ADH

**Synthesis and release** - Made in the supraoptic (mainly) and paraventricular nuclei of the hypothalamus, transported down axons bound to neurophysin II, and stored/released in the posterior pituitary (neurohypophysis). - Release is stimulated by: ↑ plasma osmolality (most sensitive trigger, detected by hypothalamic osmoreceptors; threshold ~280-285 mOsm/kg), hypovolemia/hypotension (baroreceptors; less sensitive but a more powerful stimulus when significant, >10% volume loss), angiotensin II, nausea, pain, stress, and drugs (nicotine, opioids, carbamazepine, cyclophosphamide, SSRIs). - Release is inhibited by: ↓ osmolality, alcohol, and ANP.

**Receptors and actions** - V2 (Gs → ↑ cAMP → PKA): on principal cells of the late distal tubule and collecting duct. It causes insertion of aquaporin-2 channels into the apical membrane, which ↑ free water reabsorption, ↓ plasma osmolality, and concentrates urine. It also ↑ urea transporter (UT-A1) activity in the medullary collecting duct, which maintains medullary concentration gradient. In endothelium, V2 stimulates release of vWF and factor VIII (basis for desmopressin use in mild hemophilia A and von Willebrand disease). - V1 (Gq → PLC → IP3/DAG → ↑ Ca2+): vascular smooth muscle vasoconstriction (↑ BP, hence the name "vasopressin"). Also platelet aggregation and hepatic glycogenolysis. - Also ↑ Na+/K+/2Cl- cotransporter (NKCC2) activity in the thick ascending limb.

**Clinical disorders** 1. *Central diabetes insipidus*: ↓ ADH production (head trauma, pituitary surgery, tumors such as craniopharyngioma, Langerhans cell histiocytosis, hypoxic brain injury/Sheehan). Polyuria, polydipsia, hypernatremia, dilute urine (low urine osm). Water deprivation test: urine remains dilute and **concentrates after desmopressin**. Treatment: desmopressin. 2. *Nephrogenic diabetes insipidus*: kidney is resistant to ADH (lithium, demeclocycline, hypercalcemia, hypokalemia, V2 receptor or AQP2 mutations, obstruction). Urine remains dilute **even after desmopressin**. Treatment: treat cause, thiazides, amiloride (especially in lithium-induced), low-sodium/low-protein diet, NSAIDs. 3. *SIADH*: inappropriate ADH release → water retention → euvolemic hyponatremia, low serum osm, inappropriately concentrated urine (urine osm >100, urine Na >40). Causes: small cell lung cancer (ectopic), CNS disorders (trauma, stroke, infection), pulmonary disease (pneumonia), drugs (SSRIs, carbamazepine, cyclophosphamide, vincristine), pain/nausea/postoperative state. Treatment: fluid restriction, salt tablets, loop diuretics, **demeclocycline**, **V2 antagonists (conivaptan, tolvaptan)**. For severe symptomatic hyponatremia (seizures, coma): hypertonic (3%) saline. Correct sodium slowly (≤8-10 mEq/L per 24 h) to avoid **osmotic demyelination syndrome (central pontine myelinolysis)**. 4. *Primary (psychogenic) polydipsia*: low ADH is appropriate response to water overload; low serum Na and Osm with dilute urine; urine concentrates with water deprivation (distinguishes from DI).

**Pharmacology** - Desmopressin (dDAVP): V2 agonist for central DI, nocturnal enuresis, hemophilia A, vWD. - Vasopressin (V1 effect): septic shock/vasodilatory shock, variceal bleeding (splanchnic vasoconstriction). - Tolvaptan/conivaptan: V2 antagonists for SIADH/hyponatremia (tolvaptan: avoid rapid correction and hepatotoxicity concerns). - Demeclocycline: tetracycline that induces nephrogenic DI. - Lithium: causes nephrogenic DI.

**High-yield pearls** - Exam pattern: Serum Na ↑ + dilute urine = DI; serum Na ↓ + concentrated urine + euvolemia = SIADH. - Oxytocin is the other posterior pituitary hormone (also made in hypothalamus: PVN mainly). - Posterior pituitary hormones are made in the hypothalamus, not the posterior pituitary itself. - ADH is a major mediator of the "free water" regulation, whereas aldosterone regulates sodium (and therefore volume).