Eric T. Geier

Background: Anticholinergic side effects from psychotropic medications are common and can lead to significant adverse events, including cognitive impairment and falls, particularly in vulnerable populations like the elderly. The cumulative anticholinergic burden from multiple medications is a critical concern associated with poorer clinical outcomes. Quantifying this burden is essential for safer prescribing. Methods: This article developed an anticholinergic equivalence (AE) table for various psychotropic medications. Diphenhydramine (AE=1) was used as the reference standard. AE values for other drugs were derived from their M1 muscarinic receptor binding affinities (Ki) relative to diphenhydramine. This allows estimation of the diphenhydramine equivalent burden per milligram of a given medication. Antihistaminic properties were also reviewed. Results: An AE table was generated, detailing the anticholinergic potency of numerous psychotropic agents. Values varied significantly, with older tricyclic antidepressants (eg, amitriptyline AE: 8.99) and some antipsychotics (eg, clozapine AE: 6.67, olanzapine AE: 3.08) showing high anticholinergic equivalence. Many sedating medications (eg, quetiapine, mirtazapine) are noted to have potent antihistaminic but low anticholinergic properties, clarifying that sedation is not always due to anticholinergic effects. Conclusions: The anticholinergic equivalence table provides a practical, pharmacologically based tool for psychiatrists to quantify and compare the anticholinergic potential of psychotropic medications. This can aid in minimizing cumulative anticholinergic burden, making more informed prescribing decisions, and ultimately enhancing patient safety and therapeutic outcomes, especially in high-risk groups.

Dynamic imaging providing maps of specific ventilation with a temporal resolution of ∼7 min with a spatial resolution of ∼1 cm³ using MRI was shown to be practical. The technique provides an ionizing radiation-free means of temporally following the spatial pattern of specific ventilation. Reanalysis of previously published data showed that the effects of inhaled methacholine and albuterol were largely complete at ∼22 min and ∼9 min, respectively after administration.

Measurement of ventilation heterogeneity with the multiple breath N₂ washout (MBW) is usually performed using controlled breathing with a fixed tidal volume and breathing frequency. However, it is unclear whether controlled breathing alters the underlying ventilatory heterogeneity. We hypothesized that the width of the specific ventilation distribution (a measure of heterogeneity) would be greater in tests performed during free-breathing compared to those using controlled breathing. Eight normal subjects (age range 23-50 yrs, 5F/3M) twice underwent MRI-based specific ventilation imaging consisting of 5 repeated cycles with the inspired gas switching between 21% and 100% O₂ every ~2 minutes (total imaging time ~20 minutes). In each session tests were performed free-breathing (FB, no constraints), and with controlled breathing (CB) at a respiratory rate of 12 breaths/min and no tidal volume control. The specific ventilation distribution in a mid-sagittal slice of the right lung was calculated and the heterogeneity calculated as the full-width at half-max of a gaussian distribution fitted on a log-scale (SV-width). Free-breathing resulted in a range of breathing frequencies from 8.7 to 15.9 bpm (mean 11.5 ± 2.2, P=0.62 compared to CB). Heterogeneity (SV-width) was unchanged by controlled breathing (FB: 0.38 ± 0.12, CB: 0.34 ± 0.09, P=0.18, repeated measures ANOVA). The imposition of a controlled breathing frequency did not significantly affect the heterogeneity of ventilation in the normal lung suggesting that MBW and SVI as typically performed provide an accurate measure of ventilatory heterogeneity.

Some subjects with asthma have ventilation defects that are resistant to bronchodilator therapy, and it is thought that these resistant defects may be due to ongoing inflammation or chronic airway remodeling. However, it is unclear whether regional obstruction due to bronchospasm alone persists after bronchodilator therapy. To investigate this, six young, healthy subjects, in whom inflammation and remodeling were assumed to be absent, were bronchoconstricted with a PC₂₀ [the concentration of methacholine that elicits a 20% drop in forced expiratory volume in 1 s (FEV₁)] dose of methacholine and subsequently bronchodilated with a standard dose of albuterol on three separate occasions. Specific ventilation imaging, a proton MRI technique, was used to spatially map specific ventilation across 80% of each subject’s right lung in each condition. The ratio between regional specific ventilation at baseline and after intervention was used to classify areas that had constricted. After albuterol rescue from methacholine bronchoconstriction, 12% (SD 9) of the lung was classified as constricted. Of the 12% of lung units that were classified as constricted after albuterol, approximately half [7% (SD 7)] had constricted after methacholine and failed to recover, whereas half [6% (SD 4)] had remained open after methacholine but became constricted after albuterol. The incomplete regional recovery was not reflected in the subjects’ FEV₁ measurements, which did not decrease from baseline ( P = 0.97), nor was it detectable as an increase in specific ventilation heterogeneity ( P = 0.78). NEW & NOTEWORTHY In normal subjects bronchoconstricted with methacholine and subsequently treated with albuterol, not all regions of the healthy lung returned to their prebronchoconstricted specific ventilation after albuterol, despite full recovery of integrative lung indexes (forced expiratory volume in 1 s and specific ventilation heterogeneity). The regions that remained bronchoconstricted following albuterol were those with the highest specific ventilation at baseline, which suggests that they may have received the highest methacholine dose.

The location of lung regions with compromised ventilation (often called ventilation defects) during a bronchoconstriction event may be influenced by posture. We aimed to determine the effect of prone versus supine posture on the spatial pattern of methacholine-induced bronchoconstriction in six healthy adults (ages 21–41, 3 women) using specific ventilation imaging. Three postural conditions were chosen to assign the effect of posture to the drug administration and/or imaging phase of the experiment: supine methacholine administration followed by supine imaging, prone methacholine administration followed by supine imaging, and prone methacholine administration followed by prone imaging. The two conditions in which imaging was performed supine had similar spatial patterns of bronchoconstriction despite a change in posture during methacholine administration; the odds ratio for recurrent constriction was mean (SD) = 7.4 (3.9). Conversely, dissimilar spatial patterns of bronchoconstriction emerged when posture during imaging was changed; the odds ratio for recurrent constriction between the prone methacholine/supine imaging condition and the prone methacholine/prone imaging condition was 1.2 (0.9). Logistic regression showed that height above the dependent lung border was a significant negative predictor of constriction in the two supine imaging conditions ( P < 0.001 for each) but not in the prone imaging condition ( P = 0.20). These results show that the spatial pattern of methacholine bronchoconstriction is recurrent in the supine posture, regardless of whether methacholine is given prone or supine but that prone posture during imaging eliminates that recurrent pattern and reduces its dependence on gravitational height. NEW & NOTEWORTHY The spatial pattern of methacholine bronchoconstriction in the supine posture is recurrent and skewed toward the dependent lung, regardless of whether inhaled methacholine is administered while supine or while prone. However, both the recurrent pattern and the gravitational skew are eliminated if imaging is performed prone. These results suggest that gravitational influence on regional lung inflation and airway topography at the time of measurement play a role in determining regional bronchoconstriction in the healthy lung.

Specific ventilation imaging was used to identify regions of the healthy lung (6 supine subjects, ages 21–41 yr, 3 men) that experienced a fall in specific ventilation following inhalation of methacholine. This test was repeated 1 wk later and 3 mo later to test for spatial recurrence. Our data showed that 53% confidence interval (CI; 46%, 59%) of volume elements that constricted during one methacholine challenge did so again in another and that this quantity did not vary with time; 46% CI (28%, 64%) recurred 1 wk later, and 56% CI (51%, 61%) recurred 3 mo later. Previous constriction was a strong predictor for future constriction. Volume elements that constricted during one challenge were 7.7 CI (5.2, 10.2) times more likely than nonconstricted elements to constrict in a second challenge, regardless of whether the second episode was 1 wk [7.7 CI (2.9, 12.4)] or 3 mo [7.7 CI (4.6, 10.8)] later. Furthermore, posterior lung elements were more likely to constrict following methacholine than anterior lung elements (volume fraction 0.43 ± 0.22 posterior vs. 0.10 ± 0.03 anterior; P = 0.005), and basal elements that constricted were more likely than their apical counterparts to do so persistently through all three trials (volume fraction 0.14 ± 0.04 basal vs. 0.04 ± 0.04 apical; P = 0.003). Taken together, this evidence suggests a physiological predisposition toward constriction in some lung elements, especially those located in the posterior and basal lung when the subject is supine.NEW & NOTEWORTHY The spatial pattern of bronchoconstriction following methacholine is persistent over time in healthy individuals, in whom chronic inflammation and airway remodeling are assumed to be absent. This suggests that regional lung inflation and airway structure may play dominant roles in determining the spatial pattern of methacholine bronchoconstriction.