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Page 317 Guerra et al. J Transl Genet Genom 2022;6:304-21 https://dx.doi.org/10.20517/jtgg.2022.08

[78]
cutaneous vasodilatation, nausea, diarrhea, or increased urinary frequency . Polymorphisms in CYP2A6
modify the pharmacokinetics of this drug, where the clearance of pilocarpine is significantly lower. In vivo,
these slow metabolizers have two inactive CYP2A6 alleles: CYP2A6*4A, CYP2A6*7, CYP2A6*9, or CYP2A6
[79]
*10 .

Pharyngolaryngeal reflux
Proton-pump inhibitors (PPI) and H2 receptor antagonists show improvements in gastro‐esophageal reflux
disease‐like symptoms, being PPIs more effective in subjects with negative endoscopic findings . CYP2C19
[80]
is the most prominent of the PPI-metabolizing enzymes; CYP2C19-specific single nucleotide
polymorphisms reduce clearance proportionally and increase exposure and prolong proton-pump
inhibition. Differences in CYP2C19-mediated metabolism lead to marked interpatient variability in acid
suppression, drug–drug interaction potential, and clinical efficacy [81-84] . This phenomenon has also been
[82]
observed with CYP3A4, but to a lesser degree .

Hiccup
Pharmacologically, multiple drugs with different targets are available to control hiccups. Baclofen is a drug
commonly used in intractable hiccups . The ABCC9 SNP (rs11046232, heterozygous AT versus reference
[85]
[86]
TT genotype) is associated with a two-fold increase in oral baclofen clearance . Allelic variants with the
[86]
ABCC12, SLC28A1, and PPARD SNPs generate variable responses in cerebral palsy . Chlorpromazine,
domperidone, and metoclopramide can also be useful. However, since these are antidopaminergic drugs,
they should be prescribed with caution because they may worsen dysphagia. Domperidone would be
recommended amongst these medications because of its limited transit through the blood–brain barrier and
exceptional central effects . Paradoxically, metoclopramide and other antidopaminergic drugs may be
[87]
beneficial by reducing nausea and vomiting in patients with ND, and therefore the risk of aspiration. In
these cases, dose adjustment and patient selection are essential due to the risk of adverse effects .
[45]

CONCLUSION
Treatment of ND must be comprehensive and multidisciplinary. Pharmacological treatments are support
tools for other therapeutic measures. Dopamine is the main neurotransmitter implicated in these
swallowing disorders. Of the genes that encode dopaminergic receptors, DRD1 is the most important in the
prediction and treatment of ND. Other genes such as COMT and DBH have also been considered in the
management of ND. Polymorphisms in dopaminergic and antidopaminergic agents are associated,
respectively, with undesired or insufficient effects and increased risk of swallowing impairment. SP is
another main factor in the treatment of ND, which can be altered with antidopaminergic agents. SP
degradation is blocked with TRP channel agonists such as capsaicin, piperine, menthol, and ACE inhibitors.
Genetic variants influence the therapeutic response of TRP channel agonists. When symptoms coexist that
can worsen dysphagia and increase the risk of aspiration (e.g., reflux, xerostomia, sialorrhea, and hiccups), it
is recommended to carefully associate other medications with ND treatment due to the risk of adverse
effects, which may even include swallowing disorders. Dose adjustment and choice of drug in polypharmacy
patients is one of the main objectives of a pharmacogenetic analysis.

DECLARATIONS
Acknowledgments
Joaquin Guerra would like to thank Dante Doncel Guerrero for being the source of inspiration to develop
this article.