Cognitive Risks of Anticholinergics in the Elderly
Cognitive Risks of Anticholinergics in the Elderly
Age-related physiological changes place the elderly at greater risk of adverse drug reactions than younger adults. Peripheral pharmacokinetic changes, including reduced gastrointestinal absorption, alterations in the volume of distribution (i.e., greater fat-to-muscle ratio leads to lipid-soluble drug accumulation, while reduced total body water results in a lower volume of distribution for water-soluble drugs and increased blood levels), and declining hepatic and renal clearance, may contribute to anticholinergic toxicity. Central pharmacokinetic changes with aging also influence anticholinergic sensitivity. Changes in CNS distribution and clearance lead to anticholingeric accumulation. Increased blood–brain barrier permeability and p-glycoprotein dysfunction may permit increased drug access to the CNS. Nonetheless, the degree to which each of these factors contributes to adverse anticholinergic effects in later life remains unclear.
The relationship between aging, cognition and neurotransmission is complex. There is a clear association between aging and alternations across different neurotransmitter systems. Normal aging appears to be accompanied by a gradual decline of the cholinergic system within the basal forebrain and nucleus basalis of Meynert. This decline, unlike that observed in pathological aging, results in functional impairment and secondary neuronal atrophy without cellular loss. Impaired nerve growth factor signaling induces cellular atrophy and synaptic, dendritic and axonal degeneration, which appears to contribute to age-related memory impairment and increased anticholinergic sensitivity in later life.
'Normal' Aging & the Cholinergic System
Age-related physiological changes place the elderly at greater risk of adverse drug reactions than younger adults. Peripheral pharmacokinetic changes, including reduced gastrointestinal absorption, alterations in the volume of distribution (i.e., greater fat-to-muscle ratio leads to lipid-soluble drug accumulation, while reduced total body water results in a lower volume of distribution for water-soluble drugs and increased blood levels), and declining hepatic and renal clearance, may contribute to anticholinergic toxicity. Central pharmacokinetic changes with aging also influence anticholinergic sensitivity. Changes in CNS distribution and clearance lead to anticholingeric accumulation. Increased blood–brain barrier permeability and p-glycoprotein dysfunction may permit increased drug access to the CNS. Nonetheless, the degree to which each of these factors contributes to adverse anticholinergic effects in later life remains unclear.
The relationship between aging, cognition and neurotransmission is complex. There is a clear association between aging and alternations across different neurotransmitter systems. Normal aging appears to be accompanied by a gradual decline of the cholinergic system within the basal forebrain and nucleus basalis of Meynert. This decline, unlike that observed in pathological aging, results in functional impairment and secondary neuronal atrophy without cellular loss. Impaired nerve growth factor signaling induces cellular atrophy and synaptic, dendritic and axonal degeneration, which appears to contribute to age-related memory impairment and increased anticholinergic sensitivity in later life.
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