Slide set for medical students discussing the physiology and pharmacology of nausea and vomiting. Provided by Professor John A Peters, University of Dundee.
2. Learning Objectives
Following this lecture, students should be able to:
ï Recognise that nausea and vomiting are, in an evolutionary context, adaptive
ï Describe the key events in vomiting
ï Provide a brief description of nausea
ï Appreciate pathways and stimuli which cause vomiting
ï Note some major consequences of severe vomiting
ï Be aware of the role of the chemoreceptor trigger zone (CTZ), nucleus tractus
solitarius (NTS) and âvomiting centre (VC)â in vomiting
ï Describe motor outputs that co-ordinate vomiting
ï Categorise the major classes of antiemetic drugs, their clinical uses and be
able to state, in outline, their proposed mechanisms of action
âą 5-HT3 receptor antagonists
âą Muscarinic receptor antagonists
âą Histamine (H1) receptor antagonists
âą Dopamine receptor antagonists
âą Neurokinin1 (NK1) receptor antagonists
âą Cannabinoid (CB1) receptor agonists
Recommended reading:
Rang and Daleâs 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. Biology of Nausea and Vomiting
ï Nausea and vomiting are an evolutionary strategy against food
poisoning (along with olfactory cues and taste to detect which foods are safe)
ï Emesis (vomiting), along with diarrhoea, helps rid the G.I. tract of
dangerous ingested substances
ï 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
ï 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
ï± 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 â the mechanisms cannot be the same
ï Purpose of nausea might be as an unconditioned stimulus that drives
conditioned flavour aversions (CFA) â a learned response that
discourages us from consuming food that makes us feel sick
4. Why are Nausea and Vomiting Important in a Modern World?
ï Times have changed, but food poisoning
remains a serious issue â 500,000 cases
annually in UK from known pathogens
(e.g. Campylobacter) â Salmonella
accounted for 2,500 hospital admissions
ï Protective systems can be activated by âmodern conditionsâ
ï± Many drug treatments (see later)
ï± Surgical procedures (associated with trauma, or a general anaesthetic)
ï± Motion (vection) (âânauseaââ refers to seasickness: Greek âânausââ meaning ship).
Generally attributed to sensory conflict regarding position of body in space (rather
puzzling given an early evolutionary origin)
ï Pregnancy-induced nausea and vomiting, during the first trimester,
can be viewed as an adaptive advantage
ï± Encourages âpickyâ eating during a time of rapid foetal growth (CNS
vulnerable to toxicosis)
ï± Is normally associated with a healthy pregnancy in the first trimester,
but may also dramatically compromise health and wellbeing (e.g.
hyperemesis gravidarum)
5. Overall Events in Vomiting
ïVomiting (emesis) forceful propulsion of gastric contents out of the
mouth (from the Latin, vomitorium, a âfast exitâ passageway from an ancient theatre)
ïIs not due to stomach contraction â stomach, oesophagus and
associated sphincters are relaxed
ïVomiting 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
ïVomiting is frequently preceded by profuse salivation, sweating,
elevated heart rate and the sensation of nausea
6. Nausea
ï Subjective, highly unpleasant, sensation â normally felt in throat and
stomach as a âsinkingâ sensation (âI am going to be sickâ)
ï Acute nausea interferes with mental and physical activity, often relieved by
vomiting
ï 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)
ï 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. 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
âvomiting centreâ
Key:
CTZ - chemoreceptor
trigger zone within the
area postrema (AP)
NTS â nucleus tractus
solitarius
Brainstem in cross section
= vagus
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 âvomiting
centre (VC)â
Vestibular system
[labyrinths] (e.g. motion
sickness; Meniereâs 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
10. Motor Outputs in Vomiting
ï Motor output that co-ordinates vomiting is located in the brainstem
ï âVomiting centreâ - 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
(â rate, force)
Salivary glands
(â secretion)
(relaxation)
Skin
(pallor, cold sweating)
Sphincters of
bladder and anus
(constriction)
Prodromal signs often precede vomiting
11. Consequences of Severe Vomiting
ïDehydration
ïLoss of gastric protons and chloride (causes hypochloraemic
metabolic alkalosis, raising of blood pH)
ïHypokalaemia. Mediated by the kidney, proton loss is accompanied
by potassium excretion
ïRarely, loss of duodenal bicarbonate may cause metabolic acidosis
ïRarely, eosophageal damage (Mallory-Weiss tear)
12. Drug- and Radiation-Induced Emesis
ï Many classes of drug (or treatments) predictably cause nausea
and vomiting
ï± Cancer chemotherapy (e.g. cisplatin, doxorubicin) and radiotherapy
(release of 5-HT and substance P from enterochromaffin cells in the gut)
ï± Agents with dopamine agonist properties (e.g. levodopa used in
Parkinsonâs disease). Dopamine D2 receptors are prevalent in the CTZ
ï± Morphine and other opiate analgesics (tolerance develops)
ï± Cardiac glycosides (e.g. digoxin)
ï± Drugs enhancing 5-HT function (e.g. SSRIs; 5-HT3 receptors are
prevalent in the CTZ)
ï± Operations involving the administration of a general anaesthetic [post-
operative nausea and vomiting (PONV)]
13. Major Classes of Antiemetic Drugs
5-HT3 receptor antagonists â âsetronsâ (e.g. ondansetron,
palonosetron)
ïUsed to suppress chemotherapy- and radiation-induced emesis
and post-operative nausea and vomiting
ïBlock 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
âVomiting
centreâ
Emesis
Radiation
5-HT
Circulating, or locally
released 5-HT
14. ïReduce acute nausea, retching and vomiting in cancer patients
receiving emetogenic treatments (day 1)
ïLess effective during subsequent treatments (delayed phase) â
improved by the addition of a corticosteroid (mechanism uncertain)
and a neurokinin1 (NK1) receptor antagonist (see later)
ïGenerally well tolerated â most common unwanted effects are
constipation and headaches
ïNot effective against motion sickness,
or vomiting induced by agents
increasing dopaminergic transmission
ï
15. Muscarinic acetylcholine receptor antagonists (e.g.
hyosine /scopolamine)
ïProbably block muscarinic acetylcholine receptors at multiple
sites (e.g. vestibular nuclei, NTS, vomiting centre)
ïDirect inhibition of G.I. movements and relaxation of the G.I. tract
may contribute (modestly) to anti-emetic effects
ïHave numerous unwanted effects resulting from blockade of the
parasympathetic ANS (e.g. blurred vision, urinary retention, dry
mouth) and centrally-mediated sedation
ïUsed for prophylaxis and treatment of
motion sickness (can be delivered by
transdermal patch)
ï
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
ïGenerally cause CNS depression and sedation â drowsiness
may affect performance of skilled tasks (but sedation might actually be
desirable in palliative care)
ïAction attributed to blockade of H1 receptors in vestibular nuclei
and NTS
ïUsed 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
ï
17. Dopamine receptor antagonists (e.g. domperidone and
metoclopramide)
ïUsed for drug-induced vomiting (e.g. cancer chemotherapy, treatment
of Parkinsonâs disease with agents stimulating dopaminergic
transmission) and vomiting in gastrointestinal disorders. Use in
children is restricted â consult BNF
ïDomperidone 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))
ïComplex mechanism of action (a lack of understanding of the source of
dopamine to stimulate dopamine receptors in many circumstances does not help!)
âą Centrally block dopamine D2 (and D3) receptors in the CTZ
âą Peripherally exert a prokinetic action on the oesophagus,
stomach and intestine
Phenothiazines â which owe part of their action to dopamine D2
blockade â are used for severe nausea and vomiting
ïNot effective against motion sickness
18. Cannabinoid (CB1) receptor agonists (nabilone)
ïUsed ideally in in-patient setting for treatment of cytotoxic
chemotherapy that is unresponsive to other anti-emetics
ïDecreases vomiting induced by agents stimulating the CTZ.
Evidence suggests that opiate receptors are involved in drug
effect
ïNumerous unwanted effects; drowsiness, dizziness, dry mouth,
mood changes are common
NK1 receptor antagonists (aprepitant)
ïUsed 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
ïExact site of action is uncertain, but antagonism of substance P
(which causes vomiting and is released by vagal afferents) is
assumed