How does dopamine produce inhibitory effect in the GI?
suppression of ACh release from myenteric motor neurons
Which laxative agent does not significantly decrease small bowel transit time?
Which agents increase propulsive action, mass actions and stool water?
Magnesium, Anthraquinones and Diphenylmethanes
What is the definition of laxation?
evacuation of formed fecal material from the rectum
What is the definition of catharsis?
evacuation of unformed watery fecal material from the entire colon
What laxative/cathartic agents produce the quickest onset of action?
CEO-TWO suppositories (containing sodium bicarbonate and potassium bitartrate) - onset in 5-30 minutes
What is lignin's water solubility and % fermentation?
poor / 0%
What is Cellulose's water solubility and % fermentation?
poor / 15%
What is Hemicellulose's water solubility and % fermentation?
Good / 56-87%
What are Muclages and gums' water solubility and % fermentation?
Good / 85-95%
What is Pectins' water solubility and % fermentation?
Good / 90-95%
What inputs does the ENS respond to for GI activity?
input from the local environment of the gut as well as the ANS/CNS
What are the two aspects of MMC?
migrating myoelectric complex and migrating motor complex
How many phases and how long does the MMC cycle last?
four phases over 80-110 minutes
Which phase of MMC is the most characteristic?
Phase III - consisting of clusters of rhythmic contractions that occupy short segments of the intestine for a period of 6-10 minutes before proceeding caudally
Which phase of MMC is the release of motilin associated with?
Phase II - associated with motility stimulation in the proximal gut
What are two key jobs of the MMC?
sweep debris out towards the anus and help limit overgrowth of luminal bacteria
How many contractions per minute occur during fed-state?
12-15 contractions per minute
What is peristalsis?
a series of reflex responses to a bolus in the lumen of a given segment of the intestine
What does the firing of the ascending excitatory reflex result in and what is its neurotransmitter?
contraction of the circular muscles on the oral side of the bolus / ACh
What does the firing of the descending inhibitory reflex result in and what is its neurotransmitter?
relaxation of smooth muscle on the anus side / NO
Which mucosal cells are responsible for initiation of peristalsis and what is the neurotransmitter they release?
enterochromaffin cells in the mucosa / serotonin
What does control of tension in the GI smooth muscle largely depend on?
What is the term given to agents who enhance coordinated GI motility and transit of material in the GI tract?
Why are older cholinomimetic agents and AChE inhibitors not very effective for GI issues?
they enhance contractions in an uncoordinated fashion that doesn't produce propulsive activity
What is the role of cholinergic agents?
to increase ACh content and activity on muscarinic/nicotinic receptors
What are the two key cholinergic receptors in the GI, and at what ratio do they exist?
M2 and M3 / 4:1
Of the two key cholinergic receptors in the GI, which is the most important in terms of motility?
What is a synthetic choline derivative with broad muscarinic effects?
What is an AChE inhibitor that increases ACh content in the cleft?
What are some effects of increased ACh concentration at muscarinic receptors?
salivation, lacrimation, bronchoconstriction, bradycardia, abdominal cramps, urinary incontinence
What are some effects of increased ACh at nicotinic receptors?
depolarizing neuromuscular blockade and muscle paralysis
What are some key effects of dopamine inhibition in the GI?
reduction of the LES and intragastric pressures
What neurons do dopamine receptor antagonists in the GI hit?
myenteric motor neurons, making them effective prokinetic agents
What other role do dopamine receptor antagonists fill besides motility?
relief of N/V by antagonism in the chemoreceptor trigger zone
What are two key dopamine receptor antagonists?
Metaclopramide and domperidone
What is one of the oldest prokinetic agents which actions on 5-HT4 (agonist) and 5-HT3 (antagonist) receptors, as well as muscarinic and dopamine receptors?
What effect does metaclopramide have on GI transit?
enhances GI transit, though mostly confined to the upper digestive tract where it increases LES and stimulates antral and small intestinal contractions
What is the main therapeutic use of metaclopramide?
Main role is to ameliorate N/V that often accompanies GI dysmotility syndromes
What other therapeutic roles does metaclopramide play?
relief of GERD symptoms (but not a healing) and an agent for improving gastric emptying and treating hiccups
What dopamine receptor antagonist is predominantly selective for D2 alone and is not available in the US?
What role does serotonin play in the GI?
triggers peristaltic reflex by stimulating intrinsic sensory neurons in the myenteric plexus as well as extrinsic vagal and spinal sensory neurons
What is a key AE to watch for with SSRIs?
diarrhea (b/c they inhibit reuptake of serotonin, increasing motility)
What is the 5-HT1a receptor classification?
inhibitory Gi that increases NO release
What is the 5-HT1p receptor classification?
stimulatory Go that causes slow EPSP
What is the 5-HT3 receptor classification?
stimulatory ion-channel receptor
What is the 5-HT4 receptor classification?
stimulatory Gs that increases ACh release
What is a 5-HT4 partial agonist that stimulates motility and Cl secretion leading to increased transit/decreased transit time?
What is the main use of Tegaserod?
only for emergency use for females with constipation-predominant IBS
What is an endogenous peptide and a potent contractile agent of the upper GI whose levels fluctuate with MMC?
What drug mimics the effect of motilin?
erythromycin - induces phase III MMC activity and smooth muscle contractility
What is the main role of erythromycin in the GI?
prokinetic agent in patients with diabetic gastroparesis. also used in hospitals preoperative to cleanse out the colon
What is the prostanoic acid derivative that activates ClC2 channels?
What is the role of Lubiprostone?
activates the Cl channel so you get an influx of Cl into the lumen, leading to water flow into the lumen, distension, motility/peristalsis reflex triggering
How much of normal stool weight is composed of water?
What is the result in the GI if you have too little water in the lumen?
What is the result in the GI if you have too much water in the lumen?
What are the three main classifications of laxatives?
luminally active agents, stimulants/irritants and prokinetic agents
What are some effects of laxatives?
enhances fluid retention, decreases absorption of fluid and alters motility
When you hear bulk-forming laxatives, what should you think of?
What is fiber?
a food component that resists enzymatic digestion and attracts water
What do colonic bacteria do to fiber?
ferment it to make short-chain fatty acids which are nutrients to the bacteria
What role can fatty acids play in the GI?
prokinetic effect - inducing peristalsis, increases bacterial mass/stool volume and can also stimulate gas-production
What is the general mechanism for the bulk-forming laxatives?
Absorb water --> increase bulk --> stimulate peristalsis
What bulk-forming laxative is made from psyllium husk, undergoes significant fermentation, and produces the most gas of the bulk-forming agents?
What bulk-forming laxative is a synthetic cellulose that is poorly fermentable?
What bulk-forming laxative is an acrylic acid resin polymer that is poorly fermentable?
Fibercon (Calcium polycarbophil)
What is the main difference between soluble and insoluble fiber?
the former goes through fermentation and causes bloating/flatus / the latter is poorly fermented but better at attracting water
What is one main counseling point with taking fiber?
Drink lots of water - otherwise you could end up constipated
What agents are known as saline cathartics?
Magnesium citrate, magnesium sulfate, sodium phosphate
What is the result of saline laxatives?
very quick acting laxative but with very watery perfuse diarrhea
What is the mechanism of action for saline laxatives?
creates an osmotic water retention situation that stimulates peristalsis and can produce inflammatory mediators (not an irritant though)
Of Mg and PO4, which requires larger doses and why?
PO4 - they are absorbed to a greater degree so you have to dose more to be therapeutic
What classes of patients should avoid the saline laxatives?
renal insufficiency, cardiac disease, electrolyte abnormalities and diuretic therapy
What conditions can arise from sodium phosphate treatment for constipation?
hyperphosphatemia, hypernatremia, hypocalcemia, hypokalemia
What is a galactose-fructose synthetic disaccharide?
What is one indication for the use of lactulose?
What is the term given to electrolyte solutions used as laxatives?
polyethylene glycol electrolyte solutions (PEG causes the laxative effect)
What prevents electrolyte imbalance while taking PEG?
solution is made isotonic with added sodium sulfate, sodium bicarbonate, sodium chloride and potassium chloride
What is the MOA of surfactants/stool softeners like docusate?
lowers surface tension of stool, permitting mixing/entry of water and lipids / also stimulates fluid/electrolyte secretion and alters mucosal permeability
What is a mixture of aliphatic hydrocarbons that is indigestible with minimal absorption, but penetrates and softens stool up?
What is one thing to watch for with long-term use of mineral oil?
malabsorption of the fat-soluble vitamins ADEK
What is the MOA of stimulants/irritants?
induces a low-grade inflammation that promotes accumulation of water and electrolytes that eventually stimulates motility
What stimulant/irritant can lead to cartharsis and fluid/electrolyte deficits in overdose?
What stimulant/irritant is converted in the GI to an active form by normal flora of the GI?
what is one adverse effect to watch for with Senna?
melanotic pigmentation of the colon (cathartic colon)
Which stimulant/irritant contains two noxious agents (ricin and oil)
How does castor oil work?
lypases hydrolize the triglyceride to yield glycerol and ricinoleic acid (the latter is the active ingredient)
What are two examples of opioid receptor antagonists?
Methylnaltrexone and Alvimopan (selective mu-receptor antagonists)
Why do the opioid receptor antagonists have no affect on analgesia?
they cannot cross the BBB
What specific role is methylnaltrexone used for?
for opioid-induced constipation
What role is alvimopan used for?
to shorten duration of post-op ileus
What is a major AE of metaclopramide?
EPS (nigrostriatal pathway), particularly after IV administration
What is a major AE of erythromycin?
pseudomembranous colitis and induction of resistant strains of bacteria