Nausea and vomiting

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34 Nausea and vomiting

E. Mason, P.A. Routledge

Key points

• Patients must be assessed carefully, and often reassessed frequently, to identify the primary underlying cause of their nausea and/or vomiting.
• Antiemetics are symptomatic treatments only and do not treat the underlying cause.
• Drug choice is based on an understanding of the likely pathophysiology, the receptors involved, the available route of administration and drug side effects.
• In certain situations, prophylactic regimens are beneficial, for example, motion sickness, post-operative nausea and vomiting, chemotherapy-induced nausea and vomiting.
• Simple regimens are used where possible to prevent postoperative nausea and vomiting, such as parenteral cyclizine or prochlorperazine administered at induction. These and other antiemetics can be used for rescue therapy if vomiting occurs post-operatively.
• The choice of antiemetic to use in conjunction with cytotoxic chemotherapy depends on the emetogenicity of the cytotoxic drugs used. The 5HT3 antagonists such as ondansetron are very effective antiemetic drugs when highly emetogenic chemotherapy is used. The addition of dexametasone may provide further benefit.
• Anticipatory emesis associated with chemotherapy can be treated with benzodiazepine and dexametasone is useful in alleviating delayed emesis.

Nausea and vomiting are commonly (but not universally) associated symptoms. The word nausea is derived from the Greek nautia, meaning sea-sickness, while vomiting is derived from the Latin vomere, meaning to discharge. Nausea is a subjective sensation whereas vomiting is the reflex physical act of expulsion of gastric contents. Retching is defined as ‘spasmodic respiratory movements’ against a closed glottis with contractions of the abdominal musculature without expulsion of any gastric contents, that is, ‘dry heaves’ (American Gastroenterological Association, 2001). It is important to differentiate vomiting from regurgitation, rumination and bulimia. Regurgitation is the return of oesophageal or gastric contents into the hypopharynx with little effort. Rumination is the passive regurgitation of recently ingested food into the mouth followed by re-chewing, re-swallowing or spitting out. It is not preceded by nausea and does not include the various physical phenomena associated with vomiting. Bulimia involves overeating followed by self-induced vomiting.

Epidemiology

Nausea and vomiting from all causes have significant associated social and economic costs in terms of loss of productivity and extra medical care. In the community, nausea (with or without vomiting) is most likely to be associated with infection, particularly gastro-intestinal infection. Vestibular disorders may cause vomiting as can motion sickness. Nausea and vomiting may be associated with pain, for example, migraine and severe cardiac pain. Many medicines also cause nausea and occasionally vomiting as a common dose-related (Type A) adverse effect. This is particularly common with opioid use in palliative care. Nausea and vomiting also occur post-operatively or in association with cytotoxic chemotherapy, or radiotherapy. These and other causes of nausea and vomiting are listed in Table 34.1.

Table 34.1 Selected causes of nausea and vomiting

Central
i. Intracranial Migraine
Raised intracranial pressure (tumour, infection, haemorrhage, hydocephalus, etc.)
ii. Labyrinthine Iatrogenic Labyrinthitis, motion sickness, Ménière’s disease, otitis media
Cancer chemotherapy
Many other medicines (e.g. opioids)
Radiotherapy
Post-operative
Endocrine/ metabolic Pregnancy, uraemia, diabetic ketoacidosis, hyperthyroidism, hyperparathyroidism, hypoparathyroidism, Addison’s disease, acute intermittent porpyhria
Infectious Gastroenteritis (viral or bacterial)
Other infections elsewhere
Gastro-intestinal disorders Mechanical obstruction (gastric outlet or small bowel)
Organic gastro-intestinal disorders (e.g. cholecystitis, pancreatitis, hepatitis, etc.)
Functional gastro-intestinal disorders (e.g. non-ulcer dyspepsia, irritable bowel syndrome, etc.)
Psychogenic disorders Psychogenic vomiting, anxiety, depression
Pain related Myocardial infarction

(adapted from Quigley et al., 2001)

Pathophysiology

Complex interactions between central and peripheral pathways occur in the production of the clinical features of nausea and vomiting. The most important areas involved peripherally are the gastric mucosa and smooth muscle (the enteric brain) and the afferent pathways of the vagus and sympathetic nerves. Centrally the significant areas involved are the area postrema, the chemoreceptor trigger zone (CTZ), the nucleus tractus solitarus (NTS) and the vomiting centre.

From a pharmacotherapeutic point of view, the most important aspect of this complex pathophysiology is the variety of receptors involved, including histaminergic (H1), cholinergic (muscarinic M1), dopaminergic (D2), serotonergic (5HT3) and neurokinin-1 (NK1) receptors. In the clinical situation, these become targets for various drugs directed at controlling the symptoms.

There are 108 neurons in the intestine and a complex interaction occurs between these, the mucosa, the smooth muscle in the intestine, the parasympathetic (vagus nerve) and sympathetic nerves and the higher centres in the spinal cord and brain to result in normal gastro-intestinal peristaltic activity. The enteric brain and the vagus nerve monitor stimuli from mucosal irritation and smooth muscle stretch which may result in nausea and/or vomiting.

The area postrema in the floor of the fourth ventricle contains the CTZ and is a special sensory organ rich in dopaminergic, serotonergic, histaminergic and muscarinic receptors. It is located outside the blood–brain barrier (BBB) and it is likely that chemicals, toxins, peptides, drugs and neurotransmitters in the cerebrospinal fluid (CSF) and bloodstream interact with this area to cause nausea and vomiting. However, the precise mechanism is not known.

The vomiting centre is situated in the dorsolateral reticular formation close to the respiratory centre and receives impulses from higher centres, visceral efferents, the eighth (auditory) nerve (the latter two through the nucleus tractus solitarius) and from the CTZ (Fig. 34.1). It includes a number of brainstem nuclei required to integrate the responses of the gastro-intestinal tract, pharyngeal muscles, respiratory muscles and somatic muscles to result in a vomiting episode. The vomiting centre may be stimulated in association with, or in isolation from, the nausea process.

image

Fig. 34.1 Schematic representation of pathways involved in nausea and vomiting.

The vomiting reflex can be elicited either directly via afferent neuronal connections, especially from the gastro-intestinal tract and is probably dependent on the integrity of the nucleus tractus solitarius, or from humoral factors dependent on the integrity of the area postrema. The sequence of muscle excitation and inhibition necessary for the act of vomiting is probably controlled by a central pattern generator located in the nucleus tractus solitarius, and information from the CTZ and vagus nerve converges at this point.

The central causes of nausea and vomiting include increased intracranial pressure, dilation of cerebral arteries during migraine and stimulation of the labyrinthine mechanism or of the senses of sight, smell and taste.

The peripheral causes of nausea and vomiting include motion sickness, delayed gastric emptying and gastric mucosal irritation (ulceration, NSAIDs). These mechanisms are all mediated through the vagal afferent neurons. The vomiting associated with distension or obstruction of the gastro-intestinal tract is mediated through both the sympathetic and vagal afferent neurons.

Patient management

Management of the patient with nausea and vomiting is approached in three steps.

1. Recognise and correct any complications. This includes correction of dehydration, hypokalaemia and metabolic alkalosis in the acute situation with symptoms of less than 4 weeks duration. Weight loss and malnutrition are features of chronic nausea/vomiting, that is, when symptoms have been present for 4 weeks or longer.
2. Where possible, identify the underlying cause (see Table 34.1) and institute appropriate treatment. Here it is important to be aware that metabolic or endocrine conditions such as hypercalcaemia, hyponatraemia and hyperthyroidism can result in vomiting.
3. Implement therapeutic strategies to suppress or eliminate symptoms (these depend on the severity and clinical context). Ideally, antiemetic drugs are prescribed only when the cause of the nausea and/or vomiting is known, since by suppressing symptoms, they may otherwise delay diagnosis. This is especially true in children. However, they may sometimes be necessary temporarily in situations when directly addressing the underlying cause will not bring symptom relief sufficiently rapidly.

Some scenarios illustrating common therapeutic problems in the management of nausea and vomiting are outlined in Table 34.2.

Table 34.2 Common therapeutic problems in managing patients with nausea and vomiting

Problem Possible cause/solution
Persistent nausea and vomiting despite treatment Is the cause correctly diagnosed?
Review the antiemetic agent and the dose: if both correct, change to or add a second agent
Patient with PONV is vomiting despite suitable antiemetic regimen Check analgesia: pain may be causing nausea and vomiting, or patient-controlled analgesia may require adjustment downwards to reduce analgesic dose
Patient with bowel obstruction is passing flatus Prokinetic drug is first-choice antiemetic. 5HT3 antagonists may also be effective
Patient with bowel obstruction is not passing flatus Spasmolytic drug is first choice. Prokinetic drugs are contraindicated. Similarly, bulk-forming, osmotic and stimulant laxatives are inappropriate; phosphate enemas and faecal softeners are better
A terminally ill patient receiving diamorphine is vomiting, despite use of haloperidol Levomepromazine given as a 24-h subcutaneous infusion can be very effective
A patient with renal failure (uraemia) is vomiting Consider a 5HT3 antagonist
A patient develops an acute dystonic reaction to metoclopramide Give an intramuscular injection of an antihistamine. Such extrapyramidal reactions to metoclopramide are more common in young adults (especially females) and this agent is best avoided in this group

PONV, post-operative nausea and vomiting.

Antiemetic drugs

Several classes of antiemetic drugs are available that antagonise the neurotransmitter receptors involved in the pathophysiology of nausea and vomiting. These classes of drugs are generally distinguished from each other by the identity of their main target receptor, although some act at more than one receptor.

Antihistamines

This group of medicines includes cinnarizine, cyclizine, diphenhydramine, diphenhydrinate and promethazine. They have some efficacy in nausea and vomiting caused by a wide range of conditions, including motion sickness and post-operative nausea and vomiting (PONV). They are thought to block H1 receptors in the CTZ and possibly elsewhere. However, several of these agents also have potent anticholinergic (M1) receptor antagonist activity, which may contribute significantly to their efficacy as well as their adverse effect profile (see Section ‘Anticholinergics’). The sedative effects of some antihistamines may also contribute to antiemetic activity, although this property appears not to be essential and it can be a particular problem when skilled tasks, such as driving, need to be performed. Nevertheless, the newer non-sedating antihistamines, for example, fexofenadine, are of limited value in nausea and vomiting.

Anticholinergics

This is one of the oldest classes of antiemetics, of which many members are potent inhibitors of muscarinic receptor (M1) activity both peripherally and centrally. Anticholinergic drugs such as atropine, hyoscine and glycopyrronium have been used preoperatively to inhibit salivation and excessive respiratory secretions during anaesthesia. Anticholinergics act by inhibiting cholinergic transmission from the vestibular nuclei to higher centres within the cerebral cortex, thereby explaining their predominant use in the treatment of motion sickness. Hyoscine hydrobromide (scopolamine hydrobromide) is the most widely used agent and it can be given orally, by subcutaneous or intramuscular injection, or transdermally for motion sickness. Inhibition of peripheral muscarinic receptors can cause drowsiness, dry mouth, dilated pupils and blurred vision, decreased sweating, gastro-intestinal motility and gastro-intestinal secretions and difficulty with micturition. Anticholinergic agents may also precipitate closed-angle glaucoma in susceptible individuals.

Antidopaminergics

Phenothiazines and butyrophenones

Phenothiazines (e.g. prochlorperazine, perphenazine, and trifluoperazine) and butyrophenones (e.g. haloperidol and droperidol) act as antagonists at dopamine (D2) receptors in the CTZ, but may also have cholinergic (M1) and histaminergic (H1) receptor antagonist activity. As a consequence they share several adverse effects with antihistamines and anticholinergics, including drowsiness. In addition, the dopamine-blocking effects may be associated with acute dystonia (especially in children), and tardive dyskinesias or parkinsonism when used for prolonged periods. Prochlorperazine is less sedating and available as a buccal tablet and suppository for use when vomiting precludes oral administration. Phenothiazines are sometimes used for drug-associated emesis, including chemotherapy-induced nausea and vomiting (CINV), but like the butyrophenones, have in many situations been superseded by more specific agents such as metoclopramide and the selective 5HT3 antagonists. Levomepromazine is sometimes used to relieve nausea and vomiting in terminal care.

Metoclopramide

At lower doses, metoclopramide acts as a selective D2 antagonist at the CTZ and its effects mirror those of the phenothiazines and butyrophenones. However, it also exerts peripheral D2 antagonism at these doses, and stimulates cholinergic receptors in gastric smooth muscle, thus stimulating gastric emptying. It may, therefore, be more effective than phenothiazines and butyrophenones when nausea is related to gastro-intestinal or biliary disease. At higher doses, it may exert some 5HT3-receptor antagonism but at these doses, the incidence of acute dystonic reactions, particularly in young women and the elderly, may limit its usefulness in CINV.

Domperidone

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