Neurohypophysial disorders Flashcards
What are the effects of vasopressin
Anti-diuretic - increase water reabsorption form renal cortical and medullary collecting ducts via V2 receptors
What is the mechanism of vasopressin action
- vasopressin binds to V2
- G-protein action activates adenyl cyclase
- ATP turns into cyclic AMP
4 protein kinase A activated - synthesis of aquaporin molecules (AQP2)
- aggraphores move to the apical membrane
- insertion of aquaporins onto the membrane
- Water moves through down its concentration gradient
- AQP 3 and 4 are less sensitive to vasopressin but attach to the basolateral (serosal) membrane
How is vasopressin release regulated
Osmoreceptors located in the organum vasculosum project to the hypothalamic
- Increase in extracellular NA+
- Osmoreceptor shrinks as water diffuses out
- Increased osmoreceptor firing rate
- Vasopressin released
What is the normal response to water deprivation
- Increased serum osmolality
- stimulation of osmoreceptors (thirst)
- increased vasopressin released
- increased water reabsorption from renal collecting ducts
- Reduced urine volume, increase in urine osmolality and reduction in serum osmolality
What is the consequence of a lack of vasopressin
Diabetes insipidus
What is syndrome of inappropriate ADH
Too much vasopressin.g. tumours absorb water
What are the two type of diabetes insipidus
Central/ cranial and nephrogenic
What is central/cranial DI
Lack of vasopressin
What is nephrogenic DI
Kidneys are resistant to vasopressin
What are the symptoms of DI
polydipsia (increased thirst) polyuria (large urine volume) Dilute urine (hypo-osmolar) Dehydration Possible disruption to sleep with associated problems
What is the aetiology of cranial diabetes insipidus
Acquired
Damage to neurohyophysial system
Traumatic brain injury
Pituitary surgery
Pituitary tumours, craniopharyngioma
Metastasis to the pituitary gland e.g. breast
Granulomatous infiltration of media eminence e.g. TB , sarcoidosis
Congenital is rare
What is the aetiology of nephrogenic DI
Acquired
Drugs e.g. lithium
Congenital - rare
Mutation in gene encoding V2 receptor, AQP2
What is psychogenic polydipsia
Seen in psychiatric patients
Polydipsia and polyuria but ability to secrete vasopressin in response to osmotic stimuli is preserved
May be due to dry mouth side effects of anti-cholinergic agents or patients told to drink a lot
What are the biochemical features of DI
Hypernatraemia
Raised urea
Increased plasma osmolality
Dilute (hypo-osmolar) urine
What are the biochemical features of psychogenic polydipsia
Mild hyponatraemia – excess water intake
Low plasma osmolality
Dilute (hypo-osmolar) urine - ie low urine osmolality
Where is V1 found
Vascular smooth muscle Non-vascular smooth muscle Anterior pituitary Liver Platelets CNS
Where is V2 found
Kidney
Endothelial cells
Give examples of selective vasopressin receptors peptidergic agonsists
V1 - Terlipressin
V2 - Desmopressin (DDAVP)
Describe desmopressin (administration, effect and care)
Nasal, oral administration
Reduction in urine volume and concentration for cranial DI
Tell patient not to continue dirking large amounts of fluid (may lead to hyponatraemia)
What is used to treat nephrogenic diabetes insipidus
Thiazides e.g. bendroflumethiazide
What is the possible mechanism for thiazide action
- Inhibits Na+/Cl- transport in distal convoluted tubule (→ diuretic effect)
- Volume depletion
- Compensatory increase in Na+ reabsorption from the proximal tubule (plus small decrease in GFR, etc.)
- Increased proximal water reabsorption
- Decreased fluid reaches collecting duct
- Reduced urine volume
What is a syndrome of inappropriate ADH
Plasma vasopressin concentration is inappropriately high for the existing plasma osmolality
How does a syndrome of inappropriate ADH lead to hyponatraemia
- Increased vasopressin
- Increased water reabsorption form Renal collecting ducts
- Expansion of ECF volume
- Atrial natriuretic peptide from right atrium -> natriuresis
- Euvolaemia and hyponatraemia
What are the signs or a syndrome of inappropriate ADH
Raised urine osmolality, decreased urine volume (initially)
Decreased p[Na+] (HYPONATRAEMIA) mainly due to increased water reabsorption
What are the symptoms of a syndrome of inappropriate ADH
May be symptomless
If p[Na+] <120 mM: generalised weakness, poor mental function, nausea
If p[Na+] <110 mM: confusion leading to coma and ultimately death
What are the causes of a syndrome of inappropriate ADH
CNS (SAH, stroke tumour,TBI)
Pulmonary disease (pneumonia, bronchiecstasis)
Malignancy
(Small cell lung)
Drug related (carbamazepine, SSRI)
Idiopathic
What is the treatment for a syndrome of inappropriate ADH
Reduce immediate concern e.g. hyponatraemia
Immediate: fluid restriction
Long term: use drugs which prevent vasopressin action in the kidneys
e.g. induce nephrogenic DI via demeclocyline
Inhibit action of ADH via V2 receptor antagonists
What is Vaptains
Non-Competitive V2 receptor antagonists
Inhibit AQP2 synthesis and transport to collecting duct apical membrane, preventing renal water reabsorption
Aquaresis – solute-sparing renal excretion of water, contrast with diuretics (diuresis) which produce simultaneous electrolyte loss
Licensed in the UK for treatment of hyponatraemia associated with SIADH
Very expensive – limits their current use
