Modern Approach in Treatment of Diabetes Insipidus

In this paper we have reviewed the possition of desmopressin in the treatment of diabetes insipidus. Desmopressin is a synthetic analog of vasopressin, with more pronounced antidiuretic effect. It is treatment of choice in substitution therapy of diabetes insipidus. Its application before sleeping time can reduce nocturnal enuresis, so it has a place in the treatment of enuresis nocturna. Antidiuretic effect of desmopressin is the result of agonistic effect on V receptors in the renal tubules. The efficacy and safety of desmopressin in mentioned indications was confirmed in clinical studies.


Introduction
Desmopressin is a synthetic vasopressin analog, with enhanced effect and longer duration of action than vasopressin or lypressin (lizine-vasopressin). Desmopressin differs from naturally-occurring vasopressin by deaminated hemicystein at position  and substituted D-arginine for L-arginine at position .This has been shown to diminish vasopressor activity, enhance antidiuretic-to-pressor potency, and prolong the duration of action of the compound.Vasopressin, hormone of neurohypophysis, is released when the plasma osmolarity is increased and/or blood pressure reduced.Diabetes insipidus, as a consequence of vasopressin deficit, is characterized with reduced reabsorption of water from collecting tubules of the kidney and patients suffer from polydipsia and polyuria ().

Pharmacodynamic Characteristics
Desmopressin was synthesized in , and from  is widely used in treatment of diabetes insipidus.Neurohypophysis hormones, vasopressin and oxytocine, are released from endings of neurosecretore neurons which somas are located in paraventricular and supraoptic nuclei of hypothalamus.Vasopressin is released when the plasma osmolarity is increasing and/or blood pressure dropping.Th e actions of vasopressin are mediated through interaction with two types of receptors, V and V.Vasopressin acts on V receptors, enhances generation of cyclic AMP in collecting tubules of the kidney and increases reabsorption of water according to the osmotic gradient.Th at is the essence of its antidiuretic eff ect.Diabetes insipidus, as a consequence of vasopressin defi cit, is characterized with reduced reabsorption of water from collecting tubules of the kidney and patients suff er from polydipsia and polyuria.Desmopressin is a drug of choice in the treatment of diabetes insipidus.Desmopressin is used in managment of nocturnal enuresis.Desmopressin given at bedtime to patients with nocturnal polyuria was associated with reduced nocturnal diuresis.With naturally occurring vasopressin (arginine vasopressin) the antidiuretic-to-pressor ratio is  (approximately  units/mg).Antidiuretic-to-pressor potency of desmopressin is  to : and the duration of action ranges from  to  hours.This is considerably longer than the duration of action for arginine vasopressin ( to  hours).Th e prolonged duration of action of desmopressin as compared to arginine vasopressin is most likely due to resistance to enzymatic cleavage, delayed absorption from nasal mucosa, and enhanced generation of cyclic AMP in the renal medulla ().In addition, desmopressin may be useful in the treatment of some coagulopathies, hemophilia A and von Willebrand's disease ().Desmopressin signifi cantly shortens bleeding time in healthy volunteers treated with aspirin in the duration of up to  hours.Evaluation of dose and eff ect ratio in patients with diabetes insipidus has shown that oral doses of desmopressin ranging from , milligrams to . milligrams induce significant antidiuretic effects.Desmopressin in dosage range from . to . milligrams per day has the optimal antidiuretic effect in the most patients with duration of  hours.In doses of . milligrams antidiuretic effect lasts for  hours.With increasing oral dosages the concentration of desmopressin in plasma is increasing in dose-dependent manner ().In a study of patients with nocturnal enuresis, patients who were classifi ed as responders to desmopressin therapy experienced increased fractional excretion of sodium at night compared to those classifi ed as non-responders and a group of normal control subjects ().A lack of circadian variation in the plasma osmolality was observed in both responder group and non-responder group.Normals and responders experienced a steady increase in plasma potassium during the night.Plasma sodium was stable without circadian rhythm in all three groups.Desmopressin responders did not experience signifi cant fl uctuation in diurnal variation of plasma vasopressin values but the other two groups did experience signifi cant increases peaking at : hours (p ≤ ,).Only normal control patients experienced signifi cant circadian variations in plasma atrial natriuretic peptide levels (p < ,).Patients with complete form of diabetes insipidus experienced signifi cant decrease in plasma triglyceride levels following desmopressin therapy (p = ,).However, similarly treated patients with partial diabetes insipidus did not experience signifi cant change in triglyceride levels.Favorable eff ects of desmopressin on lipid and lipoprotein metabolism in complete diabetes insipidus patients may be due to either direct eff ects or through modifi cations of factors that contribute to lipid metabolism ().

Mechanism of Action
Desmopressin increases reabsorption of water in collecting tubules of the kidney.Desmopressin, also, stimulates factor VIII and plasminogen activated release.Antidiuretic eff ect is the result of agonistic activity on V receptors placed in tubules of the kidney.Th is eff ect is the result of enhanced reabsorption of water, probably  BOSNIAN JOURNAL OF BASIC MEDICAL SCIENCES 2005; 5 (2): 38-42 based on opening of pores and channels which play role in water reabsorption according to the osmotic gradient.Molecular mechanisms of action include stimulation of adenilate cyclase and enhanced synthesis of cAMP.Vasopressin- receptors are also placed extrarenaly, and play role in factor VIII release.Desmopressin has minimal effect on V receptors that are located in smooth muscles of blood vessels walls and numerous diff erent organs ()

Pharmacokinetic Characteristics
Desmopressin is absorbed in nasal mucosa.Bioavailability of desmopressin after intranasal administration is , to , compared to intravenous or subcutaneous administration ().After oral administration, large part of desmopressin dose is degradated in gastro intestinal tract, but after high doses there absorption is suffi cient for the therapeutic eff ect ().After oral administration bioavailability is  compared to intranasal administration, and , compared to intravenous administration.Maximal concentration in plasma and AUC do not increase proportionally to administrated doses.Regardless of administrated doses, plasma half-life of desmopressin is , to , hours ().Terminal plasma half-life of desmopressin is  to  hours ().Distribution half-life of intranasal desmopressin is , minutes.Desmopressin does not penetrate hemato-encephalic barriere.Volume of desmopressin distribution is , to , L/kg.In vitro studies using human liver microsomes showed that desmopressin was not metabolized by liver.Desmopressin is almost completely excreted in urine.Elimination half-life after intranasal administration is , to , hours.

Indicationes And Dosage
Desmopressin is used in the treatment of neurohypophyseal diabetes insipidus, enuresis nocturna primaria, nocturia associated with nocturnal polyuria in adults and in testing of renal function capacity.Also, it is used in management of mild-to-moderate hemophilia A or mild-to-moderate type I von Willebrand's disease.Formulated as nasal spray, desmopressin is used in crises prevention of sickle-cell anemia by inducing hyponatremia.In patients with uremia, desmopressin reduces bleeding time by rising concentration of factor VIII. Desmopressin dosage should be individualized.Doses are titrated according to the patient's responses and pharmaceutical formulation of desmopressin.The food can reduce intensity and duration of desmopressin small doses antidiuretic effect.

Precautions
Drugs which are releasing antidiuretic hormone (tricyclic antidepressives, chlorpromazine, and carbamazepine) can cause additional antidiuretic eff ect with increased risk of fl uid retention.Nonsteroidal anti-infl ammatory drugs can cause fl uid retention and hyponatremia.Loperamide can increase concentration of desmopressin in plasma as well as the risk of fl uid retention and hyponatremia.Concomitant desmopressin and glyburide therapy has resulted in inhibition of desmopressin's eff ects and decreased antidiuretic eff ect ().Concomitant desmopressin and dimeticon therapy can reduce desmopressin absorption.Th e food can reduce intensity and duration of desmopressin small doses antidiuretic eff ect.Precaution is needed in patients with coronary artery disease and/or hypertensive vascular disease, in patients with fl uid and electrolyte disballance, in patients with allergic rhinitis, nasal congestion, and upper respiratory infections who may experience decreased effectiveness ().In the treatment of primary nocturnal enuresis or nocturia no fluid should be taken  hour before and  hours after desmopressin administration.Precaution is needed in pediatric patients.Testing of renal concentration capacity in children less than  year of age should be done only in hospital and with continuous surveillance.According to U.S. Food and Drug Administration desmopressin is classifi ed in the pregnancy risk category B ().In diuretic doses desmopressin does not have uterotonic eff ect.Physician should determine risk to benefit ratio for every individual case.Precaution is needed during lactation, considering that many of drugs are excreted in human milk ().

Clinical Studies
Three children with primary nocturnal enuresis had resolution of this condition within  days after initiation of desmopressin in dose of  micrograms intranasally.One child had primary nocturnal enuresis only, while the other  had primary nocturnal enuresis and congenital nephrogenic diabetes insipidus.In patients with congenital nephrogenic diabetes insipidus, mutations in vasopressin- receptor (VR) or aquaporin- (AQP) water-channel genes inactivate arginine-vasopressin proteins.Patients with this mutation are unable to concentrate their urine in response to secretion of arginine-vasopressin. Serum osmolality is therefore high and urinary osmolality low, despite high plasma arginine-vasopressin concentrations.After the  children were placed on desmopressin therapy, the child  BOSNIAN JOURNAL OF BASIC MEDICAL SCIENCES 2005; 5 (2): 38-42 with primary nocturnal enuresis slept through the night and did not wet the bed.Th e  youngsters with nephrogenic diabetes insipidus woke up during the night and went to the toilet to empty their bladder.All returned to their previous bed-wetting habits when desmopressin was temporarily halted.With restoration of desmopressin, all  ceased bed-wetting.Desmopressin may act outside of the renal area and may act in the central nervous system to resolve nocturnal enuresis ().Results of a randomized, double-blind, placebo controlled cross-over study demonstrated that oral desmopressin given to elderly patients with nocturnal polyuria at bedtime (n=) was associated with reduced nocturnal diuresis and nocturnal voiding and increased uninterrupted sleep.Patients with nocturnal urinary output ≥ , ml/min and ≥  nocturnal voids were eligible to participate in this study.Each patient had their dose titrated one week at a time beginning with , mg followed by , mg then , mg.Patients with nocturnal diuresis ≥ , ml/min were allowed to progress to the next dose level.Th e optimal dose of oral desmopressin in this population was identifi ed as , mg administered at bedtime with no dose-response relationship observed ().Signifi cant mean reductions in nocturnal diuresis and nocturnal voids were experienced by desmopressin patients compared to placebo after  weeks of therapy (p < ,).No change in -hour diuresis was observed.In patients with higher nocturnal contribution to the baseline -hour diuresis experienced greatest decreases in nocturnal diuresis with desmopressin therapy.Th e mean total number of hours slept per night was not changed by desmopressin treatment; however, the longest period of uninterrupted sleep was extended by , hours.No patient experienced serious adverse event during the study period.Likewise, the amount of sodium excretion, the temporal excretion pattern of sodium, and the diff erence in mean serum osmolality were not diff erent between the placebo period and the desmopressin treatment period.No dose-response relationship was observed for desmopressin ().Results of a randomized, double-blind, crossover, and placebo controlled study indicate that children with desmopressin resistant enuresis have nocturnal bladder instability yet some of these patients (/) respond to high-dose desmopressin therapy.Children  to  years of age, who had primary monosymptomatic enuresis at least  wet nights during baseline and less than  decrease in the number of wet nights while receiving desmopressin dose of , mg, were enrolled in the study.During the study, patients were treated with desmopressin , mg, desmopressin , mg, and placebo for  consecutive nights with a washout period of at least  hours between treatment periods.During double-blind therapy, the probability of enuresis and nocturia was highest with placebo compared to desmopressin , mg and desmopressin , mg (p = ,).However, no difference between the two desmopressin groups was observed.The mean number of hours between bedtime and fi rst bladder voiding during treatment periods was signifi cantly smaller for placebo compared to desmopressin (p < ,) but again no diff erences between the desmopressin groups were observed.Nine children were dry during all  nights of at least  of the  treatment periods and were treated with open-label high-dose desmopressin , mg.Complete dryness was achieved in  of these patients.Of  patients who received open-label desmopressin , mg at bedtime combined with oxybutynin  mg twice a day,  were complete responders and  were intermediate responders (number of wet nights decreased by more than  compared to baseline but still with enuretic accidents) ().Intranasal desmopressin therapy administered at bedtime to a cohort of  children with extrophy-epispadias complex and nocturnal incontinence was associated with decreased urinary output at night and six of the seven achieved nocturnal dryness.All patients, aged  to  years, had daytime continence yet experienced bed wetting  nights per week.Desmopressin therapy was titrated from  to  μg until patients were dry all night.Nighttime urinary output was decreased from a mean of  ml at baseline to  ml while on desmopressin.After  months of successful therapy, dose was down titrated to the minimum eff ective dose.Nocturnal dryness was achieved in  patients at  μg desmopressin and  required  μg.After initial  months, long-term therapy was successful at  to  μg per night in  patients,  μg in  patients and  μg in  patient.At  months follow-up, all patients remaind on desmopressin therapy.Six patients are dry at night while  still has nocturia.Th e only side eff ect reported was nosebleed in one patient.Body weight, arterial blood pressure, and serum electrolytes were not signifi cantly modifi ed on desmopressin therapy in this patients group ().One trial (n=, average age  years) employed intranasal desmopressin  μg titrated to a maximum of  μg if not dry within  hours, then continued for  to  weeks maintenance therapy.A gradual dosage reduction of  μg per month was undertaken after  weeks of complete dryness.If relapse occurred during tapering or after cessation of therapy, previous dosage was resumed.After an average -week treatment duration and -month median follow-up, the response  BOSNIAN JOURNAL OF BASIC MEDICAL SCIENCES 2005; 5 (2): 38-42 rate of  included  who remained completely dry without relapse,  who achieved complete dryness with relapse, and  who showed some improvement (less than  enuretic episodes per week) ().In a study of  patients (average age  years) with severe enuresis ( nights/week at baseline), oral desmo-pressin  to  μg applied for  months resulted in complete dryness in  of  evaluated patients ().An additional  and  achieved cure within  and  years after the study, respectively.After  years, in a follow-up,  still experienced enuresis and  required continuous desmopressin to maintain dryness ().

Conclusion
Desmopressin is a drug of choice for substitution treatment of diabetes insipidus.Antidiuretic eff ect of desmopressin is a result of agonistic activity on V receptors placed in tubules of the kidney.Molecular mechanism of action includes stimulation of adenilate cyclase and enhanced synthesis of cAMP.Except enhancing reapsorption of water in collecting tubules of kidney, desmopressin plays role in factor VIII release and it is plasmine activator.In addition, it is used in the treatment of coagulopathies, hemophilia A and von Willebrand's disease.Desmopressin is, mostly, well tolerated.Th e most common adverse eff ects are fl uid retention, hyponatremia, seizures, abdominal cramps, headache, nausea, vomiting and epistaxis.