|Year : 2013 | Volume
| Issue : 1 | Page : 15-20
Adverse affects of drugs on saliva and salivary glands
Vidhi Vinayak1, Rajeshwari G Annigeri2, Hashikesh A Patel3, Sachin Mittal1
1 Department of Oral Medicine and Radiology, Shree Bankey Bihari Dental College and Research Centre, Ghaziabad, Uttar Pradesh, India
2 Department of Oral Medicine and Radiology, College of Dental Sciences, Davangere, India
3 Department of Oral and Maxillofacial Surgery, Navodaya Dental College, Raichur, Karnataka, India
|Date of Web Publication||20-Jun-2013|
B-53 Ashoka Niketan, near Yamuna Sports Complex, New Delhi-110092
Source of Support: None, Conflict of Interest: None
Saliva is the most valuable oral fluid is critical to the preservation and management of oral health. Saliva containing various organic and inorganic substances provides primary natural protection for teeth and soft tissues in the oral cavity assists in mastication, deglutition and digestion of food. The secretion of saliva can be affected due to various local and systemic causes. However if a patient is taking medication and has altered salivary secretion the differential diagnosis should include the possibility of an adverse drug reaction. The drugs may lead to alteration in the flow rate of saliva, which can be either increased or reduced, however certain drugs have been reported to cause change in the color of the saliva. Several drugs may lead to sialadenitis associated with altered salivary secretion. These symptoms may simulate systemic diseases, Hence oral physicians need to be vigilant in recognizing these adverse drug reactions in the patients and it is incumbent upon the practitioner to try to stay abreast of this ever evolving field especially as it relates to dental therapeutics.
Keywords: Adverse drug reactions, saliva, salivary glands
|How to cite this article:|
Vinayak V, Annigeri RG, Patel HA, Mittal S. Adverse affects of drugs on saliva and salivary glands. J Orofac Sci 2013;5:15-20
|How to cite this URL:|
Vinayak V, Annigeri RG, Patel HA, Mittal S. Adverse affects of drugs on saliva and salivary glands. J Orofac Sci [serial online] 2013 [cited 2018 Jan 16];5:15-20. Available from: http://www.jofs.in/text.asp?2013/5/1/15/113684
| Introduction|| |
"Every medication can produce untoward consequences even when used appropriately. Adverse drug reactions can involve any organ and the system of the body including the mouth and are frequently mistaken for signs of underlying disease".
WHO in 1966 defined drug as any substance that is used or intended to be used to modify or explore the physiological systems or the pathological states for the benefit of the recipient.
An adverse drug reaction (ADR) is defined by the WHO as a drug response that is noxious and unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of a disease or for the restoration, correction or modification of a physiological function. All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. 
| Drug Induced Xerostomia|| |
The salivary glands are under the control of the autonomic nervous system and hence their function can be affected by a variety of drugs. Dry mouth is a common complaint in patients treated for hypertensive, psychiatric, or urinary problems and in the elderly mainly as a consequence of the large number of drugs used and polypharmacy.
Actions of drugs on salivary glands
Diuretics produce alterations in electrolyte and fluid balance. Finally, drugs can also decrease salivary flow by causing vasoconstriction in the salivary glands.
- Drugs that compete with acetylcholine in parasympathetic (and sympathetic) ganglia. These used to be the ganglion-blocking antihypertensive drugs such as pentolinium, mecamylamine, and pempidine. However these have now been superseded by more selective agents.
- Drugs that compete with acetylcholine release at the parasympathetic effector junction. Most of the drugs that cause xerostomia do so in this way. They include atropine and atropine-like antispasmodics (e.g. poldine and propantheline bromide); tricyclic antidepressants (e.g. amitriptyline); tetracyclic antidepressants (e.g. maprotiline hydrochloride); many antiparkinsonian drugs such as benzhexol, benztropine mesylate, and orphenadrine; and antihistamine drugs (H1 blockers), some of which are phenothiazines. Somewhat weaker anticholinergic activity is exhibited by the phenothiazine derivatives. However this activity is sufficient to cause dryness of the mouth. Clonidine, which is used for the treatment of hypertension and in the treatment of migraine, frequently produces xerostomia. Selective antimuscarinic drugs, such as the anti-secretions drug pirenzepine, are also associated with xerostomia.
- Drugs acting on the sympathetic effector function. Salivary flow is probably related to some extent by sympathetic as well as parasympathetic activity. Drugs acting at the sympathetic neuro-effector junction, such as amphetamine, may slightly reduce salivary flow. A high incidence of caries has been observed in amphetamine abusers. These authors suggest that this is due to both the reduced salivary flow rate and to a decrease in salivary calcium and phosphate concentration caused by this drug.
- 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.
- Drugs can also produce xerostomia without affecting the neural pathways. Inhaled medications produce the sensation of dryness but without any change in salivary flow.
- Some anti-hypertensive medications produce the symptoms of xerostomia without actually decreasing salivary flow. 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. 
Hence drugs may cause xerostomia through a number of mechanisms. Drugs that have an anticholinergic action reduce the volume of serous saliva, including antihypertensives, antihistamines, antidepressants, antipsychotics, antiemetics, antispasmotics, and anti-parkinsonian drugs. Drugs with sympathomimetic actions produce more viscous, mucinous saliva with less volume, such as decongestants, bronchodilators, appetite suppressants, and amphetamines [Table 1].
Nederfors et al. in 1994 investigated the effects of a diuretic, hydrochlorothiazide on unstimulated and stimulated whole saliva output. Hydrochlorthiazide promotes the excretion of Na + and water by inhibiting their reabsorption at the distal renal tubule of the kidney. In this double-blind, placebo-controlled crossover study, the authors found a significant reduction in stimulated whole saliva and total salivary sodium output in all 34 healthy volunteers and the study also indicated no changes in unstimulated whole saliva flow rates. 
A study reported in 1997 by Thomson et al. to evaluate the prevalence of subjective perception of dry mouth in the adult population and pharmacotherapy and to assess the comorbidity between symptoms of dry mouth and pharmacotherapy. A total of 5200 subjects divided into different age groups and were mailed the questionnaire. About 3313 subjects returned. The results showed that the prevalence of dry mouth was higher in women as compared to men in both medicated and the non-medicated patients. There was a strong association between dry mouth and continued pharmacotherapy. There was also increased prevalence of dry mouth in medicated as compared to non medicated individuals. There was found a strong association between the xerostomia and the number of medications. 
A study by Scully in 2003 reported that the prevalence of xerostomia was greater among the 308 who were taking two or more medications than the 302 who were taking one only, or the 340 not taking any (14.6%, 10.9% and 5.0%), respectively. The most prevalent categories of medication at age 32 were analgesics, nutrient supplements, hormonal contraceptives, anti-asthma drugs and antidepressants. The prevalence of xerostomia was greater among those taking an iron supplement, a cyclic antidepressant, or an antihypertensive either a beta blocker or an angiotensin-converting enzyme inhibitor. 
A study was carried by Vucićević Boras to evaluate the levels of interleukin-6 and tumor necrosis factor α in patients with drug induced xerostomia. 30 patients and controls were taken and saliva was collected for the estimation. No significant differences in salivary IL-6 and TNF-α were found between patients with xerostomia and control group. There was no correlation between levels of salivary IL-6 and TNF-α (tumor necrosis factor) and patients' age, salivary flow rate and number of medications taken. 
A study was carried out in 2006 by Thomson et al. to describe the prevalence and associations of xerostomia among adults in their early thirties, with particular attention to medication exposure as a putative risk factor. The sample that formed the basis for the longitudinal study was 1,037 children, and they were assessed within a month of their third birthdays. Follow-ups were conducted at ages 5, 7, 9, 11, 13, 15, 18, 21, 26, and, most recently, at age 32 years. At ages 26 and 32 years, medication data were collected at the time of the general medical examination and any feeling of dryness of mouth was asked verbally. 
The classic triple therapy for eradication of H. pylori is amoxicillin or tetracycline, metronidazole and a bismuth derivative. Addition of an H2-receptor antagonist to these drugs may increase the rate of eradication of Helicobacter pylori and shorten the duration. However dry mouth is found in 41% of the recipients.  Systemic retinoids are well known to cause dryness of the mouth and changes in oral and lip mucosa, as seen with the advent of etretinate and 13 cis-retinoic acid. A study to evaluate changes in salivary variables during 3 months treatment with oral isotretinoin showed a significantly lower mean flow rate of stimulated saliva during the period of medication than at baseline.
Cytokines such as interferon can have pronounced effects on salivary gland cells in vitro and may be involved in the pathogenesis of salivary disease. Interferon therapy for the treatment of chronic hepatitis C infection can cause significant dry mouth. IL-2 can also impair salivation when used, for example, for control of nasopharyngeal carcinoma and the major salivary gland dysfunction has been described in patients with hematological malignancies receiving IL-2 based immunotherapy post- autologous blood stem cell transplantation. 
| Drug Induced Hypersalivation|| |
Salivary secretion is increased by drugs that have a cholinergic action either by acting directly on parasympathomimetic receptors or by acting on cholinesterase inhibitors. Although generally a benign side effect, hypersalivation can be distressing to the patient. Intense sialorrhea may disturb sleep; some patients may describe a choking sensation and may even aspirate excess saliva at night. In addition, sialorrhea is a socially stigmatizing condition that may lead to non-compliance among patients who are often refractory to other neuroleptics.
Olanzapine, a derivative of clozapine, is an atypical antipsychotic with a receptor-binding profile similar to that of clozapine. A 20-year-old woman had a 3-year history of schizophrenia. After an initial 4-week trial of olanzapine, 10 mg/day, with substantial clinical improvement, she was treated solely with olanzapine, 15 mg/day and her early spontaneous complaints of adverse effects included experiencing morning grogginess and soaking her pillow with saliva during sleep. When the dosage of olanzapine was increased to 15 mg/day, her morning grogginess and pillow wetting worsened. 
A 34-year-old man had delusional disorder, somatic type. He had chronic neck pain as well as somatic hallucination with the hypochondriacal delusion for 4 years. olanzapine (10 mg/day) was added to fluvoxamine treatment (200 mg/day) in this case. Subsequently, hypersalivation was induced without any extrapyramidal symptoms and it is suggested that hypersalivation was an adverse effect of olanzapine. Possible interaction olanzapine with fluvoxamine might increase the risk of the adverse effect.
Clozapine is a novel and unique prototype atypical, tricyclic, dibenzodiazepine derivative, antipsychotic agent. About 17% of patients taking clozapine discontinue treatment because of adverse effects. Clozapine induced sialorrhea is the second most common side effect after sedation. It has been suggested that stimulation of both M3 and M4 muscarinic receptors present in salivary glands lead to saliva production. The balance of clozapine's opposing effects on M3 and M4receptors may mediate hypersalivation. 
Clozapine is known to exert a full-agonist effect at M4 receptors; whereas, its affinity for M3 receptors is lower. Therefore, it is possible that the effects of M4 receptor stimulation would exceed those of M3 receptor blockade, resulting in hypersalivation. Clozapine-induced sialorrhea may also be explained through its blocking actions at α2 receptors. In a study the authors suggested that clozapine interferes with normal deglutition by blocking target receptors located in the pharynx or by disrupting vagal control of esophageal peristalsis. 
Quetiapine is an antipsychotic drug with combined antagonism at dopamine and serotonin type 1 and 2. A 36 year-old female patient with a 16 years history of schizoaffective disorder and was hospitalized with relapse of mania with psychosis and was administered quetiapine 25 mg twice daily. Within a day she developed hypersalivation and when the dose was increased to 50 mg twice daily the salivation worsened, there was drooling and clothes became wet. The drug was stopped and within a day hypersalivation resolved. α2 adrenergic blockade is the mechanism by which quetipaine induces hypersalivation. Through blockade of sympathetic stimulation, parasympathetic stimulation is left unopposed to cause high salivary flow rates. 
A 29 year-old female patient suffering from paranoid schizophrenia was treated with clozapine gradually increased to 400 mg/day over a period of 4 weeks. On this dose, the patient started complaining of sialorrhea, more so in the night, along with sedation. She was started with amisulpride 100 mg in two divided doses. After about a week of this, the patient started reporting improvement in her sialorrhea.  Apart from these numerous drugs have been known to cause sialorrhea [Table 2].
| Drug Induced Sialolithiasis|| |
Drug therapy is a relatively unknown cause of stones in the salivary glands. A 36-year-old physician was being treated for adult attention-deficit/hyperactivity disorder with dextroamphetamine spansules 20 mg/d and atomoxetine 18 mg/day. Within 10 days of starting atomoxetine, he developed a left submandibular sialolith in the salivary gland, which was extruded. A second sialolith developed after another 10 days of atomoxetine treatment. Atomoxetine was stopped, and the stone passed.
Two weeks later, he restarted atomoxetine, and within 4 to 5 days, he had yet another recurrence. He again discontinued atomoxetine and repeated the cycle on three further occasions with shorter time intervals to stone recurrence on upon each re-exposure. In each case, he experienced pain and swelling of the gland. He was able to pass the stone without assistance by massaging the gland digitally. He reported passing about 10 stones over these latter two episodes that took place within a few months of each other and had no further episodes until exposure to atomoxetine 18 months later. 
| Drug Induced Salivary Discoloration|| |
Discoloration of saliva and other body fluids is seen in patients treated with the clofazimine, levodopa, rifampicin and rifabutin therapy. 
| Drug Induced Sialadenitis|| |
Several drugs have been reported to cause salivary gland enlargement which may resemble mumps. The mechanism of drug-induced sialadenitis remains unclear in most cases. Either oedema or spasm of smooth muscle in the salivary gland or a hypersensitivity reaction could be responsible.
Salivary gland swelling has been found to occur concurrently with oxyphenbutazone consumption. A 52-year-old woman was admitted with acute onset of bilateral painful swelling of the salivary glands and fever. Five days prior to admission, she was given oxyphenbutazone, 100 mg three times a day, for superficial thrombophlebitis of the right leg. On the 3 rd day of therapy she started to experience profuse salivation and discomfort when she chewed food. On the fourth day she developed dryness of the mouth, a marked swelling of both parotid glands, and a temperature of 38.8 o C. 
Nitrofurantoin is bacteriostatic and bactericidal for many gram-positive and gram-negative bacteria. A 78-year-old woman was admitted with acute onset of bilateral painful swelling of the parotid gland, dry mouth, and fever of 39°C. She gave a history of arterial hypertension and moderate heart failure, for which she had taken regularly digoxin 0-25 mg, methyldopa 750 mg, and hydrochlorothiazide 100 mg daily. Her daughter reported that 13 days before the first episode of parotid swelling her mother had begun taking nitrofurantoin 50 mg twice daily for a urinary tract infection. Before the second episode of parotid swelling she had taken nitrofurantoin 50 mg 6 h earlier. 
In most of the reported cases, the salivary gland swelling subsided after cessation of the offending drugs, with or without corticosteroid therapy. However there was also one reported case complicated by secondary bacterial infection that required antibiotic treatment. In all the reported cases, a prolonged period of xerostomia ensued after cessation of the drug.
An 18 year-old female developed serum sickness although, receiving doxycycline for inflammatory acne. Seventy-two hours later, she developed bilateral painful parotid swelling. There was tenderness, reddening and an increased temperature of the skin over the glands. Studies showed mild leukocytosis (12,700/mm), elevated ESR (52 mm in the 1 st hour), hypocomplementemia (C4, 10 mg/dl) and proteinuria (1.6 g/l) and haematuria (33 red cells per high power field). Serum protein electrophoresis and serum immunoglobulins were within normal limits. She was treated with methylprednisolone 80 mg daily intravenously and hydroxyzine 100 mg/day orally. The parotitis resolved in 24 hours and the rest of the clinical manifestations in 5 days. 
Antihypertensive drugs such as nifedipine and α-methyl dopa have been implicated to cause sialadenitis. In the case of methyldopa and bretylium the enlargement has been attributed to excessive hyperaemia in the parotid glands when they are deprived of the normal vasoconstrictor action on the sympathetic neurons. A patient with alcohol withdrawal syndrome was administered chlormethiazole (364 mg) was given and twenty minutes later the patient complained of a dry mouth and had a painful bilateral swelling of the parotid glands. He had no fever, rash, or eosinophilia. The swelling resolved over 6 h. Chlormethiazole was stopped and diazepam was given, without any side effects. 
Angiotensin converting enzyme inhibitor has been known to cause salivary gland enlargement. A 32 year-old female patient diagnosed with malignant hypertension was treated with enalaprilat injection 1.25 mg given i.v. over 5 min. Within a few minutes of injection patient developed painful swelling of both parotids, which was tender on examination.
She was given injection hydrocortisone 100 mg i.v. and oral anti-inflammatory drugs (Aceclofenac 100 mg twice a day). Her parotid swelling decreased within few hours and very little swelling persisted after 24 hours. She was given one rechallenge of enalaprilat 1.25 mg given i.v. over 5 min, which successfully controlled her blood pressure. However there was no recurrence of parotid swelling. The sialadentitis occurring due to captopril is attributed to a type B idiosyncratic adverse drug reaction. 
Salivary gland swelling has also been reported in clozapine-treated patients who do not manifest hypersalivation. The proposed mechanism in this context has been the anticholinergic effects of clozapine on the glandular tissues themselves. This results in thickening and stasis of saliva, with precipitation of calcium salts in the duct, leading to calculus formation and obstruction, resulting in distension of the gland. Hinze-Selch et al. proposed an immunologically-mediated mechanism for the development of clozapine-induced salivary gland swelling. They argue that clozapine-sensitised peripheral blood mononuclear cells are involved in the development of sialadenitis, resulting in salivary gland swelling. 
Unilateral or bilateral swelling of the parotid gland is a reported side effect of rinsing one's mouth with chlorhexidine. It has been suggested that overly vigorous rinsing may predispose individuals to unilateral or bilateral parotid swelling. This hypothesis is supported by the observation that a patient who experienced parotid swelling after using a mouthwash reported no further recurrence of symptoms after gentler rinsing was recommended. Other evidence that supports a mechanical cause of parotid swelling is that swollen parotid glands have been reported after the use of mouthwash that contains chlorhexidine, but not after other methods of chlorhexidine administration. 
Terbinafine is an effective antimycotic agent of the allylamine type which inhibits the enzyme squalene epoxidase. A 38 year-old man presented with a painful right ear 15 days after taking terbinafine 250 mg daily for tinea cruris. On examination a mild right otitis externa was noted, along with unrelated bilateral painless enlargement of the parotid glands. There was no associated hypersalivation or xerostomia. He was reviewed 12 days after stopping terbinafine treatment and the parotid swelling had significantly diminished. 
- Vigorous rinsing may cause the mouthwash to enter the parotid duct, which may lead to an inflammatory reaction involving the duct wall and the gland parenchyma. The resulting duct wall oedema and cell infiltration would then cause a narrowing of the duct lumen and a transient obstruction.
- Other authors hypothesized that chlorhexidine may reduce the natural resistance of the mucous membranes to viral infection. The reduction in bacterial load that occurs due to the bacteriostatic effect of chlorhexidine may alter the oral environment such that it may predispose individuals to viral infections. 
A 61 year-old male patient was admitted with a complaint of bilateral swelling of the salivary glands and rashes. His medical history revealed that he had a sternal fracture and was prescribed naproxen 500 mg twice daily. It was stopped after 2 days and three days later he developed bilateral swelling of the submandibular glands. Naproxen was stopped and bilateral parotid gland swelling developed. Scintigraphy of the salivary glands revealed sialadenosis. A diagnosis of naproxen induced sialadenitis was given. 
Radioiodine ( 131 I) is an important therapy for patients who have well-differentiated thyroid cancer. Although multiple side effects are observed associated with radioiodine but one of the major effect is the involvement of salivary glands. The parotid, submandibular, and sublingual glands have been reported to concentrate iodine as high as 7-700 times the plasma levels. As a result these glands can receive a significant radiation absorbed dose from the 131 I treatment resulting in a sialadenitis. However the mechanism by which iodine is concentrated in salivary glands is unknown but the major mechanism responsible could be by sodium/iodine symporter. The reported incidence of sialadentitis varies from 2% to 67%. A case of ‹iodine mumps› has been reported in which bilateral swelling of the parotid and submandibular glands developed 3 h after the injection of an iodinated contrast medium. 
Warfarin sodium has been reported to cause salivary gland swelling. A very unusual case has been reported in which submandibular gland haemorrhage occurred spontaneously in a patient receiving warfarin anticoagulant therapy. Clinically, the case presented as swelling beneath the tongue. The ducts of the submandibular gland were engorged with the clotted blood, and the submandibular glands themselves were enlarged and tender. 
| Conclusion|| |
The importance of ADRs is often underestimated, although they are common and can be life threatening, and lead to unnecessary expense. Every healthcare professional shares a responsibility for identifying the risk factors of ADRs and using that knowledge to reduce their occurrence. Oral physicians need to be vigilant in recognizing these adverse drug reactions in the patients. It is incumbent upon the practitioner to try to stay abreast of this ever evolving field especially as it relates to dental therapeutics.
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[Table 1], [Table 2]
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