Clinical Pharmacology of Hyoscine hydrobromide, D2, H1, 5HT3 and NK1 Antagonists

Question 1

(a) What is reflux?

(b) When do acid reflux symptoms become known as GERD?

(c) What can lead to acid reflux?

Answer 1

• Flow of fluid through vessel in opposite direction to normal
• When symptoms occur more than twice a week
• Failure of LES to close - acid from stomach moves up into oesophagus

Question 2

What lifestyle modifications can be introduced to improve symptoms leading to emesis?

Answer 2

• Reduction in caffeine, alcohol, smoking and obesity - relax oesophageal sphincter
• Avoid late evening meals
• Allow time for stomach emptying before lying supine
• Pharmacological treatment usually initiated with antacids and alginates

Question 3

What are the rules behind prescribing anti-emetics?

Answer 3

• Only prescribe anti-emetics when the cause of vomiting is known
• When prescribing the choice of drug is dependent on the aetiology of the vomiting

Question 4

What are the clinical indications of use for anti-emetics treating nausea due to vertigo and motion sickness?

Answer 4

• VERTIGO - H1 receptor inverse agonist: cyclizine (no sedation) or promethazine (if sedation required)
• NAUSEA - Antimuscarinic: hyoscine hydrobromide, H1 receptor inverse agonist: cyclizine (no sedation) or promethazine (if sedation required)

Question 4

How would you treat nausea due to pregnancy?

Answer 4

• Usually mild in the first trimester. However, on rare occasions if vomiting is severe short-term treatment with:
• H1 receptor inverse agonist promethazine or a D2 antagonist prochlorperazine or metoclopramide
• If symptoms do not settle in 24 to 48 hours then specialist opinion should be sought.

Question 5

How would you treat nausea due to post-operative procedures?

Answer 5

• Depends on type and duration of surgery, risk factors
• 5HT3 antagonists, dexamethasone, prochlorperazine, cyclizine
• High risk: use a combination of 2 with different MOAs

Question 6

How would you treat nausea due to migraines?

Answer 6

• D2 antagonist prochlorperazine or metoclopramide
• Metoclopramide should not be used regularly due to extrapyramidal symptoms

Question 7

How would you treat nausea due to cancer therapy? PART 1

Answer 7

• For those at low risk pre-treatment with dexamethasone or lorazepam
• For those at high risk pre- treatment with dexamethasone, aprepitant and 5HT3 receptor antagonist

Question 8

How would you treat nausea due to cancer therapy? PART 2

Answer 8

• Low risk– moderate emetogenic: D2 receptor antagonist: Domperidone, Haloperidol, Metoclopramide,
• Moderate risk- severe emetogenic:
• Before therapy: NK1 antagonist Aprepitant usually administered with 5HT3 receptor antagonist Ondansetron, and Dexamethasone (91% efficacy)
• Metoclopramide, Dexamethasone and lorazepam (63% efficacy)

Preventing emetic episodes in first 24hrs after cisplatin administration

Question 9

How do muscarinic receptors lead to vomiting?

Answer 9

• Stimulation of muscarinic receptors in GI tract increases secretion and motility
• Activation ofM1receptors in the vestibular nuclei, the nucleus of the solitary tract and the vomitingcenter triggers nausea and vomiting reflex

Question 10

How do muscarinic receptor antagonists work?

Answer 10

• Hyoscine blocks M1 receptors in the vestibular nuclei, the nucleus ofthe solitary tract and the vomiting center
• Useful for motion sickness and to dry secretions before surgery

Question 11

What are the major side effects of hyoscine?

Answer 11

• Dry mouth
• Constipation
• Blurred vision
• Difficulty passing urine
• Tachycardia

Question 12

What are the two forms hyoscine comes in?

Answer 12

• Hyoscine butylbromide cannot cross the BBB - prescribed to reduce spasms of the GI tract used to treat IBS
• Hyoscine hydrobromide can cross BBB - reduce nausea and vomiting

Question 13

How is hyoscine administered?

Answer 13

Oral or transdermal patch

Question 14

Give examples of D2 receptor antagonists and their clinical indications of use.

Answer 14

• Domperidone, metoclopramide and prochlorperazaine
• Used for nausea and vomiting, dysmotility dyspepsia and gastro-oesophageal reflux

Question 15

What are the effects of D2 antagonists and why are they considered prokinetic?

Answer 15

• Increase GI motilitythroughout the entire GI tract, therefore considered to beprokinetic
• Enhanced gastric emptying
• Reduction in the volume of acid available to reflux
• Increased lower oesophageal sphincter basal tone

Question 16

What is the general mechanism of action of D2 receptor antagonists?

Answer 16

Inhibition of dopamine binding at dopamine D2 receptors (Gi GPCR)

Question 17

What are the major side effects of D2 receptor antagonists?

Answer 17

• Parkinsonism, tardive dyskinesia(sometimes irreversible) and dystonia in 25% of patients given high doses and 5% of patients given long-term therapy
• Avoid long-term use (esp. in the elderly)
• Drowsiness, or nervousness, agitation and anxiety in 10-20% of patients
• Increased pituitary prolactin release(impotence, galactorrhea, menstrual disorders)

Question 18

Describe pharmacokinetics of D2 receptor antagonists.

Answer 18

• Metoclopramidecrosses the BBB, and therefore also has CNS actions; domperidonedoes not cross as easily so less CNS effects
• Metoclopramide: used recreationallydue to increased absorption when co-administered with pill/powder based orally administeredrecreational drugs

Question 19

Describe when 5HT3 antagonists are used.

Answer 19

• Primary agents for prevention and treatment of chemotherapy-induced nausea and vomiting
• Most effective in preventing acute phase (<24 hours after chemotherapy) if given 30 minutes prior to antineoplastic drugs
• Not particularly effective during delayed phase (2-5 days after chemotherapy) also used for postop and post-radiation nausea and vomiting

Question 20

Outline the mechanism of action of 5HT3 antagonists and where they act.

Answer 20

• Selective blockade of peripheral5HT3receptors on intestinal vagal afferents
• CNS actions at both the CTZ and vomiting center

Question 21

Outline the side effects of 5HT3 antagonists.

Answer 21

• Transient mild headache
• Dizziness
• Constipation
• Prolongation of QT interval - especially dolasetron e.g avoid in patients with cardiac pathology

Question 22

Describe the pharmacokinetics of 5HT3 antagonists. PART 1

Answer 22

• Can be administered as a single dose prior to chemotherapy (either oral or IV)
• Slow IV administration
• Longer duration of action so great for chemotherapy induced emesis

Question 23

Describe the pharmacokinetics of 5HT3 antagonists. PART 2

Answer 23

• Extensively metabolised by the liver to an active metabolite
• Dose adjustments required in hepatic insufficiency
• Urinary excretion via the kidney

Question 24

Describe the clinical indications of use for H1 receptor inverse agonists e.g cyclizine.

Answer 24

- Main use in motion sickness to control the symptoms of nauseas and vomiting - Also used for vestibular disturbances : Labrinythitis and meniéres disease

Question 25

Describe the context behind the mechanism of action of H1 receptor inverse agonists.

Answer 25

- Anti-histamine - inverse agonists NOT ANTAGONISTS - H1 receptor has 2 states active and inactive - The inverse agonist binds preferentially to the inactive form to reduce receptor activity

Question 26

Describe the major side effects of H1 receptor inverse agonists

Answer 26

- Drowsiness due to prominent CNS depressive effects - Avoid activities such as driving and hazardous work until patient has seen how much they are affected - Prolong the QT interval mechanism - Anticholinergic effects e.g dry mouth, urinary retention, dry eyes and pupil dilation

Question 27

Describe pharmacokinetics of H1 receptor inverse agonists.

Answer 27

- Well absorbed from GI tract - Reach peak plasma concentration in 2-3 hours - Distributed throughout peripheral tissues and CNS - Metabolised by liver - induce CYP450 enzymes so may affect metabolism of other drugs - Dose adjustment required in severe liver disease - Safe to use in children and pregnancy

Question 28

Describe when NK1 antagonists e.g aprepitant are used.

Answer 28

- Used in adults and children  - Prevent nausea and vomiting caused by cancer chemotherapy with moderate or high emetogenic outcomes - In adults only: pre-med for surgery

Question 29

Describe the general mechanism of action of NK1 antagonists.

Answer 29

- Preventative only - will not treat nausea or vomiting that you already have. - Antagonist of the NK1 receptor  - Substance P cannot bind

Question 30

Describe side effects and pharmacokinetics of NK1 antagonists.

Answer 30

- Side effects are fatigue and constipation - Administered orally with addition dexamethasone and a 'setron' - Metabolised by CYP3A4 enzymes - Dose adjustments required in hepatic insufficiency - Induces CYP3A4 - can shorten warfarin half life

Question 31

Describe when dexamethasone can be used.

Answer 31

- Initially used in children for tonsillectomy and adults for labyrinth disorders - It was found that the nausea and vomiting rates dropped markedly with use

Question 32

Describe how dexamethasone is used.

Answer 32

- Now used as a mainstay post operatively - 24-48 hours only short use - Be cautious in those with diabetes as it can induce increased glucose in the blood