5-Hydroxytryptamine receptor antagonists

PONV may be successfully prevented or treated by administering 5-hydroxytryptamine type 3 (5-HT₃)-receptor antagonists[18]. This finding, together with the fact that the activation of 5-HT₃ receptors on vagal gastrointestinal afferents or in the central chemoreceptor trigger zone may provoke acute emesis, indicates an involvement of the serotonin system in the pathogenesis of PONV[19,20]. There are several 5-HT₃ receptor genes (5-HT₃ A–E) with high sequence homology[21,22]. In particular, the genes for the subunits 5-HT₃A (HTR3A) and 5-HT₃B (HTR3B) are located close together on chromosome 11q23.1. The 5-HT₃B subunit is considered to be effective only in conjugation with the 5-HT₃A subunit and may specifically modify its function. Both subunits are coexpressed in diverse cerebral and intestinal regions and appear to form the 5-HT₃ receptor as a heteromeric complex[23–27].

The contribution of HTR3A and HTR3B polymorphisms, as they relate to nausea and vomiting, has been examined in a cohort of patients undergoing cancer chemotherapy, where it was demonstrated that patients who were homozygous for the 100_02 AAG deletion in the noncoding promoter region of the HTR3B gene experienced vomiting more frequently whilst receiving chemotherapy[28,29]. A pilot study investigated both HTR3A and HTR3B genes for genetic variants in a cohort of postoperative vomiting (POV) patients after general anesthesia. This study identified 16 different variants in the HTR3A gene and 19 in the HTR3B gene, reflecting a remarkable genetic heterogeneity. The HTR3A variant c1377A>G was associated with a significantly higher risk for POV and the HTR3B variants c5p+201_+202delCA and c6-137C>T were associated with a lower risk for POV. However, all significant genetic variants were located in noncoding regions of their respective genes. The study concluded that genetic variations in the HTR3A and HTR3B genes may be associated with the individual risk of developing POV[30].

Additionally, a study addressing the effects of HTR3A and HTR3B gene polymorphisms on nausea induced by the drug paroxetine in 78 Japanese psychiatric patients[31] demonstrated that the Tyr129Ser polymorphism of the HTR3B gene significantly increased the risk of nausea. They also reported that HTR3A gene polymorphisms and the CYP2D6 gene polymorphisms had no significant effect on the incidence of nausea in this cohort.

In 2013, a study investigated whether common genomic variations of the A and B subunits of HTR3 affect the incidence of POV in a Chinese Han population undergoing gynecological surgery[32]. Five SNPs in HTR3A and HTR3B were identified and one of these (rs3758987 in HTR3B) was statistically associated with an increased risk of vomiting. It was therefore concluded that the HTR3B rs3758987 SNP might serve as a predictor of POV.

Cytochromes

The cytochrome P450 (CYP450) family contains the most important phase I drug- metabolizing enzymes. All currently used 5-HT₃ antagonists are metabolized via cytochrome P450 enzymes. CYP2D6 is responsible for the majority of the metabolism of dolasetron and tropisetron[33] and partially responsible for the metabolism of ondansetron, which is also broken down by the enzymes CYP3A4, CYP2E1 and CYP1A2[34]. In contrast, granisetron is primarily metabolized by CYP3A4, with no contribution from CYP2D6[35]. Of the various CYP enzymatic pathways, CYP2D6 has gained much attention in relation to 5-HT₃ antagonists. The variable clinical response seen with the 5-HT₃-receptor antagonists may be explained by polymorphisms of the gene encoding for the CYP2D6 enzyme.

There are over 100 CYP2D6 allelic variants identified; however, there are basically four metabolizer states: poor metabolizers (PM) who have two inactive genes and have no enzymatic activity; intermediate metabolizers (IM) who have less than normal activity, usually one inactive and one low activity gene; extensive metabolizers (EM) who have one to two wild-type genes; and ultrarapid metabolizers (UM) who possess more than two wild-type genes and increased enzymatic activity[36]. UMs have a duplication or amplification of the entire CYP2D6 gene, resulting in increased enzyme production.

The 5-HT-receptor antagonists have revolutionized PONV. These agents have a high efficacy with a low incidence of adverse effects. Unfortunately, not every patient has a beneficial response when treated. This failure to respond seems in part to be due to interindividual genetic variations in the CYP2D6 gene or other as-yet-uncharacterized variations[37].

One study demonstrated that patients with three active copies of the CYP2D6 gene (UMs) who received tropisetron for the treatment of chemotherapy-induced nausea and vomiting (CINV) had a significantly higher mean number of vomiting episodes than EMs or PMs. In addition, the effects for the CYP2D6 UMs were similar for those treated with tropisetron or ondansetron[38].

Failure to respond to ondansetron prophylaxis was also investigated in a recent study on PONV[37]. Patients who possessed three functional copies of the CYP2D6 allele were more likely to experience vomiting, but not necessarily nausea, in the postoperative period despite the prophylactic administration of ondansetron. The fact that vomiting, but not nausea, increased significantly is not unexpected because ondansetron has previously been shown to be a better antiemetic than antinausea agent[39]. Similar findings were reported in two additional studies in which the efficacy of granisetron and dolasetron in preventing PONV were investigated[40,41]. Subjects receiving dolasetron, and who were carriers of the duplication of the CYP2D6 allele, had more frequent vomiting episodes than patients in the granisetron group (granisetron is not metabolized by CYP2D6). Another study in 92 surgical patients indicated that those who possessed three or greater active CYP2D6 alleles (and were thus classified as UMs) had reduced ondansetron plasma concentrations compared to those subjects that had zero to two active alleles[42]. The involvement of the CYP2D6 system in PONV was further confirmed by a study that presented data from trauma patients where it was noted that patients classified as PM had less PONV compared to patients with the EM genotype [43,44].

CYP450 enzyme synthesis may be stimulated or suppressed by environmental influences. Some experts have speculated that the protective effect of smoking against PONV might be related to the induction of CYP450 enzymes by polycyclic aromatic hydrocarbons[45]. These hydrocarbons are components of the “tar” portion of cigarette smoke. Other clinical characteristics that affect CYP450 enzyme expression, for example, the consumption of alcohol or commonly prescribed medications such as cimetidine, erythromycin or terfenadine, or vegetables like cabbage, brussels sprouts, cauliflower or red peppers, could be investigated as potential PONV risk factors.

Diagnostic tests to identify CYP2D6 isoenzyme activity are currently available for clinical use. The AmpliChip CYP450 (Specialty Laboratories, Valencia, CA, USA) is one such test that has been approved by the US Food and Drug Administration. Studies performed so far suggest that antiemetic treatment for POV could be made more efficacious by selecting a 5-HT₃ antagonist and/or another class of antiemetic drugs that is consistent with the patient’s CYP2D6 genotype. Specifically, patients that are UMs might benefit from the use of granisetron or an antiemetic that is not metabolized by CYP2D6. This is currently only a theoretical concept since the cost of running such a test far exceeds the cost of using several different antiemetic drugs at the same time. Overall, the cost-effectiveness of pharmacogenomics has not been evaluated, especially for PONV.

The frequency of CYP2D6 metabolizer states tends to vary by ethnicity. Approximately 5–10% of Caucasians are PMs and completely lack CYP2D6 activity, while approximately 2% of Caucasians are categorized as UMs with more than two active genes as a result of a duplication or even a several-fold amplification of the CYP2D6 gene. Some Hispanic groups may have an increased frequency of UMs, ranging from approximately 5% to 10%. The highest frequency of UMs appears to exist in ethnic groups originating in parts of Northern Africa and the Middle East. In general, given the low frequency of ultrarapid CY2D6 metabolizers in the general US population, the number needed-to-treat for PONV may be as high as 50[46] (this means that 50 patients would have to be genotyped to prevent one patient from vomiting).

Cholinergic muscarinic receptor type 3 polymorphism

The muscarinic acetylcholine receptors including M₃, encoded by the cholinergic muscarinic receptor type 3 (CHRM3) gene, have been associated with the emetic pathway and opioid-induced nausea/vomiting[47]. This is indicated by the fact that M₃ muscarinic antagonists impede motion sickness and opioid-induced nausea/vomiting[48]. The involvement of another SNP, in the promoter region of CHRM3 (rs2165870), was also recently confirmed to be predictive of PONV susceptibility by both a genome-wide association study in a Caucasian population[49] and a targeted genomic association study in Japanese patients[50].

Dopamine receptor polymorphism

Dopamine receptors, specifically D2 and D3, are known to play a role in nausea and emesis, most likely through inhibition of adenylate cyclase[47], which alters the amount of cyclic adenosine 3′-5′-monophosphate within neurons located in the nucleus of the solitary tract and the area postrema[51]. The competitive antagonism of D2, and possibly D3 receptors, provides an explanation for the antiemetic activity of metoclopramide, droperidol, as well as other D2-receptor antagonists. A study performed in a Japanese population showed that the dopamine type 2 receptor (DRD2) Taq1A polymorphism had a moderate strength of association with the occurrence of early PONV[52].

Mu-opioid receptor

Due to the direct association of opioids with the incidence and severity of PONV in surgical patients, a significant number of previous pharmacogenomics investigations have focused on polymorphisms in the mu-opioid receptor (MOR) gene (OPRM1), which serves as the main target of all clinically used opioid agonists. The major target of these investigations has focused on the common, nonsynonymous polymorphism in OPRM1–A118G (rs179991). The results and conclusions from the studies published so far remain controversial. Two studies reported a higher incidence of PONV in patients who were homozygous (AA) variants[53]. This trend was confirmed by another study from 2008 in postcesarean section patients, which showed that subjects who carried the AA (wild-type) for A118G had a significantly higher rate of PONV, despite a lower consumption of morphine postoperatively[54].

Other studies have not confirmed an association between the A118G polymorphism and the incidence of PONV[40,41,44]. A Chinese study investigated the association of OPRM1 A118G and the variability of nausea and vomiting from fentanyl analgesia in patients undergoing a total abdominal hysterectomy or myomectomy. They concluded that OPRM1 A118G had no effect on the individual frequency of PONV or the side effects of fentanyl in Chinese women undergoing gynecologic surgery[55].

The association of the A118G SNP was also recently questioned in a study that directly investigated whether this polymorphism was protective for PONV associated with intravenous patient-controlled opioid analgesia (IV-PCA)[56]. The study found that A118G was not protective against IV-PCA morphine-induced nausea or vomiting. In a recent meta-analysis, six clinical studies were included with a total of 838 women who received epidural analgesia with fentanyl during labor[57]. The meta-analysis indicated that there were no statistically significant differences between an AA homozygote and a G carrier (AG + GG) as it relates to the incidence of nausea and vomiting.

A Japanese double-blinded study of 85 adult patients scheduled to undergo major elective surgery was performed to determine the genotypes and haplotypes of several SNPs in the OPRM1 gene and their association with PONV during the early postoperative period for patients receiving fentanyl PCA. One out of the eight investigated SNPs rs9397685, in the intronic part of the OPRM1 gene, was associated with differences in the occurrence and severity of PONV. Four common haplotypes were identified. PONV severity in patients with the GGGAACGC haplotype was significantly lower than in carriers of other haplotypes[58].

ATP-binding cassette, subfamily B, member 1

The ATP-binding cassette, subfamily B, member 1 (ABCB1) drug transporter (also known as P-glycoprotein or multidrug resistance 1) is a transmembrane efflux pump found in many tissues, including the blood–brain barrier[59]. The ABCB1 protein transporter recognizes a broad range of substrates, including the 5-HT₃-receptor antagonists. A study investigated whether the 2677G>T/A and 3435C>T polymorphisms in the ABCB1 gene influenced the efficacy of ondansetron in preventing PONV in patients undergoing general anesthesia[60]. The incidence of PONV was lower in patients with the 2677TT variant during the first 2 h after surgery. There were no significant differences in the incidence of PONV between the different genotype groups during the period between 2 and 24 h after surgery. The authors concluded that the ABCB1 genotypes may be a clinical predictor of responsiveness for ondansetron. Another study investigated the association of several genomic factors, including ABCB1 polymorphisms with PONV[61]. The homozygous ABCB1 diplotype (GG-CC) conferred an odds ratio of 0.12 with regard to the need for curative antiemetic treatment with ondansetron for PONV. When the association between the ABCB1 and mu-opioid genes and adverse opioid drug reactions to oxycodone[62] were evaluated, it was noted that nausea and vomiting were more pronounced in the ABCB1 wild-type genotype carriers (3435CC and 2677GG) when compared with the variant allele carriers (3435CT, 3435TT, 2677GT and 2677TT).

In 2011, an Indonesian study with cancer patients investigated the use of ondansetron and dexamethasone for the prophylaxis of CINV. Multiple SNPs for ABCB1 (rs1045642, rs2032582 and rs1128503), 5-HTR3B (rs45460698, rs4938058 and rs7943062) and CYP2D6 ([rs16947-CYP2D6 2], [rs3892097-CYP2D6 4] and [rs1065852-CYP2D6 10]) were evaluated using Taqman assays. Carriers of the CTG haplotype of the ABCB1 gene experienced CINV more often than other haplotypes in the delayed phase. No associations were found with the 5-HTR3B receptor haplotypes and CYP2D6-predicted phenotypes[63].

A SNP at position 3435 in the gene for the ABCB1 transporter was recently demonstrated to affect the antiemetic efficacy of 5-HT₃-receptor antagonists. Cancer patients undergoing chemotherapy were given prophylactic granisetron, ondansetron or tropisetron, and the incidence of nausea, vomiting and the need for rescue antiemetics was examined. Patients who were homozygous for the ABCB1 3435T allele responded better to antiemetic therapy compared with individuals who were heterozygous or homozygous for the ABCB1 3435C allele. This difference reached statistical significance in the granisetron-treated group[64]. It is possible that patients with the TT genotype accumulate higher concentrations of 5-HT₃-receptor antagonists in the brain and are better protected from emesis as a result of enhanced activity of the ABCB1 transporter.

Catechol-O-methyltransferase

Catechol-O-methyltransferase (COMT) is an enzyme that acts as a key modulator of the dopaminergic and adrenergic system. COMT polymorphisms may influence nausea and vomiting as the COMT enzyme modulates neurotransmission by metabolizing the catecholamine dopamine. Blocking dopamine D2 receptors in the area postrema and vomiting center has an antiemetic effect, and enhanced dopaminergic activity in patients receiving COMT inhibitors can lead to increased nausea and vomiting. The SNP rs4680 (G472A) in the COMT gene is a missense variant leading to an amino acid exchange (Val158Met)[65]. In patients with migraines without aura, those with the Met-allele (L allele) had an increased incidence of nausea and vomiting, most likely due to the elevated levels of dopamine[66]. A study investigated whether combined COMT and mu-opioid receptor polymorphisms contribute to the morphine response in postoperative analgesia and PONV[67]. Patients received general anesthesia and were screened for the mu-opioid receptor polymorphism A118G (Asn40Asp) and the COMT G1947A (Val158Met) polymorphism. Heterozygous patients with mu-opioid receptor A118G and COMT G1947A mutations presented nausea scores that were significantly lower when compared with homozygous patients.

Neurokinin type 1 (substance P) receptors

Over 500 patents for neurokinin type 1 (NK₁)-receptor antagonists have been filed during the last 20 years, demonstrating the pharmaceutical industry’s interest in these agents[68]. Currently in the US there are two NK₁ receptor antagonists that have been shown to be safe and effective for the prevention of PONV in humans, aprepitant (EMEND)[69] and rolapitant[70].

Several preliminary reports (mostly in the abstract form) have attempted to determine the genetic influence of SNPs in the tachykinin receptor 1 (TACR1) gene, which encodes for the NK₁ receptors. In a study addressing lower abdominal surgery, it was observed that the SNP rs3755468 in the TACR1 gene was associated with an increase in the incidence and severity of PONV in female patients. Female gender and wild-type homozygote carriers of the rs3755468 SNP were identified as independent predictors of severe PONV. The odds ratios for the two factors were 6.95- and 4.83-fold higher, respectively. The rs3755468 SNP in the TACR1 gene appears to be associated with the gender difference in PONV and is located within the predicted estrogen response element and a DNase I hypersensitivity site[71].

A recent review of multiple trials of NK₁-receptor antagonists for treatment of emesis confirmed their effectiveness but also revealed that use may be associated with increased rates of infection, suggesting that ongoing safety assessment is required[72].