Vomiting and nausea (1)

Question 1

Nausea and vomiting

Answer 1

• Nausea- (prodromal- signs and symptoms before you get the illness i.e. proceeds vomiting) conscious recognition that the vomiting centre has been stimulated
• Vomiting (emesis) forcible ejection of stomach contents through the mouth

Question 2

Vomiting

Answer 2

• Defence mechanism- ingestion of toxic substances
• Bacterial and viral infection- too much can be bad- cause malnutrition or dehydration
• Vestibular disorders (motion sickness, Meniere’s disease)
• Pregnancy (usually 1st trimester, hyperemesis gravidarum- serious)
• Iatrogenic (drug-induced) vomiting- chemotherapy, Parkinson’s
• Migraine-
• Deranged biochemistry (hypercalcaemia, uraemia)

Question 3

How is vomiting controlled

Answer 3

• The vomiting centre in the brain consists of 2 areas located symmetrically in the medulla
  
  • These area’s co-ordinate the sequence of muscular contractions
• Chemoreceptor Trigger Zone (CTZ) consists of twin area’s in the floor of the 4th ventricle partially outside the BBB (good because a lot of noxious chemicals can’t cross the brain) - this is helpful as most drugs can’t cross the BBB
  
  • It detects noxious ingested chemical stimuli and may be stimulated centrally by parenteral drugs
  • The CTZ stimulates the vomiting centre

Question 4

Vomiting reflex

Answer 4

• Nausea has to reach a threshold
• 1st part is wrenching
• retroperistalsis contraction- muscle contracts to move contents of stomach toward the mouth
• Posture
• Hypersalivation
• Abdominal muscle contraction
• Relaxation of gastric fundus and lower oesophageal sphincter
• Stop respiring
• Expulsion

Question 5

The vomiting reflex

Nausea has to reach a threshold

1st part is wreching

Answer 5

• Regulated centrally by
  
  • Central pattern generator for vomiting- produce rhythmic pattern even when there is no input (Walking, breathing, chewing)
  • CTZ- D₂, 5-HT₃
• Bits of the brain involved
  
  • CTZ (area postrema) sensitive to circulating chemical stimuli (BBB permeability)
  • Area postrema neurones project into nucleus tractus solitaries which also receives input from vagus nerve (parasympathetic nervous system), enterochromaffin (endocrine cells- excrete gastric acid and histamine), vestibular and limbic system
• Proposed that afferent relay station’ relays outputs
• Lead to vomiting
• Higher centres- sight, smell, sound can also produce vomiting

Question 6

Pathways involved in nausea and vomiting

Answer 6

• Interactions between central and peripheral pathways contribute
• Peripheral- gastric mucosa, smooth muscle (parts of the enteric brain - part of the GI)
• Afferent (central)- Area pro streams, vomiting centre, NTS
• Most important receptors
  
  • H1, mACh, D₂, 5-HT3, NK-1, Mu and sigma opioid
• Enteric brain and mucosa monitors mucosal irritation, muscle contraction to trigger vomiting
• The dorsal-lateral reticular centre receives a signal from auditory nerve and visceral nerve via the NTS
• Humoural factors- transmitted through the circulatory system (hormones, proteins)
• Increased intra-cranial pressure= cause vomiting

Question 7

Control of nausea and vomiting

Answer 7

• Anatomical vomiting centre unlikely- central pattern generator for vomiting- diffuse neuronal areas in medulla

Question 8

Receptors involved in nausea and vomiting

Answer 8

• Acetylcholine (muscarinic)- mACh
• Histamine (H1)
• 5-HT 3,2,4
• D₂
• Substance P (neurokinin-1 receptors of CTZ
• Enkephalins (CTZ, Mu and sigma opioid receptor)- 40% similar
• Cannabinoids

Question 9

What drugs would interact with this system

Answer 9

*

Question 10

Classes of anti-emetics agents

1. Histamine 1 antagonists

Answer 10

• Cyclizine (mAC, H1)
• Cinnarizine (H1, mACh)
• Promethazine (D₂, H1, mACh)
• N and V of pregnancy
• General anti-emetic activity but little activity at CTZ- CTZ doesn’t have H1 or mACh receptors
• Motion sickness and vestibular disorders
• Causes drowsiness and sedation

Question 11

Classes of anti-emetics

2. Muscarinic receptor antagonists

Answer 11

• Hyoscine hydrobromide
• Motion sickness
• Transdermal patch- applied several hours before travelling
• Chewable tablets
• Side effects of anti-muscarinic agents (any at risk groups)
  
  • Elderly- at risk of falls

Question 12

Classes of anti-emetics

3. Phenothiazine related drugs

Answer 12

• Prochlorperazine
• Chlorpromazine
• Trifluoperazine
• Perphenazine
• Haloperidol
• Levomepromazine (5-HT₂ antagonism)
• Olanzapine (5-HT₂ receptor antagonism)
• D₂ antagonists- Central action (CTZ), May block H1 and M
• Dystonic reactions and hypotension
  
  • Suppositories + Buccal tablets

Question 13

Classes of anti-emetics

4. Benzamides

Metoclopramide

Answer 13

• D₂ antagonists and 5-HT₄ agonist
• Related to phenothiazines
• Central action at CTZ
• Peripheral action GIT- good as it slows down the GIT (peristalsis)
• Prolactin release- galactorrhoea
• Movement disorders- fatigue, motor restlessness, spasmodic torticollis- very painful uncontrollable contraction of muscles in the neck, oculogyric crisis- eyes deviate upwards
• NB- parkinsonian-like symptoms due to antagonism of DA
• don’t use in under the 20’s- due to irreversible tardive dyskinesia
  
  • Treat with procyclidine (anti-muscarinic)

Question 14

Classes of anti-emetics

4. Benzamides- domperidone

Answer 14

• D₂ antagonist
  
  • Related to phenothiazines
• Central action at CTZ
• Peripheral action GIT
• Not readily pass BBB, less likely to cause central side effects
• t_1/2 4-5 hours
• QT interval prolongation

Question 15

Classes of anti-emetics

5. Selective 5-HT₃ antagonists

Answer 15

• Ondansetron, granisetron, tropisetron, dolasetron
  
  • Effective at CTZ and vagal afferents in GI tract
• chemotherapy radiation-induced nausea and vomiting
  
  • Post operative N & V
• The action mainly CTZ also in the gut wall
  
  • Headache and constipation
  • Reduces analgesic effect of tramadol
  • Cost
• PONV= postoperative nausea and vomiting

Question 16

Classes of anti-emetics

6. Cannabinoids

Answer 16

• Nabilone
  
  • Some antiemetic action
• Nabilone effective at CTZ
  
  • Effect antagonised by naloxone
• Active metabolite with longer half-life than nabilone
  
  • Onset action 60-90 min, duration of action 8-12 hr- don’t have to give very often
• Occasionally used for chemotherapy associated nausea and vomiting
  
  • Side effects, drowsiness, dysphoria, dry mouth, visual disturbances

Question 17

Classes of anti-emetics

7. Dexamethasone

Answer 17

• Usually for chemotherapy induced vomiting together with other agents (doperidone, 5-HT₃ antagonist)
• Precise mode of action unclear, mediated via endorphins
• Only a short term- due to negative effects of corticosteroids

Question 18

Classes of anti-emetics

8. Neurokinin 1 receptor antagonists

Aprepitant fosapreitant

Answer 18

• Licensed for prevention of acute and delayed nausea and vomiting associated with cisplatin based regimens- chemotherapy
• Given with 5-HT₃ antagonist and dexamethasone
• cost

Question 19

How do NK-1 antagonists works

Answer 19

• Compete with substance P, and endogenous ligand
• Area Postrema and Nucleus Tractus Solitarius (NTS)
• Interfere with the terminal emetic pathway