In this chapter, the authors review the benefits of saliva and the destructive consequences of its loss. It is hoped that this will help their colleagues identify and treat patients before development of symptoms. Xerostomia is the subjective complaint of dry mouth or sensation of oral dryness. Hyposalivation is the actual decrease in measured salivary outflow. The authors discuss a compiled list of highly cited medications commonly used today that are linked with xerostomia and hyposalivation. There are numerous treatment modalities that are present, such as saliva substitutes, mouth rinses, sugar-free candy, and pilocarpine among others.
Xerostomia is the subjective complaint of dry mouth, whereas hyposalivation is the actual decrease in measured salivary outflow.
Saliva is secreted from major and minor glands of the oral cavity, which serves to lubricate, moisten, protect, and assist in digestion, taste, and smell.
Saliva is measured through multiple methods such as “spitting and drooling method”, modified schirmer test, and sialography among others.
There are numerous medications that are linked with xerostomia and hyposalivation; the authors describe 10 of the most cited medications and list numerous others.
Burning mouth syndrome is described as burning in the tongue or other oral mucous membrane that has no medical or dental-related cause.
It is fair to say that the average person does not think about the amount of saliva they have until they notice a decrease and begin to experience the discomfort associated with a decrease in saliva. The lack of saliva can grow to be a devastating experience for a patient’s oral health and can diminish their daily quality of life. The role of the oral specialist is to identify the presence, the causes, and the treatment modalities present for such conditions. This chapter helps the practicing oral specialist to review the benefits of saliva and the destructive consequences of its loss. The authors discuss the most common medications used today that are associated with diminished salivary presence and function. It is hoped that this will help their colleagues identify and treat patients even before development of symptoms by identifying high-risk individuals. These preventative measures and treatment modalities can be adapted to the daily practice of the oral specialist. These identifications and recommendations are transcribed from multiple systematic reviews and analyses.
Xerostomia versus hyposalivation
Xerostomia and hyposalivation are frequently used interchangeably, which is incorrect, and this can cause confusion to the practitioner and the patient and can affect the treatment modalities present. Xerostomia is defined as “the subjective complaint of dry mouth or subjective sensation of oral dryness.” The key term in this definition is “subjective.” Patients may have normal salivary function but have a feeling of dryness that may be a symptom or a byproduct of a larger a diagnosis. In contrast, hyposalivation is the actual decrease in measured salivary outflow. Several large studies have reported that the mean flow rate of unstimulated saliva in healthy persons during the day is in the range of 0.3 to 0.4 mL/min. An unstimulated flow of less than 0.1 mL/min is considered evidence of salivary hypofunction. In normal healthy individuals, the total daily salivary production is estimated to be 500 to 600 mL/d.
What is saliva?
Saliva is the watery liquid that is secreted into the oral cavity from the bilaterally paired major salivary glands (parotid, submandibular, and sublingual) as well as the from smaller accessory minor salivary glands found throughout the oral cavity. The parotid gland predominantly produces serous and watery secretions, whereas the sublingual glands produce mucous secretions, and the submandibular glands produce both serous and mucous secretions.
Because saliva has many different functions in the oral cavity, aiding mastication, swallowing, and digestion, its presence goes virtually unnoticed but its absence can be devastating. In the systematic review described by Dawes, saliva has a multimodal role. This role includes lubrication, moistening, and protection of the oral mucosa and esophagus, as well as assisting both taste and smell, and providing enzymes that aid in digestion.
Lubrication, Moistening, and Protection
The benefit of maintaining a moist, lubricated oral mucosa and esophagus prevents abrasion and aids in the removal of bacteria, viruses, fungi, and other microbes. This moist environment also aids in the physical movement of food, making mastication and consumption an easier task. These actions are aided due to mucin production from the submandibular, sublingual, and minor salivary glands. Mucins are heavily glycosylated glycoproteins that coat the oral cavity and act as a lubricant for opposing surfaces encountered during mastication. It is found that patients with decreased mucin will have difficulty in performing common tasks such as speaking, swallowing, or masticating.
Either passively or actively, there is a continuous flow of saliva in the average patient. The continuous outflow of saliva from the salivary ducts in the oral cavity inhibits retrograde flow of harmful microbes into the glands, thus preventing conglomeration of bacteria and the development of infection.
Taste and Smell
Saliva operates as the medium in which taste substances, or tastants, dissolve and interact with chemoreceptors, responsible for taste, located in the oral cavity. “These taste buds are present in the fungiform papillae and in the clefts of the circumvallate and foliate papillae on the tongue, the soft palate, the epiglottis the nasopharynx and esophagus. ” There are 5 basic tastes that are recognized, sweet, salty, sour, bitter, and umami/savory. Saliva acts as a protectant against noxious tastes that irritate the oral mucosa and can present a danger to the rest of the gastrointestinal tract. There will be an overproduction of saliva in this circumstance, causing dilution of the noxious taste stimuli, which gives the person the ability to spit out the noxious rich substance.
As the nose, the nasopharynx also contains olfactory receptors that are responsible for perceiving smell. When masticating solid foods, there is a release of aroma. The warmth and the enzymes in saliva also help break down solids and further release aromas that are carried by the saliva and delivered to these olfactory receptors.
As previously mentioned, enzymes in our saliva are present to help break down starches and starch-containing food. The enzyme most cited in the literature is alpha-amylase (1,4,-glucan 4-glucanohydrolase).
Saliva also acts as a buffer against very acidic foods and environments. The buffering properties come from the presence of bicarbonate and carbonic anhydrase VI. When acidic foods are introduced, salivary flow increases, and the hydrogen ions from acidic foods interact with bicarbonate to form carbonic acid. The carbonic anhydrase VI then springs into action to convert carbonic acid into water and gas. As you can imagine, vomiting can also be very harmful to the oral mucosa. The hydrochloric acid from the stomach also increases salivary flow, and the bicarbonate in the oral cavity will also work to buffer the gastric contents entering the mouth. As previously mentioned, saliva lubricates the esophagus and oral cavity, which softens and lubricates the foods we consume. The esophagus is lined by 600 to 700 mucous glands that secrete bicarbonate and mucus that help form a protective surface layer 95 μm thick.
Saliva has a very prominent role in the acquired enamel pellicle that surrounds teeth. Salivary proteins are found in bulk within this pellicle, which provides multiple protective factors. The pellicle decreases the friction from opposing teeth and provides protection against attrition, abrasion, and foreign trauma. Our enamel and dentin are composed of hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) crystals; the main components are calcium, phosphate, and hydroxide ions. Saliva is supersaturated with both calcium and phosphate ions. These ions can diffuse through the enamel pellicle to assist in remineralizing the enamel. Patients who have a decreased salivary flow or composition have an increased risk of caries formation because they have lost that protective component provided by saliva.
When the oral cavity is subjected to an acidic environment, there is an increase in the concentration of H+ ions and a decrease in the pH. In this environment, the H+ ions act to displace the phosphate from hydroxyapatite, which manifests as erosion. Saliva, being supersaturated with phosphate, helps buffer the acidic environment. In patients who have a decreased salivary function, there will be a concurrent decreased buffering capacity, and you will begin observing erosion and dental caries precipitated by acidogenic organisms in plaque. Saliva is also rich in urea. Microorganisms in plaque release urease, which converts urea into ammonia and carbon dioxide. Ammonia is a strong base that neutralizes carbon dioxide and increases the pH.
What are the other protective properties of saliva?
Along with the aforementioned properties, saliva also contains antibacterial, antifungal, and antiviral properties that keep the oral microbiota population stabilized. During dental training, the authors had a professor who described the oral microbiota as a “see-saw.” There was a balance of protective proteins living in conjunction with healthy and harmful microorganisms. Whenever you had an altered balance from external factors, the see-saw would turn and disrupt the balance, manifesting as the oral health problems we see today. The saliva is also home to multiple growth factors such as endothelia growth factor and vascular endothelial growth factor, which assist in angiogenesis and allow reepithelialization and regulation of the extracellular matrix.
How is it measured?
As previously described, xerostomia is the subjective feeling of dry mouth, whereas hyposalivation is the measured decrease in salivary outflow. Various measures are present to quantify the decrease in the measured outflow.
The most commonly and conveniently used technique is “the spitting and drooling” method. This measures the unstimulated salivary flow. A patient will allow for saliva to accumulate in the mouth for 5 minutes and spit into a collection tube, and this is repeated for a fixed time period. The stimulated flow can be measured by the patient chewing or using a sialogogue (a medication that promotes the secretion of saliva).
The modified Schirmer test (MST) uses paper strips that are placed in a blue dye that mark the amount of flow.
In sialography, a radiopaque contrast medium is introduced in the major duct of a major salivary gland, followed by routine radiographs, and the image is called a sialogram. In Sjogren syndrome, areas of destruction are seen in the radiographs. MRI sialography is more accurate than conventional sialography.
Medications with the strongest evidence of interference with salivary gland function
The authors are using the compiled list from Dr Wolff’s systematic review “Guide to medications inducing salivary gland dysfunction, xerostomia and subjective sialorrhea.” This review compiled a list of medications with documented effects on salivary gland function or symptoms. The reviewers performed an in-depth analysis in literature that found links between medications and salivary gland dysfunction. They also stratified these studies with a degree of relevance and strength. They provided a list of 56 medications with strong evidence of interference with salivary gland function. Later, the authors describe the highest cited medications commonly used that are linked to xerostomia and salivary gland dysfunction. They also include a table with the other medications that present with high evidence.
The oral specialist should be very familiar with alendronic acid and its fellow bisphosphonate derivatives. This medication is among many others to be cited in the literature for increased risk of medication-related osteonecrosis to the jaw (MRONJ) along with links causing salivary gland hypofunction.
Mechanism of action
Alendronate is a nitrogen containing bisphosphonate that attaches to hydroxyapatite crystals in the bone. When osteoclasts begin their function to resorb bone, it releases and inhibits further function by decreasing binding, resorptive activity, and inducing apoptosis.
Alendronate is most commonly used in conditions that cause excessive bone resorption such as osteoporosis, Paget disease, and metastatic bone diseases.
According to the AAOMS position paper on MRONJ, there is a derived incidence of 0.004% (4 cases per 10,000) patient-years of exposure to alendronate.
Imipramine (Tofranil) was the first drug in the tricyclic antidepressant family, although initially used to treat bed wetting (enuresis) in children during the 1950s. Increased observations at this time revealed increased evidence that in 1958, imipramine (Tofranil) was successful in the treatment of depression. Amitriptyline is among many tricyclic antidepressants that were synthesized in 1960 after the success of imipramine. These tricyclic antidepressants (TCAs) had become the first line of treatment for 30 years in the treatment of depression before the development of serotonin reuptake inhibitors.
Mechanism of action
Amitriptyline (tertiary amine), as other TCAs, are named based on their structure and side chain functions. They are divided into 2 classes: tertiary amines and secondary amines. Tertiary amines have 2 methyl groups, whereas secondary amines have one methyl group at the end of their side chain. They act primarily by increasing serotonergic and noradrenergic neurons by inhibiting central serotonin and noradrenaline reuptake at the synapse. Tertiary amines are more potent at blocking reuptake of serotonin, whereas secondary amines are more potent in blocking norepinephrine.
Amitriptyline is approved by Food and Drug Administration (FDA) for the treatment of depression. Its off-label use includes treatment of anxiety, chronic pain syndromes, migraines, sialorrhea, and posttraumatic stress disorder among others.
They are metabolized by first pass hepatic metabolism in the liver by cytochrome p450 enzymes CYP2D6 and CYP2C19 to nortriptyline.
The use of amitriptyline has decreased after the introduction of selective serotonin reuptake inhibitors (SSRIs). This decrease can be attributed to its adverse side effects, which includes its potential for cardiac toxicity, serotonin syndrome (confusion, agitation, dilated pupils, headache, nausea, vomiting diarrhea, tachycardia, twitching diaphoresis, and shivering), and antimuscarinic effect.
Cardiac effects: alone or when administered with other medications, TCAs such as amitriptyline can cause prolongation of the QT interval, which increases risk of ventricular arrhythmias.
Antimuscarinic effects include dry eyes, hyposalivary gland function, xerostomia, and sedation. As discussed previously, hyposalivation and xerostomia can increase the incidence of dental caries and other oral detriment.
Seizures: all tricyclic antidepressants decrease the seizure threshold and thus increase likeliness to increase seizures. Amitriptyline has a seizure rate of 1% to 4% at doses 250 mg/d to 450 mg/d.
Aripiprazole was cited 5 times with a high evidence of inducing xerostomia according to the world workshop oral medicine systematic review. It is classified as an atypical antipsychotic indicated for treatment of mania associated with bipolar I disorder.
Mechanism of action
Aripiprazole acts as a partial agonist of dopamine D2 and D3 and serotonin 5-HT1A receptors and also antagonizes the 5-HT2A receptor. It is hypothesized that dopamine hyperactivity contributes to mania, thus when aripiprazole binds to the receptor, it stimulates the receptor to 25% to 30% of maximal dopamine activity. Aripiprazole has moderate alpha-1 adrenergic and H1 receptor activity and mild muscarinic receptor activity.
Because of the mild alpha-1 adrenergic antagonism, there is possibility for antihypertensive when coadministered with central acting drugs or alcohol.
Abilify is extensively metabolized by the liver via dehydrogenation and hydroxylation by P450 (CYP) 3A4 and CYP2D6 enzymes and N-dealkylation by the CYP3A4 enzyme.
Atropine (Atropen) is a commonly used anticholinergic agent primarily indicated for the treatment of symptomatic bradycardia. Other uses include use as an inhibitor of salivation and secretions.
Atropine is given intravenously or intramuscularly, 0.5 to 1 mg, every 3 to 5 minutes to a maximum total dose of 3 mg for the treatment of symptomatic bradycardia.
Mechanism of action
Atropine works by inhibiting acetylcholine at parasympathetic sites in smooth muscles and secretory glands, innervated by the central nervous system, and this will cause an increase in cardiac output and inhibit secretions. It also works to reverse cholinergic poisoning.
Cardiovascular: lethal arrhythmias, asystole, atrial fibrillation, aches pain, decreased blood pressure, electrocardiogram changes, ectopic beats, ventricular fibrillation, and ventricular flutter.
Ophthalmic: abnormal eye movements, dry eyes, and decreased secretions.
Bupropion is a monocyclic aminoketone and classified as an atypical antidepressant, a different class when compared with SSRIs and TCAs. It is commonly used in patients with major depression or in situations where the other classes are not effective or are creating undesirable side effect.
Mechanism of action
Bupropion inhibits reuptake of dopamine and norepinephrine in the presynaptic terminal. It has a larger effect on dopamine than norepinephrine.
Black box warning
Bupropion has a potential effect of suicide ideation, which must be discussed with the patient.
Patients taking bupropion also are at an increased risk of seizures, dry mouth, nausea, insomnia, dizziness, anxiety, sinusitis, and tremor.
Twenty-one percent of patients on bupropion complain of dry mouth, and it is one of the most highly cited drugs in connection with xerostomia.
Similar to bupropion, clozapine is characterized as an atypical antipsychotic (second generation). It is most commonly used in the treatment of schizophrenia, especially those who fail to respond to classic antipsychotic treatment. Clozapine is also used to reduce suicidal behavior in patients with schizophrenia.
Clozapine is used for bipolar disorder, especially when standard treatment is not effective, and for psychosis/agitation and psychosis in Parkinson disease.
Mechanism of action
Clozapine is an antagonist to the dopamine type 2 (D2) and serotonin type 2A receptors. It also acts as an antagonist to histamine, cholinergic, and alpha-adrenergic receptors.
Black box warning
Clozapine can cause severe neutropenia. Because of the risks associated with clozapine, clozapine is only available through the REMS program (Clozapine Risk Evaluation and Mitigation Strategy Program). It will not be dispensed without both your doctor and pharmacist being registered in REMS. Other warnings include orthostatic hypotension, bradycardia, syncope, secures, and myocarditis. Clozapine has anticholinergic effects and is highly associated with development of xerostomia, constipation, and urinary retention.
Clozaril can cause hypertension, hypotension, tachycardia, constipation, nausea, sialorrhea, vomiting, dizziness, and drowsiness.
Duloxetine (Cymbalta) and Venlafaxine (Effexor)
Duloxetine and venlafaxine are serotonin-norepinephrine reuptake inhibitors (SNRIs) that are prescribed for depressive conditions such as unipolar major depression, persistent depressive disorder, and anxiety disorder. Duloxetine is also used for chronic pain syndromes and fibromyalgia.
Mechanism of action
SNRIs treat depression by blocking presynaptic serotonin and norepinephrine transporter proteins that cause an increase in postsynaptic stimulation. Duloxetine is also a more potent inhibitor of serotonin reuptake. ,
Black box warning
In young adults and pediatric patients, duloxetine and venlafaxine have been associated with an increased risk of suicidal ideation and suicidal behavior.
Clinical studies performed by Hudson showed adverse effects of duloxetine, which included nausea, xerostomia, constipation, insomnia, dizziness, fatigue, diarrhea, somnolence, diaphoresis, and anorexia.
Olanzapine (Zyprexa) and Quetiapine (Seroquel)
Quetiapine is a commonly used second-generation antipsychotic for bipolar I or II major depression disorders. The American Psychiatric Association’s diagnostic and statistical manual of mental disorders (DSM-5 th edition) defines major depressive disorder (unipolar major depression) as a period lasting at least 2 weeks, with 5 or more of the following symptoms: depressed mood, loss of interest or pleasure in most activities, insomnia or hypersonic, change in appetite or weight, psychomotor retardation or agitation, decreased energy, poor concentration, thoughts of worthlessness or guilt, and recurrent thoughts about death or suicide. Bipolar disorder is marked by episodes of mania, hypomania, and nearly includes episodes of major depression. For patients with bipolar major depression, olanzapine is frequently used as a monotherapy.
Black box warning
Increased mortality in elderly patients with dementia-related psychosis.
Mechanism of action
As previously described, olanzapine and quetiapine are second-generation antipsychotics and work as antagonist to the serotonin 5-HT2A and 5-HT2C, dopamine, histamine H1, and alpha-1 adrenergic receptors.
According to a systematic review and meta-analysis, quetiapine has been found to cause major adverse effects such as sedation, weight gain, xerostomia, headache, dizziness, nausea, constipation, and extrapyramidal symptoms. That same systematic analysis has found olanzapine to cause sedation, weight gain, increased appetite, xerostomia and possible hypo salivary gland function, weakness, headache, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and neutropenia.
Oxybutynin (Oxytrol and Ditropan), Solifenacin (VESIcare), and Tolterodine (Detrol)
The primary therapy involved in urinary incontinence involves conservative therapy. These include changes to lifestyle/obesity factors, kegel exercises, and bladder training. If primary measures do not improve symptoms, pharmacologic therapies are available. The 2 types of therapies include antimuscarinic agents and beta-adrenergic therapy.
Oxybutynin, solifenacin, and tolterodine are 3 of 6 commonly prescribed muscarinics for treatment of urinary incontinence.
Mechanism of action
Oxybutynin has a direct antispasmodic effect on smooth muscle and also is an acetylcholine inhibitor on smooth muscle.
Solifenacin inhibits muscarinic receptors that decrease contraction of the urinary bladder, increase residual urine volume, and decrease detrusor muscle pressure.
Tolterodine is a competitive antagonist of muscarinic receptors and very selective for receptors in the bladder.
Because of their anticholinergic activity, all 3 of these medications cause xerostomia and salivary gland dysfunction ( Table 1 ).