Antidiuretics

Chapter 42

Antidiuretics

These are drugs that reduce urine volume, particularly in diabetes insipidus (DI) which is their primary indication. Drugs are:

1. Antidiuretic hormone (ADH, Vasopressin), Desmopressin, Lapresi, Terlipressin

2. Thiazide diuretics, Amiloride. 

3. Miscellaneous: Indomethacin, Chlorpropamide, Carbamazepine.

ANTIDIURETIC HORMONE

It is a nonapeptide secreted by posterior pituitary (neurohypophysis) along with oxytocin (see Ch. 23). It is synthesized in the hypothalamic (supraoptic and paraventricular) nerve cell bodies as a large precursor peptide along with its binding protein ‘neurophysin’, and is transported down the axons to nerve endings in the median eminence and pars nervosa. Osmoreceptors present in hypothalamus and volume receptors present in left atrium, ventricles and pulmonary veins primarily regulate the rate of ADH release governed by body hydration. Impulses from baroreceptors and higher centres also impinge on the nuclei synthesizing ADH and affect its release. The two main physiological stimuli for ADH release are rise in plasma osmolarity and contraction of e.c.f. volume.

ADH secretion is enhanced by angiotensin II, prostaglandins (PGs), histamine, neuropeptide Y and ACh. It is inhibited by GABA and atrial natriuretic peptide (ANP). Opioids have agent-specific action: while morphine stimulates ADH secretion, endogenous opioid peptides are mostly inhibitory. These humoral mediators may play a role in the modulation of ADH secretion

The mammalian ADH is 8-arginine-vasopressin (AVP); 8-lysine-vasopressin (lypressin) is found in swine and has been synthetically prepared. Other more potent and longer acting peptide analogues of ADH having agonistic as well as antagonistic action have been prepared.

ADH (Vasopressin) receptors

These are G protein coupled cell membrane receptors; two subtypes V1 and V2 have been identified, cloned and structurally characterized.

V1 Receptors All vasopressin receptors except those on renal CD cells and some blood vessels are of the V1 type. These are further divided into:

V1a present on vascular and other smooth muscles, platelets, liver, etc. and V1b localized to the anterior pituitary. The V1 receptors function mainly through the phospholipase C–IP3/DAG pathway—release Ca2+ from intracellular stores—causing vasoconstriction, visceral smooth muscle contraction, glycogenolysis, platelet aggregation, ACTH release, etc. These actions are augmented by enhanced influx of Ca2+ through Ca2+ channels as well as by DAG mediated protein kinase C activation which phosphorylates relevant proteins. V1 receptors, in addition, activate phospholipase A2—release arachidonic acid resulting in generation of PGs and other eicosanoids which contribute to many of the V1 mediated effects. Persistent V1 receptor stimulation activates protooncogenes (possibly through IP3/DAG pathway) resulting in growth of vascular smooth muscle and other responsive cells.

V2 Receptors These are located primarily on the collecting duct (CD) cells in the kidney—regulate their water permeability through cAMP production. Vasodilatory V2 receptors are present in blood vessels. 

The V2 receptors are more sensitive (respond at lower concentrations) to ADH than are V1 receptors. Selective peptide agonists and antagonists of the subtypes of vasopressin receptors are:

Actions

Kidney

AVP acts on the collecting duct (CD) cells to increase their water permeability—water from the lumen diffuses to the interstitium by equilibrating with the hyperosmolar renal medulla (see Fig. IX.1). In man, maximal osmolarity of urine that can be attained is 4 times higher than plasma. When ADH is absent, CD cells remain impermeable to water → dilute urine (produced by the diluting segment) is passed as such. Graded effect occurs at lower concentration of ADH: urine volume closely balances fluid intake.

Mechanism of action The V2 subtype of ADH receptors are present on the basolateral side of CD cell membrane. Activation of these receptors increases cAMP formation intracellularly → activation of cAMP dependent protein kinase A → phosphorylation of relevant proteins which promote exocytosis of ‘aquaporin-2’ water channel containing vesicles (WCVs) through the apical membrane → more aqueous channels get inserted into the apical membrane. The rate of endocytosis and degradation of WCVs is concurrently reduced. The water permeability of CD cells is increased in proportion to the population of aquaporin-2 channels in the apical membrane at any given time. Continued V2 receptor stimulation (during chronic water deprivation) in addition upregulates aquaporin-2 synthesis through cAMP response element of the gene encoding aquaporin-2.

Other aquaporins like aquaporin-1 (in PT) and aquaporin3,4 (on basolateral membrane of CD cells) also participate in water transport at these sites.

To achieve maximum concentration of urine, activation of V2 receptors increases urea permeability of terminal part of CDs by stimulating a vasopressin regulated urea transporter (VRUT or UT-1)—which in turn augments medullary hypertonicity. Recently, V2 receptor mediated actions of AVP on AscLH have been demonstrated which further reinforce medullary hypertonicity by activating the Na+K+2Cl¯ cotransporter in the short-term and increasing its synthesis in the long-term.

The V1 receptors also participate in the renal response to ADH. While V1a receptor activation constricts vasa recta to diminish blood flow to inner medulla which will help in maintaining high osmolarity in this region and thus contribute to antidiuresis; other V1 actions augmenting PG production from interstitial cells and directly diminishing responsiveness of CD cells to V2 receptor stimulation tend to restrain V2 mediated water permeability. Since V2 action is produced at much lower concentration of AVP, physiologically V1 renal actions may serve to restrict V2 effect when blood levels of AVP are very high.

Lithium and demeclocycline partially antagonize ADH action (probably by limiting cAMP formation), reduce the urine concentrating ability of the kidney, produce polyuria and polydipsia. They have been used in patients with inappropriate ADH secretion. On the other hand NSAIDs (especially indomethacin) augment AVP induced antidiuresis by inhibiting renal PG synthesis. Carbamazepine and chlorpropamide also potentiate AVP. 

Blood vessels AVP constricts blood vessels through V1 receptors and can raise BP (hence the name vasopressin), but much higher concentration is needed than for maximal antidiuresis. The cutaneous, mesenteric, skeletal muscle, fat depot, thyroid, and coronary beds are particularly constricted. Though vasoconstrictor action of AVP does not appear to be physiologically important, some recent studies indicate that it may play a role in CHF, haemorrhage, hypotensive states, etc. Prolonged exposure to AVP causes vascular smooth muscle hypertrophy.

Blood vessels AVP constricts blood vessels through V1 receptors and can raise BP (hence the name vasopressin), but much higher concentration is needed than for maximal antidiuresis. The cutaneous, mesenteric, skeletal muscle, fat depot, thyroid, and coronary beds are particularly constricted. Though vasoconstrictor action of AVP does not appear to be physiologically important, some recent studies indicate that it may play a role in CHF, haemorrhage, hypotensive states, etc. Prolonged exposure to AVP causes vascular smooth muscle hypertrophy.

Other actions Most visceral smooth muscles contract. Increased peristalsis in gut (especially large bowel), evacuation and expulsion of gases may occur.

Uterus is contracted by AVP acting on oxytocin receptors. In the nonpregnant and early pregnancy uterus, AVP is equipotent to oxytocin. Only at term sensitivity to oxytocin increases selectively.

CNS Exogenously administered AVP does not penetrate blood-brain barrier. However, it is now recognized as a peptide neurotransmitter in many areas of brain and spinal cord: may be involved in regulation of temperature, circulation, ACTH release, and in learning of tasks.

AVP induces platelet aggregation and hepatic glycogenolysis. It releases coagulation factor VIII and von Willebrand’s factor from vascular endothelium through V2 receptors.

Pharmacokinetics AVP is inactive orally because it is destroyed by trypsin. It can be administered by any parenteral route or by intranasal application. The peptide chain of AVP is rapidly cleaved enzymatically in many organs, especially in liver and kidney; plasma t½ is short ~25 min. However, the action of aqueous vasopressin lasts 3– 4 hours.

Aqueous vasopressin (AVP) inj: 

POSTACTON 10 U inj; for i.v., i.m. or s.c. administration.

VASOPRESSIN ANALOGUES

Lypressin It is 8-lysine vasopressin. Though somewhat less potent than AVP, it acts on both V1 and V2 receptors and has longer duration of action (4–6 hours). It is being used in place of AVP—mostly for V1 receptor mediated actions. 

PETRESIN, VASOPIN 20 IU/ml inj; 10 IU i.m. or s.c. 

or 20 IU diluted in 100–200 ml of dextrose solution and infused i.v. over 10–20 min. 

Terlipressin This synthetic prodrug of vasopressin is specifically used for bleeding esophageal varices; may produce less severe adverse effects than lypressin. Dose: 2 mg i.v., repeat 1–2 mg every 4–6 hours as needed. 

GLYPRESSIN 1 mg freeze dried powder with 5 ml diluent for inj

Desmopressin (dDAVP) This synthetic peptide is a selective V2 agonist; 12 times more potent antidiuretic than AVP, but has negligible vasoconstrictor activity. It is also longer acting because enzymatic degradation is slow; t½ 1–2 hours; duration of action 8–12 hours. Desmopressin is the preparation of choice for all V2 receptor related indications. The intranasal route is preferred, though bioavailability is only 10–20%. An oral formulation has been recently marketed with a bioavailability of 1–2%; oral dose is 10–15 times higher than intranasal dose, but systemic effects are produced and nasal side effects are avoided. Most patients find oral tablet more convenient. 

Dose: Intranasal: Adults 10–40 μg/day in 2–3 divided doses, children 5–10 μg at bed time. Oral: 0.1–0.2 mg TDS. Parenteral (s.c. or i.v.) 2–4 μg/day in 2–3 divided doses.

MINIRIN 100 μg/ml nasal spray (10 μg per actuation); 100 μg/ml intranasal solution in 2.5 ml bottle with applicator; 0.1 mg tablets; 4 μg/ml inj.

Uses 

A. Based on V2 actions (Desmopressin is the drug of choice) 

1. Diabetes insipidus DI of pituitary origin (neurogenic) is the most important indication for vasopressin. It is ineffective in renal (nephrogenic) DI, since kidney is unresponsive to ADH. Lifelong therapy is required, except in some cases of head injury or neurosurgery, where DI occurs transiently.

The dose of desmopressin is individualized by measuring 24 hour urine volume. Aqueous vasopressin or lypressin injection is impracticable for long-term treatment. It can be used in transient DI and to differentiate neurogenic from nephrogenic DI—urine volume is reduced and its osmolarity increased if DI is due to deficiency of ADH, but not when it is due to unresponsiveness of kidney to ADH. Desmopressin 2 μg i.m. is the preparation of choice now for the same purpose.

2. Bedwetting in children and nocturia in adults Intranasal or oral desmopressin at bedtime controls primary nocturia by reducing urine volume. Nocturnal voids are reduced to nearly half and first sleep period in adults is increased by ~2 hr. Fluid intake must be restricted 1 hr before and till 8 hr after the dose to avoid fluid retention. Monitor BP and body weight periodically to check fluid overload. Withdraw for one week every 3 months for reassessment.

3. Renal concentration test 5–10 U i.m. of aqueous vasopressin or 2 μg of desmopressin causes maximum urinary concentration.

4. Haemophilia, von Willebrand’s disease AVP may check bleeding by releasing coagulation factor VIII and von Willebrand’s factor. Desmopressin is the preferred preparation in a dose of 0.3 μg/kg diluted in 50 ml saline and infused i.v. over 30 min.

B. Based on V1 actions

1. Bleeding esophageal varices Vasopressin/ terlipressin often stop bleeding by constricting mesenteric blood vessels and reducing blood flow through the liver to the varices, allowing clot formation. Terlipressin stops bleeding in ~80% and has been shown to improve survival. It has replaced AVP because of fewer adverse effects and greater convenience in use. Octreotide (a somatostatin analogue) injected i.v. is an alternative. However, definitive therapy of varices remains endoscopic obliteration by sclerotherapy.

2. Before abdominal radiography AVP/layperson has been occasionally used to drive out gases from bowel.

Adverse effects Because of V2 selectivity desmopressin produces fewer adverse effects than vasopressin, lypressin or terlipressin. However, transient headache and flushing are frequent. Nasal irritation, congestion, rhinitis, ulceration and epistaxis can occur on local application. Systemic side effects are: belching, nausea, abdominal cramps, pallor, urge to defecate, backache in females (due to uterine contraction). Fluid retention and hyponatraemia may develop. AVP can cause bradycardia, increase cardiac afterload and precipitate angina by constricting coronary vessels. It is contraindicated in patients with ischaemic heart disease, hypertension, chronic nephritis and psychogenic polydipsia. Urticaria and other allergies are possible with any preparation.

THIAZIDES

Diuretic thiazides paradoxically exert an antidiuretic effect in DI. High ceiling diuretics are also effective but are less desirable because of their short and brisk action. Thiazides reduce urine volume in both pituitary origin as well as renal DI; especially valuable for the latter in which AVP is ineffective. However, their efficacy is low; urine can never become hypertonic as can occur with AVP in neurogenic DI. The mechanism of action is not well understood, possible explanation is:

Thiazides induce a state of sustained electrolyte depletion so that glomerular filtrate is more completely reabsorbed iso-osmotically in PT. Further, because of reduced salt reabsorption in the cortical diluting segment, a smaller volume of less dilute urine is presented to the CDs and the same is passed out. That salt restriction has a similar effect, substantiates this mechanism of :

action. Secondly, thiazides reduce g.f.r. and thus the fluid load on tubules. Hydrochlorothiazide 25–50 mg TDS or equivalent dose of a longer acting agent is commonly used. Though less effective than AVP, it is more convenient and cheaper even for pituitary origin DI; may reduce polyuria to some extent. K+ supplements are needed.

Amiloride is the drug of choice for lithium induced nephrogenic DI (see p. 572).

Indomethacin has also been found to reduce polyuria in renal DI to some extent by reducing renal PG synthesis. It can be combined with a thiazide ± amiloride in nephrogenic DI. Other NSAIDs are less active.

Chlorpropamide It is a long-acting oral hypoglycaemic (see Ch. 19), found to reduce urine volume in DI of pituitary origin but not in renal DI. It sensitizes the kidney to ADH action; thus its efficacy depends on small amounts of the circulating hormone; it is not active when ADH is totally absent. Nearly 50% patients with partial neurogenic DI respond reasonably well. A thiazide may be added to augment the response. However, induced hypoglycaemia limits its usefulness in DI. Dose: 125–500 mg/day.

Carbamazepine It is an antiepileptic (see Ch. 30) which reduces urine volume in DI of pituitary origin, but mechanism of action is not clear. Higher doses are needed; adverse effects are marked; it is of little value in treatment of DI.