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Learning ObjectivesFollowing this lecture, students should be able to:
Recognise that nausea and vomiting are, in an evolutionary context, adaptive Describe the key events in vomiting Provide a brief description of nausea Appreciate pathways and stimuli which cause vomiting Note some major consequences of severe vomiting Be aware of the role of the chemoreceptor trigger zone (CTZ), nucleus tractus
solitarius (NTS) and ‘vomiting centre (VC)’ in vomiting Describe motor outputs that co-ordinate vomiting Categorise the major classes of antiemetic drugs, their clinical uses and be
able to state, in outline, their proposed mechanisms of action• 5-HT3 receptor antagonists• Muscarinic receptor antagonists• Histamine (H1) receptor antagonists• Dopamine receptor antagonists• Neurokinin1 (NK1) receptor antagonists• Cannabinoid (CB1) receptor agonists
Recommended reading:Rang and Dale’s Pharmacology (7th. Ed.) pp.365-367 (good Introduction to drug classes)Sanger GJ, Andrews PLR (2006). Treatment of nausea and vomiting: Gaps in our knowledge. Autonomic Neuroscience: Basic and Clinical 129: 3-16 (detailed review)
Biology of Nausea and Vomiting Nausea and vomiting are an evolutionary strategy against food
poisoning (along with olfactory cues and taste to detect which foods are safe)
Emesis (vomiting), along with diarrhoea, helps rid the G.I. tract of dangerous ingested substances
A vomiting response is present in most vertebrates, but apparently absent in several commonly used laboratory animals (e.g. mouse, rat, guinea-pig and rabbit). Perhaps due to the evolution of a specialised digestive physiology in rodents
Nausea is an aversive experience that often precedes/accompanies vomiting, but is not simply the result of low level stimulation that, if stronger, would evoke the vomiting response Drug-induced emesis in, for example, anti-cancer chemotherapy can
now be largely controlled with anti-emetic drugs, but nausea remains a very significant clinical problem – the mechanisms cannot be the same
Purpose of nausea might be as an unconditioned stimulus that drives conditioned flavour aversions (CFA) – a learned response that discourages us from consuming food that makes us feel sick
Why are Nausea and Vomiting Important in a Modern World?
Times have changed, but food poisoning remains a serious issue – 500,000 cases annually in UK from known pathogens (e.g. Campylobacter) – Salmonella accounted for 2,500 hospital admissions
Protective systems can be activated by ‘modern conditions’ Many drug treatments (see later) Surgical procedures (associated with trauma, or a general anaesthetic) Motion (vection) (‘’nausea’’ refers to seasickness: Greek ‘’naus’’ meaning ship).
Generally attributed to sensory conflict regarding position of body in space (rather puzzling given an early evolutionary origin)
Pregnancy-induced nausea and vomiting, during the first trimester, can be viewed as an adaptive advantage Encourages ‘picky’ eating during a time of rapid foetal growth (CNS
vulnerable to toxicosis) Is normally associated with a healthy pregnancy in the first trimester,
but may also dramatically compromise health and wellbeing (e.g. hyperemesis gravidarum)
Overall Events in VomitingVomiting (emesis) forceful propulsion of gastric contents out of the
mouth (from the Latin, vomitorium, a ‘fast exit’ passageway from an ancient theatre)
Is not due to stomach contraction – stomach, oesophagus and associated sphincters are relaxed
Vomiting is co-ordinated by the vomiting centre (VC) in the medulla oblongata of the brain stem
Suspension of intestinal slow wave activity
Retrograde contractions from ileum to stomach
Suspension of breathing (closed glottis - prevents
aspiration)
Relaxation of LOS- contraction of diaphragm and abdominal muscles
compresses stomach
Ejection of gastric contents through
open UOS
Repeats of the cycle
Vomiting is frequently preceded by profuse salivation, sweating, elevated heart rate and the sensation of nausea
Nausea Subjective, highly unpleasant, sensation – normally felt in throat and
stomach as a ‘sinking’ sensation (‘I am going to be sick’) Acute nausea interferes with mental and physical activity, often relieved by
vomiting
Chronic nausea is greatly debilitating
Movement of contents of upper jejunum, duodenum and pyloric
region into the body and fundus of the stomach
Contraction of upper small intestine, followed by contraction of pyloric
sphincter and pyloric region of stomach
Relaxed lower and upper eosophageal sphincters and oesophagus set the stage for retching and vomiting (which may, or may not, occur)
Nausea usually involves pallor, sweating and relaxation of the stomach and lower eosophagus resulting in tension in gastric and oesosphageal muscles triggering afferent nerve impulses: associated events are
Pathways and Stimuli Inducing VomitingToxic materials in
gut lumen (e.g. bacterial toxins, salts of heavy metals, ethanol)
Systemic toxins (e.g. cytotoxic drugs)
Stimulate Enterochromaffincells in mucosa
Release of mediators(e.g. 5-HT)
Depolarization of sensory afferent
terminals in mucosa (e.g. via 5-
HT3 receptors)
Action potential discharge in
vagal afferents to brainstem (CTZ
and NTS)
Co-ordination of vomiting by the
‘vomiting centre’
Key:CTZ - chemoreceptor trigger zone within the area postrema (AP)NTS – nucleus tractus solitarius
Brainstem in cross section
= vagus
Pathways and Stimuli Inducing VomitingAbsorbed toxic materials and drugs in blood (e.g.
morphine, chemotherapeutic agents)
Stimulate CTZ within the AP of brainstem (lacks an effective blood brain barrier (BBB)
Mechanical stimuli (e.g. pharynx); Pathology within the G.I. tract (e.g. gastritis), or other visceral organs (e.g. myocardial infarction)
Stimulate Vagal afferents to brainstem (CTZ
and NTS)
Co-ordination of vomiting by the ‘vomiting centre (VC)’
Vestibular system [labyrinths] (e.g. motion sickness; Meniere’s disease)
Vestibular nuclei
CTZ
Signalling through
Stimuli within the CNS (e.g. pain, repulsive sights and odours, fear, anticipation, psychological factors
Cerebral cortex, limbic
system
Medulla
Signalling through
Triggers for Vomiting (A Simplified Picture)
VC
CTZ
NTS
Motion (inner ear), signalling
to vestibular nucleus
Pain, repulsive sights, smells,
emotional factors
Retching, vomiting
Endogenous toxins, drugs, vagal afferents
Lacks blood brain barrier (BBB)
Pharyngeal stimulation, gastric/duodenal distension, or irritation
Motor Outputs in Vomiting Motor output that co-ordinates vomiting is located in the brainstem ‘Vomiting centre’ - a historically useful term, but not a discrete
anatomical centre - instead a group of interconnected neurones within the medulla that are driven by a central pattern generator (CPG) that in turn receives input from the NTS
Vagal efferents
Oesophagus(shortening)
Stomach(proximal
relaxation)
Small intestine
(giant retrograde
contraction)
Somatic motor neurones
Anterior abdominal
muscle(contraction)
Diaphragm(contraction)
Autonomic/somatic efferents
Heart(↑ rate, force)
Salivary glands(↑ secretion)(relaxation)
Skin(pallor, cold sweating)
Sphincters of bladder and anus
(constriction)Prodromal signs often precede vomiting
Consequences of Severe VomitingDehydration
Loss of gastric protons and chloride (causes hypochloraemic metabolic alkalosis, raising of blood pH)
Hypokalaemia. Mediated by the kidney, proton loss is accompanied by potassium excretion
Rarely, loss of duodenal bicarbonate may cause metabolic acidosis
Rarely, eosophageal damage (Mallory-Weiss tear)
Drug- and Radiation-Induced Emesis Many classes of drug (or treatments) predictably cause nausea
and vomiting Cancer chemotherapy (e.g. cisplatin, doxorubicin) and radiotherapy
(release of 5-HT and substance P from enterochromaffin cells in the gut)
Agents with dopamine agonist properties (e.g. levodopa used in Parkinson’s disease). Dopamine D2 receptors are prevalent in the CTZ
Morphine and other opiate analgesics (tolerance develops)
Cardiac glycosides (e.g. digoxin)
Drugs enhancing 5-HT function (e.g. SSRIs; 5-HT3 receptors are prevalent in the CTZ)
Operations involving the administration of a general anaesthetic [post-operative nausea and vomiting (PONV)]
Major Classes of Antiemetic Drugs5-HT3 receptor antagonists – ‘setrons’ (e.g. ondansetron, palonosetron)Used to suppress chemotherapy- and radiation-induced emesis
and post-operative nausea and vomiting Block peripheral and central 5-HT3 receptors (cation-selective ion channels)
AP (containing CTZ) and NTS
Peripheral terminal in gut
Central terminal
AP = area postrema; NTS = nucleus tractus solitarius
Vagal afferent
Cytotoxic drug
= 5-HT3 receptor
‘Vomiting centre’
EmesisRadiation
5-HT
Circulating, or locally released 5-HT
Reduce acute nausea, retching and vomiting in cancer patients receiving emetogenic treatments (day 1)
Less effective during subsequent treatments (delayed phase) – improved by the addition of a corticosteroid (mechanism uncertain) and a neurokinin1 (NK1) receptor antagonist (see later)
Generally well tolerated – most common unwanted effects are constipation and headaches
Not effective against motion sickness, or vomiting induced by agents increasing dopaminergic transmission
Muscarinic acetylcholine receptor antagonists (e.g. hyosine /scopolamine)
Probably block muscarinic acetylcholine receptors at multiple sites (e.g. vestibular nuclei, NTS, vomiting centre)
Direct inhibition of G.I. movements and relaxation of the G.I. tract may contribute (modestly) to anti-emetic effects
Have numerous unwanted effects resulting from blockade of the parasympathetic ANS (e.g. blurred vision, urinary retention, dry mouth) and centrally-mediated sedation
Used for prophylaxis and treatment of motion sickness (can be delivered by transdermal patch)
Histamine H1 receptor antagonists (e.g. cyclizine, cinnarizine + many others)
N.b. many agents in this class also exert significant blockade of muscarinic receptors that probably contributes to their activity
Generally cause CNS depression and sedation – drowsiness may affect performance of skilled tasks (but sedation might actually be desirable in palliative care)
Action attributed to blockade of H1 receptors in vestibular nuclei and NTS
Used for prophylaxis and treatment of motion sickness and acute labyrinthitis and nausea and vomiting caused by irritants in the stomach. Less effective against substances that act directly on the CTZ
Dopamine receptor antagonists (e.g. domperidone and metoclopramide)
Used for drug-induced vomiting (e.g. cancer chemotherapy, treatment of Parkinson’s disease with agents stimulating dopaminergic transmission) and vomiting in gastrointestinal disorders. Use in children is restricted – consult BNF
Domperidone does not cross the blood brain barrier and is less likely to result in the many unwanted effects of metoclopramide (e.g. disorders of movement (extrapyramidal effects))
Complex mechanism of action (a lack of understanding of the source of dopamine to stimulate dopamine receptors in many circumstances does not help!)
• Centrally block dopamine D2 (and D3) receptors in the CTZ• Peripherally exert a prokinetic action on the oesophagus,
stomach and intestine
Phenothiazines – which owe part of their action to dopamine D2 blockade – are used for severe nausea and vomiting
Not effective against motion sickness
Cannabinoid (CB1) receptor agonists (nabilone)Used ideally in in-patient setting for treatment of cytotoxic
chemotherapy that is unresponsive to other anti-emetics
Decreases vomiting induced by agents stimulating the CTZ. Evidence suggests that opiate receptors are involved in drug effect
Numerous unwanted effects; drowsiness, dizziness, dry mouth, mood changes are common
NK1 receptor antagonists (aprepitant)Used in combination with a 5-HT3 receptor antagonist and
dexamethasone in the acute phase of highly emetogenic chemotherapy. In combination with dexamethasone in the delayed phase
Exact site of action is uncertain, but antagonism of substance P (which causes vomiting and is released by vagal afferents) is assumed
