Nausea and Vomiting - an introduction

Nausea and Vomiting are biological defence mechanisms.  The major physiological function of emesis (vomiting) is to remove toxic or harmful substances from the body after ingestion ^[1],[2].  However, emesis is multifactorial in origin and can be caused by a range of stimuli, including medical interventions, some of which apparently have little to do with ingesting poisonous substances.  In addition to poison ingestion and gastroenteritis, emetic stimuli include motion, surgery, pregnancy, various drugs and radiation.   Disgusting sights, smells or memories can also cause nausea and vomiting, and this has a physiological basis leading to avoidance.

Nausea and vomiting are distressing to patients but they can also be a problem clinically.  For example, postoperative nausea and vomiting (PONV) is common and can result in extended hospital stays, increased bleeding, aspiration pneumonia and even the re-opening of surgical wounds as a result of the involuntary muscular contractions associated with vomiting.  Nausea and vomiting is also one of the most severe side effects of cancer chemotherapy.  The fear of chemotherapy-induced nausea and vomiting can result in patients receiving sub-optimal doses of chemotherapy.  The conditioned response of anticipatory nausea and vomiting can even result in up to 25% patients refusing chemotherapy treatment^[3].  Nausea and vomiting also imposes an economic burden on the healthcare system as a result of the time spent cleaning up, potential delays in recovery and discharge, and increased medical care.

The vomiting reflex

The process of emesis can be classified into three phases, nausea, retching and vomiting.

Nausea is described as an unpleasant sensation that immediately proceeds vomiting.  A cold sweat, pallor, salivation, a noticeable disinterest in the surroundings, loss of gastric tone, duodenal contractions and the reflux of intestinal contents into the stomach often accompany nausea. 

Retching follows nausea, and comprises laboured spasmodic respiratory movements against a closed glottis with contractions of the abdominal muscles, chest wall and diaphragm without any expulsion of gastric contents.  Retching can occur without vomiting but normally it generates the pressure gradient that leads to vomiting. 

Vomiting is caused by the powerful sustained contraction of the abdominal and chest wall musculature, which is accompanied by the descent of the diaphragm and the opening of the gastric cardia.  This is a reflex activity that is not under voluntary control.  It results in the rapid and forceful evacuation of stomach contents up to and out of the mouth (figure 1).

Figure 1 Muscular contractions associated with nausea and vomiting

Neuronal pathways, transmitters and receptors involved in nausea and vomiting

Mechano- and chemoreceptors located in the stomach, jejunum and ileum are involved with the detection of emetic stimuli in the gastrointestinal tract.  Mechanoreceptors are tension receptors that initiate emesis in response to distension and contraction e.g. from bowel obstruction.  Chemoreceptors respond to a variety of toxins in the intestinal lumina.  It is thought that the afferent neuronal pathways from the abdomen are the same regardless of the stimulus.

The final common pathway for efferent responses that produce emesis is the Vomiting Centre, which controls the act of vomiting.  Numerous neuronal pathways converge on the Vomiting Centre in the medulla (part of the hind brain) where the vomiting reflex is initiated.  The Vomiting Centre is not a discrete anatomical site, but represents inter-related neuronal networks.  As described above inputs to the Vomiting Centre include vagal sensory pathways from the gastro-intestinal tract and neuronal pathways from the labyrinths, higher centres of the cortex, intracranial pressure receptors and the Chemoreceptor Trigger Centre (CTZ).  When activated the Vomiting Centre induces vomiting via stimulation of the salivary and respiratory centres and the pharyngeal, gastrointestinal and abdominal muscles.

The Chemoreceptor Trigger Centre (CTZ) in the area prostrema of the 4^th ventricle of the brain acts as the entry point for emetic stimuli and humeral substances.  The CTZ is outside the blood-brain barrier and therefore responds to stimuli from either the cerebral spinal fluid (CSF) or the blood.

A representation illustrating the approximate anatomical relationship between the different parts of the brain involved with nausea and vomiting is shown in Figure 2.

Figure 2 Anatomical relationships between the different parts of the brain involved with nausea and vomiting

Schematically the major factors influencing nausea and vomiting can be illustrated as follows:

Figure 3 Schematic representation of the factors influencing nausea and vomiting

A wide variety of receptor types and neurotransmitters are found in areas of the brain thought to control vomiting, and each may have a role in emesis ^[4],[5].  Peripheral receptors in the gastrointestinal tract are also involved.  The neurotransmitters include histamine, acetylcholine, dopamine, noradrenaline, adrenaline, 5-Hydroxytryptamine (5HT) and Substance P.  In support of their role in emesis, it has been shown that antagonists of receptors for each of these transmitters have anti-emetic effects ^[6].

The main classes of anti-emetic drugs commonly used are shown in table 1, though it should be appreciated that many drugs have multiple mechanisms of action.

The causes of nausea and vomiting

A wide range of pathological and physiological conditions can induce nausea and vomiting.  The most prevalent of these are summarised in table 2.

Table 2 Major causes of nausea and vomiting

The management of nausea and vomiting

The management of patients with nausea and vomiting should address a number of important medical issues ^[7]:

• Identification and elimination of the underlying cause if possible
• Control of the symptoms if it is not possible to eliminate the underlying cause
• Correction of electrolyte, fluid or nutritional deficiencies

It is important to care for the wellbeing and comfort of the patient, since poor management of this can lead to delayed recovery, poor clinical outcome and aversion to future treatment.

Drug treatment of nausea and vomiting

A wide range of drugs has been shown to have effects on nausea and vomiting.  These include anti-histamines, anti-cholinergics, dopamine receptor antagonists, 5-HT₃ receptor antagonists, cannabinoids, benzodiazepines, corticosteroids and gastroprokinetic agents.  Each of the drugs affects different receptors, and some act at a number of different sites.  This determines their different clinical profiles.  For example the 5-HT₃ antagonists are effective against chemotherapy- and radiation- induced nausea and vomiting but do not inhibit nausea and vomiting resulting from opiate administration or motion^[8].  On the other hand, antihistamines provide effective control of PONV, emesis resulting from opioids or motion but are less effective against nausea and vomiting from aggressive cancer chemotherapy.  A summary indicating the main sites of action of anti-emetic drugs is shown in Figure 4.

A recent review provides a more detailed discussion of the antiemetic drugs and their mechanisms of action^[9].

A multi-drug approach to the treatment of different types of nausea and vomiting is often used in clinical practice, based on knowledge of the causes of the underlying nausea and vomiting and the sites of action of each of the available drugs.

Summary

• Nausea and vomiting is distressing for patients, can cause significant clinical problems and imposes an economic burden.
• Rapid and effective management of nausea and vomiting is important, notably in cancer therapy and post-operatively.
• There are multiple causes of nausea and vomiting involving a number of central and peripheral neurotransmitter pathways.
• Reflecting the multi-neurotransmitter origins of nausea and vomiting, different drugs are effective against nausea and vomiting of different origins.  Treatment of nausea and vomiting can be guided by this knowledge, and often a multidrug approach is appropriate in high risk patients.

References