Bill Russell was a hall of fame basketball player for the Boston Celtics in the 1960s. He was famous for his defensive ability, rebounding, and leadership and, strangely, for his ritual of vomiting prior to every game. Most of us, with the possible exception of bulimics, would fear vomiting more than playing against Wilt Chamberlain (another superstar of that same era).
Anyone who has experienced an upset stomach, queasiness, pallor, copious amounts of saliva, and chills, all followed by the sudden forceful, frightening expulsion of stomach contents, would surely agree that vomiting is not fun. The aftertaste sickens us even more, the color and texture of the fluid are repellent, and the odor is foul and unforgettable. Vomiting thus begets more vomiting.
The nausea and vomiting cascade can be the result of food poisoning and many other causes. Nausea is the most frequent complaint for which patients consult physicians.1 Cancer patients undergoing chemotherapy rank it as the worst part of treatment, and women who have had children recall their experience with nausea long after the pain of childbirth fades from memory.
As pharmacists, we soon learn that nausea is one of the major side effects of many drugs. Unfortunately, we are less knowledgeable about its physiology, etiology, and management. This article will briefly address each of these topics and list a number of drugs frequently associated with nausea and vomiting.
The word nausea is borrowed almost directly from the Greek word nausia, which means "seasickness."Only later did nausea acquire the broader meaning. Vomit comes from the Latin vomere, "to throw up from the stomach."2 Emesis comes from the Greek emetikos, "to vomit."Sometimes emesis is used to encompass both nausea and vomiting. Nausea can be defined as an unpleasant but not painful sensation associated with the back of the throat and the gut and giving rise to the feeling that vomiting is imminent.
Nausea disturbs normal stomach rhythm, causing a slowing or complete cessation of gastric motility, which stops digestion of food and absorption of toxins. When nausea occurs, secretion of gastric acid decreases and salivation increases. Tachycardia also can occur.
Nausea does not necessarily culminate in vomiting. The latter is defined as a forceful expulsion of gastric contents produced by involuntary contraction of the abdominal musculature when the gastric fundus and the lower esophageal sphincter are relaxed.3 Vomiting is for the most part a protective mechanismit preserves survival.4 This aspect is evident in those instances where poisonous substances are ingested. Vomiting expels the material from the body and removes the danger.
The process, however, is not as easy to explain in cases of motion sickness or morning sickness. Neither condition (being in motion or being pregnant) is particularly harmful or undesirable.3 Motion sickness develops due to a sensory mismatch involving the visual, vestibular (the inner ear), and proprioceptive (sensory) systems.5 Morning sickness may have evolved to reduce an embryo's exposure to natural toxins.1 Hormonal changes that include higher levels of circulating estrogen, human chorionic gonadotropin, and thyroxine also may play a role. These agents may directly stimulate the chemoreceptor cells in the medulla, adjacent to the point where the emetic response is believed to be coordinated.5
The vomiting reflex is triggered by stimulation of chemoreceptors in the upper gastrointestinal (GI) tract and mechanoreceptors in the wall of the GI tract, which are activated by both contraction and distention of the gut as well as by physical damage. A coordinating center in the central nervous system controls the emetic response. Afferent nerves to the vomiting center arise from the abdominal splanchnic and vagal nerves, the vestibulolabyrinthine receptors, the cerebral cortex, and the chemoreceptor trigger zone (CTZ).6 The CTZ is located in the brain outside the blood-brain barrier, and therefore it is sensitive to agents circulating in the blood. Ingested toxins may stimulate chemoreceptors or may release 5- hydroxytryptamine (5-HT) from enterochromaffin cells in the gut wall. This action can result in vagal stimulation, and pathways to the CTZ are stimulated.
Vomiting can be caused by a diverse range of factors, all of which trigger the same mechanism. A psychological component also is involved. Factors such as foul smells, horrific sights, and violent motion (in travel) are external events perceived by higher brain centers and translated into the act of vomiting. Other factors have more obvious physical or chemical actions, such as overindulgence in food or drink, chemotherapy, chemicals including pesticides, bites and stings, some plants, opiate analgesics, or radiation.4
A number of diseases or conditions are associated with nausea and vomiting. They include adrenal insufficiency, hepatitis, Reye's syndrome, Addison's disease, diabetic ketoacidosis, myocardial infarction, hypercalcemia, some cancers, bacterial or viral infections, multiple sclerosis, labyrinthitis, vestibular neuronitis, pancreatitis, diabetic gastroparesis, irritable bowel syndrome, gallstones, peptic ulcers, gastroesophageal reflux, and intestinal obstruction.
Other causes include extreme pain, surgical procedures, raised intracranial pressure, and anxiety.4 Anxiety-inducing, threatening, or distasteful circumstances can result in so-called self-induced psychogenic vomiting. Vomiting may express hostility, as when a child vomits during a temper tantrum.3
Drugs as Causes
As mentioned earlier, many drugs including anesthetic agents, together with chemicals and biologicalscan cause nausea and vomiting as manifestations of systemic toxicity.5 Chemotherapeutic drugs are notorious for their emetogenic properties. The severity of chemotherapyinduced emesis depends on the particular drug used, the dose of the drug, and the method of administration.6 Unfortunately, the fact that most cancer treatments cause vomiting is common knowledge. This expectation creates anxiety, which compounds the problem for the pharmacist, nurse, and physician.
Women who undergo chemotherapy are more prone to vomiting than men, and younger patients are more susceptible. Young patients also are more prone to the side effects of certain antiemetics.4 Other factors predisposing patients to nausea and vomiting with chemotherapy include alcohol intake, previous morning sickness or motion sickness, course of treatment, poor antiemetic control in the past, and the treatment setting.
It has been found that chemotherapy patients actually experience 3 separate types of nausea and vomiting. An "acute"type occurs within minutes to hours of receiving a dose and then gradually resolves. In many patients, the nausea and vomiting return after a day or 2, an effect called "delayed emesis."About 25% of patients have "anticipatory nausea and vomiting,"with symptoms occurring before the drugs are administered. There is no current antiemetic drug treatment for this last type.1
Many commonly used drugs are known to cause nausea and vomiting. They include acetaminophen (early symptoms of overdose), antibiotics, AIDS drugs, selective serotonin reuptake inhibitors, antiparkinsonian drugs, calcium channel blockers, digoxin, digitoxin, phenytoin, disulfiram, ipecac, quinidine, thyroid drugs, theophylline, and caffeine. Package inserts generally will list the incidence of nausea and vomiting reported in a drug's clinical trial in the Adverse Reactions section.
The choice of an appropriate antiemetic drug will depend on a variety of factors: the cause of the nausea and vomiting, patient demographic factors, the dosage form and method of administration, and the risk of extrapyramidal reactions or other side effects.4 Antiemetics are composed of a pharmacologically diverse group of drugs. Many were not developed for this use but were borrowed from other areas of medicine serendipitously. This situation changed with the understanding of the role of 5-HT in emesis and the development of selective 5-HT3- receptor antagonists (5-HT3 is the 5-HT receptor involved in vomiting).
The majority of currently available antiemetics are dopamine receptor antagonists.4 Dopamine is involved in the control of gastric motility, and dopamine receptor antagonists are used in a variety of GI disorders. Drug classes used for nausea and vomiting include phenothiazines, which act in the CTZ to block dopamine receptors; antihistamines, which act at the level of the vestibular afferents; prokinetic or cholinergic agents; anticholinergics; 5-HT3 receptor antagonists, which include ondansetron and granisetron; corticosteroids; tetrahydrocannabinol (the active ingredient in marijuana); benzodiazepines; tricyclic antidepressants; bismuth subsalicylate; ginger; and the newest, neurokinin-1 or substance P antagonists.6
It has been quite common to think of nausea and vomiting as part of the same phenomenon. A drug that affects one, however, may not affect the other, because separate programs in the brain may be involved. Additionally, there are a host of pathways to the brain responsible for vomiting, and nausea can be triggered by a host of different stimuli. Thus, all of the currently used drugs have their limitations, and uncontrolled nausea remains a persistent problem.1
Mr. Sherman is president of Sherman Consulting Services Inc.
For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: firstname.lastname@example.org. Antiemetics are composed of a pharmacologically diverse group of drugs.