosomal dominant or recessive

• Lithium - most common drug cause; blocks AQP2 insertion into cell membrane
• Demeclocycline - intentionally used to cause nephrogenic DI to treat SIADH
• Hypercalcemia (calcium interferes with cAMP signaling)
• Hypokalemia
• Chronic kidney disease
• Ureteric obstruction (downregulates AQP2)

Clinical Features of DI (Both Types)

Diagnosis of DI

• Urine osmolality <100 mOsm/kg → water diuresis (DI or psychogenic polydipsia)
• Urine osmolality 100-300 mOsm/kg → partial DI or mixed
• Urine osmolality >300 mOsm/kg → solute diuresis (diabetes mellitus, high protein diet, etc.)

• Deny fluids → measure urine osmolality repeatedly
• Then give desmopressin → measure again
• Central DI: Urine osmolality rises significantly after desmopressin (kidneys work fine, just needed the hormone)
• Nephrogenic DI: Urine osmolality barely rises after desmopressin (kidneys are resistant)
• Primary polydipsia: Urine concentrates normally during water deprivation

• Copeptin is the prohormone of ADH, has a longer half-life, easier to measure
• Baseline copeptin ≥1.4 pmol/L without water deprivation = nephrogenic DI (kidneys resistant, body compensates with high ADH)
• Copeptin >4.9 pmol/L after hypertonic saline infusion (when Na ≥150 mmol/L) = diagnoses central DI with 97% accuracy
• Harrison's Principles of Internal Medicine, 22nd Ed.

Treatment of DI

• Desmopressin (DDAVP) - synthetic ADH analog, first-line treatment
  • Intranasal: 10-40 mcg in 2-3 divided doses
  • Oral: 0.1-0.2 mg 2-3 times daily
  • Subcutaneous: 1-4 mcg every 12-24 hours
• Also replace fluid losses, treat underlying cause

• Remove the cause (stop lithium if possible, correct hypercalcemia/hypokalemia)
• Low-sodium, low-protein diet (reduces solute load, decreases obligatory urine volume)
• Thiazide diuretics (paradoxical effect - create mild volume depletion → proximal tubule reabsorbs more water → less reaches the dysfunctional collecting duct)
• Amiloride (especially for lithium-induced DI - blocks lithium entry into cells)
• NSAIDs (e.g., indomethacin - block prostaglandins that normally antagonize ADH)
• Desmopressin alone is NOT effective in nephrogenic DI
• Brenner and Rector's The Kidney, 2-Volume Set

PART 2: SIADH (Syndrome of Inappropriate ADH Secretion)

The Core Concept

Analogy: SIADH is like someone who keeps closing the drain even when the bathtub is already full. Water overflows (dilutes everything).

Diagnostic Criteria for SIADH

• Low serum uric acid (uric acid is lost in urine)
• Urine osmolality/serum osmolality ratio >2
• Murray & Nadel's Textbook of Respiratory Medicine, 2-Volume Set

Causes of SIADH

• Head trauma, meningitis, encephalitis
• Subarachnoid hemorrhage, stroke
• Brain tumors
• Pituitary surgery

• Pneumonia, tuberculosis
• Positive-pressure ventilation
• Small cell lung cancer (SCLC) - most important malignancy cause; SCLC accounts for ~75% of all SIADH cases (only ~10% of SCLC patients develop it, but SCLC is so common that it dominates the SIADH statistics)

• Small cell lung cancer (most common)
• Pancreatic, prostate, bladder cancers

• Carbamazepine (classic exam answer)
• SSRIs / SNRIs (antidepressants)
• NSAIDs
• Antipsychotics
• Morphine / opioids
• Cyclophosphamide (chemotherapy)
• MDMA / ecstasy (club drug - common in ER)
• Chlorpropamide (old sulfonylurea)
• Vincristine (chemo)

• Nausea, pain, surgery (physiologic stimuli that can be excessive)
• HIV/AIDS

Why Is Sodium Low in SIADH? (Mechanism)

1. ADH is secreted inappropriately → V2 receptors activated in collecting duct
2. AQP2 channels inserted → water reabsorbed from tubule → water enters blood
3. Blood becomes diluted (too much water relative to solute)
4. Serum osmolality falls → serum Na falls (hyponatremia)
5. The expanded blood volume causes the kidneys to excrete some sodium (natriuresis) to try to "offload" volume → urine Na is HIGH (paradox - body is losing sodium despite low blood sodium)
6. The normal feedback (low osmolality → suppress ADH) is broken in SIADH → ADH keeps secreting regardless

Symptoms of SIADH (= Symptoms of Hyponatremia)

Treatment of SIADH

Mild/Asymptomatic Hyponatremia:

• Fluid restriction (500-1000 mL/day) - first line
• Address underlying cause (stop offending drug, treat infection, treat tumor with chemo)

Moderate Symptoms (confusion, nausea, gait problems):

• Continue fluid restriction
• Add demeclocycline (900-1200 mg/day orally) - induces nephrogenic DI, blocks ADH action on kidneys. Onset 2-5 days, so not for emergencies. Watch for nephrotoxicity.
• Vaptans (tolvaptan oral or conivaptan IV) - V2 receptor antagonists, cause aquaresis (free water excretion without sodium loss)

Severe/Life-threatening (seizures, coma, Na <115 mEq/L):

• 3% Hypertonic NaCl - give 300 mL over 3-4 hours, often combined with a loop diuretic (furosemide)
• Why add a loop diuretic? Hypertonic saline alone can worsen volume overload; furosemide helps excrete water while keeping Na
• Target: raise Na by 1-2 mEq/L/hour initially until symptoms resolve

The Most Dangerous Complication of Treatment: Osmotic Demyelination Syndrome (ODS)

• Quadriplegia (paralysis of all 4 limbs)
• Dysarthria (slurred speech)
• Dysphagia (difficulty swallowing)
• Pseudobulbar palsy
• Altered mental status, locked-in syndrome

• Maximum: ≤8 mEq/L in 24 hours and ≤15 mEq/L in 48 hours
• Never exceed 20 mEq/L in the first 24 hours
• Check sodium levels frequently (every 2-4 hours) when actively treating

Key rule: Go slow. Too fast = ODS.

• Harrison's Principles of Internal Medicine, 22nd Ed.

PART 3: DI vs SIADH - The Master Comparison Table

PART 4: Memory Mnemonics

• Pulmonary disease (pneumonia, TB)
• Infection (meningitis, encephalitis)
• Neoplasm (SCLC, pancreatic ca)
• Drugs (carbamazepine, SSRIs, opioids)
• Operation/surgery (post-op stress)
• Whacking brain (head trauma, SAH)
• Not (normal) thyroid, adrenal (these must be normal for diagnosis)

• DI = Dilute urine, high serum (D for Dry blood)
• SIADH = Concentrated urine, dilute serum (S for Soggy blood)