What are common anticholinergic and dopaminergic medications that can cause behavioral disinhibition?

Common Anticholinergic and Dopaminergic Medications That Can Disinhibit Behavior

Anticholinergic medications—particularly diphenhydramine, cyclobenzaprine, and oxybutynin—and dopaminergic medications like levodopa can cause behavioral disinhibition, with anticholinergics producing confusion, delirium, and paradoxical agitation, while dopaminergics may trigger hallucinations, psychotic-like behavior, and aggressive behavior.

Anticholinergic Medications That Disinhibit Behavior

High-Risk Anticholinergic Agents

Older antihistamines, muscle relaxants, and overactive bladder agents have strong anticholinergic effects that are poorly tolerated in aged patients and adversely affect cognition and functionality. 1

• Diphenhydramine (older antihistamine) causes sedation, confusion, and episodes of delirium, and is associated with injurious falls, emergency department visits, and hospitalizations 1
• Cyclobenzaprine (muscle relaxant) produces strong anticholinergic effects with negative impacts on cognition and functionality 1
• Oxybutynin (overactive bladder agent) has strong anticholinergic properties that result in cognitive impairment and behavioral changes 1
• Hydroxyzine (antihistamine) has sedative effects and anticholinergic properties that can worsen agitation 1

Additional Anticholinergic Medications

• Prochlorperazine and promethazine (antiemetics) should be avoided in older adults due to high anticholinergic properties 1
• Tricyclic antidepressants and paroxetine have high anticholinergic properties that can induce delirium 1
• Histamine2-receptor antagonists (e.g., cimetidine) are associated with increased postoperative delirium 1

Mechanism of Behavioral Disinhibition

Anticholinergic medications produce broad muscarinic receptor blockade resulting in negative effects on cognition, with a decline in acetylcholine physiology associated with aging being further blocked by these agents. 1

• Patients taking multiple anticholinergic drugs experience "anticholinergic burden" that adversely affects cognition, functional status, and activities of daily living scores 1
• Anticholinergic drugs can cause paradoxical behavioral disinhibition, especially in younger children and those with developmental disabilities 1
• Benzodiazepines may cause paradoxical agitation in approximately 10% of elderly patients 1, 2

Dopaminergic Medications That Disinhibit Behavior

Levodopa and Carbidopa-Levodopa

Levodopa-containing medications are associated with hallucinations, psychotic-like behavior, confusion, aggressive behavior, agitation, and delirium. 3

• Hallucinations and psychotic-like behavior present shortly after initiation of therapy and may be responsive to dose reduction 3
• Abnormal thinking and behavior may present with paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium 3
• Patients with a major psychotic disorder should not be treated with carbidopa-levodopa because of the risk of exacerbating psychosis 3

Impulse Control and Compulsive Behaviors

Dopaminergic medications (medications that increase central dopaminergic tone) can cause patients to experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and inability to control these urges. 3

• In some cases, these urges stop when the dose is reduced or the medication is discontinued 3
• Patients may not recognize these behaviors as abnormal, requiring prescribers to specifically ask about development of new or increased gambling urges, sexual urges, or uncontrolled spending 3

Other Dopaminergic Agents

• Bromocriptine (dopamine agonist) can affect cognitive performance, though it may improve working memory and cognitive sequencing in Parkinson's disease 4
• Antipsychotics (dopamine antagonists) are used to treat agitation but can themselves cause behavioral changes and should be used cautiously 1

Critical Clinical Considerations

Cognitive Effects Differ by Mechanism

Anticholinergic drugs produce impairment in processes underlying immediate registration of information, while dopaminergic therapy can improve working memory and cognitive sequencing but may trigger psychotic symptoms. 4

• Anticholinergic drugs in Parkinson's disease patients produce cognitive impairment in short-term memory processes 4
• Lipophilic anticholinergics that pass the blood-brain barrier may compromise cognitive functions, especially in geriatric patients already on cholinesterase inhibitors 5, 6

Medications to Avoid in Older Adults

The 2012 AGS Beers Criteria identifies anticholinergics, benzodiazepines, and sedative-hypnotics as potentially inappropriate medications in older adults because of high incidence of adverse drug events. 1

• Meperidine is specifically associated with increased delirium risk 1
• Midazolam (benzodiazepine) is associated with increased delirium 1
• Drugs contributing to serotonin syndrome can increase delirium risk 1

Safer Alternatives with Lower CNS Penetration

Trospium, 5-hydroxymethyl tolterodine, darifenacin, and solifenacin have favorable pharmacodynamic and pharmacokinetic properties with regard to CNS side effects compared to other anticholinergics. 6

• These agents have reduced blood-brain barrier penetration, resulting in fewer cognitive and behavioral side effects 6
• Substances that are absorbed slowly or available as slow-release formulations are tolerated better 5