Improved prophylaxis of postoperative nausea vomiting: Palonosetron a novel antiemetic

Abstract

Many anti-emetics are used in clinical practice. Palonosetron hydrochloride is one of them. It is a novel, centrally acting antiemetic, and anti-nausea agent. This drug is an antagonist of serotonin receptor subtype 3 (5-HT3). This drug has longer duration of action which makes it useful in the prevention and treatment of acute and delayed onset of nausea and vomiting. This drug was initially used for chemotherapy induced nausea and vomiting. Federal drug agency (FDA) has approved it for prevention and treatment of post-operative nausea and vomiting. The literature search for this article was done using Google scholar and Pubmed using the terms “Palonosetron,” “longer duration of action,” “nausea,” “vomiting,” and “postoperative”.

INTRODUCTION

Nausea is the sensation of being about to vomit. Vomiting or emesis is the expulsion of stomach contents through the mouth. Like pain it is also an unpleasant sensation one can have. Postoperative nausea and vomiting (PONV) are one of the most distressing side effects following anesthesia. It can result in morbidity, delayed hospital discharge and unexpected hospital admission, thereby increasing the total medical costs.[1] More importantly PONV has been a major cause of decreased patient satisfaction.[2] Patients and health care professionals report the avoidance of PONV is of equal or sometimes even greater concern than avoidance of postoperative pain.[3,4] Although the overall incidence of PONV in modern anesthetic practice has been reported as 30%, in high risk group it is reported to be as high as 70%.[5,6] The vomiting reflex and site of action of various antiemetics are shown in [Figure 1].

Figure 1.

Vomiting reflex and site of action of various drugs

Different pharmacological and non-pharmacological methods are practiced to prevent or to treat nausea and vomiting.[7]

The classification of antiemetic drugs is described in [Table 1].

Table 1.

Classification of antiemetics

Currently, the drugs range from droperidol, metoclopramide, glucocorticoids to 5-HT₃ antagonists.[8] These drugs are not free from side effects like, drowsiness (dose-dependent), dysphoria, restlessness, insomnia, extrapyramidal symptoms, and life threatening arrhythmias.[9] Considering these side effects, much safer drugs have been introduced. Single or multiple drug combinations have been used to prevent or to treat PONV. The combination of different class of drugs with lower concentration are found to be very effective.[10] 5 Hydroxytryptamine receptor antagonists (5 HT3RAs) have been widely and effectively used against PONV because of their efficacy and a favorable side-effect profile. Palonosetron is the only drug of its class approved for prophylaxis against both acute and delayed chemotherapy-induced nausea and vomiting (CINV). Following successful Phase III clinical trials, the FDA approved its use for prevention of PONV in March 2008.[11] Palanosetron is a new, potent second generation5-HT₃ antagonist drug with improved profile which acts for longer duration.[12] A recent study where palonosetron was compared with ondansetron in high-risk patients receiving fentanyl-based PCA after thyroidectomy and other laparoscopic surgeries revealed palonosetron is much superior to ondansetron especially 2-24 h after surgery.[13,14,15] PONV is a major concern to patient, anesthesiologist and to the surgeon. A new safe, long acting and cost effective drug should be utilized in clinical practice. This review is aimed to discuss the distinct structural and pharmacological properties of Polonosetrone and its role in the prevention of PONV. The literature search for this article was done using Google scholar and Pubmed using the terms “Palonosetron,” “longer duration of action,” “nausea, vomiting” and “postoperative”.

CHEMICAL FORMULATION

Chemical formula of Palonosetron is (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a, 4,5,6-hexahydro- 1-oxo-1 Hbenz[de] isoquinoline hydrochloride. The empirical formula is C₁₉ H₂₄ N₂O.HCl. Its molecular weight is 332.87.[16] The structure of palonosetron is structurally different from other 5-HT₃ antagonists by a fused tricyclic ring system conjugated to a quinuclidine moiety as shown in [Figure 2].

Figure 2.

Structure of Palonosetron

PHARMACODYNAMICS

Palonosetron is the newest 5-HT₃ (serotonin) receptor antagonist. Unlike other drugs in this class, it exhibits simple bimolecular binding and positive co-operatively in binding to its receptors. The molecular structure does not mimic that of serotonin and it therefore does not bind at the serotonin binding site of the 5-HT₃ receptor.[17] Palonosetron has a three-member ring moiety bound to a quinuclidine ring and does not resemble serotonin. Hence, it does bind more tightly to the receptor and allow multiple palonosetron molecules to bind to a single receptor, and make it less likely to be displaced by serotonin molecules.[18] Prolonged duration of action of the drug is mainly due to palonosetron-triggered receptor internalization. This was confirmed in a study by visualizing by confocal fluorescence microscopy using cells transfected with 5-HT₃ receptor fused to enhanced cyan fluorescent protein. When granisetron and ondansetron were studied, these drugs showed minimal to no effect on receptor internalization or prolonged inhibition of receptor function.[19]

PHARMACOKINETICS

Absorption

Following oral administration, it is well absorbed with its absolute bioavailability reaching 97%.

Distribution

The volume of distribution is approximately 8.3 ± 2.5 L/kg. Approximately 62% of the drug is bound to plasma proteins.

Metabolism and Elimination

Palonosetron is eliminated by different routes and approximately half of it is metabolized to two primary metabolites: N-oxide-palonosetron and 6-Shydroxy- palonosetron. These have less than 1% of the 5-HT₃ receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron.

Dosage and formulation

Palonosetron injection is available as a solution as 5 ml vial containing 0.25 mg (0.05 mg/ml). In the US, FDA has already approved for oral formulation of palonosetron for CINV.[20] An effective dose of palonosetron 0.50 mg oral has been favored for the prevention of CINV in patients receiving moderately emetogenic chemotherapy without a side effect disadvantage. Probably, this single dose in high risk patient before anesthesia may prevent PONV.[21]

Special population

There is no drug dosage adjustment required for renal, hepatic function impairment and also for elderly age group.

Pregnancy and lactation

No well controlled human study has been done. Eventhough the animal studies are favorable to use it, such study will not predict human response. It is designated category B agent and should be used cautiously whenever required.[22] There is no currently available data for the safe use in lactating women.[11]

Drug interaction

Most of the drugs are having effect on cytochrome P450 pathway. This drug does have minimal effect on this pathway. There is no report on induction or inhibition of this enzyme. There is a report of profound hypotension and altered consciousness due to the use of apomorphine.[23]

Indications

This is indicated for acute onset, moderate degree of nausea and vomiting which is induced by chemotherapy. Recently, it is used by anesthesia care providers to prevent postoperative nausea vomiting. Major disadvantages of PONV are delayed recovery leading to prolonged hospital stay, wound dehiscence, pulmonary aspiration, bleeding, dehydration, and electrolyte imbalance that can occur if vomiting is prolonged.[24] PONV is not only a burden to the patient but also for the care givers. FDA has approved the use of a single Inj Palonosetron 0.075 mg for post-op nausea and vomiting for preventing it up to 24 h after surgery.[25] Efficacy beyond 24 h has not been demonstrated. The dose required for PONV is also lesser than the dose used in chemotherapy induced nausea and vomiting.[13] This drug can be used in day care surgery. PONV is one of the worrisome factor in day care surgery. Studies have proven this drug is a better choice than ondansetron in such scenarios due to prolonged duration of action with good safety profile. Successfully, the drug has been used in day care surgeries and hence preventing post discharge nausea and vomiting (PDNV).[26]

Contraindications

It is contraindicated in patients with a known hypersensitivity reaction, patients with prolonged corrected QT interval (QTc) in electrocardiogram, high-dose anthracycline therapy, hypokalemia, and hypomagnesemia. Some studies showed palonosetron does not prolong the QTc in electrocardiogram,[27] but it should be used with caution.

Comparison of palonosetron with the most commonly used antiemetic ondansetron is described in Table 2.

Table 2.

Comparison of palonosetron and ondensetron

Safety and tolerability

5-HT₃ blockers are commonly associated with side effects like dizziness, headache, somnolence, drowsiness and cardiac rhythm disturbances.[13] These adverse effects may be dose limiting. The recent study showed palonosetron was well tolerated without severe adverse events.[28] When drug was administered to healthy volunteers of both sex, i.e. a single dose intravenous palonosetron even up to nine times the approved intravenous dose, no dose-related electrocardiograph effects or any evidence of QTc interval prolongation were observed.[29] Studies have shown this drug was safely and successfully used for the prevention of CINV.[30,31]

CONCLUSION

Palonosetron, a newer second generation 5-HT₃ blocker is already popular in treating acute onset, moderate nausea and vomiting in patients receiving chemotherapy. As droperidol and ondansetron have entered the black box of FDA due to safety issue, palonosetron is going to be popular in routine anesthesia practice for PONV. Since it is a potent anti-emetic, cost effective and no or minimal side effects make this drug superior. Due to its prolonged duration of action the drug can also be considered to prevent PDNV in day care surgeries. It is difficult to answer whether palonosetron replaces all other available anti-emetics, as there is limited number of published studies in anesthetized patient. The drug interactions, safety profile in anesthesia practice, side effect profile and pharmacoeconomic impact need to be confirmed in further studies.