Postoperative nausea and vomiting (PONV) are common problems following surgery. This chapter is designed to educate the readers on the spectrum of antiemetic therapy available, and to which populations the modalities may prove most useful. The pharmacology of both traditional and novel drugs is discussed as well as synergies gained from multi-modal combination drug therapy. The use of routine antiemetic prophylaxis is essential for a successful enhanced recovery pathway.
KeywordsMultimodal drug therapy, Risk-based prophylaxis, Antiemetic prophylaxis vs. rescue therapy, Enhanced Recovery after Surgery
In the first half of the 20th century, one of the most feared complications of general anesthesia was postoperative vomiting (POV), primarily because aspiration of gastric contents into the lungs could lead to death. Early prophylaxis sometimes consisted of advising patients to consume olive oil before general anesthesia to shield the intestinal wall from emetogenic gases. Prevention of POV was one of the primary motivations for developing local/regional anesthesia blocks, first with cocaine and procaine, then with lidocaine. Postoperative nausea, on the other hand, was considered too minor a complication to measure—until the development in the 1950s and 1960s of anesthetic drugs that could be cleared more rapidly (e.g., halothane, barbiturates, and novel opioids), which meant that patients spent more of the immediate postoperative period awake.
While the antiemetic effect of some drugs, such as anticholinergics, were first described more than a century ago, modern understanding of the specific receptor pathways and intracellular processes involved in postoperative nausea and vomiting (PONV) is relatively recent. It was not until the 1950s that interest in antiemetic drugs took off, with the identification of histamine and dopamine receptors in the nausea and vomiting pathway, and hence the clinical utility of H 1 – and D 2 -receptor antagonists like cyclizine, chlorpromazine, and promethazine. This surge in research on antiemetics was largely driven by advances in chemotherapy and a focus on chemotherapy-related outcomes. For example, neuro-oncologists first noticed the antiemetic effect of corticosteroids before the same observation was made for PONV in the 1990s.
The development of 5-hydroxytryptamine type 3 (5-HT 3 )-receptor antagonists marks the greatest advance in antiemetic drug research. Early 5-HT 3 -receptor antagonists were not more effective than other available antiemetics, but they were the first to be specifically designed by the pharmaceutical industry to target chemotherapy-induced nausea and vomiting (CINV) and PONV. This led to an increase in large, well-designed PONV studies, marketing of antiemetic agents, and a focus on PONV as a significant postoperative outcome. The first-generation 5-HT 3 -receptor antagonists are associated with QTc prolongation, but the newest 5-HT 3 -receptor antagonists, palonosetron, appears to have improved efficacy, duration of action, and side effect profile compared with its predecessors. Neurokinin-1 (NK1)-receptor antagonists, such as aprepitant and rolapitant, are the newest class of antiemetic drugs, and they too benefit from a long duration of action and favorable side effect profile. As the current understanding of the nausea and vomiting pathway, pharmacokinetics and pharmacodynamics, and genetics continues to improve, antiemetic drugs are likely to become safer and easier to tailor to individual patients.
Mechanisms of Nausea and Vomiting
Despite thousands of studies, new insights into target receptor function, and the successful development of novel antiemetic agents, the actual mechanisms of nausea and vomiting remain unclear. Most antiemetic drugs act on one of several putative neurotransmitter pathways. 5-HT 3 – receptor antagonists are the most commonly used antiemetic class of drugs ( Table 34.1 ). Other classes include dopamine (D 2 ), histamine (H 1 ), NK1, gamma-aminobutyric acid (GABA) A , opioid, and muscarinic cholinergic receptor antagonists.
|Chemical Name||Empirical Formula||Administration||Daily Dosage (mg)||C max (ng/mL)||AUC (ng•hr/mL)||T max (hr)||Bioavailability (%)||V d (L/kg)||Protein Bound (%)||Metabolism||Plasma Half-Life (hr)||Adverse Effects||Other|
|5-HT 3 Receptor Antagonists||Constipation, headache, QTc prolongation||No sedation|
|Ondansetron (Zofran)||1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate||C 18 H 19 N 3 O||IV||4||32 (0.15 mg/kg × 3)||0.4||56||70–76||CYP 3A4, CYP 1A2, CYP 2D6||4|
|Oral||16||8 × 2||1.5–2.2|
|Granisetron (Kytril)||endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride||C 18 H 24 N 4 O||IV||1||10 µg/kg||64||60||3||65||CYP 3A||3–14|
|Dolasetron (Anzemet)||(2α,6α,8α,9αβ)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-lH- indole-3-carboxylate monomethanesulfonate, monohydrate||C 19 H 20 N 2 O 3||IV||12.5||0.6||75||5.8||69–77||CYP 2D6, CYP 3A, flavin monooxygenase||8||HPB black box warning (Canada)|
|Tropisetron (Navoban)||1αH,5αH-Tropan-3α-yl indole-3-carboxylate||C 17 H 20 N 2 O 2||IV||2||5||15.1||20.7||60–80||71||CYP 3A4, CYP 1A2, CYP 2D6||6–8|
|Palonosetron (Aloxi)||(3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3α,4,5,6-hexahydro-1- oxo-1 H benz[ de ]isoquinoline hydrochloride||C 19 H 24 N 2 O||IV||0.075||0.25||5.6||35.8||97||8.3||62||CYP 2D6, CYP 3A, CYP 1A2||40||No QTc prolongation|
|D 2 Receptor Antagonists||EPS, QTc prolongation|
|Droperidol||1-[1-[3-(p-Fluorobenzoyl) propyl]-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone||C 22 H 22 FN 3 O 2||IV||0.625–1.25 × 6–8||25||3.2||69||17.8||1.5||>90||2–3||FDA black box warning|
|IM||0.625–1.25 × 6–8|
|Haloperidol (Haldol)||4-[4-(p-chloro-phenyl)-4-hydroxypiperidino]-4′—fluorobutyrophenone||C 21 H 23 ClFNO 2||IV||1–2||50–60||18||92||12–36|
|Metoclopramide (Reglan)||4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide monohydrochloride monohydrate||C 14 H 22 ClN 3 O 2||IV||25–50||100 (1–2 mg/kg) × 8–12||1–2||80||3.5||30||5–6||Cumulative CINV doses associated with significant EPS||10 mg PONV dose insufficient EPS <1% at 25–50 mg|
|Dexamethasone||9-fluoro-11β, 17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione||C 22 H 29 FO 5||IV||4||4 × 4||80–90||70||CYP 3A4||36–54 a||Hyperglycemia||Most dose response studies suggest that 4 mg is sufficient|
|IM||4 × 4|
|Oral||4 × 4|
|NK1 Receptor Antagonists||No sedation|
|Aprepitant (Emend)||5-([(2 R ,3 S )-2-(( R )-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-1 H -1,2,4-triazol-3(2 H )-one||C 23 H 21 F 7 N 4 O 3||Oral||40||125 D1/80 D2-3||0.7 (40 mg); 1.6 (125 mg); 1.4 (80 mg)||7.8 (40 mg); 19.6 (125 mg); 21.2 (80 mg)||3 (40 mg); 4 (80–125 mg)||60–65 (80–125 mg)||>95||CYP 3A4, CYP 1A2, CYP 2C19||9–13|
|Transdermal scopolamine (Transderm Scop)||α-(hydroxymethyl) benzeneacetic acid 9-methyl-3-oxa-9-azatricyclo [126.96.36.199 ] non-7-yl ester||C 17 H 21 NO 4||TD||0.5||<24||10–50||72 a|
|Opioid Receptor Antagonists|
|Alvimopan (Entereg)||[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate||C 25 H 32 N 2 O 4||Oral||2||6||80–90||Intestinal flora||Sedation||Limited evidence|
|Diazepam (Diastat, Valium)||7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one||C 16 H 13 ClN 2 O||IV||0.5–2||90–100||0.8–1.0||95–98||CYP 2C19, CYP 3A4||20|
|Lorazepam (Ativan)||7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one||C 15 H 10 Cl 2 N 2 O 2||IV||1.5 mg/m 2||20||2||90||85||9–16|
|Oral||2.5 × 2|
|Midazolam||8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a][1,4]benzodiazepine hydrochloride||C 18 H 13 ClFN 3||IV||>90||1–3.1||97||CYP 3A4||2–6|
|H 1 Receptor Antagonists|
|Dimenhydrinate (Dramamine)||2- (diphenylmethoxy)-N,N -dimethylethylamine hydrochloride||C 17 H 21 NO||IV||50–100 × 4–6||61||78||CYP 2D6||2–9|
|IM||50–100 × 4–6|
|Oral||50–100 × 4–6||80–110||2–3|
|Promethazine (Phenergan)||10-[2- (Dimethylamino)propyl] phenothiazine monohydrochloride||C 17 H 20 N 2 S||IV||12.5–25 × 4–6||25||93||16–19||Necrosis that may require amputation||FDA black box warning|
|IM||12.5–25 × 4–6|
|Oral||25 × 2|
|Sup||25 × 2|
The receptors on which antiemetics act certainly play a role in nausea and vomiting. However, given that only 20% to 30% of patients respond to any one agent, nausea and vomiting cannot be solely attributed to activity of one—or several—of these receptor classes. It is also likely that individual variability plays a larger role than previously acknowledged. Although it is essential to understand and investigate the drug-receptor relationship, the therapeutic potential of targeting specific receptor classes is limited.
Nausea and vomiting can be triggered by a variety of stimuli, including toxins, anxiety, adverse drug reactions, pregnancy, radiation, chemotherapy, and motion. These stimuli are integrated by the vomiting center in the nucleus tractus solitarius (NTS), located primarily in the medulla as well as in the lower pons. The vomiting center receives input from the adjacent chemoreceptor trigger zone (CTZ), the GI tract, the vestibular system, and the cerebral cortex ( Fig. 34.1 ).
The CTZ is located at the caudal end of the fourth ventricle in the area postrema, a highly vascularized structure that lacks a true blood-brain barrier. Therefore chemosensitive receptors in the CTZ can be directly stimulated by toxins, metabolites, and drugs that circulate in the blood and cerebrospinal fluid. The CTZ communicates with the vomiting center primarily via D 2 receptors as well as 5-HT 3 receptors. Enterochromaffin cells in the GI tract release serotonin, which stimulates vagal afferents that terminate in the CTZ and communicate information regarding intestinal luminal compounds and gastric tone. The vestibular system, located in the bony labyrinth of the temporal lobe, detects changes in equilibrium, which can cause motion sickness. Histamine (H 1 receptor) and acetylcholine (muscarinic acetylcholine receptors) are the neurotransmitters that communicate between the vestibular system and the vomiting center. Anticipatory or anxiety-induced nausea and vomiting probably originates in the cerebral cortex. The cortex has direct input to the vomiting center via several types of neuroreceptors.
Serotonin Receptor Antagonists
Serotonin (5-HT 3 ) receptors are ligand-gated sodium ion (Na + ) and potassium ion (K + ) channels found throughout the central and peripheral nervous systems, notably in the CTZ and afferent fibers of the vagus nerve in both the gut and central nervous system (CNS; see Fig. 34.1 ). Serotonin activation of the CTZ and vagal afferents can both trigger the vomiting reflex. Serotonin plays an important role in anesthesia-, chemotherapy-, and radiation-induced nausea and vomiting. Serotonin receptor antagonists can be used as antiemetic treatment because they inhibit both central and peripheral stimulation of 5-HT 3 receptors, and they are effective, nonsedative, and generally well tolerated. Thus 5-HT 3 -receptor antagonists are currently the most commonly used antiemetic agents for PONV, CINV, and rescue treatment.
Ondansetron was the first 5-HT 3 -receptor antagonist approved by the U.S. Food and Drug Administration (FDA), and at the time of its development, was the safest and most effective treatment for early CINV. Its reputation for superior CINV prophylaxis carried over to PONV, but a factorial trial in more than 5000 patients showed that 4 mg ondansetron was only as effective as 4 mg dexamethasone and 1.25 mg droperidol for PONV. Contrary to the common clinical impression that ondansetron is less effective against nausea than against vomiting, the relative risk reduction (RRR, risk ratio) of ondansetron is the same for nausea and for vomiting. However, ondansetron’s plasma half-life is only about 4 hours, which is probably why several studies found it to be more efficacious when administered toward the end rather than at the beginning of anesthesia. Like other 5-HT 3 -receptor antagonists, ondansetron’s side effects are generally mild to moderate and include constipation and headache, the latter of which is increased by about 3%. First-generation 5-HT 3 -receptor antagonists like ondansetron have also been associated with QTc prolongation, which potentially increases the risk of cardiac arrhythmia and cardiac arrest. The QTc prolongation associated with ondansetron use is similar to that caused by droperidol.
Even though 5-HT 3 -receptor antagonists are among the most effective antiemetic treatments for CINV, 20% to 30% of patients do not respond to 5-HT 3 -receptor antagonism in the early phase of CINV. Furthermore, 50% to 60% of high-risk patients do not respond to these drugs in the late phase of CINV. Several studies have shown that responsiveness to ondansetron appears to be modulated by variations in cytochrome P450 enzyme 2D6 (CYP 2D6) activity and the ABCB1 gene. The ability to predict patient responsiveness to 5-HT 3 -receptor antagonists based on genetic testing for known polymorphisms could prove to be an important breakthrough in individualizing antiemetic therapy.
Ondansetron is partially metabolized by hepatic CYP 2D6. There are numerous CYP 2D6 polymorphisms, each associated with one of four metabolic phenotypes: poor (no functional alleles), intermediate (less activity than one functional allele), extensive (two functional alleles, and the most common phenotype), and ultrarapid (three functional alleles). Ultrarapid metabolizers can degrade ondansetron more quickly and are therefore less likely to benefit from prophylaxis with the drug. In fact, several studies have shown that patients with three CYP 2D6 alleles, especially those with three functional alleles, are significantly more likely to experience PONV after prophylaxis with ondansetron than patients with fewer alleles ( Fig. 34.2 ). Ultrarapid metabolism by CYP 2D6 is believed to be partially responsible for prophylactic ondansetron failures in individuals with an ultrarapid metabolic genotype, whereas other enzymes that metabolize ondansetron—namely, CYP 3A4, CYP 2E1, and CYP 1A2—are thought to play a larger role in drug clearance in individuals with poor, intermediate, and extensive metabolism genotypes.
Ondansetron pharmacokinetics also appear to be modulated by polymorphisms of the gene that codes for the drug efflux transporter adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1). The ABCB1 pump transports at least three 5-HT 3 -receptor antagonists, including ondansetron, across the blood-brain barrier, thereby limiting accumulation of these drugs in the CNS. Polymorphisms of ABCB1 that reduce its activity increase the concentration of 5-HT 3 -receptor antagonists in the brain, which enhances efficacy. Indeed, cancer patients with a 3435C>T genetic polymorphism were less likely to experience chemotherapy-induced vomiting (CIV) in the first 24 hours after prophylaxis with ondansetron. Similarly, 3435C>T and/or 2677G>T/A polymorphisms are associated with a lower incidence of PONV in surgery patients, but only within the first 2 postoperative hours.
Granisetron and Dolasetron
Other first-generation 5-HT 3 -receptor antagonists include granisetron and dolasetron. Both drugs have a plasma half-life about twice as long as ondansetron. In general, 5-HT 3 -receptor antagonists are considered equally effective at equipotent doses. Compared with 4 mg ondansetron, 12.5 mg dolasetron and 1 mg granisetron appear to be the minimal effective dose for the prevention of PONV. Both drugs are associated with side effects similar to those of ondansetron, including QTc prolongation. CYP 2D6, the enzyme responsible for partial metabolism of ondansetron, is the primary enzyme for dolasetron metabolism. In contrast, granisetron is primarily metabolized by CYP 3A4 and not at all by CYP 2D6. Therefore the efficacy of dolasetron might be modulated by the CYP 2D6 polymorphisms mentioned earlier, whereas ABCB1 polymorphisms might play a larger role in enhancing the efficacy of granisetron.
Palonosetron is the newest and most effective 5-HT 3 -receptor antagonist for preventing acute and delayed emesis associated with chemotherapy and for reducing nausea severity ( Fig. 34.3 ). Palonosetron is characterized by 2500-fold greater affinity than serotonin and 100-fold greater affinity than other 5-HT 3 -receptor antagonists. Palonosetron also has a long half-life of 40 hours. However, palonosetron’s high binding affinity and long half-life cannot explain its superiority to other 5-HT 3 -receptor antagonists. High binding affinity does not account for palonosetron’s superiority against higher doses of dolasetron or ondansetron (i.e., higher doses of less potent drugs do not overcome the potency difference). Similarly, a long half-life cannot account for palonosetron’s superiority against more frequent redosing of ondansetron.