Anti-emetics Flashcards
what is nausea?
subjective, unpleasant sensation in the throat and stomach; often precedes vomiting.
what is vomiting?
forceful propulsion of stomach contents out of the mouth.
what precedes nausea and vomiting?
salivation, sweating and increased heart rate.
describe the physiological vomiting pathway
o Deep breath, glottis closes and the larynx rises to open the upper oesophageal sphincter. Soft palate elevates.
o Diaphragm contracts sharply to create a negative intrathoracic pressure to facilitate sphincter opening.
o Whilst diaphragm contracts, abdominal walls contract to squeeze the stomach and raise intra-gastric pressure. With the pylorus closed and the upper sphincters open, pressure escapes proximally.
what are the consequences of acute and chronic nausea?
o Acute nausea – interferes with mental/physical activity.
o Chronic nausea – very debilitating.
what are the consequences of severe vomiting?
1) Dehydration.
2) Hypochloraemic metabolic alkalosis (Loss of gastric HCl)
3) hypokalaemia.
(Reduction in renal HCO3- excretion / increased reabsorption–> increased sodium reabsorption and potassium excretion)
where is the vomiting centre located?
the area postrema specifically is located in the medulla of the brainstem
where is the chemoreceptor trigger zone located?
in the medulla
what is significant about the location of the vomiting centre and the CTZ?
they have very porous BBBs
what cranial nerves are involved signalling vomiting?
CN IX and X
what system is involved in motion sickness (children particularly)?
vestibular system (labrinyth)
what are some causes of nausea and vomiting?
- chemotherapy e.g. cisplatin
- motion sickness
- gastroparesis
how does cisplatin induce nausea and vomiting?
- cisplatin is toxic to enterochromaffin cells that line the GIT
- damage leads to the release of free radicals
- there is excess 5HT release which activates the CTZ by binding to its 5HT3a receptors
what does 5HT bind to in the CTZ to induce nausea and vomiting?
5HT3a receptors (ligand gated ion channel)
what is the treatment option for chemotherapy induced vomiting?
Ondansetron (serotonin receptor antagonist)
given as triple therapy with cortiocosteroids e.g. glucocorticoids and aprepitant (neurokinin-1 receptor antagonist)
o Preventing anti-cancer drug-induced vomiting.
o Radiotherapy-induced sickness.
o Post-operative nausea and vomiting.
what is ondansetron? what does it do?
Serotonin (5-hydroxytryptophan) receptor antagonists
–> 5-HT3a
- Blocks transmission in visceral afferents (vagus and splanchnic nerves) that use serotonin receptors
- primary site: CTZ and GIT
why is ondansetron given with glucocorticoids at times?
serotonin receptor antagonist:
to have an anti-inflammatory effect
reduce the production of free radicals
use for anti-cancer drugs like cisplatin
why is ondansetron given as triple therapy?
anti-cancer treatment e.g. chemotherapy induced nausea and vomiting is biphasic
ondansetron is used to treat the first stage while the other 2 drugs are used to treat the second stage
describe ondansetron pharmacokinetics
Oral (well absorbed, excreted in urine)
– needs good renal function
what are some unwanted side effects of ondansetron?
o Headache.
o Sensation of flushing and warmth.
o Constipation – increased large bowel transit time.
how does motion sickness induce nausea and vomiting?
- there is a labyrinthine neuronal mismatch leading to the activation of H1 receptors
- these histamine receptors on the vestibular nuclei
- they have an afferent to the CTZ which bind to muscarinic receptors on the CTZ
- N&V induced
what is the treatment option for motion sickness induced nausea and vomiting?
promethazine and/or hyoscine
promethazine (H1 antagonist)used in: o Motion sickness – used prophylactically normally. o Disorders of the labyrinth – i.e. Meniere’s disease. o Hyperemesis gravidarium – a complication of pregnancy. o Pre- and post-operatively. o relief of allergy, combat anaphylaxis, night sedation.
hyoscine can be used in pre-operative medication.
what is promethazine?
- order of potency
Mixed receptor antagonist: phenothiazine derivative
Consider it as H1 antagonist
o Potency on receptors: H1>M>D2.
o other phenothiazines can have greater antagonistic effects on D2 to acts as neuroleptics.
describe the pharmacokinetics of promethazine
o Administration= Oral.
o Onset of action= 1-2 hours - Maximum effect at 4 hours.
o Duration of action= 24 hours.
what are the unwanted side effects of promethazine?
- Dizziness.
- Fatigue.
- Sedation
- Anti-muscarinic effects.
- Tinnitus.
- Excitation in excess
- Convulsions.
what is hyoscine?
- order of receptor potency
- systems it acts on
non-selective muscarinic receptor antagonist
mainly for motion sickness
o Antagonistic potency order: Muscarinic >>> D2/H1. o Acts centrally: - vestibular nuclei--> , mAChR, H1 MAIN - CTZ --> D2 - vomiting centre-->mAChR,H1
when should hyoscine be given?
as Prophylaxis:
before nausea has been established (has little effective after nausea is established) therefore preoperatively
describe the pharmacokinetics of hyoscine
Muscarinic receptor antagonist
- peak effect in 1-2 hours
- oral, trans-dermal.
what are the unwanted side effects of hyoscine?
- Drowsiness
- Dry mouth
- Cycloplegia – paralysis of ciliary muscles.
- Mydriasis
- Constipation
what is gastroparesis?
delayed stomach emptying due to reduced contractions
how does gastroparesis induce nausea and vomiting?
- release of 5HT (serotonin)
- activates 5HT3aR on the CTZ
- N&V via D2 receptors on CTZ
what is the treatment option for gastroparesis induced nausea and vomiting?
Metoclopramide, Domperidone (D2 antagonists)
these have pro-kinetic effects
what are Metoclopramide and Domperidone?
- potency order
- system target
- additional effect
D2-Receptor Antagonists
oAntagonistic potency order:
D2»_space; H1»_space;> muscarinic receptors.
o Acts centrally, especially on the CTZ.
o Pro-kinetic effects in the GI tract – i.e. effects of PNS
what is the benefit of using D2 receptor antagonists like metoclopramide in gastroparesis?
Has pro-kinetic effects in the GI tract:
- Increase SM motility
- accelerate gastric emptying
- accelerate transit through tract
- Less to vomit.
why do D2 receptor antagonists acting on the CTZ not treat motion sickness?
Vestibular system puts direct input into the vomiting centre
blocking H1 would be most effective in this case
what are the use of metoclopramide?
D2 antagonist
o Uraemia – due to renal failure. o Radiation sickness. o GI disorders. o Cancer chemotherapy – high doses. o Schizoprenia o Parkinson’s disease treatments – block the large DA transmission induced by the Parkinson’s drugs ONLY in the CTZ and not where the treatments are working on.
describe the pharmacokinetics of D2 receptor antagonists like metoclopramide and domperidone?
o Administration: Oral (extensive 1st-pass metabolism), IV.
o Metoclopramide crosses the BBB (so CNS side effects).
o both cross the placenta
– care must be taken with the bioavailability of both drugs.
o Absorption/effectiveness of digoxin may be reduced.
o Nutrient supply may be compromised; especially important in diabetes mellitus patients.
what are the unwanted side effects of the metoclopramide and domperidone?
have CNS effects (as they cross BBB) and have an endocrine effect
CNS effects (mainly metoclopramide): - Drowsiness - Dizziness - Anxiety. - Extra-pyramidal reactions (EPS) – children more susceptible – Parkinson’s-like syndrome.
Endocrine system effects:
- Hyperprolactinaemia (dopamine inhibits prolactin)
- Galactorrhoea
- Disorders of menstruation
what are some mechanistic triggers of nausea and vomiting?
- cytotoxic drugs
- bacterial toxins
- motion sickness
- GI problems
- pregnancy
- higher function problems
what are the main categories of drugs used to treat nausea and vomiting?
- Muscarinic receptor antagonists (motion sickness)
- Histamine receptor antagonists (motion sickness)
- D2 receptor antagonists (gastroparesis)
- 5HT3a receptor antagonists (chemotherapy)
- cannabinoids
summary of main side effects
musc –> drowsiness, dry mouth , blurred vision
H1–> drowsiness
D2–> EPS, sedation, fatigue, restlessness
5HT3a–> headaches, GI upsets (uncommon)
what are the receptor targets of promethazine?
what are the system targets ?
as its a mixed receptor competitive antagonist: - histaminergic (H1) MAIN - cholinergic (muscarinic) - dopaminergic (D2) receptors. [H1>mAChR>D2]
Acts centrally
- vestibular nucleus–> H1
- CTZ–> Musc, D2
- vomiting centre (VC)
what are the projections from the vestibular system to the vomiting centre?
vestibular nuclei projections
also to CTZ
what are the projection from the GIT and periphery to the vomiting centre?
vagus
glossopharyngeal
splanchnic
SNS ganglia
(vagus and splanchnic only to CTZ)
