ADH (Vasopressin) & Diabetes Insipidus - Study Notes

1. ADH (Antidiuretic Hormone / Vasopressin) - Overview

• Guyton and Hall Textbook of Medical Physiology
• Katzung's Basic and Clinical Pharmacology, 16th Edition

2. Regulation of ADH Secretion

Primary stimulus: Plasma osmolality

• Osmoreceptors in the supraoptic and paraventricular nuclei of the hypothalamus (possibly also the AV3V region) sense changes in ECF tonicity.
• When ECF is too concentrated → osmoreceptors shrink → ADH secretion increases.
• When ECF is too dilute → osmoreceptors swell → ADH secretion decreases.
• ADH levels can change up to 20x normal within minutes.

Secondary stimulus: Blood volume & pressure

• Decreased blood volume (15-25% or more) → ADH rises up to 50x normal.
• Stretch receptors in the atria inhibit ADH when overfilled; when underfilled they stimulate ADH.
• Baroreceptors in the carotid/aortic/pulmonary regions also feed into this pathway.
• At high concentrations, ADH constricts arterioles → hence the name vasopressin.

Other stimuli for ADH release:

• Nausea, pain, stress, angiotensin II
• Certain drugs (opioids, nicotine)

3. ADH Mechanism of Action

• V2 activation triggers insertion of aquaporin-2 (AQP2) water channels into the luminal membrane of collecting duct cells, increasing water permeability.
• Extrarenal V2-like receptors also regulate release of factor VIII and von Willebrand factor, increasing platelet aggregation.
• Katzung's Basic and Clinical Pharmacology, 16th Edition
• Goldman-Cecil Medicine, International Edition

4. Diabetes Insipidus (DI) - Definition & Epidemiology

5. Types of Diabetes Insipidus

A. Central (Neurogenic/Hypothalamic) DI

• Tumors (e.g., craniopharyngioma, pituitary adenoma resection)
• Head trauma / basal skull fracture
• Neurosurgical procedures
• Infiltrative disease: neurosarcoidosis, histiocytosis, tuberculous meningitis
• Multiple sclerosis
• Congenital/genetic: autosomal dominant - mutations in the neurophysin portion of the pre-prohormone; presents later in childhood as neuronal cell death accumulates
• Idiopathic (some cases)
• Brain death

• As few as 10-15% of normal vasopressinergic neurons is sufficient to maintain asymptomatic urine volumes; loss of even a few more neurons rapidly escalates polyuria.
• Collecting duct cannot concentrate the dilute filtrate → large volume of hypotonic urine → rising serum osmolality → thirst → secondary polydipsia.
• Plasma AVP levels are low or unmeasurable relative to plasma osmolality.

• Polyuria (often >3-4 L/day before patient notices), polydipsia
• Preference for cold liquids
• Nocturia impairs sleep
• Serum sodium tends high-normal; urine sodium is usually low
• If thirst mechanism is also impaired: hypernatremia, dehydration, risk of brain damage

B. Osmoreceptor Dysfunction (Variant of Central DI)

• Neurohypophysis is intact; osmoreceptive cells in the anterior hypothalamus are damaged.
• No osmotically stimulated vasopressin secretion AND no thirst sensation.
• Baroreceptor-mediated ADH release (via hypovolemia) is preserved.
• Patients are chronically dehydrated with high serum sodium (hypovolemic hypernatremia).
• Also called adipsic/hypodipsic DI or "essential hypernatremia."
• Unique cause: anterior communicating artery aneurysm clipping.

C. Nephrogenic DI

• Congenital: vomiting, constipation, failure to thrive, fever in neonates; hypernatremia with hypotonic urine.
• Adults: polyuria and polydipsia but usually normal sodium (adequate thirst response).
• Plasma AVP levels are high or appropriate for plasma osmolality (unlike central DI).

D. Gestational DI

• Elevated activity of placental vasopressinase (cysteine aminopeptidase/oxytocinase) rapidly degrades circulating ADH.
• Occurs during pregnancy; usually resolves after delivery.
• Can unmask pre-existing partial central or compensated nephrogenic DI.
• Plasma vasopressin often unmeasurable due to circulating vasopressinase.

E. Primary Polydipsia (Dipsogenic / Psychogenic)

• Disorder of excess fluid intake, not of ADH secretion or action.
• Psychogenic: associated with schizophrenia, mania, OCD (prevalence up to 40% in psychiatric hospitals).
• Dipsogenic: excess thirst from hypothalamic lesions or idiopathic (no psychiatric illness).
• Excessive intake suppresses ADH → dilute urine mimics DI.
• Prolonged intake causes medullary "washout" → even after stopping, urine concentrating ability is slow to recover.
• Serum sodium tends low-normal or below normal; uric acid levels typically lower than other DI types.

6. Diagnosis

• Low (<135 mmol/L) → suggests primary polydipsia (patients drink themselves into hyponatremia).
• High (>147 mmol/L) → suggests central or nephrogenic DI - proceed to desmopressin (DDAVP) test.
• Normal (136-146 mmol/L) → proceed to further testing.

• After water deprivation, measure urine osmolality, then give desmopressin.
• Urine Osm >800 mOsm/kg after deprivation → mild primary polydipsia.
• Urine Osm 300-800, then >9% rise with DDAVP → partial central DI.
• Urine Osm <300, then >50% rise with DDAVP → complete central DI.
• Urine Osm <300, then <50% rise with DDAVP → nephrogenic DI.
• Diagnostic accuracy only ~70% overall (41% for primary polydipsia).

• Copeptin is the C-terminal fragment of pre-pro-AVP; it is a stable, easily measured surrogate for AVP.
• Baseline copeptin ≥21.4 pmol/L (without prior water deprivation) → complete/partial nephrogenic DI.
• Copeptin <21.4 pmol/L → hypertonic saline infusion test: stimulated copeptin >4.9 pmol/L at sodium ≥150 mmol/L → primary polydipsia; <4.9 pmol/L → central DI (97% diagnostic accuracy).

• Loss of the posterior pituitary bright spot on T1-weighted MRI (normally present as hyperintense signal representing neurosecretory vesicles containing AVP). Absence is suggestive but not diagnostic.
• Goldman-Cecil Medicine, International Edition
• Harrison's Principles of Internal Medicine, 22nd Edition (2025)

7. Treatment

Central DI

• Desmopressin (DDAVP) - synthetic analogue of ADH with:
  • Selective V2 activity (minimal V1/pressor activity)
  • Antidiuretic-to-pressor ratio 4,000x that of vasopressin
  • Half-life 1.5-2.5 hours (vs. 15 min for vasopressin)
  • Routes: IV/SC, intranasal (10-40 mcg/day in 2-3 doses; bioavailability 3-4%), oral (0.1-0.2 mg 2-3x/day; bioavailability <1%)
  • Oral absorption reduced 50% with food; dose on empty stomach
  • Key complication: hyponatremia - mild (131-134 mmol/L) in ~25% of patients; severe (<130 mmol/L) in ~15%. Use "desmopressin escape" (allow periodic brief aquaresis) to reduce risk.

Nephrogenic DI

• Desmopressin generally ineffective (V2 receptor absent/non-functional).
• Thiazide diuretics (e.g., hydrochlorothiazide) + amiloride + low-sodium diet ± NSAIDs - reduces polyuria by causing mild volume contraction → increased proximal tubular reabsorption.
• Caution: thiazide + lithium → decreased lithium excretion → risk of lithium toxicity.
• Discontinue causative drugs where possible.

Primary Polydipsia

• Gradual reduction of fluid intake; treat underlying psychiatric illness.
• Ice chips/hard candy to reduce mouth dryness.
• GLP-1 analogues have shown promise in reducing fluid intake and thirst.
• Katzung's Basic and Clinical Pharmacology, 16th Edition
• Harrison's Principles of Internal Medicine, 22nd Edition (2025)
• Goldman-Cecil Medicine, International Edition

8. Quick Comparison Table