VIVA: Pharmacology - Gastrointestinal Flashcards
What classes of drug can be used as antiemetics?
5HT3 antagonists: ondansetron, ganisetron, tropisetron*
Phenothiazines: prochlorperazine (typical antipsychotic), chlorpromazine, promethazine*
Butyrophenones: haloperidol, droperidol
Substituted benzamides: metoclopramide (dopamine antagonist)*
H1 antagonists: diphenhydramine, meclizine
Anticholinergics: hyoscine
Benzodiazepines
Corticosteroids
Cannabinoids
*needed to pass
Compare the mechanisms of action of ondansetron and metoclopramide
Act at different receptors:
- Ondansetron: peripheral 5HT3 blockade* (vagal and spinal afferents, reduces sensory visceral output) and central 5HT3 blockade (vomiting centre and chemoreceptor trigger zone)
- Metoclopramide: D2 blockade (chemoreceptor trigger zone)*, increases oesophageal motility, increases lower oesophageal sphincter tone, increases gastric emptying
*needed to pass
Describe the potential adverse effects of metoclopramide
CNS: restlessness, drowsiness, insomnia, anxiety, agitation (common especially in elderly 20%)
Extrapyramidal effects (more likely with higher doses): acute dystonia*, akathisia, Parkinsonian effects, tardive dyskinesia (with chronic dosing)
Hyperprolactinaemia: galactorrhoea, gynaecomastia, impotence, menstrual disorders
*needed to pass + one other CNS effect
Describe the potential adverse effects of prochlorperazine?
Acute dystonia due to dopamine blockade*
Sedation (antihistamine effects)
Anticholinergic effects (dry mouth, urinary retention, constipation, blurred vision, delirium)
Allergy
*needed to pass + one other
List the major categories of antiemetic agents and describe their mechanism of action
Need 3/7 categories and 2/3 mechanisms to pass
1. Antihistamines:
- Antimuscarinic and sedative effects + H1 blocking effects
- Specific depression of conduction in vestibulocerebellar pathway
- Effective for nausea and vomiting associated with motion sickness
- E.g. diphenydramine, hydroxyzine
- Anticholinergics (scopalamine) also helpful
2. Phenothiazines:
- Block dopamine receptors in chemoreceptor trigger zone
- Use limited by degree of sedation
- Also cause extrapyramidal symptoms, especially dystonia
- E.g. prochlorperazine, promethazine
3. Benzamides:
- Central dopamine antagonist + 5HT4 agonist
- Releases ACh from cholinergic neurons in myenteric plexus of the enteric nervous system, may sensitise intestinal smooth muscle cells to action of ACh
- Does not increase gastric or pancreatic secretion
- Hastens oesophageal clearance, raises lower oesophageal sphincter pressure
- Accelerates gastric emptying, shortens bowel transit time
- E.g. metoclopramide
4. 5HT inhibitors:
- Very effective in controlling acute nausea and vomiting associated with ordinary dose of chemotherapy
- Effective in delayed emesis and that from high dose cancer chemotherapy
- E.g. ondansetron, granisetron, dolasetron (equal efficacy, adverse reactions, convenience of administration, cost)
5. Cannabinoids:
- Effective in some patients
- Receptors in chemoreceptor trigger zone
- E.g. tetrahydrocannabinol (THC), dronabinol
6. Corticosteroids:
- Mechanism unknown
- E.g. dexamethasone
7. Sedative hypnotics:
- Benzodiazepines can control anticipatory nausea and vomiting
8. Neurokinin receptor antagonists (e.g. aprepitant)
Using examples, outline the mechanism of action of the various types of laxatives
Need 3/4 mechanisms with at least one correct example to pass:
1. Irritants or stimulant:
- Act on intestinal mucosa or nerve plexus to stimulate peristalsis
- E.g. castor oil (acts early); cascara, senna, aloes (act late); bisacodyl (prolonged action by enterohepatic circulation)
2. Bulk-forming:
- Add bulk and water to the stools to increase peristaltic activity
- E.g. hydrophyllic colloids, agar, psyllium husk, bran
3. Osmotic:
- Increase water in stools
- E.g. magnesium citrate and magnesium hydroxide, polyethylene glycol, sorbitol, lactulose
4. Stool softeners:
- Agents that emulsify with the stool and permit water and lipids to penetrate to soften; increase peristaltic activity
- E.g. mineral oil, glycerine, docusate
Polyethylene glycol is used as a prep for endoscopic procedures. What features make it safe for all patients?
- Balanced: osmotically active sugar (PEG) with NaCl, NaHCO3 and KCl
- No significant osmotic shifts, best ingested rapidly for bowel cleansing
Describe the mechanisms of action of metoclopramide
Dopaminergic (D2) antagonist*
Acts centrally at chemoreceptor trigger zone* in area postrema
Peripheral blockade of GI dopamine receptors allows cholinergic smooth muscle stimulation and results in:
- Increased oesophageal motility
- Increased lower oesophageal sphincter pressure
- Increased gastric emptying
*needed to pass + one other
How is the effect of ondansetron mediated?
Mostly peripheral 5HT3 blockade* on extrinsic intestinal vagal and spinal afferent nerves
Some effect on central 5HT3 receptor blockade in vomiting centre and chemoreceptor trigger zone
Anti-emetic action mostly restricted to emesis attributable to vagal stimulation (e.g. postoperative) and chemotherapy; less effect for other emetic stimuli (e.g. motion sickness)
*needed to pass
What are possible adverse effects of ondansetron?
1 needed to pass:
- Headache
- Dizziness
- Constipation
- Diarrhoea
- Uncommonly small degree of QT prolongation
What are the doses and routes of administration of ondansetron?
4-8mg* sublingual, oral, IV, IM, subcut
*needed to pass + 3/5 routes of administration
In which disease state would you need to modify ondansetron dosing?
Hepatic failure*
Not with renal failure or advanced age
What are the clinical uses of ondansetron?
2/3 needed to pass:
- Chemotherapy-induced nausea and vomiting
- Postoperative and post-radiation nausea and vomiting
- Other indications include acute or chronic medical conditions or gastroenteritis (not well-evaluated)
Describe the mechanism of action of PPIs
Irreversibly inactivates H+/K+ ATPase*, blocking the proton pump
Inhibits >90% of acid secretion for up to 24hrs (time taken to synthesise new enzymes)
*needed to pass
Why is IV infusion of PPI preferred to single bolus dose?
PPIs only inactivate actively secreting acid pumps (<10% in fasting patients)*
Hence single dose only decreases acid secretion for a few hours
*needed to pass
