Anti- diuretic hormone disorder

posterior pituitary hormones

• oxytocin and ADH: synthesis and secretion

• synthesised by neurone in the paraventricular and supraoptic nuclei of the hypothalamus

• classified as nonpeprides (each composed of 9 amino acids)

• transported along the hypothalamic hypophyseal tract to the posterior pituitary

• stored in the posterior pituitary until stimulated by neural signals

• upon stimulation released into the bloodstream

nonapeptides

• a peptide class consisting of nine amino acids and very similar structures

• despite their structural similarity, these nonapeptides play vastly different physiological roles

oxytocin

• STIMULATE Milk let down- expressive of breast milk

• uterine smooth muscle- contraction

• maternal behaviour/ sexual behaviour

antidiuretic hormone/ arginine vasopressin

• ADH is secreted by the cells in the hypothalamus, transported to the posterior pituitary and stored until nervous stimuli

• ADH acts in the kidney to promote the insertion of aquarporin 2 water channels in the apical membrane of late DCT and collecting ducts to increase the water permeability thus increasing blood volume

osmolarity and homeostasis

• the body maintains plasma osmolarity around 290 miliosmoles per litre which reflects a balance of approximately 30% solutes and 70% water. this balance is critical for cellular function and overall fluid distribution

• ADH plays a central role in maintaining this osmotic equilibrium.

• when plasma becomes too concentrated, ADH is released to conserve water when plasma becomes too dilute, ADH secretion is suppressed to allow water excretion

diabetes insipidus

there is either a deficiency of ADH or renal insensitivity to ADH

• As a result the kidney are unable to reabsorb water effectively

• this leads to excessive water loss in the urine, producing large volumes of dilute urine, consequently the body becomes dehydrated and plasma osmolarity increases

Overview of diabetes insipidus

• diabetes insipidus is a rare endocrine disorder that results form a deficiency in the secretion or action of antidiuretic hormone also know as arginine vasopressin

• this hormone plays a role in regulating water balance in the body

• when ADH is deficient or ineffective the kidney are unable to concentrate urine, leading to excessive water loss

clinical features of diabetes insipid

• excessive urination

• dilute urine

• excessive thirst

types of DI

• central DI

• nephrogenic DI

• Gestational DI

• dipsogenic DI

central diabetes insipidus

This form results from damage to the hypothalamus or posterior pituitary, which impairs the production or release of ADH. Causes may include head trauma, neurosurgery, tumours, or genetic mutations affecting the AVP gene.

nephrogenic diabetes

In this type, the kidneys are unresponsive to ADH. The defect may lie in the V2 receptors or in the aquaporin-2 (AQP2) water channels. It can be inherited (e.g., mutations in the AVPR2 or AQP2 genes) or acquired due to medications (such as lithium), chronic kidney disease, or electrolyte disturbances

gestrational diabetes intpidus

This rare form occurs during pregnancy and is caused by the increased activity of an enzyme called vasopressinase, which is produced by the placenta. Vasopressinase degrades ADH, reducing its effectiveness and leading to symptoms of DI.

dipsogenic diabetes insipidus

This type is not due to a defect in ADH itself but rather to a dysfunction in the thirst mechanism. Individuals with dipsogenic DI have an abnormally low threshold for thirst, leading to excessive fluid intake. This suppresses ADH secretion and results in polyuria

central DI treatment

• desmopressin

• vasopressin

• terlipressin

• thiazide diuretics

• fluid management

desmopressin

Desmopressin, also known as 1-deamino-8-D-arginine vasopressin, is

a synthetic analogue of vasopressin. It is the first-line treatment for Central

DI and has several important pharmacological properties:

•Potency: Desmopressin is approximately 10 times more potent than

natural vasopressin in stimulating water reabsorption.

•Receptor Selectivity: It selectively activates the V2 receptors in the

kidneys, which promotes the insertion of aquaporin-2 channels into the

collecting duct membranes. This enhances water reabsorption and

reduces urine output.

•Reduced Vasoconstriction: Unlike vasopressin, desmopressin

vasopressin

Vasopressin is the natural form of ADH and activates all three receptor subtypes: V1, V2, and V3. While effective, its vasoconstrictive effects via V1 receptors limit its use in chronic therapy. It is more commonly used in acute settings, such as vasodilatory shock.

terlipressin

Terlipressin is a synthetic derivative of vasopressin and acts as a weak agonist at vasopressin receptors. It is primarily used in conditions like variceal bleeding and hepatorenal syndrome, rather than in DI.

thiazide diuretics

Interestingly, thiazide diuretics can be used in the management of DI, despite being diuretics. They exert a paradoxical antidiuretic effect by reducing the delivery of sodium and water to the distal nephron, thereby decreasing urine volume. This is particularly useful in nephrogenic DI, but may also be used adjunctively in central DI.

fluid management

Patients with DI must maintain adequate fluid intake to compensate for water loss and prevent dehydration. In some cases, intravenous fluids may be required

nephrongenic DI

causes DI; lithium salts, foscarnet; clozapine

causes of nephrogenic DI

• medications

• electrolyte balances

• genetic defects

medications

• Patients with DI must maintain adequate fluid intake to compensate for water

  loss and prevent dehydration. In some cases, intravenous fluids may be

electrolyte imbalance

Hypercalcaemia (high calcium levels)

• Hypokalaemia

genetic defects

Mutations in the AQP2 gene, leading to congenital

nephrogenic DI

treatment for nephrogenic DI

• discontinuation of contributing medication

• thiazide diuretics

• carbamazepine

• diaterary management

• emerging therapies

discontinuation of contributing medication

Stopping drugs like lithium or foscarnet can sometimes

reverse or improve the condition.

thiazide diuretics

These paradoxically reduce urine output, although the exact

mechanism is not fully understood. They may work by

inducing mild volume depletion, which enhances proximal

tubular reabsorption of sodium and water.

carbamazepine

This anticonvulsant has been shown to sensitise the kidneys

to ADH, improving water reabsorption in some cases.

dietary manament

A renal diet low in sodium, protein, and phosphorus helps

reduce solute load and urine volume.

2. Adequate fluid intake is essential to prevent dehydration.

emerging therapies

Statins are being investigated for their potential

to upregulate aquaporin-2 expression, offering a novel

therapeutic avenue

gestational diabetes insidious treatment

desmopressin

dipsogenic diabtetes inspidous treatment

Behavioural therapy to reduce excessive water intake

•Dietary modifications to maintain fluid and electrolyte balance

•Antipsychotic medications in cases where the condition is linked to

psychiatric disorders

SIADH causes

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

tolvaptan: a selective V2 receptor antagonists MOA

Tolvaptan is a selective antagonist of the vasopressin V2 receptor, which is

located in the renal collecting ducts. Under normal conditions, ADH binds to

these receptors and promotes the insertion of aquaporin-2 (AQP2) water

channels into the apical membrane of tubular cells, allowing water

reabsorption.

By blocking the V2 receptors, Tolvaptan:

•Prevents the insertion of aquaporins.

•Reduces water reabsorption.

•Increases urine volume and electrolyte-free water clearance.