Chapter Notes: Antidiuretics

Antidiuretics

Antidiuretics (more precisely anti-aquaretics, because they reduce water excretion without directly altering salt excretion) are drugs that decrease urine volume. Their principal clinical use is in the management of diabetes insipidus (DI), together with several other indications discussed below.

Antidiuretic hormone (Arginine vasopressin - AVP)

The human antidiuretic hormone is arginine vasopressin (AVP), an octapeptide (nonapeptide in older nomenclature including a carrier sequence), synthesised in the hypothalamic supraoptic and paraventricular nuclei and released from the posterior pituitary (neurohypophysis). AVP is synthesised as a larger precursor together with the carrier protein neurophysin, transported down axons and stored in nerve terminals for regulated release.

AVP release is primarily regulated by:

• Osmoreceptors in the hypothalamus (sensitive to small rises in plasma osmolality).
• Volume and baroreceptors in the atria, ventricles and large veins (respond to changes in effective circulating volume and blood pressure).

Portal and hepatic osmoreceptors can detect ingested salt and initiate an anticipatory ADH release even before systemic plasma osmolality rises. Higher central nervous system centres and several neurotransmitters and hormones modulate AVP secretion.

Factors that increase AVP release include angiotensin II, prostaglandins, histamine, neuropeptide Y and acetylcholine. Factors that reduce AVP release include GABA and atrial natriuretic peptide (ANP). Opioids have dose-dependent effects (low-dose morphine may inhibit, high doses may enhance AVP release). Nicotine and imipramine stimulate AVP secretion; alcohol, haloperidol, phenytoin and glucocorticoids reduce it.

AVP receptor subtypes

AVP acts via G-protein coupled receptors. Two major receptor families are clinically important: V1 and V2.

V1 receptors

V1 receptors (also classified as V1a and V1b) are widely distributed outside the renal collecting duct:

• V1a receptors: vascular smooth muscle (including vasa recta), uterine and other visceral smooth muscles, renal medullary interstitial cells, cortical collecting duct cells, adipose tissue, platelets, liver and brain.
• V1b receptors: anterior pituitary and selected brain and pancreatic regions.

V1 receptors couple to the phospholipase C → inositol trisphosphate (IP₃)/diacylglycerol (DAG) pathway, mobilising intracellular Ca²⁺, activating protein kinase C and, in some cells, phospholipase A₂ with eicosanoid generation. V1 activation produces vasoconstriction, visceral smooth muscle contraction, platelet aggregation and ACTH release. Chronic V1 stimulation can promote vascular smooth muscle hypertrophy.

V2 receptors

V2 receptors are located mainly on the basolateral membrane of principal cells of the renal collecting ducts and on the thick ascending limb (TAL) cells. Endothelial V2 receptors mediate vasodilator responses via nitric oxide. V2 receptors couple to adenylyl cyclase → cyclic AMP (cAMP) → protein kinase A (PKA).

V2 receptors in the kidney increase water permeability by promoting insertion of aquaporin-2 channels into the apical membrane of collecting duct cells and by increasing expression of transport proteins. V2 receptors on TAL cells increase activity and expression of the Na⁺-K⁺-2Cl^- cotransporter (NKCC2), supporting medullary hypertonicity.

V2 receptors are more sensitive to AVP (respond at lower concentrations) than V1 receptors.

Selective agonists and antagonists (summary)

Examples of selective receptor ligands include:

• Selective V2 agonist: Desmopressin (dDAVP) - a synthetic V2-selective analogue with potent antidiuretic action and minimal vasoconstrictor activity.
• V1a and V1b agonists: various peptide analogues (e.g., [Phe₂, Ile₂, Orn₈] AVP and other modified peptides) have been prepared for research/clinical uses.
• Selective V2 antagonists: nonpeptide agents such as tolvaptan and mozavaptan.
• Mixed V1a/V2 antagonists: conivaptan (parenteral formulation).

Several peptide antagonists and orally active nonpeptide antagonists for V1a, V1b and V2 receptors have been developed; clinical use is currently most established for V2 antagonists in correcting euvolaemic and hypervolaemic hyponatraemia.

Renal actions and mechanism of antidiuresis

The major antidiuretic action of AVP is on the collecting duct principal cells, increasing water permeability so that water can be reabsorbed from the tubular lumen into the hyperosmolar renal medulla.

Mechanism at the cellular level:

• AVP binds V2 receptors on the basolateral membrane → stimulates adenylyl cyclase → increases intracellular cAMP → activates PKA.
• PKA phosphorylates proteins that promote exocytosis of aquaporin-2 (AQP2)-containing vesicles; AQP2 channels are inserted into the apical membrane, increasing water permeability.
• Endocytosis and degradation of AQP2 are reduced, and chronic V2 stimulation upregulates AQP2 gene expression through cAMP response elements, increasing long-term water reabsorption capacity.
• Other aquaporins (AQP1 in proximal tubule, AQP3 and AQP4 on basolateral membrane of collecting duct cells) participate in transepithelial water movement.
• AVP also increases urea permeability in the terminal inner medullary collecting duct by activating vasopressin-regulated urea transporters (UT-1), enhancing medullary interstitial hypertonicity necessary for urine concentration.
• On TAL cells, AVP induces translocation and activation of the Na⁺-K⁺-2Cl^- cotransporter and increases its expression, reinforcing the corticomedullary osmotic gradient.

Rapid and long-term antidiuretic actions

1. Rapid insertion of AQP2 channels into the apical membrane of collecting duct principal cells (primary acute antidiuretic effect).
2. Reduced endocytotic removal of AQP2 from the apical membrane.
3. Activation of vasopressin-regulated urea transporter in inner medullary collecting ducts, increasing urea recycling and medullary tonicity.
4. Translocation and activation of NKCC2 (Na⁺-K⁺-2Cl^-) cotransporter in TAL cells, enhancing countercurrent multiplication.
5. V1a-mediated vasoconstriction of vasa recta reducing medullary washout and supporting medullary hypertonicity.
6. Long-term: increased synthesis (gene expression) of AQP2 and of transport proteins such as NKCC2, increasing sustained concentrating ability.

Interactions with other drugs and modulators

• Lithium and demeclocycline antagonise AVP action (likely by impairing cAMP signalling), reducing urine concentrating ability and producing polyuria and polydipsia.
• NSAIDs (notably indomethacin) enhance AVP-induced antidiuresis by inhibiting renal prostaglandin synthesis, which otherwise diminishes V2 receptor signalling. Carbamazepine and chlorpropamide also potentiate AVP action.

Extraparenchymal actions

Vascular system

AVP constricts blood vessels via V1 receptors, increasing peripheral resistance. At low doses the rise in pressure may be offset by reflex cardiac changes; pressor effects are prominent at higher doses or when compensatory reflexes are impaired (for example in shock). AVP is used as a vasopressor in certain hypotensive states. Prolonged exposure can cause vascular smooth muscle hypertrophy.

V2 receptor activation on endothelium can produce vasodilatation through endothelium-dependent nitric oxide generation; this is unmasked when V1 effects are blocked or with selective V2 agonists such as desmopressin.

Other tissues

• Visceral smooth muscle contraction (gut, uterus) - AVP can increase gut motility and may contract the non-pregnant uterus via oxytocin receptors.
• CNS: AVP acts as a neurotransmitter/neuromodulator in several brain regions; it may influence thermoregulation, autonomic functions and behaviour.
• Haemostasis: AVP and especially desmopressin release factor VIII and von Willebrand factor from endothelial stores and promote platelet aggregation; this property is exploited therapeutically.

Pharmacokinetics

Native AVP is inactive orally (susceptible to proteolysis) and is given parenterally or intranasally. Plasma half-life is short (~20-30 minutes) due to rapid enzymatic cleavage (primarily in liver and kidney), but physiologic effects can last longer. Many synthetic analogues have prolonged durations of action and altered receptor selectivity.

Vasopressin analogues

Lypressin

Lypressin (8-lysine vasopressin) is slightly less potent than AVP but has longer duration (about 4-6 hours). It acts on both V1 and V2 receptors and has been used for V1-mediated actions.

Terlipressin

Terlipressin is a synthetic prodrug of vasopressin used specifically in the management of bleeding oesophageal varices; it produces vasoconstriction of splanchnic vasculature and is longer acting with fewer adverse effects than AVP. Usual intravenous regimen: 2 mg IV, repeated 1-2 mg every 4-6 hours as needed in acute bleeding.

Desmopressin (dDAVP)

Desmopressin is a synthetic, V2-selective analogue with potent antidiuretic action (approximately 10-12 times more antidiuretic than AVP) and negligible vasoconstrictor activity. It is resistant to enzymatic degradation (t½ ~1-2 hours) and its antidiuretic duration is prolonged (commonly 8-12 hours).

Routes and typical doses:

• Intranasal: adults 10-40 µg/day in 2-3 divided doses; children (for nocturnal enuresis) 5-10 µg at bedtime. Nasal bioavailability ≈10-20%.
• Oral tablets: 0.1-0.2 mg three times daily (oral bioavailability ≈1-2%, hence higher doses required compared with intranasal). Many patients prefer oral tablets for convenience.
• Parenteral (IV or SC): 2-4 µg/day in 2-3 divided doses for indications requiring systemic delivery.

Desmopressin formulations are used for central DI, nocturnal enuresis, and for haemostatic indications (see below).

Clinical uses

A. Uses based on V2 receptor (desmopressin is the drug of choice)

• Central (neurogenic) diabetes insipidus: deficiency of ADH. Desmopressin is the treatment of choice. Aqueous vasopressin or lypressin injections may be used for acute or transient DI or to distinguish central from nephrogenic DI (see next point). Lifelong therapy is often required in permanent central DI.
• Diagnosis - renal concentration test: administration of 5-10 U intramuscular AVP or 2 µg desmopressin IM produces maximal urinary concentration in normal or central DI patients; measuring urinary osmolality or specific gravity after administration helps distinguish central from nephrogenic DI (in central DI, urine concentrates after AVP/desmopressin; in nephrogenic DI it does not).
• Nocturnal polyuria and bed-wetting: intranasal or oral desmopressin at bedtime reduces nocturnal urine production. Fluid intake should be restricted from 1 hour before dosing until about 8 hours after dosing to reduce risk of water retention and hyponatraemia. Periodic reassessment and drug holidays (e.g., stop for one week every three months) are recommended.
• Haemophilia A and von Willebrand disease: desmopressin promotes release of factor VIII and von Willebrand factor from endothelial stores. A common IV dose for haemostatic effect is 0.3 µg/kg diluted and infused over 30 minutes.

B. Uses based on V1 (vasoconstrictor) actions

• Bleeding oesophageal varices: AVP or terlipressin reduces splanchnic blood flow and portal hypertension, promoting haemostasis. Terlipressin is widely used due to fewer adverse effects and longer duration; definitive treatment is endoscopic therapy (sclerotherapy or band ligation).
• Adjunctive use: AVP analogues have been used in selected situations to reduce bowel gas or in other diagnostic/therapeutic roles, but such uses are limited.

Adverse effects

Desmopressin, because of V2 selectivity, produces fewer systemic adverse effects than AVP or nonselective analogues. Reported adverse effects include:

• Headache and flushing.
• Nasal irritation, congestion, rhinitis, local ulceration or epistaxis with intranasal use.
• Gastrointestinal upset (nausea, abdominal cramps), pallor, and uterine cramping (female patients) from uterine smooth muscle stimulation.
• Fluid retention and hyponatraemia, which can lead to cerebral oedema producing headache, confusion, lethargy, nausea, vomiting and seizures; children are particularly susceptible. Restrict fluid intake around dosing and use the minimum effective dose.
• AVP and nonselective analogues can cause bradycardia, increased afterload and precipitate angina by coronary vasoconstriction; they are relatively contraindicated in ischaemic heart disease, uncontrolled hypertension and severe chronic renal disease.
• Allergic reactions including urticaria are possible with any peptide preparation.

Diuretics and other agents used paradoxically in DI

Thiazide diuretics (for example, hydrochlorothiazide 25-50 mg once or twice daily) paradoxically reduce urine volume in both central and nephrogenic DI. The mechanisms proposed include increased proximal tubular reabsorption of sodium and water due to reduced extracellular fluid volume and decreased glomerular filtration rate, and a reduced delivery of dilute fluid to the collecting duct. Dietary salt restriction produces a similar effect. Because thiazides cause potassium loss, potassium supplements are often necessary.

Thiazides are particularly valuable in nephrogenic DI in which AVP/desmopressin is ineffective; however, they usually cannot restore hypertonic urine as AVP can in central DI.

Amiloride is the drug of choice for lithium-induced nephrogenic DI because it blocks the epithelial sodium channel (ENaC) in the collecting duct and also reduces lithium entry into principal cells, ameliorating the nephrogenic DI.

Demeclocycline can antagonise AVP action and is used in chronic inappropriate ADH secretion, though it has nephrotoxicity risks. Indomethacin and some other NSAIDs reduce polyuria in nephrogenic DI by inhibiting renal prostaglandin synthesis and potentiating residual AVP action; indomethacin is the most active in this context and may be combined with a thiazide ± amiloride.

Chlorpropamide (a long-acting sulfonylurea) sensitises the kidney to ADH and reduces urine volume in central DI but not in nephrogenic DI; its use is limited by hypoglycaemia and other adverse effects. Carbamazepine reduces urine volume in central DI but its efficacy and safety profile limit routine use.

Vasopressin antagonists (aquaretics)

Orally active nonpeptide AVP receptor antagonists have clinical applications in the management of hyponatraemia due to conditions with inappropriate AVP activity (for example, syndrome of inappropriate ADH secretion, congestive heart failure and cirrhosis).

• Tolvaptan - an oral selective V2 receptor antagonist that increases free water clearance (aquaresis) and corrects dilutional hyponatraemia. It is metabolised by CYP3A4 (avoid coadministration with strong CYP3A4 inhibitors). Reported adverse effects include thirst, dry mouth, fever, gastrointestinal upset and hyperglycaemia. Excessively rapid correction of hyponatraemia risks osmotic and thrombotic complications due to haemoconcentration; careful monitoring is required. Typical dosing is once daily; elimination half-life about 6-8 hours.
• Mozavaptan - another V2 selective antagonist used in similar settings.
• Conivaptan - a combined V1a/V2 antagonist available for parenteral use.

Summary

Antidiuretic therapy centres on modulation of AVP pathways. Desmopressin is the preferred agent for central DI and for haemostatic uses, because of its V2 selectivity and longer action. Thiazides, amiloride and NSAIDs have important roles in nephrogenic DI. Vasopressin analogues with V1 activity (for example, terlipressin) are useful in acute variceal bleeding and certain vasodilatory states. V2 antagonists (tolvaptan, mozavaptan, conivaptan) are clinically valuable in correcting dilutional hyponatraemia by increasing free water excretion. Careful dosing, fluid management and monitoring for hyponatraemia or overly rapid correction of serum sodium are essential in clinical use.