W6 ADH disorders (SM) Flashcards
Posterior Pituitary Hormones:
Which hormones are stored here?
Oxytocin and ADH (nonapeptides) are produced by neurons in the paraventricular and supraoptic nuclei of the hypothalamus.
These hormones are transported through the hypothalamic-hypophyseal tract to the posterior pituitary, where they are stored
until needed (also called neural hormones).
Upon appropriate stimuli, the hormones are released into the bloodstream and exert their respective physiological effects on target tissues and organs.
What are nonapeptides?
Nonapeptides
* A peptide class consisting of nine amino acids and very similar structures.
* Despite their structural similarity, these
nonapeptides play vastly different physiological roles.
What are the functions of Oxytocin?
- Stimulate “milk let-down”, expression of breast milk
- Uterine smooth muscle - contraction
- Maternal behaviour / sexual behaviour /
social bonding ? - Clinical use: Induction/enhancement of labour
(Positive feedback axis)
Antidiuretic Hormone (ADH)/ Arginine Vasopressin (AVP) :
What is hypovolemia and what does it lead to?
Anti-diuresis: Stopping the ‘diuresis’ process- passing urine
Hypovolemia: Increase in tissue fluid osmolality (loss of blood volume) triggers ADH release
- ADH is secreted by the cells in the hypothalamus, transported to the posterior pituitary and stored until nervous stimuli.
- ADH acts (V2 receptor- GPCR) in the kidney to promote the insertion of aquaporin 2 water channels in the apical membrane
of late DCT (P-cells) and collecting ducts to increase the water permeability, thus increasing blood volume, venous return,
cardiac output and blood pressure. - ADH (at higher concentration) constricts peripheral vessels via activating the V1 receptor (reason for the alternative name, vasopressin)
- Together, ADH play a key role in water/osmotic homeostasis in the body
ADH play a key role in water/osmotic homeostasis:
- Dec ADH/AVP (hyposecretion)= Dec Aquaporins= More water is EXCRETED in URINE (Dilute Urine)
- Diabetes Insipidus
- Inc ADH/AVP (hypersecretion) = Inc Aquaporins = <ore Water is RETAINED in the Blood (Dilute Blood)
- SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)
Osmolarity- 290 mOsm/L (Homeostasis) ( 30% solute & 70% water)
ADH or AVP Disorders- Diabetes Insipidus:
What are the criteria?
A deficiency of anti-diuretic hormones leads to Diabetes Insipidus
(rare disease, prevalence-1:25000, affects any age and sex)
* excessive diuresis/ urine output, hypotonic polyuria (> 50ml/Kg)
* dilute urine (osmolality <300 mOsm/L)
* compensatory increased thirst, polydipsia (water intake of up to 20L/day)
What are the types of Diabetes insipidus? (genetic or acquired) (4(
- Central DI: Neurohypophyseal neurons injury or mutations in ADH/AVP (decrease in the release of ADH)
- Nephrogenic DI: Dysfunction of ADH receptor (V2 receptors) or aquaporins
- Gestational DI: Degradation of ADH by the enzyme cysteine aminopeptidase, vasopressinase
- Dipsogenic DI: Abnormally low thirst threshold leading to excessive thirst
Central DI: Neurohypophyseal neurons injury or mutations in ADH/AVP (decrease in the release of ADH)
Causes?
Diagnosis?
Marker?
Causes of DI: Brain injury; Infection; Loss of blood to posterior pituitary/hypothalamus;
Neurosurgery; Tumor; Genetic defects in ADH synthesis
Diagnosis: Urine osmolality increases >50% following water deprivation and DDAVP
(Desmopressin) administration; Copeptin <4.9 pmol/L following osmotic stimulation; MRI of the pituitary gland
(Copeptin is a polypeptide that is released as part of normal ADH production and thus it is an effective surrogate marker for the measurement of ADH and helps to differentiate the central DI
from nephrogenic DI)
Central DI: Neurohypophyseal neurons injury or mutations in ADH/AVP (decrease in the release of ADH)
Treatment?
Treatment: Desmopressin/vasopressin, thiazide diuretics (paradoxical effect!) and fluids
* Desmopressin, 1-deamino-8-O-arginine-vasopressin (DDAVP) is a synthetic analogue of vasopressin (or ADH/AVP- agonist); It is more potent (10 times) than vasopressin, selectively activates the V2 receptor to
upregulate the aquaporin levels and increase water reabsorption (prevent water loss in the urine).
* DDAVP has less vasoconstriction effect (2000 folds less potent effects compared to vasopressin). Also used to treat nocturnal polyuria and nocturnal enuresis (bedwetting).
* Vasopressin activates all V1,2,3 receptors, whereas its derivative, Terlipressin acetate, is a weak agonist
Side effect: Hyponatremia (dilution of intravascular volume)
-sodium levels must be monitored to avoid seizures.
Nephrogenic DI: Dysfunction of ADH receptor (V2 receptors) or aquaporins
Causes?
Diagnosis?
Treatment?
Causes of DI: Lithium salts; Foscarnet; Clozapine, congenital defect in AQP2 gene;
Hypercalcaemia; Hypokalaemia; Protein malnutrition; Aging
Diagnosis: Urine osmolality increases <50% following water deprivation and DDAVP
administration. Baseline copeptin >21.4 pmol/L
Treatment: Complex and more challenging
* Discontinue contributing therapy/medication
* Thiazide diuretics (MOA is unknown!)
* Carbamazepine (ADH sensitiser at the renal tubules and collecting ducts)
* Fluids and renal diet (low sodium, protein, and phosphorous)
* In the pipeline: use of statins to upregulate aquaporin 2 levels
Gestational DI: Degradation of ADH by the enzyme cysteine aminopeptidase, vasopressinase
Causes?
Diagnosis?
Treatment
Causes of DI: Pregnancy; Genetics; Diet; Sedentary lifestyle
Diagnosis: Serum osmolality greater than 285 mOsm/kg with persistent urine osmolality less than 300
mOsm/L.
Treatment: Desmopressin/vasopressin
Dipsogenic DI:
What is it?
Causes?
Diagnosis?
Treatment
Abnormally low thirst threshold leading to excessive thirst
Causes of DI: Psychotic or neuro-developmental disorders; Damage to the hypothalamus; Hippocampus deformations; Brain lesions to the amygdala; Stress-reducing behaviours, Genetics
Diagnosis: Excretion of dilute urine exceeding 40-50 ml/kg of body weight
Treatment: Behavioural therapy (reduce water intake and balanced diet); Antipsychotic medications)
ADH or AVP Disorders- SIADH:
What is it?
Syndrome of inappropriate ADH secretion (SIADH) is a condition in which the body makes too much (excess) antidiuretic hormone (ADH):
Excess anti-diuresis, retention of water in the body (dilute blood and concentrated urine) and hyponatremia (perhaps related to the dilution effect, not due to sodium loss)
Causes of SIADH?
- CNS pathologies (meningitis, encéphalites, thromboses and others)
- Cerebral malignancy
- Pulmonary diseases
- Post-surgery nausea and pain
- CNS drugs (antidepressants, antipsychotics, SSRIs)
- Chemotherapeutics (cyclophosphamide, vincristine, vinblastin)
- ADH sensitising drugs (carbamazepine, tolbutaminde, chlorpropamide)
- Administration of ADH or its analogues (desmopressin, vasopressin
SIADH
Treatment: ADH/AVP receptor antagonists:
Example?
Mechanism of action?
Side effects?
C/I or Cautions?
Tolvaptan is a selective vasopressin V2 receptor antagonist
MOA: By antagonising V2 receptors in the renal collecting ducts, Tolvaptan
downregulates the aquaporins (AQP2) insertion into the walls and prevents
water absorption. This ultimately increases urine volume, decreases urine
osmolality, and increases electrolyte-free water clearance to reduce
intravascular volume and increase serum sodium levels.
Side effect: Hypernatraemia; appetite decreased; asthenia; constipation;
dehydration; diarrhoea; dizziness; dry mouth; dyspnoea; gastrointestinal
discomfort; gastrooesophageal reflux disease; gout; headache; hepatic
disorders; hyperglycaemia; hyperuricaemia; insomnia; muscle spasms;
palpitations; polydipsia; skin reactions; thirst; urinary disorders; weight loss
Contraindicated in anuria (no clinical benefit in anuric patients),
hypernatraemia, hypovolaemic hyponatraemia (may lead to hypotension
and renal failure), volume depletion and altered thirst perception
Cautioned in hepatic injury, diabetes mellitus and urinary obstructions
Tolvaptan is indicated to treat hyponatraemia in congestive heart failure
and to prevent renal failure in autosomal polycystic kidney disease.
