Motility Pharmacology Flashcards
Describe the difference between intrinsic and extrinsic networks of enteric nervous system
Intrinsic network can operate autonomously (works in spinal cord injury pts) and NT is serotonin for iPANs
Extrinsic input from cholinergic, adrenergic and dopaminergic neurons to control motor/secretory activity
What are three serotonin receptor subtypes in enteric nervous system?
5HT3: on extrinsic afferent nerves to induce nausea and abdominal pain (some effect on colonic activity)
5HT1P: on iPANs which contain Ach and calcitonin gene related peptide and project to myenteric plexus interneurons
5TH4: on presynaptic terminals of iPANs to enhance release of Ach and CGRP to promote reflex activity (GI motility and peristalsis)
What is effect of other NTs?
Dopamine
Ach
Epinephrine
DA: binds D2 receptors and reduces cholinergic effects
Ach: Binds mAchRs to stimulate intestinal motility
Epinephrine: binds adrenergic receptors and has nominal effect on motility
Three phases of emesis
Pre-ejection: gastric relaxation and retro-peristalsis
Retching: rhythmic contraction of abdominal, intercostal and diaphragmatic muscle against a closed glottis
Ejection: intense contraction of abdominal muscles and relaxation of upper esophageal sphincter
Describe the central control in emesis: what is the vomiting center?
What are inputs to it? (4)
Vomiting center in medulla next to chemoreceptor trigger zone (CTZ)
Input: CTZ, vestibular apparatus, vagus nerve, cerebral cortex
What is the CTZ and why is called that?
The chemoreceptor trigger zone, area of medulla next to 4th ventricle.
It has high concentrations of receptors (i.e histamine, 5HT3, DA, Ach, neurokinin)
Describe therapeutic approach for controlling emesis?
Sine there are so many receptors, should know the cause of emesis first– this way you can block the appropriate receptor (cannot block them all)
Which histamine receptor is involved in emesis?
What drug do you use to block this receptor and in which situations?
H1 receptor (involved in rhinitis,
Use diphenhydramine as antihistamine– it is a reversible H1 antagonist in situations such as motion sickness and vertigo
What are significant effects that are observed with antihistamines as antiemetics? (2)
Muscarinic and sedative effects
What are some of the functions of serotonin as it relates to GI? (5)
Vasoconstrictor
Intestinal smooth muscle stimulant
Mediator of symptoms of carcinoid syndrome (ECL neoplasm)
Involved in vomiting
Which serotonin receptor is in GIT and vomiting center?
In which situations is it stimulated?
5HT3 is in both GIT and vomiting center as part of vomiting reflex.
Chemotherapy drugs cause an increase in ECL serotonin release– stimulates vagus nerve to induce nausea via 5HT3R in CTZ
What are the 5HT3 receptor antagonists? (2)
Are they effective?
Ondansetron and granisetron
Very effective in severe nausea/vomiting associated with chemo
How does DA affect GI motility? (2)
Decreases esophageal and gastric motility
Inhibits cholinergic SMC stimulation
What is MOA of drugs that target DA-mediated emesis?
How does this relate to adverse effects?
D2 receptor antagonists– but they are dirty and also antagonize histamine and 5HT3 receptors.
AE profile due to activity and DA and nonDA receptors in dose dependent manner
What are four D2 antagonists?
What are they used for? (2)
Chlorpromazine, promethazine, prochlorperazine, metoclopramide
Used in chemo, motion sickness
What are AE of D2 antagonists? (3)
Extrapyramidal effects, dystonia, hypotension
Describe metoclopramide: Activity on receptors, use, AE (3)
Has 5HT3 activity at higher doses. It is effective in treating chemo-induced nausea BUT it is passed into breast milk and is associated with restlessness, tremor, drowsiness
Describe antiemetic drugs that target acetylcholine. What is its use and AE
M1 receptor antagonists: scopolamine
Used as prophylaxis against motion sickness, only AE is dry mouth
Drug that targets Neurokinin?
NK1 antagonist– novel drug
What is dorabinol?
Describe MOA and its use (2)
A cannabinoid that activates CB1 receptor close to CTZ
Used in combination with other antiemetics and as an appetite stimulant
What is the toxicity for dorabinol? (3)
What are symptoms of withdrawal? (3)
Tachycardia, high, paranoia
Withdrawal==>irritability, insomnia, restlessness
Which receptors increase motility?
Which ones decrease?
D2 Receptors: Decrease motility
5HT Receptors: Increase motility
M3 Receptors: Increase motility
What is effect of metoclopramide?
Why is its use limited?
It is a D2 antagonist– diminished inhibitory impact increases gastric motility
Extrapyramidal AE: Use limited due to restlessness, tremor, drowsiness
What are indications for metoclopramide? (3)
Diabetic gastroparesis
Antiemetic agent for chemo pts
Third line for GERD
How does bethanechol work?
What is it used for?
Bethanechol is a muscarinic agonist that directly stimulates cholinergic receptors, increasing gastric motility
Used for autonomic neuropathy when GERD/urinary retention coexist
How do motilin/analogs work?
Clinical indication
Both motilin and erythromycin bind to motilin receptors on GI smooth muscle and stimulate gastric motility
Used for diabetic gastroparesis
Achalasia is characterized by what?
Overactive cholinergic response leading to hypermotility
What drugs are used for achalasia?
Anticholinergics: hyposcamine, probanthine, dycyclomine
Ca Channel antagonists: lower LES pressure
Botox: reduce neuromuscular transmission (less Ach release)
What are causes of drug-induced constipation? (2)
Cation containing agents: Fe, Ca, antacids, Al, Ba
Altered neurotransmission: anticholinergics, opiates
What are therapeutic approaches to constipation? (3)
Laxatives: stimulant, bulk forming, lubricant, emollient, osmotic
Receptor mediated therapy
Cl-channel mediated approach
What are some stimulant laxatives? (big list)
Food: caffeine, fats, calories, nicotine
Derivatives of anthraquinone (senna) and dimethylethylane (basically)
How do stimulate laxatives work?
Increase intestinal motility and fluid secretion into the colon
What are examples of bulk forming laxatives?
Complex polysaccharides or cellulose derivatives– bran and fiber
What is an example of a lubricant laxative?
How does it work
Mineral (cod liver) oils that coat the bowel
Work by reducing H20 absorption from the bowel to treat chronic constipation when bulking agent fails
What is the difference between emollient laxatives (stool softness) and osmotic laxatives?
Emollient laxatives increase water secretion in SI and colon and act as a surfactant to increase fecal mixing
Osmotic laxatives cause rapid movement of H20 into SI and colon
What are examples of emollient laxatives (1) and osmotic laxatives? (3)
Emollient laxative: docusate Na/Ca
Osmotic laxative: Magnesium oxide, lactulose, glycol (bowel prep)
How does prucalopride work to resolve constipation?
It is a 5HT4 receptor agonist==>increases Ach release in myenteric plexus to increase motility
How does lubiprostone work to resolve constipation?
Stimulates type 2 Cl channel in SI.
It is highly effect with 50% patients experiencing a bowel movement within 24hours of a single dose
What is main approach for treating diarrhea? (2)
Adequate hydration
Avoid foods that increase intestinal secretion (caffeine, ETOH, spicy foods, dairy)
What are drug approaches for diarrhea?
Antisecretory agents
Opioid agonists
Anticholinergics
5HT3 receptor antagonists
What are two antisecretory agents?
SS analog: octreotide==>Inhibits secretion of serotonin
Bismuth subsalicylate==>inhibits small bowel secretion
What are two opiod agonists?
Loperamide and diphenoxylate
They inhibit cholinergic input in myenteric and submucosa plexus
What are examples of anticholinergics–how do they work?
Hyoscamine, probanthine, dycyclomide are antagonists to M3 receptor in the myenteric/submucosal plexus.
They reduce colonic motilty
What is an example of a 5HT3 receptor antagonist? How does it work? (2)
Alosetron– decreases GI afferent sensation and inhibits 5HT3 receptors on the terminals of enteric cholinergic neurons to reduce colonic motility
What are side effects of alosetron? (2)
Severe constipation and ischemic colitis
