Introduction

Antiemetics are widely used on a daily basis both in and out of hospital. Nausea is a common symptom that you will be expected to manage appropriately, in much the same way as effectively managing pain. This article runs through a step wise approach to understanding why nausea happens, and thus the best way to manage it effectively.

Physiology of Nausea and Vomiting

Vomiting is the emptying of upper GI tract contents, and is a feature of the body’s defence against toxin ingestion.
Nausea is the unpleasant sensation that is often a prodrome to vomiting itself.

• Control of vomiting is orchestrated by the Vomiting Centre (VC), a collection of nuclei in the medulla.
• Many inputs from a range of sources which act as triggers (See below)
• Efferent nervous stimulation to trigger vomiting is conducted by cranial nerves 5, 7, 9, 10 and 12, when a specific threshold is reached.

This causes vomiting through:

• Antiperistalsis
• The Vomiting Act
  • Deep breath
  • Upper oesophageal sphincter relaxation
  • Closure of the glottis (protects airway)Soft palate elevation (protects nasal passage)
  • Diapragmatic contraction
  • Abdominal wall contaction
  • Lower oesophageal sphincter relaxation

The causes of nausea are complex and multifactorial, but are most easily understood when broken down into 3 categories, based on the afferent inputs to the vomiting centre:

1. Visceral Stimulation
2. Chemoreceptor Trigger Zone (CTZ)
3. Higher cortical inputs (including vestibular system)

Visceral Stimulation

• Afferent fibres mainly from GI tract (but also cardiac)
• Mechanical or chemosensory receptors
• Conducted by both sympathetic and parasympathetic fibres (primarily the Vagus Nerve)

• Triggers: Direct visceral irritation and/or distension

• Neurotransmitters: Seretonin (5HT), Dopamine (DA)

• E.g. Gastroenteritis

CTZ

• Located on the floor of the 4^th ventricle
• Outside the blood brain barrier so exposed to systemic toxins, drugs etc.
• The prime site of ‘systemic’ triggers of vomiting.

• Triggers: Drugs, hormones, toxins, metabolic abnormalities

• Neurotransmitters: 5HT, DA

• E.g. Action of opioids at CTZ, causing nausea.

Higher Neurological Inputs

• Nervous inputs from higher neurological centres, including other cranial nerves.
• CN VIII (vestibular component) in particular can be linked to nausea
• The Gag reflex(CN IX afferent fibres) provides a strong trigger
• As with pain, there is a psychological component of nausea.

• Triggers: Emotions, smells, anticipatory nausea, motion sickness, vertigo, taste, gag reflex

• Neurotransmitters: Acetylcholine (ACh), Histamine (H), 5HT

• E.g. watch, listen and smell someone else being sick. Feeling nauseous?

Causes of Nausea and Vomiting

Before treating you should always have considered a cause, as nausea can be a symptom of a disease process.
The above physiology provides a good model for thinking about causes

Visceral

1. Obstructions: Small bowel obstruction, pyloric obstruction
2. Inflammatory: Pancreatitis, cholecystitis, appendicitis
3. Mechanical: gastroperesis,
4. Enteric infection: Viral or bacterial
5. Cardiac: Don’t forget MI as a cause

CTZ

1. Drugs: Opiates, Antibiotics, cytotoxics, NSAIDs
2. Metabolic: High Calcium, Low sodium, Uraemia, DKA, Pregnancy
3. Toxins: Alcohol

Higher neurological

1. Vestibular: Vertigo, Meniere’s disease.
2. Intracranial: Raised intracranial pressure, Infection
3. Psychological: Fear, anticipatory,
4. Sensory: Smell, taste, Pain (can be a trigger in itself)

Antiemetic Therapy

• Several different classes of antiemetics are available.
• Each have a slightly different efficacy and side effects profile.
• Choice should be guided by your understanding of the process that is causing the nausea.

Antihistamines

E.g: Cyclizine, Promethazine

• Act by blocking H₁ receptors within the VC
• Also have antimuscarinic properties, leading to some of their side effects profile.
• Good ‘broad spectrum’ of action, though not as potent as other classes in disorders not involving labyrinthine disorders.
• Conversely, the best class for labyrinthine disorders such as vertigo, motion sickness and Meniere’s disease.
• Also first choice in pregnancy associated nausea and vomiting, due to greater experience with them and apparent absence of teratogenic effects.

Side effects:

• Sedation: Particularly with promethazine
• Antimuscarinic properties: dry mouth and blurred vision. Should be used with caution when these actions could be problematic e.g. risk of urinary retention when prostatic hypertrophy, susceptibility to angle closure glaucoma.
• Hypotension: rare but caution demanded in heart failure patients

My favourite: Cyclizine (50mg) 8 hourly. IV, IM, or Oral route
A good starting point if not contraindicated, with multiple routes of administration.

Antimuscarinics

E.g. Hyoscine hydrobromide (a.k.a. scopolamine)

• Only really used for treatment of motion sickness
• Available in patch form for this indication

Side effects:

• Antimuscarinic properties: as above

Dopamine Receptor Antagonists

• Include the Phenothiazines, Metoclopramide, and Domperidone.
• All act at the CTZ by blocking dopamine receptors.
• Therefore valuable in the sickness caused by drugs, cytotoxics and diffuse malignancy

Phenothiazines and related drugs (the anti-psychotics)

e.g. Chlorpromazine, Prochlorperazine, Haloperidol

• Have anti-emetic actions at doses lower than for their anti-psychotic indication

Metoclopramide

• Also has some GI tract effect via its 5HT action.
• This action increases gut motility, and increasing gastro-oesophageal sphincter tone.
• This makes it a particularly effective choice against nausea of a visceral origin e.g. biliary disease.
• It also means it is contraindicated in gastrointestinal obstruction or perforation.

Domperidone

• Unlike the other classes does not cross the blood brain barrier.
• Lower incidence of the central side effects

Side Effects:

• Sedation
• Extrapyramidal side effects: Parkinsonian like symptoms, tardive dyskinesias, acute dystonic reactions.
• QT interval prolongation

My Favourite: Metoclopramide (10mg) 8 hourly. IV, IM, or Oral
Better action for visceral causes of nausea.

5HT₃ Receptor Antagonists

E.g. Ondansetron, granisetron

• Act by blocking the 5HT₃ receptors in the CTZ and in the gut.
• Highly effective, particularly against sickness caused by chemotherapy agents and in post operative nausea.
• More expensive so usually a second line agent.

Side effects:

• QT interval prologation: Avoid concomitant use of drugs which do the same
• Constipation
• Headache
• Flushing

Dexamethasone

• Weak anti-emetic on own but useful synergist when given with 5HT₃ receptor antagonists or some dopamine receptor antagonists.
• Can be given when high likelihood of nausea that may be difficult to control e.g. chemotherapy, previously bad post operative nausea.

Using Antiemetics

Now that we’ve learnt all about the cause of nausea, and the different drug classes available, it’s easier to work out how to treat different presentations.

1. Pregnancy associated nausea

• Antiemetics generally avoided where possible unless vomiting is becoming problematic e.g. dehydration.
• Short term use of an antihistamine is first choice, as greater history of use and better evidence of no teratogenic effects.
• Specialist advice should be sought if nausea is problematic for any longer than 48 hours.

2. Drug Induced

• Opioids: cyclizine or dopamine antagonists are usually an effective choice
• Chemotherapy:
  • Nausea is strongly mediated by 5HT.
  • If moderate effects predicted, dexamethasone and metoclopramide are usually sufficient.
  • If severe, a 5HT₃ receptor antagonist will be employed with dexamethasone, usually to good effect (80% control).

3. Post operative

• Risk of N&V can often be identified pre-operatively.
• Risk factors include: female, previous post-op nausea, non-smoker, peri-operative opioid use, general anaesthesia (particularly volatile agents), and type of surgery (particularly abdominal, gynae and ENT procedures).
• Preventative is usually better than reactive treatment, but blanket prophylaxis is not recommended, and should be guided by risk.
• Most classes of antiemetics will be effective, and can be combined as necessary to achieve control.
• Peri-operative antiemetics are frequently used and can be augmented with dexamethasone in higher risk individuals, or when vomiting will be particular problematic e.g. after eye surgery.
• Metoclopramide is one drug which is not as effective for this indication, and so its use is not recommended.

4. Motion sickness

• Hyoscine or an antihistamine (e.g. cyclizine) is generally effective.

References

• Textbook of Medical Physiology (11^th ed). Guyton A, Hall J. Elsevier Saunders. 2006
• Harrisons Principles of Internal Medicine (15^th ed). Braunwald E et al. McGraw-Hill. 2001
• The Merck Manual (18^th ed). Beers M et al. Merck Research Laboratories. 2006
• BNF. Issue 62
• Medicine at a Glance (2^nd ed). Davey P. Blackwell Publishing Ltd. 2006
• Medical Pharmacology and Therapeutics (2^nd Ed). Waller D et al. Elsevier. 2005
• Guideline for the Management of Postoperative Nausea and Vomiting. McKracken G et al. J Obstet Gynaecol Can 2008;30(7):600–607
• Society for Ambulatory Anesthesia Guidelines for the Management of Postoperative Nausea and Vomiting. Gan T et al. Anesth Analg 2007;105:1615–28.
• Practical Selection of Antiemetics. Zachary A et al. Am Fam Physician 2004;69:1169-74,1176.

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