Transcript CTZ - Dundee MBChB

Physiology and Pharmacology of
Nausea and Emesis
Professor John Peters
E-mail: [email protected]
Learning Objectives
Following this lecture, students should be able to:
 Provide a brief description of nausea
 Describe the key events in vomiting
 List the major consequences of severe vomiting
 Describe the various triggers for vomiting
 Be aware of the role of the chemoreceptor trigger zone (CTZ) and vomiting centre
(VC) in vomiting
 Know the major classes of antiemetic drugs, their clinical uses and be able to outline
their proposed mechanisms of action
• 5-HT3 receptor antagonists
• Muscarinic receptor antagonists
• Dopamine receptor antagonists
• Cannabinoids
Events in Vomiting
 Vomiting (emesis) forceful propulsion of gastric contents out of the
mouth
 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
oblogata of the brain stem
Deep inhalation
Repeats of
the cycle
Closure of glottis and
raising of soft palate
Ejection of
gastric
contents
Suspension of
breathing
Contraction of diaphragm
and abdominal muscles
compresses stomach
 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
 Acute nausea interferes with mental and physical activity, often relieved by
vomiting
 Chronic nausea is greatly debilitating
 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
Contraction of upper small intestine,
followed by contraction of pyloric
sphincter and pyloric region of
stomach
Movement of contents of upper
jejunum, duodenum and pyloric
region into the body and fundus of
the stomach
Relaxed lower and upper eosophageal sphincters and oesophagus set the stage for
retching and vomiting (which may, or may not, occur)
Consequences of Severe Vomiting
 Dehydration
 Loss of gastric protons and chloride (causes hypochloreamic
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)
Triggers for Vomiting
 Pain, repulsive sights, smells and
emotional factors
CTZ
 Motion sickness and vestibular
disorders
 Endogenous toxins, numerous
drugs, radiation
VC
Medulla
 Stimuli from pharynx, G.I. tract
and other viscera
 Pregnancy
Output to vagus nerve and spinal motor neurones
 Intracranial pathology
VC = Vomiting centre
CTZ = Chemoreceptor trigger zone (located in the area postrema, detects
circulating emetic agents e.g. toxins, opiates, apomorphine)
Triggers for Vomiting
Pain, repulsive
sights, smells,
emotional factors
Motion (inner
ear), signalling
to vestibular
nucleus
Pharyngeal stimulation,
gastric/duodenal
distension, or irritation
NTS
CTZ
Retching,
vomiting
VC
NTS = nucleus tractus solitarius
Endogenous
toxins, drugs,
vagal afferents
Lacks blood brain
barrier (BBB)
Drug- and Radiation-Induced Emesis
Many classes of drug (or treatments) predictably cause nausea
and vomiting
 Cancer chemotherapy and radiotherapy (release of 5-HT from
enterochromaffin cells in the gut)
 Operations involving the administration of a general anaesthetic [postoperative nausea and vomiting (PONV)]
 Agents with dopamine agonist properties (e.g. 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 (5-HT3 receptors are prevalent in the
CTZ)
Major Classes of Antiemetic Drugs
5-HT3 receptor antagonists (e.g. ondansetron)
 Used to suppress chemotherapy- and radiation-induced emesis
and post-operative nausea and vomiting
 Block peripheral and central 5-HT3 receptors
Cytotoxic drug
Circulating, or locally
released 5-HT
Peripheral
terminal in gut
5-HT
Vagal afferent
Central
terminal
AP (containing
CTZ) and NTS
Vomiting centre
Radiation
= 5-HT3 receptor
AP = area postrema; NTS = nucleus tractus solitarius
Emesis
 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)
 Not effective against motion sickness, or vomiting induced by
agents increasing dopaminergic transmission
 Generally well tolerated – most common unwanted effects are
constipation and headaches
Muscarinic acetylcholine receptor antagonists (e.g. hyosine
/scopolamine)
 Used for prophylaxis and treatment of motion sickness (can be
delivered by transdermal patch)
 Probably block muscarinic acetylcholine receptors at multiple
sites (e.g. vestibular nuclei, nucleus of the solitary tract, 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
Histamine H1 receptor antagonists (e.g. cyclizine + many others)
N.b. many agents in this class also exert significant blockade of
muscarinic receptors that probably contributes to their activity
 Used for prophylaxis and treatment of motion sickness and
acute labyrinthitis
 Action attributed to blockade of H1 receptors in vestibular nuclei,
nucleus of the solitary tract and area postrema
 Generally cause CNS depression and sedation – drowsiness
may affect performance of skilled tasks
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
 Complex mechanism of action
•Centrally block dopamine D2 receptors in the CTZ
•Peripherally exert a prokinetic action on the oesophagus,
stomach and intestine
 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))
 Not effective against motion sickness
Phenothiazines – which owe part of their action to dopamine D2
blockade – are used for severe nausea and vomiting
Cannabinoids (e.g. 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