INTRODUCTION:

Nocturia, defined as awaking to void during the night¹, is the most troublesome lower urinary tract symptoms (LUTS) ^{2, 3}. The incidence increases with age.⁴It has been shown to rise from 30% to 60% in a population with mean age of 49 years to 60% to 90% in a population aged 60 to 80 years.⁵In woman these symptoms are often considered to result from aging, childbirth or just “being a woman”⁶.Nocturia affects the patients by various ways with respect to quality of life, sleep patterns, and increased mortality ⁷.

Pathological categories

There are three categories for nocturia i.e. nocturnal poly uria, low nocturnal bladder capacity or a combination of nocturnal polyuria and low functional bladder capacity. Overproduction of urine at night time is the main cause of nocturia.because of the decreased secretion of antidiuretic hormone (arginine vasopressin) also called (AVP)^8,9.

Nocturia is not a trivial complaint and can affect several aspects of a patient’s state of health. Even rising once-nightly to void is bothersome for many people. The standardization committee of the international continence society (ICS) is currently developing a world wide definition of nocturia and comprehensive framework to improve the diagnosis and treatment of this condition.

Multifactorial Etiology of Nocturia-

The production of urine by the kidney follows a circadian rhythm that changes with age in early childhood, when the pattern is developing, diurnal urine production in 3 times the nocturnal volume. This circadian rhythm is well established by the age of 7 years and by adulthood, nighttime urine production comprises just 25% of the total daily amount.

Pathological condition causing nocturia include cardiovascular disease, diabetes mellitus and insipidus, lower urinary tract obstruction to void for other reason, such as anxiety or primary sleep disorders⁵.

Behavioral and environmental factors contributing to nocturia include consumption of diuretic medication, caffeine, alcohol or excessive fluid shortly before retiring for the night.¹⁰ prostatic diseases, and neurogenic and unstable bladders have been reported to lead to frequent nocturnal rising.^10,12 in addition ,nocturia may result from stroke, congestive heart failure peripheral edema ( for example due to venousihsu efficiency or nephrosis) and myeloneuropathy secondary to vertebral disk disease or spondylosis¹¹

Effects of sleep deprivation

Sleep is important for physical and mental well-being. It is generally through that adults need about 7 to 8 hours sleep per night and that adequate sleep has a restorative effect. the quality of sleep deteriorates with increasing age and older adults have shallower and more fragmented sleep patterns, possibly as a result of the reduction in growth hormone secretion with age.¹³Few physiology changes are seen with sleep loss and mainly are noted with total asleep as opposed to partial sleep deprivation, including changes in temperature regulation, mood status (temporary euphoria in depressed subjects) and central nervous system function (paranoia, delusion).¹⁴ However, insufficient or disrupted sleep has commonly been linked with physical and mental disorders, particularly depression and mood alteration,^15,16as well excessive daytime sleepiness leading to poor motivation and job performance.¹⁷

Mechanism of Nocturia

Although in many cases nocturia may be caused by bladder dysfunction (for example inflammation or prostatic obstruction) or sleep apnea,¹⁸ simple overproduction of urine during the night is another common etiology.⁶ There are three broad categories of pathophysiology which account for nocturia, which refer to as noctural polyuria, low noctural bladder capacity and mixed nocturia (a combination of noctural polyuria and noctural bladder capacity). These categories are generated through interpretation of a single 24- hour voiding diary in which each voided volume is tabulated with corresponding time as to whether voiding was within hours awake or asleep. Polyuria defined as 24-hour urine output greater than 2,500 ml¹⁹ may cause nocturia through generally increased urine production when noctural urine output exceeds functional bladder capacity as it is does with noctural polyuria. However, polyuria and nocturnal polyuria are not mutually inclusive.

Nocturnal polyuria

The nocturnal polyuria syndrome was defined by asplund as increased urine output during the night. However, in contrast to diabetes insipidus (when intake and output are increased), 24-hour urine production remains normal ,indicating a variation in normal diurnal production of urine. This increased nocturnal diuresis results in nocturnal urine volume in excess of bladder capacity, creating the need for night time voiding in the form of nocturnal enuresis or nocturia.²⁰ Several definition of nocturnal polyuria have been used, such as nocturnal urine volume in excess of 6.4 ml/kg.14 or exceeding a third of the total daily urine output 13 and nocturnal diuresis 0.9 ml or greater per minute^21,22 but none has achieved widespread acceptance .The preferred definition is when nocturnal urine volume is more than 35% of the total 24-hour urine production and we defined the nocturnal polyuria index as nocturnal urine volume (NUV) per 24-hour urine greater than 0.35.²³ Another precise definition characterizes nocturnal polyuria according to the exact number of hours asleep and the fraction of urine output that would be expected during this time.

Diminished nocturnal bladder capacity

Problems with low nocturnal bladder capacity exist when nocturnal voiding occurs at bladder volume less than functional bladder capacity.²⁴ Nocturia index is nocturnal urine volume /functional bladder capacity, with the first morning void included in the nocturnal urine volume. Nocturia index minus 1 equals the predicted number of nightly voids. The nocturnal bladder capacity index is defined as the difference between the predicted numbers of nightly voids (ANV). The significance of this difference is that the greater the nocturnal bladder capacity index, the more nocturia may be attributed to diminished nocturnal bladder capacity and sensory urge disorders.

Therapeutic Strategies

Nocturnal polyuria remediable medical causes of nocturnal polyuria should be identified and treated but in some cases nocturia persists and in most clearly identifiable remediable conditions are not evident. Empirical treatment options include evening fluid restriction (a form of behavior modification), timed diuretics, symptomatic treatment agents.^{25, 26}

Elderly patients with nocturia due to bladder instability have been treated with anti-cholinergic therapy, such as propantheline, oxybutynin and scopolamine.^27,28These agents reduce but do not eliminate the number of nocturnal voids. Side effects include dry mouth, drowsiness, facial flushing and confusion. Patient diagnosed with sleep disorders causing or due to nocturia are commonly treated with hypnotics. Traditionally barbiturates have been used but due to problems of dependence and tolerance, benzodiazepines now are more commonly prescribed and occasionally effective to help some patient resume sleep after awaking.²⁹

Anti-cholinergics

Drugs in this category act by blocking the parasympathetic nerves that control voiding or by exerting a direct spasmolytic effect on the detrucer muscle of the bladder. Thus, they target bladder dysfunction rather than imbalance between nocturnal urine production and bladder capacity.

Oxybutynin

Oxybutynin is used for the treatment of urinary frequency, urgency and incontinence, characteristics features of overactive or irritable bladder. It is associated with a high incidence of unpleasant side effects and the dosage needs to be carefully assessed, particularly in the elderly. Tolterodine- tolterodine is a bladder- selective agent with similar activity to oxybutynin. It is equally effective, but better tolerated, thanoxybutynin in the treatment of overactive bladder.

Tricyclic antidepressants

The mode of action of TCAS in the treatment of nocturia is unclear due to narrow therapeutic window and their toxicity following overdose.

Flavoxate hydrochloride

It is a smooth muscle relaxant with antimuscarinic effects. It is used for symptomatic relief of pain and urinary frequency associated with inflammatory disorders of the urinary tract.

Desmopressin

It is a synthetic replacement for anti-diuretic hormone, the hormone that reduces urine production during sleep. It may be taken nasally, intravenously, or as a pill. Doctors prescribe Desmopressin³⁰ most frequently for treatment of diabetes insipidus or bedwetting.

formula C46H64 N14O12S2, mol.mass 1069.22g/mol. Desmopressin has also been shown to cause a significant decrease in nocturnal urinary volumes.³¹

Chemistry of Desmopressin

Two structural changes, which increase the stability and action of desmopressin, distinguish it from vasopressin deamination p of l-arginin at the molecule and substitution of L-arginin at position 8 with the enantiomer d-arginine. The desmopressin molecule is, therefore polarized with a basic amino acid at position 8 and alipophilic n-terminal³¹.

Mechanism of Action

Vasopressin receptors found in the kidney, liver, brain, pituitary gland, aortic smooth muscle and platelets. These receptor are divided into sub types:

Vasopressin receptor type 1 (v1)

Vasopressin receptor type 2 (v2)

The v1 receptor mediates the unwanted mediate vasopressin effects of the hormone and the v2 receptors are responsible for its anti diuretic properties. Desmopressin is a pure v2 receptor agonist and, therefore does not have the unwanted pressure activities of vasopressin, but retains the anti diuretic properties of the natural hormone.

When bound to the v2 receptors in the kidney distal nephrons, desmopressin increases the permeability of the collecting ducts and tubules there by enhancing water re-absorption. As a consequence, the extra cellular fluid becomes more dilute while the urine becomes more concentrated thereby reducing the volume of urine produced. Desmopressin provides efficacy and safety in the Nocturia in women.³²

CONCLUSION:

Impact of nocturia on quality of life produces the miserable incidences. Nocturia is not only detrimental to the quality of sleep and well being but is also related to increased mortality and risk of falling at night particularly in the elderly. Desmopressin significantly prolonged the duration of sleep until the first nocturnal void, which is an important indicator of quality of life. There are the various treatments available for nocturia but safest and proper treatment according to dug profile is Desmopressin. Because of mechanism of action related to AVP levels. Other drug shows its usefulness on other problems like nocturia due to bladder disorders.

REFERENCES:

1. Van Kerre Broeck P and Weiss J. Standardization and terminology of nocturia BJU INT 1999;84:14

2. Miller M. Nocturnal polyuria in older people: Pathophysiology and clinical implication. J Am Geriatr. Soc. 2000; 48:1321-9

3. Peters TJ, Donovan Jl, Kay He, ABRAMS P, De Ia Rosette JJ and Porru D. The international continence society “ Benign Prostatic Hyperplasia “ study : the bothersoeness of urinary symptoms . J. Urology. 1997;157: 900-1

4. Donahue JL and Lowenthal DT. Nocturnal polyuria in the elderly person. Am J. Med. Sci. 1997; 314: 232-8

5. Barker JG, Mitteness LS. Nocturia in the elderly. Gerontologist 1998;28:99-104

6. Stewart RB, Moore MT and May FE. Nocturia: A risk factor for falls in the elderly. J Am Geriatr Soc. 1992; 40: 1217.

7. Umallauf M, Goode and Burgio KI. Psycosocial issues in geriatric urology: problems of treatment and seeking. Urol. Cl; In North Am.1996; 23: 127.

8. Asplund R. Mortality in the elderly in relation to nocturnal micturation. Bju. Int. 1999; 84:.297-301

9. Asplund R. The nocturnal polyuria syndrome (NPS). Gen Pharmacol, 1995; 26: 1203.

10. Rembratt A, Norgard JP and Anderson KE. Nocturnal polyuria: an inescapable consequence of aging. Neuroural Urodyn. 2001; 20: 460-2

11. Saito M, Kondo A, Kato T. Frequency-volume charts: comparison of frequency between elderly and Adult patients. Br. J. Urology. 1993; 72: 14, 38.

12. Asplund R and Aaand Aberg HE. Micturition habits of older people voiding frequency and urine volume. Scand J. Nephrol. 1992; 26: 345.

13. Sullivan MP and Yalla SV. Urodynamics assessment of benign prostatic hypertrophy. In alternate methods in the treatment of benign prostate hyperlassia. Edited by N.A. Romas and ED Vaghn. New York Springer–Verlag. 1993; 66-89.

14. Van Cauter E and Conpinschi G. Altered hormonal secretion in aging: roles of sleep and circadian rhythms. Aging Male, Suppl.1998; 1: 8.

15. Naitoh P, Kelly TI and Englund C. Health effect of sleep deprivation. Occup Med. 1990; 5: 209.

16. Hetta J, Rimon R and Almqvist M. Mood alterations and sleep. Ann. Clin. Res. 1985; 17: 252.

17. Lindberg E, Janson C and Gislason T. Sleep disturbance in a young adult population. Cangender differences be explained by differences in psychological status. Sleep. 1997; 20: 381.

18. Broman JE, Lundh LG and Hetta J. In sufficient sleep in the general population Neurophysioly Clin. 1996; 26: 30

19. Pressman MR, Figueroa WG and Kandrick Mohd J. Nocturia a rarely diagnose symptom of sleep apnea and other occult sleep disorders. Arch. Intern. Med. 1996;156: 545.

20. Weiss JP, Blaivas JG and Stember DS. Nocturia in adults: etiology and classification. Neurourol Urodyn. 1998; 17: 467.

21. Norgaard JP. Pathophysiology of nocturnal inuresis .Scand. J. Urol. Naphrol. Suppl. 1991;140: 13.

22. Asplund R, Sundbrg B and Bengtesson P. Oral Desmopressin for nocturnal polyuria in elderly subjects: a double blind, placebo-controled, randomized exploratiory study. Br. J. Urol. 1999; 83: 591.

23. Asplund R, Sundbrg B and Bengtesson P. Desmopressin for the treatment of nocturnal polyuria in elderly subjects:a dose titration study. Br. J. Urology. 1998; 82: 642.

24. Rollema H. Clinical significance of symptoms, signs and uerodynamic patterns in BPH. Clinical Eurology Chap.61, 1994; 847-880.

25. Abrans PJG and Stanton SL et al. The standardization of terminology of LUT function the international continence society commety on standardization of terminology. Scand. J. Urol. Naphrol. Suppl. 1988; 114: 5.

26. Reynard JM, Cannon A and Yang Q et al. A novel therapy for nocturnal polyuria : a double – blind monitor daily weights randomized trial for furosemide against placebo . BR J Urol. 1998; 81: 215.

27. Pederson PA and Johanson PB. Prophylactic treatment of adult nocturia with bumetanide. Br. J. Urology. 1998; 62: 145.

28. Muskat Y, Bukovsky L and Schiender D. et al. The use of scopolamine in the treatment of detrusor instabihty. J. Urol. 1996; 1561 -1989.

29. Gajewski JB and Awad SA. Oxybutynin in patient with multiple sclerosis and detrusor hyperreflexia. J. Urol. 1996; 1567 -1989.

30. Takami N and Okada A. Trizolam and nitrazepam use in elderlyn outpatients. Ann Pharmacother. 1993; 27: 506.

31. Vilhardt H. Basic Pharmacology of Desmopressin a review: Drug Invest 1990; 2: 28

32. Eckford SD, Carter PG and Jackson SR. Penneymd, Abramsp. An Open, inpatient, incremental safety and efficacy study of Desmopressin in women with multiple sclerosis and nocturia. Bju. Int. 1999; 83: 591-5

Received on 12.11.2008 Modified on 10.12.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008;Page 324-327