Week 3: Celiac Disease, GI Infections, & snow day GI drugs! Flashcards
What is the drug class that can be both a laxative and an anti-diarrheal?
Bulk Forming
What is the MOA of bulk forming drugs?
What 2 classes of GI drugs can they fall under?
*Mechanical Laxative or Anti-Diarrheal*
Absorbs H2O and forms gels in intestine that can either induce peristalsis or slow passage through intestine
What are contraindications of bulk forming drugs (though these are also shared by many laxatives)?
GI obstruction, perforation, gastric retention, undiagnosed abdominal pain, vomiting, signs of appendicitis, toxic colitis, ileus, megacolon
What interactions can bulk forming drugs have?
Impact absorption of other drugs (requiring separate administration by at least 1 hour)
What are some other considerations w/ bulk forming agents as laxatives?
As unmetabolized plant fibers, avoid giving to patients w/ difficulty swallowing
severely slow colon
diverticulitis
watch Na [CHF]/ K [kidney failure]/Aspartame content
What are 2 ex’s of bulk forming laxatives that can also be anti-diarrheals?
Psyllium “silly plant” *swipes leaf*
Carboxymethycellulose
What is the class & indications of osmotic laxatives?
*Mechanical Laxatives*
Constipation
Colon prep for GI procedures
Toxin Removal
In addition to the usual contraindications of laxatives, what are some that are unique to osmotic laxatives?
What is a major AE?
UC
Diverticulitis
Colostomy/Ileotomy
Renal Insufficiency
Heart Block
Rectal Bleeding
AE: electrolyte abnormalities
What are 2 possible interactions for osmotic laxatives?
1) Link between oral sodium phosphates (OSP) & acute phosphate nephropathy, also to be avoided in kidney disease or decreased renal function; caution in patients taking diuretics, ACE I, ARB, NSAIDs
2) Drugs given before colon prep can be flushed out before they’re absorbed
What are some examples of osmotic laxatives? What are some significant AE’s w/ 1 in particular?
Magnesium Hydroxide: (-) ↓ ab absorption
(-) early release of enteric coated drugs
Magnesium Citrate, Sodium Phosphates, Polyethylene Glycol & Electrolytes, Lactulose, Sorbitol, Glycerin
What is the MOA & drug class of *Surfactant*? When is it indicated?
*Mechanical Laxative*
MOA: anionic detergent, stool softener
Indication: Hemorrhoids*
When is surfactant contraindicated?
Fecal impaction, obstruction, acute surgical abdomen
(X) mineral oil toxicity: w/ Lubricant
What is something to consider with Surfactant?
NOT useful once constipation has occured
What are some ex’s of Surfactants?
Detergents: docusate diocytyl
sodium sulfoceinate [Ca] [K]
*Docusate: weak contact laxative*
What is the class & MOA of Lubricants?
When is it indicated?
*Mechanical Laxative*
MOA: penetrates feces for easier passage, prevents H2O absorption
Fecal impaction [CI w/ Surfactant], post MI, surgery, partum
What are 2 things that can result from chronic use of Lubricants?
1) Malabsorption of fat soluble minerals
2) Chronic intestinal hypomotility
What is the class & MOA of stimulant/irritant/contact laxatives?
*Mechanical Laxative*
MOA: irritant effects on enterocytes, enteric neurons & muscle; cause H2O & electrolyte accumulation & stimulate intestinal motility via pathways (Prostaglandin, cAMP, NO, cGMP, inhibition of Na, K-ATPase)
What are stimulant laxatives contraindicated & 2 other considerations?
CI: Rectal bleeding; N/V, Acute Abdomen, Bowel Obstruction, Appendicitis, Gastroenteritis
*Not for chronic use
*Do not chew enteric coated tablets
*All prodrugs must be metabolized in stomach into active forms
What are the AE’s of stimulant laxatives?
Senna: Melanosis Coli,
Castor Oil & Diphenylmethanes: mucosal damage
Cathartic Colon, Cramps, Severe diarrhea, Dependency
What are some ex’s of stimulant laxatives?
Anthraquinones: Cascara Sagrada, Senna/Sennosides, Cassia Plant, Aloe, Castor Oil, Diphenylmethane, Bisacodyl
What is the class, MOA & PK of Methylnaltrexone & Alvimopan?
*Receptor Mediated Laxatives*
MOA: opioid receptor antagonist
PK: slow dissociation from receptor
higher affinity for peripheral receptors
poor systemic availability
metabolized by intestinal flora, not hepatic P450
Substrate for P Glycoprotein
What are the receptors affected in receptor mediated laxatives?
Mu opioid receptors
ClC-2 Cl Channels
Guanylate Cyclase (GC-C) Receptors
When are the opioid anatagonists (receptor mediated laxatives) Methylnaltrexone & Alvimopan indicated?
When are they contraindicated?
Post-op ileus
Short-term in hospital use (X >15 doses post op)
CI: therapeutic doses of opioids used for >7 consecutive days
When are the AE’s & interactions that opioid anatagonists (receptor mediated laxatives) Methylnaltrexone & Alvimopan can have?
AE: Dyspepsia, Hypokalemia, Urinary Retention
Interactions: Drugs that inhibit P Glycoprotein
What is the class & MOA of Lubiprostone?
*Receptor mediated Laxative*
MOA: Agonist at GI ClC-2 Cl channels, activates channels in apical membrane of intestine leading to incr production of Cl-rich intestinal fluids w/o affecting serum Na+ or K+ levels
Essentially an osmotic laxative
PG derivative
What is the PK of Lubiprostone?
Poor systemic absorption (plasma serum levels not even detectable w/ therapeutic doses)
What are 2 unique considerations of Lubiprostone?
No restriction on length use
No evidence of tolerance, dependence, or rebound effects
What is a shared indication among the receptor mediated laxative drugs: Lubriprostone, Linaclotide & Plecanatide?
Chronic idiopathic constipation
IBS w/ constipation
*Lubiprostone: fems 18+ y/o*
What is a CI shared by Lubiprostone & Linaclotide?
CI: known or suspected mechanical GI obstruction
Does Lubiprostone have drug interactions?
No, based on structure, protein binding, in vivo studies
What is the shared MOA of Linaclotide & Plecanatide?
MOA: 14 aa (L) and 16 aa oligopeptide (P)
GC-C receptor agonists that increases cGMP levs
PK: acts locally, once daily dosing
What is Linaclotide’s boxed warning? How does it compare w/ Plecanatide’s CI?
Both share extreme dehydration
L: avoid in patients 6-17 y/o (up to 6 yrs)
P: avoid in <6 y/o
Does Linaclotide have drug interactions?
What is a unique consideration?*
No bc neither drug nor metabolite occurs at measurable levs
No interaction via P450/P Glycoprotein
*Anti-hyperalgesic; more SN to pain, reducing IBS GI discomfort
What are 3 “other” anti-diarrheal drugs?
What is the MOA & Indications for the plant-derived one?
1) GI Serotonin (5-HT4) Receptor agonists (though, not used for general diarrhea Tx)
2) Anticholinergics
3) Crofelemer: plant derivative
‘goalie “fell” & subsequently blocked Cl ‘
MOA: blocks CFTR & Anoctamin I, & thereby Cl currents
“it knocked him hard”
Indication: Non-infectious diarrhea in adult HIV/AIDs patient
Give an ex of an anti-diarrheal bulk forming drug
Kaolin-Pectin
When are narcotic analogues (ie: opiate agonists) vs. diarrhea contraindicated?
Infectious diarrhea: E Coli, Salmonella, Shigella
What are 2 AE’s and 3 possible interactions that narcotic analogues can have?
AE:
1) Constipation
2) Toxic Megacolon
CI’s:
1) Other anticholinergic drugs (ie: Atropine)
2) Sedative drugs
3) Monoamine Oxidase Inhibitors (MAO Inhibitors)
“No MAO”
What are ex’s of narcotic analogues?
Phenylpiperidine analgesic analogues
Loperamide
Diphenyloxylate-Atropine
What is the MOA of non-specific anti-diarrheals?
When are they indicated?
MOA: may bind bacterial toxins
anti-secretory effects, non-SP anti-inflammatory effects
Traveller’s Diarrhea: ETEC-non-inflammatory gastroenteritis
When are non-specific anti-diarrheals CI & what are their AE’s?
CI: Hypersensitive to ASA/salicylates
Not for <16 y/o w/ viral infections (Reye’s Syndrome: progressive encephalopathy)
Chronic use in renal failure patients
AE: Temporary black tongue & stools, salicylate toxicity at high doses
What interactions can non-specific anti-diarrheals have?
What is one consideration & ex?
W/ tetracyclines & other salicylates (additive effects)
Consider if tablets used: ensure they are chewed!
Ex: Bismuth Subsalicylate
“under the radar and non-SP”
What is the class, MOA and indications for Bile Acid Binders?
*Anti-diarrheal*
MOA: binds bile acids, anion exchange resins
Indications: Secretory Diarrhea & Post-Op
What are the CI’s, AE’s, and interactions of Bile Acid Binders?
CI: Pts sensitive to constipation bc
AE: constipation and bloating
Interactions: can bind other drugs (req sep admin times) & interferes w/ some dx tests
What are 3 ex’s of Bile Acid Binders?
Which is not absorbed or metabolized, leading to fewer drug interactions?
1) Cholestyramine
2) Colestipol
3) Colesevelam*
What is the MOA and indications for the anti-diarrheal anti-secretory agents?
MOA: Somatostatin receptors; hyperpolarizes gut neurons, decreases Ach and slows peristalsis
Indications: AIDS-related diarrhea
Refractory endocrine tumor related diarrhea
What are the AE’s and interactions of anti-secretory agents?
Give an ex:
AE: gallbladder stasis, inhibition of pancreatic secretions
Interacts w/ Cyclosporine
Ex: Octreotide: somatostatin analogue, w/ a longer T1/2 is more potent at inhibiting gastric & pancreatic secretions
How are antacids viewed in treating peptic disorders?
Largely replaced by H2 receptor blockers & PPI’s
But they are inexpensive & widely used for self-Tx
Describe the rates of reaction for the various metal hydroxides in antacids
Al: slow
Mg: slow/moderate
Na & Ca bicarbonates: fast
What are two examples of non-acid neutralizing compounds?
1) Simethicone (gas sx)
2) Alginic acid
How do tablet vs. liquid antacid formulas compare?
Tablets neutralize less acid/dose & have a longer onset of action than Liqs
Describe the CI’s, AE’s, and interactions of antacids
CI: renal function
AE: minimal (constipation/diarrhea)
Many interactions
What is the MOA & PK of topical mucosal protectants?
MOA: Complexes w/ protein exudates at ulcer sites, acting as protecting barrier
PK: minimal absorption w/ minor AE’s
What are the interactions & CI’s of topical mucosal protectants?
Interactions: may bind to other medications, so reqs separate doses
CI: renal failure; do not give w/ antacids, H2 blockers, PPI’s
What is an example of a non-specific anti-diarrheal with mucosal protective properties?
Bismuth subsalicylate
What is the MOA & indications of systemic mucosal protectants?
MOA: As PG E1 analogue, inhibits gastric acid secretions and promotes mucosal protective properties
Indications: prevent NSAID induced gastric ulcers
What are the drug interactions and CI’s of systemic mucosal protectants?
Interactions: NO effect on P450 system (despite hepatic metabolism), aspirin or NSAID PK
CI’s: Pregnancy Category X; miscarriages possible bc of induced labor
What is an ex of a systemic mucosal protectant?
Misoprostol
Compare and contrast the presentations, GI areas affected and treatments of invasive & non-invasive gastroenteritis
Invasive: fever, bloody diarrhea [dysentery], fecal leukocytes present, involves colon more involved Tx
Non-invasive: non-inflammatory, toxin producing, usually watery diarrhea, affects upper GI; self-limiting
What is the #1 cause of gastroenteritis in the US?
Norovirus
What is an ex of an agent that can induce non-inflammatory gastroenteritis & cause villus blunting on histology?
Why is there a 30% secondary attack rate for contacts?
Norovirus: “winter vomiting disease”
Many genotypes, high recurrence
What is an agent that can induce non-inflammatory gastroenteritis but can still cause fever?
Rotavirus
Describe the sources of these agents that can cause non-inflammatory gastroenteritis:
a) Staph Aureus
b) Bacillus Cereus: 2 forms
c) Clostridium Perfringens
d) Entertoxigenic E Coli
a) Food: ham, potato salad, cream filled pastries
b) Emetic form: contaminated fried rice
Diarrheal form: meat & vegs
c) Catered evts w/ reheated food
d) Food & H2O
Why is Clostridium Perfringens’ toxin unique compared to that of other non-inflammatory gastroenteritis agents?
Clostridium Perfringen’s entertoxin is released from the organism during sporulation in small intestine, whereas Staph Aureus’ toxin is preformed & Bacillus Cereus’ entertoxin is also preformed
What condition is Entertoxigenic E Coli (ETEC) most responsible for?
What is the MOA of its two toxins?
What is unique about its Tx?
Traveler’s Diarrhea
Heat Stable Toxin (ST) and Heat Labile Toxin (LT) increase cAMP
Tx: Ab’s can shorten duration: Cipro or TMP-Sulfa
What is unique about Nontyphoidal Salmonella diarrhea even though it is an agent that induces inflammatory gastroenteritis?
Watery rather than expected bloody
Although it is self-limiting (no 1st or alternative ab choices), when would ab’s be administered in Nontyphoidal Salmonella?
Risk for metastatic complications: newborns, elderly, lymphoproliferative disorders, prosthetic joints, HIV +, valvular heart disease, hemoglobinopathies
What is an oxidase + agent that can induce inflammatory gastroenteritis?
Campylobacter
Which agent of inflammatory gastroenteritis can lead to terminal ileitis, mesenteric lymphadenitis & appendicitis-like sx?
Yersinia Enterocolitica
What are the sources of Enterohemorrhagic E Coli & characteristics of its toxin?
Sources: poorly cooked meat, unpasteurized foods, municipal water, petting zoos
Shiga Toxin Producing E Coli (STEC) w/ O157:H7 strain
Shiga toxin detected in stool: preferred dx method
What are potential complications of EHEC?
Toxic megacolon, intussusception, HUS
Would you administer ab’s in EHEC?
Abx contraindicated bc can increase risk of HUS
What gross pathology might you sometimes find in C Diff induced inflammatory gastroenteritis?
How would you Tx C Diff?
“Pseudomembranous Colitis:” plaques from Toxins A & B
Tx: eliminate inciting agent (ab’s)
Metronidazole, Vancomycin (PO), Fidaxomycin
What is the 1st choice & alternative ab Tx for Campylobacter?
1st: Azithromycin “zip the camp”
Alt: Ciprofloxacin “roll back the revolver”
What is the 1st choice & alternative ab Tx for C Diff?
1st: Vancomycin
2nd: Fidaxomicin *not rec for <18 y/o, so Metronidazole “play nice for the kids”
What is the 1st choice & alternative ab Tx for Salmonella enterica Typhi?
1st: Ceftriaxone/Ciprofloxacin
Alt: Ampicillin/TMP-SMX or Azithromycin
“bringing the forgotten A game, round II”
What is the 1st choice & alternative ab Tx for Paratyphi Shigella? Exception?
1st: Azithromycin, Ciprofloxacin, Ceftriaxone
Alt: Ampicillin, TMP-SMX
*Shigellois: fluoroquinolones shouldn’t be prescribed if ciprofloxacin MIC is 0.12 ug/mL or incr even if lab report says isolate susceptible
What is the 1st choice & alternative ab Tx for Vibrio Cholerae?
1st: Doxycycline: incr cAMP remediated w/ D
Alt: Ciprofloxacin, Azithromycin, Ceftriaxone
What is the 1st choice & alternative ab Tx for non-Vibrio Cholerae?
Usually not indicated for non-invasive disease or single agent Tx for non-invasive disease
1st: Ceftriaxone + Doxycycline (invasive case)
Alt: TMP-SMX + Aminoglycoside
What is the 1st choice & alternative ab Tx for Yersinia Enterocolitica?
1st: TMP-SMX
Alt: Cefotaxime or Ciprofloxacin
What is the type of inheritance and the most severe form in Alpha1 Antitrypsin Deficiency?
Describe its pathogenesis
Autosomal Codominant; PiZZ
AA substitution in SERPINA1 gene, protein misfolding and polymerization, stuck in ER and causes hepatocyte apoptosis
What is the type of inheritance and mutations in Hereditary Hemochromatosis?
Describe its pathogenesis
Autosomal recessive, low penetrance
Mutations in HFE: C282Y (N Eur) and H63D (worldwide)
HFE mutation ↓ Hepcidin, ↑ Ferroportin & Plasma Fe (overload in tissues)
What are 2 significant clinical features in Hereditary Hemochromatosis?
Cardiac dysfunction and Bronze Diabetes
What is the inheritance of Wilson’s Disease and the associated mutation?
Describe its pathogenesis
Autosomal recessive; ATP7B mutation
Mutaton in CU transport ATPase->impaired Cu excretion in bile and failure to incorporate Cu into ceruloplasmin
What are three ways to treat Wilson’s Disease?
1) Cu Chelators
2) Zn (induces methallothionein to bind Cu in enterocyte)
3) Avoid Cu rich foods (shellfish, liver, chocolate, whole grains)
What is the EPI, inheritance and mutation in Cystic Fibrosis?
EPI: most common AR disorder in Caucasians
Mutation in CFTR, deltaF508: most common
What are three ways to treat Cystic Fibrosis?
1) Pancreatic enzyme replacement
2) Vit/mineral supplementation
3) Pancreas-liver-lung transplant
What are two possible inheritance patterns in Hereditary Pancreatitis?
AD: PRSS1 mutation in cationic trypsinogen gene, alters site for inactivation of trypsin by itself; inappropriate trypsin activation
AR: SPINK1 mutation in trypsin inhibitor
Describe the pathogenesis, Tx & cancer risk in FAP
Germline mutation in APC
Tx: Prophylactic total colectomy
100% CRC risk by 40 y/o
Describe the pathogenesis of MUTYH Associated Polyposis
AR mutation in MUTYH: BER enzymes that prevents oxidative damage mutations
Describe the pathogenesis of Polymerase Proofreading Associated Polyposis (PPAP)
Apart from CRC, what are other possible cancer risks?
AD mutation in exonuclease domain of POLE or POLD1 (polymerase)
Other: endometrial, brain
Describe the pathogenesis of Peutz Jeghers Syndrome
AD mutation in LKB1/STK11 (tumor suppressor gene)
Describe the histologic characteristics of MSI
Crohn’s like reaction
Tumor infiltrating lymphocytes
Pushing border
Poor differentiation
Describe the pathogenesis of Lynch Syndrome
Mutation in DNA mismatch repair genes (MLH1 [major], PMS2 [minor], MSH2 [major], MSH6 [minor])
Describe the main diagnostic feature of Lynch-like Syndrome
IHC shows loss of DNA MMR proteins but mutation testing shows no mutations in genes
*Somatic Mutation*
What condition accounts for 85% of all CRC’s?
Sporadic CRC
How can you categorize Familial CRC Type X (FCCTX)?
HNPCC w/o MSI
& w/ strong family history of CRC meeting clinical criteria for Lynch Syndrome but also w/o germline DNA MMR gene mutations
What inherited GI condition can occur in a background of polyposis & also be a HNPCC w/o MSI?
Polymerase Proofreading Associated Polyposis (PPAP)
