Nicotine replacement therapy-associated syndrome of inappropriate antidiuretic hormone.

Abstract: Nicotine has been documented to regulate the release of plasma arginine vasopressin (AVP). The literature is inconclusive about the effects of nicotine replacement therapy on AVP release, although cigarette smoking has been shown to increase the release of AVP. No clinical case reports have documented the possible association between nicotine replacement and hyponatremia through AVP release. We report a case of a 39-year-old man who experienced syndrome of inappropriate antidiuretic hormone while on nicotine patch therapy. We theorize that the constant serum concentration of nicotine levels provided through the patch may cause hyponatremia through the continuous stimulation of vasopressin.

Key Words: hyponatremia, nicotine, smoking, syndrome of inappropriate antidiuretic hormone

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Nicotine's numerous effects on the central nervous system are neuroregulatory in nature. When nicotine is ingested or administered (through cigarette smoking or nicotine replacement therapy), its centrally mediated effects increase in a dose-dependent manner as plasma levels rise. These effects result from an increased secretion of hormones from the pituitary gland. (1) It is well documented that nicotine may play a role in the nonosmotic release of plasma arginine vasopressin (AVP) from the posterior pituitary. We report the case of a patient who experienced hyponatremia and syndrome of inappropriate antidiuretic hormone (SIADH) after the administration of a nicotine patch.

Case Reports

A 39-year-old black man, previously in good health, presented to the emergency department complaining of a worsening cough that had progressed over the past month. The patient described greenish sputum mixed with blood and recent episodes of shortness of breath, chest pain, night sweats, and fever and chills. He was a frequent heavy drinker and had smoked two packs of cigarettes per day for 15 years. He was taking no medications.

On presentation, his temperature was 98.4[degrees]F, his heart rate was 120 beats/min, his respiratory rate was 25 breaths/min, his blood pressure was 109/76 mm Hg, and his oxygen saturation was 75% on room air. The patient was placed on supplemental oxygen, and his oxygen saturation increased to 92%. A chest radiograph revealed pneumonia with bilateral lower lobe infiltrates. He was placed in respiratory isolation and begun on ticarcillin/clavulanate 3.1 g administered IV every 4 hours, tobramycin 180 mg administered IV every 12 hours, nicotine patch (21 mg/d), nebulized albuterol and ipratropium administered every 6 hours, and D5-0.45% NS with 20 mmol/L KCI at 150 ml/h. A complete metabolic panel on Day 2 of hospitalization revealed a sodium level of 137 mmol/L (normal range, 135-145 mmol/L) and a potassium level of 3.1 mmol/L (normal range, 3.6-5.0 mmol/L). Vancomycin 1.9 g administered intravenously every 18 hours was added for Gram-positive cocci found on sputum Gram stain.

Pulmonary function continued to decline, requiring 100% supplemental oxygen. Methylprednisolone 60 mg administered IV every 6 hours was prescribed for 2 days. Delirium tremens precautions were also initiated. On Day 6, the sodium and potassium were 144 mmol/L and 3.8 mmol/L, respectively, and the white blood cell count continued to increase to 26.7 X [10.sup.3] cells/[mm.sup.3] (4.0-11.6 X [10.sup.3] cells/[mm.sup.3]). On Day 8, serum sodium fell to 132 mmol/L (Fig. 1) and IV fluids were decreased to 40 ml/h. The patient continued to tolerate a regular diet. Fluid intake was further restricted to 2.5 L/d on Day 10. He remained stable and afebrile and the white blood cell count began to decrease. Urine sodium and osmolality were 156 mmol/L and 550 mOsm/kg, respectively, confirming the diagnosis of SIADH. All IV antibiotics were discontinued on Day 11 and gatifloxacin 400 mg administered PO every day was begun. On Day 12, serum sodium was 130 mmol/L. The serum sodium continued to decrease despite fluid restriction to 128 mmol/L and 126 mmol/L on Days 14 and 15, respectively. The nicotine patch was reduced to 14 mg/d on Day 16. The patient continued the same fluid restriction and regular diet while the serum sodium remained low at 129 mmol/L. The nicotine patch was further reduced to 7 mg/d on Day 17. The patient was discharged after 18 days of hospitalization with a sodium level of 131 mmol/L.

Discussion

The antidiuretic effects of nicotine were first identified in the 1940s. (2) Small studies were conducted with IV nicotine in rats and with cigarette smoke and IV nicotine in humans. At this time, it was theorized that nicotine stimulates the hypothalamus and results in a release of antidiuretic hormone from the posterior pituitary gland. Nicotine injected intraventricularly or intracisternally into the brains of cats has been shown to stimulate the release of AVP. (3) Thus, nicotine was also used to test the function of this system in patients with clinical diabetes insipidus in the early 1950s. (4) When the release of AVP was inadequate, it was considered that the system had been largely destroyed.

[FIGURE 1 OMITTED]

Since that time, it has been well established that cigarette smoking stimulates increased plasma AVP. (5) However, it is unclear whether nicotine administered by other routes exhibits the same response. Also, it is unclear whether the nausea and vomiting related to nicotine administration could explain this increase in plasma AVP.

In a small study of nine patients, only one patient had an increased AVP level after 2-mg nicotine gum. (6) However, this patient experienced nausea, which may have stimulated vasopressin secretion. In a more recent study of 16 patients with primary monosymptomatic nocturnal enuresis, a higher dose of 4-mg nicotine gum caused a small but statistically insignificant increase in AVP without a change in plasma osmolality. (7) In a study using the 22-mg/d nicotine patch in 30 smokers who had refrained from smoking for 48 hours, no effect was seen on vasopressin concentrations. (8) However, the patients were only exposed to the nicotine patch for 2 days. One to 3 mg of IV nicotine, administered with hypertonic saline, has been shown to increase AVP concentrations coinciding with antidiuresis. (9)

Some have cited that an airway-specific mechanism from cigarette smoke induces AVP release. (10) No change in AVP levels was seen after an infusion of 2 mg of IV nicotine over 5 minutes in healthy subjects, but a statistically significant increase in AVP was seen after smoking both high (1.2 mg) and low (0.6 mg) nicotine content cigarettes. The increase was significantly greater with the higher nicotine content cigarettes. Cigarette smoking has been shown to induce an increase in serum AVP levels in other trials. (11)

Some investigation has been conducted regarding the theory that cigarette smoking is associated with hyponatremia because of AVP release in polydipsic schizophrenics. One study examined the relationship between amount of water ingested and urinary output before and after smoking in patients who had experienced hyponatremia in the past. (12) No relationship was found between amount of water ingested or urinary output after cigarette smoking. It was theorized that schizophrenic patients with polydipsia have a higher incidence of repetitive behaviors such as cigarette smoking. Similarly, in a study of 10 smokers with self-induced water intoxication and psychosis, no relationship was found between serum nicotine levels, AVP, plasma osmolality, or urine osmolality. (13)

Nicotine has also been suggested to be implicated in idiopathic edema. (14) The example has been given that if a patient smokes several cigarettes after a water load, there is a fall in urine output because of stimulation of the posterior pituitary gland and release of antidiuretic hormone. Therefore, the constant supply and stimulation provided by a nicotine patch could lead to chronic overproduction of antidiuretic hormone.

There are numerous causes of SIADH, and a thorough review of all would be beyond the scope of this article. However, bacterial, viral, and fungal pneumonia have been noted to be a cause of SIADH. Alterations in AVP have also been found during pulmonary tuberculosis. Typically, AVP levels are elevated early in the infection and return to baseline within a few days. (15,16) However, in our patient, once the pneumonia was improved, the patient continued to have a low serum sodium. Although the pneumonia could not be definitively ruled out as the single cause of SIADH and complicated the diagnosis, it was not considered likely at the time because of the length and extent of the hyponatremia, which pointed to a more iatrogenic source. Also, according to the adverse drug reaction probability scale of Naranjo et al, (17) our patient case would be classified as a "possible" adverse drug event with a score of 3.

Conclusion

Nicotine has long been considered a nonosmotic regulator of vasopressin release. Unfortunately, this is not a widely known fact. Actually, several prominent medical texts include nicotine as a cause of drug-induced SIADH; however, there have been no clinical patient case reports of this finding documented in the medical literature. (18,19) Although previous literature stated that the nicotine patch had no effect on vasopressin release, we suggest that the nicotine replacement therapy may have caused a syndrome of inappropriate antidiuretic hormone in our patient. The typical patient only smokes during waking hours; however, our patient wore the patch continuously, 24 h/d. We think that the maintenance of elevated nicotine levels in the serum, without the normal peaks and troughs that accompany smoking, may have led to enhanced AVP secretion. Therefore, pending longer, controlled clinical trials, the nicotine patch should be considered as a potential cause of SIADH.

Accepted May 2, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9703-0322

References

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11. Chiodera P, Volpi R, Capretti L, et al. Abnormal effect of cigarette smoking on pituitary hormone secretions in insulin-dependent diabetes mellitus. Clin Endocrinol (Oxf) 1997;46:351-357.

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13. Vieweg WV, David JJ, Rowe WT, et al. Correlation of cigarette-induced increase in serum nicotine levels with arginine vasopressin concentrations in the syndrome of self-induced water intoxication and psychosis (SIWIP). Can J Psychiatry 1986;31:108-111.

14. Dalessio DJ. Nicotine and the antidiuretic hormone. JAMA 1969;207:954 (letter).

15. Dixon BS, Anderson RJ. Pneumonia and the syndrome of inappropriate antidiuretic hormone secretion: Don't pour water on the fire. Am Rev Respir Dis 1988;138:512-513 (editorial).

16. Hill AR, Uribarri J, Mann J, et al. Altered water metabolism in tuberculosis: Role of vasopressin. Am J Med 1990;88:357-364.

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19. Jackson EK. Vasopressin and other agents affecting the renal conservation of water, in Hardman JG, Limbird LE, Gilman AG (eds): Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 2001, ed 10, pp 789-809.

RELATED ARTICLE: Key Points

* A sodium level of 137 mmol/L was obtained on Day 2 of therapy with nicotine patch 21 mg daily. Sodium levels declined to 126 mmol/L on Day 15.

* It is well documented that nicotine may play a role in the nonosmotic release of plasma arginine vasopressin from the posterior pituitary.

* We theorize that the constant serum concentration of nicotine levels provided through the patch may cause hyponatremia through the continuous stimulation of vasopressin.

Christopher K. Finch, PHARMD, Miranda R. Andrus, PHARMD, and William A. Curry, MD

From the Harrison School of Pharmacy, Auburn University, and the University of Alabama School of Medicine, Tuscaloosa, AL.

Reprint requests to Christopher K. Finch, PharmD, Department of Pharmacy, Methodist University Hospital, 1265 Union Avenue, Memphis, TN 38104. Email: [e-mail]