Anticholinergic drugs block the action of acetylcholine in the nervous system, inhibiting the parasympathetic response.
Anticholinergic drugs are medications that block the neurotransmitter acetylcholine at muscarinic or nicotinic receptors in the central and peripheral nervous systems.
Anticholinergic medications inhibit parasympathetic muscarinic signaling.
Anticholinergic drugs block the neurotransmitter acetylcholine from binding to receptors in the nervous system.
By inhibiting these signals, they block the parasympathetic nervous system, known as (the “rest and digest” system), which treats conditions like overactive bladder, COPD, Parkinson’s disease, and allergies, but often causes side effects like dry mouth and constipation.
These agents competitively inhibit acetylcholine binding to cholinergic receptors, thereby reducing cholinergic neurotransmission.
Acetylcholine is a chemical messenger in the body that activates involuntary muscle movements, glands, and the “rest-and-digest” processes of the autonomic nervous system.
Acetylcholine plays critical roles in numerous physiological functions, including learning, memory, smooth muscle contraction, glandular secretion, and autonomic nervous system regulation.
They competitively antagonize muscarinic acetylcholine receptors, reducing gland secretions, relaxing smooth muscle, and increasing heart rate.
Anticholinergic medications are classified based on receptor selectivity.
Antimuscarinic agents (the primary class used therapeutically) act on muscarinic acetylcholine receptors, while antinicotinic agents target nicotinic receptors.
Only antimuscarinic agents have significant clinical utility for most indications.
Tertiary-amine muscarinic receptor antagonists (e.g., trihexyphenidyl, biperiden, benztropine, procyclidine, diphenhydramine) have good central nervous system penetration, while quaternary amines (e.g., trospium) have limited blood-brain barrier permeability.
Common uses: Respiratory: Ipratropium, tiotropium (COPD, asthma) GI/GU: Oxybutynin, tolterodine (overactive bladder); hyoscine (IBS, nausea) Neurological: Benztropine, trihexyphenidyl (Parkinson’s tremor) Ophthalmology: Atropine, cyclopentolate (pupil dilation) Anesthesia: Glycopyrrolate (reducing secretions pre-op) Cardiac: Atropine (bradycardia/heart block)
Classic side effects — remembered as the anticholinergic toxidrome: “Dry as a bone” — decreased secretions (dry mouth, skin) “Red as a beet” — flushing “Blind as a bat” — mydriasis, blurred vision “Hot as a hare” — hyperthermia (reduced sweating) “Mad as a hatter” — confusion, agitation, hallucinations “Full as a flask” — urinary retention Tachycardia, constipation
Elderly patients are particularly vulnerable to cognitive side effects; anticholinergic burden is a real clinical concern linked to falls and dementia risk with long-term use.
Anticholinergic toxicity (overdose) is treated with physostigmine, a cholinesterase inhibitor.
Many common drugs have incidental anticholinergic activity — antihistamines (diphenhydramine), tricyclic antidepressants, antipsychotics, acccumulative burden matters.
Some medications achieve their therapeutic effect through anticholinergic activity (bladder antimuscarinics, antispasmodics, antiparkinsonians), while others have unintended anticholinergic effects that are not the primary mechanism of action (first-generation antihistamines, tricyclic antidepressants, certain antipsychotics).
Anticholinergic medications are prescribed for diverse clinical conditions across multiple organ systems.
One-third to one-half of medications commonly prescribed for older adults have anticholinergic activity, with prevalence of use ranging from 8% to 37% in this population.
Overactive bladder (OAB) represents the most common indication for antimuscarinic anticholinergics. FDA-approved agents include darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride.
Antimuscarinic anticholinergics medications block muscarinic receptors on detrusor smooth muscle, inhibiting detrusor contraction and improving storage symptoms of urgency, frequency, urge incontinence.
Anticholinergics jam these signals to produce a variety of targeted therapeutic effects.
Anticholinergics produce modest but important improvements compared to placebo: reduction in urgency episodes, reduction in micturitions and patient-reported cure or improvement.
Gastrointestinal indications include adjunctive therapy for peptic ulcer disease, control of gastric secretions, visceral spasm and hypermotility in spastic colitis, pylorospasm, irritable bowel syndrome, functional gastrointestinal disorders, diverticulitis, and acute enterocolitis.
Hyoscyamine sulfate is commonly used for these indications.
Genitourinary applications extend beyond OAB to include neurogenic bladder, neurogenic bowel disturbances, spastic bladder, and cystitis.
Other approved uses include symptomatic relief of biliary and renal colic (in combination with narcotics), acute rhinitisas a drying agent, Parkinson’s disease to reduce rigidity, tremors, sialorrhea, and hyperhidrosis, infant colic, and poisoning by anticholinesterase agents.
Urinary Incontinence & Overactive Bladder: Blocks involuntary bladder contractions.
Examples: Oxybutynin (Ditropan, Oxytrol), Tolterodine (Detrol), Solifenacin (Vesicare).
COPD & Asthma: Relaxes airway muscles and reduces mucus production.
Examples: Ipratropium (Atrovent), Tiotropium (Spiriva).
Allergies & Motion Sickness: Blocks histamine and prevents nausea/vomiting pathways.
Examples: Diphenhydramine (Benadryl), Dimenhydrinate (Dramamine), Scopolamine.
Parkinson’s Disease: Used to reduce tremors and muscle stiffness. Examples: Benztropine (Cogentin), Trihexyphenidyl.
Gastrointestinal Disorders: Relaxes smooth muscles in the GI tract to stop spasms and diarrhea.
Hyoscyamine (Levsin), Dicyclomine (Bentyl).
Combination therapy with alpha-blockers is used for lower urinary tract symptoms related to benign prostatic obstruction, achieving synergistic effects by blocking both alpha-adrenergic and muscarinic cholinergic receptors.
For overactive bladder, anticholinergics demonstrate moderate efficacy.
Anticholinergics reduced urinary incontinence episodes by 53% to 80% and urinary frequency by 12% to 32%, compared to placebo improvement rates of 30% to 47% for incontinence and 8% to 15% for frequency.
The proportion of patients reporting symptom control with anticholinergics is approximately 49%.
Quality of life improvements are modest.
Comparative effectiveness among agents shows some differences.
Solifenacin demonstrated superior efficacy compared to tolterodine for quality of life, patient-reported cure/improvement and reduction in leakage episodes.
Fesoterodine showed better efficacy than extended-release tolterodine but with higher risk of withdrawal due to adverse events and dry mouth.
Extended-release preparations of oxybutynin and tolterodine have similar efficacy to immediate-release formulations but with reduced risk of dry mouth.
For lower urinary tract symptoms in men, all anticholinergic medications have similar efficacy, reducing frequency by 2-4 voids per day and incontinence episodes by 10-20 per week.
Adverse Effects
Common peripheral anticholinergic effects include dry mouth, constipation, blurred vision, dry eyes, urinary retention, tachycardia, nausea, vomiting, abdominal pain, pruritus, nasopharyngitis, and dizziness.
Dry mouth and constipation affect up to 70% of patients taking anticholinergics for lower urinary tract symptoms
Urinary retention is the most serious acute adverse effect, occurring in approximately 1% of patients but with a risk ratio of 3.52 compared to placebo.
Short-term use is associated with a relative risk of acute urinary retention of 8.3, while long-term use (>30 days) carries a relative risk of 2.0.
Discontinuation rates are high.
Withdrawal due to adverse events is more likely with anticholinergics than placebo.
Less than 50% of patients continue prescribed anticholinergic medication beyond 6 months, and less than 36% beyond 1 year.
Central nervous system effects range from subtle cognitive impairment to delirium and may result from the cumulative effect of multiple medications with modest antimuscarinic activity.
Acute impairment in working memory, attention, and psychomotor speed has been demonstrated in single-dose experimental studies.
Older adults are particularly vulnerable due to age-related changes in pharmacokinetics and pharmacodynamics, reduced acetylcholine-mediated transmission in the brain, and increased blood-brain barrier permeability.
Anticholinergic use may decrease sweating, resulting in heat prostration, fever, or heat stroke; caution is advised for febrile patients or those exposed to elevated environmental temperatures.
The anticholinergic burden is the cumulative anticholinergic effect of all medications a person takes and has emerged as a significant safety concern, particularly regarding long-term cognitive outcomes.
Epidemiological evidence demonstrates a dose-dependent association between anticholinergic burden and dementia risk.
Anticholinergic is associated with increased odds of cognitive decline or dementia.
A meta-analysis of 14 longitudinal and case-control studies including 1,564,181 subjects found that anticholinergic drug use was associated with increased risk of all-cause dementia and Alzheimer’s disease, with both low and high anticholinergic burdens showing associations.
Long-term use (>365 days) of anticholinergics has been associated with dementia risk.
Specifically among patients with overactive bladder, seven observational studies reported that anticholinergics were associated with 10% to 65% increased risk for dementia.
The cumulative use of strong anticholinergics is associated with incident dementia, with the association persisting even after accounting for dose and duration of exposure.
However, the dementia association remains controversial.
A retrospective propensity-matched cohort study with 782 matched pairs showed no association of anticholinergic medication use with cognitive decline.
The cholinergic hypothesis of Alzheimer’s disease, proposes that disruption of cholinergic neurotransmission contributes to pathology and cognitive deterioration.
Anticholinergics may also increase risk through cerebral vascular dysregulation, potentially heightening risk for vascular dementia.
A meta-analysis found that antiparkinson drugs, urological anticholinergics, and antidepressants increased dementia risk, while cardiovascular and gastrointestinal anticholinergics played potentially protective roles.
Among patients with overactive bladder, a case-control study found bladder anticholinergics were prescribed to 11.7% of patients with dementia versus 8.3% of controls.
Contraindications and Precautions
Absolute contraindications include untreated narrow-angle glaucoma (though this is an uncommon condition).
Anticholinergic therapy may exacerbate narrow-angle glaucoma and should be avoided in patients with this condition.
Used with caution in patients with autonomic neuropathy, hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, hypertension, renal disease, and hiatal hernia associated with reflux esophagitis.
Anticholinergics may aggravate existing cardiac arrhythmias.
Any tachycardia should be investigated before administering anticholinergic drugs, as they may increase heart rate.
Incomplete bladder emptying with postvoid residual volume >150 mL, warrants caution due to urinary retention risk.
Additive adverse effects from cholinergic blockade may occur when anticholinergics are administered concomitantly with other antimuscarinics, amantadine, haloperidol, phenothiazines, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, or some antihistamines.
Antacids may interfere with absorption of hyoscyamine sulfate.
Anticholinergics may produce drowsiness, dizziness, or blurred vision, and should not engage in activities requiring mental alertness such as operating motor vehicles or machinery while taking these drugs
The American Urological Association recommends anticholinergic medications as second-line therapy for overactive bladder after behavioral interventions fail.
Recommend avoiding anticholinergic medications to treat OAB in individuals older than 70 years due to dementia concerns, though several studies demonstrate increased dementia risk below this age threshold.
Anticholinergic OAB medications as potentially inappropriate medications for elderly individuals, considering disease and syndrome interactions.
Guidelines recommend antimuscarinics or beta-3 agonists as first-line pharmacological treatment for overactive bladder in women, with therapy choice guided by individual patient factors.
Extended-release formulations are preferred over immediate-release preparations to minimize adverse effects, and once-daily dosing may improve adherence.
Minimizing anticholinergic burden should always be encouraged in clinical practice to improve short-term memory, confusion, delirium, quality of life, and daily functioning.
Taking multiple medications with these properties has a cumulative effect known as the anticholinergic burden.
In older adults, chronic, heavy anticholinergic burden is heavily associated with a higher risk of cognitive decline, falls, and dementia.
Agents:
Atropine is an anticholinergic and antimuscarinic agent that can result in CNS and cardiac excitation, photophobia, palpitations, tachycardia, constipation and difficulty urinating.
Belladona and opium can be associated with photophobia, constipation, difficulty urinating, and somnolence.
Belladona and opium supplied as a suppository with 16.2 mg of belladona and 60mg of opium.
Dicyclomine is anticholinergic and antispasmodic.
Glycopyrrolate can be used as a preoperative medication on order to reduce salivary, tracheobronchial, and pharyngeal secretions, as well as decreasing the acidity of gastric secretion.
Glycopyrrolate also used in conjunction with neostigmine, a neuromuscular blocking reversal agent, to prevent neostigmine’s muscarinic effects such as bradycardia.
Glycopyrrolate also used to reduce excessive saliva.
Glycopyrrolate reduces the body’s sweating ability, it can even cause fever and heat stroke in hot environments.
Glycopyrrolate can be associated with dry mouth, difficulty urinating, headaches, diarrhea, constipation, induces drowsiness or blurred vision, an effect exacerbated by the consumption of alcohol.
Glycopyrrolate usually administered IV/IM.
Hyoscyamine anticholinergic and antimuscarinic agent associated with nausea, vomiting, drowsiness, delirium and coma.
Methscopolamine an antimucularinic and anticholinergic agent which mat cause thermoregulatory abnormalites, diarrhea and CNS effects.
Scopolamine anticholinergic and antimuscularinic drug: patches (contain 1.5 mg) q 72 hours achieve maximum blood levels in 12 hours, subcutaneous, intravenous or intramuscular dose 0.3-0.6 mg q 4-8 h.
Scopolamine may precipitate dementia, and acute glaucoma. . Excess scopolamine can be treated with phsostigmine intravenously.
A relationship exists in the elderly between such agents and global cognitive function, psychomotor speed, visual and declarative memory and learning.
In a retrospective study of 592 elderly an accelerated decline of psychomotor speed and executive functioning was associated with anticholinergic usage (Botiggi).
Continuous use of agents among 372 elderly patients revealed an associated with poorer performance on cognitive function (Ancelin).
Use is a strong predictor of mild cognitive impairment.
In a study of 544 community dwelling older male individuals with hypertension exposure to such agents resulted in poor performance of verbal memory over a 2 year period (Han L).