Final GI Flashcards
5-HT3 Receptor Antagonists: Agents
Palonosetron 5-HT3A CYP3A4
Dolasetron 5-HT3B CYP3A4
Granisetron 5-HT3A, 5-HT3B, 5-HT3C CYP3A4
Ondansetron 5-HT3B, 5-HT1B, 5-HT1C CYP3A4
Please Don’t Grow Old
-setron
5-HT3 Receptor Antagonists: MOA
MOA: Selective
Central blockade of CTZ and vomiting center
Peripheral Blockade on intestinal vagal and spinal afferent nerves-> drives antiemetic benefit
No affinity for H1, M1, or D2 receptor
Ondansetron, Granisetron, Dolasetron, Palonosetron**
Equal efficacy at equipotent doses
Palonosetron has longer t1/2 = 40 Hrs greater binding affinity (IV)
Cornerstone for chemotherapy-induced N/V
5-HT3 Receptor Antagonists: ADEs
Generally well tolerated
HA, Dizziness, Constipation
Small but statistically significant prolongation of the QTc interval
Primarily by K+ channel blockade
-Check for what medications?
Least common with Palonosetron
Serotonin Syndrome (rare)
What meds?
Dopamine (D2) Receptor Antagonists: Agents
Prochlorperazine / Promethazine D2, M1, H1, a-Adrenergic
Olanzapine D2, 5-HT1c, 5-HT3,
Trimethobenzamide D2, H1 (weak)
Metoclopramide D2, 5-HT3 (weak)
Prokinetic action-> also used for gastroparesis
ADEs: Dystonia, akathisia, parkinsonian, sedation, hyperprolactinemia, hypotension, dry mouth, etc.
Neurokinin-1 (NK1) Receptor Antagonists: MOA
MOA: Central blockade of the NK1 receptors in CTZ
Blocks binding of substance P
Aprepitant, Netupitant, Rolapitant** (PO)**
Netupitant & Rolapitant t1/2= 90&180 HRs respectively
Netupitant/Palonosetron (Akynzeo)
Fosaprepitant** (IV)**
Converted to aprepitant 30 minutes after infusion
Used for prevention of CINV along with 5-HT3 antagonists and corticosteroids
Neurokinin-1 (NK1) Receptor Antagonists: ADEs
Well tolerated
Fatigue, dizziness
CYP 3A4 substrate and inhibitor
Concomitant use of CYP 3A4 inhibitors can cause toxicity
Aprepitant + Warfarin = decreased INR (Leads to clotting)
MISC Anti-emetics
Antihistamines and antimuscarinic drugs
Dimenhydrinate, diphenhydramine, meclizine, etc
-H1 > M1
Scopolamine (patch)
-M1 > H1
Ginger - 5-HT3 antagonism
Mirtazapine - 5-HT3 antagonism, H1 antagonism
Cannabinoids (CIII)
Dronabinol
Nabilone
-THC reduces vomiting by binding to CB1 receptors
Use for refractory N/V induced by Chemotherapy
Constipation defined
A decrease in frequency of fecal elimination characterized by the difficult passage of hard, dry stools
PTs will commonly report the following signs and symptoms of constipation:
Straining to pass stool
The passage of hard, dry stool
Feelings of incomplete evacuation
Passage of small stools
Bloating
Decreased Stool frequency
Anti-constipation overview
Watery evacuation within 1-6 hours
Magnesium citrate, hydroxide & sulfate (high-dose)
Sodium phosphates
Bisacodyl (rectal)
Semi-fluid stool in 6-12 hours
Bisacodyl (oral)
Senna
Magnesium sulfate (high dose)
Softening of feces in 1-3 days
Bulk-forming agents
Emollients
PEG 3350
Mineral oil
OTC Laxatives - Bulk Forming
MOA: Dissolves or swells in the intestinal fluid, forming emollient gels that facilitate the passage of intestinal contents and stimulate peristalsis
OTC products:
Methylcellulose
Polycarbophil
Psyllium
DOC for constipation, good for PTs on low fiber diet
OTC Laxatives: Emollients
MOA: Increases the wetting efficacy of intestinal fluid and facilitate a mixture of aqueous and fatty substances to soften fecal mass
OTC product: Docusate sodium
Good for PTs with c/o dry stools, straining when defecating
OTC Laxatives: Lubricants
MOA: Soften fecal contents by coating them, thereby preventing colonic reabsorption of fecal water
OTC Products: Mineral oil
Saftey concern of lipid pneumonia
OTC Laxatives: Saline Laxatives
MOA: Draws water into the intestine, increasing intraluminal pressure, which acts as a stimulus to increase intestinal motility
OTC products:
Magnesium citrate
Magnesium hydroxide
Sodium phosphate/diphosphate
Screen elders and those with renal and cardiac disease
OTC Laxatives: Hyperosmotic Laxatives
MOA: Draws water into rectum to stimulate a bowel movement
OTC Products: Glycerine, Polyethylene Glycol 3350
-Take with 4-8 ounces of water
OTC Laxatives: Stimulant Laxatives
MOA: Increase the propulsive peristaltic activity of the intestine by local irritation of the mucosa. Stimulates the secretion of water and electrolytes in the large intestine
OTC products:
Senna
Bisacodyl
-Can cause electrolyte and fluid deficiencies along with malabsorption
Laxative Abuse
Utilized for weight loss
Rush food through the GI tract before absorption
Mainly-> loss of water, electrolytes, and minerals
Na+, K+, Mg+, and PO4
Tremors, weakness, blurry vision, fainting, kidney injury, metabolic alkalosis or arrythmias
Abuse may lead to dependence
Chronic abuse may cause “lazy” colon infection, INC risk of colon cancer
When to suspect
More common in women, eating disorders, PMH inconsistency, altered diarrhea constipation complaints
Opioid-Induced Constipation (OIC)
Opioids
Delay Gastric emptying
Interrupt Bowel Peristalsis
Reduce Intestinal Secretion of fluid
-Less Bowel Movements, possible drier stools
Predictable ADE-> PTs do NOT develop tolerance
Traditional laxatives used first-line due to:
Cost
Accessibility
Saftey Profile
OIC Agents (2nd Line)
Methylnaltrexone
Alvimopan
MOA: Peripheral acting u opioid receptor antagonists
MInimal Absorption in the GIT
Does not cross the BBB
ADEs: abdominal pain and/or distention, diarrhea, HA, chills
DO not use methylnaltrexone if PY has HX of GI obstruction
Long term use of Alvimopan increases risk of MI
-Short term use only
Chronic Constipation 1
Lubiprostone
Bicyclic fatty acid derived from prostaglandin E1
MOA: Activates chloride channel-2 (CIC-2) in GI epithelial cells -> efflux of Cl- into lumen of GI tract -> followed by efflux of Na2 -> followed by water
- Increase fluid secretion
- Increases intestinal transport
ADEs: Nausea (31%), diarrhea, abdominal pain, and distention, HA
Chronic Constipation Linaclotide
Linaclotide
MOA: Activates guanylate cyclase in response to a meal -> increases -> cGMP -> stimulates chloride, sodium bicarbonate, and water secretion into intestinal lumen
Also activates colonic sensory and motor neurons
-Reduces abdominal pain and increases smooth muscle contraction
ADEs: diarrhea, dehydration, dizziness, hypokalemia
-Black Box Warning: Serious dhydration - Do not use < 18 Y/O
Diarrhea - Bismuth Subsalicylate
Bismuth Subsalicylate (pepto)
MOA: Reactis with HCL to form bismuth oxychloride and salicylic acid
Bismuth -> direct antimicrobial effects (H. Pylori)
Salicylic acid -> inhibits chloride secretion in intestine to reduce liquid content of stools
Avoid if documented allergy or sensitivity to ASA
Do not use in children <12 Y/O (Reye’s syndrome)
ADEs: Blackening of tongue and stools (benign), tinnitus, dry stools, confusion
Diarrhea - Loperamide
Loperamide (Immodium)
MOA: Synthetic, peripheral u opioid agonist that stimulates receptors located in the intestinal circular muscles
Slows intestinal contractions
Inhibits secretion of electrolytes and water
No tolerance has been reported
ADEs: Dizziness, mild constipation, Abdominal pain/distention
No CNS effects at standard doses
Loperamide Abuse
At high dose in a Mu-agonist, but also leads to cardiac arrhythmias/syncope/arrest
Suspect overdose when:
Fainting
Tachycardia
Unresponsiveness
Fatal at 4-100 x dose (8mg OTC, 16mg RX)
FDA -> request limited doses per package from manufactureres
Diarrhea - Diphenoxylate/Atropine
Diphenoxylate/Atropine
Diphenoxylate is a peripheral u opioid agonist
CNS effects at high dose
Prolonged use can lead to tolerance
Co-formulated with small doses of atropine
- 5 mg diphenoxylate with .025 mg of atropine per tablet or teaspoonful
- Discourages OD
- Anticholinergic properties can constribute to antidiarrheal effect
RX only
Federally classified as a controlled supstance CV
ADEs: dry mouth, constipation,
Euphoria, respiratory depression (high dose)
Antacids
MOA: Neutralizes pH
Provides Symptomatic relief only-> appropriate for episodic GERD, “sour stomach”, acid indigestion
Products contain at least one of the following salts
Magnesium, Aluminum, Calcium Carbonate, Sodium Bicarbonate
Liquids have faster onset of action vs Pills
Side effects are determined by the salt form
Magnesium -> diarrhea
Calcium, Aluminium -> constipation
Sodium -> Flatulence/belching, fluid retention
Watch for Renal insufficiency
No preventative, only response, action w/in 5 minutes duration 20-30 minutes
Antacids ADE/Agents
Can Decrease absorption of other drugs
FQ, Tetracycline, Iron, Itraconazole, etc.
-Seperate doses by 2-4 hours
Calcium Carbonate (Tums / rolaids)
Sodium Bicarbonate (Alka-seltzer - 500 mg Sodium per tab)
Magnesium & Aluminum hydroxide (Maalox advanced, Mylanta, Gaviscon)
Histamine2 - Receptor antagonist (H2RA)
MOA: Reversibly decreases fasting and food-stimulated acid secretion by inhibiting histamine on the H2 receptor of the parietal cell
Indicated for the treatment of mild-moderate, infrequent, episodic heartburn
60-70% acid suppression
Cimetidine, Ranitidine, famotidine, have extensive first pass effect
Nizatidine minimal first pass
Proton Pump Inhibitors (PPI)
MOA: Irreversibly inactivates the hydrogen-potassium adenosine triphosphate (H+/K+-ATPase) “proton” pump resulting in impairment of acid secretion
Pro-drug is protected by enteric coating (EC)
In the intestinal lumen, the EC dissolves and the drug is released and absorbed -> carried to the parietal cell for activation
Forms strong covalent bonds with proton pump
Most potent inhibitors of acid suppression
90-98% acid suppressed
PPI Agents
Omeprazole OELDPR -prazole
Esomeprazole
Lansoprazole
Dexlansoprazole
Pantoprazole
Rabeprazole
Equally Efficacious
Buioavailability decreased with food
3-4 days for maximal suppression of acid, not for acute relief
PPI ADE/DDI
ADEs: D/HA, abdominal pain, B12 def, Reduced absorption of Iron/Ca/Mg, osteoporosis, fractures, CAP, c. difficile (others?)
Do not abruptly stop - Taper to avoid rebound acid secretion
DDIs: Ketoconazole, itraconazole, atazanavir, rilpivirine, Calcium carbonate, iron salts
Omeprazole + clopidogrel = therapeutic failure of clopidogrel
Sucralfate
Sucrose + complexed aluminum hydroxide
Mixes with HCL to form viscous paste that bindfs directly to ulcers and erosions
-Physical barrier to protect stomach lining
Stimulates mucosal prostaglandin and bicarbonate secretion
~3% systemically absorbed -> very few ADEs
Constipation (aluminum)
-Aluminum tox can occur in renal disease
Limited clinical utility
Misoprostal
PGE1 analog
Increases mucosal and bicarbonate secretion
Enhances mucosal blood flow
-Stomach protectant
Used clinically for prevention of NSAID-related ulcers or labor induction (OB/GYN)
Comes in combination product with diclofenac sodium
ADEs: D, enhanced uterine contractions
Do not take if pregnant
Inflammatory Bowel disease
Disease of Chronic relapsing inflammation
Idiopathic causes
Genetic susc
Environment
Microbial factor
Immune response
Ulcerative colitis
Disease involvement: Colon and/or rectum
Proctitis = inflammation of the rectum
Continuous inflammation of the colon
Affects the innermost lining of the colon
Crohn’s Disease
Disease involvement: entire GIT
Mix of Healthy and inflamed areas
Can affect all layers of the bowel walls
Aminosalicylates
MOA: Largely unknown
Interferes with production of inflammatory cytokines
Modulates inflammatory mediators derived from COX and lipoxygenase
Meant to work typically with minimal systemic effects
Efficacy is dependent on achieving high concentration at the site of disease
Contraindicated in those with Salicylate allergy
Sites of 5 ASA release from different drug formulations
5-ASA Agents
Mesalamine (5-ASA)
PO (do not crush)
- Time release: Pentasa
- pH-dependent release: Asacol/Aprisco/Lialda
Enema: Rowasa
Suppository: Canasa
Preferred due to tolerability
5-ASA Prodrug Agents
Given PO
Sulfasalazine
Balasalazide
Olsalazine
Aminosalicylate ADEs
Mesalamine: Well tolerated -> N/HA, Abdominal Pain
Olsalazine: Secretory diarrhea
Sulfasalazine: Most side effects due to sulfapyridine moiety
Rash/hypersensitivity, photosensitivity, hemolytic anemia, folate def, pancreatitis, hepatitis
-Monitor CBC LFT
Avoid if sulfa Allergy
Supplement with Folic Acid
DDIs: Meds that alter stomach pH (can alter dissolution)
Corticosteroids
Budesonide - PO
Synthetic analog of prednisolone
pH controlled, delayed release
- Entocort (pH 5.5)
- Uceris (pH >7)
Extensively metabolized via CYP3A4 - watch for potent inhibitors
Hydrocortisone enema/foam/suppository
Rectum, distal colon
-15 to 30% absorbed systemically
Systemic steroids (prednisone, prednisolone, etc)
For acute flares -> try to minimize long-term exposure
IBS - Thiopurines
MOA: Purine antagonist -> inhibit DNA/RNA synthesis -> decreased T-Cell Function -> immunosuppresion
3-6 months to clinical benefits
Azathioprine -PO
Pro-drug metabolized to 6-mercaptopurine (6-MP)
6-mercaptopurine -PO
Active metabolite of Azathioprine
ADEs: N/V, bone marrow suppression (leukopenia), hepatoxicity
DDI: allopurinol febuxostat (gout)
IBS - Other immunosuppressants
Methotrexate (MTX) - IM/SQ
MOA: Inhibits dihydrofolate reductase-> reduces purine metabolism -> inhibits DNA synthesis, repair and replication
ADEs: hepatotoxicity, myelosuppression, nausea
Cyclosporine -IV
MOA: Calcineurin inhibitor-> decreases transcription of IL-2, TNF-alpha, IL-3, IL-4, etc.
ADEs: nephrotoxicity, HTN
