GI-Block 1 Flashcards
Acid-Peptic Diseases: Antacids
- Sodium Bicarb
- Calcium Bicarb
- Magnesium hydroxide
- Aluminum hydroxide
- Magnesium hydroxide + Aluminum hydroxide
Mech: Weak bases that neutralize gastric acid
CU: intermittent heartburn and dyspepsia
Prob: Sodium bicarbonate and calcium bicarbonate: -Gas from CO2 production -Higher doses, metabolic alkalosis -fluid retention (NaHCO3)
Magnesium hydroxide:
-diarrhea
Aluminum hydroxide:
-constipation, encephalopathy, myopathy
Cimetidine, Ranitidine, Famotidine
Mech: H2 antagonist (rev. compete)
CU: ulcers, GERD
Effectiveness:
-Very effective at inhibiting nocturnal acid secretion
Prob:
- tolerance occurs
- cimitidine inhibits CYP450
Sucralfate
Mech: Forms viscous paste through cross-linking that binds selectively to ulcers or erosions
CU: Limited (reduce upper GI bleed in critically ill patients, stress related bleeding)
Disadv: not as effective as H2 antagonists or PPIs
Prob: Few
Glucocorticoids:
Hydrocortisone, Methylprednisolone
Action: bind nuclear hormone receptor, translocate to nucleus, affect gene transcription
-Anti-emesis mech is unclear
Clinical Use:
moderate to severe IBD for short periods; not ideal for maintenance of remission –
-taper dose after patient has been stable for 2-4 weeks.
Of note: enhances anti-emetic efficacy of 5-HT3 receptor antagonists
Problems: See slide on powerpoint
Prochlorperazine
Mech: antagonist of D2 receptor
CU: emesis, particularly induced by chemotherapy
Prob: Antimuscarinic effects
Cannabinoids:
Dronabinol (delta-9 THC)
Action: stimulation of cannaboind receptors in vomiting center
Clinical Use:
- prophylactic in cancer chemotherapy,
- appetite stimulant (AIDS, anorexia)
Problems:
- central sympathomimetic activity (tachycardia, palpitations, bloodshot eyes)
- can experience paranoid reactions
Lubiprostone
Action: Stimulates chloride channels. Increase chloride-rich fluid secretion into intestine, thus stimulating intestinal motility
Clinical Use: constipation-predominant IBS (approved for women)
Problems: nausea
Opioid Receptor Antagonist:
Methylnaltrexone
Opioids produce constipation by decreasing intestinal motility thus prolonging transit time and increasing absorption of fecal water
-Methylnaltrexone blocks this
Unlike naloxone and naltrexone, methylnaltrexone does not readily cross BBB
Loperamide
Action: mu opioid receptor agonist
Clinical Use: diarrhea
Problems: torsades de pointes
Of note: available over-the-counter because it does not cross blood-brain barrier and thus has no potential for addiction
-Pt. should contact MD if after 48 hours if no benefit
Bismuth Subsalicylate
Action: salicylate inhibits formation of prostaglandins and chloride secretion to reduce stool frequency and liquidity, bismuth has antimicrobial effects
Clinical Use:
- diarrhea
- as part of 4-drug regimen for eradication of H. pylori
Problems: harmless blackening of stool and darkening of tongue may occur
Tricyclic Antidepressant (TCAs): Amitriptyline
Action: Inhibits reuptake of serotonin and norepinephrine
Clinical Use: low-doses for visceral pain associated with IBS
Problems:
- prolong QT interval
- high-risk medication for geriatric population due to antimuscarinic effects
Of note: analgesic dose lower than doses for depression
10 mg QHS (IBS pain) vs. 100 mg BID (depression)
Antispasmodic:
Dicyclomine and Hyoscyamine
Action: Block muscarinic cholinergic receptors in the enteric plexus and on smooth muscle
==>reduce colonic motility
Clinical Use:
- IBS on an as-needed basis (provide short-term symptom relief, no long term efficacy established)
- Pre-op anesthesia (hyoscyamine)
Problems:
- Low dose: minimal autonomic adverse effects
- Higher doses: antimuscarinic
Note: due to adverse effects and the lack of small/large bowel spasm contributing to IBS symptoms, these drugs are not first-line
Sulfasalazine (5-ASA)
Action: not completely understood
- Modulate inflammatory mediators derived from cyclooxygenase and lipoxygenase pathways.
- May also interfere with production of inflammatory cytokines
Clinical Use:
- Mild IBD.
- Induce remission in ulcerative colitis (may be >90% of patients)
Administration: many 5-ASAs are formulated for rectal administration (suppositories and enemas)
Problems:
Up to 40% may discontinue due to nausea, GI upset, headaches, arthralgias, myalgias, bone marrow suppression, malaise.
Azathioprine and 6-Mercaptopurine
Action: decrease lymphoid cell proliferation
Azathioprine: pro-drug of 6-mecaptopurine: purine pathway inhibitor
Clinical Use: IBD, immunosuppression of other autoimmune disorders, cancer chemotherapy
Problems:
Response may take weeks to months
Adverse effects can occur immediately: nausea, vomiting, bone marrow suppression (usually manifested as leukopenia), teratogenicity (avoid pregnancy)
Of note: 6-MP is inactivated by thiopurine methyltransferase (TPMT). 11% have reduced TPMT activity resulting in accumulation of 6-MP and potential for bone marrow toxicity and myelosuppression.
Monitoring: routine lab monitoring of complete blood count and liver function
Methotrexate
Action: inhibitor of dihydrofolate reductase thus inhibiting synthesis of tetrahydrofolate and subsequently thymidine and purine nucleotides
Clinical Use: Crohn’s (efficacy in ulcerative colitis not as clear), other autoimmune disorders, cancer chemotherapy
Advantages: potentially steroid sparing
Anti-TNF: Infliximab
Action:
- prevent TNF-alpha from interacting with receptor
- decreasing proinflammatory cytokines, T-cell activation and proliferation
Clinical Use: moderate to severe IBD
Pharmacokinetics:
-IV infusion (infliximab) or SubQ injection (other anti-TNFs) due to negligible oral bioavailability
Problems:
- Infusion reactions (flu-like symptoms)
- serious infections (bacterial sepsis, TB, invasive fungal organisms, reactivation of hep B, listeriosis)
- lymphoma
Effectiveness: clinical response in more than 60% patients and disease remission in 40%, however, as many as 1/3rd of patients eventually lose responsiveness
Cyclosporine A
Action: Inhibits T-cell mediated immunity by inhibiting production of IL-2
Clinical Use: severe ulcerative colitis
Advantages: very little bone marrow toxicity
Problems: numerous
Linaclotide
Action: minimally absorbed peptide agonist of the guanylate cyclase-C receptor that stimulates chloride channels in small intestine to increase intestinal secretion
Clinical Use: constipation-predominant IBS
Problems: may cause severe dehydration in pediatric patients (avoid)
Orlistat
Mechanism of action
Alters fat digestion by inhibiting pancreatic lipases
Efficacy
3.45 kg (7.6 lbs) more than placebo at one year (pooled study data; intent-to-treat population)
Adverse effects
CV: reduced BP, improvement in lipid panel
GI: cramps, flatus, fecal incontinence, oily spotting, and flatus with discharge
Renal: oxalate-induced acute kidney injury
Decreased absorption of fat soluble vitamins (A, D, E, and K)
Contraindications
Chronic malabsorption, cholestasis, or history of calcium oxalate stones
Liraglutide
Mechanism of action
Chemically modified version of human GLP-1
Efficacy
3.9 to 5.2 kg (8.1 to 11.4 lbs) more than placebo at 56 weeks (pooled analysis; intent-to-treat population)
Adverse effects
CV: reduction in major CV events in adults with type 2 diabetes
GI: nausea, vomiting, diarrhea, pancreatitis (rare)
Injection site reactions
Contraindications
Patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B
Lorcaserin
MOA
Selective serotonin 2C receptor agonist
It activates central serotonin 2C receptors with a functional selectivity of approximately 15 and 100 times over that for serotonin receptors 2A and 2B, respectively
Nonselective serotonergic agonists also enhanced weight loss in clinical trials
However, they increased the risk of serotonin-associated cardiac valvular disease, thought to occur through activation of serotonin receptor 2B
Efficacy
3.3 kg (7.24 lbs) more than placebo at one year (pooled analysis; intent-to-treat population; study duration one to two years)
Adverse effects
Generally mild: headache, upper respiratory infections, nasopharyngitis, dizziness, and nausea
Contraindications
CKD (CrCl <30)
Use in combination with other serotonergic drugs (SSRIs, SNRIs, TCA, etc.)
2D6 inhibitor
Phentermine
MOA
Stimulate release of NE or inhibit its reuptake into nerve terminals
Reduce food intake by causing early satiety
Efficacy
- 6 kg (~8 lbs) more than placebo (pooled analysis; study duration two to 24 weeks)
- 16 kg (5 lbs) more than placebo (retrospective study)
Adverse effects
Tachycardia, elevated BP, insomnia, dry mouth, constipation, nervousness
Contraindications
Coronary heart disease, uncontrolled HTN, hyperthyroidism, or history of drug abuse
Phentermine-topiramate
Mechanism: sympathomimetic/appetite reduction
Efficacy: 9 kg (~19 lbs) more than placebo with 15 mg/92 mg once daily at one year
Adverse effects: dry mouth, constipation, paresthesia
Contraindications: hyperthyroidism, glaucoma, MAOI use within 14 days, h/o renal stones
Bupropion-naltrexone
Mechanism: appetite/craving reduction
Efficacy: < 4.1 kg (9 lbs) more than placebo at 56 weeks
Adverse effects: nausea, headache, constipation, insomnia, dry mouth
Contraindications: uncontrolled HTN, seizure disorders, chronic opioid use, MAOI use within 14 days
Therapies to avoid (Obesity)
Dietary supplements
Evidence to support their efficacy and safety is limited
Safety concerns: increase in BP, hepatic failure, CV events, etc.
Human chorionic gonadotropin (hCG)
Lacks clinical trials to support its claim to weight loss
Calcium
Meta-analysis of randomized trials revealed no significant effect of calcium on body weight
