Ondansetron

Ondansetron was the first serotonin antagonist marketed[1]. Ondansetron is available for administration by oral or intravenous (IV) route. The compound is a carbazole derivate, structurally related to serotonin and metoclopramide[2]. The drug is available as a racemic mixture, which contains the S (+) and R (−) stereoisomers. Both isomers display a high affinity for the 5-hydroxytryptamine type 3 (5-HT₃) receptor[3]. However, the agent demonstrates non-5-HT₃ receptor-specific binding: 5-HT1B, 5-HT1C, alpha-1-adrenergic and opioid receptors. Non-5-HT₃ receptor binding accounts for 20% of the total binding. Thus, ondansetron is less selective in receptor binding compared to other 5-HT₃ receptor antagonists; chemical structure and/or metabolism may contribute to this difference in binding affinity. This property may be an asset to ondansetron treatment in view of emesis being due to more than 5-HT₃ receptor activation. In humans, the R-isomer, administered in isolation, presents a better safety profile and antiemetic efficacy compared with the racemic mixture[4,5].

In humans, ondansetron is extensively and rapidly metabolized. Five percent of the parent compound is recovered in urine, and hepatic metabolism accounts for 95% of ondansetron clearance[6]. Hydroxylation at the indole ring followed by conjugation is the major route of metabolism. A minor route of metabolism is N-demethylation. Due to first-pass metabolism, drug bioavailability is approximately 56% and the beta elimination is 3.7–4.7 h following oral administration. Multiple cytochrome P450 (CYP450) enzymes are involved in ondansetron metabolism: CYP1A1, CYP1A2, CYP2D6 and the CYP3A subfamily[7]. Patients with genetic polymorphism of the CYP2D6 allele metabolize ondansetron at an ultrarapid rate[8]. As a result, an increased incidence of prophylactic postoperative nausea and vomiting (PONV) therapy failure with ondansetron is found in this patient population[9].

Some of the nonconjugated metabolites possess pharmacologic activity; however, contribution to the biological activity of ondansetron is minimal due to low plasma concentrations. Volume of distribution remains unchanged with increasing age, whereas clearance decreases[6]. Gender differences are slightly present: plasma clearance is slower in females. Although the cause for such a difference is unclear, a slower plasma clearance in females may be beneficial, considering the increased likelihood of developing PONV in females[10].

In humans, the predominant route of excretion is via the urine[11]. No effect on ondansetron pharmacokinetics was found in patients with renal impairment[12]. Patients with hepatic insufficiency had significantly decreased clearance at a degree analogous to the extent of hepatic impairment[13]. In children, ondansetron displayed pharmacokinetics similar to adults[14].

Clinical findings of ondansetron in antiemetic treatment for chemotherapy- and radiation-induced emesis were followed by the application of the medication for the treatment of PONV. In a meta-analysis including 7,177 patients receiving ondansetron prophylaxis and 5,712 receiving placebo or no treatment, the investigators found that out of 100 surgical patients receiving adequate prophylactic dose of ondansetron, treatment would prevent 20 episodes of postoperative vomiting[15]. In the prevention of PONV, a 1-mg dose administered intravenously was not significantly different from placebo and increasing the dose beyond 8 mg did not further improve efficacy[16]. In contrast, in a nauseated or vomiting patient, 1 mg IV ondansetron was more efficacious than placebo in preventing further episodes of nausea or vomiting. Nevertheless, the results suggested no evidence of a clinically relevant dose–response between 1 and 8 mg.

A cost-effectiveness analysis demonstrated that prophylaxis with effective doses (i.e., 4 or 8 mg) was less cost-effective and less safe than treatment of PONV with effective doses (i.e., 1 or 4 mg)[17]. The aforementioned results might not be applicable now as ondansetron is currently a generic drug. Prophylactic IV administration at the end of surgery compared to before induction of anesthesia was associated with lower nausea scores, earlier intake of normal food, decreased incidence of frequent emesis (more than two episodes) and increased emesis-free time during the first 24 h postoperatively[18]. Half-life may explain these differences in clinical efficacy for different administration times. These results demonstrate that optimal timing of administration is at the end of surgery.

Minimal adverse effects have been found with ondansetron administration. Of 100 patients receiving prophylactic ondansetron, the incidence of headache was 3%[15]. To a lesser extent, constipation and elevated liver enzymes were also reported. All age groups tolerated ondansetron well, that is, there was no increase in adverse events associated with increased age[19]. Ondansetron did not potentiate general anesthesia-induced respiratory depression[20]. Although extrapyramidal symptoms are generally not considered to be a complication of ondansetron, there are case reports of patients receiving ondansetron and experiencing extrapyramidal reactions and psychiatric symptoms both in the postoperative setting and in patients undergoing chemotherapy[21,22]. The good safety profile of ondansetron may be explained by its highly specific binding to 5-HT₃ receptors. Nonetheless, some studies have demonstrated negative effects of ondansetron on QT interval prolongation, which has led to a warning from the US Food and Drug Administration (FDA) about the use of high-dose ondansetron for chemotherapy-induced nausea and vomiting (CINV).

Drug interactions between ondansetron and other compounds is low. Since the hepatic CYP450 enzyme system is active in ondansetron metabolism, inducers and inhibitors of this system are anticipated to affect ondansetron plasma concentration. Elimination of ondansetron was prolonged in a group of patients taking morphine[20]. This analysis was, however, conducted in a small patient population (n = 8).

Dolasetron

Dolasetron mesylate was approved for use for the treatment nausea and vomiting by the FDA in 1997. Unlike ondansetron, which binds to the 5-HT₁B, 5-HT₁C, alpha-adrenergic and opioid receptors, dolasetron is a pure 5-HT₃-receptor antagonist for the treatment of nausea and vomiting. Following dolasetron administration, the enzyme carbonyl reductase converts the drug to its active form, hydrodolasteron. Hydrodolasetron has a much higher affinity for the 5-HT₃ receptor[23]. Despite the brief elimination half-life of dolasetron of 0.13–0.24 h, the active form of the drug, hydrodolasteron, has a half-life of 4–8 h. Thus, the duration of pharmacologic effect seen after the administration of dolasetron is significantly longer than that of ondansetron. On first glance, such properties make dolasetron a more appealing pharmacologic modality for extended treatment of nausea and vomiting.

Metabolism of hydrodolasetron occurs from both conjugation and the CYP450 system. The majority of glucuronide or sulfate conjugated to hydrodolasetron is excreted in the urine[23–35]. However, the well-known genetic variation that occurs in the CYP2D6 component of the CYP450 system means that there will be a wide variation in the rates of metabolism of hydrodolasetron ranging from ultrarapid metabolizers (UM) to poor metabolizers (PM). Thus, the efficacy of this drug, like any other pharmacologic agent dependent on the cytochrome P450 system, may be widely disparate.

The high bioavailability of oral administration of dolasetron makes it an attractive option for patients who can tolerate the oral administration of the drug despite their underlying nausea and vomiting[2]. The previous use of intravenously administered dolasetron was suspended by the FDA in 2010 secondary to the risk of hemodynamically unstable tachyarrhythmias. The prolongation of the QTc interval on the electrocardiogram (ECG) seen with dolasetron is noted to be less than the QTc prolongation observed with ondansetron. Potassium channel blockade and subsequently delayed repolarization of the myocardium may be a significant contributor of such arrhythmogenic effects. Dolasetron does slow cardiac depolarization by blocking fast sodium channels[26]. This can also lead to changes in heart rate, PR interval length, QRS duration and QTc prolongation. Patients who receive dolasetron should receive a screening ECG to assess for the presence of QTc prolongation, thereby identifying the patients at highest risk of such phenomena.

The dose of dolasetron administered for control of nausea and vomiting in clinical trials has ranged from 12.5 to 200 mg[2,27]. The use of the medication at doses of 12.5–25 mg in postoperative gynecology patients was shown to achieve significant suppression of nausea and vomiting[2]. Higher doses of the drug have a clinical ceiling effect. Given the increased risk of side effects with higher plasma levels of the drug (i.e., tachyarrhythmias), the minimum effective dose for clinical control of the patient’s symptoms should be targeted. The utilization of a 50-mg dose of dolasetron was shown to be as effective as 4 mg of ondansetron in the prevention of nausea and vomiting[2]. Clearly, dolasetron use for the prevention of nausea and vomiting has been shown to be noninferior to ondansetron[28,29].

Despite the large amount of experience with dolasetron, which was approved for use over 15 years ago, its use is significantly limited by its arrhythmogenic side-effect profile, necessitating oral use. Additionally, newer 5-HT₃ antagonists that have a greater duration of action, such as palonosetron, make the use of dolasetron inferior to those agents and to intravenously administered ondansetron.

Granisetron

The empirical formula of granisetron is C₁₈H₂₄N_4O*HCl; it is an indazole. Granisetron is available for administration by way of mouth or IV route. For IV administration, 0.35–3.0 mg is the recommended dose for the prevention of PONV. This administration may occur before induction of anesthesia or at the end of surgery[30]. Granisetron exhibits little or no affinity for serotonin receptors other than 5-HT₃. Further, suggestive of the affinity of granisetron for the 5-HT₃ serotonin receptor, increasing concentrations of the natural ligand will not displace the antagonist[31,32]. Compared to ondansetron, granisetron is more selective for the serotonin 5-HT₃ receptor. However, in a meta-analysis comparing the efficacy of ondansetron and granisetron in the treatment of CINV, the authors concluded that the compounds have similar antiemetic efficacy[33]. The same conclusion was found in a separate meta-analysis comparing all four serotonin antagonists in the treatment for CINV[34]. This meta-analysis reached an additional conclusion that granisetron demonstrated greater efficacy than tropisetron in the treatment for CINV.

Ondansetron and granisetron exhibit similar clinical antiemetic efficacy. For patients at high risk of PONV, combination therapy is recommended. Granisetron and promethazine coadministration was more effective than promethazine alone in the prevention of PONV in females undergoing outpatient laparoscopies[35,36]. Prophylactic granisetron 1 mg IV was ineffective in the prevention of intraoperative nausea and vomiting during elective cesarean delivery under spinal anesthesia[37]. Granisetron treatment for CINV was significantly affected by genetic polymorphism for the gene for adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), a transmembrane efflux pump[35,38]. Individuals with the TT genotype for the nucleotide at position 3435 of the gene for the ABCB1 protein transporter displayed better control of emesis than individuals who had the heterozygous or homozygous CC genotype[39]. A possible explanation is that the antiemetic agents accumulate to a higher concentration in the brain in individuals with the TT genotype due to enhanced activity of the ABCB1 transporter than individuals with the heterozygous or homozygous CC genotype[39].

Granisetron metabolism in the liver is rapid. Following incubation of granisetron with human liver microsomes, N-demethylation or hydroxylation metabolites via the CYP system were identified as major products, with the hydroxyl product predominating. Ketoconazole is a CYP3A inhibitor. The inhibition of granisetron metabolism by chemical inhibitors suggests that CYP3A is responsible for the metabolism of granisetron[40]. Metabolism by way of CYP3A isoenzyme is unique to granisetron compared to other serotonin antagonists. No inhibition of other CYP activities was found in the presence of granisetron.

Granisetron has an elimination half-life between 5 and 8 h. Its prolonged duration of action is an attractive property of this drug. However, because multiple factors besides serotonin contribute to PONV, granisetron’s high selectivity for serotonin receptors may make this drug less attractive when compared to a less-selective drug such as ondansetron. Within 24 h of drug administration, 12% of granisetron dose is found excreted unchanged in the urine[40]. Because granisetron is metabolized primarily by the CYP3A subfamily, patients who are CYP2D6 UM do not experience a change in the clinical efficacy of granisetron. Accordingly, granisetron may be appropriate with the concomitant administration of drugs, which may have inhibitory or induced effects on the CYP2D6 isoenzyme. The incidence of side effects did not differ between granisetron treatment and placebo groups in an analysis of pediatric patients in the postoperative setting[41].

Adverse drug interactions have not been observed when granisetron is concomitantly administered with benzodiazepines, antipsychotics, anti-ulcer medications and chemotherapeutic agents. The effects of a selective serotonin re-uptake inhibitor would be expected to be reduced in the presence of granisetron due to the latter’s prolonged antagonism at 5-HT₃ receptors[42,43].

Tropisetron

Tropisetron has not been approved by the FDA. However, it is available internationally. In addition to antagonizing 5-HT₃ receptors, tropisetron is also an alpha-7-nicotinic receptor agonist[44]. In addition to its use for the treatment of nausea and vomiting, the drug has also been used experimentally for the treatment of pain secondary to fibromyalgia. When compared to ondansetron, which has a beta half-life of 3–5 h, tropisetron has a beta elimination half-life of 6 h leading to a longer duration of action[45].

Metabolism of tropisetron occurs via the CYP2D6 isoenzyme component of the hepatic cytochrome P450 system. Following its oxidative hydroxylation by this system, the metabolite is made soluble by conjugation with glucuronide and sulfate moieties. Thus, tropisetron and its respective metabolites undergo renal excretion[46,47]. The contrast in the metabolism of tropisetron when compared to ondansetron is an important consideration clinically. Patients who experience genetic variation of the CYP2D6 and are UM experienced more CINV when compared to UM who received ondansetron[48].

Diagnostic tests are now available to identify genetic variation in CYP2D6 activity, and such information may be particularly useful in utilizing drugs such as tropisetron for the treatment of nausea and vomiting. However, the cost-effectiveness of genetically targeted drug therapy remains an unknown variable that warrants future investigation. Nonetheless, the largely CYP2D6 metabolism pathway of tropisetron warrants concern for interactions with other pharmacologic agents that also rely heavily on CYP2D6 metabolism. Agents such as doxorubicin, tamoxifen, amiodarone, cimetidine, ranitidine and tricyclic antidepressants are additional pharmacologic agents that are metabolized by this pathway and may compete with tropisetron metabolism via the CYP2D6 pathway.

Dosing of IV tropisetron has varied between 2 and 5 mg[30,49–51]. Whilst some studies have shown a significant clinical benefit of using higher doses, other studies have demonstrated the appearance of a ceiling effect, much like that noted with other 5-HT₃ antagonists. Perhaps, such variable results are related to the different emetogenic potential of different surgical procedures, and stratification of at-risk patients would be useful in determining which patients may benefit from a higher dosing regimen. Because of the advantageous duration of action of tropisetron, it has been used for once-daily dosing in the treatment of nausea and vomiting.