GI Disorders 3: Diarrhea, Constipation, IBS/IBD Flashcards
Agents that influence GI motility treat? (2)
role of G proteins?
Constipation (enhance motility) - laxatives (stimulant, osmotic, bulk) Diarrhea (reduce motility) - restoring fluid and electrolyte balance - eradicating infection - opioid-based drugs - can be due to bacteria, cholera toxin - G proteins will cause increase of cAMP/cGMP which will increase Cl- secretion, inhibit Na+ absorption water follows electrolytes
Stimulant laxatives
Name 4
When should laxatives not be used?
Bisacodyl Sodium picosulfate Senna Dantron most potent laxatives
never use when there is an obstruction in the bowel - can cause atonic colon
- colon’s natural propulsive activity diminished, don’t want to risk dependence
Stimulant laxatives
MOA?
senna and dantron?
- these drugs increase electrolyte secretion (and thereby water secretion) by the mucosa
- Senna and Dantron increase peristalsis (stim of enteric nerves?)
- may cause abdominal cramping
Bulk Laxatives
what do they include (4)
which types of fibers and what is the diff?
- methylcellulose, sterculia, agar bran ispaghula husk
- complex carbohydrates
- fermentable/non-ferm fibers that add bulk to the stool
- fermentable fiber attracts bacteria to ferment fiber
- non-ferm attracts water to bulk up
Bulk Laxatives
how do they work?
- polysaccharide polymers that are not digested in upper GI tract
- promote peristalsis and improve fecal consistency
- take several days to work, no serious AE (ab distension, bloating, flatulence with bloating fibers)
Osmotic Laxatives
Magnesium salts (magnesium sulfate)
how do they work?
who should avoid using these?
- produce an osmotic load thereby trapping water leading to increased volume in bowel lumen
- results in distention and purgation within an hour
- minimal side effects (diarrhea) but should be avoided in small children and pt with renal dysfunction (heart block, NMJ block, CNS depression)
Osmotic Laxatives
Lactulose
how do they work?
general AE?
- a semisynthetic disaccharide (fructose and galactose)
- lactulose poorly absorbed and creates osmotic load in lumen
- attracts water to facilitate stool movement
- takes 2-3 days to work
- side effects include cramps, flatulence, diarrhea, electrolyte disturbances (tolerance can develop)
- usually take something to keep electrolytes high
Osmotic Laxatives
Polyethylene Glycol (PEG) (MiraLax)
how do they work?
- polyether with wide ranging applications
- osmotic agent that binds water and causes water to be retained in stool
- facilitate stool evacuation w/o affecting stool weight or colonic transit time
- is preferred over lactulose for chronic constipation
- side effects: nausea, abdominal cramps, stomach upset, flatulence, dizziness
Agents for Opioid-Related Constipation
Lubiprostone
how does it work?
- chronically taking opioids can lead to constipation
- activates on Cl- channel-2 on apical membrane cells in small intestine to promote Cl- and fluid secretion
- increase risk for fetal loss?
Agents for Opioid-Related Constipation
Naloxegol
how does it work? special?
- Mu (u) receptor antagonist that is pegylated (attached to PEG) which prevents/limits penetration into BBB and CNS
- inhibit u that act on constipation (GI) while still getting analgesic effect
Diarrhea
causes (4)
pathology (3)
- underlying disease, infection, toxins, AE of drugs or radiation therapy
Pathology
- increased GI tract motility accompanied by increased secretion
- decreased absorption of fluid
- loss of electrolytes (Na+) and water
Diarrhea
approaches to manage it (3)
- Maintence of fluid and electrolyte balance
- oral rehyrdation 1st priority - Treatment with anti-infective agents
- many GI infections are bacterial or viral in origin - Treatment with spasmolytic or other antidiarrheal agents
- opioids
- musc receptor antagonists
Diarrhea
Opiods
name 3 main ones
how do they work?
AE (2)
- codeine (not the choice for diarrhea)
- diphenoxylate
- loperamide (drug of choice for traveler’s diarrhea)
- Racecadotril
- increase tone and rhythmic contractions of instestine but diminish propulsive activity
- *constipation, paralytic ileus
- other: abd cramps, drowsiness, dizziness
codeine (not the choice for diarrhea)
diphenoxylate
loperamide (drug of choice for traveler’s diarrhea)
Racecadotril
type and use?
opioids for treating diarrhea
Opiods
Loperamide (Imodium)/diphenoxylate
MOA?
- Mu (u) receptor agonist
- activation of u receptor in bowel results in inhibition of peristalsis in colon
- delayed passage of deces through bowel
- increases absorption of fluid from feces
- leads to drying effect on stool
- anal sphincter tone enhanced
- limited CNS penetration, low solubility
Opiods
Racecadotril
what does it act on?
MOA?
compare with loperamide
- prodrug of thiorphan (inhibits enkephalinase)
- enkephalins are agonists of delta (d) receptors
- inhibits intestinal secretion (fluid, Cl-) to treat diarrhea
- used in combo with rehydration therapy
- doesn’t enter CNS
- less risk for constipation for loperamide
- higher risk for itch than loperamide
Bismuth Subsalicylate/Pepto Bismol
- GI symptoms, diarrhea
- MOA not well understood, contains clays that may act as a bulk-forming agent
- Bismuth compounds may also have anti-secretory and antimicrobial effects
Chronic Bowel Disease - Irritable Bowel Syndrome (IBS)
characteristic (1)
- bouts of diarrhea, constipation, abdominal pain
- etiology poorly understood
IBS-related diarrhea/constipation
Eluxadoline (diarrhea)
receptors? effect?
- mixed u and K opiod receptor agonist, d receptor antagonist acting on enteric neurons to slow transit
- low oral bioavail.
IBS-related diarrhea/constipation
Linaclotide
use for?
receptor? effect?
- synthetic peptide that acts as an agonist of guanylate cyclase C receptor in intestinal epithelial cells, which increases cGMP levels
- increases Cl-, bicarbonate secretion
(constipation)
Chronic Bowel Disease - Inflamm Bowel Disease (IBD)
types (2)
preferred glucocorticoids for short term? (2)
- Ulcerative colitis, Crohn’s disease are forms of IBD that affect colon or ileum (autoimmune inflamm conditions)
- prednisolone, budesonide preferred for acute reduction of inflam in IBD/IBS (oral/local)
- not for long-term treatment
Anti-inflamm for IBS/IBD
Methotrexate
MOA?
- folic acid ant that has both cytotoxic and immunosuppressant activity
- competitively inhibits dihydrofolate reductase (DHFR) and thus inhibits DNA synthesis
- DHFR needed to make purines
Anti-inflamm for IBS/IBD
Sulfasalazine
what is it linked to?
AE(1)
- sulfonamide sulfapyridine linked to 5-ASA
- others 5-ASA products are olsalazine, mesalazine
- not understood how it works, may reduce by scavenging free radicals, decrease superoxide generation
- inhibit leukotriene production
- decrease neutrophil chemotaxis
Hypersensitivity
Immunosuppressants for IBS/IBD
Ciclosporin
main action?
AE (3) - toxicity where?
other AE?
- binds to cyclophilin, *inhibits calcineurin which decrease IL-2 synthesis and prolif of T cells
- nephrotoxicity, hepatotoxicity, hypertension
- other anorexia, lethargy, hirsutism, tremor, paresthesia, GI distrubances
Immunosuppressants for IBS/IBD
Azathioprine
main action?
AE (1) - depression where?
- interferes with purine synthesis for DNA via metabolism to mercaptopurine
- bone marrow depression
Biologics for IBS/IBD
Infliximab
- chimeric neutralizing antibody against tumor necrosis factor a (TNFa)
- TNFa master regulator of immune system
Biologics for IBS/IBD
Adalimumab/Golimumab
- humanized MAB against TNFa
what drugs target membrane bound TNFa, SC injection
TNFa is a pro-inflamm cytokine (2)
Infliximab
Adalimumab/Golimumab
Biologics for IBS/IBD
Biologics for IBS/IBD
Vedolizumab
MAB against a4b7 integrin on Th lymphocytes
- prevents Th lymphocyte interaction w/ mucosal cell adhesion molecule 1 on GI tract epithelial cells to reduce inflamm
Biologics for IBS/IBD
Ustekinumab
- only if ppl don’t respond to others
- MAB targets p40 protein subunit in IL-12, IL-23
- prevents binding o these cytokines to their respective IL-12 and IL-23 receptors on immune cells to decrease inflamm
what is eluxadoline used for?
IBS-related diarrhea
what is linaclotide used for?
IBS-related constipation
what is methotrexate used for?
Anti-inflamm for IBS/IBD
what is sulfasalazine used for?
Anti-inflamm for IBS/IBD
what is ciclosporin used for?
Immunosuppressants for IBS/IBD
what is azathioprine used for?
Immunosuppressants for IBS/IBD
name the biologics for IBS/IBD (4 types)
Infliximab
Adalimumab/Golimumab
Vedolizumab
Ustekinumab
name 2 agents for treating opiod-related constipation
Lubiprostone
Naloxegol
