Neurohypophyseal disorders

Question 1

What are the 2 posterior pituitary hormones?

Answer 1

Vasopressin (=anti diuretic hormone)

Oxytocin

Question 2

What radiological method is used to visualise the PP?

Answer 2

MRI

-> PP bright spot on the MRI

Question 3

What are the actions of VP? What receptors does it act on?

Answer 3

a) V1 receptors: arterial SM -> vasoconstriction -> increased BP and also ACTH production
b) V2 receptors in principal collecting duct cells: increases water reabsorption by inserting AQP2 into cell membrane

Question 4

Diuresis

Answer 4

Increase in urine production

Question 5

What is the main action of VP?

Answer 5

Principal effect of vasopressin = ANTI-DIURETIC ie increases water reabsorption from renal cortical and medullary collecting ducts via V2 receptors

Question 6

What happened once VP binds to a V? receptor?

Answer 6

1) G-protein activares adenyl cyclase
2) ATP is transformed into cAMP through AC
3) cAMP activates PKA
4) PKA activates other cellular mediators
5) AQP2 synthesis occurs
6) aggraphores migrate to the apical membrane
7) insertion of AQP2 in apical membrane
8) water enters the cell along osmotic gradient
9) water is reabsorbed on the basolateral side via AQP3 and AQP4

Question 7

Organum vasculosum

Answer 7

• deviod of a BBB
• communicates with systemic circulation, can sense changes in plasma osmolarity
• one of the 4 circumventricular organs of the brain

Question 8

Which osmoreceptors act on the release of VP?

Answer 8

• osmoreceptors located in the organum vasculosum
• project into hypothalamic paraventricular and supraopticc nuclei
• osmoreceptors = neurones

Question 9

How do osmoreceptors sense changes in osmolarity and cause VP release?

Answer 9

• osmoreceptors located in the organum vasculosum sense changes in osmolarity and shrink (due to water release) when it rises
• this shrinking leads to increased firing of osmoreceptors
• firing -> VP release

Question 10

What are the 2 types of Diabetes Insipidus?

Answer 10

• Cranial/central - absence or lack of circulating VP
• Nephrogenic - end organ (kidney) resistance to VP
  - > very rare!!!

Question 11

Aetiology of cranial DI

Answer 11

Acquired (generally)

• traumatic brain injury
• pituitary surgery
• pituitary tumors (craniopharyngioma)
• metastasis to the pituitary (e.g. breast)
• granulomatous infiltration of median eminence eg TB, sarcoidosis

Congenital - rare

Question 12

Aetiology of nephrogenic DI

Answer 12

Congenital
- rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel)

Acquired
- Drugs (e.g. lithium)

Question 13

Signs and Symptoms of DI

Answer 13

• Polydipsia
• Polyuria
• Nocturia
• Hypoosmolar urine
• Dehydration (and consequences) if fluid intake is not maintained - can lead to death

Question 14

Psychogenic polydipsia

Answer 14

• most frequently seen in psychiatric patients, aetiology unclear, may reflect anti-cholinergic effects of medication
• can be in patients told to drink plenty

-> excess fluid intake (polydipsia) and therefore excess urination (polyuria). However, in contrast to DI patients the ability to secrete VP in response to osmotic stimuli is preserved.

Question 15

What are biochemical features of DI?

Answer 15

• hypernatraemia
• raised urea
• increased plasma osmolarity
• hypo-osmolar urine

Question 16

biochemical features of psychogenic polydipsia

Answer 16

• mild hyponatraemia
• low plasma osmolarity
• hypo-osmolar urine

Question 17

How does the body respond to exogenous VP?

Answer 17

Response at V1 AND V2 receptors!!

Question 18

Where are V1 receptors located?

Answer 18

Vascular smooth muscle
Non-vascular smooth muscle
Anterior pituitary
Liver 
Platelets
CNS

Question 19

Where are V2 receptors located?

Answer 19

• Kidney (principal collecting duct cells)

- endothelial cells

Question 20

Selective V1 Receptor VP agonist exampled

Answer 20

TERLIPRESSIN

Question 21

VP agonist that acts selectively on V2 receptors

Answer 21

Desmopressin (DDAVP)

Question 22

Desmopressin administration

Answer 22

• nasally
• tablets
• subcutaneous

Question 23

Desmopressin

Answer 23

SELECTIVE VASOPRESSIN RECEPTOR PEPTIDERGIC AGONIST for V2 receptors

-> reduces urine volume in cranial DI + concentration

Question 24

How do you treat cranial DI?

Answer 24

• Desmopressin

- care to tell patients not to continue drinking massive amounts of fluid - risk of hyponatraemia

Question 25

How do you treat nephroggenic DI?

Answer 25

- thiazides (e.g. bendoflumethiazide)

Question 26

Possible mechanism of thiazides in treatment of nephrogenic DI

Answer 26

- 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

Question 27

SIADH

Answer 27

Syndrome of inaproppraite Anti-Diuretic Hormone the plasma vasopressin concentration is inappropriately high for the existing plasma osmolality

Question 28

Signs of SIADH

Answer 28

- raised urine osmolality - decreased urine volume (initially) - decreased p[Na+] (HYPONATRAEMIA) mainly due to increased water reabsorption

Question 29

Symptoms of SIADH

Answer 29

- can be symptomless - however if p[Na+] <120 mM: generalised weakness, poor mental function, nausea - if p[Na+] <110 mM: CONFUSION leading to COMA and ultimately DEATH

Question 30

Causes of SIADH

Answer 30

- idiopathic - CNS (stroke, tumor, TBI, Sub arachnoid haemorrhage) - malignancy (lung, small cell ca) - pulmonary (pneumonia, bronchiectasis) - drug related (SSRI, carbamazepine)

Question 31

Vaptans

Answer 31

- 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

Question 32

Treatment of SIADH

Answer 32

- Appropriate treatment (e.g. surgery for tumour) To reduce immediate concern, i.e. hyponatraemia 1. Immediate: fluid restriction 2. Longer-term: use drugs which prevent vasopressin action in kidneys e.g. induce nephrogenic DI ie reduce renal water reabsorption - demeclocyline inhibit action of ADH - V2 receptor antagonists

Question 33

Give an example of what causes ANP release

Answer 33

- high extra cellular fluid (ECF) volume - right atrium releases atrial natriuretic peptide - this causes natriuresis which a) restores euvolaemia b) may cause or contribute to hyponatraemia

Question 34

Aquaresis

Answer 34

- solute sparing renal excretion of water (contrast with diuretic which cause diuresis and therefore produce simultaneous electrolyte loss - can be induced by vaptans (V2 receptor antagonists, used in SIADH)