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Physiology and Pharmacology of
Nausea and Emesis
Professor John Peters
E-mail: j.a.peters@dundee.ac.uk
Learning Objectives
Following this lecture, students should be able to:
 Recognise that nausea and vomiting are, in an ev...
Biology of Nausea and Vomiting
 Nausea and vomiting are an evolutionary strategy against food
poisoning (along with olfac...
Why are Nausea and Vomiting Important in a Modern World?
 Times have changed, but food poisoning
remains a serious issue ...
Overall Events in Vomiting
Vomiting (emesis) forceful propulsion of gastric contents out of the
mouth (from the Latin, vo...
Nausea
 Subjective, highly unpleasant, sensation – normally felt in throat and
stomach as a ‘sinking’ sensation (‘I am go...
Pathways and Stimuli Inducing Vomiting
Toxic materials in
gut lumen (e.g.
bacterial toxins, salts of
heavy metals, ethanol...
Pathways and Stimuli Inducing Vomiting
Absorbed toxic materials
and drugs in blood (e.g.
morphine, chemotherapeutic
agents...
Triggers for Vomiting (A Simplified Picture)
VC
CTZ
NTS
Motion (inner
ear), signalling
to vestibular
nucleus
Pain, repulsi...
Motor Outputs in Vomiting
 Motor output that co-ordinates vomiting is located in the brainstem
 ‘Vomiting centre’ - a hi...
Consequences of Severe Vomiting
Dehydration
Loss of gastric protons and chloride (causes hypochloraemic
metabolic alkalo...
Drug- and Radiation-Induced Emesis
 Many classes of drug (or treatments) predictably cause nausea
and vomiting
 Cancer c...
Major Classes of Antiemetic Drugs
5-HT3 receptor antagonists – ‘setrons’ (e.g. ondansetron,
palonosetron)
Used to suppres...
Reduce acute nausea, retching and vomiting in cancer patients
receiving emetogenic treatments (day 1)
Less effective dur...
Muscarinic acetylcholine receptor antagonists (e.g.
hyosine /scopolamine)
Probably block muscarinic acetylcholine recepto...
Histamine H1 receptor antagonists (e.g. cyclizine,
cinnarizine + many others)
N.b. many agents in this class also exert si...
Dopamine receptor antagonists (e.g. domperidone and
metoclopramide)
Used for drug-induced vomiting (e.g. cancer chemother...
Cannabinoid (CB1) receptor agonists (nabilone)
Used ideally in in-patient setting for treatment of cytotoxic
chemotherapy...
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Physiology and pharmacology of nausea and emesis 2015 jap

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Slide set for medical students discussing the physiology and pharmacology of nausea and vomiting. Provided by Professor John A Peters, University of Dundee.

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Physiology and pharmacology of nausea and emesis 2015 jap

  1. 1. Physiology and Pharmacology of Nausea and Emesis Professor John Peters E-mail: j.a.peters@dundee.ac.uk
  2. 2. Learning Objectives Following 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)
  3. 3. 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
  4. 4. 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)
  5. 5. Overall Events in Vomiting Vomiting (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
  6. 6. 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
  7. 7. Pathways and Stimuli Inducing Vomiting Toxic materials in gut lumen (e.g. bacterial toxins, salts of heavy metals, ethanol) Systemic toxins (e.g. cytotoxic drugs) Stimulate Enterochromaffin cells 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
  8. 8. Pathways and Stimuli Inducing Vomiting Absorbed 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
  9. 9. 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
  10. 10. 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
  11. 11. Consequences of Severe Vomiting Dehydration 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)
  12. 12. 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)]
  13. 13. Major Classes of Antiemetic Drugs 5-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’ Emesis Radiation 5-HT Circulating, or locally released 5-HT
  14. 14. 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 
  15. 15. 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) 
  16. 16. 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 
  17. 17. 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
  18. 18. 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

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