Anti-emetics

Question 1

Differentiate between nausea and vomiting

Answer 1

§ 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.

Question 2

Summarise the vomiting process

Answer 2

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.

Question 3

What abdominal organs contract in the vomiting pathway

Answer 3

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

Question 4

What are the consequences of acute and chronic nausea

Answer 4

o Acute nausea – interferes with mental/physical activity.

o Chronic nausea – very debilitating

Question 5

What are the consequences of severe vomiting

Answer 5

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)

Question 6

Summarise the role of the vomiting centre and the chemoreceptor trigger zone

Answer 6

§ 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

Question 7

How do signals reach the CTZ and vomiting centre from the stomach

Answer 7

§ CN 9 and 10 mediate signals from the stomach/heart to vomit- information detected by mechanoreceptors and chemoreceptors

Question 8

Which classes of drug are known for causing nausea and vomiting

Answer 8

Chemotherapy (Cisplatin) for lung cancer

Chemotherapy induced nausea & vomiting (CINV)

Question 9

Outline the pathophysiology of chemotherapeutic drug and how they cause nausea

Answer 9

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

Question 10

When are anti-emetic drugs given

Answer 10

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

Question 11

Summarise the treatment for chemotherapy induced nausea and vomiting

Answer 11

Ondansetron - 5-HT3A receptor antagonist
Glucocorticoids - reduce free radical production(anti-inflammatory).
Aprepitant - neurokinin-1 receptor antagonist

Question 12

Where is the CTZ located

Answer 12

Int the area postrema (lower medulla)

Has a very porous BBB- hence it can detect toxins in the blood.

Question 13

Where is the vomiting centre located

Answer 13

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

Question 14

Describe the potential inputs into the CTZ

Answer 14

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

Question 15

Describe the cross-talk between the CTZ and the vomiting centre

Answer 15

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.

Question 16

List the 5-HT3 receptor antagonists

Answer 16

Granisetron, ondansetron and palonosetron

Question 17

Describe how 5-HT3 receptor antagonists work to prevent nausea and vomiting

Answer 17

§ 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.

Question 18

Describe the pharmacokinetics of ondasetron

Answer 18

Adminsitered orally

Excreted in urine (good kidney function required)

Question 19

What are the side effects of ondasetron

Answer 19

o Headache.

o Sensation of flushing and warmth.

o Constipation – increased large bowel transit time

Question 20

What does substance P act on

Answer 20

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.

Question 21

Why is ondensatron used in conjunction with corticosteroids

Answer 21

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.

Question 22

Explain the bi-phasic response of vomiting

Answer 22

First phase- targeted by ondensatron

Second (later phase)- targeted by glucocorticoids and aprepitant

Question 23

Which system is particuarly important in children with motion sickness

Answer 23

§ Vestibular system is particularly important in children with motion sickness

Question 24

Outline the pathophysiology of motion sickness

Answer 24

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

Question 25

Summarise the treatment for motion sickness

Answer 25

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

Question 26

Describe the pharmacodynamics of Hysocine

Answer 26

§ Antagonistic potency order: o Muscarinic >>> 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.

Question 27

Describe the side effects of hysocine

Answer 27

``` Typical anti-muscarinic side-effects: drowsiness dry mouth cycloplegia mydriasis constipation (not usually at anti-emetic doses) ```

Question 28

Describe the pharmacokinetics of hysocine

Answer 28

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

Question 29

Ultimately, what is hysocine used for

Answer 29

Prevention of MOTION SICKNESS | Sometimes used in operative pre-medication

Question 30

What is Promethazine an example of

Answer 30

A mixed receptor antagonist

Question 31

What is Promethazine a derivative of

Answer 31

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.

Question 32

Describe the mode of action of promethazine

Answer 32

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.

Question 33

Describe the potential uses of Promethazine

Answer 33

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

Question 34

Describe the unwanted effects of Promethazine

Answer 34

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

Question 35

Describe the pharmacokinetics of Promethazine

Answer 35

Administer orally Onset of action 1-2 hours Maximum effect circa 4 hours Duration of action 24 hours

Question 36

Describe how gastroparesis can lead to nausea and vomiting

Answer 36

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

Question 37

Summarise the treatment of nausea and vomiting caused by gastroparesis

Answer 37

``` Metoclopramide Dopamine D2 receptor antagonist Prokinetic – stimulates gastric emptying Inhibits D2 receptors in CTZ 5-HT3A receptor antagonist Inhibits activation of CTZ ```

Question 38

What are the benefits of the prokinetic effects of metoclopramide on the G.I tract

Answer 38

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

Question 39

State another dopamine antagonist

Answer 39

Domperidone | But this can't cross the BBB

Question 40

Describe the antagonist potency order of meoclopamride and where it has its actions

Answer 40

§ Antagonistic potency order: o D2 >> H1 >>> muscarinic receptors. § Acts centrally, especially on the CTZ. § Pro-kinetic effects in the GI tract – i.e. effects of PNS.

Question 41

Why are dopmaine antaognists poor at treating motion sickness

Answer 41

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

Question 42

Describe the uses of metoclopramide

Answer 42

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)

Question 43

Describe the unwanted central actions of metoclopramide

Answer 43

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

Question 44

Describe the unwanted endocrine effects of metoclopramide

Answer 44

hyperprolactinaemia galactorrhoea disorders of menstruation

Question 45

What are the pharmacokinetic considerations of metoclopramide

Answer 45

may be administered orally; rapidly absorbed; extensive first pass metabolism may also be given i.v. crosses BBB crosses placenta

Question 46

Describe the care that must be given of the bioavailability of co-administered drugs when patients have also been given dopamine antagonists

Answer 46

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

Question 47

Summarise the pysiological control of nausea and voimiting and its mechanistic triggers

Answer 47

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

Question 48

Identify the main classes of anti-emetic drugs

Answer 48

5-HT3A receptor antagonists Histamine H1 receptor antagonists Muscarinic receptor antagonists Dopamine D2 receptor antagonists

Question 49

Describe how cannabinoids act as anti-emetics

Answer 49

§ 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.

Question 50

Outline the principal clinical uses of each drug class

Answer 50

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

Question 51

Why is the drowsiness associated with H1 receptor antagonism beneficial

Answer 51

You want to fall asleep when you have motion sickness.

Question 52

Summarise the important receptors involved in vomiting

Answer 52

• 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