Anti-emetics Flashcards
Differentiate between nausea and vomiting
§ Nausea – subjective, unpleasant sensation in the throat and stomach; often precedes vomiting.
§ Vomiting – forceful propulsion of stomach contents out of the mouth.
o Both preceded by salivation, sweating and increased heart rate.
Summarise the vomiting process
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 abdominal organs contract in the vomiting pathway
Contraction of upper small intestine, pyloric sphincter and pyloric region of stomach
Contents of upper jejunum, duodenum and pyloric region of stomach move to the body and fundus of the stomach
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
Dehydration
Hypochloraemic metabolic alkalosis
Contributes to reduction in bicarbonate excretion and increase in bicarbonate reabsorption
Increase in sodium reabsorption and increase in potassium excretion (hypokalaemia)
Summarise the role of the vomiting centre and the chemoreceptor trigger zone
§ The vomiting centre and chemoreceptor trigger zone (CTZ) sit in a location in the brain with a very porous BBB.
o The CTZ and vomiting centre act as an early warning centre for the brain from toxin damage
How do signals reach the CTZ and vomiting centre from the stomach
§ CN 9 and 10 mediate signals from the stomach/heart to vomit- information detected by mechanoreceptors and chemoreceptors
Which classes of drug are known for causing nausea and vomiting
Chemotherapy (Cisplatin) for lung cancer
Chemotherapy induced nausea & vomiting (CINV)
Outline the pathophysiology of chemotherapeutic drug and how they cause nausea
Cisplatin is toxic to enterochromaffin cells (ECs) – release of free radicals (located in the stomach antrum)
Free radicals – excessive 5-HT release
5-HT – activates 5-HT3A receptors on nerve fibres to chemoreceptor trigger zone (CTZ)
CTZ activates nerves fibres to vomiting centre (VC)
VC nausea
When are anti-emetic drugs given
These drugs are indicated ONLY when the cause of the nausea/vomiting is known, otherwise they mask the diagnosis of potentially serious conditions,e.g. digoxin excess, diabetic ketoacidosis
Summarise the treatment for chemotherapy induced nausea and vomiting
Ondansetron - 5-HT3A receptor antagonist
Glucocorticoids - reduce free radical production(anti-inflammatory).
Aprepitant - neurokinin-1 receptor antagonist
Where is the CTZ located
Int the area postrema (lower medulla)
Has a very porous BBB- hence it can detect toxins in the blood.
Where is the vomiting centre located
Actually, this is not a discrete anatomical location but a network of neural pathways that integrate signals arriving from other locations.
Lower medulla, reticular formation, dorsal vagal nucleus
Describe the potential inputs into the CTZ
Endogenous toxins, drugs (infections, chemotherapy, radiation damage, morphine, cardiac glycosides, estrogen (early pregnancy), recovery from general anaesthesia)- these can be found in the blood or lead to the release of emetogenic agents (such as 5-HT, prostanoids and free radicals) WHICH EACH FEED INTO THE CTZ (ematogenics can also feed into visceral afferents).
Motion sickness- Labyrinth- vestibular nuclei- CSF- CTZ
Stimuli from pharynx, stomach and duodenum e.g heart,viscera (bladder and uterus and testicles) — visceral afferents — Nucleus of the solitary tract – Vomiting centre
Visceral afferents can also feed straight into the CTZ
Pain, repulsive sight and smell, emotional factors -sensory afferents and CNS pathways – higher centres- vomiting centre
Describe the cross-talk between the CTZ and the vomiting centre
The CTZ receives inputs from the labyrinth in the inner ear through the vestibular nuclei (which explains the mechanism of motion sickness) and vagal afferents arising from the GI tract. Toxic chemicals in the bloodstream can also be detected directly by the CTZ because the blood–brain barrier is relatively permeable in this area. The CTZ is therefore a primary site of action of many emetic and antiemetic drugs
The VC contains M1-5 receptors.
List the 5-HT3 receptor antagonists
Granisetron, ondansetron and palonosetron
Describe how 5-HT3 receptor antagonists work to prevent nausea and vomiting
§ Blocks transmission in visceral afferents (vagus and splanchnic nerves) and the CTZ.
o This block in the CTZ and from the peripheries makes it good at treating sickness from chemo and radio.
Describe the pharmacokinetics of ondasetron
Adminsitered orally
Excreted in urine (good kidney function required)
What are the side effects of ondasetron
o Headache.
o Sensation of flushing and warmth.
o Constipation – increased large bowel transit time
What does substance P act on
Substance P (see Ch. 19) acting at neurokinin-1 receptors in the CTZ This explains the use of aprepitant
Substance P- released in inflammation but also can make you feel sick.
Why is ondensatron used in conjunction with corticosteroids
o 5-HT3 receptor antagonists may be used for low emetogenic chemotherapy.
o Corticosteroids (e.g. dexamethasone) may be used in combination for high or moderately high emetogenic chemotherapy.
o Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids.
Explain the bi-phasic response of vomiting
First phase- targeted by ondensatron
Second (later phase)- targeted by glucocorticoids and aprepitant
Which system is particuarly important in children with motion sickness
§ Vestibular system is particularly important in children with motion sickness
Outline the pathophysiology of motion sickness
Labyrinth - neural mismatch between what you’re seeing and your position in space activates histamine receptors on vestibular nuclei
Vestibular nuclei activate muscarinic receptors on CTZ
CTZ activates VC, which causes nausea
Muscarinic receptors also present on VC
Summarise the treatment for motion sickness
Promethazine - H1 receptor antagonist (blcoks afferent signal to vestibular nuclei)
Hyoscine (scopolomine) – non-selective muscarinic receptor antagonist (blocks afferent signal to CTZ and VC)- used for more severe cases of motion sickness
Describe the pharmacodynamics of Hysocine
§ Antagonistic potency order:
o Muscarinic»_space;> D2/H1.
Acts centrally,
USE AS AN ANTI-EMETIC
Prevention of motion sickness
Has little effects once nausea/emesis is established
In operative pre-medication
NOTE: Atropine is less effective
§ Acts centrally, especially on vestibular nuclei, CTZ and vomiting centre to block activation.
o Prevents motion sickness.
Describe the side effects of hysocine
Typical anti-muscarinic side-effects: drowsiness dry mouth cycloplegia mydriasis constipation (not usually at anti-emetic doses)
Describe the pharmacokinetics of hysocine
Can be administered orally (peak effect in 1-2 hours), i.v., transdermally
Ultimately, what is hysocine used for
Prevention of MOTION SICKNESS
Sometimes used in operative pre-medication
What is Promethazine an example of
A mixed receptor antagonist
What is Promethazine a derivative of
Phenothiazine (other phenothiazines are used as neuroleptics)
c.f. other phenothiazines, which are used as neuroleptic drugs, have a different order of potency with greater antagonistic effects at D2 receptors.
Describe the mode of action of promethazine
It is a competitive antagonist for the following receptors:
• Histaminergic
• Muscarinic
• Dopaminergic
Order of potency of antagonist activity: H > M > D
§ Acts centrally (vestibular nucleus, CTZ, vomiting centre (VC)) to block activation of the VC.
Describe the potential uses of Promethazine
Motion sickness – normally used prophylactically, but some benefit may be gained if it is taken after the onset of nausea and vomiting
Disorders of the labyrinth e.g., Meniere’s disease
Hyperemesis gravidarium- pregnancy complication
Pre- and post-operatively (sedative and anti-muscarinic action are also useful).
Due to H1 blockade and sedative effects
Relief of allergic symptoms
Anaphylactic emergency
Night sedation; insomnia
Describe the unwanted effects of Promethazine
Dizziness Tinnitus Fatigue Sedation (‘do not drive or operate machinery’) Excitation in excess Convulsions (children more susceptible) Antimuscarininc side-effects
Describe the pharmacokinetics of Promethazine
Administer orally
Onset of action 1-2 hours
Maximum effect circa 4 hours
Duration of action 24 hours
Describe how gastroparesis can lead to nausea and vomiting
Gastroparesis – delayed emptying of the stomach
Reduced stomach contraction
5-HT – activates 5-HT3A receptors on CTZ
CTZ activates nerves fibres (vagal and splanchnic) to vomiting centre (VC)
VC nausea
Summarise the treatment of nausea and vomiting caused by gastroparesis
Metoclopramide Dopamine D2 receptor antagonist Prokinetic – stimulates gastric emptying Inhibits D2 receptors in CTZ 5-HT3A receptor antagonist Inhibits activation of CTZ
What are the benefits of the prokinetic effects of metoclopramide on the G.I tract
They have PROKINETIC effects on the GI tract:
• Increase smooth muscle motility
• Accelerate gastric emptying
• Accelerate the transit time of intestinal contents
Less contents to vomit
State another dopamine antagonist
Domperidone
But this can’t cross the BBB
Describe the antagonist potency order of meoclopamride and where it has its actions
§ Antagonistic potency order:
o D2»_space; H1»_space;> muscarinic receptors.
§ Acts centrally, especially on the CTZ.
§ Pro-kinetic effects in the GI tract – i.e. effects of PNS.
Why are dopmaine antaognists poor at treating motion sickness
The vestibular system has connections to the CTZ and it has direct connections to the vomiting centre
The dopamine antagonists block dopamine receptors in the CTZ but they are not blocking the rest of the signals that are going directly from the vestibular system to the vomiting centre
Describe the uses of metoclopramide
Used to treat nausea and vomiting associated with:
uraemia (severe renal failure)
radiation sickness
gastrointestinal disorders
cancer chemotherapy (high doses) e.g.. Cisplatin (intractable vomiting)
Describe the unwanted central actions of metoclopramide
drowsiness
dizziness
anxiety
extrapyramidal reactions; children more susceptible than adults (Parkinsonian-like syndrome: rigidity, tremor, motor restlessness)
Describe the unwanted endocrine effects of metoclopramide
hyperprolactinaemia
galactorrhoea
disorders of menstruation
What are the pharmacokinetic considerations of metoclopramide
may be administered orally; rapidly absorbed; extensive first pass metabolism
may also be given i.v.
crosses BBB
crosses placenta
Describe the care that must be given of the bioavailability of co-administered drugs when patients have also been given dopamine antagonists
These drugs have prokinetic effects on the GI tract hence they accelerate the transit through the GI tract – this may mean that some drugs are not sufficiently absorbed in the GI tract e.g. digoxin
Summarise the pysiological control of nausea and voimiting and its mechanistic triggers
Physiological control: Chemoreceptor Trigger Zone (CTZ): receives multiple inputs from areas including stomach & vestibular nuclei
CTZ: communicates with the vomiting centre nausea & vomiting
Mechanistic triggers: Cytotoxic drugs, motion sickness, gastrointestinal problems, pregnancy, other higher functions
Identify the main classes of anti-emetic drugs
5-HT3A receptor antagonists
Histamine H1 receptor antagonists
Muscarinic receptor antagonists
Dopamine D2 receptor antagonists
Describe how cannabinoids act as anti-emetics
§ THC is the active agent.
§ Treats emesis from anti-cancer drugs when other anti-emetics are not effective – e.g. cisplatin.
§ Acts via the CB1 receptors located pre-synaptically à decrease release of NTs associated with vomiting.
o Also, inhibit prostaglandin synthesis which is implicated in emesis from anti-cancer drugs.
Outline the principal clinical uses of each drug class
5-HT3A receptor antagonists: chemotherapy induced N&V
Histamine H1 receptor antagonists: motion sickness
Muscarinic receptor antagonists: motion sickness
Dopamine D2 receptor antagonists: gastroparesis induced N&V
Why is the drowsiness associated with H1 receptor antagonism beneficial
You want to fall asleep when you have motion sickness.
Summarise the important receptors involved in vomiting
• Acetylcholine + Histamine receptors are found on:
o Vestibular systems
o Medullary vomiting centre
• D2 receptors + 5HT-3 receptors are found on:
o Chemoreceptor trigger zone
