One of the major side effects of medications prescribed to elderly patients is the qualitative and quantitative alteration of saliva (salivary hypofunction). Saliva plays a pivotal role in the homeostasis of the oral cavity because of its protective and functional properties, including facilitating speech, swallowing, enhancing taste, buffering and neutralizing intrinsic and extrinsic acid, remineralizing teeth, maintaining the oral mucosal health, preventing overgrowth of noxious microorganisms, and xerostomia. With salivary hypofunction, a plethora of complications arise, resulting in decreased quality of life. The anticholinergic effects of medications can be overcome, and the oral cavity can be restored to normalcy.
Key points
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The elderly population is increasing and has the highest number of users of prescription and over-the-counter (OTC) medication.
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Age-related changes occur in the body, which affect pharmacokinetics and pharmacodynamics.
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Prescription and OTC medications can cause myriad side effects in the oral cavity, and the elderly are more vulnerable.
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The adverse events in the oral cavity may cause discomfort and loss of function and decrease quality of life in the elderly.
Introduction
Early diagnoses and treatment of diseases have led to longer life expectancy. However, the treatments of these diseases involve pharmacologic agents, and as people age, they develop multiple health ailments, which can lead to polypharmacy. There are age-related changes in the systems of the body, which alter the pharmacokinetics and pharmacodynamics of medications and make the elderly more vulnerable to adverse events. A major side effects of medications is the qualitative and quantitative change the cause in saliva (salivary hypofunction), by their anticholinergic effects. Saliva plays a pivotal role in the homeostasis of the oral cavity because of its protective and functional properties, which include facilitating speech, swallowing, enhancing taste, buffering and neutralizing intrinsic and extrinsic acid, remineralizing teeth, maintaining the oral mucosal health, preventing overgrowth of noxious microorganisms and xerostomia. With salivary hypofunction, a plethora of complications arise, resulting in decreased quality of life in the elderly. However, the anticholinergic effects of medications can be overcome, and the oral cavity can be restored to normalcy.
Introduction
Early diagnoses and treatment of diseases have led to longer life expectancy. However, the treatments of these diseases involve pharmacologic agents, and as people age, they develop multiple health ailments, which can lead to polypharmacy. There are age-related changes in the systems of the body, which alter the pharmacokinetics and pharmacodynamics of medications and make the elderly more vulnerable to adverse events. A major side effects of medications is the qualitative and quantitative change the cause in saliva (salivary hypofunction), by their anticholinergic effects. Saliva plays a pivotal role in the homeostasis of the oral cavity because of its protective and functional properties, which include facilitating speech, swallowing, enhancing taste, buffering and neutralizing intrinsic and extrinsic acid, remineralizing teeth, maintaining the oral mucosal health, preventing overgrowth of noxious microorganisms and xerostomia. With salivary hypofunction, a plethora of complications arise, resulting in decreased quality of life in the elderly. However, the anticholinergic effects of medications can be overcome, and the oral cavity can be restored to normalcy.
Changes in the elderly population
With improvements in health care, nutrition, lifestyles, habits, and safety practices, the life expectancy of people in the United States is increasing. This trend is true regardless of race or sex. From 1950 to 2010, the life expectancy of Americans of all races, both male and female, rose from 68.2 years to 78.7 years. The average life expectancy for white Americans (78.9 years) is longer than that of black or African Americans (75.1 years). Further, the life expectancy of white women is 81.3 years, compared with that of white men at 76.5 years. The life expectancy of black women is also longer than that of black men, at 78 years and 71.8 years, respectively.
Globally, with the increase in life expectancy, the demographics of the total population are changing. In 2011, 14% of the total population of the United States was older than 65 years. It is estimated that in 2020, this percentage will increase to 16.76%, and by 2050, the percentage of people, both male and female, older than 65 years in the total population will increase to 20.95%.
Age-related effects on the body
Chronologic aging is a process that affects various biological and physiologic processes in the human body. With advancing age, the functional abilities of organ systems tend to decrease. Although there is variability in the age-related changes that take place within each individual, aging generally affects all of the major biological and physiologic systems of the body.
For example, as one ages, there is a change in the composition of the body leading to a decrease in total body water and lean body mass, countered by an increase in body fat. Together, these age-related changes result in a diminished ability to distribute, metabolize, and excrete (clear) certain drugs. This situation causes water-soluble medications to be processed differently and less effectively. Lipophilic drugs because they have an increased volume of distribution, causing a prolonged half life, whereas water-soluble drugs have a smaller volume of distribution and a shorter half life.
The liver is affected in several ways as the body ages. Specifically, there is a decrease in hepatic mass, hepatic blood flow, and enzymatic efficiency. The kidneys also undergo age-related alterations, such as a decrease in renal plasma flow, glomerular filtration rate, and tubular secretion. After these changes, as one ages, there is an increased sensitivity to medications, which can result in medication-induced hepatotoxicity and nephrotoxicity. In the cardiovascular system, the elasticity of blood vessels begins to decrease with age. This stiffening of blood vessels results in the decreased mechanical effectiveness of the heart. Furthermore, in the gastrointestinal system, the secretion of hydrochloric acid and pepsin decreases with the aging of the body. This situation then results in changes in absorption in the gastrointestinal tract.
In the salivary glands, the aging process may cause the number of acinar cells to be reduced and to be replaced by fibrous and fatty tissue. This process may cause the composition of saliva to change.
The elderly and medications
The elderly population is more susceptible to acute and chronic medical problems. Hence, to cure or treat the ailments, either prescription medications or nonprescription (over-the-counter [OTC]) medications are introduced in the body system. In 2007 to 2008, more than 88% of Americans older than 60 years took at least 1 prescription medication, 76% used 2 or more prescription medications, and 37% used 5 or more. The use of at least 1 prescription medication follows a linear trend as the aging process advances. This trend is different in men and women, with women using more prescription drugs than men. Significantly more non-Hispanic whites take medications than non-Hispanic blacks or Mexican Americans. Even although the elderly represent only 13% of the population, one-third of the prescriptions written are dispensed to this population.
In addition, as more prescription medications are being changed to OTC status, increasingly older adults self-manage medications to treat common medical conditions, especially the common cold, pain, diarrhea, constipation, indigestion, and headache. Surveys indicate that the elderly use 2 to 4 nonprescription medications daily, most commonly nonsteroidal antiinflammatory drugs, antihistamines, antacids (H 2 blockers), laxatives, and sedatives.
Also, the increased use of illicit drugs by senior has become an emerging issue which prompted the National Institutes of Health to circulate an alert in 2012 about improper use of substances, to strengthen public awareness of substance use disorders in the elderly.
Most Common Anticholinergic Medications
The most common anticholinergic medications are listed in Table 1 .
| Indication | Drug |
|---|---|
| First-generation antihistamines (as single agent or as part of combination products) | Chlorpheniramine Cyproheptadine Brompheniramine Carbinoxamine Chlorpheniramine Clemastine Cyproheptadine Dexbrompheniramine Diphenhydramine (oral) Doxylamine Hydroxyzine Promethazine Triprolidine |
| Antidepressants SSRI and SNRI |
SSRI Fluoxetine Paroxetine Sertraline Fluvoxamine Citalopram SNRI Venlafaxine Duloxetine Desvenlafaxine |
| Antidiarrheal | Diphenoxylate atropine |
| Anti-Parkinson | Amantadine benztropine Biperiden trihexyphenidyl |
| Muscle relaxants | Cyclobenzaprine dantrolene Orphenadrine |
| Antivertigo | Meclizine scopolamine Phenothiazine |
| Tricyclic antidepressants, alone or in combination | Amitriptyline Chlordiazepoxide-amitriptyline Clomipramine Doxepin Imipramine Perphenazine Trimipramine |
| Cardiovascular | Furosemide Digoxin Nifedipine Disopyramide |
| Antispasmodic medications | Belladonna alkaloids Clidinium–chlordiazepoxide Dicyclomine Hyoscyamine Propantheline Scopolamine |
| Antiulcer | Cimetidine ranitidine |
| Antipsychotic | Chlorpromazine clozapine Olanzapine thioridazine Mesoridazine |
| Urinary incontinence | Oxybutynin probantheline Solifenacin tolterodine Trospium |
| Antiemetics | Prochlorperazine promethazine |
Side Effects of Medications
Apart from their therapeutic effect, pharmacologic agents also bind to other unwanted potential sites causing side effects that affect the central nervous system (CNS) and/or the peripheral nervous system. Central side effects include confusion/disorientation, hallucinations, sleepiness, clumsiness or unsteadiness, convulsions, mental status/behavior changes such as distress, excitement, nervousness, attention deficits, cognitive decline (memory loss), and delirium. Peripheral side effects of medications can be salivary hypofunction, difficulty in speech and swallowing, mucous membrane dryness of the nose and skin, blurred vision, light sensitivity, increased breathing difficulty, difficulty urinating, bloating, and constipation in older adults.
The perception of dry mouth has been reported to be directly proportional to the total number of drugs taken per day. Dry.org reports 1800 drugs in 80 drug classes that have the capacity to induce xerostomia. Because there are more new medications in the pipeline in production to cure and treat diseases, the list of salivary hypofunction-inducing medications will only increase.
How Does Anticholinergic Medication Work?
To achieve therapeutic benefits and manage diseases, medications with anticholinergic properties are used. Anticholinergic medications competitively block or prevent acetylcholine molecules, which are neurotransmitters, from adhering to receptors of the cell membrane in both the central and peripheral nervous systems. Molecular cloning has defined 5 distinct muscarinic cholinergic receptor subtypes, designated M 1 to M 5 , with each subtype being encoded by distinct cellular genes.
M 3 receptors are found in the CNS, airway smooth muscles, and glandular tissues (such as salivary gland tissue). When the anticholinergics adhere to the receptors, especially on the M 3 receptors of the salivary gland, cell membrane changes are prevented (like the inhibition of adenylate cyclase, or the alteration in calcium permeability that leads to cholinergic responses). When multiple medications are being taken at the same time for the treatments of various ailments of the elderly, their anticholinergic properties are potentiated. The cumulative anticholinergic burden of multiple medications and metabolites, rather than of a single compound causes the toxicities that are seen in the elderly. Each year, adverse drug events affect millions causing considerable morbidity and mortality.
Anticholinergic agents compete with the muscarinic receptors in the salivary glands and alter their function, but do not interact with or prevent the formation of acetylcholine.
Beers criteria
Mark Beers, MD, a geriatrician, created the Beers criteria which catalogs medications that cause adverse drug events in older adults because of their pharmacologic properties and/or the physiologic changes of aging. In 2011, the American Geriatrics Society (AGS) updated the criteria, assembling a team of experts, using an enhanced, evidence-based methodology. Each criterion is rated using the American College of Physicians’ Guideline Grading system, which is based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) developed by Guyatt and colleagues.
Role of saliva
Saliva is produced by 3 pairs of major salivary glands and 400 to 600 minor salivary glands. The serous (watery) portion of the saliva is mostly produced by the parotid and submandibular (mixed serous and mucous) glands, and the mucus (mucin-containing) part is produced by the submandibular, sublingual, and minor salivary glands. Ninety-five percent of the saliva is produced by the salivary glands. The rate of whole unstimulated salivary flow is about 0.3 mL/min (average), and stimulated is on average 1.5 mL/min (with large individual variability). The critical level of saliva is considered to be less than between 0.1 and 0.16 mL/min when the complications from the salivary hypofunction arise. Bicarbonates, Sialin, ammonia, urea and water in saliva buffer and neutralize the intrinsic and extrinsic acid and restore the normal pH in the oral cavity. Because of lubricating actions, saliva is necessary for speech, the bolus formation, and swallowing. Saliva also aids in flushing away food debris, dead tissue, and biofilm. Antimicrobial proteins and peptides in saliva (eg, histatins, lysozyme, lactoperoxidase, and lactoferrin) keep the deleterious microorganisms in check in the microenvironment of the oral cavity.
Because secretory salivary IgA and mucins are reduced in the healthy elderly, the oral soft tissues become more susceptible to environmental factors as a result of a reduction of both immunologic and nonimmunologic defense systems of the oral cavity.
Adverse events of salivary hypofunction in the oral cavity
The peripheral side effects of anticholinergic drugs can lead to a plethora of dental and oral complications. Some of the common complications are listed later. The Anticholinergic Risk Scale (ARS) is useful tool that helps to assess the risk of adverse effects caused by anticholinergic drugs. Within the scale, medications are categorized with, each category being assigned points. To use the ARS, the points are added up with the higher the total points, having the greater the risk.
Xerostomia
The subjective sensation of dryness in the oral cavity is called xerostomia. The aging process may cause the number of acinar cells to be reduced and to be replaced by fibrous and fatty tissue, but the composition remains the same in nonmedicated elders. Xerostomia is not a natural consequence of aging, but its prevalence increases with age. When the basal volume of unstimulated saliva, which usually coats the soft and hard tissue, is decreased by 50% to 70% of the original volume, the subjective sensation of dryness occurs, resulting in xerostomia. Initially, the serous portion of the whole saliva is lost, leaving primarily the mucous portion. Consequently, secretion of thick and viscous saliva leads to a perception of having excessive saliva in the oral cavity. The anticholinergic load of drug(s) determines the severity of the reduction of salivary production that leads to xerostomia. It is more prevalent in the elderly population, primarily because of their increased use of drugs and their susceptibility to disease. Many drugs and drug classes have been linked to xerostomia; the xerogenic effect increases with poly pharmacy.
Dental Carious Lesions
Just like bone, teeth are mineralized tissues that constantly undergo demineralization and remineralization controlled by saliva. Saliva is normally supersaturated with calcium and phosphate ions acid either extrinsic or intrinsic leaches mineral from teeth. Fluoride acts as a catalyst to promote remineralization and is incorporated in the crystal to create a harder less soluble tooth structure, thus maintaining homeostasis in the oral cavity.
In salivary hypofunction, because of a decreased quantity of saliva and the loss of the antimicrobial functions of saliva, the number of cariogenic microorganisms ( Streptococcus mutans lactobacilli) and Candida increases. In addition, the food (carbohydrate) substrate and dead cells are no longer debrided/lavaged well, thereby providing more substrate from which microorganisms produce bacterial acid to demineralize the tooth structure. Also, the loss of saliva enhances aggregation and adherence of noxious microorganisms, resulting in an increased population of bacteria. Normally, the demineralized structures are remineralized, but in the compromised microenvironment of the oral cavity, the potential to remineralize is decreased, thus increasing the risk of developing new and recurrent carious lesions. With elderly Americans living longer, retaining their teeth longer, resulting in a significant reduction in edentulism. With this change, along with receding gingival levels, more root surfaces are exposed, leading to an increased surface at risk (SAR) ( Figs. 1 and 2 ). More than half of the individuals older than 65 years have experienced root caries.
