3. Neurohypophysial disorders Flashcards
How does vasopressin have an antidiuretic effect?
- Acts on the renal (cortical and medullary) collecting ducts
- Stimulates synthesis and assembly of Aquaporin 2
- Increased water transport
- Increased water reabsorption
Apart from being an antidiuretic, what are the other actions of vasopressin?
- Vasoconstriction - V1a
- Corticotrophin (ACTH) release - V1b
- Factor VIII and von Willebrand Factor release - V2
- Central effects
What are actions of oxytocin?
- Constriction of myometrium (middle layer of uterine wall) at parturition
- Milk ejection reflex
- Central effects
- Acts on oxytocin receptors
What does a lack of oxytocin cause?
- Not that bad
* Parturition and milk effects are induced/replaced by other means
What does a lack of vasopressin lead to?
Diabetes insipidus
• Central/cranial - absence or lack of circulating vasopressin
• Nephrogenic - kidneys resistant to vasopressin
• Water isn’t reabsorbed
What can cause central diabetes insipidus?
• Damage to neurohypophysial system:
- injury to neurohypophysis
- surgery
- cerebral thrombosis
- tumours (intrasellar and suprasellar)
- granulomatous infiltration of median eminence
• Idiopathic (unknown cause/spontaneous origin)
• Familial (rare) - usually receptor gene mutations
What can cause nephrogenic diabetes insipidus?
- Drugs e.g. lithium, DMCT
* Familial (rare)
What are the signs and symptoms of diabetes insipidus?
- Polyuria (lot of urine)
- Very dilute urine (hypo-osmolar)
- Thirst and increased drinking (polydipsia)
- Dehydration
- Disruption of sleep
- Electrolyte imbalance
Outline how a lack of vasopressin leads to the effects this has on the body
- Can’t reabsorb water => increased urine excretion and reduced ECF volume
- This leads to increased plasma osmolarity => osmoreceptors trigger vasopressin release and thirst
- Increased drinking, decreased pOsm, expansion of ECF volume
What is psychogenic polydipsia?
- Vasopressin system works fine
- Central disturbance - increased drive to drink
- Fall in plasma osmolarity => vasopressin inhibited
- Polyuria => reduced ECF volume, increased plasma osmolariy
Describe the tests used to compare polydipsia, central DI and nephrogenic DI in a person?
• Initially all have similar urine osmolarities when hydrated
• Fluid deprivation test:
- normal person releases vasopressin and concentrates urine => increased urine osmolarity (pOsm remains)
- in polydipsia, urine osmolarity is slightly lower due to washed out osmotic gradient (polyuria has already removed some ions in the patient previously)
- no/little change in central and nephrogenic diabetes insipidus
• DDAVP administration:
- central DI urine osmolarity increases - vasopressin receptors work
- nephrogenic DI doesn’t respond
When a diabetes insipidus patient is dehydrated, how does their urine and plasma osmolarity change?
- Normally, urine and plasma osmolarity increase when dehydrated
- In DI, plasma osmolarity increases but urine osmolarity barely increases
How can you test if someone has central DI without dehydration?
- Give patient hypertonic saline IV
- Quick increase in pOsm
- Stimulates vasopressin release
- Rapid increase in plasma vasopressin in normal people, polydipsics and nephrogenic DI patients
- Central DI - no change in vasopressin
What is SIADH and what does it lead to?
• Syndrome of inappropriate ADH
- increased ADH
- increased water reabsorption
- decreased plasma osmolarity (hyponatraemia)
- decreased urine volume
- natriuresis - more sodium excreted in urine
What are the symptoms of SIADH, referring to responses to changing [Na+]?
• Can be asymptomatic • When [Na+] falls <120 mM - generalised weakness - poor mental function - nausea • When [Na+] falls <110 mM - confusion - coma - death
What are the different causes of SIADH?
- Tumours (ectopic secretion)
- Neurohypophysial malfunction e.g. meningitis
- Thoracic disease e.g. pneumonia
- Endocrine disease e.g. Addison’s disease
- Physiological - normal circumstances where vasopressin release is stimulated by non-osmotic stimuli e.g. hypovolaemia, pain, surgery
- Drugs e.g. chlorpropamide
- Idiopathic
How is SIADH treated?
• Treatment depends on cause e.g. surgery for tumour
• If hyponatraemic
- immediate: fluid restriction
- longer-term: drugs that prevent vasopressin action in kidneys e.g. lithium, DMCT, V2 receptor antagonists
What is the response in the body to exogenous vasopressin (argipressin)?
- V1 actions as well as V2
- V1: vasoconstriction on VSMCs, affects non-vascular smooth muscle in intestines, liver, platelets and CNS
- V2: effect on kidneys
What effect does Argipressin have on sodium?
- Natriuresis
- Unexplained side effect
- V2 mediated
- Only when given in high doses
- Contributes to hyponatraemia
What effect does Argipressin have on the CVS?
- Pressor action (elevated arterial BP)
- V1 mediated
- Coronary vessels are particularly sensitive to vasopressin
- Can cause cardiac ischaemia or angina attacks
What effect does Argipressin have on ACTH and Factor VIII + von Willebrand factor?
- Increased ACTH secretion (V1b)
* Increased Factor VIII and von Willebrand factor production (V2)
Give 2 examples of selective vasopressin receptor peptidergic agonists
• Terlipressin
- analogue of vasopressin
- only V1 effects
• Desmopressin (DDAVP)
- larger dose than argipressin needed for contraction effects (∴ little effect on vasculature)
- lower dose needed for osmolarity effects (∴ higher effect in the kidneys)
What are the clinical uses of desmopressin?
- Cranial diabetes insipidus
- Nocturnal eneuresis (bedwetting)
- Haemophilia - for V2 receptor stimulation
How can desmopressin be administered?
- Nasally
* Orally
What is the immediate effect of oral desmopressin?
- Prompt sustained decrease in urine volume
* Increase in urine osmolarity
Outline the distribution, metabolism and half-life of desmopressin?
- Retained in ECF
- Hepatic/renal metabolism
- Half-life = 5 hours
What are the negative side-effects of desmopressin?
- Fluid retention and hyponatraemia
- Abdominal pain
- Headaches
- Nausea
What does ‘peptidergic’ mean?
Describes nerve cells or fibres that use small peptide molecules as their neurotransmitters
What is terlipressin used for?
• Treating oesophageal varices
- causes vasoconstriction
- V1 agonist
What is felypressin used for?
• Added to anaesthetics that dentists use
• Prolongs action of local anaesthetics
- causes vasoconstriction in injected area, keeping it more local ∴ lasts longer
What can be used to treat nephrogenic diabetes insipidus and how does it work?
Thiazides
• Inhibits Na+/Cl- transport in distal convoluted tubule (leads to diuretic effect)
• Volume depletion
• Compensatory increase in Na+ reabsorption from PCT (+ small decrease in GFR)
• Increased proximal water reabsorption
• Decreased fluid reaching the collecting duct
• Reduced urine volume
What are Vaptans and what are they used for?
• Non-peptide vasopressin analogues
• e.g. Tolvaptan - V2 receptor ANTAGONIST
- treatment of hyponatraemia associated with SIADH
- treatment of congestive heart failure
What drugs affect vasopressin secretion?
Increase • nicotine Decrease • alcohol • glucocorticoids
