Treating nausea and vomiting.
In recent years the drugs available for the treatment of vomiting (and, to a lesser extent, nausea) have increased, as our understanding of the mechanisms underlying these symptoms improves. The ability to provide best care to patients suffering from nausea and vomiting requires knowledge of these mechanisms, how anti-emetic drugs work and adverse effects associated with anti-emetic therapy.
From an evolutionary perspective, nausea and vomiting are protective mechanisms that help to rid the gastrointestinal (GI) tract of ingested toxins, and to condition humans to stay away from potentially toxic food sources. In early pregnancy, the development of nausea and associated food intolerances is designed to protect the rapidly developing fetus from potential poisons. The presence of morning sickness in the first trimester of pregnancy is associated with a decreased risk of miscarriage and, possibly, enhanced neurodevelopment. (1)
The development of anaesthetics in the mid 19th century was associated with high rates of post-operative nausea and vomiting (PONV). Up to 80 per cent of patients who were administered ether or chloroform experienced PONV and it was a significant cause of mortality in early anaesthetic practice. (2) This created increased interest in the underlying mechanisms of vomiting. In the 1950s, regions of the brain most involved in emesis--the vomiting centre and chemoreceptor trigger zone--and a key neurotransmitter, dopamine, were isolated. Anti-emetic therapies that targeted the action of dopamine in the central nervous system were developed. The introduction of highly emetic chemotherapy agents (eg cisplatin) in the 1970s, and the failure of anti-dopaminergic drugs to control associated nausea and vomiting lead to the recognition that nausea and vomiting involved many more pathways and neurotransmitters than was previously understood. (3)
Since the 1980s there have been a number of new drug developments in the quest to control nausea and vomiting. These range from the serotonin (5-HT) antagonists, such as ondansetron, to the newer Substance P-receptor antagonist aprepitant, and synthetic cannabinoids, eg nabilone. (4) While these drugs have varying efficacy in the treatment or prevention of vomiting, they are much less successful in controlling nausea.
Vomiting is usually preceded by nausea. Exceptions occur in states of raised intracranial pressure, where projectile vomiting may occur without any nausea, and it has also been reported in some cases of radiotherapy--and pregnancy-induced vomiting. (5) That anti-emetic drugs are less effective at treating nausea than vomiting shows that nausea and vomiting are separate phenomena. The mechanisms by which conscious sensations of nausea arise remain largely unknown. (6)
Some research supports the involvement of ghrelin in development of nausea. Ghrelin is a hormone, secreted in the stomach, that increases appetite and gastric motility and decreases feelings of satiety. The highly emetogenic chemotherapy drug cisplatin inhibits secretion of ghrelin, causing anorexia and nausea, although the exact mechanisms involved are not known. Early clinical trials with ghrelin have shown some success in controlling anorexia and nausea. (7,8)
Other gastrointestinal hormones such as glucagon-like peptide (GLP-1) and incretins may also play a role in the development of nausea.
Nausea is now considered to be the most debilitating effect of chemotherapy for many patients, impairing quality of life and physical well-being. Nausea interferes with normal functioning, ability to work, appetite and food intake, resulting in dehydration, weight loss, insomnia and exhaustion, as well as economic losses. (9,10) Moreover, there is evidence that health care professionals underestimate the occurrence of nausea in post-operative and chemotherapy patients, and that it is also poorly assessed and underreported. (11)
Assessment of nausea is problematic because it is an entirely subjective symptom. Just as when assessing pain, nurses cannot rely on objective observations (signs of discomfort, reduced appetite and oral intake, etc) to determine an individual's experience of nausea. Nausea is a situational event and has somatic (eg fatigue, dizziness, diaphoresis), emotional (eg anxiety, distress) and GI dimensions. (12)
Tools used to assess nausea must address frequency, severity and duration, as well as the level of distress or discomfort the nausea is causing. (13) It is the degree of emotional distress associated with nausea--varying with duration, severity and situational factors such as presence of other distressing symptoms, illness experience and life events--that determines the patient's need to have their nausea addressed. From a clinical perspective, nausea must be managed if it is affecting nutrient and fluid intake, or if it delays essential treatments such as chemotherapy.
The development of anticipatory nausea during chemotherapy occurs in up to 30 per cent of patients by their fourth chemotherapy cycle. Greatest risk is for those receiving highly emetogenic chemotherapy. It is widely accepted that prevention, from the first cycle of treatment, through anti-emetic therapy, is the best way of tackling anticipatory nausea. (14,15)
Management of nausea is challenging. Anti-emetic drugs have variable success and are often least effective for the worst nausea. Self-management strategies that can work for those with chemotherapy or pregnancy-induced nausea include modifying diet--meal size, frequency, consistency and content--or using distraction, rest, and complementary therapies such as acupressure, ginger or peppermint, and hypnosis. (1,10)
Regardless of the initiating stimulus, anatomical events in retching and vomiting are well established. Vomiting is normally preceded by a prodromal phase. This involves autonomic stimulation that induces hypersalivation (a reflex designed to protect teeth from stomach acid), vasoconstriction and pallor, cold sweat and the release of antidiuretic hormone. Nausea occurs in most cases, but the degree of nausea may not reflect the severity of vomiting. (16)
Stimulation of vagal nerve efferent fibres leading to the stomach and thorax cause disordered gastric contractions, relaxation of the upper stomach and oesophagus, a decrease in thoracic pressure and an increase in abdominal pressure. A deep inspiration occurs and the glottis is closed to prevent aspiration of gastric contents. A giant retrograde contraction in the upper small intestine and stomach causes gastric contents to move up into the oesophagus. This also requires recruitment and strong contraction of skeletal muscles in the abdominal wall. If the upper oesophagus remains contracted, retching occurs. An increase in thoracic pressure and relaxation of the upper oesophagus causes gastric contents to be expelled through the mouth.
Once the vomit occurs, the upper oesophagus contracts, remaining gastric matter returns to the stomach and the lower oesophageal sphincter then closes. (16,17)
Consequences of vomiting
Aside from its impact on patients' quality of life, vomiting can have several potentially serious physical effects. Strong contraction of abdominal wall and thoracic skeletal muscles can increase post-operative pain. Pressures may also burst wounds open following abdominal surgery, place increased stress on the eye following ophthalmic surgery, and can dangerously increase intracranial pressure in cases of intracerebral haemorrhage or injury. Oesophageal inflammation and tearing can also occur.
Chronic or prolonged vomiting may cause pitting and erosion of tooth enamel due to acid exposure, which is worsened where there is also low saliva flow, eg where the patient is also taking drugs that cause a dry mouth. This can cause tooth decay, increased thermal sensitivity and brittleness of the teeth. (18) Patients should be advised to rinse their mouths with water, or baking soda and water, after vomiting, but not to brush teeth immediately, as this will worsen the damage. When experiencing nausea, the act of brushing the teeth may cause vomiting.
The acid secretions of the stomach are composed mainly of water, hydrochloric acid (HCl) and pepsinogen, with a pH of 1 to 2. HCI is formed when hydrogen ions are secreted into the lumen of the stomach by parietal cells. Chloride then follows, but in greater amounts, so there is also loss of potassium into the lumen to maintain an electrical balance. Prolonged vomiting will cause disruption in the fluid, electrolyte and acid-base balance of the body. Loss of acid results in a metabolic alkalosis. The associated loss of chlorine and potassium, and dehydration make it difficult for the renal system to rectify the body's pH because compensation for water and electrolyte imbalances are prioritised. (19)
Prolonged vomiting or nausea can cause calorie and nutrient deficits, which in some cases may severely affect patients' health.
PATHWAYS IN VOMITING
Neural pathways in the development of vomiting are complex, involving central and peripheral receptors and numerous neurotransmitters.
Chemoreceptor trigger zone
The chemoreceptor trigger zone (CTZ) is a specialised region of the brainstem identified as the site for chemical stimulation of vomiting, and perhaps, nausea. Also known as the area postrema, the CTZ is found at the floor of the fourth ventricle and has an extensive capillary network that lacks a blood brain barrier. This exposes the neurons in the CTZ to toxins, drugs (eg opioids) and endogenous chemicals in the blood. (20,21)
The biochemical events within the CTZ neurons that convert chemical stimuli into the neuronal signals that induce nausea and vomiting are poorly understood. (21) The CTZ also receives input from vagal neurons, and exchanges neurons with the nucleus tractus solitarius (NTS).
Nucleus tractus solitarius and the vomiting centre
The nucleus tractus solitarius (NTS) is a region in the brainstem that receives input from the cardiovascular, respiratory and GI systems, and from the taste buds. Many autonomic nervous system reflexes are mediated by the NTS, including the carotid, gag and cough reflexes, and those regulating motility and secretion in the GI tract.
The NTS may form the final common pathway in the integration of vomiting because it sends signals to other regions of the brainstem that regulate the motor events in emesis and prodromal sensations, and possibly to higher brain centres to trigger the sensation of nausea. Researchers no longer think there is a discrete location in the brainstem that acts as a vomiting centre. Rather the NTS and other reflex centres act together in what is termed the central pattern generator (CPG) for vomiting, although precise neurotransmitters involved are not known. (16,20)
Some evidence suggests the existence of an anti-vomiting or anti-emetic centre that inhibits the CPG. This may be the site of action of some anti-emetic substances such as cannabis (acting via CB1 receptors) and ghrelin. (20) High concentrations of morphine, acting possibly through mu or kappa receptors in this anti-emetic centre, are also able to inhibit vomiting. (22)
Nausea and vomiting can be triggered by four main pathways, the underlying mechanisms of which are sometimes poorly understood. There are a variety of chemical neurotransmitters involved in these pathways, which are the targets of anti-emetic therapies. These are illustrated in figure 1 (see p23) and described below.
1. The vagus nerve
Stimulation of chemical and stretch receptors in the abdomen and cardiac regions sends nerve signals to the CPG. Here, 5-HT acting on [5-HT.sub.3] receptors and substance P acting on NK1 receptors, activate the CPG and lead to nausea, prodromal symptoms and vomiting. Other neurotransmitters involved include histamine and acetylcholine.
Ingested toxins and drugs: Highly toxic drugs or toxins from microorganisms in food will trigger vomiting. The layer of cells lining the GI tract includes a set of specialised enterochromaffin cells. Toxins in the lumen of the gut trigger production of free radicals in these cells. In response, the cells secrete serotonin (5-HT), substance P (S-P) and possibly cholecystokinin. These activate nearby receptors for the vagus nerve, which then transmits signals to the CPG and, to a lesser extent, the CTZ in the brainstem. (20)
Drugs that may induce nausea are not limited to those used in chemotherapy. Some drugs are given to deliberately cause vomiting: hypertonic salt solutions or ipecac syrup used to be recommended for inducing vomiting in cases of accidental ingestion of poisons. They each act as chemical irritants in the GI tract. Use of these remedies is strongly opposed in current guidelines, which do not support inducing vomiting following ingestion of any poison.
GI tract distension and stasis: GI, particularly duodenal, distension triggers stretch receptors in the gut wall, stimulating vagal afferent pathways to the CPG. Distension of the GI tract occurs with gastric or intestinal stasis (eg diabetic gastroparesis) and bowel obstruction. This also accounts for nausea that some people experience with constipation. (23) Inflammatory processes in the GI tract (including pancreatitis, hepatitis and cholecystitis) may also induce nausea and vomiting through irritation of vagal receptors.
Dopamine acts within the GI tract, via D2 receptors, to relax the lower oesophageal sphincter and reduce contractions along the tract. These two actions promote reflux and GI stasis, both of which may trigger nausea and vomiting. Dopamine receptor antagonists, like domperidone and metoclopramide, counter these effects of dopamine in the GI tract. (24) Cardiac ischaemia: Stimulation of cardiac vagal fibres causes nausea and vomiting for many people, particularly women, who are experiencing angina or myocardial infarction.The exact mechanisms here are not known. (5)
2. The systemic circulation
Emetic stimuli entering the general circulation can trigger the nerve receptors in the CTZ directly because, unlike the rest of the central nervous system, this region of the brainstem has a reduced blood-brain barrier. In the CTZ there are two main neurotransmitters involved in this process, dopamine and 5-HT. Histamine and acetylcholine acting on muscarinic receptors (mAch) may also be present.
Drugs and poisons, including alcohol, entering general circulation (either absorbed from the GI tract or injected) trigger vomiting via CTZ pathways. Highly toxic drugs or pathogens that cause destruction of body cells may also trigger vomiting through the release of cellular debris and inflammatory mediators into the circulation.
This may be the underlying mechanism for delayed phase chemotherapy-induced nausea and vomiting (CINV), and for vomiting associated with radiotherapy. (21)
Apomorphine is a drug used in specialist treatment for people severely disabled by refractory episodes of Parkinson's disease. This drug strongly activates dopamine receptors and also acts as an agonist at 5-HT receptors. Apomorphine given subcutaneously without previously administered prophylactic domperidone, will trigger vomiting within three to five minutes. (23) Many other drugs (apart from emetic chemotherapeutic regimes) are known to cause nausea--some at therapeutic doses, eg opioids, and some in toxicity, eg digoxin.
Metabolic effects of disease may cause nausea and vomiting. Accumulation of endogenous toxins, such as from diabetic ketoacidosis, uraemia and hypo-or hyperparathyroidism, may trigger the CTZ, although these conditions may also involve alteration in intracranial pressures or neurovascular irritation.
Nausea (with or without vomiting) is an acknowledged effect of hypoxia and hypotension. It is not known whether this arises as a direct effect of hypoxia on the CTZ, or due to impaired blood supply to the GI tract. During hypoxic or hypotensive states, sympathetic stimulation causes vasoconstriction of blood vessels to the GI tract and decreased tract motility. Ensuing GI stasis may trigger vagal nerve pathways, leading to nausea and vomiting.
Pregnancy-induced nausea and vomiting (PINV): The CTZ has receptors for human chorionic gonadotrophin (hCG), the levels of which increase during early pregnancy and decrease as PINV resolves. High levels of hCG have been correlated with the development and severity of hyper-emesis gravidarium but not all women with high concentrations of hCG will develop PINV. (1)
Other factors implicated in the development of PINV are high levels of oestrogen, hyperthyroidism, progesterone, growth hormone, gastrooesophageal reflux and the presence of Helicobacter pylori infection. All of these are possibly minor contributors to the development of PINV, and the mechanisms involved are not understood. (1)
3. The vestibular system
The vestibular system is the sensory organ in the inner ear that provides our sense of balance and spatial orientation. Abnormal activation of the vestibular system leads to motion sickness and Meniere's disease. Inputs from the vestibular system to the CPG use histamine (via H1 receptors) and mAch as neurotransmitters.
There is some evidence that vestibular inputs modify the emetic response from other stimuli: a history of motion sickness is a risk factor for development of PINV, PONV and CINV. (20) There is also an apparent genetic component to susceptibility to motion sickness, but it is not known if this is related to vestibular, neural pathway or CPG mechanisms.
4. Cortical mechanisms
Little is known about how higher centers--the brain cortex rather than the brainstem--trigger vomiting. Repulsive sights, smells and tastes may travel direct to the CPG or indirectly, via cortical pathways, to cause nausea or vomiting. (6)
Conditioning or learning that causes anticipatory nausea and vomiting is certainly related to higher brain functions. Pain, eg migraine and facial pain, may induce nausea via higher centres but again the mechanisms are not known. (5)
RISK FOR DEVELOPING NAUSEA AND VOMITING
There are recognised risk profiles for the development of PONV and CINV, which can be divided into patient and treatment characteristics.
Being female is the strongest predictor for PONV (27) and CINV. (28) The reason for this is unknown, but it is not likely to be related to hormonal fluctuations in the menstrual cycle. (27) The physiological basis of this risk is demonstrated by the effectiveness of aprepitant, an NK1/S-P inhibitor drug. When added to combination therapy for CINV, it increased the number of women protected from vomiting by 25 per cent, while for men the increase was only by 13 per cent. (8)
There appears to be a genetic factor associated with risk--personal or family history of PONV or motion sickness (and perhaps morning sickness) increases an individual's chances of also developing PONV and CINV. (8,27)
A history of high alcohol intake reduces risk of vomiting in CINV, (14) whereas smokers have reduced risk of PONV. (27) There is some suggestion that these protective effects are due to increased numbers of liver enzymes that metabolise drugs more rapidly, but for nicotine use at least, it may be that alteration in neurotransmitter receptors is the underlying mechanism. (27)
Risk of both PONV and CINV decreases with age in adults, but increases with age in children. Again the reasons are not known, although it may be linked to immaturity or ageing of the autonomic nervous system. (27)
The emetogenicity of chemotherapy drugs is well established and guidelines use this knowledge to determine optimal anti-emetic regimes both for individual drugs and in combination during complex treatment schedules. (14,29) The three distinct phases of CINV complicate anti-emetic treatments. These phases are: (14)
* Acute--occurring within a few minutes to hours following drug administration, peaking at five to six hours and resolving within 24.
* Delayed--occurring 24 hours after drug administration and peaking within 4g to 72 hours.
* Anticipatory--occurring before drug administration, a conditioned response due to previous negative experiences.
PONV increases where there is administration of volatile anaesthetics, nitrous oxide and postoperative opioids, and with duration of anaesthesia. The evidence that links specific types of surgery to increased risk is controversial but there may be increased PONV with cholecystectomy, laparoscopic procedures and gynaecological surgery. (27)
ANTI-EMETIC DRUG THERAPY
Before starting anti-emetic therapy, it is essential to determine the underlying cause. Giving anti-emetics to a patient with raised intracranial pressure may mask worsening symptoms. Anti-emetics, especially dopamine antagonists, may also worsen the effects of obstruction in the GI tract.
Anti-emetic drugs have much more success in reducing vomiting than nausea. Multiple neurotransmitters and receptors are involved in the generation of nausea and vomiting, so multiple targeting by a variety of anti-emetic drugs may increase effectiveness of treatment.
Most anti-emetic therapies act as antagonists on receptors in the central nervous system or periphery. Antagonist drugs are those that block the action of a neurotransmitter at its receptor. An exception is nabilone, which is an agonist drug. It appears to inhibit vomiting by stimulating the cannabinoid CB1 receptor, although the subsequent pathways involved are not known. Figure 1 (see p23) shows the main neurotransmitters for each emetic pathway.
Table 1 (see p21) describes the main classes of anti-emetic drugs, their sites of action and main roles in anti-emetic therapy. (14,22,30)
Dopamine acts throughout the body via a variety of receptors. The [D.sub.2] receptor family is the most important in vomiting. Normal functioning of dopamine neurotransmission is essential for motor control, reward and motivation, and secretion of prolactin. (4) In the peripheral nervous system, dopamine causes inhibition of GI motility and relaxation of the oesophageal sphincter. Dopamine is a neurotransmitter of the monoamine class, which includes noradrenaline, 5-HT, Ach and histamine. Medications targeted at the receptors for one of these neurotransmitters will bind, in varying degrees, to receptors for others in the class, causing unintended effects. (4)
Early anti-emetic drugs included drugs that are now more commonly identified as antipsychotics: chlorpromazine (Largactil) and prochlorperazine (Stemetil, Buccastem). These drugs are still useful in the treatment of vomiting, but more specifically targeted drugs are available. All dopamine antagonists (with the exception of domperidome) and, to a lesser extent, the other monoamine antagonist agents, carry a risk of movement disorders and tardive dyskinesia.
Tardive dyskinesia is an irreversible chronic movement disorder with involuntary movements of the face, tongue, lips and extremities. Risk of development is increased in children and young adults, and older women, with prolonged or high-dose therapy with dopamine antagonists (especially metoclopramide) and concomitant diabetes or antipsychotic medication. (31)
Both metoclopramide and domperidone have a prokinetic effect--they increase GI motility. This may assist with anti-emetic therapy but increases risks associated with bowel obstruction. The key difference between metoclopramide and domperidone is that the former crosses the blood-brain barrier and affects the central nervous system while the latter doesn't. This makes domperidone a more attractive choice where there is high risk of extrapyramidal motor effects or in the presence of Parkinson's disease. However, domperidone carries an increased risk of QTc prolongation--a form of cardiac arrhythmia that can trigger episodes of Torsades des Pointes and sudden cardiac death. (30)
Acupressure at the wrist has shown some effect in reducing nausea in a number of clinical conditions, including PONV and CINV. (3,32) Ginger, at a dose of one gram per day, may also help alleviate nausea but the research evidence to support this is inconclusive, (3) although it appears to be more effective in PINV and CINV than PONV. (32) Similar lack of definitive research evidence surrounds interventions such as dietary modification, distraction therapy and relaxation. (8)
There is no universal anti-emetic therapy that will treat nausea and vomiting from all causes. Given the complex underlying mechanisms in vomiting, and the lack of understanding about neural pathways involved in nausea, it seems this goal is far from being achieved. Current therapeutic interventions consist of providing the most appropriate drug or combination of drugs to address nausea and vomiting, according to their underlying cause. Effective therapy requires timely assessment and documentation of nausea and vomiting and the impact of administered drugs on the patient's experience of these.
* References for this article can be found at www.cpd4nurses.co.nz.
Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of cpd4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
After reading this article and completing the accompanying online learning activity you should be ale to:
* Outline the physical processes involved in emesis and its physiological consequences.
* Describe neuronal pathways and neurotransmitters involved in nausea and vomiting.
* Discuss the underlying mechanisms of common triggers for nausea and vomiting.
* Outline the actions and adverse effects of common classes of anti-emetic drugs.
Earn two hours of CPD
By reading this article and doing the associated online learning activities, you can receive a certificate for two hours of continuing professional development (CPD). Go to www.cpd4nurses.co.nz to complete the learning activities for this article. The online service costs $19.95 per article. These articles are supplied by CPD4nurses, an independent education company. CPD4nurses is not an NZNO service.
Table 1. Classes of anti-emetic drugs Class Drug name Most effective in Dopamine [D.sub.2] Metoclopramide PONV receptor Domperidone PINV (metoclopramide) Prochlorperazine 5-HT3 Ondansetron CINV (acute) receptor Tropisetron PONV antagonists Substance P Aprepitant CINV (delayed) NK-1 receptor PONV antagonists Histamine [H.sub.1] Promethazine Motion sickness receptor Cyclizine PINV (dimenhydrinate antagonists Dimenhydrinate and diphenhydramine) Diphenhydramine Acetylcholine Hyoscine Motion sickness muscarinic Cyclizine PONV receptor antagonists Cannabinoid Nabilone (not CINV CB1 receptor currently agonists available in NZ) Corticosteroids Dexamethasone CINV Class Key adverse effects Dopamine [D.sub.2] Sedation receptor See p24, 'Dopamine antagonists' 5-HT3 Headache receptor Constipation antagonists QTc prolongation Substance P Fatigue NK-1 receptor Hiccoughs antagonists Dyspepsia Histamine [H.sub.1] Sedation receptor antagonists Acetylcholine Caution with muscarinic urinary retention, receptor glaucoma antagonists Cannabinoid Euphoria CB1 receptor Anxiety agonists Hallucinations Psychosis Corticosteroids Insomnia Hyperglycaemia Weight gain
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|Title Annotation:||CONTINUING PROFESSIONAL DEVELOPMENT|
|Publication:||Kai Tiaki: Nursing New Zealand|
|Date:||Dec 1, 2012|
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