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Acetylcholine is a neurotransmitter that transfers signals between cells to regulate how the body functions[1,2]. With a particular role in the regulation of movement, thought and emotions, acetylcholine works through two types of receptors — muscarinic and nicotinic. Muscarinic receptors function in the peripheral and central nervous system and are present in various body organs, while nicotinic receptors function in the central nervous system and the neuromuscular junction. Anticholinergic drugs work by blocking both types of receptors and are useful for treating respiratory disorders, such as chronic obstructive pulmonary disease (COPD), asthma, overactive bladder, urinary incontinence, cardiovascular disease, Parkinson’s disease, and as antispasmodics or muscle relaxants[3,4]. In the UK, the proportion of patients per month prescribed at least one medication with anticholinergic properties increased from 6.1% to 16.7% from 1989 to 2000 and to 18.6% between 1989 and 2016. This may be, at least partly, owing to increased prescription rates for antidepressants and drugs for urinary incontinence and overactive bladder.
Anticholinergic medication indications
There are more than 600 medications with anticholinergic properties, including:
- Those that are prescribed primarily for their anticholinergic effect (see Box 1);
- Those that are primarily prescribed for other reasons (see Box 2).
Box 1: Examples of medication primarily prescribed for its anticholinergic effect
- Treatment of Parkinson’s disease (e.g. trihexyphenidyl hydrochloride);
- Treatment of urinary incontinence (e.g. oxybutynin);
- Treatment of gastrointestinal spasms (e.g. hyoscine butyl bromide);
- Treatment of COPD (e.g. glycopyrronium bromide);
- Treatment of extrapyramidal side effects induced by psychotropic medication (e.g. procyclidine);
- Treatment of anterior uveitis in the eye and in cycloplegic refraction (e.g. atropine sulfate);
- Treatment of hypersalivation (e.g. hyoscine hydrobromide)[8,9].
Box 2: Examples of medications with anticholinergic properties that are primarily prescribed for other indications
- Antipsychotics (e.g. clozapine);
- Antidepressants (e.g. amitriptyline);
- Antihistamines (e.g. chlorphenamine);
- Analgesics for neuropathic pain (e.g. nortriptyline);
- Opioid analgesics (e.g. codeine);
- Medication for cardiovascular disease (e.g. disopyramide);
- H2 receptor antagonists (e.g. ranitidine);
- Anticonvulsants (e.g. carbamazepine);
- Anxiolytics (e.g. benzodiazepines)[8,10,11].
Irrespective of the primary indication, all patients prescribed medication with anticholinergic properties are vulnerable to anticholinergic side effects. The use of such medications is highest within three particularly vulnerable patient groups: older people, people with learning disabilities and people with mental health conditions[8,10,12–14]. For many people within these vulnerable groups, the medication may be prescribed for clinical indications that are different from the primary diagnosis. For example, anticholinergic medications are prescribed in more than half of patients with Parkinson’s disease for clinical indications other than Parkinsonism.
Anticholinergic burden and pathophysiology
Anticholinergic drugs act on muscarinic acetylcholine receptors. There are five subtypes of the muscarinic receptors: M1, M2, M3, M4 and M5. Anticholinergics block acetylcholine by binding to these receptor sites and competitively blocking the effects of parasympathetic nerve activity in the nervous system, as well as those affecting smooth muscle function in the digestive and urinary systems. Many patients tend to be on several drugs with anticholinergic properties at any one time. This concomitant use increases the risk of side effects. The cumulative effect of taking one or more medications with anticholinergic activity is referred to as the anticholinergic burden (ACB)[16–18]. Common side effects linked to ACB are listed below. They can be the cause of significant morbidity and mortality:
- Blurred vision;
- Increased risk of falls;
- Urinary retention;
- Dry mouth;
- Increased heart rate;
- Dry eyes;
- Narrow-angle glaucoma;
- Vascular events;
- Cognitive impairment;
ACB is particularly pronounced in the vulnerable patient groups mentioned previously. For example, patients with mental health conditions, such as psychosis, often experience a prescribing cascade. First, they are treated with antipsychotic medications, many of which have inherent anticholinergic properties, and if they develop extrapyramidal side effects owing to the antipsychotic, they are also prescribed anticholinergics, thus creating a cumulative effect[12,19]. Adults with an intellectual disability are also exposed to a greater risk of having a very high ACB through polypharmacy from several classes of medications. An example would be in those with an intellectual disability, behaviour that challenges and co-existing mental health conditions, such as depression or psychosis. These patients are often prescribed antipsychotics, antidepressants and/or mood stabilisers in combination, many of which have anticholinergic properties. In addition, many of these patients develop extrapyramidal side effects because of antipsychotic medication use and are then prescribed more anticholinergic drugs to combat this. Any over-the-counter medication with anticholinergic effects (e.g. antihistamines) could make this worse. Overall, the prescription of anticholinergics appears to start early in this population and continues for several years.
Cognitive impairment is another aspect of ACB that has been studied extensively. Owing to sedation and delirium as a result of ACB, the risk of adverse outcomes, including falls and hospitalisation, increases with increasing anticholinergic exposure. Cumulative use of strong anticholinergics is associated with a higher risk for dementia[12,17].
Measuring anticholinergic burden
Although there is no gold standard tool to measure ACB, there are several instruments that clinicians, including pharmacists, can use to quantify it and thus optimise medication regimes:
- Anticholinergic Effect on Cognition (AEC) scale: this scale was developed in the UK by considering anticholinergic potency, the capacity of the drug to penetrate the blood–brain barrier and reports of cognitive adverse effects. The AEC is available as an application that GPs can use to check a patient’s ACB. The list of drugs a person is taking can be added and a total AEC score can be calculated.
- Anticholinergic Risk Scale (ARS): this is a ranked list of medications with anticholinergic potential, ranging from 0 (no or low risk) to 3 (high anticholinergic potential). The rankings were assigned to the medications by an expert panel. A study found that a high ARS score was associated with the risk of central anticholinergic adverse effects (falls, dizziness and confusion), as well as peripheral adverse effects (dry mouth, dry eyes and constipation) in older patients.
- The ACB calculator: this calculator was created by using a combination of the German Anticholinergic Burden Score and the Anticholinergic Cognitive Burden Scale[24,25]. Entering the name of the medication into the calculator automatically generates a score from 0 to 3. Drugs with no anticholinergic effects score 0, drugs with possible anticholinergic effects score 1 and drugs with definite anticholinergic effects score 2 or 3. A score of 3+ on this calculator is associated with increased cognitive impairment and mortality.
The side effects of anticholinergics can frequently affect oral health. In 2016, the FDI World Dental Federation stated that “oral health is multi-faceted and includes the ability to speak, smile, smell, taste, touch, chew, swallow and convey a range of emotions through facial expressions with confidence and without pain, discomfort, and disease of the craniofacial complex”.
There is a significant correlation between ACB and the presence of xerostomia (i.e. dry mouth)[14,27]. Dry mouth is experienced subjectively by the patient as a symptom and can be demonstrated objectively by measuring the salivary output. Deutsch and Jay summarise how normal salivary function is essential in speech, digestion, and swallowing. Antimicrobials in saliva prevent decay and tooth wear. Stimulated saliva has a high serous volume, with higher bicarbonate buffering concentrations to neutralise mouth, food and plaque acids than resting saliva. The high-flow volumes enhance effective buffering capacity, and aid in clearing glucose and bacteria. Anticholinergics alter the stimulation of saliva and reduce the salivary flow. The alteration of saliva’s protective functions in the oral cavity leads to more oral health problems. A reduction of 5% saliva flow may happen before patients become aware of their oral health problems.
Oral health problems can, in turn, lead to a range of serious health consequences, including diabetes, cardiovascular disease and cancer[32,33]. Early identification and intervention to address these oral side effects is therefore important. Pharmacists have a critical role in this — they can educate service users about dry mouth and its causes, consequences and management; make referrals to appropriate service providers, such as dentists, dental hygienists, psychiatrists and GPs; support hospitals with mouth care policies and audits; and signpost patients to appropriate dental services on discharge from hospital.
Prevention and intervention strategies
Pharmacists can contribute to the prevention and intervention of anticholinergic side effects on oral health in several areas[13,27,34,35].
Medication reviews conducted by primary care and hospital pharmacists can identify all drugs with potential anticholinergic effects. Additionally, medicines optimisation can assist by reducing or eliminating anticholinergic polypharmacy, based on advice to prescribers from primary care or hospital pharmacists. Prescribers can also use medication with a lower ACB score and prescribe only if needed, particularly in high-risk groups[6,36–38]. Once anticholinergic drugs have been prescribed, pharmacists should:
- Teach the patient self-monitoring and providing specific advice on how to seek help (e.g. reporting dry mouth symptoms to a pharmacist, dentist, GP, treating psychiatrist, etc.);
- Ensure regular reviews of efficacy and monitor for side effects;
- Address any side effects proactively, including lifestyle changes (such as reducing intake of acidic drinks, alcohol, caffeinated drinks, tobacco and substance misuse, as these can cause poor oral health);
- Advise on use of frequent sips of water throughout the day to relieve dry mouth, sugar-free chewing gum to stimulate salivary flow and use of mouth moisturising products;
- Consider deprescribing of anticholinergic drugs, if clinically appropriate[34,39].
Pharmacists can suggest that patients should receive regular oral health check assessments by the dental service — community or hospital pharmacists can monitor whether these are happening as expected. The dental service may decide whether salivary tests are needed or not. See Box 3 for specific advice for patients on oral health.
Box 3: Advice for patients to promote good oral hygiene
- Brush twice daily with pea size amounts of high fluoride (5,000 parts per million) toothpaste to help remineralise teeth and prevent or slow decay. Advise patients to spit out but not to rinse so product stays on teeth;
- Restrict sugar intake to twice daily and ensure the intake time is as short as possible;
- Floss twice per day with interdental brushes;
- Encourage service users to have regular (every three to six months) dental appointments;
- Dry mouth products or mouth moisturising products, including gels, sprays, and toothpastes (e.g. Biotene products, Bioxtra gel/spray/toothpaste, Glandosane spray, Saliva Orthana spray, Saliveze oral spray). The gels can be applied to all parts of the mouth, including the lips, tongue and cheeks, and should be slowly massaged into the tissues[9,34,36,39–43]
- In addition, dental services may recommend fluoride varnish and amorphous calcium phosphate — fluoride dental varnish either with or without amorphous calcium phosphate has the potential to arrest/reverse root caries, especially non-cavitated lesions for patients with xerostomia[39,44,45].
A recent study showed beneficial effects for oral pilocarpine drops to relieve xerostomia in older people. Pilocarpine is prescribed orally or topically to stimulate saliva production in patients with functioning salivary glands and is approved for use in patients with Sjögren’s syndrome or radiotherapy-induced xerostomia, but there is little evidence supporting its effectiveness in dry mouth associated with psychotropic medications[34,46].
There is also some recent evidence that 1% malic acid topical sialogogue spray is an effective method for the treatment of xerostomia.
Pharmacists should carefully consider if the patient is in a high-risk group for ACB (e.g. older, cognitive deficits, intellectual disability, mental health condition). Wherever possible, there should be a careful discussion between the prescriber and patient about the risks and benefits of anticholinergic medication. This can involve summarising the reasons for the prescription, response to the medication, adherence, side effects and patient’s views about continuing the medication. If the patient lacks capacity to participate in such a discussion, the principles of best interest decision making should be followed.
Before deciding to commence or continue treatment with a drug with anticholinergic effects, consider the following:
- Have non-pharmacological strategies been optimised?
- Has the option of treating the condition using drugs without anticholinergic effect or with lower anticholinergic potential been considered?
- Has there been a review to minimise co-prescribing of other drugs with anticholinergic properties (including over-the-counter medicines such as antihistamines)?
Use the minimum dose of the anticholinergic that is required to manage the condition for the shortest duration[10–14,33,36].
Many patients, particularly older people, those with intellectual disability and those with mental health conditions, are on several drugs with anticholinergic properties at any one time. This concomitant use increases the risk of side effects and the cumulative effect of taking one or more medications with anticholinergic activity is referred to ACB. Side effects related to oral health are among the most common manifestation of this. There is a sequence of events ranging from xerostomia through to periodontal disease, caries, dysphagia, dysgeusia and increased risk of inflammation and infections. These can in turn lead to a range of serious health consequences, including diabetes, cardiovascular disease and cancer. Pharmacists have a crucial role in advising patients and prescribers about prevention, early identification and treatment of these oral side effects.
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