Medication Use and Xerostomia

Xerostomia is a subjective complaint associated with salivary gland hypofunction.¹ However, the symptom of dry mouth can occur without an actual reduction in salivary flow. Etiologies of xerostomia include both salivary and nonsalivary causes.² Identifying those with true salivary hypofunction is key due to the risk of oral disease. A thorough review of systems and medication history is essential to determining the origin of xerostomia symptoms.²

Medications

More than 500 drugs are reported to cause xerostomia as a side effect, and medication use is the most frequent cause of xerostomia complaints, especially among the elderly.^3,4 The severity of the xerostomia complaint often increases among the elderly due to a synergistic effect when taking multiple medications.^3,5 Both stimulated and unstimulated salivary flow rates decrease with an increasing number of medications taken.⁶ The most common cause of drug-induced xerostomia is the altering of neural pathways that stimulate salivary gland secretion.⁷ These are drugs that have either an anticholinergic or sympathomimetic effect.⁴ Stimulation of the parasympathetic nerves (cholinergic action) produces an increase in fluid volume (serous saliva). Stimulation by the sympathetic nerves (sympathomimetic action) produces less volume and viscous saliva.^4,8 Thus, drugs that have an anticholinergic action reduce the volume of serous saliva, including antihypertensives, antihistamines, antidepressants, antipsychotics, antiemetics, antispasmotics, and anti-parkinsonian drugs.^3,4,7 Drugs with sympathomimetic actions produce a more viscous, mucinous saliva with less volume, such as decongestants, bronchodilators, appetite suppressants, and amphetamines.⁴ Drugs may also exert their neural effects in the higher centers of the brain; stimulation of certain adrenoreceptors in the frontal cortex can produce inhibitory effects on salivary nuclei.³ Drugs can also produce xerostomia without affecting the neural pathways. Inhaled medications produce the sensation of dryness but without any change in salivary flow.³ Interestingly, some anti-hypertensive medications produce the symptoms of xerostomia without actually decreasing salivary flow.⁹ How antihypertensive medications actually cause xerostomia is unknown, although it is hypothesized that xerostomia may result from decreased fluid volume and loss of electrolytes secondary to increased urination and dehydration.⁹ Diuretics produce alterations in electrolyte and fluid balance.^3,7 Finally, drugs can also decrease salivary flow by causing vasoconstriction in the salivary glands.³

The list of medications associated with xerostomia continues to grow as new drugs are released. Other drug classes now known to cause xerostomia include the proton pump inhibitors, protease inhibitors and reverse transcriptase inhibitors for HIV infection, analgesics and narcotics for pain control, a variety of anti-infective agents, and some anti-neoplastic agents.^4,7 Table 1 lists the drug classes that cause xerostomia. Dental professionals can work with their patients’ physicians to address chronic dryness. When possible, the patient may be taken off a medication or switched to another that is less xerogenic. The dosing regimen can be altered so that peak plasma levels of the drug do not correspond with periods of maximum dryness, such as nighttime. Dosages can be split into smaller quantities and ingested more frequently to allow for natural periods of salivary stimulation, eg, eating, to counteract the drying effects of the drugs.³

Diseases of the Salivary Glands

Sjögren’s syndrome (SS) is an autoimmune disorder characterized by intense lymphocytic infiltration of the exocrine glands. This infiltration destroys much of the glandular structure, making it difficult to produce fluids for normal function. Common symptoms include chronic dry eyes and dry mouth. There are two forms of the disease: primary SS not associated with any other autoimmune disease and secondary SS associated with other connective tissue diseases, including rheumatoid arthritis, systemic lupus erythematosus, and scleroderma.⁴ International diagnostic criteria are published to assist with the diagnosis of the disease, which among others include measures of salivary gland inflammation, and the presence of specific autoantibodies in the serum.¹⁰ Biopsy of the labial minor salivary glands demonstrates a characteristic focal lymphocytic infiltration.¹¹ Glandular swelling is characteristic of SS. However, persistent swelling of the parotid glands also may indicate bacterial infection or lymphoma.¹² Lymphocytic invasion, causing local salivary tissue inflammation and fibrosis, combined with the autoimmune-mediated interference with neurotransmitter and receptor function appear to be responsible for the clinical manifestations of SS.¹² Interestingly, labial salivary gland biopsies taken from patients with severe oral and ocular dryness reveal that as many as 50% of their glandular cells remain intact.¹³ This allows patients with SS to benefit from salivary stimulating medications.

Chronic salivary gland enlargement and xerostomia are also symptoms of sarcoidosis, HIV disease, and hepatitis C viral infection (HCV).⁴ HIV salivary gland disease occurs in up to 8% of infected individuals and most frequently affects the parotid glands with bilateral enlargement and xerostomia. It usually arises late in the course of HIV infection but occasionally may be the first manifestation of HIV disease. Kaposi’s sarcoma and nonHodgkin’s lymphoma associated with HIV infection may also cause salivary gland enlargement.⁴ Medications used to treat HIV disease also produce xerostomia.⁴ HCV salivary gland disease affects up to 33% of affected persons, with xerostomia as the predominant symptom.⁴ Histologically, the salivary gland changes with this disease resemble those seen with SS but with a lesser degree of inflammation. Other diseases that are associated with xerostomia include amyloidosis, cystic fibrosis, autoimmune thyroiditis, rheumatoid arthritis, chronic graft-versus-host disease, and diabetes.^4,13-16 Medication use, elevated glycosylated hemoglobin levels, and elevated fasting blood glucose levels are identified as factors leading to dehydration and xerostomia in Type I diabetics.¹⁶

Cancer Therapies

Salivary glandular tissues are highly sensitive to the radiation therapy used to treat oral carcinomas, and serous acinar cells found in the parotids are more radiosensitive than the mucous cell types.^4,8 Serous cells may contain more heavy metals that absorb radiation energy, which promotes the release and action of free radicals.⁸ Amifostine is a chemoprotective drug used to reduce the incidence of moderate to severe xerostomia in patients undergoing radiation therapy that includes a significant portion of the parotid glands. The drug acts as a scavenger of free radicals found in the tissues.¹⁷

The degree of xerostomia is associated with the dose of radiation and the amount of salivary tissue affected. Whenever possible, a portion of the parotid gland should be spared from the radiation field. After 5 weeks of radiation, salivary flow is greatly reduced and rarely recovers completely.^4,8 Patients may experience some recovery from radiation damage within the first year after treatment.⁸ Salivary flow from the contralateral glands may increase to compensate for radiation damage, although the recovery of the less radiosensitive mucous glands appears to be important for residual lubrication.⁸ After radiation, the saliva becomes more viscous and changes to a yellowish-brown color. Salivary buffering capacity is reduced, resulting in an acidic oral pH, compromised antimicrobial activities, and increased incidence of oral diseases.

Chemotherapy causes changes in salivary flow rates and composition during treatment, and the effects vary with the types of agents used and the duration of treatment.⁸ Chemotherapy causes systemic immunosuppression that alters the concentration of salivary immunoglobulins, resulting in oral mucositis, progression of gingival disease, caries, and opportunistic infections.⁸ A number of antineoplastic drugs cause xerostomia and the degree of xerostomia is related to the total number of chemotherapeutic agents used.⁴ The exact mechanisms by which these drugs damage salivary and other oral tissues are unknown. However, increased salivary drug concentration and prolonged contact of the drug-containing saliva with the oral epithelium is observed in patients with low flow rates. A high concentration of a biologically active drug may result in increased toxicity to oral tissues.⁸ Amifostine is also used to detoxify the reactive metabolites of cisplatin, a drug used to treat many cancers, including advanced ovarian, lung, and some head and neck cancers.^4,8,17

Salivary Stimulation & Replacement Therapies

Salivary stimulation can be achieved mechanically by chewing sugarless gum and by chemical (gustatory) stimulation by sucking on sugarless candies or products that contain citric acid, such as vitamin C tablets, lemon drops, or lozenges.¹⁸ Caution must be used with citric acid due to its acidity. Sonic toothbrushing may also increase salivary flow in patients with SS.¹⁹

Artificial salivary substitutes can be recommended. They do provide short-term relief, however, compliance may be poor. Most products in this category contain sodium carboxymethylcellulose, which mimics the viscosity of natural saliva. Water-based moisturizing gels can be used intraorally as a saliva substitute and extraorally on the lips to provide ⁸ hours of relief from xerostomia symptoms.

Two prescription drugs have been approved by the Food and Drug Administration for the treatment of xerostomia: pilocarpine and cevimeline. These drugs are cholinergic agonists that produce parasympathetic stimulation of the exocrine glands to increase serous secretions. Pilocarpine is approved for use in both head and neck radiation therapy patients and patients with SS; cevimeline is approved for SS. Because these are systemic medications, they turn on secretions from all exocrine glands-an advantage for relieving multiple symptoms of SS. However, patients may experience adverse events related to their cholinergic effects, most notably excessive sweating. These drugs must be used with caution in patients with cardiovascular disease, chronic respiratory conditions, and kidney disease. Use of these medications is contraindicated in patients with narrow-angle glaucoma, uncontrolled asthma and liver disease. These are common disorders among the elderly who frequently present with xerostomia. Several clinical trials have demonstrated their efficacy in relieving xerostomia symptoms and increasing salivary flow in radiation therapy and SS patients.²⁰

Current research is investigating the use of other medication classes that may relieve dry mouth symptoms, as well as biogenetic engineering technology to regenerate damaged tissues, and salivary transplantation.^4,20 These discoveries will undoubtedly improve the oral health and quality of life of patients suffering from this chronic condition.

REFERENCES

1. Sreebny LM. Dry mouth and salivary gland hypofunction. Part I. Diagnosis. Compendium. 1988;9:569-578.
2. Fox PC. Differentiation of dry mouth etiology. Adv Dent Res. 1996;10:13-16.
3. Sreebny LM, Schwartz SS. A reference guide to drugs and dry mouth-2nd ed. Gerodontology. 1997;14:33-47.
4. Porter SR, Scully C, Hegarty AM. An update of the etiology and management of xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97:28-46.
5. Porter SR, Scully C. Adverse drug reactions in the mouth. Clin Dermatol. 2000;18:525-532.
6. Närhi TO, Meurman JH, Ainamo A, et al. Association between salivary flow rate and the use of systemic medication among 76-, 81- and 86-year-old inhabitants in Helsinki, Finland. J Dent Res. 1992;71:1875-1880.
7. Närhi TO, Meurman JH, Ainamo A. Xerostomia and hyposalivation: causes, consequences and treatment in the elderly. Drugs Aging. 1999;15:103-116.
8. Jensen SB, Pedersen AM, Reibel J, Nauntofte B. Xerostomia and hypofunction of the salivary glands in cancer therapy. Support Care Cancer. 2003;11:207-225.
9. Atkinson JC, Shiroky JB, Macynski A, Fox PC. Effects of furosemide on the oral cavity. Gerodontology. 1989;8:23-26.
10. Vitali C. Classification criteria for Sjögren’s syndrome. Ann Rheum Dis. 2003;62:94-95.
11. Daniels TE. Labial salivary gland biopsy in Sjögren’s syndrome. Assessment as a diagnostic criterion in 362 suspected cases. Arthritis Rheum. 1984;27:147-156.
12. Wall GC, Magarity ML, Jundt JW. Pharmacotherapy of xerostomia in primary Sjögren’s syndrome. Pharmacotherapy. 2002;22:621-629.
13. Fox RI, Stern M. Sjögren’s syndrome: mechanisms of pathogenesis involve interaction of immune and neurosecretory systems. Scand J Rheumatol Suppl. 2002;116:3-13.
14. Chang CP, Shiau YC, Wang JJ, Ho ST, Kao CH. Decreased salivary gland function in patients with autoimmune thyroiditis. Head Neck. 2003:25:132-137.
15. Jensen JL, Uhlig T, Kvien TK, Axell T. Characteristics of rheumatoid arthritis patients with self-reported sicca symptoms: evaluation of medical, salivary and oral parameters. Oral Dis. 1997;3:254-261.
16. Moore PA, Guggenheimer J, Etzel KR, Weyant RJ, Orchard T. Type I diabetes mellitus, xerostomia, and salivary flow rates. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92:281-291.
17. Koukourakis MI. Amifostine in clinical oncology: current use and future applications. Anticancer Drugs. 2002;13:181-209.
18. Nieuw Amerongen AV, Veerman EC. Current therapies for xerostomia and salivary gland hypofunction associated with cancer therapies. Support Care Cancer. 2003;11:226-231.
19. Papas A, Stack KM, Spodak D. Sonic toothbrushing increases saliva flow rate in Sjögren’s syndrome patients. Abstract #2795. J Dent Res. 1998;77(special issue):981.
20. Fox PC. Salivary enhancement therapies. Caries Res. 2004;38:241-246.

From Dimensions of Dental Hygiene. July 2005;3(7):22-24.