Water Hazard Posterior Pituitary Regulation

4.2 - "Wat "Water er Hazard": Posterior pituitary regulation (ADH, DDAVP, ADH Receptor Antagonists) ADH (aka vvasopressin) asopressin) • responsible for regulating tonicity of plasma by regulating free water absorbed by the nephron ( water hazard). • Collecting duct is the site of ADH action & water resorption, as well as mineralocorticoid action & Na resorption (ADH boy). ADH released by posterior pituitary (water jug on posterior). ADH has antidiuretic properties and vasopressor properties. Act via two subtypes of receptors o V1 receptors are responsible for vasopressor activity. GqPCR, activates PLC → IP3 + DAG →↑intracellular Ca2+ (V1 hole on Q shaped green). Found in vascular smooth muscle cells → vasoconstriction & increased BP (angry golfer constricting golf club) o V2 receptors are GsPCR → activation of adenylyl cyclase →↑cAMP (V2 hole on S shaped green). Found on basolateral membrane of the collecting duct (location). Causes translocation of aquaporin 2 to the apical membrane of luminal cells → increased water permeability → reabsorption of free water (water boy at collecting duct translocating pure water). o There are extrarenal V2 receptors found in the vascular endothelium (endothelial tile). Activation →↑ release of coagulation factor VIII and vWF from endothelial cell Weibel-Palade bodies → increased platelet aggregation (8 ball on von Wille brand pool table). ADH activation of V2 stimulates factor 8. • Administered exogenously, directly constricts mesenteric arterioles, which can be useful in the management of esophageal variceal bleeding d/t reduction in portal pressure (bulging mucosal colored golf bag with blue veiny golf clubs) • DDAVP (desmopressin acetate) o Long acting synthetic analog of ADH (saving desert mobile). o High specificity for V2 receptor, which means minimal pressor activity (V2 engine). o Indications: ▪ Activity at vascular V2 Rs can be used to increase vWF release from vascular endothelium, useful for treating von Willebrand deficiency (scratched felt on pool table). • Von Willebrand disease will often present with increased bruising & mucosal bleeding (e.g. GI, oropharyngeal, uterine) (cue ball beating up player) ▪ Factor 8 deficiency (hemophilia A) (missing 8 ball & A-frame). • Usually presents with intramuscular bleeding, prolonged bleeding, hemarthrosis (bleeding knee) ▪ Night enuresis d/t ↓urine production (wet mattress) o May cause hyponatremia (falling peanuts) Diabetes insip insipidus idus • inability to concentrate urine (endless insipid trickle of a fountain shaped like a urinator) • Central (not producing sufficient ADH) (brain shaped dehydrating sand traps). Can be caused by number of processes (radiation, tumor, AI process) (crawling thirsty golfer). o Can administer DDAVP • nephrogenic (not responding to ADH) (brain & kidney shaped dehydrating sand traps). Usually d/t blockade by pharm agents, occasionally genetic (frustrated golfer ignoring water boy). Lithium is a common cause of nephrogenic DI (“lift-ium” balloons). Generally resolves with discontinuation of drugs. o Thiazide diuretic (pasty thigh guy) → volume reduction → proximal resorption of sodium & water, decreasing dependence on collecting duct activity. Treats polyuria & polydipsia. However, diuretics can decrease lithium clearance, increasing risk of toxicity. o Amiloride (K+ sparing diuretic) (almond snack cart) can treat lithium-induced nephrogenic DI. Blocks lithium entry into CD cells. o NSAIDs (fire extinguisher) Decrease PG production that normally antagonize ADH. SIADH (syndro (syndrome me of inappropri inappropriate ate ADH) • Overproduction of ADH resulting in excess water retention & hyponatremia (inappropriate water boy). May result from CNS disorders, traumas, ectopic production in lung cancer, or certain pharmacologic agents. • Treat with V2 receptor antagonisms, including conivaptan, tolvaptan (Vaporizer model water gun for -vaptan suffix). o Promote free water excretion by inhibiting aquaporin translocation. Can be used in conjunction with hypertonic saline & free water restriction. • Be careful in correcting hyponatremia too rapidly. May cause hypernatremia or, in severe cases, central pontine myelinolysis (osmotic demyelination syndrome) → irreversible CNS damage (salty peanuts being thrown at head) o Maximum rates of correction: less than 10 mEq/L at 24h and less than 18 mEq/L at 48 hours. Monitor sodium levels closely • Demeclocycline – a tetracycline – can be used to treat SIADH by interfering with V2 receptor activity. MOA not known. Not first line.