Week 12 - Nausea & Vomiting and Pharmacological Management

Question 1

What is nausea and vomitting (NV)

Answer 1

NV can be chemotherapy (CINV) and radiotherapy induced (RINV)
- have drugs which can contorl CINV
- drugs that target many receptors are reserved for refactory or breakthrough NV HOWEVER have more side effects due to this
- up to 80% patients experience CINV, can lead to AKI, deterioration in nutritional status

5 Types of Emesis (process of vomitting)
1. Acute NV = onset during first 24 hrs starting treatment
2. Delayed NV = onsent > 24hrs up to 6/7 days later
3. Anticipatory = a learned / anxiety response, onset at the beginning of a new cycle of chemo
4. Breakthrough = develop NV symptoms despite anti-emetic therapy
5. Refactory = standard and rescue anti-emetics fail / don’t help

CTCAE Grading used for NV
Grading system is used to assess symptoms
- 5 grades
- HOWEVER never use grade 5 (death)
- grade 3-4 leads to hospital admissions

Question 2

What are risk factors when choosing anti-emetics

Answer 2

If have 3 or more risk factors consider additional anti-emetics

Risk Factors:
- Femal
- < 30years old
- Pre-exisiting NV
- History of sickness
- Anxiety
- Poor control with prior treatment
- History og high alcohol intake, substance misuse, smoking etc. reduce risk of emesis

Question 3

What pathways are involved in nausea and vomitting

Answer 3

Emesis (process of vomitting) is coordinated by the vomitting centre (VC) in the medulla

• The chemoreceptor trigger zone (CTZ) in the VC is stimulated by circulating drugs or toxins as it is NOT protected by the BBB
  - CTZ has many dopamine receptors = dopamine drugs stimulate VC = NV
  - dopamine antagonist ↓ NV
• CTZ also has many 5HT3 receptors (which can be stimulated)

Vomitting Centre is also activated if the following are stimulated:
1. Gut wall
2. Cerebal cortex
3. Vestibular nuclei
4. Area postrema

Question 4

What is used in breakthrough N&V

Answer 4

1st line - Domperidone or metclopramide
2nd line - cyclizine
3rd line - olanzapine or levomepromazine
- hit more receptors BUT have more side effects

Question 5

What receptors are targeted / MoA of anti-emetics

Answer 5

1. NK1 receptor
   
   • neurokinin receptor
   • anti-emetic acts as NK1 receptor antagonist
   • stops the release of substance P
2. 5HT3
   - sertonergic receptors
   - anti-emetic acts a as 5HT3 antagonsit
   - e.g. ondansetron
3. 5HT4 receptor
   - serotonin receptors
   - antagonist at this receptor
4. D2 receptor (dopamine)
   - antagonist at this receptor
   - e.g. metoclopramide (allergy / CI for parkinson’s disease as disease is treated via binding to D2 receptor)

Anti-emetic Examples;
- Olanzapine (hits alost every receptor)
- all above + H1 (histamine receptor), M1-4 (muscarainic receptor), a1 (adrenergic)
- more receptors you hit = more side effects

Common side effects of anti-emetics
- Constipation
- Headaches
- Diarrhoea
- Diziness

Risk of some anti-emertics (MHRA ALERT)
- QT prolongation

Question 6

How does metoclopramide work

1st line anti-emetic | Doperidone = 2nd line

Answer 6

Both are D2 (dopamine-2) receptor antagonist
- acts on GI tract
- blocking dopamine receptor = ↑ acetylcholine = GI motility stimulated
- acetylcholine stimulates muscarinic receptors = ↑ smooth muscle contraction in GI tract = ↑ gastric emptying = ↓ NV

DOSE: 5-10mg TDS PRN
SIDE EFFECTS: dizziness, diarrhoea, movement disorders
Contraindications: parkinsons (treatment = dopamine), breastfeeding, CVD, hypotension

NOTE: (in brain) Have CTZ (chemoreceptor trigger zone) has many dopamine receptors = dopamine drugs stimulate VC = NV

Question 7

How does Ondansetron work

(5HT3 (seretonin)receptor antagonist)

Answer 7

Is a 5HT3 receptor antagonist
- Acts in GI tract and CNS
- CNS: blocks seretonin receptors in CTZ (what nitiats vomitting)
- GI tract: reduces vagus nerve activity + the reflex which triggers NV (by blocking receptor)

DOSE: 8mg BD, 2/7 days
SIDE EFFECTS: headache, constipation,
Contraindications: QT interval prolongation

Question 8

What is the MoA of the 2 agents in Akynzeo and how does palonosetron differ to other 5-HT3 receptor antagonists

Answer 8

AGENTS:
1. Netupitant - Neurokinin (NK1) antagonist
2. Palonosetron - long acting 5HT3 antagonist
- different to other 5-HT3 receptors as it has a very long half life = stays in system for 7 to 10 days

DOSE: 1 tablet (within the hour of treatment)
SIDE EFFECTS: constipation, headache, fatigue
Contraindications:

NOTE:
- cant be used in combination with other NK1 or 5-HT3 receptor antagonists
- drug can interact with steroids = need to reduce steroid dose (dexamethasone) by 50%

Question 9

Dexamethasone: Anti-emetic and Corticosteroid

Answer 9

• USUAL DOSE: 8mg prior to treatment, 4mg BD days after treatment
  - advised to take before 12pm, if take later may have trouble sleeping
• MoA is not understood

SIDE EFFECTS:
- insomnia
- indigestion
- agitation
- increased appetite = weight gain
- facial rash

Steroids can affect glucose levels, can increase appetite = require blood glucose control (esp. if diabetic)

Question 10

How do we treat / manage RINV

RINV - radiotherapy induced nausea and vomitting

Answer 10

1. Dexamethasone
2. Ondansetron (5HT3 receptor antagonist)