Anticholinergic medication: Related dry mouth and effects on the salivary glands

Abstract

Objective.

Salivary glands are among the most sensitive target organs of medications with anticholinergic (AC) properties, interrupting the neural stimulation of saliva secretion and reducing saliva flow. Hyposalivation results in dry mouth, leading to dental caries, intraoral infection, orofacial pain, problems with speaking and swallowing, and diminished oral health–related quality of life. Current understanding of the pharmacokinetics of AC medications and their effect on muscarinic receptors in the salivary glands were reviewed to assist clinicians in predicting salivary damage in patients with AC medication–induced dry mouth.

Study Design.

We summarized the literature related to the mechanisms and properties of AC medications, anticholinergic adverse effects, and their effect on salivary function and management strategies to prevent oral health damage.

Results.

Although a large number of studies reported on the frequencies of medication-induced dry mouth, we found very limited data on predicting individual susceptibility to AC medication–caused hyposalivation and no prospective clinical studies addressing this issue.

Conclusion.

Dry mouth is most frequently caused by medications with AC properties, which interrupt the neural stimulation of saliva secretion. Interdisciplinary care should guide pharmacotherapeutics and dental interventions should aim in preventing AC salivary adverse effects and reducing the oral health burden from AC medication–induced dry mouth.

Anticholinergic (AC) toxicity syndrome¹ with cognitive impairment and delirium² recently gained increased attention as a harmful adverse reaction of AC medications.³ A considerably less studied issue, the most frequent AC adverse effect is decreased saliva secretion (hyposalivation), resulting in dry mouth, from over 600 medications that possess AC properties.⁴ Salivary variables are sensitive indicators of systemic health⁵ and are indeed commonly affected by medications, but only 2 recent publications offered insights into salivary secretion rates in relation to the AC burden of medications.⁶ Accordingly, the overall load of AC drugs showed a statistically significant association with lower saliva flow rates, which was further lowered by increased medication intake and polypharmacy (using 5 or more medications). Polypharmacy has risen by 70% during the past decade⁷; it affects 1 in 5 patients in the United States⁸ and is widespread in treating chronic diseases in patients of all ages. AC drugs are used to successfully treat conditions such as depression, psychological entities, urinary incontinence, gastroesophageal reflux, peptic ulcer disease, cardiovascular diseases, muscle spasm, neuropathic pain, irritable bowel syndrome, obstructive pulmonary disease, allergy, Parkinson disease, and epilepsy.⁹

Because decreased saliva flow rates are more prevalent among older adults, dry mouth and its destructive effects on oral health are almost exclusively described in the context of older adults.^10,11 Prolonged AC exposure from medications has been linked to increased dementia incidence and irreversible cognitive decline in frail, older people,¹² as confirmed by a recent large case-control study including 284,000 individuals.¹³ However, long-term exposures to AC medications and their combinations have also increased in younger age groups. The pharmacologic management of various common chronic conditions and diseases^8,14 is frequently based on drugs with AC properties. Combination therapy with AC medications adds up to a cumulative AC effect with the prominent risk for adverse effects irrespective of age.¹⁵

The autonomic nervous system¹⁶ controls salivary secretion from the 3 major salivary glands (parotid, submandibular, and sublingual glands) and hundreds of minor salivary glands. Acetylcholine release from postganglionic neurons in the parasympathetic (or cholinergic) system binding to muscarinic receptors on salivary glands is the dominant stimulus for saliva fluid secretion and can be compromised by a large number of medications¹⁷ with the potential to block (antagonize) these receptors. Emerging scientific evidence^18,19 supports a strong association between impaired salivary function and the intake of medications possessing properties that can antagonize acetylcholine transmission (i. e., AC effect). AC medications affect the oral health²⁰ because of the ancillary impairment of salivary function such as hyposalivation (reduction in saliva secretion), resulting in dry mouth and/or xerostomia (the subjective sensation of oral dryness). Dry mouth is a known risk factor for dental caries^21,22 and other maladies in the oral cavity.²³ It has mostly been studied in older age groups because of the higher medication exposure in the geriatric population.²⁴

The purpose of this review is to provide an evidence-based synopsis of the current knowledge and pharmacologic concepts of medications with AC properties and their effect on salivary function. We compiled a scientific synthesis of pertinent dental implications and summarized the most potent and often prescribed AC drugs because the oral health aspects of this significant problem have been understudied. We created a muscarinic receptor “map” of salivary functional units and a detailed figure of muscarinic receptors in the major and minor salivary glands. The tables provide a novel aspect of relevant data corresponding to clinical scenarios for patient care and based on pharmacologic and geriatric expert opinion as a reference for managing dry mouth.

PHARMACOLOGY OF ANTICHOLINERGIC MEDICATIONS

The most frequently prescribed medications with AC properties and their therapeutic indications are shown in Table I. A large group of medications (tricyclic antidepressants, antipsychotics, etc.) exerts unwanted or side effects owing to their nonselective antagonism of cholinergic (also known as muscarinic) receptors. In the central nervous system, acetylcholine modulates cognitive function and motor control.^2,25 In the peripheral cholinergic nervous system, the most sensitive receptors to AC drugs can be found in the salivary, bronchial, and sweat glands.¹⁹ The adverse effects of AC drugs in the human body depend on the organ- or tissue-specific cholinergic innervation and the cholinergic receptor expression pattern.²⁶ The muscarinic (M) receptors are classified into 5 subtypes: M₁, M₃, M₅ excitatory and M₂, M₄ inhibitory receptors. The functional variety of these muscarinic receptors is based on structural differences and intracellular signal transmission pathways.²⁷ The spatial distribution of muscarinic receptor subtypes is characteristic to specific tissues and organs; M₁ receptors are more abundant in the central nervous system²⁸; M₂ receptors are more frequent in the heart, colon, and urinary bladder²⁹; M₃ receptors have a dominant role in the salivary glands,^30,31 urinary bladder, and respiratory tract innervation; M₄ receptors are expressed mainly in the basal ganglia in the brain; and M₅ receptors are scattered throughout the central nervous system.²⁸

Table I.

Conditions and diseases that are frequently treated by medications with anticholinergic properties

Clinical conditions often treated with anticholinergic medications
Psychiatric conditions
Schizophrenia, schizoaffective disorder
Bipolar disorder
Depression
Obsessive-compulsive disorder
Anxiety
Insomnia
Neurologic conditions
Parkinson disease
Epilepsy
Somatic problems
Urinary incontinence
Gastroesophageal reflux, peptic ulcer disease
Cardiovascular diseases
Muscle spasm
Low back pain
Neuropathic pain
Irritable bowel syndrome
Obstructive pulmonary disease
Allergy

The therapeutic and side effects of systemic AC drugs depend on the distribution of various muscarinic receptors in the target tissues; therefore, tissues expressing the same receptor subtypes might be similarly affected. In Figure 1, we provide an updated overview of organs and tissues in the human body containing M₃ receptors, the predominant muscarinic receptor in the salivary glands. Additionally, we provide an illustration of the distribution of all muscarinic receptor subtypes in the 3 majors as well as minor salivary glands in Figure 1, based on currently available and published research results. The peripheral parasympathetic signals from the salivary nuclei to the salivary glands are principally mediated through the efferent fibers of chorda tympani lingual nerve (CN VII) toward the submandibular and sublingual glands. The parotid gland is supplied through the glossopharyngeal (CN IX), auriculotemporal (CN V), and facial (CN VII) nerves. The minor salivary glands receive parasympathetic nerve fibers from the mandibular (CN V), lingual (CN V), and palatine (CN V) nerves.

Fig. 1.

Salivary flow secretion principally mediated through muscarinic type 3 receptors. The heterogeneity of muscarinic receptors and their specific localization in the major and minor salivary glands, as well as other muscarinic type 3 receptor–mediated organs, were mostly established in animal studies. M₁, muscarinic type 1 receptor; M₃, muscarinic type 3 receptor; M₅, muscarinic type 5 receptor.

To reduce the unwanted side effects of anticholinergic drugs, a unique pharmaco-physiologic approach (the concept of tissue selectivity³²) was developed, which is based on the histologic and functional variation of the muscarinic receptor subtypes. Accordingly, organ-selective anticholinergic drugs with high affinity to a specific muscarinic receptor subtype achieve a selective therapeutic blockade of those muscarinic receptors within a particular organ.³³ New selective antimuscarinic agents targeting organs such as the bladder rather than the the salivary glands demonstrated a lower risk for dry mouth.³⁴

Multiple tools to estimate the AC toxicity of a patient’s medications have been developed and can be used to calculate each individual’s AC burden (e.g., Beers criteria,³⁵ Rudolph risk scale,³⁶ AC drug scale; Anticholinergic Drug Scale [ADS]³⁷). The AC burden has been used to estimate the risk of dementia and mortality in older adults.³⁸ Few dental studies^6,39 have investigated the salivary secretion in relation to the AC burden¹⁴ and established a positive correlation between AC burden (measured by ADS) and dry mouth.^40,41 The ADS, compiled by Carnahan et al.³⁷ and Duran et al.,⁴² includes over 100 commonly prescribed muscarinic receptor antagonists²⁷ according to their anti-muscarinic activity on muscarinic receptors.

EFFECT OF ANTICHOLINERGIC MEDICATIONS ON SALIVARY GLANDS

As discussed above, the current view on the mechanism of AC medication–induced dry mouth is that salivary function is either directly inhibited by AC drugs that block acetylcholine binding to muscarinic receptors in the salivary glands or indirectly inhibited by the AC drug effects in the central nervous system. Blocking the muscarinic receptors has been considered the mechanism responsible.⁴³ Although mechanistic studies in humans were not conducted, an in vivo study⁴⁴ suggested that muscarinic receptor antagonists cause detectable histologic and ultrastructural changes in rat salivary glands leading to the glandular tissue atrophy. Figure 2 illustrates the theoretical fine-tuned interaction between the stimulatory M₁, M₃ muscarinic receptors in salivary acinar cells and the inhibitory/modulatory M₂, M₄ receptors in postganglionic, presynaptic parasympathetic neurons, evoking the normal secretory responses⁴⁵ of salivary glands as animal studies have confirmed. It should be noted that salivary glands also receive potentiating stimulation from non-cholinergic sources, such as neuropeptides, that are colocalized with acetylcholine and released from the glandular nerves.⁴⁶

Fig. 2.

Localization of the muscarinic receptor subtypes in the salivary glands.^81–83 The schematic drawing depicts a secretory unit (secretory, aka acinar cells connected to the ductal compartment) of salivary glands, surrounded by efferent nerves, contractible myoepithelial cells, and blood vessels. The secretory activity is regulated by the peripheral parasympathetic (CN VII and IX) and sympathetic (T1-T3) nerves through muscarinic prejunctional (M₁, facilitatory; M₂ or M4, inhibitory) effects on the secretory unit cells. The neurotransmitter acetylcholine is released into the synaptic cleft and responsible for signal transmission through the muscarinic receptors, and the mixture of mostly M₃ and M₁ receptors mediates cholinergic salivary signaling.³⁰ Acetylcholine released from parasympathetic nerve endings binds to acinar M₃ and M₁ receptors (G protein–coupled receptors), which activates the intracellular coupling mechanisms for salivary fluid and protein secretion. The intracellular increase of calcium concentration from endoplasmic reticulum stores triggers the transmembrane sodium-potassium pumps, which create an osmotic gradient to secrete fluid into the ductal system. Parasympathetic signals may also activate protein exocytosis from acinar cells by a vasoactive intestinal peptide–coupled intracellular cyclic adenosine monophosphate generation pathway or a cyclic adenosine monophosphate–independent pathway. M₁, muscarinic type 1 receptor; M₂, muscarinic type 2 receptor; M₃, muscarinic type 3 receptor; M₄, muscarinic type 4 receptor; M₅, muscarinic type 5 receptor.

AC medications may also affect the function of minor salivary glands.⁴⁷ Hundreds of these minor salivary glands secrete saliva continuously into the oral cavity, and their flow rates are not in response to salivary stimuli. Though the secretion of minor salivary glands comprises only 7% to 10% of the whole saliva, it is driven under an exclusive parasympathetic influence and cholinergic transmission; thus, the secretion rates may be directly affected by AC drugs. However, most of the existing published evidence related to medication-induced dry mouth is based on studying the 3 major salivary glands, with very little information regarding the effects of AC medications on minor salivary glands.^48,49

AC DRUGS MOST RELEVANT TO ORAL HEALTH

The most commonly reported adverse side effect associated with AC drugs is dry mouth (frequencies range between 16% and 30%), which has been confirmed by randomized clinical trials^50–52 and a worldwide doubleblind placebo-controlled trial performed at 167 centers (patients were enrolled in Australia, Europe, and North America).⁵³ Furthermore, a recent meta-analysis⁵⁴ of 26 studies calculated a high risk of dry mouth from AC psycholeptics and bladder antimuscarinics. A large computational model⁵⁵ of 578,228 individuals established a significant correlation between AC toxicity and incidence rates of the most common adverse effects, including dry mouth. Considering probable relevant clinical scenarios and various medications that patients are taking, the most common drugs with known AC effects are presented in Table II, including information on each drug’s antimuscarinic potency representing the binding affinity to block muscarinic receptors. The lower the inhibitory constant (K_i), the greater the blocking of the predominant M₃ receptors in the salivary glands. For example, the tricyclic antidepressant amitriptyline (K_i = 25.9) is significantly more potent at blocking muscarinic receptors compared with the antidepressant trazodone (K_i = 324,000). However, because K_i values are generally calculated from experiments in vitro, they may not explicitly predict dry mouth. Therefore, risk ratios calculated in various human clinical studies for dry mouth may reflect higher risk than expected solely based on K_i values. Table II summarizes K_i values of various AC drugs and risk ratios from published data. These data may be useful in clinical practice for evaluating known AC medications causing dry mouth. The patient’s medication list reflecting comorbidities and ongoing treatments allows anticipation of dry mouth–triggered dental and oral health problems. Recognizing a medication with high risk for dry mouth and substituting (when medically possible) with a less potent AC drug is a favorable approach.

Table II.

Commonly prescribed anticholinergic drugs associated with dry mouth

Medication (frequency of usage)	Xerostomia risk	Muscarinic receptor antagonism (Ki)*
Selective serotonin reuptake inhibitors (22%)
Paroxetine	1.98	72.0
Escitalopram	2.19	1240.0
Sertraline	1.48	1300.0
Fluoxetine	1.64	2000.0
Citalopram	2.01	2200.0
Serotonin-norepinephrine reuptake inhibitors (11%)
Duloxetine	6.02	3000.0
Venlafaxine	2.67	>10,000.0
Antidepressant agents (50%)
Mirtazapine	1.42	800.0
Vilazodone	1.50	28,000.0
Bupropion	2.00	48,000.0
Trazodone	1.51	324,000.0
Tricyclic antidepressants (27%)
Dothiepin		25.0
Amitriptyline	3.28	25.9
Nortriptyline		50.0
Doxepin	2.91	52.0
Imipramine	3.81	102.0
Antipsychotics
Olanzapine		13.0
Chlorpromazine	4.00	67.0
Quetiapine	2.42	1320.0
Risperidone		>10,000.0
Overactive bladder medications (30%)
Trospium		0.8
Darifenacin	7.41	0.8
Tolterodine	4.82	3.4
Oxybutynin	18.85	11.2
Fesoterodine	6.94	26.9
Solifenacin	5.34	64.3
Asthma (20%)
Tiotropium		0.2
Ipratropium		0.5
Muscle control
Biperiden		3.9
Cyclobenzaprine		6.0

Medications are reported by indication and frequency and further ranked by their muscarinic anticholinergic potency: Lower values of K_i denote higher potency. Available xerostomia risk is reported by relative risk ratio. (Relative risk ratio based on published data^{35,44,46,65–67}; K_i extracted from the Psychoactive Drug Screening Program database.)

Ki, muscarinic receptor inhibitor constant.

IMPLICATIONS FOR DENTAL PRACTITIONERS

Many individuals in all age groups in the United States are affected by the side effects of AC drugs. Early recognition of dry mouth, as 1 of the most frequent side effects of AC medication use, is best achieved by dental providers. Commonly accepted confounding factors, such as age and sex, may modify the symptoms of dry mouth and xerostomia. The symptoms may worsen with age because decreased saliva flow is more prevalent among patients of older ages¹⁰ owing to polypharmacy (taking multiple medications)²⁴ and age-related changes in salivary function.¹⁸ Although salivary secretion in healthy aging individuals has been found intact with stable saliva flow, age-related dehydration and diminishing biting force may also result in hyposalivation. Moreover, systemic conditions, diseases, and medication-induced salivary changes contribute to a more prevalent oral dryness among geriatric patients.⁵⁶ A logistic regression analysis established a correspondence in the increase of xerostomia prevalence by the odds ratio of 1.24 per decade of age.⁵⁷ In contrast, other investigations^20,58–61 could not verify the effect of aging on salivary function and found that secretion rates in healthy individuals were not age dependent. As emphasized by Ship et al.⁵⁶ healthy aging does not tend to present salivary flow concerns and presumably dry mouth is secondary to medical conditions and medications.

Additionally, the female sex is associated with a higher total number of medications, a higher risk of AC exposure, reduced saliva secretion, and oral dryness.⁶²

Long-term AC drug exposure^3,63 has been associated with the increased prevalence of AC side effects in patients with defective genetic variants of certain cytochrome P450 enzymes⁶⁴ in the liver, responsible for the metabolic clearance of these drugs. A pioneer study⁶⁵ examining the association between the genetic polymorphism of cytochrome P450 enzymes and xerostomia in older adults measured a significant difference in the level of serum AC activity between metabolizing phenotypes. Although genetic variations of various drug-metabolizing enzymes are responsible for an increased prevalence of AC adverse events in patients are well documented, pharmacogenetics is not considered currently in the management of xerogenic medication–induced dry mouth.

Our suggested management of patients taking high-risk AC drugs is based on 3 pillars, including a comprehensive dental evaluation with salivary assessment, a multidisciplinary pharmacologic review and optimization,¹⁸ and frequent reassessment of overall oral health, salivary function, and management success, as detailed in Table III. Patients presenting at the dental office with medication-induced dry mouth might have chewing or swallowing problems, speaking difficulties, intraoral mucosal lesions, increased rate of dental caries, tooth loss,²¹ and orofacial pain due to reduced saliva flow. The executive summary of evidence-based clinical recommendations of the American Dental Association identified medication-induced dry mouth as a significant risk factor for dental caries.⁶⁶ Dental caries status has been previously associated with dry mouth.^20,21,23,67 Salivary gland hypofunction based on parameters such as the decayed, missing, and filled teeth indices was recommended to identify patients with high risk for dry mouth,⁶⁸ because the risk for dry mouth is associated with a lower number of remaining natural teeth.⁶⁹ Root caries is significantly associated with lower salivary flow rates^23,70 even from the minor salivary gland.^48,71 Furthermore, a recent retrospective study⁷² conducted by the Department of Veterans Affairs investigated 95,850 dentate patients and found an 8% increase in the rate of dental caries–-related treatment in individuals taking at least 1 drug with strong AC activity. Dry mouth increases susceptibility to bacterial colonization or inflammation in the oral cavity as well as infections in the upper respiratory tract, which further impairs patients’ quality of life.⁷⁰ Affected patients should receive intensive preventive care, including oral hygiene instruction, dietary advice, and regular topical fluoride treatments.

Table III.

Evaluation and management of dry mouth based on the multidisciplinary approach

Dental Evaluation/Dry Mouth Assessment	• Comprehensive Dental Evaluation/Dry Mouth Assessment • Measurement of Salivary Gland Flow Rate/Xerostomia • Oral Health Assessment
Multidisciplinary Medication Assessment and Management	• Refer to Primary Care Physician/Other Medical Specialists/Clinical Pharmacologist • Management of Associated Systemic Diseases to Reduce Vulnerability (Comorbidities and Polypharmacy • Discontinue/Reduce Dose or Frequency/Higher Ki or Substitute Non-anticholinergic Medications
Dental Management	• Frequent Dental Examinations • Reassessment of Salivary Function • Reassessment of Risk Category and Preventive Regimen • Palliative Recommendations as Necessary

Ki, muscarinic receptor inhibitor constant.

Measurable clinical features can support identifying patients with dry mouth who are taking AC drugs at the dental office. Assessing saliva secretion is a feasible tool to screen patients with a suspected AC medication–induced dry mouth at their regular dental visit. Clinical signs of reduced saliva secretion status can be confirmed by quantifying the resting saliva flow rate,⁷³ which has been validated by randomized control studies to determine hyposalivation (saliva flow rate <0.1 mL/min). Xerostomia questionnaires are reliable evidence-based tools for the subjective perception of oral dryness,^67,74 because the feeling of mouth dryness is correlated to the amount of resting (unstimulated) saliva.⁷⁵ Xerostomia sensation generally occurs when saliva volume decreases to half or more of the normal secretion levels.⁷⁶ However, the perceived oral dryness of a patient is not always reflected by reduced saliva flow.

Dental practitioners should promote medication management by working with patients’ medical providers to reduce the number of AC medications, adjusting their dosage, and possibly replacing them with medications with fewer AC side effects. As dentistry is integrated into systemic health care, informed decisions regarding AC toxicity are among the responsibilities of dental providers to advocate for reducing oral health complications. Concern for hyposalivation should be evaluated based on individual patient risk-benefit assessments, and that concern should be discussed with patients’ physicians. An up-to-date medication list and the revision of pharmaco-medical history at dental visits may prevent AC medication–related morbidity among affected patients. Collaborating with the prescribing physicians is the most suitable action plan to address drug-induced dry mouth issues. Based on limited clinical studies, alternative pharmacotherapeutics with less salivary antagonism can alleviate the severity of the AC adverse effect on salivary function.^39,77 Tailored interventions such as choosing AC medications for patients with lower binding affinity to salivary muscarinic receptors may reduce oral health problems.

Identifying individuals taking known high-risk AC drugs often necessitates personalized pharmacotherapy choices to complement the accepted standards of xerostomia treatment based on a multidisciplinary approach between dental and other medical professionals. Interactions among AC medications^52,78 are known modifiers of adverse effects, and the endogenous AC activity from stress,⁷⁹ inflammatory processes,¹³ and comorbidities⁸⁰ should be considered as well. Considerations for special needs populations should include renal or hepatic impairment, which modifies AC medications’ bioavailability and clearance. Counseling patients about the side effects of AC medications is essential, because without aggressive preventive actions, dry mouth–related changes in oral and systemic health will become permanent. Currently available symptomatic management or salivary substitutes are not effective in preventing or reversing the damage but only alleviate the complaints. Clinical investigations of AC medication–induced hyposalivation and AC burden are needed to compare preventive strategies and support salivary function. New evidence-based guidelines for tailored preventive measures to control AC medication–induced dry mouth and salivary damage are required for all patients regardless of age. Studies should address whether novel pharmacogenetic assays can be employed in predicting poor metabolizing profiles of patients and potentially severe xerostomia cases.

CONCLUSION

The exposure to AC medications has increased significantly among adults of all ages. The most sensitive parasympathetic receptor organs to AC drugs are the salivary glands and the most commonly reported peripheral adverse effect of AC drugs is dry mouth. Medication-induced dry mouth can have a devastating effect on the oral health status of patients, and such patients should receive intensive preventive care, including the assessment of reduced saliva secretion, oral dryness, caries status, comorbidities, and pharmacologic interactions. Accordingly, the management of AC medication–induced dry mouth should involve discussion with patients’ other health care providers. Recognizing and avoiding high-risk anticholinergics can aid dental care of the affected patients, because no standard test is available for predicting AC susceptibility. Identification and management of AC medication–induced dry mouth is not possible without understanding and clarifying the underlying mechanisms. The molecular pathway behind the notable sensitivity of the salivary glands to AC medications is largely unexplored. The lack of available clinical research on AC drug–induced salivary effects calls for future clinical studies to explore this existing knowledge gap.

Statement of Clinical Relevance.

The article provides an evidence-based background of the current pharmacological trends of anticholinergic drug use, which increases the risk for anticholinergic toxicity. We compiled a scientific synthesis of dental implications and created figures with direct relevance for patient care.