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J Transl Genet Genom 2022;6:304-21. 10.20517/jtgg.2022.08 © The Author(s) 2022.
Open Access Review

Neurogenic dysphagia: current pharmacogenomic perspectives

1Neuro-Otolaryngology Unit, EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, Bergondo 15165, Corunna, Spain.

2Department of Neuroscience, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Bergondo 15165, Corunna, Spain.

3Genomic Medicine, EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, Bergondo 15165, Corunna, Spain.

Correspondence to: Dr. Joaquin Guerra, Neuro-Otolaryngology Unit, EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo 15165, Corunna, Spain. E-mail:

    This article belongs to the Special Issue Genomics, Epigenomics and Pharmacogenomics of Brain Disorders
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    © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (, which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


    Neurogenic dysphagia (ND) is characterized by a swallowing disorder where nervous system, muscle, and neuromuscular diseases are involved. DRD1, COMT, BDNF, and APOE are genes that may have a predictive role in the occurrence and evolution of ND. Many drugs that improve swallowing or can induce or exacerbate swallowing difficulties are related to dopamine metabolism and substance P. These pharmacological treatments for ND include dopamine precursors (levodopa), dopamine agonists (amantadine, apomorphine, cabergoline, and rotigotine), and TRP channel activators (capsaicin, piperine, and menthol). Since treatment outcomes are highly dependent on the genomic profiles of ND patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutic interventions. Knowledge of the pharmacogenetic profiles of these drugs would minimize the occurrence of adverse drug reactions (especially to antidopaminergic medications) that may induce dysphagia and optimize pharmacological treatment that can ameliorate it. This knowledge should also be applied to the use of medications that control symptoms associated with dysphagia, such as sialorrhea, xerostomia, reflux, or hiccups.


    Neurogenic dysphagia (ND) refers to any swallowing disorder associated with central and peripheral nervous system conditions, as well as muscle and neuromuscular diseases. ND is linked to multiple degenerative and nondegenerative congenital, traumatic, vascular, neoplastic, and iatrogenic disorders as diverse as cerebral palsy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s syndromes, myasthenia gravis (MG), and myositis[1]. Based on clinical observations, ND can be classified into the following seven distinct phenotypes, which are particularly useful when etiological diagnosis is in doubt: (i) premature bolus spillage; (ii) delayed swallowing reflex, both characteristic of stroke; (iii) predominance of residue valleculae, common in patients with Parkinson’s disease; (iv) predominance of residue in the piriform sinus, characteristic of myositis, motor neuron disease, or brainstem stroke; (v) pharyngolaryngeal movement disorder, observed in patients with parkinsonism and stroke; (vi) fatigable swallowing weakness in individuals with myasthenia gravis; and (vii) complex disorder, as occurs in ALS[2].

    The importance of dysphagia stems mostly from the increased risk of death caused by aspiration pneumonia, and conditions related to dehydration or malnutrition[3,4]. In addition to these factors, aging reduces the frequency of spontaneous swallowing[5]. To ensure proper diagnosis and management of ND, it is mandatory to: (i) obtain a complete medical history; (ii) perform screenings that assess the risk of aspiration (e.g., a swallowing test with water and other consistencies); (iii) conduct counseling tests and clinically evaluate dysphagia by videofluoroscopy (VFSS), swallowing endoscopy (FEES), or manometry, and other additional tests such as ultrasonography or electromyography); (iv) perform treatments based on dietary therapeutic interventions, behavioral interventions, oral hygiene measures, neurostimulation, pharmacotherapy, and surgical treatments[6]. In this third step, the management of special groups such as tracheostomized patients and patients with nasogastric tubes is of particular interest[6].

    The treatment of ND is mainly based on rehabilitation therapies performed by speech therapists and other non-pharmacological approaches. However, some medications may be effective in improving impairment during the different phases of swallowing[6,7]. The majority of medications used to treat oropharyngeal dysphagia have a general effect on swallowing function that is independent of the underlying neurological disease; this allows for standardized use[8]. Pharmacotherapy, however, produces limited results and should therefore not be used as a stand-alone treatment, but rather as an adjunct to other therapies[8]. Furthermore, medications such as antidopaminergic agents, anticholinergic drugs, or benzodiazepines induce or exacerbate dysphagia[9-12].

    In view of these considerations, research into specific ND-related genes may be useful in the prognosis of this condition. Because pharmacogenetics also plays a key role in both the diagnosis and the correct pharmacological management of patients with dysphagia, to increase the benefit of compounds that can improve swallowing difficulty and minimize the risk with the use of dysphagia-inducing drugs, in this review, we highlight these ND mechanisms from a pharmacogenomic perspective.


    Dopamine is a neurotransmitter of high relevance in the swallowing process. Its precursor, L-DOPA, is synthesized from the essential amino acid tyrosine or indirectly through phenylalanine, a non-essential amino acid. Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE), and NE is then converted into epinephrine by phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as the cofactor. Dopamine is degraded by monoamine oxidase (MAO-A and MAO-B), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), which act sequentially[13].

    Dopamine is synthesized and acts primarily in the central nervous system (CNS). Dopaminergic neurons project to different brain regions along the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways. Dopamine exerts its effects by binding to five G-protein-coupled receptors (D1-D5); of these, D1 receptors are the most abundant in the CNS. These receptors are divided into D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. D1-like receptors exert a stimulatory effect through sodium channels or an inhibitory effect through potassium channels. At the peripheral level, dopamine does not cross the blood–brain barrier and is synthesized independently. Dopamine is present in plasma as dopamine sulfate, and only a small unconjugated amount can be synthesized by peripheral tissues[14,15].


    The swallowing process requires, at least in part, dopamine activity and its binding to its receptors[16]. Although most dopamine receptors would theoretically be relevant to ND, the role of the dopamine D1 receptor (DRD1) is particularly important in this condition. For example, DRD1 antagonists alter the swallowing reflex and reduce substance P (SP) levels in peripheral organs[17]. Specifically, in the striatum in an animal model of Huntington’s chorea, Drd1a, SP, and dynorphin expression is downregulated, whereas the expression of the dopamine D2 receptor (Drd2) and enkephalin is upregulated after ablation of D1 receptor-expressing cells[18]. In this animal model, the resulting phenotype includes swallowing disturbances and poor oromotor coordination with tongue protrusion[18]. This role of DRD1 has also been observed in certain single nucleotide polymorphisms (SNPs) in humans. The DRD1 rs4532 polymorphism confers a worse prognosis of swallowing function in individuals over the age of 65 following a stroke. Other SNPs, such as DRD2 rs1800497 and DRD3 rs6280, do not appear to be involved in ND[19]. Moreover, interactions between the COMT rs165599 and BDNF rs10835211 polymorphisms are linked to dysphagia with increasing age; the effect of the SNP rs10835211 heterozygosity is dependent on the status of SNP rs165599[20].

    The use of dopaminergic agonists in the treatment of neurogenic dysphagia

    Levodopa, rotigotine, cabergoline, apomorphine, and amantadine are dopamine agonists that have been used generically to treat a variety of neurological conditions associated with oropharyngeal dysphagia[8]. The drug that provides the best outcome is controversial because of conflicting outcomes across different studies. However, among these, levodopa is the most widely used, and it is also used to evaluate the swallowing response during the Fiberoptic Endoscopic Evaluation of Swallowing (FEES) test[21,22]. Most studies have focused on the effect of dopaminergic agonists in Parkinson’s disease, and several publications show that these drugs improve dysphagia, especially in the oral phase and, to a lesser extent, in the pharyngeal phase[23-25]. This clinical improvement is related to swallowing alterations due to nigrostriatal dopamine deficits and to other structures such as the pedunculopontine nucleus or the medulla[23]. In a small group of patients, an improvement in bolus fragmentation, vallecular stasis, and laryngeal penetration was observed, together with a shortening of the swallowing phase; these findings are associated with an improvement in bucco-linguo-facial motility[26]. Paradoxically, and despite most articles reporting a beneficial effect, one clinical trial showed that levodopa could worsen dysphagia by inhibiting brainstem reflexes[27]. Overall, however, the results appear to support its use in PD patients despite the lack of high-quality evidence[28]. Although dopaminergic agonists have a modest effect on the motor symptoms of progressive supranuclear palsy, they help some patients improve their swallowing[21]. However, these drugs can also be employed in acquired neurological conditions. Following a lacunar stroke involving the basal ganglia, for example, levodopa decreases the risk of aspiration by shortening the latency of the swallowing reflex, as shown after examining the submental electromyographic activity and the visual observation of the laryngeal movement[29]. This reduction, according to monocentric randomized trials in which imaging and physical signs were evaluated, is also observed with other dopamine agonists such as cabergoline and amantadine; the elderly population, in particular, may benefit from treatment with dopamine agonists[30,31].

    The search for new compounds to treat ND also includes natural supplements that contain dopamine, for use mainly in groups where dosage or side effects may be contraindicated, such as children or the elderly. Natural sources of dopamine include Mucuna pruriens, Vicia faba, or Musa cavendishii[32-34]. In fact, several studies in patients with Parkinson’s disease reveal the effectiveness of these treatments with extracts derived from these products; these compounds reduce the risk of adverse effects such as dyskinesias as well as induce epigenetic and pharmacoepigenetic modifications[35,36].

    Pharmacogenetics of dopaminergic agonists in the treatment of neurogenic dysphagia

    Anti-ND drugs exhibit different specific pharmacogenetic profiles [Table 1][37]. All of the medications used to treat ND show, among others, DRD1 as a mechanistic gene and the binding of drugs to this receptor. All of the anti-ND drugs have COMT as substrates, where COMT shortens the activity of these dopaminergic drugs[38]. Moreover, the COMT rs4680 polymorphism may induce motor complications such as dyskinesia during treatment with levodopa[38-40]. Levodopa also has DBH as substrate[37]. ADORA2A SNPs and HOMER1 variants are associated with L-DOPA-induced adverse motor (e.g., dyskinesia) and psychotic symptoms[41,42]. A haplotype integrating -141CIns/Del, rs2283265, rs1076560, C957T, TaqIA, and rs2734849 polymorphisms at the DRD2/ANKK1 gene region is linked to L-DOPA-induced motor dysfunction[43]. SLC6A3 is a genetic modifier of the treatment response to L-DOPA[44]. The multi-drug resistance gene (MDR1) C1236T polymorphism may also influence pharmacotherapy[45] and SNPs in genes that encode the dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2)[46]. Despite the fact that dopamine agonist therapy has applicability in other ND diseases, these studies focus on Parkinson’s disease, which limits inferences in other acquired or degenerative neurological illnesses.

    Table 1

    Pharmacogenetics of dopaminergic agonists in the treatment of neurogenic dysphagia

    Name: Levodopa
    IUPAC Name: l-Tyrosine-3-hydroxy
    Molecular Formula: C9H11NO4
    Molecular Weight: 197.19 g/mol
    Mechanism: Levodopa circulates in the plasma to the blood–brain barrier,
    where it crosses and is then converted by striatal enzymes to dopamine. Carbidopa inhibits the peripheral plasma breakdown of levodopa by inhibiting its carboxylation, and thereby increases available levodopa at the blood–brain barrier
    Effect: Antiparkinsonian agents, dopamine precursors
    Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2
    Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, OPRM1
    Metabolic genes: Substrate: COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DBH, DDC, G6PD, MAOB, TH, UGT1A1, UGT1A9
    Transporter genes: SLC22A1, SLC6A3, SLC15A1 (inhibitor). SLC16A10 (inhibitor), SLC7A5, SLC7A8
    Pleiotropic genes: ACE, ACHE
    Name: Cabergoline
    IUPAC Name: Ergoline-8β-carboxamide, N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonil]-6-(2-propenyl)
    Molecular Formula: C26H37N5O2
    Molecular Weight: 451.60 g/mol
    Mechanism: A long-acting dopamine receptor agonist.
    Has high binding affinity for dopamine D2-receptors and lesser affinity for D1, α1- and α2-adrenergic, and serotonin (5-HT1 and 5-HT2) receptors.
    Reduces serum prolactin concentrations by inhibiting release of prolactin from the anterior pituitary gland (agonist activity at D2 receptors)
    Effect: Antiparkinsonian agents, ergot-derivative dopamine receptor agonists
    Pathogenic genes: BDNF, GSK3B
    Metabolic genes: Substrate: COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4 (minor), CYP3A5, DDC
    Transporter genes: ABCB1
    Name: Rotigotine
    Molecular Formula: C19H25NOs
    Molecular Weight: 315.47 g/mol
    Mechanism: A non-ergot dopamine receptor agonist with specificity for D3-, D2-, and D1-dopamine receptors.
    Although the precise mechanism of action of Rotigotine is unknown,
    it is believed to be due to stimulation of postsynaptic dopamine D2-type autoreceptors within substantia nigra in brain, leading to improved dopaminergic transmission in motor areas in basal ganglia, notably caudate nucleus/putamen regions
    Effect: Antiparkinsonian agents, non-ergot-derivative dopamine receptor agonists
    Pathogenic genes: ANKK1, BDNF, LRRK2
    Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, OPRM1, HTR1A, ADRA2B
    Metabolic genes:
    Substrate: COMT, MAOB, CYP3A4, CYP2D6
    Inhibitor: CYP2D6, CYP2C19
    Transporter genes: SLC22A1, SLC6A3
    Pleiotropic genes: ACE, APOE
    Name: Apomorphine
    Molecular Formula: C17H17NO2HCl1/2H2O
    Molecular Weight: 312.79 g/mol
    Mechanism: Stimulates postsynaptic D2-type receptors within the caudate-putamen in the brain
    Effect: Antiparkinsonian agents, non-ergot-derivative dopamine receptor agonists
    Pathogenic genes: PARK2
    Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, CALY, DRD1, DRD2, DRD3, DRD4, DRD5, HTR1A, HTR1B, HTR1D, HTR2A, HTR2B, HTR2C
    Metabolic genes:
    Substrate: COMT, CYP1A2 (minor), CYP2B6, CYP2C9 (minor), CYP2C19 (minor), CYP2D6, CYP3A4 (minor), CYP3A5, DDC, UGT1A1, UGT1A9, SULT1A1, SULT1A2, SULT1A3, SULT1E1, SULT1B1
    Inhibitor: CYP1A2 (weak), CYP2C19 (weak), CYP3A4 (weak)
    Transporter genes: SLC18A2
    Name: Amantadine
    IUPAC Name: Tricyclo[,7]decan-1-amine, hydrochloride
    Molecular Formula: C10H17NHCl
    Molecular Weight: 187.71 g/mol
    Mechanism: Antiparkinsonian activity may be due to inhibition of dopamine reuptake into presynaptic neurons or by increasing dopamine release from presynaptic fibers
    Effect: Antiparkinsonian agents, adamantanes, dopamine agonists
    Pathogenic genes: PARK2
    Mechanistic genes: CCR5, CXCR4, DRD1, DRD2, GRIN3A, CHRNA3, CHRNA4, CHRNA7
    Metabolic genes:
    Substrate: COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC, UGT1A1, UGT1A9
    Inhibitor: MAOB
    Transporter genes: SLC22A1 (Substrate/inhibitor), SLC22A2 (Substrate/inhibitor)

    Antidopaminergics and neurogenic dysphagia

    In a significant number of cases, the causes of ND can be induced or exacerbated by certain drugs[9-11]. Many patients with different neurological conditions are treated with antidopaminergic medication[10,11]. Adverse reactions are especially frequent in senescence and are relevant since they are reversible, and dysphagia may be the only or the predominant extrapyramidal symptom. Although it is recommended that drug intake be minimized as much as possible, this is not feasible in many cases. It is therefore recommended that the drug dose be adjusted to avoid the aforementioned side effects. Knowing the pharmacogenetic profiles of these drugs is, therefore, very important to therapeutic strategies[37] [Table 2].

    Table 2

    Pharmacogenetics of antidopaminergic drugs and the risk of neurogenic dysphagia

    Name: Haloperidol
    IUPAC Name: 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one
    Molecular Formula: C21H23ClFNO2
    Molecular Weight: 375.864223 g/mol
    Mechanism: Haloperidol is a butyrophenone antipsychotic which blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in brain. Depresses release of hypothalamic and hypophyseal hormones. Believed to depress reticular activating system
    Effect: Antipsychotic agent, Serotonergic antagonist, Dopaminergic antagonist, antiemetic, antidyskinesia agent, sedative effects, hypotension
    Pathogenic genes: ADRA1A, ADRA2A, ADRA2B, ADRA2C, BDNF, DRD1, DRD2, DRD3, DRD4, DTNBP1, GRIN2B, HTR2A
    Metabolic genes:
    Substrate: CBR1, CYP1A1 (minor), CYP1A2 (minor), CYP2A6, CYP2C8 (minor), CYP2C9 (minor), CYP2C19 (minor), CYP2D6 (major), CYP3A4/5 (major), CYP3A7, GSTP1, UGT1A9
    Inhibitor: CYP2D6 (moderate), CYP3A4 (moderate)
    Transporter genes: ABCB1 (substrate/inhibitor), ABCC1, KCNE1, KCNE2, KCNH2, KCNJ11, KCNQ1, SLC6A3
    Pleiotropic genes: CHRM2, FOS, GSK3B, HRH1, HTR2A, HTT, IL1RN
    Name: Sulpiride.
    IUPAC Name: N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulfamoylbenzamide
    Molecular Formula: C15H23N3O4S
    Molecular Weight: 341.42582 g/mol
    Mechanism: It is a selective antagonist at postsynaptic D2 and D3 receptors. It appears to lack effects on norepinephrine, acetylcholine, serotonin, histamine, or GABA receptors. It also stimulates secretion of prolactin.
    Effect: Antipsychotic agent, dopaminergic antagonist, antidepressant effect, antiemesis, sedation (> 600 mg/day), dopamine reuptake inhibition (< 200 mg/day), antiemesis, antimigraine effects, antivertiginous activity, prolactin-releasing stimulation
    Pathogenic genes: DRD2, DRD3, DRD4
    Mechanistic genes: DRD2, DRD3, DRD4, PRLH, CA2, CA3
    Metabolic genes:
    Substrate: CYP1A2, CYP2B1, CYP3As
    Inhibitor: BCHE, CYP1A2, CYP2B1, CYP3As
    Transporter genes: SLC22A1, SLC22A2, SLC47A1, SLC47A2, SLC22A3, ABCB1, ABCG2
    Name: Aripiprazole.
    IUPAC Name: 7-{4-[4-(2,3-dichlorophenyl) piperazin-1-yl]butoxy}-1,2,3,4-tetrahydroquinolin-2-one
    Molecular Formula: 448.38538 g/mol
    Molecular Weight: C23H27Cl2N3O2
    Mechanism: Partial agonist at the D2 and 5-HT1A receptors, and as an antagonist at the 5-HT2A receptor
    Effect: Antipsychotic agent, H1-receptor antagonist, serotonergic agonist
    Pathogenic genes: DRD1, DRD2, DRD3, DRD4, HTR1A, HTR2A, HTR2C
    Metabolic genes:
    Substrate: CYP1A2, CYP2A6, CYP2D6 (major), CYP3A4 (major), CYP2C8, CYP2C9, CYP2C19, CYP3A5, FMO3, UGT1A4
    Inhibitor: CYP2D6, CYP3A4, CYP2C19
    Transporter genes: ABCB1
    Name: Olanzapine.
    IUPAC Name: 5-methyl-8-(4-methylpiperazin-1-yl)-4-thia-2,9-diazatricyclo[,7]tetradeca-1(14),3(7),5,8,10,12-hexaene
    Molecular Formula: C17H20N4S
    Molecular Weight: 312.4325 g/mol
    Mechanism: It displays potent antagonism of serotonin 5-HT2A and 5-HT2C, dopamine D1-4, histamine H1 and α1-adrenergic receptors, moderate antagonism of 5-HT3 and muscarinic M1-5 receptors, and weak binding to GABA-A, BZD, and β-adrenergic receptors.
    Effect: Antipsychotic agent, GABA modulator, muscarinic antagonist, serotonin uptake inhibitor, dopaminergic antagonist, serotonergic antagonist, histamine antagonist, antiemetic activity
    Pathogenic genes: COMT, DRD1, DRD2, DRD3, DRD4, GRM3, HTR2A, HTR2C, LPL
    Metabolic genes:
    Substrate: COMT, CYP1A2 (major), CYP2C9, CYP2D6 (major), CYP3A4, CYP3A5, FMO1, FMO3, GSTM3, TPMT, UGT1A1, UGT1A4, UGT2B10
    Inhibitor: CYP1A2 (weak), CYP2C9 (weak), CYP2C19 (weak), CYP2D6 (weak), CYP3A4 (weak)
    Inducer: GSTM1, MAOB, SLCO3A1
    Transporter genes: ABCB1 (substrate/inhibitor), KCNH2, SLC6A2, SLC6A4, SLCO3A1
    Pleiotropic genes: APOA5, APOC3, GNB3, LEP, LEPR, LPL
    Name: Quetiapine
    IUPAC Name: 2-[2-(4-{2-thia-9-azatricyclo[,8]pentadeca-1(15),3,5,7,9,11,13-heptaen-10-yl}piperazin-1-yl)ethoxy]ethan-1-ol
    Molecular Formula: C46H54N6O8S2
    Molecular Weight: 883.08636 g/mol
    Mechanism: Antagonist at multiple neurotransmitter receptors: serotonin 5-HT1A and 5-HT2, dopamine D1 and D2, histamine H1, and adrenergic α1- and α2-receptors.
    Effect: Antipsychotic agent, Adrenergic antagonist, histamine antagonist, serotonergic antagonist, dopaminergic antagonist, sedative activity, orthostatic hypotension
    Pathogenic genes: ADRA2A, DRD1, DRD2, DRD4, HTR1A, HTR2A, RGS4
    Metabolic genes: Substrate: CYP2D6 (minor), CYP3A4/5 (major), CYP3A7,CYP2C19
    Transporter genes: ABCB1 (substrate/inhibitor), KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A, SLC6A2 (inhibitor)
    Name: Risperdone
    IUPAC Name: 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidin-4-one
    Molecular Formula: C23H27FN4O2
    Molecular Weight: 410.484483 g/mol
    Mechanism: Antagonist at multiple neurotransmitter receptors: serotonin 5-HT1A and 5-HT2, dopamine D1 and D2, histamine H1, and adrenergic α1- and α2-receptors.
    Effect: Antipsychotic agent, H1-receptor antagonist, dopaminergic antagonist, alpha-adrenergic antagonist, serotonergic antagonist, somnolence, orthostatic hypotension
    Pathogenic genes: ADRA2A, BDNF, COMT, DRD1, DRD2, DRD3, DRD4, GRM3, HTR2A, HTR2C, HTR7, PON1, RGS4
    Mechanistic genes: ADRA1A, ADRA1B, ADRA2B, ADRA2C, DRD1, DRD2, DRD3, DRD4, FOS, HRH1, HTR1A, HTR2A, HTR2C, HTR3A, HTR3C, HTR6, HTR7, NR1I2, STAT3
    Metabolic genes:
    Substrate: COMT, CYP2D6 (major), CYP3A4/5 (minor)
    Inhibitor: CYP2D6 (weak), CYP3A4 (weak)
    Inducer: MAOB
    Transporter genes: ABCB1 (substrate/inhibitor), KCNH2, SLC6A4
    Pleiotropic genes: APOA5, BDNF, RGS2
    Name: Chlorpromazine
    IUPAC Name: [3-(2-chloro-10H-phenothiazin-10-yl)propyl]dimethylamine
    Molecular Formula: C17H19ClN2S
    Molecular Weight: 318.86416 g/mol
    Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors in the brain. Has actions at all levels of CNS, particularly at subcortical levels; also acts on multiple organ systems. It also exhibits weak ganglionic blocking, has a strong α-drenergic blocking effect, and depresses the release of hypothalamic and hypophyseal hormones. Depresses the reticular activating system
    Effect: Antipsychotic agent, dopaminergic antagonist, antiemetic, anticholinergic effects, sedative effects, antihistaminic effects, anti-serotonergic activity, hypotension
    Pathogenic genes: BDNF, DRD1, DRD2, DRD3, DRD4, HTR2A
    Mechanistic genes: ADRA1A, ADRA1B, CHRM1, CHRM2, CHRM3, DRD1, DRD2, DRD3, DRD4, DRD5, HRH1, HRH4, HTR1A, HTR2A, HTR2C, HTR6, HTR7, KCNH2, SMPD1, CALM1
    Metabolic genes: Substrate: CYP1A2(minor), CYP2A6, CYP2C9, CYP2C19, CYP2D6(major), CYP3A (minor), FMO1, UGT1A3, UGT1A4
    Inhibitor:CYP1A2, CYP2D6(strong), CYP2C19, CYP2E1 (weak), CYP3A4, DAO, BCHE
    Inductor: CYP3A4
    Transporter genes: ABCB1 (substrate/inhibitor), ABCB11 (inhibitor), CFTR
    Pleiotropic genes: ACACA, BDNF, FABP1, LEP, NPY
    Name: Metoclopramide
    IUPAC name: 27. Benzamide, 4-amino-
    5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy-, monohydrochloride, monohydrate,
    Molecular formula: C14H22ClN3O2 HCl H
    Molecular Weight: : 354.2 g/mol
    Mechanism: Blocks dopamine receptors and (when given in higher doses) also blocks serotonin receptors in chemoreceptor trigger zone of CNS. Enhances response to acetylcholine of tissue in upper GI tract causing enhanced motility and accelerated gastric emptying without stimulating gastric, biliary, or pancreatic secretions. Increases lower esophageal sphincter tone
    Effect: Prokinetic agents, antiemetic
    Pathogenic genes: DRD2
    Mechanistic genes: DRD2, CHRM1, HTR4, HTR3A
    Metabolic genes:
    Substrate: CYP2D6 (minor), CYP3A4, CYP1A2 (minor)
    Inhibitor: CYP2D6 (strong)
    Transporter genes: ABCB1
    Pleiotropic genes: ACHE

    Antipsychotics, as antidopaminergic medications, are primarily metabolized through CYP1A2/2D6/3A4/2C19[47]. Of these, CYP2D6 is the most relevant because 40% of these neuroleptics are major substrates of this enzyme. CYP2D6, however, is associated with side effects. Other genes such as HTR2A, SLC18A2, GRIK3, and DRD2 are linked to extrapyramidal reactions[48]. Drugs that exert an antidopaminergic effect on DRD1 are of particular interest. In ND, DRD1 is the pathogenic gene that is involved in the pharmacogenomic response to haloperidol, aripiprazole, olanzapine, quetiapine, or risperdone. Other DRDs (not DRD1) pathogenic variants mediate the adverse effects of antipsychotic drugs such as sulpiride, domperidone, and metroclopramide, causing oropharyngeal dysphagia; this suggests that other dopamine- and non-dopamine pathways mediate blocking of the swallowing phase[37].


    Transient receptor potential (TRP) channel genes encode ion channels that are classified into two broad groups: (i) Group 1 includes TRPC (canonical), TRPV (vanilloid), TRPVL (vanilloid-like), TRPM (melastatin), TRPS (soromelastatin), TRPN (no mechanoreceptor potential C), and TRPA (ankyrin); (ii) Group 2 consists of TRPP (polycystic) and TRPML (mucolipin)[49]. Some of these targets represent a therapeutic strategy of interest for dysphagia by stimulating areas that evoke the swallowing reflex. Group 1 genes are the most relevant where TRPV1, TRPA1, and TRPM8, for example, are involved in stimulation of thermal sensitivity and the release of CGRP and inflammatory mediators[50]. These receptors are expressed on trigeminal, vagal, and glossopharyngeal nerve terminals; these nerves are critical in the swallowing process[51,52]. Three compounds of clinical relevance in ND that stimulate these receptors are capsaicin, piperine, and menthol. Capsaicin increases the frequency of spontaneous swallowing by stimulating TRPV1 receptors, piperine stimulates TRPV1/A1 receptors, and menthol stimulates TRPM8 receptors[53,54]. A recent meta-analysis revealed the effectiveness of TRP channel agonists in treating ND[55]. Capsaicin produces the highest therapeutic outcomes by lowering the risk of laryngeal penetration and pharyngeal residue and increasing bolus velocity[54]. Capsaicin also induces the release of SP, a neurotransmitter involved in amplifying the inflammatory response and nociceptive sensitization. Since DBH inhibits capsaicin, a pharmacogenetic study in patients with variants of interest is mandatory[37]. As mechanistic genes, TRPV1 Val585Ile and UCP2 -866 G/A variants correlate with the capsinoid therapeutic response[56]. All three, but mainly capsaicin, inhibit CYP group enzymes (CYP3A4, CYP2C9, and weak in CYP2D6). Furthermore, capsaicin and piperine inhibit CYP1A2[57]. In silico, piperine weakly inhibits CYP2D6 WT and CYP2D6*53[58]. Capsaicin and the other compounds, in addition to exhibiting large heterogeneity in their metabolic genes, exert anti-inflammatory effects by modulating pleiotropic genes such as TNF and ILs[37] [Table 3].

    Table 3

    Pharmacogenetics of other drugs in the treatment of neurogenic dysphagia

    Name: Capsaicin
    IUPAC name: 6-Nonenamide, (E)-N-[(4-hydroxy-3-methoxy-phenyl)
    Molecular Formula: C18H27NO3.
    Molecular Weight: 305.41 g/mol
    Mechanism: Induces release of substance P (main chemomediator of pain impulses from the periphery)
    from peripheral sensory neurons, depletes the neuron of substance
    P (after repeated stimulation), and prevents reaccumulation.
    Effect: Skin and Mucous Membrane Agents, local anesthetics, topical
    Pathogenic genes: DBH, MPO, BCHE, TACR2
    Mechanistic genes: TRPV1, PHB2, ABCB1, ACOX1, ACSL3, ALOX5, CFTR, F2, FOS, HTR1D, NOS3, NPC1, PPARA, TAC1, TGFB1, UCP2
    Metabolic genes:
    Substrate: GLU, CYP2E1 (minor), UGT1A1, UGT1A7, UGT1A9, UGT1A10, GSTP1
    Inhibitor: CYP3A4 (strong), CYP2C9, CYP2D6 (weak), PTGS2, MPO, CYP1A2 (strong), CYP1A2 (strong), CYP19A2 (strong), CYP2E1, DBH, BCHE
    Inductor: CYP1A1, CYP1A2
    Transporter genes: ABCB1
    Pleiotropic genes: TNF
    Name: Piperine
    IUAC name: (2E,4E)-5-(2H-1,3-Benzodioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one.
    Molecular Formula: C17H19NO3
    Molecular Weight: 285.34 g/mol
    Mechanism: An alkaloid isolated from the plant Piper nigrum that has a role as an NF-kappaB inhibitor, a plant metabolite, a food component, and a human blood serum metabolite. It is a member of benzodioxoles, an N-acylpiperidine, a piperidine alkaloid, and a tertiary carboxamide.
    Effect: Skin and mucous membrane agents, local anesthetics, topical
    Mechanistic genes: TRPV1, TRPA1, NR1I2, FOS
    Metabolic genes:
    Substrate: CYP1A1
    Inhibitor: CYP3A4, CYP2C9, CYP2D6 (weak)
    Transporter genes: ABCB1 (inhibitor)
    Pleiotropic genes: TNF, IL1B, IL6
    Name: Menthol
    IUPAC name: (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol
    Molecular Formula: C10H20O
    Molecular Weight: 156.26 g/mol
    Mechanism: A local anesthetic with counterirritant qualities, widely used to relieve minor throat irritation. Menthol also acts as a weak κ-opioid receptor agonist.
    Effect: Skin and mucous membrane agents, local anesthetics, topical
    Mechanistic genes: TRPM8, TOP1, FOS
    Metabolic genes:
    Substrate: CYP2A6
    Name: Imidapril
    IUPAC name: (4S)-3-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid;hydrochloride
    Molecular Formula: C2H27N3O6
    Molecular weight: 405,44 g/mol
    Mechanism: Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.
    Effect: Angiotensin-converting enzyme inhibitors
    Mechanistic genes: ACE, AGT, AGTR1, BDKRB2, CES1, CES2, NOS3
    Name: Lisinopril
    IUPAC name: L-Proline, 1-[N 2-(1-carboxy-3-phenylpropyl)-L-
    lysyl]-, dihydrate, (S)
    Molecular Formula: C21H31N3O52H2O
    Molecular Weight: 441.52 g/mol
    Mechanism: Competitive inhibitor of angiotensin-converting enzyme (ACE). Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.
    Effect: Angiotensin-converting enzyme inhibitors
    Mechanistic genes: ACE, ACE2, REN, AGT; BDKRB2, MMP3, NOS3, NPPA
    Metabolic genes:
    Substate: CYP3A4/5 (major)
    Name: Perindopril
    IUPAC name: 1H-Indole-2-carboxylic acid, 1-[2-[[1-(ethoxycarbonyl)butyl]amino]-1-oxopropyl]octahydro-, [2S-[1[R*(R*)],2α,3aβ,7aβ]]-
    Molecular Formula: C19H32N2O5 C4H11N
    Molecular Weight: 441.60 g/mol
    Mechanism: A prodrug for perindoprilat, which acts as competitive inhibitor of angiotensin-converting enzyme. Prevents c conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and causes an increase in plasma renin activity and reduction in aldosterone secretion.
    Effect: Angiotensin-converting enzyme inhibitors
    Mechanistic genes: SFRP4, ACE, AGT, AGTR1, MMP2, TGFB1
    Metabolic genes:
    Substate: BCHE
    Transporter genes: SLC15A1, SLC15A2
    Name: Levetiracetam
    IUPAC name: 1-Pyrrolidineacetamide, α-ethyl-2-oxo-, (α S)-
    Molecular Formula: C8H14N2O2
    Molecular Weight: 170.21 g/mol
    Mechanism: The precise mechanism by which levetiracetam exerts its antiepileptic effect is unknown and does not appear to derive from any interaction with known mechanisms involved in inhibitory and excitatory neurotransmission.
    Effect: Anticonvulsants, miscellaneous
    Mechanistic genes: SV2A, CACNA1B, MT-TK
    Metabolic genes:
    Unknown: CYP2D6, CYP3A4
    Transporter genes: ABCB1


    Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit substance P degradation[59]. These drugs reduce the cough threshold and subsequently can be used in aspiration prophylaxis; however, results from studies on perindopril, lisinopril, or imidapril are inconclusive[59-61]. Imidapril is effective in controlling dysphagia after stroke[30]. In one study, levetiracetam was beneficial to the recovery of dysphagia in post-stroke patients[62]. Several reports describe the usefulness of cough provocation tests with irritants (citric acid, tartaric acid, and mannitol) as a diagnostic tool[63-65], but it remains to be determined whether such agents are useful for treating dysphagia. Table 3 shows the pharmacogenetic profiles of other drugs used to treat ND[37]. It should furthermore be noted that drugs used to treat ND (including dopaminergic agonists) may influence neuroplasticity and axonal regrowth or sprouting to improve, for example, the level of consciousness that would facilitate swallowing[66].


    Few reports have linked other genes to dysphagia. However, the BDNF gene has been studied the most in this regard; the influence of the COMT gene on symptomatic dysphagia has been previously discussed[20]; rs6265 polymorphisms exert disparate effects on pharyngeal stimulation in healthy subjects[67] and appear to influence a better prognosis in swallowing after stroke or poor tolerance to esophageal electrostimulation in carriers of the Met allele[68-70]. Furthermore, a study with a large sample of elderly individuals showed that e4 homozygous APOE carriers have low swallowing evaluation scores[71]. Finally, The T allele of rs17601696 (parent gene FGFR2) is reported to be associated with ND[72].


    Together with strategies aimed at controlling ND, it is also important to manage those factors that may exacerbate symptoms and increase the risk of aspiration. Many patients with CNS conditions exhibit sialorrhea, hiccups, xerostomia, or reflux with swallowing difficulties. Prior to considering systemic drugs, it is recommended that local treatment or physical measures be initiated first [Table 4][37].

    Table 4

    Pharmacogenetics of drugs in associated symptoms and neurogenic dysphagia

    Name: Omeprazole
    IUPAC name: 1H-Benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]
    Molecular Formula: C17H19N3O3S
    Molecular weight: 345.42 g/mol
    Mechanism: Concentrates in acid conditions of parietal cell secretory canaliculi. Forms active sulfenamide metabolite which irreversibly binds to and inactivates hydrogen-potassium ATPase (proton or acid pump), blocking final step in secretion of hydrochloric acid. Acid secretion is inhibited until additional hydrogen-potassium ATPase is synthesized, resulting in prolonged duration of action. Suppresses H. pylori in duodenal ulcer and/or reflux esophagitis infected with organism.
    Effect: Antiulcer agents and acid suppressants, proton-pump inhibitors, substituted benzimidazole
    Mechanistic genes: ATP4A, AHR, ADH1C, ALDH3A1, AHR, ATP4A, ATP4B, CASR, CBR1, CFTR, CHRM3, FMO1, HRH2, MMP2, NR1I2, NR1I3, RRAS2, SNAP25,
    Metabolic genes:
    Substrate: CYP1A1, CYP2C8 (minor), CYP2C9 (minor), CYP2C18 (minor), CYP3A4 (major), CYP2C19 (major), CYP2A6 (minor), CYP2D6 (minor)
    Inhibitor: CYP1A2 (moderate), CYP2C9 (moderate), CYP2D6 (moderate), CYP3A4 (moderate), CYP2C19 (strong)
    Inducer: CYP1A1, CYP1A2, CYP1B1, CYP3A4, CYP2B6
    Transporter genes ABCG2 (inhibitor), ABCC3 (inducer), ABCB1, ABCC6 (substrate/inhibitor), ABCC6, UGT1A1
    Name: Pantoprazole
    IUPAC name: (1) 1H-Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]
    Molecular Formula: C16H15F2N3O4S. Molecular weight: 383.37 g/mol
    Action: Suppresses gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump
    Effect: Antiulcer agents and acid suppressants, proton-pump inhibitors, substituted benzimidazole
    Mechanistic genes: ATP4A, DDAH1, ABCC2, CASR, CHRM3, HRH2, IL1B, PPAs, SNAP25, SSTR2
    Metabolic genes:
    Substrate: CYP3A4 (major), CYP2C19, CYP2C19 (major), CYP2D6 (minor), SULTs, UGTs
    Inhibitor: CYP2C19 (strong),CYP1A2 (weak), CYP2C9 (moderate), CYP2D6 (weak), CYP3A4 (moderate)
    Inducer: CYP1A2, CYP3A4
    Transporter genes: ABCB1 (substrate/inhibitor), ABCG2 (substrate/Inhibitor), SLC22A8 (inhibitor)
    Name: Lansoprazole
    IUPAC name: 1H-Benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-
    Molecular Formula: C16H14F3N3O2S
    Molecular Weight: 369.36 g/mol
    Mechanism: Decreases acid secretion in gastric parietal cells through inhibition of (H +, K +)-ATPase enzyme system, blocking final step in gastric acid production
    Effect: Antiulcer agents and acid suppressants, proton-pump inhibitors, substituted benzimidazole
    Mechanistic genes: ATP4A; CASR, MAPT, CYP1A1, CYP1B1, HRH2, SNAP25, SSTR2
    Metabolic genes:
    Substrate: CYP2C8 (major), CYP2C9 (major), CYP2C18 (major), CYP2C19 (major), CYP3A4/5
    (major); POR
    Inhibitor: CYP2C9, (moderate), CYP2C19 (strong), CYP3A4 CYP2D6 (moderate), CYP2E1 (moderate), CYP3A4 (moderate), PPA1
    Inducer: CYP1A2, CYP1A1, CYP1B1, CYP2C9, CYP3A4
    Transporter genes: ABCG2 (inhibitor), ABCB1 (substrate/inhibitor), SLC22A8 (inhibitor), SLC22A1, SLC22A2, SLC22A3
    Name: Rabeprazole
    IUPAC name: 1H-Benzimidazole, 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]
    Molecular Formula: C18H20N3NaO3S
    Molecular weight: 381.42 g/mol
    Action: Suppresses gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump
    Effect: Antiulcer agents and acid suppressants, proton-pump inhibitors, substituted benzimidazole
    Mechanistic genes: ATP4A, DDAH1, ATP4B, CASR, CHRM3, HRH2, HTR1D, NR1I2, SNAP25, SSTR2
    Metabolic genes:
    Substrate: CYP3A4 (major), CYP2C19 (major), CYP2D6 (major)
    Inhibitor: CYP2C9 (moderate), CYP2C8 (moderate), CYP2C19 (strong), CYP2D6 (moderate)
    Transporter genes: ABCB1 (substrate/
    inhibitor), ABCG2 (substrate/inhibitor), SLC22A8 (inhibitor)
    Name: Famotidine
    IUPAC name: Propanimidamide, N’-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]-
    Molecular formular: C8H15N7O2S3
    Molecular weight: 337.45 g/mol
    Action: Famotidine works by reducing the amount of acid in the stomach, thereby reducing pain and allowing the ulcer to heal, and through a competitive inhibition of histamine at H2 receptors of gastric parietal cells, which inhibits gastric acid secretion.
    Effect: Antiulcer agents and acid suppressants, histamine H2-antagonists
    Pathogenic genes: HRH2
    Mechanistic genes: HRH2, CAT, FOS
    Metabolic genes:
    Inhibitor: CYP1A2
    Transporter genes: SLC22A6, SLC22A8 (Substrate/inhibitor), SCL22A2 (Inhibitor), SLC47A1 (Inhibitor)
    Name: Pilocarpine
    IUPAC name:. 2(3H)-Furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl]-, monohydrochloride, (3S-cis)-
    Molecular Formula: C11H16N2O2
    Molecular weight: 244.72 g/mol
    Mechanism: Directly stimulates cholinergic receptors in eye causing miosis (by contraction of iris sphincter) and loss of accommodation (by constriction of ciliary muscle) and lowering of intraocular pressure (with decreased resistance to aqueous humor outflow)
    Effect: Antiglaucoma agents, miotics, cholinergic agonists
    Pathogenic genes: BDNF
    Mechanistic genes:CHRM3,CHRM1, CHRM2, CHRM4 BDNF; CHRNs; FOS; GRIA3
    Metabolic genes: Substrate: CYP1A2 (minor), CYP2C9 (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (minor)
    Inhibitor: CYP2A6, CYP3A4 (weak), CYP2A6 (weak), CYP2E1 (weak)
    Name: Amitriptyline
    IUPAC Name: dimethyl(3-{tricyclo[,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}propyl)amine
    Molecular Formula: C20H24ClN
    Molecular Weight: 313.86426 g/mol
    Mechanism: Increases synaptic concentration of serotonin and/or norepinephrine
    in the central nervous system by inhibiting their reuptake in the presynaptic
    neuronal membrane
    Effect: Adrenergic uptake inhibition, antimigraine activity,
    analgesic (nonnarcotic) activity, antidepressant action
    Pathogenic genes: ABCB1, GNB3, HTRs, NTRK2, SLC6A4, TNF
    Mechanistic genes: ADRA1A, ADRA1B, ADRA1D, ADRA2A, HTRs, HRH1, HRH2, HRH4, SIGMAR1, NTRK1, NTRK2, OPRD1, OPRK1, OPRM1
    Metabolic genes: Substrate: CYP1A2 (minor), CYP2B6 (minor), CYP2C8, CYP2C9 (minor), CYP2C19 (minor), CYP2D6 (major), CYP3A4/5 (major), GSTP1, UGT1A3, UGT1A4, UGT2B10
    Inhibitor: CYP1A2 (moderate), CYP2C9 (moderate), CYP2C19 (moderate), CYP2D6 (moderate), CYP2E1 (weak)
    Transporter genes: ABCB1 (substrate/inhibitor), ABCC2 (inhibitor), ABCG2 (inhibitor), KCNA1, KCNE2, KCNH2, KCNQ1, KCNQ2, KCNQ3, SCN5A, SLC6A2, SLC6A4
    Pleiotropic genes: FABP1, GNAS, GNB3, NTRK1, TNF
    Name: Scopolamine
    IUPAC Name: Benzeneacetic acid,
    α-(hydroxymethyl)-, 9-methyl-3-oxa-9-azatricyclo[,4]non-7-yl ester, hydrobromide, trihydrate,
    Molecular Formula: C17H21NO4HBr3H2O
    Molecular weight: 438.31 g/mol
    Mechanism: Competitively inhibits acetylcholine and other cholinergic stimuli at autonomic effectors innervated by postganglionic cholinergic nerves and, to a lesser extent, on smooth muscles that lack cholinergic innervation. Doses used to decrease gastric secretions likely to cause dryness of mouth (xerostomia). Antagonizes histamine and serotonin
    Effect: Anticholinergic agents, antimuscarinics/antispasmodics
    Mechanistic genes: CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, CHRNA4, CHRNB2, SI
    Metabolic genes: Substrate:CYP3A4
    Name: Glycopyrrolate
    IUPAC Name: Pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-, bromide
    Molecular Formula: C19H28BrNO3 Molecular Weight: 398.33 g/mol
    Mechanism: Blocks action of acetylcholine at parasympathetic
    sites in smooth muscle, secretory glands, and CNS
    Effect: Anticholinergic agents, antimuscarinics/antispasmodics
    Mechanistic genes: CHRM1, CHRM2, CHRM3, CHRM4, CHRM5
    Metabolic genes: Substrate: CYP1A2, CYP2B6, CYP2C9, CYP2D6,CYP2C18, CYP2C19, CYP3A4
    Transporter genes: SLC22A2, SLC47A1
    Name: Trihexyphenidyl
    IUPAC Name: 1-Piperidinepropanol,α-cyclohexyl-α-phenyl
    Molecular Formula: C20H31NO
    Molecular Weight: 301,46 g/mol
    Mechanism: Exerts direct inhibitory effect on parasympathetic nervous system. It also has a relaxing effect
    on smooth musculature, exerted both directly on muscle itself and indirectly through parasympathetic nervous system (inhibitory effect)
    Effect: Antiparkinsonian agents, anticholinergic agents
    Pathogenic genes: PARK2
    Mechanistic genes: CHRM1, CHRM2, CHRM3, CHRM4, CHRM5
    Name: Atropine
    IUPAC Name: Benzeneacetic acid, α-(hydroxymethyl)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-(–)
    Molecular Formula: C17H23NO3
    Molecular Weight: 289.37 g/mol
    Mechanism: Blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and CNS. Increases cardiac output, dries secretions. Reverses the muscarinic effects of cholinergic poisoning
    Effect: Mydriatics, anticholinergic agents, antimuscarinics/antispasmodics, antidote
    Mechanistic genes: CHRM1, CHRM2; CHRM3, CHRM4, CHRM5, CHRNA4, CHRNB2, FOS, GLRA1, PTGS2, TP53
    Transporter genes: ABCB11
    Pleiotropic genes: ACHE, CES1
    Name: Domperidone
    IUPAC name: 2H-Benzimidazol-2-one, 5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydro-
    Molecular Formula: C 22H24ClN5O2
    Molecular weight: 425.91 g/mol
    Mechanism: Has peripheral dopamine receptor blocking properties. Increases esophageal peristalsis; lowers
    esophageal sphincter pressure, gastric motility, and peristalsis; and enhances gastroduodenal coordination, therefore facilitating gastric emptying and decreasing small bowel transit time
    Effect: Prokinetic agents, dopamine antagonist
    Pathogenic genes: DRD2, DRD3
    Mechanistic genes: DRD2, DRD3
    Metabolic genes: Substrate: CYP3A5 (major), CYP3A7, CYP3A4 (major), CYP1A2 (minor), CYP2B6 (minor), CYP2C8 (minor), CYP2D6 (minor), CYBs (major)
    Transporter genes: ABCB1
    Name: Baclofen
    IUPAC name: Butanoic acid, 4-amino-3-(4-chlorophenyl)-
    Molecular Formula: C10H12ClNO
    Molecular weight: 213.66 g/mol
    Mechanism: Inhibits the transmission of mono/polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization of primary afferent fiber terminals
    Effect: GABA-derivative skeletal muscle relaxants
    Mechanistic genes: GABBR1, GABBR2, CXCR4, CFTR
    Transporter genes: ABCC9, ABCC12, SLC28A1


    The most used treatments for the control of hypersalivation in patients with neurological damage are based on their anticholinergic profiles. This includes a heterogeneous group of drugs such as amitriptyline, scopolamine, glycopyrronium chloride, trihexyphenidyl, atropine, or thiopium bromide. These anticholinergic agents present an added benefit in the control of other motor symptoms, as occurs in patients with Parkinson’s disease[73]. However, their main drawback is the occurrence of frequent side effects that include sedation, cognitive deficits, constipation, urinary retention, tremor, and blurred vision. Within a population where the prevalence of dementia is high, elderly patients often use drugs with anticholinergic effects, and frequently in combination. Furthermore, in this patient population, polymedication may mask symptoms that are misdiagnosed as pathology unrelated to drug toxicity[74].

    Concerning the pharmacogenetic profile, anticholinergic drug exposure shows associated variants located at chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene[75]. Subjects with CYP2D6/CYP2C19 PM phenotype increase the risk of adverse reactions due to increased serum drug concentrations[76]. In contrast, polymorphisms of the ARGEF10, ADRB3, ROCK2, and CYP3A4 genes in the cholinergic pathway do not appear to significantly modify parameters related to clinical improvement[77].


    The first line of treatment for xerostomia is to employ local therapies (artificial saliva, sialogogues), avoiding the use of systemic medications (pilocarpine) as the first choices due to their common negative effects. Side effects include blurred vision, bronchoconstriction, hiccup, sweating, hypotension, bradycardia, cutaneous vasodilatation, nausea, diarrhea, or increased urinary frequency[78]. 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*10[79].

    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[80]. CYP2C19 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 observed with CYP3A4, but to a lesser degree[82].


    Pharmacologically, multiple drugs with different targets are available to control hiccups. Baclofen is a drug commonly used in intractable hiccups[85]. The ABCC9 SNP (rs11046232, heterozygous AT versus reference TT genotype) is associated with a two-fold increase in oral baclofen clearance[86]. Allelic variants with the ABCC12, SLC28A1, and PPARD SNPs generate variable responses in cerebral palsy[86]. 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[87]. Paradoxically, metoclopramide and other antidopaminergic drugs may be 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].


    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.



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

    Authors’ contributions

    Made substantial contributions to conception and design of the review and interpretation: Guerra J

    Read, adjusted and approved the final manuscript: Naidoo V, Cacabelos R

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship


    Conflicts of interest

    All authors declared that there are no conflicts of interest.

    Ethical approval and consent to participate

    Not applicable.

    Consent for publication

    Not applicable.


    © The Author(s) 2022.


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    Cite This Article

    OAE Style

    Guerra J, Naidoo V, Cacabelos R. Neurogenic dysphagia: current pharmacogenomic perspectives. J Transl Genet Genom 2022;6:304-21.

    AMA Style

    Guerra J, Naidoo V, Cacabelos R. Neurogenic dysphagia: current pharmacogenomic perspectives. Journal of Translational Genetics and Genomics. 2022; 6(3):304-21.

    Chicago/Turabian Style

    Guerra, Joaquin, Vinogran Naidoo, Ramón Cacabelos. 2022. "Neurogenic dysphagia: current pharmacogenomic perspectives" Journal of Translational Genetics and Genomics. 6, no.3: 304-21.

    ACS Style

    Guerra, J.; Naidoo V.; Cacabelos R.  Neurogenic dysphagia: current pharmacogenomic perspectives. J. Transl. Genet. Genom.  20226, 304-21.




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