NAUSEA AND VOMITING Chemotherapy- induced nausea and vomiting (CINV) Post-operative nausea and vomiting (PONV) Nausea and vomiting during pregnancy (NVP)

Introduction Nausea and vomiting are unpleasant symptoms caused by self-limiting disorders or serious conditions such as cancer. Uncontrolled vomiting can lead to dehydration, electrolyte imbalances, malnutrition, aspiration pneumonia, and esophageal tears. Clinicians can improve the care of patients by recommending appropriate preventive medications in situations where nausea and vomiting can be predicted (e.g., postoperative, chemotherapy-induced and radiation-induced symptoms).

Phases of the emetic response The emetic response can be described in three phases: Nausea is the subjective feeling of the need to vomit. It includes an unpleasant sensation in the mouth and stomach and can be associated with salivation, sweating, dizziness, and tachycardia. Vomiting is the forceful expulsion of the stomach contents through the mouth, but is preceded by the relaxation of the esophageal sphincter, contraction of the abdominal muscles, and temporary suspension of breathing. Retching is the rhythmic contraction of the abdominal muscles without actual emesis. It can accompany nausea, or occur before or after emesis.

Causes of nausea and vomiting Description Central nervous system CNS causes include increased intracranial pressure, migraine, brain metastases, vestibular dysfunction, alcohol intoxication, and anxiety. Infectious diseases Infectious disease causes include viral gastroenteritis, food poisoning, peritonitis, meningitis, and urinary tract infections. Metabolic causes Metabolic causes include hypercalcemia, uremia, hyperglycemia, and hyponatremia. GI disorders Gastrointestinal disorders, such as gastroparesis, bowel obstruction, distention, and mechanical irritation, can cause nausea and vomiting. Medications Among the many medications that can cause nausea and vomiting are cancer chemotherapy, antibiotics, antifungals, and opiate analgesics.

Mechanisms of the emetic response The CNS, the peripheral nervous system, and the gastrointestinal (GI) tract are all involved in initiating and coordinating the emetic response.

Mechanisms of emetic response: The vomiting centre In the CNS, the vomiting center (VC) receives incoming signals from other parts of the brain and the GI tract and then coordinates the emetic response by sending signals to the effector organs. The VC is located in the medulla oblongata of the brain, near the nucleus tractus solitarius (NTS). The VC is stimulated by neurotransmitters released from the chemoreceptor trigger zone (CTZ), the GI tract, the cerebral cortex, the limbic system, and the vestibular system . The major neurotransmitter receptors associated with the emetic response include serotonin (the 5-hydroxytryptamine type 3) receptors, neurokinin-1 receptors, and dopamine receptors. Other receptors involved include corticosteroid, acetylcholine, histamine, cannabinoid, gabaminergic, and opiate receptors. Many of these receptors are targets for antiemetic therapy.

Mechanisms of emetic response: CTZ In the CNS, the CTZ is located in the area postrema on the floor of the fourth ventricle in the brainstem; It lies outside the blood–brain barrier. When the CTZ senses toxins and noxious substances in the blood and cerebrospinal fluid, it triggers the emetic response by releasing neurotransmitters that travel to the VC and the NTS. The major neurotransmitter receptors involved in this pathway include serotonin, dopamine, and neurokinin-1.

Mechanisms of emetic response: Cerebral cortex, limbic and vestibular systems The cerebral cortex and limbic system can stimulate the emetic center in response to emotional states such as anxiety, pain, and conditioned responses (anticipatory nausea and vomiting). The neurotransmitters involved in this pathway are less well understood. Disorders of the vestibular system, such as vertigo and motion sickness, stimulate the VC through acetylcholine and histamine release.

Mechanisms of emetic response: GI Tract The GI tract contains enterochromaffin cells in the GI mucosa. When these cells are damaged by chemotherapy, radiation, or mechanical irritation, serotonin is released, which can stimulate the vagal afferents as well as directly stimulate the VC and NTS. The vomiting center then propagates the emetic response.

Sites involved in the emetic response

Sites and receptors involved in the emetic response

Chemotherapy induced nausea and vomiting Chemotherapy-induced nausea and vomiting (CINV) occurs in many patients receiving chemotherapy for cancer. The major neurotransmitter receptors involved in these pathways include serotonin, NK-1 and dopamine receptors.

Patterns of CINV Phase of CINV Description Acute phase Acute phase CINV symptoms occur within a few hours after the administration of the chemotherapy. These symptoms often peak several hours after administration and can last for the first 24 hours. Delayed CINV Some antineoplastic agents can also cause nausea and vomiting symptoms for a longer period of time after chemotherapy administration. Delayed CINV symptoms peak in about 2 to 3 days and can last 6 to 7 days. Anticipatory nausea and vomiting Some patients who have received previous chemotherapy treatments may experience a conditioned response in which they have symptoms even before the chemotherapy starts. This is called anticipatory nausea and vomiting and it is difficult to treat because it is primarily triggered by poor nausea and vomiting control in previous cycles. Breakthrough nausea and vomiting Breakthrough nausea and vomiting occur if the primary prophylactic antiemetics fail to work completely. Of course, regardless of the time course and cause, these are very distressing, unpleasant, and disruptive symptoms for the patient.

Predictive factors: Acute and delayed CINV symptoms The predictive factors most associated with acute CINV symptoms included age, disease site and stage, comorbid conditions, chemotherapy agent, absence of alcohol abuse, increasing number of chemotherapy cycles, and nonprescription drug use. The factors associated with increased delayed CINV included age, type of antiemetics used, prior nausea and vomiting, including that with pregnancy, increasing number of chemotherapy cycles, previous acute CINV, and nonprescription drug use.

Patient-related factors influencing occurrence of CINV The likelihood of CINV depends on several factors. Patient-related factors that increase the risk of acute- phase CINV include: age <50 years, female gender, poor control of symptoms in prior cycles, history of motion sickness or nausea with pregnancy, anxiety, or depression. A significant history of alcoholism actually protects against CINV. Delayed symptoms are more common in women and in those who have had poor emetic control in the acute phase.

Chemotherapy-related factors influencing likelihood of CINV Chemotherapy-related factors also predict the likelihood of symptoms. Factors such as shorter infusion time, higher dose, and more chemotherapy cycles, increase the risk of CINV. With multiday chemotherapy regimens, the symptoms usually peak on about the 3rd to 4th day of chemotherapy This occurs because the acute symptoms caused by the later days' doses are overlapping with the delayed symptoms from the first days' doses.

Chemotherapy related factors: Emetogenicity The most predictive factor is the chemotherapy agent's inherent ability to cause CINV, or its emetogenicity. Antineoplastics that are most likely (>90% of patients) to cause symptoms are classified as highly emetogenic chemotherapy. Agents that cause nausea and vomiting in 30% to 90% of patients are classified as moderate-risk agents. Low emetogenicity agents cause symptoms in 10% to 30% of patients. Other chemotherapy agents have a minimal risk, causing CINV in <10% of patients.

Emetogenicity of antineoplastic agents Certain antineoplastic agents are more likely to cause delayed CINV symptoms. These include cisplatin, carboplatin, cyclophosphamide, doxorubicin, epirubicin, and ifosfamide. Patients receiving more than one of these agents are at high risk for delayed symptoms.

Emetogenicity of combination regimens Most chemotherapy agents are given in combinations, rather than as single agents. Estimating the emetogeniticity of chemotherapy combinations has always been difficult. Chemotherapy regimens that contain cyclophosphamide and an anthracycline, such as doxorubicin, are highly emetogenic (symptoms in >90% of patients.)

Emetogenicity of combination regimens (cont’d) The primary literature should be examined for the incidence of nausea and vomiting for established chemotherapy combination regimens. In the absence of specific information regarding the risk of CINV in certain combinations, the antiemetic regimen should be geared toward the chemotherapy agent with the highest emetogenicity level given on that day. For example, for a chemotherapy combination with one agent with a high risk and one with a moderate risk, the antiemetic regimen should be appropriate for the high-risk chemotherapy agent.

Antiemetic efficacy Antiemetic efficacy, or complete emetic response, is usually defined as no emesis and no nausea or only mild nausea in the first 24 hours after chemotherapy administration. With currently recommended antiemetic regimens, most but not all patients will be protected from emesis in the acute phase (first 24 hours). Nausea, however, is more difficult to control. In addition, delayed CINV symptoms are more difficult to prevent.

Antiemetic therapy Appropriate antiemetic therapy is based on: The emetogenicity of the chemotherapy regimen Patient risk factors. Since the pathophysiologic response of nausea and vomiting involves many neurotransmitters, combinations of antiemetics from different therapeutic classes will be more effective in most situations than a single agent. The predominant classes of antiemetics used for CINV include serotonin (5HT3) antagonists, the neurokinin-1 antagonist and corticosteroids.

i. 5-HT3 receptor antagonists The 5-HT3 antagonists inhibit the action of serotonin in the GI tract and the CNS and thereby block the transmission of emetic signals to the VC. Serotonin antagonists are both highly effective and have minimal side effects. Examples of agents in this class include ondansetron (Zofran®), granisetron, dolasetron, and palonosetron.

Characteristics of 5-HT3 antagonists All of these agents have a threshold effect and so a sufficiently large dose must be given to block the relevant receptors. The dose-response curve is relatively flat, such that escalating doses do not enhance efficacy. When given in appropriate doses, all of these agents have similar efficacy for acute CINV, with response rates ranging from about 60% - 80%

Characteristics of 5-HT3 antagonists The effectiveness of 5-HT3 antagonists is enhanced by the addition of dexamethasone. The response rate increases by about 15% to 20% in regimens that include dexamethasone and a 5-HT3 antagonist. Oral and IV 5-HT3 administration are equally effective assuming the patient can take oral medications. The side effects of the 5-HT3 antagonists are similar and fairly mild and include headache, constipation, diarrhea, and transient elevations of liver function tests.

ii. Corticosteroids The mechanism of action of corticosteroids as antiemetics has not been fully determined. Some suggest that corticosteroids may decrease serotonin release, antagonize serotonin receptors, or activate corticosteroid receptors in the NTS of the medulla in the CNS. Dexamethasone and methylprednisolone are effective in the prophylaxis of CINV symptoms but dexamethasone is much more widely studied and utilized. Dexamethasone improves the antiemetic control of serotonin antagonists by about 15% to 20%. In addition, dexamethasone is one of the cornerstone agents used to prevent delayed CINV. It is inexpensive and available in both IV and oral formulations.

Dexamthasone: Uses and dosages For moderately emetogenic chemotherapy in the acute phase, a single 8-mg dose is effective In highly emetogenic cisplatin-based chemotherapy, higher doses of 12 or 20 mg should be used If used with aprepitant, the lower 12-mg prechemotherapy dose is recommended because of inhibition of steroid metabolism by aprepitant. For prevention of delayed CINV symptoms, the most commonly used dose of dexamethasone is 8 mg twice daily on days 2 and 3 after chemotherapy without aprepitant. The dose should be reduced to 8 mg daily when used with aprepitant.

Antitumor effects of corticosteroids Corticosteroids also have antitumor properties and are a part of the antineoplastic regimen for some malignancies, such as lymphoma, lymphoid leukemia, and myeloma. In these cases,there is no need to administer additional dexamethasone for the antiemetic protection; However, the corticosteroid should be administered before the rest of the chemotherapy to provide antiemetic activity. If aprepitant is part of an antiemetic regimen in a situation where the corticosteroid is given for antitumor effects, the dose of the corticosteroid should not be reduced

Neurokinin-1 Receptor Antagonists Substance P is a peptide neurotransmitter that binds to the NK1 receptors in the area postrema and NTS. Aprepitant is a NK-1 receptor antagonist used for the prevention of CINV caused by moderately and highly emetogenic chemotherapy. It is usually given as a 3-day oral regimen 125 mg on day 1 and 80 mg on days 2 and 3. Aprepitant is used in conjunction with corticosteroids and a serotonin antagonist for prevention of CINV. Aprepitant is a better choice than a serotonin antagonist during the delayed phase of CINV.

NK-1 receptor antagonists: Adverse effects Aprepitant is generally well tolerated with mild side effects, including fatigue, hiccups, headache, and diarrhea. A potential disadvantage of aprepitant is the unavailability of an IV formulation.

Aprepitant: Interaction with steroids Aprepitant is metabolized by the CYP3A4 enzyme system. It is a moderate inhibitor and inducer of CYP3A4, and an inducer of CYP2C9. Consequently, several drugs potentially interact with aprepitant. The most commonly encountered interaction is with the corticosteroids. Aprepitant increases the area under the curve of dexamethasone such that the dexamethasone dose (when used as an antiemetic) should be reduced by about one-half of the usual dose when these drugs are used together. The effect is greatest when the corticosteroid is administered orally. When the corticosteroid is also given as part of the antitumor regimen, however, the dose should not be reduced because of concern that the antineoplastic activity might be compromised.

Aprepitant: Other drug interactions Aprepitant may also enhance warfarin metabolism by inducing CYP2C9. Several chemotherapy agents (paclitaxel, etoposide, paclitaxel, ifosfamide, irinotecan, imatinib, vinca alkaloids, and others) are metabolized by the CYP3A4 enzyme system and the metabolism of these agents may be altered by aprepitant. Other drugs that may interact with aprepitant include oral contraceptives, itraconazole, terfenadine, and phenytoin.

Other antiemetics Medications from other drug classes have also been used as antiemetics for CINV. These include dopamine antagonists (prochlorperazine, promethazine), benzodiazepines (lorazepam), butyrophenones (droperidol, haloperidol), benzamides (metoclopramide) and cannabinoids. Many of these agents were used widely until more effective antiemetic agents became available. These agents remain useful for breakthrough symptoms or for patients who are refractory to standard therapy. Many of these agents have more side effects than standard agents, especially sedation and extrapyramidal side effects, such as dystonia and akathesia.

Other antiemetics (cont’d) Agent Mechanism of action Uses Lorazepam Its mechanism of action as an antiemetic may involve disruption of the cortical impulses to the VC, as well as anxiolytic activity. Lorazepam is commonly used as a rescue antiemetic. Olanzapine Olanzapine is an atypical antipsychotic agent that antagonizes several serotonin and dopamine receptors as well as other neurotransmitter receptors. It is effective in patients with refractory nausea or vomiting and advanced cancer. It also prevents acute and delayed CINV associated with moderately and highly emetogenic chemotherapy Cannabinoids They bind to the CNS cannabinoid receptors on the CTZ, the NTS, and the VC. They are used for refractory nausea and vomiting. Cannabinoids are associated with side effects, such as drowsiness, dry mouth, dysphoria, vertigo, and euphoria. Side effects and a lack of pronounced efficacy limit their use in the general population of chemotherapy patients.

Post-operative nausea and vomiting Postoperative nausea and vomiting (PONV) is a common complication of surgery, affecting 25% to 30% of all patients In surgical patients, PONV can lead to hospitalizations, stress on the surgical closure, hematomas, and aspiration pneumonitis. Patient-related, surgical and anesthetic factors can increase the risk of PONV.

Risk factors for PONV Risk factor Description Patient-related factors Patient risk factors include female gender, history of motion sickness, nonsmoking status, obesity, and a history of PONV. Children are twice as likely to develop PONV as adults.The risk increases with the child's age but declines after puberty. Surgical risk factors Some surgical risk factors for PONV include long duration of surgery and type of surgical procedure (e.g., laparoscopy, ear-nose-throat procedures, gynecologic surgeries, and strabismus repair). Anesthetic risk factors These include the use of volatile anesthetics or nitrous oxide (as opposed to IV propofol) and the use of intraoperative or postoperative opioids. Certain anesthesia practices may reduce the risk of PONV. These include use of regional anesthesia (instead of general anesthesia), use of intraoperative oxygen, hydration and avoidance of nitrous oxide, and volatile anesthesia therapy

Antiemetic therapy for PONV An optimal prophylactic regimen for PONV matches medication choice with the patient's risk level. Appropriate choices for monotherapy include droperidol, a serotonin antagonist, or dexamethasone. Patients at the highest risk for PONV should be given prophylaxis with a combination of two to three antiemetics. Dual therapy choices include a serotonin antagonist plus either droperidol or dexamethasone. Triple therapy would combine a serotonin antagonist plus dexamethasone plus droperidol.

Nausea and vomiting in pregnancy Nausea and vomiting during pregnancy (NVP) is a common condition occurring in approximately 50% to 80% of pregnancies, during weeks 5 to 12 of gestation. For most women, NVP is a self-limiting condition that resolves after the first trimester with no long-term detrimental effect on the fetus. The cause of NVP is unknown, but is most likely multifactorial including hormonal, psychological, and neurologic factors. Changes in hormonal levels of estrogen, progesterone, and hCG have been implicated as a possible cause of NVP

Hyperemesis gravidarum Severe NVP can persists in less than 1% of pregnancies leading to a condition called hyperemesis gravidarum This condition can lead to detrimental effects on the mother and fetus Hyperemesis gravidarum can cause: Weight loss of >5% of prepregnancy weight, ketonuria, electrolyte abnormalities

Hyperemesis gravidarum: Treatment Treatment of hyperemesis gravidarum often requires hospitalization for: Parental fluid administration, Electrolyte replacement, Vitamin supplementation, Antiemetic therapy.

Nonpharmacologic management of NVP Most mild forms of NVP can be managed with psychological support, and lifestyle and dietary changes. Eating smaller frequent meals consisting of a low-fat, bland, and dry diet (e.g., bananas, crackers, rice, toast), Avoiding spicy and highly aromatic foods, Eliminating pills with iron Rest and avoidance of sensory stimuli that contribute to the effects of NVP can also be helpful

Pharmacological management of NVP Antiemetics are indicated for the treatment of : Moderate to severe nausea and vomiting that fails to respond to nonpharmacologic interventions Nausea or vomiting that threatens the mother's metabolic or nutritional status (e.g., hyperemesis gravidarum). Traditionally, medications for NVP have been avoided during the first trimester because of fear of the possible teratogenic effects. Most antiemetic therapies (e.g., antihistamines, multivitamins, phenothiazines) are classified in pregnancy category B or C The goal of antiemetic therapy is to choose an effective medication to improve a woman's quality of life by maintaining her nutrition and hydration needs, while ensuring fetal safety.

i. Doxylamine with pyridoxine Doxylamine with pyridoxine (vitamin B6) can be considered first-line therapy for the treatment of NVP. Because of its safety and efficacy profile, doxylamine and pyridoxine are still considered a first-line therapy and are available separately as over-the-counter products.

ii. Other drugs Other antihistamine H1 receptor blockers (e.g., diphenhydramine, hydroxyzine, meclizine) have been studied for NVP. Phenothiazines e.g. promethazine and prochlorperazine are generally considered safe for both the mother and fetus if used occasionally in low doses. Metoclopramide can control vomiting and gastric reflux associated with pregnancy. 5-HT3 antagonists can be used in hyperemesis gravidarum