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.