Week 19 Pharmacology - GI Drugs Flashcards
What are the common stimulants of nausea /vomiting?
Bloodstream toxins
Sensory stimuli (any of the senses!)
Gut distension or noxious chemical content
Psychological stimuli
What are the ‘sensors’ when it comes to stimulating vomiting?
Chemoreceptor trigger zone (near 4th ventricle)
GI tract: mechanoreceptors, chemoreceptors
Descending systems (pain, anxiety, fear)
What are the afferent pathways involved in transmission of nausea signalling?
- Vagus nerve (to the NTS): main receptors involved are 5-HT3, D2, H1 and muscarinic.
- Vestibular apparatus: main receptors involved are H1 and muscarinic.
- Ill-defined central pathways (to the CTZ): main receptors involved are 5-HT3, D2, H1 and muscarinic.
What are the central processors of this information?
- Nucleus of the solitary tract (NTS) integrates inputs from: a) vagus nerve and b) the vestibular apparatus
- Chemoreceptor trigger zone (CTZ) integrates inputs from:
a) the higher CNS
b) vestibular apparatus
c) direct action of blood-borne toxins
What are the major neurotransmitters responsible for signalling in these pathways?
Dopamine
Serotonin
Acetylcholine
(+ Histamine)
Simplistically, what transmitters are involved in visceral stimulation of vomiting efferents?
Serotonin
Dopamine
Simplistically, what transmitters are involved in CTZ stimulation of vomiting efferents?
Serotonin
Dopamine
Simplistically, what transmitters are involved in vestibular stimulation of vomiting efferents?
Histamine
Acetylcholine
What is the mechanism of action of ondansetron?
Antagonism of 5-HT receptors peripherally and in CTZ
What are the PK of ondansetron?
A: 60% oral BA
D: VD 2L/kg, 70% protein bound
M: Hepatic
E: renal, half life 3 hrs IV, 4-11 PO
What are adverse effects of ondansetron?
Prolonged QT, headache, muscle pain, constipation
Contraindicated in severe hepatic impairment
What is the MOA of metoclopramide?
Central and peripheral D2 receptor antagonism
- Central: at CTZ, inhibition of dopaminergic transmission, reduced signalling to effector organs
- Peripheral: D2 antagonism inhibits gastric smooth muscle contraction, as well as increasing LES pressure, increasing gastric emptying
What are the PK of metoclopramide?
A: 30-60 mins onset, well absorbed
D: Vd 2-3L/kg, t 1/2 4 hrs
M: hepatic
E: renal
What are adverse effects of metoclopramide?
Dystonic reaction
EPS long term
Elevated prolactin –> galactorrhea, gynaecomastia, impotence
What is the mechanism of action of promethazine?
1st Gen antihistamine, competitive H1 antagonist acting on vomiting centre and vestibular apparatus, with some associated antimuscarinic, antiserotonergic and anti-adrenergic effects
What are the PK of promethazine?
- A: orally active
- D: widely distributed, crosses BBB
- M: extensive hepatic
- E: renal
What is the major difference between promethazine and loratadine (2nd gen)?
Loratadine doesn’t cross BBB
What is the MoA of scopolamine/hyoscine?
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
What is the PK of hyoscine?
- 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
What is the shared mechanism of chlorpromazine (largactil) and prochlorperazine (stemetil)?
Central and M1 and D2 antagonism (first gen anti-psychotics)
What is the MoA of PPIs?
Irreversible inhibition of H/K ATPase on apical surface of parietal cells in body of stomach. Reduced gastric acid secretion by up to 99%.
What are the PK of PPIs?
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
How can PPIs affect other medications?
Decreased stomach acidity can reduced absorption of digoxin, ketoconazole.
Inhibition of CYP450 can reduced metabolism of warfarin, phenytoin, diazepam
What are the adverse effects of PPIs?
Side effects rate.
Theoretical increased risk of C diff infection, (less hostile environment for pathogens) as well as pneumonia)
What is the basis for wide variety of effects of octreotide/somatostatin?
Wide range receptor profile throughout GIT. In pancreas, small bowel, stomach, splanchnic circulation.
What are the effects of somatostatin stimulation/octreotide?
- inhibits gastrin, CCK, glucagon, insulin, 5HT
- decreases gastric/pancreatic fluid secretion/GI motility/inhibits gallbladder contractility
- decreases portal and splanchnic blood flow
What is octreotide clinically most useful for?
Inhibition of endocrine tumour effects, diarrhoea, variceal haemorrhage - reducing portal pressure
Out of docusate and Senna, what is a softener, and what is a stimulant?
Docusate = softener
Senna = stimulant
What classes of medications are common anti-diarrhoeals?
Opioids and opioid receptors agonists
i.e. Loperamide = u receptors agonist in myenteric plexus, no analgesis effect, doesn’t cross BBB, no addiction potential
When are antidiarrhoeals contraindicated?
Bloody diarrhoea, fevers, systemic toxicity (rarely used in acute viral gastroenteritis, contraindicated in dysentry)
