Anticholinergic medications have a wide range of physiologic effects, including effects on circulation, respiration, alertness, and vision. Drugs with anticholinergic activity are useful for the treatment of respiratory disorders (asthma, COPD), Parkinson’s, cardiovascular disease, urge incontinence, psychiatric disorders, depression, mydriasis, and allergies. Greater than 600 medications possess some level of anticholinergic activity, and except in the case of a few drugs, experts consider the anticholinergic properties to be the cause of adverse rather than therapeutic effects. Examples of specific anticholinergic medications where the anticholinergic activity is considered therapeutic are listed below along with the conditions they treat:
Ipratropium and tiotropium: Function to bronchodilate and relieve shortness of breath and FDA approved for the use in patients with chronic obstructive pulmonary disease.
Medications like antipsychotics, tricyclic antidepressants, and diphenhydramine (when used to treat allergies) all possess anticholinergic properties despite it not being responsible for their therapeutic qualities.
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. 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. 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. Medications with anticholinergic activity predominantly affect muscarinic receptors.
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 the treatment of COPD, can be administered orally or intranasally. Diphenhydramine can be administered orally, intramuscularly (IM), and intravenously (IV). 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.
The adverse effects of anticholinergic medications divide into central and peripheral effects. Central effects are a result of 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. At high dosages and approaching the range of anticholinergic toxicity, central adverse effects include signs of agitation, confusion, delirium, and seizures. Drugs that more readily cross the blood-brain barrier tend to cause central adverse effects more frequently than those with limited ability to cross the border. Common peripheral adverse effects of medications with anticholinergic activity are described below, organized by organ system:
Overall, the potential to cause anticholinergic side effects is based on the drug's affinity for cholinergic receptors.
The use of anticholinergics requires caution, particularly with the elderly, those with high anticholinergic burden, and those with conditions susceptible to increased anticholinergic activity such as dementia. 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. Additionally, many of the conditions that require 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. 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. Glaucoma, hyperthyroidism, tachyarrhythmia, and prostate hypertrophy are all conditions that be negatively impacted by anticholinergic drugs and are prevalent in elderly populations.
Serum anticholinergic assay is one technique used to measure the total anticholinergic burden of all substances within an individual. 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. 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. 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 high anticholinergic burden, however further studies are needed to verify an association between the score and clinical outcomes.
Toxicity from anticholinergic medications is essentially an extreme version of the before 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. 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.
The use of anticholinergic medications is extremely prevalent throughout the healthcare system, and many drugs that are not used explicitly for their anticholinergic properties still have anticholinergic side effects. Healthcare workers should monitor overall anticholinergic burden, make attempts 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.
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