Week 19 Pharmacology - GI Drugs

Question 1

What are the common stimulants of nausea /vomiting?

Answer 1

Bloodstream toxins
Sensory stimuli (any of the senses!)
Gut distension or noxious chemical content
Psychological stimuli

Question 2

What are the ‘sensors’ when it comes to stimulating vomiting?

Answer 2

Chemoreceptor trigger zone (near 4th ventricle)
GI tract: mechanoreceptors, chemoreceptors
Descending systems (pain, anxiety, fear)

Question 3

What are the afferent pathways involved in transmission of nausea signalling?

Answer 3

1. Vagus nerve (to the NTS): main receptors involved are 5-HT3, D2, H1 and muscarinic.
2. Vestibular apparatus: main receptors involved are H1 and muscarinic.
3. Ill-defined central pathways (to the CTZ): main receptors involved are 5-HT3, D2, H1 and muscarinic.

Question 4

What are the central processors of this information?

Answer 4

1. Nucleus of the solitary tract (NTS) integrates inputs from: a) vagus nerve and b) the vestibular apparatus
2. Chemoreceptor trigger zone (CTZ) integrates inputs from:
   a) the higher CNS
   b) vestibular apparatus
   c) direct action of blood-borne toxins

Question 5

What are the major neurotransmitters responsible for signalling in these pathways?

Answer 5

Dopamine
Serotonin
Acetylcholine
(+ Histamine)

Question 6

Simplistically, what transmitters are involved in visceral stimulation of vomiting efferents?

Answer 6

Serotonin
Dopamine

Question 7

Simplistically, what transmitters are involved in CTZ stimulation of vomiting efferents?

Answer 7

Serotonin
Dopamine

Question 8

Simplistically, what transmitters are involved in vestibular stimulation of vomiting efferents?

Answer 8

Histamine
Acetylcholine

Question 9

What is the mechanism of action of ondansetron?

Answer 9

Antagonism of 5-HT receptors peripherally and in CTZ

Question 10

What are the PK of ondansetron?

Answer 10

A: 60% oral BA
D: VD 2L/kg, 70% protein bound
M: Hepatic
E: renal, half life 3 hrs IV, 4-11 PO

Question 11

What are adverse effects of ondansetron?

Answer 11

Prolonged QT, headache, muscle pain, constipation

Contraindicated in severe hepatic impairment

Question 12

What is the MOA of metoclopramide?

Answer 12

Central and peripheral D2 receptor antagonism

1. Central: at CTZ, inhibition of dopaminergic transmission, reduced signalling to effector organs
2. Peripheral: D2 antagonism inhibits gastric smooth muscle contraction, as well as increasing LES pressure, increasing gastric emptying

Question 13

What are the PK of metoclopramide?

Answer 13

A: 30-60 mins onset, well absorbed
D: Vd 2-3L/kg, t 1/2 4 hrs
M: hepatic
E: renal

Question 14

What are adverse effects of metoclopramide?

Answer 14

Dystonic reaction
EPS long term
Elevated prolactin –> galactorrhea, gynaecomastia, impotence

Question 15

What is the mechanism of action of promethazine?

Answer 15

1st Gen antihistamine, competitive H1 antagonist acting on vomiting centre and vestibular apparatus, with some associated antimuscarinic, antiserotonergic and anti-adrenergic effects

Question 16

What are the PK of promethazine?

Answer 16

• A: orally active
• D: widely distributed, crosses BBB
• M: extensive hepatic
• E: renal

Question 17

What is the major difference between promethazine and loratadine (2nd gen)?

Answer 17

Loratadine doesn’t cross BBB

Question 18

What is the MoA of scopolamine/hyoscine?

Answer 18

Stereoisomer of atropine, anticholinergic –> competitive antagonist for muscarinic ACh receptors

Works to prevent signalling in CTZ also, as well as increasing tension on LES, relaxing bowel smooth muscle

Question 19

What is the PK of hyoscine?

Answer 19

• A: well absorbed po, 1st pass effect so only moderate bioavailability
• D: Vd 1.2 L/kg
• M: almost completely metabolised
• E: t1/2 redistribution 5mins/elimination 2 hrs

Question 20

What is the shared mechanism of chlorpromazine (largactil) and prochlorperazine (stemetil)?

Answer 20

Central and M1 and D2 antagonism (first gen anti-psychotics)

Question 21

What is the MoA of PPIs?

Answer 21

Irreversible inhibition of H/K ATPase on apical surface of parietal cells in body of stomach. Reduced gastric acid secretion by up to 99%.

Question 22

What are the PK of PPIs?

Answer 22

A: Good oral absorption, 40-80% bioavailability (decreased with food), prodrug, enteric coating allows it to pass through stomach and get absorbed in small bowel, activated in canaliculi of parietal cells to active drug
D: t 1/2 2 hrs, 3-4 days to full effect
M: CYP450
E: Renal

Question 23

How can PPIs affect other medications?

Answer 23

Decreased stomach acidity can reduced absorption of digoxin, ketoconazole.

Inhibition of CYP450 can reduced metabolism of warfarin, phenytoin, diazepam

Question 24

What are the adverse effects of PPIs?

Answer 24

Side effects rate.

Theoretical increased risk of C diff infection, (less hostile environment for pathogens) as well as pneumonia)

Question 25

What is the basis for wide variety of effects of octreotide/somatostatin?

Answer 25

Wide range receptor profile throughout GIT. In pancreas, small bowel, stomach, splanchnic circulation.

Question 26

What are the effects of somatostatin stimulation/octreotide?

Answer 26

• inhibits gastrin, CCK, glucagon, insulin, 5HT
• decreases gastric/pancreatic fluid secretion/GI motility/inhibits gallbladder contractility
• decreases portal and splanchnic blood flow

Question 27

What is octreotide clinically most useful for?

Answer 27

Inhibition of endocrine tumour effects, diarrhoea, variceal haemorrhage - reducing portal pressure

Question 28

Out of docusate and Senna, what is a softener, and what is a stimulant?

Answer 28

Docusate = softener
Senna = stimulant

Question 29

What classes of medications are common anti-diarrhoeals?

Answer 29

Opioids and opioid receptors agonists

i.e. Loperamide = u receptors agonist in myenteric plexus, no analgesis effect, doesn’t cross BBB, no addiction potential

Question 30

When are antidiarrhoeals contraindicated?

Answer 30

Bloody diarrhoea, fevers, systemic toxicity (rarely used in acute viral gastroenteritis, contraindicated in dysentry)