Date of Award

January 2018

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

David Silverman

Abstract

Microcirculatory function is an important component of cardiovascular pharmacology as related to cardiovascular dysfunction. We used photoplethysmography (PPG) to compare the microcirculatory effects of transdermal patches of rivastigmine (Exelon, Novartis), nicotine, nitroglycerin (NTG) and topically applied EMLA (eutectic mixture of lidocaine/prilocaine). We anticipate that this initial pilot comparison of single doses of each medication will catalyze future multi-dose comparisons of the various vasodilatory features of these and other drugs.

Methods: With IRB approval, 10 healthy volunteers were monitored with PPG at the time each transdermal patch was applied and every 8 minutes afterwards for a total of 40 minutes. 1x1 cm portions of patches of rivastigmine, nicotine, and NTG were placed and monitored on different sites of the forehead. Another site was isolated and pretreated 6 hours earlier with EMLA, since this drug requires many hours to induce vasodilation.1 All voltage changes were changed to ACmults, i.e., in multiples of the change in voltage associated with delivery of the stroke volume to the given site under resting conditions2. A linear mixed model was used to compare patch effects on maximum change in AC, DC, and ΔAC/ΔDC. This model accounts for the variance that can be attributed to an individual’s multiple measurements within an unstructured covariance matrix. A p-value <0.05 was given to be statistically significant. Data were expressed as mean within a 95% confidence interval.

Results: The max ∆AC change for each drug were significantly different from that of its control while only the max ∆DC of NTG was significantly greater than that of its control. Changes in the ΔAC/ΔDC ratio were found to be inconsistent. Rivastigmine and control had significantly lower ΔAC/ΔDC values at 8 minutes compared to that of EMLA; the differences were not significant at following time points.

Discussion: These results may provide some insight into the cardiovascular effects of the study agents used. NTG, a direct NO donor, caused significant increases in AC (arteriolar) and DC (venous) values. Acting at the pre/post ganglionic junction of local parasympathetic pathways to the region of the precapillary sphincter, nicotine caused a significant increase in AC, whereas the change in DC was not found to be significant. Rivastigmine, which inhibits the metabolic degradation of acetylcholine, caused a selective increase in AC. The local anesthetic (EMLA) caused a significant increase in AC. Rivastigmine caused significantly lower ΔAC/ΔDC ratio at 8 minutes when compared to EMLA (which had been on for 6 hours previously). At >16 minutes, the ΔAC/ΔDC values of rivastigmine and EMLA did not differ significantly, findings that may reflect the time needed for acetylcholine to to increase over time via the inhibition of its breakdown as opposed to an immediate introduction of additional agonist via the nicotine or NTG patch. Future studies using different and/or additional drug combinations may help give further insight into the convoluted physiology of the microvasculature.

Comments

This is an Open Access Thesis.

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