Diarrhea, Abdominal Pain, and Constipation Pharmacology Flashcards
Agent classes used to tx diarrhea
Prostaglandin inhibitors (bismuth)
Opioid agonists
5-HT3 antagonists
Cl- channel inhibitors
FDA-issued drug safety communication regarding Loperamide (opioid agonist used for diarrhea)
Cardiac toxicity leading to death
MOA of Loperamide
Slows peristalsis via direct action on circular and longitudinal muscles in intestinal wall —> allows for fluid/electrolyte reabsorption and increasing bulk/density of feces
Side effects of loperamide
Dizziness
Fatigue
Drowsiness
Urinary retention (anticholinergic effects)
What are the opioid agonists used to tx diarrhea?
Loperamide
Diphenoxylate
Eluxadoline
Diphenoxylate is a category ____ synthetic opiate agonist with which opioid-effects can be seen at very high doses. A small quantity of _____ is added to discourage deliberate abuse/overdose
5; atropine
MOA and kinetics of diphenoxylate
Believed to exert effect locally and centrally on GI smooth muscle cells; inhibits GI motility and slows excess GI propulsion
Kinetics: active metabolite with long half-life
SE’s of diphenoxylate
Dizziness
Drowsiness
Urinary retention (d/t atropine)
MOA of Eluxadoline
Agonist at opioid mu and kappa receptors in GI tract —> slows peristalsis and delays digestion
Antagonist at delta opioid receptors in GI tract —> decreased secretions from stomach, pancreas, and biliary tract
Indication for Eluxadoline
IBS-D
Eluxadoline is a C-IV scheduled drug. What are the side effects?
N/V/Abdominal pain
Hepatic/pancreatic toxicity — pancreatitis in high risk patients (those without gallbladder)
CNS-related effects: dizziness, fatigue, sedation, euphoria, impaired cognition
Contraindications to Eluxadoline
Biliary duct obstruction Sphincter of Oddi dysfunction Alcoholism Hx of pancreatitis Severe hepatic impairment
Stop therapy if severe constipation develops and lasts 4+ days
Which 5-HT3 antagonist is indicated for diarrhea? What is its MOA?
Alosetron
MOA: selectively blocks GI-based 5-HT3 receptors —> regulates visceral pain, colonic transit, and GI secretions
Specific indication for alosetron
Chronic, severe, IBS-D that is not responsive to other conventional therapies (women)
Side effects of Alosetron
Constipation, dyspepsia, GERD, N/V
Black box warning = Ischemic colitis! — physicians must enroll in prescribing program prior to utilizing this drug
Contraindications to Alosetron
Hx or active:
GI obstruction, perforation, stricture, adhesions, or toxic megacolon
Diverticulities, Crohns, or UC
Impaired intestinal circulation, thrombophlebitis, or hypercoagulable state
Severe constipation
What Cl- channel inhibitor is indicated for diarrhea and what is its MOA?
Crofelemer (derived from dark red sap of Croton lechleri tree = botanical pharmaceutical)
MOA: inhibits Cl secretion by blocking CFTR and CaCC channels responsible for regulating fluid secretion by intestinal epithelial cells
Specific indication for Crofelemer
Non-infectious diarrhea in HIV/AIDS pts on anti-retroviral therapy
SE’s associated with Crofelemer
Abdominal distention, elevated AST/ALT/bilirubin
Respiratory or urinary infections
What drug class is utilized in the tx of cramping abdominal pain? What drugs are included?
Antimuscarinic agents:
Hyoscyamine
Dicyclomine
Clidinium/Chlordiazepoxide
Specific indication and MOA of antimuscarinic therapy in GI patients
Indication: abdominal pain/spasms typically associated with IBS
MOA: competitively inhibit autonomic post-ganglionic cholinergic receptors at multiple sites —> decreased GI motility and spasms (pain)
Side effects of antimuscarinics used in IBS abdominal pain
Classic anticholinergic-based:
Dry mouth, urinary retention, constipation, drowsiness, mental confusion, blurred vision
What drug classes are utilized in tx of constipation?
Laxative and cathartic agents
Peripheral opioid antagonists
Guanylate cyclase-C agonists
Selective chloride (C2) channel activators
What 3 drugs are included in the peripheral opioid antagonist family utilized in tx of constipation?
Methylnaltrexone
Naloxegol
Alvimopan
What drug is included in the guanylate cylcase C agonist family utilized in tx of constipation?
Linaclotide
What drug is included in the selective chloride (C2) channel activators family utilized in tx of constipation?
Lubiprostone
MOA of Linaclotide
Selective guanylate cyclase-C (GC-C) Agonist
[binds to GC-C on luminal surface of intestinal epithelium and increases intracellular/extracellular concentrations of cGMP; stimulates secretion of chloride/bicarb into intestinal lumen via activation of CFTR ion channel —> increased intestinal fluid and accelerated transit]
Indications for tx with Linaclotide
IBS-C
Chronic idiopathic constipation (CIC)
Side effects of linaclotide
Diarrhea (dehydration, electrolyte imbalance)
GERD, dyspepsia, N/V
MOA of lubiprostone
Lubiprostone is a bicyclic fatty acid prostaglandin-E1 derivative that increases intestinal fluid secretion by activating GI-specific Cl- channels (ClC-2) in luminal cells of intestinal epithelium
Indications for tx with Lubiprostone
IBS-C (women)
CIC
opioid-induced constipation (OIC) [chronic pain, non-cancer/past cancer adults]
Side effects of lubiprostone
Nausea
Dyspepsia
Dizziness
MOA of methylnaltrexone, naloxegol, and alvimopan
Peripheral mu-opioid receptor antagonists [no common, significant CNS penetration/action or induction of withdrawal/pain symptoms]
Indications for tx with one of the peripheral mu-opioid receptor antagonists [methylnaltrexone, naloxegol, or alvimopan]
Opioid-induced constipation (OIC)
Which of the peripheral mu-opioid receptor antagonists is used for accelerating time to GI recovery following bowel resection surgery with primary anastomosis as a way of preventing postoperative ileus?
Alvimopan
Side effects of the peripheral mu-opioid receptor antagonists
Abdominal pain Diarrhea Nausea Flatulence Vomiting
Warning associated with alvimopan
Alvimopan carries risk of MI with use; REMS program requires use only in approved institutions for a maximum of 15 doses
Classifications of laxatives and cathartics for tx of constipation
Stimulants Osmotics Salines Bulk forming Stool softeners
What are the drugs in the stimulants class of laxatives and cathartics?
Bisacodyl Castor oil Glycerin Senna Na+ Picosulfate
What are the drugs in the osmotics class of laxatives and cathartics?
Lactulose
Mg Citrate
Polyethylene glycol
Sorbitol (glycerin)
What are the drugs in the salines class of laxatives and cathartics?
Mag. Hydroxide
Na+ phosphate
What are the drugs in the bulk forming class of laxatives and cathartics?
Dietary fiber Psyllium Methylcellulose Carboxymethylcellulose Calcium polycarbophil
What are the drugs in the stool softeners class of laxatives and cathartics?
Docusate
Mineral oil
AEs and drug interactions with bulk-forming or hydrophilic colloidal agents used to tx constipation
Bloating/obstruction — must drink fluids (caution in renal failure)
Drug interactions: LOTS — mainly with psyllium and the celluloses (recommendation is to take at a different time than other meds)
Stool softeners are also known as ____ or ____ laxatives
Surfactant; emollient
[anionic surfactants soften/lubricate stool via reduction in surface tension as well as increase fluid secretion into GI tract; Mineral oil is hydrocarbon-based (indigestible) and penetrates stool thereby softening it]
Adverse effects of stool softeners
Bloating/flatulence
Abdominal cramps
Mineral oil can leak past anus in some; aspiration caution in elderly/debilitated/stroke
Which GI stimulant (irritant) also contains magnesium oxide/anhydrous citric acid and thus can be metabolically converted to Mg citrate — an osmotic drug?
Sodium picosulfate
MOA of the GI stimulants
Stimulates peristalsis — irritant to enterocytes, GI smooth muscle —> inflammation
Promote water/electrolyte accumulation in GI tract (castor oil is hydrolyzed to ricinoleic acid)
Glycerin is a tri-hydroxyl alcohol and functions as an irritant and an osmotic and lubricant agent
Adverse effects of GI stimulants
Abdominal cramping
Urine discoloration with senna (yellow-brown/red-pink)
Fluid/electrolyte disturbances with long-term use
Drug interactions and cautions with saline agents
Drug interactions: diuretics (electrolyte balance concerns)
Cautions:
- renal disease (electrolytes)
- CHF/HTN (sodium balance)
Osmotic agent that is a disaccharide of galactose and fructose which aids in fluid retention in GI tract
Lactulose
Osmotic agent that is a non-absorbable sugar hydrolyzed to SCFAs — retaining fluid in GI (increased motility)
Sorbitol
Which osmotic agent is also used for severe liver disaease patients (hyperammonemia) because change in pH traps ammonia in the GI tract
Lactulose
AEs of osmotic agents
Electrolyte disturbances — must watch closely!
Abdominal pain/distention/flatulence
Which of the osmotic agents is also used for bowel prep prior to GI scopes, radiological procedures, or surgery? What is the MOA?
Polyethylene glycol (PEG-3350)
MOA: isotonic solution of long-chain PEGs = not absorbed and retain water in GI tract
