Continuing Education Activity

Anticholinergic medications are used to manage and treat a wide range of diseases. This activity illustrates the indications, action, and contraindications for anticholinergic drugs as valuable agents in managing cholinergic toxicity, urinary incontinence, Parkinson disease, respiratory disorders, cardiovascular disease, and numerous other diseases. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the care of patients with the disorders mentioned above and related conditions.

Objectives:

• Identify the mechanism of action of anticholinergic drugs.
• Describe the potential adverse effects f anticholinergic drugs.
• Review the need for monitoring patients when using anticholinergic drugs.
• Summarize interprofessional team strategies for improving care coordination and communication to advance anticholinergic drugs and improve outcomes.

Indications

Anticholinergic medications (shorthand: "anticholinergics") are drugs that block and inhibit the activity of the neurotransmitter acetylcholine (ACh) at both central and peripheral nervous system synapses.[1] In doing so, these drugs inhibit the actions of the parasympathetic nervous system (the "rest and digest" function of the autonomic nervous system) via selective blockade of ACh from binding to its receptors in neurons. Functions under the control of the parasympathetic nervous system include involuntary actions of smooth muscle located in the GI tract, lungs, urinary tract, and other areas of the body.  

Generally speaking, anticholinergic agents can be subdivided into two categories based on their specific central and peripheral nervous system targets, as well as at the neuromuscular junction. These two categories are antimuscarinic blockers and antinicotinic blockers.

Anticholinergic medications have a wide range of physiologic effects, including effects on circulation, respiration, alertness, and vision.[2][3] Drugs with anticholinergic activity are useful for treating respiratory disorders (asthma, COPD), Parkinson’s, cardiovascular disease, urge incontinence, psychiatric disorders, depression, mydriasis, and allergies.[4][5][6][7] More than 600 medications possess some level of anticholinergic activity, and except in the case of a few drugs, experts generally consider the anticholinergic properties to be the cause of adverse rather than therapeutic effects.[4] Examples of specific anticholinergic medications where the anticholinergic activity is deemed to be therapeutic are listed below, along with the conditions they treat:

Ipratropium and tiotropium: Function to dilate the bronchi and relieve shortness of breath and FDA approved for the use in patients with chronic obstructive pulmonary disease.[6]

• Benztropine and trihexyphenidyl: Used to counter reduced dopamine levels and relieve symptoms of Parkinson disease [6]
• Oxybutynin and tolterodine: FDA approved for the treatment of urge incontinence and detrusor hyperactivity[6]
• Oxybutynin has an off-label use for the treatment of hyperhidrosis. 
• Diphenhydramine and other anti-histamines: FDA approved as a sleeping aid
• Scopolamine: Used as a prophylactic anti-emetic[8]
• Atropine: Used to dilate pupil during retina visualization and in the treatment of cholinergic toxicity[9]
• Vecuronium and Succinylcholine: Antinicotinic medications used as a neuromuscular blockade in surgeries[6]
• Mecamylamine: Used strictly in research settings as a ganglionic blocker[6]
• Glycopyrrolate: A type of quaternary amine used in anesthesia to decrease salivary and tracheal secretions[10]

Medications like antipsychotics, tricyclic antidepressants, and diphenhydramine (when used to treat allergies) possess anticholinergic properties despite not being responsible for their therapeutic qualities.

Mechanism of Action

Anticholinergic medications are competitive antagonists of the neurotransmitter acetylcholine at receptor sites within the cholinergic system. The cholinergic system utilizes two types of receptors, the plasma membrane-bound G protein-coupled muscarinic receptors, and the ligand-gated ion channel nicotinic receptors.[11] Nicotinic receptors are found in the postganglionic dendrites and nerve bodies of the autonomic nervous system and on the motor endplate of the neuromuscular junction.[11] 

Muscarinic receptors are present on the target organ cells of the parasympathetic nervous system and sweat glands in the sympathetic nervous system. Antagonism of the cholinergic system reduces or, in some cases, prevents the effects of cholinergic neurotransmission in the central nervous system and peripheral tissue.[4][5][7][12] Medications with anticholinergic activity predominantly affect muscarinic receptors.[6]

Administration

Administration of anticholinergic medications varies across the large group of drugs with anticholinergic properties; many are available in oral and intravenous forms. For example, ipratropium, used in treating COPD, can be administered orally or intranasally.[13] Diphenhydramine can be administered orally, intramuscularly (IM), and intravenously (IV).[14] Antipsychotics are available in IM and oral forms, and atropine is available in IV and IM dose forms. Vecuronium and succinylcholine are available intravenously, and both oxybutynin and trihexyphenidyl administration is via the oral route. 

Adverse Effects

The adverse effects of anticholinergic medications divide into central and peripheral effects. Central effects result from the excess blockade of cholinergic receptors within the central nervous system, and peripheral adverse effects result from the blockade of exocrine glandular secretion, muscle contraction, and end-organ targets of the peripheral parasympathetic nervous system. Common central anticholinergic adverse effects include headache, impaired memory, reduced cognitive function, behavioral disturbances, anxiety, and insomnia at low dosages.[6] 

At high dosages and approaching the range of anticholinergic toxicity, central adverse effects include signs of agitation, confusion, delirium, and seizures.[6] Drugs that more readily cross the blood-brain barrier tend to cause central nervous system adverse effects more frequently than those with limited ability to cross the border.[15] Common peripheral adverse effects of medications with anticholinergic activity are described below, organized by organ system:

• General: Hyperthermia and anhidrosis[6]
• Cardiovascular: Tachycardia, flushing, and arrhythmias[6][16]
• Gastrointestinal: Reduced gut motility, constipation, vomiting, reduced saliva, and tear production
• Genitourinary: Urinary retention[6][17][18]
• HEENT: Blurred vision, mydriasis, narrow-angle glaucoma, and potentially vision loss[6]
• Skin: Inhibition of sweating[11][19]
• Musculoskeletal: Diminished muscle contraction

Overall, the potential to cause anticholinergic side effects is based on the drug's affinity for cholinergic receptors. 

Contraindications

The use of anticholinergics requires caution, particularly with the elderly, those with a high anticholinergic burden, and those with conditions susceptible to increased anticholinergic activity such as dementia.[15] Elderly adults are more vulnerable to the effects of anticholinergic medications due to increased permeability of the blood-brain barrier and decreased acetylcholine-induced transmission within the central nervous system.[20] Additionally, many conditions requiring treatment with anticholinergic medications occur in the elderly (e.g., urinary incontinence, COPD). As such, they are more likely to be taking drugs with anticholinergic activity and are at greater risk.[11] 

Patients with high anticholinergic burdens are at higher risk for adverse effects and anticholinergic toxicity; providers need to consider the total anticholinergic burden when prescribing new medications. Patients with dementia also have a relative contraindication to the use of anticholinergics. Dementia correlates with reduced acetylcholine in the brain and thus can become worse with the use of anticholinergics.[15] Glaucoma, hyperthyroidism, tachyarrhythmia, and prostate hypertrophy are all conditions negatively impacted by anticholinergic drugs and are prevalent in elderly populations.[15]

Monitoring

Serum anticholinergic assay is one technique used to measure the total anticholinergic burden of all substances within an individual.[4] This technique has allowed for the scaling, from low to high, of anticholinergic activity levels within medications. Previously medications were labeled as either anticholinergic or not; having a more comprehensive scaling of drugs allows providers to weigh better the pros and cons of prescribing medications with anticholinergic activity, especially for high-risk populations, such as the elderly and those with mental illness.[6] 

It is worth mentioning that the assay cannot detect CNS anticholinergic levels directly and that it lacks specificity for muscarinic receptor subtypes. Another tool used to monitor the risk of anticholinergic medications is the Anticholinergic Drug Scale. The anticholinergic drug scale ranks anticholinergic activity per medication on a scale of 0 to 3, with 0 being no reported anticholinergic activity and 3 signifying high levels of anticholinergic activity.[6] The sum of all the drug scores provides a final score. The hope is that ADS can provide some direction on which medications to discontinue in patients with a high anticholinergic burden; however, further studies are needed to verify an association between the score and clinical outcomes.[6]

Toxicity

Toxicity from anticholinergic medications is essentially an extreme version of the previously mentioned central and peripheral adverse effects. Clinical characteristics of anticholinergic toxicity include anhidrosis, anhidrotic hyperthermia, vasodilation-induced flushing, mydriasis, urinary retention, and neurological symptoms, including delirium, agitation, and hallucinations. The memory aid “red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask’ often serves as means of remembering the common symptoms of anticholinergic toxicity.[21] Absent bowel sounds and tachycardia are among the first indications of acute anticholinergic toxicity. Anticholinergic toxicity is considered a clinical diagnosis, and there is currently no available testing to support the diagnosis.[21]

Enhancing Healthcare Team Outcomes

Anticholinergic medications are quite prevalent throughout the healthcare system, and many drugs that are not used explicitly for their anticholinergic properties still have anticholinergic side effects. The entire interprofessional healthcare team, including all clinicians (MDs, DOs, NPs, and PAs), nurses, and pharmacists, need to be well-versed in both the therapeutic and adverse properties of anticholinergic drugs. This is most important regarding the contribution of anticholinergics to adverse events. The team should monitor the overall anticholinergic burden, attempt to limit unnecessary use of anticholinergic medications, and pay special attention to high-risk groups such as the elderly and those receiving treatment for depression and schizophrenia.

When prescribing agents with anticholinergic properties, clinicians need to be aware of other such agents the patient may already be taking; this is where a pharmaceutical consult can prove helpful, with the pharmacist performing complete medication reconciliation and reporting back to the prescriber. Nurses can instruct the patient on proper administration and also counsel them regarding the onset of potential adverse events so that if they occur, the patient will recognize their onset early and be able to reach out to members of the interprofessional team for appropriate intervention; this can be contact with the nursing staff or even the pharmacist where the pick up their medication. Once any team member has been alerted or perceives an issue, it must be communicated to all members of the healthcare team and noted in the patient's chart or electronic health record (EHR). With interprofessional communication and collaborative efforts, these medications can exert their therapeutic effects with a reduced chance of causing adverse events, leading to improved patient outcomes. [Level 5]