4 - Intestines_student2024.ppt

Intestines: Poop is a Problem Courtney Harris, PharmD Objectives  Integrate their knowledge of the mechanisms of action, indications, contraindications and side effects of drugs used to treat infectious and noninfectious diarrhea, in their appropriate use  Integrate their knowledge of the mec...

Intestines: Poop is a Problem Courtney Harris, PharmD Objectives  Integrate their knowledge of the mechanisms of action, indications, contraindications and side effects of drugs used to treat infectious and noninfectious diarrhea, in their appropriate use  Integrate their knowledge of the mechanisms of action, indications, contraindications and side effects of drugs used to treat inflammatory bowel disease, in their appropriate use Objectives   Integrate their knowledge of the mechanisms of action, indications, contraindications and side effects of drugs used to treat irritable bowel syndrome, in their appropriate use Integrate their knowledge of the mechanisms of action, indications, contraindications and side effects of drugs used to treat diverticulitis, in their appropriate use Noninfectious Diarrhea    Diarrhea can have many sources and causes besides bacterial or viral infection. Increased GI motility or decreased fluid absorption from the gut can both cause diarrhea to occur. Antidiarrheals can be classified into 3 categories: anti-motility, adsorbents, or agents that modify fluid and electrolyte transport. Diphenoxylate + atropine (Lomotil)     An anti-motility agent MOA: diphenoxylate inhibits excessive GI motility and GI propulsion; atropine is present to only discourage abuse Side effects: dizziness, drowsiness, euphoria, nausea, urinary retention, headache Concerns: do not use in the treatment of infectious diarrhea Loperamide (Immodium A-D)     An anti-motility agent MOA: acts directly on circular and longitudinal intestinal muscles, through the opioid receptor, to inhibit peristalsis and prolong transit time; reduces fecal volume, increases vicosity, and diminishes fluid & electrolyte loss Side effects: dizziness, constipation, nausea, abdominal cramping Concerns: do not use in the treatment of infectious diarrhea Adsorbents     MOA: act by adsorbing intestinal toxins or microorganisms and/or by coating or protecting the intestinal mucosa Side effects: constipation Concerns: interfere with the absorption of other drugs Examples: aluminum hydroxide (Alternagel), methylcellulose (Citrucel) Bismuth Subsalicylate (Pepto-Bismol)     Modifies fluid and electrolyte transport MOA: salicylate moiety provides antisecretory effect; bismuth exhibits antimicrobial effects Side effects: fecal discoloration, tongue discoloration Concerns: cannot be given to children Infectious Diarrhea     Caused by an infectious agent (ex. Salmonella, Shigella, Vibrio, etc.) One of the most concerning types of infectious diarrhea is that caused by Clostridioides difficile (previously Clostridium difficile). C. difficile is a spore-forming Gram positive bacteria that is a part of the natural flora of the intestinal tract. If a change occurs in the intestinal flora, C. difficile can take over and cause infectious diarrhea. Causes of C. diff  Exposure to antibiotics  Clindamycin, 3rd generation cephalosporins, and fluoroquinolones have a high association with C. diff  Exposure to healthcare settings (ex. hospital, dialysis clinic, nursing home)  Acid-suppressing medication (ex. PPIs) Symptoms of C. Diff  Watery stools (diarrhea, duh)  Distinctive foul stool odor  Fever  Abdominal pain Complications of C. Diff  Toxic megacolon  Pseudomembranous colitis Treatment **was previously a preferred first-line treatment** Metronidazole (Flagyl)    MOA: interacts with DNA to cause a loss of helical DNA structure and strand breakage resulting in the inhibition of protein synthesis and cell death Side effects: headache, metallic taste, disulfiramlike reaction, peripheral neuropathy (long duration of use), diarrhea, nausea Concerns: dose adjust in hepatic impairment; NO ALCOHOL while taking and for 3 days after stopping the medication Vancomycin (Vancocin)     Glycopeptide antibiotic MOA: inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding tightly to D-alanyl-D-alanine portion of cell wall precursor Given PO or rectally for C. Diff Side effects: bad taste, abdominal pain, nausea, flatulence, diarrhea, headache Fidaxomicin (Dificid)     A macrolide antibiotic approved only for C. diff treatment MOA: inhibits RNA polymerase which inhibits protein synthesis Side effects: nausea, GI hemorrhage, abdominal pain, anemia Concerns: 20 tablets = ~$4000 C. Diff Prevention  WASH YOUR HANDS!!!  Proper protective apparel when treating C. Diff patients  Antibiotic Stewardship Bezlotoxumab (Zinplava)   MOA: human IgG1 monoclonal antibody which binds C. difficile toxin B and neutralizes it; does not bind to toxin A Side effects: heart failure, worsening HF, nausea, infusion reactions, headache, fever Bezlotoxumab (Zinplava)    Concerns: higher risk of heart failure pls higher mortality rate due to cardiac failure, infection, and respiratory failure compared to placebo for patients with heart failure For patients with a history of C. difficile w/i the past 6 months or for those with high risk of recurrence Given a single IV dose during antibacterial treatment to prevent recurrence Inflammatory Bowel Disease (IBD)  Ulcerative Colitis  Crohn’s Disease Ulcerative Colitis Ulcerative Colitis Treatment  Based upon disease severity  Treatment will focus on suppressing the immune system and immune response to decrease inflammation. Treatment of Mild Ulcerative Colitis Treatment of Mild Ulcerative Colitis Topical Mesalamine (5-Aminosalicylate)     Examples: Canasa suppository; Rowasa enema MOA: unknown; thought to modulate local chemical mediators of the inflammatory response Side effects: headache, abdominal pain, diarrhea, gas, abdominal distention Concerns: best in distal disease due to their ability to specifically reach and target that area; enemas must be retained for 8 hours or as long as possible; suppositories, at least 1-3 hours Topical Steroids     Examples: hydrocortisone suppositories, foam, or enemas MOA: anti-inflammatory and immunomodulator Side effects: burning, pain, bleeding, itching Concerns: best in distal disease due to their ability to specifically reach and target that area Mesalamine     Examples: Apriso, Asacol HD, Delzicol, Lialda, Pentasa MOA: unknown; thought to modulate local chemical mediators of the inflammatory response Side effects: headache, pain, abdominal pain, nausea, diarrhea, dyspepsia, constipation Concerns: allergies (mesalamine,salicylates), oligospermia, mesalamine-induced cardiac hypersensitivity Maintaining Remission of Mild UC Treatment of Moderately to Severely Active UC Treatment of Moderately to Severely Active UC 6-Mercaptopurine (Purixan)  MOA: purine antagonist which inhibits DNA and RNA synthesis  Side effects: malaise, rash, anorexia, diarrhea, nausea, vomiting, bone marrow suppression  Concerns: test for thiopurine methyltransferase (TPMT) - those with low activity are at increased risk for toxicity; dose adjust in renal impairment Azathioprine (Imuran)    MOA: imidazolyl derivative of mercaptopurine; halts DNA replication Side effects: malaise, nausea, vomiting, diarrhea, leukopenia, myalgia Concerns: test for thiopurine methyltransferase (TPMT) - those with low activity are at increased risk for toxicity; dose adjust in renal impairment Infliximab (Remicade)     MOA: chimeric monoclonal antibody that binds and interferes with TNF alpha activity Given IV with diphenhydramine and acetaminophen premedication Side effects: headache, nausea, diarrhea, abdominal pain, infections, fatigue, fever Concerns: hypersensitivity or infusion reactions; must test for tuberculosis before starting; avoid in patients with heart failure Adalimumab (Humira)     MOA: recombinant monoclonal antibody that binds to human TNF-alpha Given SQ Side effects: headache, rash, injection site reaction, nausea, hypertension Concerns: do not give to those with heart failure; increased risk for infection and TB Golimumab (Simponi)    MOA: TNF alpha inhibitor Side effects: antibody development, injection site reactions, upper respiratory tract infection Concerns: infection; malignancy; heart failure Vedolizumab (Entyvio)    MOA: binds to alpha4beta7 integrin and blocks its interaction with MAdCAM-1; this inhibits migration of T-lymphocytes Side effects: headache, antibody development, arthralgia, nasopharyngitis, fever, fatigue, nausea Concerns: given IV; test for infections prior to starting; hypersensitivity reactions; do not use with TNF inhibitors Tofacitinib (Xeljanz)    MOA: inhibits Janus kinase Side effects: infection, headache, Concerns: CYP3A4 interactions; dose adjust in renal or hepatic impairment; infections; malignancy Mirikizumab (Omvoh)    MOA: humanized IgG4 monoclonal antibody that binds p19 subunit of human IL-23 and inhibits its interaction with the IL-23 receptor Side effects: infection, URI rash, injection site reactions, headache Concerns: Starts as IV induction at weeks 0, 4, and 8 then moves to SQ injection at week 12 then every 4 weeks; used in moderately to severely active UC Etrasimod (Velsipity)    MOA: sphingosine 1-phosphate receptor modulator that results in partial, reversible lymphocyte egress from lymphoid organs decreasing lymphocytes in the blood stream Side effects: infection, increased liver enzymes, dizziness, headache, pain Concerns: given PO; contraindicated in severe hepatic impairment and history of various cardiac issues (MI, stroke, etc); used in moderately to severe active UC Maintaining Remission in Moderately to Severely Active UC Crohn’s Disease Describing Crohn’s Disease Symptoms Classifying Disease Severity Disease Modifiers   NSAIDs – exacerbate Crohn’s Cigarette smoking – exacerbates disease activity and accelerates disease recurrence Goals of Treatment Mild to Moderate Active Disease Treatment Sulfasalazine (Sulfazine)  MOA: unknown; thought to modulate local chemical mediators of the inflammatory response  Side effects: headache, rash, nausea, dyspepsia, oligospermia, abdominal pain  Concerns: sulfa or salicylate allergy Budesonide (Entocort EC, Uceris)    MOA: depresses migration of polymorphonuclear leukocytes and reduces inflammation Side effects: headache, acne, redistribution of body fat, nausea, edema, dyspepsia Concerns: high first pass metabolism; decreases bioavailability; recommended to not be used to maintain remission over 4 months Initial Treatment of Moderate to Severe Disease Prednisone    MOA: anti-inflammatory activity Side effects: insomnia, hyperglycemia, irritability, fluid retention, hypertension Concerns: with extended use, side effects can cause serious problems  osteoporosis, peptic ulcer, moon face, fat redistribution (buffalo hump), cataracts Treatment for Moderate to Severe Disease 6-Mercaptopurine (Purixan)  MOA: purine antagonist which inhibits DNA and RNA synthesis  Side effects: malaise, rash, anorexia, diarrhea, nausea, vomiting, bone marrow suppression  Concerns: test for thiopurine methyltransferase (TPMT) - those with low activity are at increased risk for toxicity; dose adjust in renal impairment Azathioprine (Imuran)    MOA: imidazolyl derivative of mercaptopurine; halts DNA replication Side effects: malaise, nausea, vomiting, diarrhea, leukopenia, myalgia Concerns: test for thiopurine methyltransferase (TPMT) - those with low activity are at increased risk for toxicity; dose adjust in renal impairment Methotrexate     MOA: folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication; in Crohn’s, may have immune modulator & antiinflammatory activity Given IM or PO most commonly Side effects: dizziness, alopecia, diarrhea, nausea, photosensitivity Concerns: bone marrow suppression, hepatotoxicity, opportunistic infections; dose adjust in renal impairment Use of Biologics in Crohn’s Use of Biologics in Crohn’s Use of Biologics in Crohn’s Infliximab (Remicade)     MOA: chimeric monoclonal antibody that binds and interferes with TNF alpha activity Given IV with diphenhydramine and acetaminophen premedication Side effects: headache, nausea, diarrhea, abdominal pain, infections, fatigue, fever Concerns: hypersensitivity or infusion reactions; must test for tuberculosis before starting; avoid in patients with heart failure Adalimumab (Humira)     MOA: recombinant monoclonal antibody that binds to human TNF-alpha Given SQ Side effects: headache, rash, injection site reaction, nausea, hypertension Concerns: do not give to those with heart failure; increased risk for infection and TB Certolizumab Pegol (Cimzia)     MOA: pegylated humanized antibody Fab’ fragment that binds and neutralizes TNFalpha activity Given SQ Side effects: nausea, infection, hypertension, headache, rash, arthralgia Concerns: do not give to patients with heart failure; development of TB or infections Vedolizumab (Entyvio)    MOA: binds to alpha4beta7 integrin and blocks its interaction with MAdCAM-1; this inhibits migration of T-lymphocytes Side effects: headache, antibody development, arthralgia, nasopharyngitis, fever, fatigue, nausea Concerns: given IV; test for infections prior to starting; hypersensitivity reactions; do not use with TNF inhibitors Natalizumab (Tysabri)     MOA: monoclonal antibody given IV that binds the alpha-4 subunit of integrin molecules that prevents transmigration of leukocytes Side effects: headache, fatigue, depression, nausea, abdominal discomfort, flu-like syndrome, diarrhea Do not give to anyone with current or a history of progressive multifocal leukoencephalopathy (PML) or to those on TNF inhibitors Concerns: hypersensitivity or infusion reactions; hepatoxicity; development of PML Ustekinumab (Stelara)    MOA: monoclonal antibody that binds and interferes with proinflammatory cytokines, IL-12, and IL-23 Side effects: nasopharyngitis, headache, acne, nausea, vomiting Concerns: antibody formation; hypersensitivity reactions; infection risk Maintaining Remission  The agent that achieve remission is the a good choice for maintaining remission. Continue the drug of choice as long as side effects are not an issue and remission is maintained. Treatment of Severe/Fulminant Disease Irritable Bowel Syndrome Two Types     Irritable bowel syndrome (IBS) Chronic idiopathic constipation (CIC) IBS and CIC are two of the most common functional GI disorders worldwide. Not associated with abnormal radiologic or endoscopic abnormalities or a reliable biomarker IBS  “Given its prevalence, the frequency of symptoms, and their associated debility for many patients and the fact that IBS typically occurs in younger adulthood, an important period for furthering education, embarking on careers, and/or raising families, the socioeconomic impact of IBS is considerable.” IBS Diagnosis IBS Classification  Subtyped according to predominant bowel habit      IBS with constipation (IBS-C) IBS with diarrhea (IBS-D) Mixed type (IBS-M) Unclassified (IBS-U) Bowel habit type is based on the patient’s description of stool form by referring to the Bristol Stool Scale. Medications for IBS         Dicyclomine Alosetron Linaclotide Plecanatide Lubiprostone Eluxadoline Tenapanor Tricyclic Antidepressants (TCAs) Dicyclomine (Bentyl)    MOA: blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and CNS Side effects: dizziness, dry mouth, nausea, blurred vision, drowsiness Provides symptomatic short-term relief in IBS Alosetron (Lotronex)    MOA: potent antagonist of 5-HT3; reduces pain, abdominal discomfort, urgency, and diarrhea Side effects: constipation, nausea, fatigue, headache Concerns: ischemic colitis (REMS); use is limited to women with severe diarrheapredominant IBS Linaclotide (Linzess)    MOA: agonist of guanylate cyclase-C, which increases cGMP concentrations and results in chloride and bicarbonate into the intestines; intestinal fluid increases; GI transit time decreases Side effects: diarrhea, flatulence, abdominal distension Used in constipation-predominant IBS Plecanatide (Trulance)     MOA: agonizes guanylate cyclase-C on the luminal surface of intestinal epithelium; this increase chloride and bicarb secretions in the intestinal lumen Side effects: diarrhea, gas, abdominal distention, nausea Concerns: use in pediatric patients (dehydration); mechanical GI obstruction (known or suspected) Used in constipation-predominant IBS Lubiprostone (Amitiza)     MOA: chloride channel activator that increases intestinal fluid secretion and intestinal motility Dose adjust in hepatic impairment Side effects: headache, nausea, diarrhea, flatulence, abdominal distention Used in constipation-predominant IBS Eluxadoline (Viberzi)     Treatment of IBS-D MOA: mixed mu-opioid receptor agonist, delta opioid receptor antagonist, and kappa opioid receptor agonist which acts locally to reduce pain and diarrhea Cannot be used in severe liver impairment Side effects: dizziness, fatigue, constipation, nausea, abdominal pain Eluxadoline (Viberzi)  Concerns:     Given PO twice daily Dose depends on if patient has a gallbladder Cannot be used in those who drink more than 3 glasses of EtOH per day C-IV Controlled Substance Tenapanor (Ibsrela)     Treatment of IBS-C MOA: sodium/hydrogen exchanger 3 inhibitor, which acts locally to reduce sodium absorption from the small intestine and colon Side effects: diarrhea, gas, abdominal distention Concerns: administered immediately prior to breakfast or first meal of the day and immediately prior to dinner TCAs      Have been shown to help reduce pain Examples: amitriptyline (Elavil), desipramine (Norpramin) MOA: increase serotonin and/or norepi in the CNS by preventing their reuptake Side effects: anticholinergic side effects, hypotension, dizziness, drowsiness, fatigue, nausea, sexual dysfunction Concerns: dose titration CIC    aka functional constipation More common in females, in older subjects, and those of lower socioeconomic status Linked to impaired quality of life, most notably among the elderly CIC Diagnosis CIC Treatment  Increased fiber intake        may increase stool frequency Osmotic laxatives Stimulant laxatives Linaclotide Lubiprostone Plecanatide Lactitol PEG 3350 (Miralax)  MOA: osmotic agent that causes water retention in the stool and increase stool frequency  Side effects: bloating, cramping, diarrhea, flatulence, nausea Bisacodyl (Dulcolax)  MOA: stimulates peristalsis by directly irritating the smooth muscle of the intestine; alters water and electrolyte secretion producing net intestinal fluid accumulation and laxation  Side effects: abdominal cramps, nausea, vomiting Lactulose (Enulose)  MOA: produces an osmotic effect in the colon with resultant distention promoting peristalsis  Side effects: dehydration, abdominal discomfort, abdominal distention, belching, cramping, diarrhea, flatulence, nausea, vomiting Plecanatide (Trulance)   MOA: bind and agonize guanylate cyclase-C on the luminal surface of the intestinal epithelium, which increases cGMP causing chloride and bicarbonate secretion into the intestinal lumen Side effects: diarrhea, abdominal distension, abdominal tenderness, gas Prucalopride (Motegrity)    MOA: selective, high affinity 5-HT4 receptor agonist which promotes cholinergic and nonadrenergic, noncholinergic neurotransmission by enteric neurons leading to stimulation of peristaltic reflex, intestinal secretions, and GI motility Side effects: headache, nausea, abdominal pain, diarrhea, dizziness, gas Concerns: dose adjust in renal impairment; contraindicated in severe inflammatory conditions and intestinal perforation or obstruction Lactitol (Pizensy)    MOA: a simple monosaccharide sugar that produces a laxative effect in color by causing water influx in the small intestine Side effects: gas, diarrhea, abdominal distention Concerns: administer other medications 2 hours before and after lactitol Diverticulitis  Inflammation of a diverticulum   A diverticulum is a sac-like protrusion of mucosa through the muscular colonic wall Classified as:   Simple - no complications Complicated - abscesses, fistula, obstruction, peritonitis, sepsis Diverticulitis Diverticulitis Symptoms  Left lower quadrant pain  Fever  Leukocytosis  Rebound tenderness **Patients with mild pain/tenderness and no systemic symptoms** Diverticulitis Outpatient Treatment   Acute low-residue diet (liquid diet) Antibiotics that cover for E. coli and B. fragilis  SMX/TMP or ciprofloxacin  Metronidazole  Or amoxicillin + clavulanate alone  Or moxifloxacin alone Antibiotics are used between 7 to 14 days Improvement should be seen with 48 to 72 hours; if not, look for a collection intra-abdominally    plus Sulfamethoxazole + Trimethoprim (Bactrim)     Sulfa abx MOA: sequential inhibition of enzymes of the folic acid pathway Side effects: rash, photosensitivity, diarrhea, nausea, hyperkalemia (high doses) Concerns: do NOT given to neonates; dose adjust in renal impairment; allergy Ciprofloxacin (Cipro)     MOA: inhibits DNA-gyrase in susceptible organisms thus inhibiting relaxation of supercoiled DNA and promoting double-stranded DNA breakage Dose adjust in renal impairment Side effects: dizziness, rash, GI upset, photosensitivity Concerns: do not take these with multivitamins, calcium, iron, or dairy products; QT prolongation; tendonitis; avoid use in children Metronidazole (Flagyl)    MOA: interacts with DNA to cause a loss of helical DNA structure and strand breakage resulting in the inhibition of protein synthesis and cell death Side effects: headache, metallic taste, disulfiramlike reaction, peripheral neuropathy (long duration of use), diarrhea, nausea Concerns: dose adjust in hepatic impairment; NO ALCOHOL while taking and for 3 days after stopping the medication Amoxicillin + Clavulanate (Augmentin)     Combination drug with a beta-lactam antibiotic plus a beta-lactamase inhibitor MOA: inhibits bacterial cell wall synthesis by binding one or more penicillin-binding proteins (PBPs) Side effects: nausea, vomiting, diarrhea, abdominal pain Concerns: dose adjust in renal impairment Moxifloxacin (Avelox)    MOA: inhibits DNA-gyrase in susceptible organisms thus inhibiting relaxation of supercoiled DNA and promoting doublestranded DNA breakage Side effects: dizziness, rash, GI upset, photosensitivity Concerns: do not take these with multivitamins, calcium, iron, or dairy products; QT prolongation; tendonitis; avoid use in children Diverticulitis Inpatient Treatment Diverticulitis Inpatient Treatment     Metronidazole plus Ciprofloxacin or Levofloxacin or Cefotaxime, ceftriaxone)     Pip/tazo Ampicillin/sulbactam Imipenem Meropenem Antipseudomonal FQs      Ciprofloxaxin (Cipro) and levofloxacin (Levaquin) MOA: inhibits DNA-gyrase in susceptible organisms thus inhibiting relaxation of supercoiled DNA and promoting double-stranded DNA breakage Dose adjust in renal impairment Side effects: dizziness, rash, GI upset, photosensitivity Concerns: do not take these with multivitamins, calcium, iron, or dairy products; QT prolongation; tendonitis; avoid use in children Ceftriaxone (Rocephin)      3rd Generation Cephalosporin (IM/IV only) MOA: inhibits bacterial cell wall synthesis by binding one or more PBPs Does NOT require dose adjustment for renal impairment Side effects: injection site reactions, diarrhea, rash Concerns: do NOT use in neonates (28 days) Cefotaxime (Claforan)     3rd generation cephalosporin (IM/IV only) MOA: inhibits bacterial cell wall synthesis by binding to one or more penicillin-binding proteins (PBPs) Dose adjust in renal impairment Side effects: rash, diarrhea, nausea, vomiting, injection site reaction Piperacillin-Tazobactam (Zosyn)     IV antipseudomonal PCN MOA: inhibits bacterial cell wall synthesis by binding to one or more penicillin-binding proteins (PBPs) Dose adjust in renal impairment Side effects: diarrhea, headache, nausea, insomnia Ampicillin + sulbactam (Unasyn)    MOA: ampicillin - inhibits bacterial cell wall synthesis by binding one or more PBPs; sulbactam – beta-lactamase inhibitor Side effects: rash, diarrhea, thrombophlebitis Concerns: dose adjust in renal impairment; IV only Imipenem-cilastatin (Primaxin I.V.)     Carbapenem abx  Active against Pseudomonas MOA: imipenem - inhibits bacterial cell wall synthesis by binding to one or more penicillin-binding proteins (PBPs); cilastatin – prevents renal metabolism of imipenem Side effects: diarrhea, injection site reactions, alterations in blood count Concerns: dose adjust in renal impairment; avoid in those with history of seizures Meropenem (Merrem)  Carbapenem abx     Active against Pseudomonas MOA: inhibits bacterial cell wall synthesis by binding to one or more penicillinbinding proteins (PBPs) Dose adjust in renal impairment Side effects: headache, diarrhea, nausea or vomiting, pain Diverticulitis Prevention  Diet high in fruit and vegetable fiber  Physical activity References       Chapter 31 IDSA-SHEA-CDI Guidelines ACG Treatment Guideline for Diverticular Disease ACG Crohn’s Disease Guidelines ACG Ulcerative Colitis Guidelines ACG IBS and CIC Guidelines