Vasopressin and Other Agents Affecting the Renal Conservation of Water

Precise regulation of body fluid osmolality is essential. It is controlled by a finely tuned, intricate homeostatic mechanism that operates by adjusting both the rate of water intake and the rate of solute-free water excretion by the kidneysi.e., water balance. Abnormalities in this homeostatic system can be caused by genetic diseases, acquired diseases, or drugs and may result in serious and potentially life-threatening deviations in plasma osmolality. The goals of this chapter are to describe the physiological mechanisms that regulate plasma osmolality, to discuss the diseases that perturb those mechanisms, and to examine pharmacological approaches for treating disorders of water balance.

Argininevasopressin (the antidiuretic hormone in human beings) is the main hormone involved in regulation of body fluid osmolality. Many diseases of water homeostasis and many pharmacological strategies for correcting such disorders pertain to vasopressin. Accordingly, vasopressin is the major focus of this chapter and is discussed with regard to: (1) chemistry (including the chemistry of vasopressin agonists and antagonists); (2) physiology (including anatomical considerations; the synthesis, transport, and storage of vasopressin and the regulation of vasopressin secretion); (3) basic pharmacology (including vasopressin receptors and their signal transduction pathways, renal actions of vasopressin, pharmacological modification of the antidiuretic response to vasopressin, and nonrenal actions of vasopressin); (4) diseases affecting the vasopressin system (diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, and other water-retaining states); and (5) clinical pharmacology of vasopressin peptides (therapeutic uses, pharmacokinetics, toxicities, adverse effects, contraindications, and drug interactions). A small number of other drugs can be used to treat abnormalities of water balance; a discussion of these agents is integrated into the section on diseases affecting the vasopressin system.

Immunoreactive vasopressin has been observed in neurons from organisms belonging to the first animal phylum with a nervous system (e.g., Hydra attenuata), and vasopressin-like peptides have been isolated and characterized from both mammalian and nonmammalian vertebrates as well as from invertebrates (Table 301). Genes encoding vasopressin-like peptides probably evolved more than 700 million years ago.

With the emergence of life on land, vasopressin became the mediator of a remarkable regulatory system for the conservation of water. The hormone is released by the posterior pituitary whenever water deprivation causes an increased plasma osmolality or whenever the cardiovascular system is challenged by hypovolemia and/or hypotension. In amphibians, the target organs for vasopressin are skin and the urinary bladder, whereas in other vertebrates, including human beings, the site of action is primarily the renal collecting duct. In each of these target tissues, vasopressin acts by increasing the permeability of the cell membrane to water, thus permitting water to move passively down an osmotic gradient across skin, bladder, or collecting duct into the extracellular compartment.

In view of the long evolutionary history of vasopressin, it is not surprising that vasopressin acts at sites in the nephron other than the collecting duct and on tissues other than the kidney. Vasopressin is a potent vasopressor, and its name was originally chosen in recognition of its vasoconstrictor action. Vasopressin is a neurotransmitter; among its actions in the central nervous system (CNS) are apparent roles in the secretion of adrenocorticotropic hormone (ACTH) and in the regulation of the cardiovascular system, temperature, and other visceral functions. Vasopressin also promotes the release of coagulation factors by the vascular endothelium and increases platelet aggregability; therefore, it may play a role in hemostasis.

Chemistry of Vasopressin Receptor Agonists

du Vigneaud and coworkers (1954) determined the structures of vasopressin and oxytocin and accomplished the complete synthesis of each. A number of vasopressin-like peptides occur naturally (Table 301). All are nonapeptides; contain cysteine residues in positions 1 and 6; have an intramolecular disulfide bridge between the two cysteine residues (essential for agonist activity); have additional conserved amino acids in positions 5, 7, and 9 (asparagine, proline, and glycine, respectively); contain a basic amino acid in position 8; and are amidated on the carboxyl terminus. In all mammals except swine, the neurohypophyseal peptide is 8-arginine vasopressin, and the terms vasopressin, arginine vasopressin (AVP), and antidiuretic hormone (ADH) are used interchangeably. The chemical structure of oxytocin is closely related to that of vasopressin, i.e., oxytocin is [Ile³, Leu⁸]AVP. Oxytocin binds to specific oxytocin receptors on myoepithelial cells in the mammary gland and on smooth muscle cells in the uterus, causing milk ejection and uterine contraction, respectively. Inasmuch as vasopressin and oxytocin are structurally similar, it is not surprising that vasopressin and oxytocin agonists and antagonists can bind to each other's receptors. Therefore, most of the available peptide vasopressin agonists and antagonists have some affinity for oxytocin receptors; at high doses, they may block or mimic the effects of oxytocin (Manning and Sawyer, 1989).

With the advent of solid-phase peptide synthesis, many vasopressin analogs were synthesized with the goal of increasing duration of action and selectivity for vasopressin receptor subtypes (V₁versus V₂ vasopressin receptors, which mediate pressor responses and antidiuretic responses, respectively). In 1967, Zaoral and coworkers announced the synthesis of desmopressin: 1-deamino-8-D-arginine vasopressin (DDAVP) (Table 301). Deamination at position 1 increases duration of action and increases antidiuretic activity without increasing vasopressor activity. Substitution of D-arginine for L-arginine greatly reduces vasopressor activity without reducing antidiuretic activity. Thus, the antidiuretic-to-vasopressor ratio for desmopressin is approximately 3000-fold greater than that for vasopressin, and desmopressin now is the preferred drug for the treatment of central diabetes insipidus (Robinson, 1976). Substitution of valine for glutamine in position 4 further increases the antidiuretic selectivity, and the antidiuretic-to-vasopressor ratio for deamino[Val⁴, D-Arg⁸] AVP (Table 301) is approximately 11,000-fold greater than that for vasopressin. Increasing V₁ selectivity has proved more difficult than increasing V₂ selectivity (Thibonnier, 1990). However, a limited number of agonists have been developed with modest selectivity for V₁ receptors (seeTable 301).

Vasopressin receptors in the adenohypophysis that mediate vasopressin-induced ACTH release are neither classical V₁ nor V₂ receptors. Since the vasopressin receptors in the adenohypophysis appear to share a common signal transduction mechanism with classical V₁ receptors, and since many vasopressin analogs with vasoconstrictor activity release ACTH, V₁ receptors have been subclassified into V_1a (vascular/hepatic) and V_1b (pituitary) receptors (Jard et al., 1986). Vasopressin agonists selective for both V_1a (Thibonnier, 1990) and V_1b receptors (Schwartz et al., 1991) have been described (seeTable 301).

Chemistry of Vasopressin Receptor Antagonists

The impetus for the development of specific vasopressin receptor antagonists is the belief that such drugs may be useful in a number of clinical settings. Selective V_1a antagonists may be beneficial when total peripheral resistance is increased (e.g., congestive heart failure and hypertension); selective V₂ antagonists could be useful whenever reabsorption of solute-free water is excessive (e.g., the syndrome of inappropriate secretion of antidiuretic hormone and hyponatremia associated with a reduced effective blood volume). Combined V_1a/V₂ receptor antagonists might be beneficial in diseases associated with a combination of increased peripheral resistance and dilutional hyponatremia (e.g., congestive heart failure).

Shortly after the synthesis of vasopressin, du Vigneaud and coworkers began designing antagonists of vasopressin's pharmacological effects. Since that time, numerous vasopressin receptor antagonists have been synthesized (Manning et al., 1993; Lszlet al., 1991). Highly selective V₁ and V₂ peptide antagonists that are structural analogs of vasopressin have been synthesized (seeTable 302 for examples), including both cyclic and linear peptides. [1-(-mercapto- -cyclopentamethyleneproprionic acid),2-O-methyltyrosine]. Arginine vasopressin, also known as d(CH₂)₅[Tyr(Me)²]AVP, has a greater affinity for V_1a receptors than for either V_1b or V₂ receptors; this antagonist has been widely employed in physiological and pharmacological studies (Manning and Sawyer, 1989). Although [1-deaminopenicillamine, 2-O-methyltyrosine] arginine vasopressin, also called dP[Tyr(Me)²]AVP, is a potent V_1b receptor antagonist with little affinity for the V₂ receptor, it also blocks V_1a receptors. No truly selective V_1b receptor antagonist currently is available. Peptide antagonists currently available have limited oral activity, and the potency of peptide V₂ antagonists is species-dependent. Also, with prolonged infusion, peptide V₂ antagonists appear to express significant agonist activity (Kinter et al., 1993). However, in the early 1990s a nonpeptide, orally active V₁-selective antagonist (OPC-21268) (Yamamura et al., 1991) and a nonpeptide, orally active V_1a-/V₂-selective antagonist (OPC-31260) (Yamamura et al., 1992) were synthesized. Neither compound had partial agonist activity. Other highly potent nonpeptide vasopressin receptor antagonists, such as SR 49059, SR 121463A, VPA-985, and YM 087 (Mayinger and Hensen, 1999) have been synthesized (seeTable 302).

Diabetes Insipidus (DI)

DI is a disease of impaired renal conservation of water due either to an inadequate secretion of vasopressin from the neurohypophysis (central or cranial DI) or to an insufficient renal response to vasopressin (nephrogenic DI). Very rarely, DI can be caused by an abnormally high rate of degradation of vasopressin by circulating vasopressinases (Durr et al., 1987). Pregnancy may accentuate or reveal central and/or nephrogenic DI by increasing plasma levels of vasopressinase and by reducing the renal sensitivity to vasopressin. Patients with DI excrete large volumes (more than 30 ml/kg per day) of dilute (less than 200 mOsm/kg) urine and, if their thirst mechanism is functioning normally, are polydipsic. In contrast to the sweet urine excreted by patients with diabetes mellitus, urine from patients with DI is tasteless, hence the name, insipidus. Fortunately, the urinary taste test for DI devised by Willis in the seventeenth century has been supplanted by the more palatable approach of simply observing whether the patient is able to reduce urine volume and increase urine osmolality after a period of carefully observed fluid deprivation. Central DI can be distinguished from nephrogenic DI by administration of desmopressin, which will increase urine osmolality in patients with central DI but have little or no effect in patients with nephrogenic DI. DI can be differentiated from primary polydipsia by measuring plasma osmolality, which will be low to low-normal in patients with primary polydipsia and high to high-normal in patients with DI. For a more complete discussion of diagnostic procedures, see Vokes and Robertson (1988).

Central DI

Head injury, either surgical or traumatic, in the region of the pituitary and/or hypothalamus may cause central DI. Postoperative central DI may be transient, permanent, or triphasic (recovery followed by permanent relapse) (Seckl and Dunger, 1992). Other causes include hypothalamic or pituitary tumors, cerebral aneurysms, CNS ischemia, and brain infiltrations and infections. Finally, central DI may be idiopathic or familial. Familial central DI is usually autosomal dominant (chromosome 20) and has been associated with point mutations in the signal peptide and VP-neurophysin (seeFigure 301), leading to defects in the synthesis, processing, and transport of the preprohormone complex (Raymond, 1994). Since familial central DI is autosomal dominant, the defective preprohormone coded by the mutant allele must interfere in some way with the synthesis of hormone coded by the normal allele.

Antidiuretic peptides are the primary treatment for central DI, with desmopressin being the peptide of choice. (See'Clinical Pharmacology of Vasopressin Peptides,' below, for discussion of antidiuretic peptides in the treatment of central DI.) For patients with central DI who cannot tolerate antidiuretic peptides because of side effects or allergic reactions, other treatment options are available. Chlorpropamide, an oral sulfonylurea that potentiates the action of small or residual amounts of circulating vasopressin, will cause a reduction in urine volume in more than half of all patients with central DI at a dose of 125 to 500 mg daily and is particularly effective in patients with partial central DI, where it potentiates the action of low levels of circulating vasopressin. If polyuria is not satisfactorily controlled with chlorpropamide alone, addition of a thiazide diuretic (Chapter 29: Diuretics) to the regimen usually results in an adequate reduction in the volume of urine. Carbamazepine (800 to 1000 mg daily in divided doses) and clofibrate (1 to 2 g daily in divided doses) also reduce urine volume in patients with central DI. Long-term use of these agents may induce serious adverse effects; therefore carbamazepine and clofibrate are rarely used to treat central DI. The antidiuretic mechanism(s) of chlorpropamide, carbamazepine, and clofibrate are not clear. These agents are not effective in nephrogenic DI, which indicates that functional V₂ receptors are required for the antidiuretic mechanism to be expressed. Since carbamazepine inhibits and chlorpropamide has little effect on vasopressin secretion, it is likely that carbamazepine and chlorpropamide act directly on the kidney to enhance V₂ receptormediated antidiuresis.

Nephrogenic DI

Nephrogenic DI may be acquired or genetic. Hypercalcemia, hypokalemia, postobstructive renal failure, lithium, and demeclocycline can induce nephrogenic DI. As many as one in three patients treated with lithium may develop nephrogenic DI. Familial, X-linked, recessive nephrogenic DI is caused by mutations in the gene coding for the V₂ receptor (a gene located in the q28 region of the X chromosome). A number of missense, nonsense, and frame-shift mutations in the gene encoding the V₂ receptor have been identified in patients with familial, X-linked nephrogenic DI (Oksche and Rosenthal, 1998; Morello et al., 2000). Of all mutant alleles reported to date, mutations encoded result predominantly in abnormal synthesis, processing, or intracellular transport of V₂ receptors. Autosomal recessive nephrogenic DI is caused by inactivating mutations in aquaporin 2 (13 different mutations have been identified to date). These findings indicate that aquaporin 2 is essential for the antidiuretic effect of vasopressin in human beings (Deen et al., 1994).

Although the mainstay of treatment of nephrogenic DI is assurance of an adequate intake of water, drugs also can be used to reduce polyuria. Amiloride (Chapter 29: Diuretics) blocks the uptake of lithium by the sodium channel in the collecting duct system and is therefore the drug of choice for lithium-induced nephrogenic DI. Paradoxically, thiazide diuretics cause a reduction in the polyuria of patients with DI and often are used to treat nephrogenic DI. The use of thiazide diuretics in infants with nephrogenic DI may be crucially important, since uncontrolled polyuria may exceed the child's capacity to imBIBe and absorb fluids. The antidiuretic mechanism of thiazides in DI is incompletely understood. It is possible that the natriuretic action of thiazides and resultant depletion of extracellular fluid volume play an important role in the thiazide-induced antidiuresis in DI. In this regard, whenever extracellular fluid volume is reduced, compensatory mechanisms increase reabsorption of NaCl in the proximal tubule, with a resultant reduction of volume delivered to the distal tubule. Consequently, less free water can be formed, and this should diminish polyuria. However, recent studies in rats with vasopressin-deficient DI seriously challenge this hypothesis (Grnbeck et al., 1998). Nonetheless, the antidiuretic effects appear to parallel the ability of thiazides to cause natriuresis, and the drugs are given in doses similar to those used for mobilization of edema fluid. In patients with DI, a 50% reduction of urine volume is a good response to thiazides. Moderate restriction of sodium intake can enhance the antidiuretic effectiveness of thiazides.

A number of case reports describe the effectiveness of indomethacin in the treatment of nephrogenic DI (Libber et al., 1986); however, other prostaglandin synthase inhibitors (e.g., ibuprofen) appear to be less effective. The mechanism of the effects of indomethacin is unclear but may involve a decrease in glomerular filtration rate, an increase in medullary solute concentration, and/or enhanced proximal reabsorption of fluid (Seckl and Dunger, 1992). Also, since prostaglandins attenuate vasopressin-induced antidiuresis in patients with at least a partially intact V₂ receptor system, a portion of the antidiuretic response to indomethacin may be due to enhancement of the effects of vasopressin on the principal cells of the collecting duct.

Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

SIADH is a disease of impaired water excretion with accompanying hyponatremia and hypoosmolality caused by the inappropriate secretion of vasopressin. The clinical manifestations of plasma hypotonicity resulting from SIADH may include lethargy, anorexia, nausea/vomiting, muscle cramps, coma, convulsions, and death. A multitude of disorders can induce SIADH (Zerbe et al., 1980) including malignancies, pulmonary diseases, CNS injuries/diseases (head trauma, infections, tumors), general surgery, and drugs (e.g., cisplatin, vinca alkaloids, cyclophosphamide, chloropropamide, thiazide diuretics, phenothiazines, carbamazepine, clofibrate, nicotine, narcotics, and tricyclic antidepressants). In a normal individual, an elevation in plasma vasopressin levels per se does not induce plasma hypotonicity, because the person simply stops drinking due to an osmotically induced aversion to fluids. Therefore, plasma hypotonicity only occurs when excessive fluid intake (oral or intravenous) accompanies inappropriate secretion of vasopressin. Treatment of hypotonicity in the setting of SIADH includes water restriction, intravenous administration of hypertonic saline, loop diuretics (which interfere with the concentrating ability of the kidneys), and drugs that inhibit the ability of vasopressin to increase water permeability in the collecting ducts. To inhibit vasopressin's action in the collecting ducts, demeclocycline is the preferred drug (however, see'Prospectus,' below).

Although lithium can inhibit the renal actions of vasopressin, it is effective in only a minority of patients, may induce irreversible renal damage when used chronically, and has a low therapeutic index. Therefore, lithium should be used only in patients with symptomatic SIADH who cannot be controlled by other means or in whom tetracyclines are contraindicated, e.g., patients with liver disease. It is important to stress that the majority of patients with SIADH do not require therapy because plasma Na⁺ stabilizes in the range of 125 to 132 mM; such patients usually are asymptomatic. Only when symptomatic hypotonicity ensues, generally when plasma Na⁺ levels drop below 120 mM, should therapy with demeclocycline be initiated. Since hypotonicity, which causes an influx of water into cells with resulting cerebral swelling, is the cause of symptoms, the goal of therapy is simply to increase plasma osmolality toward normal. For a more complete description of the diagnosis and treatment of SIADH, see Kovacs and Robertson (1992).

Other Water-Retaining States

In patients with congestive heart failure, liver cirrhosis, and nephrotic syndrome, effective blood volume often is reduced, and hypovolemia is frequently exacerbated by the liberal use of diuretics in such patients. Since hypovolemia stimulates vasopressin release, patients may become hyponatremic due to vasopressin-mediated retention of water. The development of potent, orally active V₂ receptor antagonists and specific inhibitors of water channels in the collecting duct would provide an effective therapeutic strategy, not only in patients with SIADH but also in the much more common setting of hyponatremia in patients with heart failure, liver cirrhosis, and nephrotic syndrome.

Therapeutic Uses

Only three antidiuretic peptides are available for clinical use in the United States. (1) Vasopressin (synthetic 8-L-arginine vasopressin; PITRESSIN SYNTHETIC) is available as a sterile aqueous solution; it may be administered subcutaneously, intramuscularly, or intranasally. (2) Lypressin (synthetic 8-lysine vasopressin; DIAPID) is supplied as an aqueous nasal spray. (3) Desmopressin acetate ( DDAVP ) is available as a sterile aqueous solution packaged for intravenous or subcutaneous injection, in a nasal solution for intranasal administration with either a nasal spray pump or rhinal tube delivery system, and in tablets for oral administration. The therapeutic uses of vasopressin and its congeners can be divided into two main categories according to the type of vasopressin receptor involved.

V₁ receptormediated therapeutic applications are based on the rationale that V₁ receptors cause contraction of gastrointestinal and vascular smooth muscle. V₁ receptormediated contraction of gastrointestinal smooth muscle is useful to treat postoperative ileus and abdominal distension and to dispel intestinal gas before abdominal roentgenography to avoid interfering gas shadows. V₁ receptormediated vasoconstriction of the splanchnic arterial vessels reduces blood flow to the portal system and thereby attenuates pressure and bleeding in esophageal varices (Burroughs, 1998). Although endoscopic sclero-therapy is the treatment of choice for bleeding esophageal varices, V₁ receptor agonists can be used in an emergency setting until endoscopy can be performed. Simultaneous administration of nitroglycerin with vasopressin has been reported to reverse the cardiotoxic effects of vasopressin while enhancing the beneficial splanchnic effects of the drug (Gimson et al., 1986). Also, V₁ receptor agonists can be used during abdominal surgery in patients with portal hypertension to diminish the risk of hemorrhage during the procedure. Finally, V₁ receptormediated vasoconstriction of the gastric vascular bed reduces bleeding in acute hemorrhagic gastritis (Peterson, 1989). 8-Arginine vasopressin should be used for all V₁ receptormediated therapeutic applications. Although not yet available in the United States, terlipressin (GLYPRESSIN) appears to be effective for bleeding esophageal varices, with reduced side effects compared with vasopressin (Soederlund, 1993).

V₂ receptormediated therapeutic applications are based on the rationale that V₂ receptors cause water conservation and release of blood coagulation factors. Central, but not nephrogenic, DI can be treated with V₂ receptor agonists, and polyuria and polydipsia are usually well controlled. Some patients experience transient DI (e.g., in head injury or surgery in the area of the pituitary); however, for most patients with DI, therapy is lifelong. Desmopressin is the drug of choice for the vast majority of patients, and numerous clinical trials (Robinson, 1976; Cobb et al., 1978) have demonstrated that desmopressin is an effective agent in both adults and children and has few side effects. The duration of effect from a single intranasal dose is from 6 to 20 hours, and twice-daily administration has proven to be effective in most patients. There is considerable variability in the intranasal dose of desmopressin required to maintain normal urine volume, and the dosage must be individually tailored. The usual intranasal dosage range in adults is 10 to 40 g daily, either as a single dose or divided into two or three doses. In view of the high cost of the drug and the importance of avoiding water intoxication, the schedule of administration should be adjusted to determine the minimal amount required. An initial dose of 2.5 g can be used, and therapy should first be directed toward the control of nocturia. An equivalent or higher morning dose controls daytime polyuria in most patients, although a third dose occasionally may be needed in the afternoon. In some patients, chronic allergic rhinitis or other nasal pathology may preclude reliable absorption of the peptide following nasal administration. Oral administration of desmopressin in doses 10 to 20 times the intranasal dose provides adequate blood levels of desmopressin and controls polyuria (Fjellestad-Paulsen et al., 1993). Subcutaneous administration of 1 to 2 g daily of desmopressin also is effective in central DI.

Lypressin nasal spray also can be used to treat central DI; however, lypressin's duration of action is short (4 to 6 hours), making it less convenient than desmopressin. Also, lypressin, like vasopressin, can induce V₁ receptormediated adverse effects. Nonetheless, for patients refractory to desmopressin or who experience side effects with desmopressin, lypressin provides an alternative. 8-Arginine vasopressin has little if any place in the long-term therapy of DI because of its short duration of action and V₁ receptormediated side effects. Vasopressin can be used as an alternative to desmopressin in the initial diagnostic evaluation of patients with suspected DI and to control polyuria in patients with DI who have recently undergone surgery or experienced head trauma. Under these circumstances, polyuria may be transient, and long-acting agents may produce water intoxication.

An additional V₂ receptormediated therapeutic application is the use of desmopressin in bleeding disorders (Mannucci, 1997; Sutor, 1998). In most patients with type I von Willebrand's disease (vWD) and in some with type IIN vWD, desmopressin will elevate von Willebrand factor and shorten bleeding time. However, desmopressin is generally ineffective in patients with types IIa, IIb, and III vWD. Desmopressin may cause a marked, transient thrombocytopenia in individuals with type IIb vWD and may be dangerous in such patients. Desmopressin also increases factor VIII levels in patients with moderately severe hemophilia A. Desmopressin is not indicated in patients with severe hemophilia A, those with hemophilia B, or those with factor VIII antibodies. The response of any given patient with type I vWD or hemophilia A to desmopressin should be determined at the time of diagnosis or 1 to 2 weeks before elective surgery to assess the extent of increase in factor VIII or von Willebrand factor. Desmopressin is employed widely to treat the hemostatic abnormalities induced by uremia (Mannucci et al., 1983). In patients with renal insufficiency, desmopressin shortens bleeding time and increases circulating levels of factor VIII coagulant activity, factor VIIIrelated antigen, and ristocetin cofactor. It also induces the appearance of larger von Willebrand factor multimers. Desmopressin is effective in some patients with liver cirrhosisinduced or druginduced (heparin, hirudin, antiplatelet agents) bleeding disorders. Desmopressin, given intravenously at a dose of 0.3 g/kg, increases factor VIII and von Willebrand factor for more than 6 hours. Desmopressin can be given at intervals of 12 to 24 hours, depending on the clinical response and the severity of bleeding. Tachyphylaxis to desmopressin usually occurs after several days (due to depletion of factor VIII and von Willebrand factor storage sites) and limits its usefulness to preoperative preparation, postoperative bleeding, excessive menstrual bleeding, and emergency situations.

Another V₂ receptormediated therapeutic application is the use of desmopressin for primary nocturnal enuresis (Sukhai, 1993). In this regard, desmopressin should be used only intranasally and may be used alone or in combination with behavioral conditioning. Finally, desmopressin has been found to relieve postlumbar puncture headache, probably by causing water retention and thereby facilitating rapid fluid equilibration in the CNS.

Pharmacokinetics

When vasopressin, lypressin, and desmopressin are given orally, they are quickly inactivated by trypsin, which cleaves the peptide bond between amino acids 8 and 9. Inactivation by peptidases in various tissues (particularly the liver and kidneys) results in a plasma half-life of vasopressin of 17 to 35 minutes. The plasma half-life of desmopressin has two components, a fast component of 6.5 to 9 minutes and a slow component of 30 to 117 minutes.

Toxicity, Adverse Effects, Contraindications, Drug Interactions

Most adverse effects are mediated through the V₁ receptor acting on vascular and gastrointestinal smooth muscle; consequently such adverse effects are much less common and less severe with desmopressin than with vasopressin or lypressin. After the injection of large doses of vasopressin, marked facial pallor as a result of cutaneous vasoconstriction commonly is observed. Increased intestinal activity is likely to cause nausea, belching, cramps, and an urge to defecate. Most serious, however, is the effect on the coronary circulation. Vasopressin and lypressin should be administered only at low doses and with extreme caution in individuals suffering from vascular disease, especially disease of the coronary arteries. Other cardiac complications include arrhythmia and decreased cardiac output. Peripheral vasoconstriction and gangrene have been encountered in patients receiving large doses of vasopressin.

The major V₂ receptormediated adverse effect is water intoxication, which can occur with desmopressin, lypressin, or vasopressin. In this regard, carbamazepine, chlorpropamide, and NSAIDs can potentiate the antidiuretic effects of these peptides. Desmopressin, lypressin, and vasopressin should be used cautiously in disease states in which a rapid increase in extracellular water may impose risks (e.g., in angina, hypertension, heart failure) and should not be used in patients with acute renal failure. Also, it is imperative that these peptides not be administered to patients with primary or psychogenic polydipsia, because severe hypotonic hyponatremia will ensue.

Allergic reactions, ranging from urticaria to anaphylaxis, may occur with desmopressin, lypressin, or vasopressin. Intranasal administration may cause local adverse effects in the nasal passages, such as edema, scarring, rhinorrhea, congestion, irritation, pruritus, and ulceration.

It is likely that nonpeptide, orally active V₂-selective receptor antagonists will become available in the near future for the treatment of dilutional hyponatremia induced by heart failure, liver cirrhosis, nephrotic syndrome, and SIADH (Schrier et al., 1998; Mayinger and Hensen, 1999). In addition, orally active combined V_1a-/V₂-selective antagonists may become available for diseases such as congestive heart failure, in which both increased peripheral vascular resistance and dilutional hyponatremia are present (Yatsu et al., 1999). Whether or not sporadic administration of membrane-permeant, nonpeptide V₂ receptor antagonists will achieve successful in vivo cell surface-receptor delivery of certain alleles of X-linked nephrogenic DI, as demonstrated in vitro, remains to be ascertained in clinical trials (Morello et al., 2000).

Several important new clinical applications of the ancient hormone vasopressin are under active investigation. Vasopressin may prove superior to epinephrine as a pressor agent in cardiopulmonary resuscitation (Chugh et al., 1997), and it may be particularly effective in refractory hypotension after cardiopulmonary bypass (Overland and Teply, 1998). Vasopressin levels in patients with septic shock are inappropriately low, and septic shock patients are extraordinarily sensitive to the pressor actions of vasopressin (Landry et al., 1997). Vasopressin also reverses intractable hypotension in the late phase of hemorrhagic shock (Morales et al., 1999). Thus, vasopressin may become the preferred pressor agent in emergency and critical care medicine.