## 5 SSRIs and AAC: Potential Mechanisms
This observation is supported by the results of a retrospective population-based study conducted by [PERSON] et al. where paroxetine along with citalopram was the most frequently used SSRI in patients diagnosed with AAC [13]. Several hypotheses may explain the more frequent occurrence of AAC associated with paroxetine administration compared to other SSRIs. Paroxetine is characterized by the greatest affinity for SERT and is the most potent 5-HT reuptake inhibitor among SSRIs [50; 51]. These pharmacological properties suggest that the serotonergic mechanism may be a crucial factor connecting paroxetine with a higher incidence of AAC. A similar hypothesis was formulated in relation to the occurrence of AAC associated with the use of SNRIs, a similar group of antidepressants, as all described cases are associated with the intake of venlafaxine and duloxetine, which are characterized by the highest ratio of 5-HT:NE reuptake among SNRs [10]. Paroxetine also has a stronger effect on norepinephrine reuptake than the other SSRIs, which shows both the low value of the inhibitor constant (Ki) for NET and low half maximal inhibitory concentration (IC\({}_{50}\)) for NE reuptake [15; 50]. Stimulation of the \(\alpha_{1}\)-adrenergic receptors located in the pupil dilator muscle may act synergistically with the serotonergic stimulation, which \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Mechanism** & **Receptor** & **Stimulation/Inhibition** & **Localization** & **Effect in the Eye Tissue** \\ \hline \multirow{4}{*}{Serotonergic} & \multirow{2}{*}{5-HT\({}_{7}\)} & \multirow{2}{*}{Stimulation} & Iris & Increase IOP \\  & & & Ciliary body & Mydrais-relaxation of the iris \\  & & & Iris sphincter muscle & sphincter muscle \\ \cline{2-5}  & & & & \\ \cline{2-5}  & \multirow{2}{*}{5-HT\({}_{2\text{C}}\)} & \multirow{2}{*}{Inhibition} & Iris & Possible co-stimulation of adrenergic \\  & & & & & and dopaminergic transmission in the \\  & & & & & CNS \\ \hline \multirow{4}{*}{Adrenergic} & \multirow{2}{*}{\(\alpha_{\text{-1}}\)} & \multirow{2}{*}{Stimulation} & Iris dilator muscle & Mydrais-contraction of the iris \\  & & & & & \\ \cline{2-5}  & & & & & \\ \cline{2-5}  & \multirow{2}{*}{\(\alpha_{\text{-2}}\)} & \multirow{2}{*}{Stimulation} & E-W nucleus & Mydraisis-inhibition of the \\  & & & & & parasympathetic innervation of the \\ \cline{2-5}  & & & & & iris muscles by stimulation of the \\ \cline{2-5}  & \multirow{2}{*}{\(\beta_{\text{-2}}\)} & \multirow{2}{*}{Stimulation} & Ciliary body & \multirow{2}{*}{\begin{tabular}{} \end{tabular} } \\  & & & & \\ \cline{2-5}  & & & & & \\ \hline \multirow{2}{*}{Dopaminergic} & D1-like & \multirow{2}{*}{Stimulation} & Ciliary body & \multirow{2}{*}{\
\begin{tabular}{} \end{tabular} } \\  & (D1 and D5) & & & & \\ \cline{2-5}  & & & & & \\ \hline \multirow{2}{*}{Anticholinergic} & M1; M3; & \multirow{2}{*}{Inhibition} & Ciliary body & \multirow{2}{*}{
\begin{tabular}{} \end{tabular} } \\  & & & & \\ \cline{2-5}  & M5 & & Iris sphincter muscle & \\ \hline \hline \end{tabular} References: [10; 15; 38; 45]. Abbreviations: IOP, intraocular pressure; CNS, central nervous system; E-W nucleus, Edinger-Westphal nucleus.  
\end{table} 
Table 2: Potential mechanisms linking SSRIs with the occurrence of AAC. cause mydriasis, as a result of relaxation of the pupil-sphincter muscle due to stimulation of the 5-HT\({}_{7}\) receptors [15]. Moreover, paroxetine is characterized by the highest affinity for the muscarinic receptors among SSRIs [51], due to which anticholinergic mechanism may also act synergistically with serotonergic and noradrenergic mechanisms and cause mydriasis, resulting in AAC in the pupillary block mechanism in suspected patients [26, 45]. Furthermore, paroxetine is metabolized by the CYP2D6 subunit and is a potent inhibitor of this isoenzyme [37, 52]; thus, paroxetine can inhibit its own metabolism [34].