Pharmacology 15 – Anti-Emetics

Anil Chopra

  1. To describe, in broad terms, the control of vomiting
  2. To state the receptor specificity, the main sites of action and the specific antiemetic uses of promethazine, metoclopramide, hyoscine and ondansetreon (see Fig.).
  3. To list the main pharmacokinetic features and unwanted actions of specific drugs.

Anti emetics are used only when the cause of nausea/vomiting is known. Stimuli include:

-Peripheral organs

  • Pharynx
  • Stomach
  • Duodenum
  • Heart
  • Bladder
  • Uterus
  • Viscera
  • Testicles

-Endogenous Toxins

  • Infections
  • Cancer
  • Chemotherapeutic agents
  • Radiation damage
  • Morphine
  • Cardiac glycosides,
  • Estrogen (early pregnancy)
  • Recovery from general anaesthesia

-Motion sickness

-Emotional

-

There are 4 main stimuli for the vomiting pathway:

  • Peripheral Organs – e.g. pharynx, stomach, duodenum, heart, testicles, bladder, uterus etc
  • Endogenous Toxins – e.g. drugs, infections, cancer, radiation damage, morphine, chemotherapeutic agents, cardiac glycosides, estrogen (early pregnancy) and recovery from general anaesthesia
  • Motion Sickness
  • Pain etc - repulsive sights and smells, and emotional factors

All of these inputs feed to the vomiting centre (lower medulla, reticular formation, dorsal Vagal nucleus) which gives a co-ordinated response to nerves supplying somatic and visceral receptors (e.g. respiratory and abdominal muscles) to allow for vomiting

-Receptors and neurotransmitters involved:

  • AChM = Muscarinic ACh receptor
  • H1 = Histamine receptors
  • 5-HT3 = Serotonin receptors
  • D2 = Dopamine Receptor

Inducing Vomiting

Name:

Promethazine

Uses

-Motion sickness

-Disorders of labyrinth e.g. Meniere’s disease

-Hyperemesis gravidarium (morning sickness in pregnancy)

-Pre and post operatively (sedative and anti muscarinic actions useful)

-Relief of allergic symptoms

-Anaphylactiv emergency

-Night Sedation (in insomnia)

Mode of Action

It acts as a competitive antagonist at histaminergic (H1) cholinergic (muscarinic, M) and dopaminergic (D2). Potency H1 > M > D2 receptors. It also acts on the labyrinth, NTS (nucleus of the solitary tract), vomit centre to block its activation.

Side-Effects

  • Dizziness
  • Tinnitus
  • Fatigue
  • Sedation (‘do not drive or operate machinery')
  • Excitation in excess
  • Convulsions (children more susceptible)
  • Antimuscarininc side-effects

Pharmacokinetics

Administer orally

Onset of action 1-2 hours

Maximum effect circa 4 hours

Duration of action 24 hours

Name

Metoclopramide

Uses

Used to treat nausea and vomiting associated with:

  • uraemia (severe renal failure)
  • radiation sickness
  • gastrointestinal disorders
  • cancer chemotherapy (high doses) eg. cisplatin (intractable vomiting)

Mode of Action

It is also a dopamine receptor antagonists. Order of antagonistic potency: D2 > H1 > Muscarinic receptors. It acts centrally at the chemoreceptor trigger zone and on the gastrointestinal tract by increasing smooth muscle motility (from oesophagus to small intestine), accelerating gastric emptying and accelerating transit of intestinal contents (from duodenum to ileo-coecal valve).

Side Effects

As it increases GI motility, it can cause reduce nutrient supply and effectiveness of certain drugs such as digoxin.

In CNS

  • drowsiness
  • dizziness
  • anxiety
  • extrapyramidal reactions; children more susceptible than adults (Parkinsonian-like syndrome: rigidity, tremor, motor restlessness)

NOTE: No anti-psychotic actions

In the endocrine system

  • hyperprolactinaemia
  • galactorrhoea
  • disorders of menstruation

Pharmacokinetics

  • may be administered orally; rapidly absorbed; extensive first pass metabolism
  • may also be given i.v.
  • crosses Blood brain barrier
  • crosses placenta

Name

Hyoscine

Uses

  • Prevention of motion sickness
  • Has little effects once nausea/emesis is established
  • In operative pre-medication

NOTE: Atropine is less effective

  • Also has sedative properties unlike atropine which is exctiatory

Mode of Action

It is an anti-muscarinic drug but also acts in the vestibular nuclei, nucleus of the solitary tract, and vomiting centre to block activation.

Side Effects

Typical anti-muscarinic side-effects:

  • drowsiness
  • dry mouth,
  • cycloplegia
  • mydriasis
  • constipation (not usually at anti-emetic doses)

Other

Can be administered orally (peak effect in 1-2 hours), i.v., transdermally

Name

Ondansetron

Uses

  • main use in preventing anticancer drug-induced vomiting, especially cisplatin
  • radiotherapy-induced sickness
  • post-operative nausea and vomiting

Mode of Action

Acts to block transmission in visceral afferents and chemoreceptor trigger zone.

Side Effects

  • headache
  • sensation of flushing and warmth
  • increased large bowel transit time (constipation)

Other

Administer orally; well absorbed, excreted in urine.