Exam #1 Flashcards
1
Q
Pirenzepine
A
MOA: Muscarinic antagonist
blocks parasympathetic nervous system (Ach) at the paracine cell. Acts on the ECL cell
used for peptic ulcer
SE: all due to parasympathetic nervous system (dry mouth, blurred vision, drowsiness, dizziness, nausea) corrects over time as body adjusts to medication.
Not used much anymore because of side effects and other options
2
Q
Cimetidine
A
MOA: H2 antagonist
competitive inhibitor of H2 receptor
treat acid reflux due to increased stomach acid
SE: causes an inhibition of cytochrome P450 oxidative metabolism of other drugs. Slows metabolism (warfarin, phenytoin, sulfonylureas and calcium channel blockers).
Can decrease absorption of itraconazole and ketoconazole.
renally adjust
Site of action: H2 receptor on parietal cell
Place in therapy: mild-moderate non-complicated GERD with no alarm symptoms
3
Q
Ranitidine, famotidine, nizatidine
A
MOA: H2 antagonists
competitive inhibitors of H2 receptors.
treat acid reflux due to increased stomach acid.
SE (rare): headache, nausea, dizziness, stimulation of breast tissues (gynecomastia in men) after long-term use, CNS effects of elderly such as delirium, confusion, slurred speech.
can decrease absorption of itraconazole and ketaconazole
renal adjust
place in therapy: patients with mild-moderate non-complicated GERD with no alarm symptoms
4
Q
Omeprazole (prilosec, zegerid), esomeprazole (nexium), pantoprazole (protonix), rabeprazole (AcipHex), lansoprazole (Prevacid), dexlansoprazole (Dexilant), ilaprazole
A
Proton Pump Inhibitors
MOA: bind covalently to active site on pump to prevent acid secretion. Act on parietal cells.
SE: headache, dizziness, nausea, diarrhea or constipation, Infections (community acquired pneumonia [CAP], Clostridium difficult associated diarrhea [CDAD - C. diff]), fractures (reduced Ca2+ absorption), hypomagnesemia
5
Q
Alarm symptoms associated with erosive esophagitis
A
dysphagia (difficulty swallowing) odynophagia (painful swallowing) GI bleeding Anemia (low blood counts) weight loss (unexplained) chest pain ANY of these symptoms, need upper endoscopy
6
Q
medications that decrease LES tone
A
anticholinergics estrogen & progesterone nicotine tetracycline theophylline dopamine barbiturates calcium channel blockers
7
Q
treatment goals for PUD and GERD
A
decrease frequency, recurrence & duration of symptoms
promote healing of injured mucosa
prevent complications and improve QOL
8
Q
GERD & PUD therapy is directed at
A
decreasing acidity of refluxate decreasing the gastric volume improving gastric emptying increase LES pressure protect esophageal mucosa
9
Q
when are OTC PRN or scheduled medications appropriate for GERD?
A
mild, intermittant, non-erosive GERD
10
Q
when should you use Rx medications for GERD?
A
moderate-severe or complicated GERD acid suppression therapy pro motility agents mucosal protectants combination therapy
11
Q
Brand name & dosage forms for Esomeprazole
A
Nexium delayed release capsule (20mg/40mg) IV solution (20- and 40- mg vials) delayed release oral suspension (10-, 20-, 40- mg packets)
12
Q
Brand name & dosage forms for Omeprazole
A
Prilosec, Prilosec OTC, Zegerid, Zegerid OTC
delayed release capsule (10 mg/ 20 mg/ 40 mg)
delayed release 20 mg tablet (magnesium salt)
Immediate release powder for oral suspension (20- and 40- mg packets); sodium bicarbonate buffer = 460 mg of Na+/dose (two 20-mg packets are not equivalent to one 40-mg packet)
Zegerid OTC 20 mg immediate-release capsules with sodium bicarbonate (1100 mg/capsule)
13
Q
Brand name & dosage forms for lansoprazole
A
Prevacid, Prevacid 24HR
Prevacid 24HR 15-mg delayed-release capsule
delayed-release capsule (15 mg/30 mg)
delayed release oral suspension (15 mg/30 mg)
delayed release orally disintegrating tablet (15mg/30 mg)
14
Q
brand name & dosage forms for Rabeprazole
A
AcipHex
delayed-release enteric-coated tablet (20 mg)
15
Q
Brand name & dosage forms for Pantoprazole
A
Protonix
delayed release tablet (20 mg/40 mg)
IV solution (40 mg/vial)
pantoprazole granules 40 mg/packets
16
Q
Brand name & dosage forms for Dexlansoprazole
A
Dexilant
delayed release capsule (30 mg/60 mg)
17
Q
PPI dosing
A
once daily initially 30-60 minutes before eating twice daily IF: suboptimal response to once daily dosing (try it for a couple of weeks & not working) Erosive disease reflux chest pain syndrome extraesophageal GERD syndromes
18
Q
Extraesophageal/Atypical Features of GERD
A
Established association: reflux cough reflux laryngitis reflux asthma reflux dental erotions
Proposed associations: sinusitis pulmonary fibrosis pharyngitis recurrent otitis media
19
Q
Metoclopramide
A
(Reglan)
MOA/class: pro-motility agent. dopamine 2 receptor antagonist
Role in therapy: possibly as adjunctive therapy. For patients with motility defect (diabetic gastroparesis), also used in ICU when someone is intubated & stomach contents are constantly coming up. MUST be used in conjunction with acid suppression therapy
SE: dizziness, fatigue, somnolence, drowsiness, hyperprolactinemia (elevated serum prolactin). FDA warning: tardive dyskinesia
requires dose adjustment for renal impairment
20
Q
Duration of treatment for GERD
A
reassess initially with in 4-6 weeks. Erosive disease, continuous for at least 8 weeks to make sure healing process is completed. NO need for endoscopy after 8 weeks.
many patients remain on therapy forever. Use smallest dose possible. consider H2RAs
21
Q
How to manage referred patients with typical reflux syndrome
A
- daily OTC H2RA use per labeling with continued symptoms: try Rx strength H2RA. If that doesn’t work, try PPI
- Daily Rx PPI use per labeling with continued symptoms: try PPI 2 times per day
- Extraesophageal symptoms: PPI twice per day + endoscopy
22
Q
How to manage referred patients with erosive esophagitis or motility disorders
A
- new diagnosis of GERD with alarm symptoms, risk factors for Barrett’s esophagus: endoscopy, treat with PPI twice per day
- GERD with delayed upper GI emptying (diagnosed): Metoclopramide (Reglan) with PPI once per day - move to twice per day if necessary.
23
Q
What are the higher risk populations for CAP?
A
extremes of age
comorbidities (DM, COPD, cancer, ALD, etc.)
hospital vs. outpatient
24
Q
confounding factors for hip fracture & what to do about it
A
diet & exercise
smoking
comorbidities (CKD, RA, etc)
age related changes in acid secretion ( as we get older we don’t produce a lot of acid in our stomachs) - manage risk factors with diet & lifestyle, use H2RAs when possible and PPIs as last resort
25
How should you manage the risk of hypomagnesemia with the use of PPIs
clinical manifestations: tetany (involuntary muscle contractions), arrhythmias or seizures
take baseline Magnesium level, monitor level 6-8 weeks later- we just monitor, can't really do much about it
26
what are causes of peptic ulcer disease?
H. pylori (causes up to 48% of ulcers)
NSAIDs (5-20% of chronic NSAID users get ulcers)
SRMD (stress-related mucosal damage)
27
What are complications of PUD?
bleeding
perforation
Gastric outlet obstruction
28
What is the treatment for H. pylori
regimens should include 2 antibiotics AND acid suppressive agent (PPI)
duration: 10-14 days (14 is better)
retest 4-8 weeks after treatment IF they have:
H. pylori associated PUD
Mucosa-associated lymphoid tissue (MALT) lymphoma
Gastric cancer
continued symptoms
29
What is the first line treatment for H. pylori?
Triple therapy:
PPI given twice daily (except esomeprazole which would just be once)
Clarithromycin 500 mg twice daily
Amoxicillin 1000 mg twice daily
may substitute metronidazole 500 mg twice daily for penicillin allergic patient
30
What is PrevPac
lansoprazole, clarithromycin, amoxicillin packaged together for treatment of h. pylori
31
Clarithromycin
antibiotic
SE: not very well tolerated, diarrhea, nausea, metallic taste, drug interactions: CYP3A4 (lots of them)
10% of H. pylori are clarithromycin resistant
32
What is triple therapy fails for treatment of H. pylori?
```
Quadruple Therapy:
PPI twice daily (except esomeprazole)
Bismuth subsalicylate or subcitrate
Metronidazole
Tetracycline
BMT 4 times/day
```
33
What is Helidac
```
Quadruple therapy for h. pylori
contains:
Bismuth subsalicylate 525 mg (2 tabs),
metronidazole 250 mg,
tetracycline 500 mg
dose: 4 pills 4 times/day + H2RA
chew chew swallow swallow
```
34
What is Pylera
Quadruple therapy for H. pylori contains:
Bismuth subcitrate 140 mg
metronidazole 125 mg
tetracycline 125 mg
dose: 3 pills 4 times/day + PPI
Each BMT dose is all tougher in one capsule
35
triple vs. quadruple therapy for H. pylori
adherence & pregnancy - better with triple
| drug allergies, resistance and drug interactions - better with quadruple
36
What is the mechanism of NSAID-induced GI injury?
COX inhibition --> inhibits prostaglandin, decreases bicarbonate secretion, decreases mucus formation, causes vascular alterations
not getting good blood flow impairs mucosal healing
37
What are the risk factors for NSAID induced GI injury?
History of PUD (complications = VERY high risk)
Age > 65 years (> 75 years VERY high risk)
Concurrent use of:
corticosteroids (prednisone etc)
Anticoagulants (warfarin, heparin, dabigatran, rivaroxaban, apixiban)
aspirin/NSAIDs
possible:
female
smoking
alcohol,
underlying rheumatic disease
CV disease
use of SSRIs
Stress
dose, duration, COX-1 vs. COX-3 selectivity
38
What does COX 1 target?
stomach
kidney
platelets
intestinal endothelium
39
What does COX-2 target?
Macrophages
leukocytes
fibroblasts
endothelial cells
40
Celecoxib
COX-2 selective NSAID
41
Gastric toxicity and NSAIDS - which are high risk, moderate risk and low risk
COX-2 selective least risk
Low risk: Etodolac, diclofenac, meloxicam, nabumetone
Moderate risk: ibuprofen, naproxen
High risk: aspirin, ketorolac, piroxicam, indomethacin, ketoprofen
42
Risk factor stratification of GI complications
```
High risk:
1. history of previous complicated ulcer
2. multiple (MORE than 2) risk factors
Moderate risk:
1. Age >65 yrs
2. high dose NSAID therapy
3. previous history of uncomplicated ulcer
4. concurrent use of aspirin (including low dose), corticosteroids or anticoagulants
Low Risk:
NO risk factors
```
43
How are NSAIDs thought to increase CV risk
through COX-2 - endothelial cells lining the cardiovascular system
44
What are the best ways to prevent NSAID induced GI toxicity?
reevaluate need for NSAID
determine GI and CV risk
use lowest effective dose for shortest period of time
use other non-NSAID adjunctive therapies
educate patient on potential signs/symptoms of toxicity
eradicate H. pylori if long term NSAID use is needed
45
What are prophylactic therapies to prevent NSAID induced GI toxicity?
```
Prostaglandin replacement:
Misoprostol (Cytotec) - replaces PGE1
Arthrotec - NSAID + misoprostol
need >600 mcg/day, dosed 3-4 times per day
PPI + NSAID (to protect against gastric destruction)
Combo products:
NapraPAC 500
Vimovo
```
46
Misoprostol
(Cytotec)
PGE1 replacement
SE: diarrhea
47
Arthrotec
Misoprostol + NSAID
| prevents ulcers and complications
48
NapraPAC 500
PPI + NSAID combo product
49
Vimovo
PPI + NSAID combo product
50
How do you manage CV risk, GI risk and NSAIDs
```
Low CV risk + low GI risk: lowest dose of least ulcerogenic NSAID
Low CV risk + moderate GI risk:
NSAID + PPI or misoprostol
low CV risk + high GI risk:
COX-2 inhibitor + PPI or misoprostol
high CV risk + low GI risk:
Naproxen + PPI or misoprostol
high CV risk + moderate GI risk:
Naproxen + PPI or misoprostol
high CV risk + high GI risk:
avoid NSAIDs or COX-2 inhibitors
```
51
How should you heal NSAID-induced ulcers?
Assess need for continued therapy (stop NSAID if possible)
use lowest effective dose or COX-2 inhibitor (unless they are at high CV risk)
use alternate agents
PPIs are the most effective to date and efficacious in preventing subsequent ulcers
duration of therapy: 8-12 weeks
52
does enteric coating protect against GI bleeding
NOPE
53
IBS
| IBD
Irritable Bowel Syndrome
| Inflammatory Bowel Disease
54
Where do ulcerative colitis and Crohn's disease manifest themselves?
UC: mainly in the rectum only
CD: can be anywhere from mouth to anus
55
Know large intestine anatomy
```
Ileum
ascending colon
hepatic flexure
transverse colon
splenic flexure
descending colon
sigmoid colon
rectum
anal canal
anus
```
56
Know small intestine anatomy
duodenum
jejunum
ileum
57
How far does inflammation extend in UC and CD?
UC: just through mucosa but continuous inflammation
CD: can go all the way through the gut wall - fistulas but can be cobblestoned (skip lesions)
58
Pancolitis
UC affecting the majority of the large intestine or colon
59
left sided colitis
continuous inflammation extending from rectum to splenic flexure
60
what are the differences in clinical presentation between UC and CD
UC: tenesmus, rectal bleeding, mucus/blood/watery diarrhea, variable abdominal pain, cramps
CD: diarrhea, bloody stool, crampy abdominal pain, perianal lesions, growth retardation in children, weight loss, fever, nausea, fistulas, perforations, strictures
61
What are systematic manifestations of CD and UC?
Hepatobiliary: Gall stones, fatty inflammation in the liver, hepatitis/cirrhosis, cholangiocarcinoma
Ocular: iritis/uveitis, episcleritis
Rheumatologic: arthritis, sacroiliitis, ankylosing spondylitis (arthritis in the spine)
Dermatologic: erythema nodosum (red, tender lumps on skin), apthous ulcers, pyoderma gangrenosum
62
distinguish between 3 types of fistulas:
enterocutaneous
enteroenteric
enterovesicular
enterocutaneous: GI tract to skin
enteroenteric: 2 segments of GI tract
enterovesicular: intestinal tract to bladder or vagina
63
Distinguish disease severity of UC
mild: < 4 stools/ day, no systemic disturbance
moderate: > 4 stools/day, minimal systemic disturbance
severe: > 6 stolls/day + blood, fever, ab pain, dehydration, elevated ESR, decreased HCT, increased WBC
fulminant: > 10 stools/day + blood, fever, ab pain, dehydration, - ESR, decreased HCT, increased WBC, colonic dilation
64
Distinguish disease severity of Crohn's
mild: tolerating oral intake, no fever/abdominal pain, no dehydration/weight loss
Moderate: failing treatment for mild, (+) fever/abdominal pain, (+) decreased HCT, N/V, weight loss
severe: failing treatment for moderate, (+) fever/ab pain, (+) lower HCT, N/V, wt loss
fulminant: failed oral steroids, obstruction, abscess, cachexia (extremely malnourished), dehydration (+) fever/ab pain
65
what are therapeutic goals in treating UC & CD
```
resolution of acute inflammation
resolution of complications
induction & maintenance of remission
alleviate systemic symptoms
improve QOL
```
66
What are non-pharm treatments for UC and CD?
focus on nutrition
enteral nutrition - favorable effects on reducing inflammation & cytokine production - may lead to mucosal healing & induction & maintenance of remission in CD patients
probiotics (?)
surgery - more successful in UC than in CD
67
What are the main drug treatment options for UC and CD?
adjunctive therapies
5-aminosalicylates (sulfasalazine, mesalamine, olsalazine, balsalazide)
antibiotics (metronidazole, ciprofloxacin)
corticosteroids (prednisone, budesonide)
immunomodulators (Azathioprine, 6-Mercaptopurine, Methotrexate, Cyclosporine)
biological response modifiers (infliximab, Adalimumab, Certolizumab, Natalizumab)
68
What information do you need to know to make a treatment recommendation?
1. Disease (UC or CD),
2. Severity (active vs remission, symptoms, systemic disturbances)
3. Extent & location of disease
4. Pick drugs based on: onset of action, effectiveness, formulation, adverse effects
69
What are the adjunctive therapies we can use for CD and UC?
Loperamide (Imodium-AD)
may be useful for diarrhea
dose: 2 mg after each loose stool (16 mg/day max)
Antispasmodics: for intermittent cramping
Dicylomine (Bentyl), 10-40 mg PO QID
Hyoscyamine (Levsin), 0.125-0.25 mg PO/SL 1 4h prn
70
What are some precautions with adjunctive therapies & UC or CD?
may precipitate paralytic ileum and megacolon, so limit use of these products unless disease is under control first
ALWAYS stop anti-motility agents (narcotics and anticholinergics)
71
Aminosalicylates
MOA: anti-inflammatory and immunomodulatory effects
active component: 5-aminosalicylate (5-ASA or mesalamine)
must be delivered to site of action & has mostly topical effects
role in therapy: mild to severe UC disease, mild to moderate CD
can prevent recurrence of acute UC
72
Sulfasalazine
(Azulfidine)
Diazo bond is cleaved by colonic bacteria
works in the colon
5-ASA is released & acts topically
Sulfapyridine is absorbed & renal excreted
dosing: avoid in patients with sulfa allergy, titrate when starting (we don't need to know exact dose. inducing remission may take 2-4 weeks, topical agents are superior for distal disease (combined oral + topical is good), following remission, reduce dose to maintenance after >/= 6 months, may try to wean from medication, but some patients may remain on 5-ASA indefinitely
available as: azulfidine 500mg tablets, azulfidine -EN 500 mg enteric coated tablets, generic 500 mg tablets
SE: GI disturbances (nausea, vomiting, diarrhea, anorexia), headache, arthralgia, anemia (need folic acid supplementation), rash/fever, pneumonitis, hepatotoxicity, thrombocytopenia, bone marrow suppression, hemolytic anemia, pancreatitis, low sperm production
73
non-sulfa aminosalicylates
Mesalamine (asacol, pentasa, rowasa)
Olsalazine (dipentum)
Balsalazide
74
Choosing an aminosalicylate agent
non-sulfa 5-ASA products are preferred - all fairly equal in efficacy
choose formulation based on location of disease
Oral: colon
Enema: descending colon & rectum (can get up to the splenic flexure)
Suppository: rectum
75
5-ASA products and their sites of action
Mesalamine:
Rowasa - enema - descending colon & rectum - left sided
Canasa - suppository - rectum
pentasa - microgranule coated capsule - small intestine & colon
Asacol HD - delayed release resin tablet (ph) - terminal ileum and colon
Delzicol - delayed release resin capsule (ph)- colon
Lialda - tablet- multimatrix system, releases evenly - colon
Apriso - enteric coated granules in a delayed release polymer capsule - colon
Balsalazide:
Colazal - msalamine prodrug (capsule) - colon
Olsalazine:
Dipentum - capsule - colon
76
what are the patient education points for 5-ASAs?
educate on proper use: enemas, suppositories
Adverse effects: 5-ASA products generally well tolerated
headache, dyspepsia, anorexia
Olsalazine: 25% incidence of secretory diarrhea
77
Corticosteroids
MOA: immune modulation, lower cytokine production
place in therapy: moderate or severe disease unresponsive to 5-ASA or for acute disease flares
EXCEPT Budesonide: indicated for mild-moderate disease as 1st line for CD or alternated first line for UC
watch for adrenal suppression
SE: CNS: insomnia, psychosis, adrenal suppression, glucose intolerance, hypertension, edema, cataracts, osteoporosis, glaucoma hirsutism (male-pattern hair growth in women), aseptic necrosis, acne, striae, myopathy, impaired wound healing
78
Corticosteroid products
Predisone (Deltasone): tablet, liquid - systemic
Budesonide (Entocort EC) Controlled release capsule - terminal ileum/ ascending colon. (Uceris): extended release tablet - colon
Hydrocortisone (Solu-Cortef): IV solution - systemic
Methylprednisolone (Solu-Medrol): IV solution - systemic
Hydrocortisone (Cortenema): enema - descending colon & rectum. (Cortifoam): foam enema - descending colon & rectum. (Anucort HC/ Proctocort HC): suppository - rectum
79
Corticosteroid dosing
Fulminant, prior to colectomy:
methylprednisolone IV 48-60mg IV once daily
Hydrocortisone IV 100mg Q 6-8h
Duration: minimize & taper over 3-4 weeks
NO ROLE in maintenance of remission
systemic doses work faster than 5-ASA
80
Immune Modulators
Azathioprine (Imuran): 50 mg tablets
6-Mercaptopurine (Purinethol): active metabolite of azathioprine, 50 mg tablets
MOA: purine antagonists - may possess direct anti-inflammatory effects. metabolized by thiopurine methyltransferase (TPMT) so check TPMT activity - patients w/genetically slower metabolism may experience more profound leukopenia
Role in Therapy: steroid refractory or dependent patients with UC/CD. Consider starting after 6 weeks if unable to wean steroids
May combine with TNF alpha antagonists (biologics)
Slow onset of action (3-15 MONTHS)
may result in steroid sparing effect & may prolong remission (consider after ileocolonic resection)
Monitoring: CBC every 1-2 weeks to start, then every 1-3 months for maintenance, also LFTs
SE: pancreatitis in 3-15% patients during 1st 6 weeks (CI to use), bone marrow suppression,
lymphoma, leukopenia, thrombocytopenia, neutropenia, N/V/D, rash/fever, possible hepatic toxicity
81
Methotrexate
MOA: folate antagonist (so give folate back when using this - doesn't inhibit it from working if you give back folate) Immunomodulator
role in therapy: moderate/severe CD, may be able to reduce steroid dose
Dose: IM/SQ weekly
SE: leukopenia, hypersensitivity, pnneumonitis, hepatic fibrosis, renal dysfunction, teratogenic (X)
82
Infliximab
(Remicade)
Chimeric monoclonal antibody vs. tumor necrosis factor
role in therapy:
preferred to chronic steroid use
moderate/severe UC and CD
FISTULIZING CROHN'S DISEASE
maintenance of severe disease
dosen (IV): mod/severe: 5 mg/kg x 1
dose (IV): fistulizing: 5 mg/kg at 0, 2, 6 weeks. every 8 weeks for maintenance
expensive
SE: may develop antibodies over time (ATI = antibodies to infliximab)
infusion reactions - so infuse over >/= 2 hours, urticaria, lower BP, CP, SOB, headache
delayed hypersensitivity reaction after 3-10 days, fever, rash, HA, sore throat, myalgia
infections (bacterial, fungal, viral (hep B, herpes), mycobacterial(need TB test first)
heart failure (avoid in NYHA class III/IV HF), lymphoma - increased risk if combined with azathioprine or 6 mercaptopurine
lupus like syndrome
83
Adalimumab
(Humira)
recominant IgG to TNFalpha
indicated for mod/severe CD or UC
not responsive to traditional treatments or for patients losing response to infliximab
very expensive
dosing: SQ
SE: may develop antibodies over time
injection site reactions
delayed hypersensitivity reactions usually after 3-10 days, fever, rash, HA, sore throat, myalgia
infections (bacterial, fungal, viral (hep B, herpes), mycobacterial(need TB test first)
heart failure (avoid in NYHA class III/IV HF), lymphoma - increased risk if combined with azathioprine or 6 mercaptopurine
lupus like syndrome
84
Certolizumab
(Cimzia)
Chimeric Fab vs. TNFalpha (fragment of humanized TNF inhibitor monoclonal antibody)
some murine component
PEG (polyethylene glycol)
Role: similar to infliximab - usually try infliximab or humira first
patients with higher CRP (C-reactive protein - inflammatory marker) (>10mg/l) respond better
dose: 400 mg SQ at 0, 2, 4 weeks then monthly
SE: injection site reactions
delayed hypersensitivity reactions, usually after 3-10 days, fever, rash, HA, sore throat, myalgia,
infections (bacterial, fungal, viral (hep B, herpes), mycobacterial(need TB test first)
heart failure (avoid in NYHA class III/IV HF), lymphoma - increased risk if combined with azathioprine or 6 mercaptopurine
lupus like syndrome
85
Natalizumab
(Tysabri)
humanized monoclonal antibody: alpha 4-integrin inhibitor. interferes with leukocyte adhesion
indicated for mod/severe CD after failure of other therapies
should not be used with immunosuppressants or TNF alpha inhibitors
can only be prescribed through CD TOUCH program
Black box warning: progressive multifocal leukoencephalopathy (PML)
dose: IV every 4 weeks, 12 weeks max
86
Antibiotics and CD/UC
typically only used in CD
MOA: interruption of bacterial role in inflammatory response
role in therapy:
consider adding antibiotic when patients w/mild/moderate CD not adequately responding to 5-ASA
perianal disease (for sure antibiotics b/c abscess often happens here)/fistulas (+ anti-TNF)
Colonic disease
usually in combination with 5-ASA
87
Metronidazole
(Flagyl)
antibiotic
SE: peripheral neuropathy, metallic taste, disulfiram reaction
dose: 10-20mg/kg/day po divided TID or QID
don't drink while using this drug
88
Ciprofloxacin
```
(Cipro)
antibiotic
dose: 500mg po BID
may combine with metronidazole
SE: N/V diarrhea
Drug interactions with Fe, Ca, Al, Mg
```
89
Cyclosporine
MOA: combines with cyclophilin to inhibit calcineurin to prevent production of IL-2
use in therapy: short-term for steroid refractory UC or CD and/or fistulizing Crohn's D
dose: 4 mg/kg/day IV infusion X 7-14 days then PO
if patient responds, can be switched to oral maintenance - azathioprine should be added
SE: renal dysfuction, HTN, tremor, HA, seizure, infection - especially with long-term use
90
nicotine patches
may try for patients with UC
| works better in ex-smokers
91
Treatment of mild UC
Induction: oral sulfasalazine or mesalamine, mesalamine enema or suppository (proctitis), CCS enema
Maintenance: reduce dose by 50%. sulfasalazine > melamine
distal disease or proctitis: melamine enemas or suppositories, combination of oral & topical is superior to each regimen alone
92
treatment of moderate UC
Induction:
Tx for mild + oral prednisone 40-60 mg/day
if no response, may add azathioprine, mercaptopurine or infliximab
Maintenance:
taper prednisone, then after 1-2 mo., reduce sulfasalazine or melamine
steroids do NOT have a role in maintenance of remission
93
treatment of severe/fulminate UC
induction:
may require hospitalization. NPO. hydrocortisone IV 100mg Q 6-8 hrs, methylprednisolone 48-60 mg once daily. If no response in 5-7 days give cyclosporin IV 4 mg/kg/day. Colectomy.
Maintenance:
change to prednisone (gradually withdraw after 3-4 weeks) reintroduce sulfasalazine, melamine.
Steroid dependent patient, add azathioprine, mercaptopurine or infliximab
94
treatment of mild-moderate CD
induction:
ileocolonic or colonic: mesalamine or sulfasalazine
perianal: mesalamine or sulfasalazine and/or metronidazole +/- ciprofloxacin
small bowel: oral melamine or metronidazole, budesonide (terminal ileal or ascending colonic)
Maintenance:
more difficult with CD than UC
minimal evidence for sulfasalazine, melamine but still routinely used for maintenance
Budesonide no more than 3 months
azathioprine & mercaptopurine effective for up to 4 years specifically in steroid induced remission.
methotrexate for patients who initially respond to methotrexate
infliximab q 8 weeks for patients who initially respond to infliximab or for fistulizing disease
adalimumab
certolizumab
natalizumab
95
treatment of moderate-severe CD
induction:
mesalamine or sulfasalazine or budesonide
if patient has failed above options add oral prednisone (not effective for perianal fistulas)
refractory and/or fistulizing disease, add infliximab, adalimumab or certolizumab
may consider methotrexate
natalizumab if no response to steroids or TNFalpha inhibitor
Maintenance:
more difficult with CD than UC
minimal evidence for sulfasalazine, melamine but still routinely used for maintenance
Budesonide no more than 3 months
azathioprine & mercaptopurine effective for up to 4 years specifically in steroid induced remission.
methotrexate for patients who initially respond to methotrexate
infliximab q 8 weeks for patients who initially respond to infliximab or for fistulizing disease
adalimumab
certolizumab
natalizumab
96
treatment of fulminant CD
fulminant: hospitalization: NPO. hydrocortisone IV 100 mg Q 6-8 hrs. methylprednisolone 48-60 mg once daily. If no response in 5-7 days give cyclosporin IV 4 mg/kg/day
Maintenance:
more difficult with CD than UC
minimal evidence for sulfasalazine, melamine but still routinely used for maintenance
Budesonide no more than 3 months
azathioprine & mercaptopurine effective for up to 4 years specifically in steroid induced remission.
methotrexate for patients who initially respond to methotrexate
infliximab q 8 weeks for patients who initially respond to infliximab or for fistulizing disease
adalimumab
certolizumab
natalizumab
97
What are the 5 areas that can trigger nausea/vomiting?
CNS (cortex, thalamus, hypothalamus, meninges)
Vestibular system (H2 receptor M1 receptor)
Chemoreceptor trigger zone (chemoreceptors, D2 receptors, NK1 receptor (?), 5-HT3 receptor)
Vomiting center (nucleus of tracts solitaries (H1 receptor, M1 receptor, NK1 receptor, 5-HT3 receptor
TI tract and heart (mechanoreceptors, chemoreceptors 5-HT3 receptor)
98
What are drugs that can cause N/V
chemotherapy
opiates (morphine, oxycodone, hydrocodone, codeine, meperidine, fentanyl)
Antibiotics (erythromycin, clarithromycin, azithromycin, trimethoprim/sulfamethoxazole, metronidazole)
NSAIDs (ibuprofen, naproxen, indomethacin, diclofenac, etc)
Digoxin (sign of toxicity)
Estrogens, progesterone (oral contraceptives, megesterol)
dopamine agonists (levodopa, pramipexole, ropinorole, bromocriptine)
99
Prochlorperazine
(Compazine)
MOA: Phenothiazine: blocks dopamine (10X more than promethazine), ACh & alpha adrenergic receptors in brain & depresses brainstem reticular system
DI: CNS depressants, may intensify or prolong CNS effects --> dose reduction
drugs which decrease seizure threshold such as tramadol (can increase seizure risk)
drugs with anticholinergic effects (increase effect)
Levodopa (may decrease effects from levodopa)
drugs that increase QT prolongation (azithromycin, ciprofloxacin, citalopram, etc.)
CI: children < 2yrs or under 20 lbs
black box warning: elderly patients w/dementia-related psychosis treated with atypical drugs --> may lead to mortality
dosing: oral: 5-10mg TID/QID
suppository: 25mg BID
SE: EPS, akinesia (inability to initiate movement), akathisia (inability to remain motionless), excessive sedation, orthostatic hypotension
avoid alcohol & other CNS depressants, do not take Ca and Mg-based antacids, may increase sun sensitivity -use sunscreen
100
Promethazine
(Phenergan)
MOA: phenothiazine: blocks dopamine, ACh and alpha adrenergic receptors in brain, depresses brainstem reticular system and competes with histamine for H1 receptor.
DI: CNS depressants, may intensify or prolong CNS effects --> dose reduction
drugs which decrease seizure threshold such as tramadol (can increase seizure risk)
drugs with anticholinergic effects (increase effect)
Levodopa (may decrease effects from levodopa)
drugs that increase QT prolongation (azithromycin, ciprofloxacin, citalopram, etc.)
CI: children < 2 yrs
Black Box warning: children no IV or subQ administration; ONLY deep IM injection
dosing: treatment: oral/suppository 12.5/25mg q 4-6h
prevention of motion sickness: oral/rectal 25mg 1 hr prior to travel and q 8-12 h prn
SE: EPS, akinesia (inability to initiate movement), akathisia (inability to remain motionless), excessive sedation, orthostatic hypotension
avoid alcohol & other CNS depressants, do not take Ca and Mg-based antacids, may increase sun sensitivity -use sunscreen
101
special populations and prochlorperazine
pregnancy category C (risk vs. benefit)
elderly: use doses in lower ranges
children: avoid if s: avoid use or use cautiously
Seizure disorder: avoid or use cautiously
history of neuroleptic malignant syndrome (NMS): avoid use
102
special populations and Promethazine
Pregnancy category C (risk vs benefit)
elderly: use low starting dose
children: avoid if < 2 yrs
seizure disorder: avoid or use cautiously
history of Neuroleptic Malignant Syndrome (NMS): avoid use
103
5HT3 Serotonin Receptor Antagonists
Ondansetron (Zofran)
Granisetron (Kytril)
Dolasetron (Anzemet)
Palonosetron (Aloxi)
104
Ondansetron
(Zofran) 5HT3 receptor antagonist
MOA: block presynaptic 5HT3 receptors on sensory vagal fibers in gut wall (& may additionally inhibit 5HT3 centrally in CTZ, but this is not certain)
DI: other QT prolonging meds (i.e. dronedarone, amidoarone, methadone)
formulations: tablet, ODT, film, oral solution, IV, IM
CI: concomitant use with apomorphine
precautions: QT prolongation, EKG changes. Mgmt: monitor EKG in pts w/electrolyte abnormalities (low K, Low Mg), bradyarrhythmias, CHF, concurrent QT prolonging meds
dosing: 8mg bid for severe or refractory hyperemesis gravidum (morning sickness). treats various causes of N/V - can be used for viral gastroenteritis
SE: headache, constipation, fatigue, malaise, contact dr if experience reduced HR, lightheadedness, passing out.
105
special populations & patient ed for ondansetron
pregnancy category B
severe hepatic impairment: max 8 mg/day
film: after opening pouch, immediately place film on top of tongue (dissolves in 4-20 seconds). once dissolves, swallow w/or w/out water
ODT: do not push tablets through foil backing. with dry hands peel back foil backing of 1 blister & gently remove tablet. immediately place ODT on tongue where it will dissolve in seconds, then swallow w/saliva. no need for liquid
106
Granisetron
(Kytril)
MOA: serotonin receptor antagonist: blocks presynaptic 5HT3 receptors on sensory vagal fibers in gut wall (and may additionally inhibit 5HT3 centrally in CTZ, but this is not certain).
DI: other QT prolonging meds (i.e. dronedarone, amidoarone, methadone)
formulations: tablet, oral solution, IV, transdermal patch
precautions: QT prolongation, EKG changes. Mgmt: monitor EKG in pts w/electrolyte abnormalities (low K, Low Mg), bradyarrhythmias, CHF, concurrent QT prolonging meds
CI: concomitant use with apomorphine
Dosing: IV administered for surgery, chemo,
oral tablet initiated 1 hr prior to chemo
patch applied 24-48 hrs before chemo
SE: headache, constipation, fatigue, malaise, contact dr if experience reduced HR, lightheadedness, passing out.
107
special populations and patient ed for Granisetron
pregnancy category B
children: do not use < 2 yrs
Patient Ed: Patch: wear protective clothing around patch as sunlight can degrade granisetron.
108
Metoclopramide
(Reglan, Metolzolv ODT)
antiemetic
MOA: blocks dopamine receptors in CTZ; increases LES tone; aids gastric emptying; accelerates transit through small bowel possibly through release of ACh
DI: relative CI: SSRIs (i.e. fluoxetine), promethazine, prochlorperazine, antipsychotics, trazodone, trimethobenzmide--> risk of EPS
CI: epilepsy, drugs that may cause EPS; GI hemorrhage, perforation, obstruction; pheochromocytoma (adrenal gland tumor)
black box warning: tar dive dyskinesia: related to duration & cumulative dose --> avoid use > 12 weeks; no treatment for this; REMS program
Precautions: cirrhosis, congestive heart failure, depression
109
Special populations & pt. ed for metoclopramide
pregnancy category B
CrCl < 40 ml/min & for elderly: initiate 50% of recommended dose
Parkinson's: avoid use or use cautiously
seizure disorder: avoid or use cautiously
Hx of NMS (neuroleptic malignant syndrome): avoid use
Pt. Ed: 10 mg qid 30 minutes before meals & at bedtime for diabetic gastroparesis (max duration 12 weeks. Do not drink alcohol while taking this med
SE: diarrhea, asthenia (weakness), headache, somnolence, fatigue
110
Trimethobenzamide
(Tigan)
antiemetic
MOA: believed to affect CTZ; no effects on 5HT3, D2, H1-->fewer SE
Not used much
111
Droperidol
(Inapsine)
antiemetic
MOA: unknown, possibly acts in CTZ and/or blocks dopamine receptors
used pre-operatively in hospital to prevent nausea/vomiting
needs cardiac monitoring 2-3 hours after you give it b/c of QT prolonging effects
not used very much
112
Scopolamine
```
transdermal patch (Transderm Scop)
prevention of motion sickness
MOA: Belladonna alkaloid that acts in CNS by blocking ACh transmission from vestibular nuclei to higher centers in CNS from reticular formation to the VC
DI: sedatives, tranquilizers, alcohol (increase sedation); anticholinergics (other belladonna alkaloids, antihistamines, TCAs muscle relaxants)
CI: narrow angle glaucoma & hypersensitivity to belladonna
precautions: elderly, pediatrics, & other conditions which can be worsened with anticholinergic medications (BPH, urinary bladder neck obstruction, history of psychosis, pyloric obstruction, history of seizures, wide-angle glaucoma)
```
113
Scopolamine special populations & patient Ed
pregnancy category C
minimal risk w/lactation
elderly, renal impairment, hepatic impairment; increased risk of CNS effects (elevated intraocular pressure, urinary difficulty & retention, constipation, increased risk of falls, confusion)
infants & children: should not be used
Blondes: close supervision recommended as increased responsiveness to belladonna alkaloids has been reported & dosage adjustments are often required
apply 1 patch 4 hours prior to activity & then every 72 hours as needed to prevent motion sickness
wash & dry hands before application
do not cut patch
apply to dry, hairless skin behind the ear
do not drink alcohol while on this medication
may experience pupil dilation
114
What is the pathophysiology of diarrhea?
for non infectious:
increased frequency & decreased consistency: disruption of water & electrolyte balance:
change in active ion transport by either decreased sodium absorption or increased chloride secretion
increase in intestinal motility
increase in luminal osmolarity
increase in tissue hydrostatic pressure
115
types of diarrhea
osmotic diarrhea (osmotically active solutes)
secretory diarrhea (excess of fluids & electrolytes)
motility diarrhea (shortened transit time)
maldigestion or malabsorption of fat
maldigestion or malabsorption of carbohydrates
lymphocytic or collagenous colitis
exudative diarrhea (protein-losing enteropathy)
pseudomembranous colitis (bacterial proliferation)
C. Diff
116
list drugs that can cause diarrhea
```
Antibiotics (clindamycin, tetracyclines, sulfonamides, broad-spectrum)
chemotherapy
alpha-glucosidase inhibitors
antacids with magnesium
colchicine (used for gout)
erythromycin
laxatives (osmotics, stimulants)
metformin (slows down absorption of carbohydrates)
metoclopramide
NSAIDs
Orlistat (fat blocker - inhibits absorption of fats)
Sorbitol
```
117
Diphenoxylate 2.5mg/atropine 0.025mg
(Lomotil)
antidiarrheal
MOA: Mu opioid receptor agonist: acts both locally & centrally on opioid receptors to reduce intestinal motility prolonging contact & absorption
DI: opioids, CNS depressants, MAOIs, digoxin
formulations: tablet, oral solution -schedule V drug
CI: infectious diarrhea, obstructive jaundice
Special populations: pregnancy category C, elderly: anticholinergic effects
children: do not use if < 2yrs
liver dysfunction: may precipitate hepatic coma
dosing: 5 mg QID until control achieved, then rduce dose (max 20 mg/day)
SE: constipation, dizziness, sedation, euphoria
118
OTC Loperamide
(Imodium) antidiarrheal
MOA: Mu opioid receptor agonist: acts only locally on opioid receptors to reduce intestinal motility --> prolonging contact & absorption (does not pass BBB)
DI: no clinically significant
formulations: tablet, oral solution, liquid, capsule, chewable, suspension
CI: infectious diarrhea, UC
special populations: pregnancy category B
children; do not use if < 2 yrs
Liver dysfunction: reduced first pass metabolism
dosing: initiate at 4 mg followed by 2 mg after each loose stool (max 16 mg/day)
SE: constipation, dizziness, somnolence, xerostomia
119
What are the 3 primary subtypes of constipation?
1. Normal transit: functional constipation - most common. Normal GI motility & stool frequency but difficulty evacuating, passage of hard stools, or bloating & abdominal discomfort
2. slow transit: abnormality of GI transit time --> infrequent defecation
3. Disordered defecation: pelvic floor muscle and/or anal sphincter contract & impede evacuation
120
What are drug-induced causes of constipation?
Pain: opioids
Allergies or motion sickness: antihistamines (diphenhydramine, chlorpheniramine, doxylamine)
Hypertension: Calcium channel blockers (amlodipine, verapamil, etc)
Diuretics (hydrochlorothiazide, furosemide, etc.)
Beta Blockers (metoprolol, atenolol, etc)
Heartburn: Aluminum hydroxide, calcium carbonate
Mineral supplementation: iron, calcium
Depression: tricyclic antidepressants (amitriptyline, nortriptyline, desipramine)
121
Non-opioid drug-induced constipation treatment
discontinue medication if possible
Nondrug therapy: at least 2 L/day hydration, 150 min/wk physical activity, 20-35g/day of dietary fiber, avoid constipating foods, bowel training
Drug Therapy: (only if non drug isn't working)
Hyperosmotic laxative: polyethylene glycol (miralax )
Fiber laxatives (psyllium [Metamucil], methylcellulose [citrucel], calcium polycarbophil [FiberCon], wheat dextrin [Benefiber], Inulin [FiberChoice], Powdered cellulose [Unifiber])
fiber should not be used if the patient is debilitated, hydration is difficult to maintain or if bowel obstruction is suspected
122
What is the MOA of Opioid-induced constipation?
prolongation of intestinal transit time by causing spastic, non propulsive contractions; may also include increase in electrolyte absorption
oral opioids are MORE constipating than parenteral opioids
123
How do you prevent opioid-induced constipation?
nondrug therapy: same as for non-opioid drug induced constipation prevention
drug therapy: nonprescription drugs for prevention
senna or biscodyl stimulant (Senna, Senokot, Ex-Lax, dulcolax) - works w/in 10 hours. Take every day
or stimulant +/- docusate (stool softener) (Senna Plus, PeriColace)
or polyethylene glycol (Miralax) - works w/in 1-3 days
124
opioid-induced constipation treatment
non drug therapy - same as for non-opioid prevention
Drug therapy: initiate or modify nonprescription laxative therapy (if obstruction is NOT present). select medicate based on patient preference & onset of action
if patient fails nonprescription laxative therapy, consider lubiprostone (last line)
125
Methylnatrexone
(Relistor)
MOA: peripheral mu opioid receptor antagonist does not cross BBB or antagonize analgesia from opioids. used for palliative care only. very expensive
administered via SQ injection every other day.
for opioid induced constipation
126
What is the pathophysiology of IBS?
motility disorder attributed to neurologic or muscular hypersensitivity of the colon.
visceral hypersensitivity may be the result of abnormal afferent CNS processing
Serotonin type 3 (5HT3) and Serotonin type 4 (5-HT4) are responsible for secretion, sensitization & motility. IBS-D have an increase in the postprandial levels of 5-HT
Contributing factors: genetics, motility factors, inflammation, colonic infections, mechanical irritation to local nerves, stress
127
What are the characteristics of IBS?
chronic or recurrent abdominal pain for at least 6 months or recurrent abdominal pain or discomfort at least 3 days per month for the last 3 months
lower abdominal pain
disturbed defecation (constipation, diarrhea or alternating pattern of both)
bloating
mucus in stool may be present
128
Treatment for IBS-C
Non-drug therapy:
adequate fiber 20-35g/day
adequate fluid 2L/day
adequate physical activity 30-60 minutes 3-5 days/week
stress reduction
avoid gas producing food if bloating is problem
reassess every 2-4 weeks. If needed, initiate drug therapy:
Constipation: psyllium 0.5-1 T./daily, titrate to bid-tid
Consider polyethylene glycol (Miralax) if psyllium fails
If constipation persists following Miralax therapy, consider initiating lubiprostone or linaclotide
Pain: consider adding on an as needed antispasmodic to treat abdominal pain which continues to occur despite adequate constipation treatment
Depression, anxiety& pain: antidepressants if patient has depression, anxiety OR if abdominal pain continues to persist after initiating the above treatments. Refer to behavioral health for psychotherapy & stress management if needed
129
Treatment for IBS-D
Non-Drug Therapy
adequate dietary fiber
adequate fluid intake
adequate physical activity
stress reduction
avoid gas producing food if bloating is problem
avoid or limit caffeine, alcohol, & artificial sweeteners
if symptoms are associated w/dairy and/or wheat, recommend lactose-free and/or gluten-free diet
Reassess every 2-4 weeks. Initiate drug therapy if needed
OTC loperamide - 1st line treatment for episodic management of urgent diarrhea
consider diphenoxylate/atropine (lamotil) if loperamide can't be used. Consider probiotics
Pain: consider adding on an as needed antispasmodic to treat abdominal pain which continues to occur despite adequate diarrhea treatment
Depression, anxiety & pain: antidepressants if patient has depression, anxiety or if abdominal pain continues to persist after initiating above treatments
refer to behavioral health for psychotherapy & stress management if needed.
130
Lubiprostone
(Amitiza) for IBS-C
$359/month
MOA: chloride channel activator that enhances chloride-rich intestinal fluid secretion & improves fecal transit
capsule
precautions: avoid in severe diarrhea; dyspnea (shortness of breath - generally occurs after the first dose, but may recur -- resolves within a few hours)
CI: mechanical GI obstruction
Special pop: pregnancy category C, moderate-severe hepatic impairment: dose reduction recommended
dosing: OIC: 24mcg bid (for men and women)
IBS-C: 8 mcg bid (only approved for use in women)
SE: diarrhea, abdominal distension/pain, flatulence, nausea, headache
take w/food & water, do not break chew or crush, report severe diarrhea, dyspnea, nausea
131
Linaclotide
(Linzess) for IBS-C: minimally absorbed, so safer than lubiprostone
$333/month
MOA: guanylate cyclase agonist - stimulates secretion of chloride & bicarbonate into intestinal lumen, causing an increase in intestinal fluid secretion & transit
capsule
precautions: avoid in severe diarrhea
Black box warning: CI in children < 6 yrs. avoid in children 7-17 yrs
dosing: 290 mcg at least 30 minutes prior to first meal of the day
SE: diarrhea, abdominal distention and/or pain, flatulence
leave in original container, do not crush or chew, report/discontinue if severe diarrhea, especially if accompanied by hematochezia (blood in stools) or melena (black, tarry stools)
132
Tegaserod
(Zelnorm)
for IBS-C
MOA: 5HT4 partial agonist; stimulates peristalsis secretion & reduces visceral sensitivity
w/drawn from market in 2007 due to increased risk of cardiovascular ischemic events. 2008: only available for emergent situations - rEMS program, FDA has to determine it is okay to use this med on case by case basis.
133
Alosetron
(Lotronex) IBS-D treatment
0.5mg $867/month
1mg $1487/month
MOA: selective 5HT3 antagonist; manages IBS by blocking activation of ligand-gated cation channels & delaying transit & secretion: may also improve abdominal pain
DI: fluoroquinolones
tablet
Black box warning: serious GI adverse events have been reported including ischemic colitis & serious complications of constipation --> restricted prescribing program (REMS)
special populations: pregnancy category B, elderly: increased risk of constipation complications
hepatic impairment: risk of serious adverse reactions due to increased exposure
children & males: not approved
dosing: initiate at 0.5 mg by mouth bid then increase to 1mg bid after 4 weeks if necessary/tolerated
only approved in women >/= 18 yrs w/IBS-D symptoms > 6 months not relieved by conventional therapy
SE: constipation, abdominal pain/discomfort
134
Diclomine
(Bentyl) Antispasmodic (abdominal pain/bloating related to IBS)
MOA: antispasmodic & anticholinergic agent which alleviates smooth muscle spasm of GI tract
DI: other anticholinergics (increase effect)
capsule, tablet, syrup, IM
precautions: Cardiovascular conditions
CI: GI (obstruction, severe UC), glaucoma, myasthenia gravis, unstable cardiovascular status
Special Pop: pg category B, CI for breastfeeding, elderly: increased risk of adverse effects
renal, hepatic, children: not studied
children: CI in < 6 months (respiratory distress, coma, death)
10-20 mg qid (can increase to 40 bid after 1 week)
discontinue if no improvement after 2 weeks of TDD 80mg/day or if adverse effects limit dose escalation
SE: drowsiness, dizziness, xerostomia, blurred vision
antacids interfere w/absorption - take before meals & antacids after meals
do not take w/alcohol
135
Hyoscyamine
(Levsin) for Abdominal pain/bloating related to IBS
antispasmodic
MOA: belladonna alkaloid that inhibits action of ACh on smooth muscles; inhibits GI propulsive motility & decreases gastric acid secretion
precautions: Cardiovascular conditions
CI: GI (obstruction, severe UC), glaucoma, myasthenia gravis, unstable cardiovascular status
special pop: pg category C
elderly, renal impairment: increased risk of adverse effects
children: safe for use
dosing: 0.125-0.25 mg po or SL tid-qid
SL tabs can be swallowed or chewed
SE: drowsiness, dizziness, xerostomia, blurred vision
antacids may interfere w/absorption - take before meals & antacids after meals. Do not take with alcohol
136
Antidepressant options for IBS
Tricyclic antidepressants
reduce visceral sensitivity (pain), alter GI transit time, treat underlying comorbidities (depression)
can be used in both forms, but caution in IBS-C (so better for IBS-D)
amitriptyline, nortriptyline, doxepin, desipramine
SSRAs/SNRIs (paroxetine, sertraline, citalopram, fluoxetine, venlafaxine, etc.) for patients w/depression & IBS-C & IBS- mixed
137
Rifaximin
(Xifaxan)
550mg po tid (off-label) $1414/month
last line med
2 week trial for patients with moderate/severe IBS with bloating WITHOUT constipation who have failed other therapies
138
2 complementary therapies for IBS
Peppermint oil
| Probiotics
139
causes of chronic liver disease (cirrhosis)
```
chronic alcohol consumptio (ALD)
chronic viral hepatitis
metabolic liver disease
immunologic disease
drugs (isoniazid, methyldopa, amiodarone, methotrexate, tamoxifen, retinol (vitamin A), propylthiouracil, didanosine)
vascular disease
```
140
Spectrum of Alcoholic Liver disease
Steatosis (fatty liver): most common hepatic manifestation. fat accumulates in liver due to ethanol's interference w/normal cellular metabolism, little functional impairment & reversible w/discontinuation of alcohol after 4-6 weeks
Steatohepatitis (Alcoholic Hepatitis): fat accumulation w/in hepatocytes leads to lysis & hepatocellular necrosis & inflammation. symptoms, laboratory abnormalities & signs of decompensation may be present, poor short-term prognosis, reversal may occur w/3-8 months of abstinence
Chronic Liver Disease/Cirrhosis: (irreversible damage), Acetaldehyde stimulates synthesis of collagen w/in parenchyma of liver. Fibrous tissue is deposited around terminal hepatic venues & hepatocytes to cause obstruction of hepatic flow & severe alterations of function. Lab abnormalities & complications frequently present. continued alcohol abuse drastically affects prognosis.
Hepatic failure: liver transplantation or death
141
Risk factors for ALD
1. amount of alcohol ingested (long term >10 yrs, intake of > 30 g pure alcohol/day increases risk, >80 g/day ALD is nearly certain)
2. drinking outside of meals & binge drinking
3. type of alcohol (spirits)
4. women > men, African-American & Hispanic > caucasion
5. presence of hepatitis C infection (20% of ALD have a secondary/co-existing liver disease
142
Liver enzymes
AST - aspartate aminotransferase
| ALT - alanine aminotransferase
143
what are laboratory abnormalities present in ALD?
elevated AST & ALT with ratio of 2-3/1 AST/ALT but not super elevated
ALP (alkaline phophatase): elevated ALP less common in ALD
GGT (gamma-glutamyl transpeptidase): elevated GGT suggests alcohol intake
Bilirubin, conjugated (direct): elevated suggests decreased liver excretory capacity
Albumin: significant decrease due to diminished hepatic synthesis of proteins, sequestration into ascites, and malnutrition. Poor prognostic sign
Prothrombin time (PT) or International Normalized Ratio (INR): can be significantly increased due to lower hepatic production of coagulation factors. Increased risk for bleeding & poor prognostic sign
Hyponatremia: due to increased antidiuretic hormone activity, fluid restrict if serum Na < 120-125 mEq/L
Anemia: due to folate deficiency, enlarged spleen, direct toxic effect of alcohol to bone marrow, and GI blood loss
Thrombocytopenia: due to splenic sequestration of platelets, lower hepatic thrombopoietin production, bone marrow suppression, raised platelet destruction. increased risk for bleeding. typically asymptomatic until platelet count falls below 20,000
144
Clinical manifestations of ALD
jaundice, scleral icterus (yellow eye): due to increased conjugated bilirubin
spider angioma, palmer erythema: small dilated blood vessels near surface of skin with radiating capillary branches due to vasodilation (increased NO) and increased estradiol (reduced degradation in liver)
Hepatosplenomegaly: due to portal hypertension and splenic congestion
Caput medusae (engorged abdomen veins): due to portal hypertension & reopening of umbilical vein
White nails: due to hypoalbuminemia
Finger clubbing: hypoxemia due to right-to-left shutting or portopulmonary hypertension
Gynecomastia, loss of male hair: due to increased estradiol (reduced degradation in liver)
Hypogonadism: direct toxic effect of alcohol on gonadal function
asterixis "liver flap": sign of hepatic encephalopathy due to disinhibition of motor neurons
anorexia, weight loss, fatigue, muscle wasting: due to hyper catabolic metabolism
145
how do you diagnose acute alcoholic hepatitis?
recent alcohol consumption/abuse
mild fever, malaise & tachycardia are common
elevated AST/A:T (ratio 2:1)
AST or ALT usually 500 need to seek out alternate diagnosis)
Jaundice (total bilirubin typically > 5mg/dL)
Maddrey's Discriminate Function (MDF): bilirubin (mg/dL) + 4.6(patient's PT (prothrombin time) - control PT)
used to determine severity & benefit of treatment
DF >/= 32 = severe = ~ 50% mortality w/in 2 months
146
Galsgow alcoholic hepatitis score
>/= 9 means person has severe alcoholic hepatitis
147
Treatment of Alcoholic Hepatitis
Low Risk: MDF < 32 & 1st week decrease in bilirubin, or MELD < 18 and 1st week decrease in MELD by 2 points --> nutritional assessment/intervention --> supportive care & close follow-up
High risk: MDF >/= 32, presence of HE (hepatic encephalopathy), or MELD >/= 18 --> nutritional assessment/intervention --> consider liver biopsy if diagnosis is uncertain --> prednisolone or if steroid CI (sepsis/infection; hepatorenal syndrome, GI bleed & chronic Hep B infection) or early renal failure --> pentoxifyline
only treat ALD if it's severe
148
Prednisolone for Alcoholic Hepatitis
40 mg po once daily for 4 weeks, then taper over 2 weeks or stop
decreases inflammatory response of hepatitis
used with MDF >/= 32
studies have shown decrease in short term mortality (1 month)
Don't use with chronic Hep C infection, other severe infections, or people in renal failure
149
Pentoxifylline (PTX) for alcoholic hepatitis
400 mg po tid X 4 weeks
oral phosphodiesterase inhibitor - decreases tumor necrosis factor (TNF) production - reducing inflammation
recommended for patients w/severe alcoholic hepatitis who cannot take steroids
150
Child-Pugh scores
Class A: < 7 points
Class B: 7-9 points
Class C: 10-15 points
1 year survival: Class A = 100%, Class B = 81%, Class C = 45%
151
MELD scoring
Model for End-stage Liver Disease
includes INR, total bilirubin, & Scr
used to determine transplant priority & predict prognosis
MELD score >/= 17 considered candidates for transplantation
3 month mortality based on MELD score:
>/= 50 = 71.3%, 30-39 = 52.6%, 20-29 = 19.6%, 10-19 = 6.0%, < 9 = 1.9%
152
What is the difference between compensated vs. decompensated cirrhosis?
compensated: Childs-Pugh A. Median survival ~ 9 yrs
Decompensated: marked by development of any one of the following: jaundice, encephalopathy, vatical hemorrhage, or ascites
Childs-Pugh B or C
Abstain from alcohol = 60% 5 yr survival vs. 30% 5 yr survival if continue to drink
153
hepatic encephalopathy
spectrum of neuropsychiatric symptoms due to liver disease - mainly a diagnosis of exclusion
eventually occurs in up to 50% of patients w/cirrhosis (Type C = resulting from cirrhosis)
Classification: episodic: spontaneous or frequently due to a precipitating factor
Recurrent: two episodes w/in 1 yr
persistant: chronic & affecting quality of life
154
classifying hepatic enchephalopathy impairment
West Haven Criteria
Grade 0: normal
Minimal: normal exam, minor abnormalities on psychometric tests, subtle changes in work or driving
Grade 1: personality changes, attention deficits, depressed state, tremor, incoordination
Grade 2: changes in sleep-wake cycle, lethargy, mood & behavioral changes, cognitive dysfunction, asterixis, ataxic gait, slow & slurred speech
Grade 3: somnolence, confusion, disorientation, nystagmus (involuntary eye movement), clonus (involuntary relaxation & contraction of muscles), hyporeflexia, babinski sign (big toe goes up when sole is stimulated)
Grade 4: stupor and coma; unresponsive to noxious stimuli
SONIC (Spectrum of neurocognitive impairment in Cirrhosis) criteria:
Grade 0 = normal
Minimal to Grade 1 = Covert
Grade 2-4 = Overt
155
Mechanism of hepatic encephalopathy
Accumulation of gut-derived nitrogenous substances (ammonia) enter the CNS & cause alterations of neurotransmission
ammonia is normally converted to urea in the liver
decreased conversation due to decreased hepatic functioning & shunting of blood through collaterals bypassing the liver
156
precipitating factors of hepatic encephalopathy
GI bleed: increased ammonia production through breakdown of hemoglobin in gut
Excess dietary protein: increased ammonia production through breakdown of protein in the gut
Metabolic/electrolyte disturbances (alkalosis & hypokalemia): facilitates the conversion of NH4+ to NH3
Infection: possible increase tissue catabolism --> increase nitrogenous compound production
Constipation: reduced elimination of ammonia as ammonium ion (NH4+) in the gut
Azotemia (diuretic-induced renal failure): decreased clearance of urea, ammonia, and other nitrogenous compounds
Drugs: opiates, benzodiazepines, antidepressants, antipsychotics: additive CNS effects such as CNS depression
precipitating factors are what push them over into HE about 80% overt HE due to precipitating factor
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Treatment of episodic Overt HE
directed at reducing ammonia levels in blood
alternative causes should be ruled out
find & correct precipitating factors
possible temporary reduction in protein intake
drug therapy: lactulose, rifaximin, lactulose + rifaximin
neomycin & metronidazole are rarely used clinically due to adverse effect profiles
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Lactulose
1st line choice for overt episodic HE
MOA: degraded by colonic bacteria to acetic and lactic acid which decreases colonic pH. Acidic pH promotes conversion of ammonia (NH3) to poorly absorbed ammonium ion (NH4+)
acts as osmotic laxative
reduces ammonia producing bacteria
acute dosing: 30-45mL po every 1-2 hrs until stool, then 15-30mL every 8-12 hrs to maintain 2-3 soft stools/day (have to titrate it to that)
SE: excessive diarrhea, abdominal distension, flatulence, electrolyte abnormalities
poor adherence due to frequent dosing & unpalatable taste
indefinite treatment after 1st episode to prevent recurrence
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Rifaximin
2nd line choice for episodic overt HE
add-on therapy in patients w/out adequate response to lactulose alone OR by itself if unable to take lactulose (not approved for this indication)
MOA: non absorbable antibiotic that eliminates urease-producing bacteria in the colon which convert protein to ammonia
Acute dosing: 400 mg po tid or 550 mg po bid
SE: diarrhea, nausea, vomiting, peripheral edema
concerns for increased antimicrobial resistance with use
very expensive compared to lactulose
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Esophageal Varices
Extremely dilated sub-mucosal veins in the lower third of the esophagus
Mechanism: liver cirrhosis/fibrosis + decrease in intrahepatic vasodilators (nitric oxide) --> constriction of portal system & poor blood flow through liver --> increase in portal vein pressure (portal hypertension) --> increase in production of systemic vasodilators (nitric oxide) --> splanchnic arteriole vasodilation --> increase in flow to the portal system --> worsening of portal pressure --> increased collateral blood flow into other vessels such as the left gastric vein --> varices
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when should you screen for esophageal varices
screen using EGD (esophagogastroduodenoscopy) in any patient with a diagnosis of cirrhosis
present in 50% of patients w/cirrhosis
40% in Childs-Pugh Class A
85% in Childs-Pugh Class C
Variceal hemorrhage occurs in 25-40% of patients with cirrhosis
mortality rate from 1st bleed ~ 7-15%
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Prevention of variceal hemorrhage
Variceal hemorrhage: bleeding from an esophageal varice into the esophagus or bleeding of other collateral varices into the stomach
consider drug therapy for prevention of 1st bleed if:
high risk or medium-large varices are identified by EGD
high risk = red whale marks on varices or Child-Pugh C
Any patient with a bleed should be considered for secondary prevention
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What is the primary prevention of variceal hemorrhage?
non-selective beta blockers
Propranolol, nadolol and possibly carvedilol
1st line option for medium/large or high risk varicies
MOA: reduce portal flow and pressure by:
1. inhibiting beta2 adrenergic receptors -> vasoconstriction of splanchnic capillaries/arterioles
2. inhibiting beta 1 adrenergic receptors to decrease cardiac output
starting doses: propranolol 20mg po bid, nadolol 20 mg po daily
titrate every 2-3 days to maximally tolerated dose (typically a target heart rate of 55-60 bpm - shows that you've maximally beta blocked)
do not use in patients w/refractory ascites
consider discontinuing beta-blocker therapy in patients presenting w/sepsis, hepatorenal syndrome & spontaneous bacterial peritonitis (these cause lower blood pressure already)
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another prevention of variceal hemorrhage (non-drug)
endoscopic variceal ligation
placement of rubber bands around varices (every 1-2 weeks) until obliteration
1st line option in med-large varices (especially those at high risk for bleeding) or patients that cannot take non-selective beta-blockers
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what is the treatment for acute variceal hemorrhage?
medical emergency 15-20% mortality
treatment: supportive: fluids, blood transfusion
Prophylaxis with antibiotics (translocatin of bacteria) x 7 days to decrease risk of infection, decrease re-bleeding and increase short-term survival
drug therapy + endoscopic variceal ligation (banding) or sclerotherapy (injection of a sclerosing agent).
and Octreotide
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Octreotide
for acute variceal hemorrhage - drug that is used to stop bleeding
MOA: decrease portal pressure & collateral flow by
1. inhibiting the release of vasodilatory GI peptides such as glucagon and
2. local vasoconstrictor effects in the splanchnic vascular
50 mcg IV bolus followed by IV infusion of 25-50 mcg/hr for 3-5 days
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prevention of second variceal hemorrhage
once patient has bled once, they are at greater risk for bleeding again
60% re-bleed w/in 1-2 yrs if untreated
33% mortality for re-bleed
1st line therapy: non-selective blockers + chronic EVL
do not use in patients with refractory ascites
consider discontinuing beta-blocker therapy in patients presenting w/sepsis, hepatorenal syndrome and spontaneous bacterial peritonitis
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What are ascites?
Pathologic accumulation of free fluid within the peritoneal cavity
most common complication of portal hypertension
50% of patients over 10 yrs.
mortality rate of 50% at 2 yrs
If new-onset should have a diagnostic paracentesis
if serum-ascities albumin gradient (SAAG) >/= 1.1 g/dL, confirms ascites is due to portal hypertension with 97% accuracy (make sure it's due to portal hypertension & not cancer)
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what is the pathophysiology of ascites?
Portal hypertension --> release of vasodilators (NO) --> peripheral & splanchnic arterial vasodilation --> decreased effective circulating arterial volume --> #1 activation of the renin-angiotensin aldosterone system (kidney feels low pressure coming in, releases renin in response, leads to sodium & water retention), activation of sympathetic nervous system, release of antidiuretic hormone --> sodium/water retention by the kidneys.
3 things go wrong to cause leak:
1. low plasma oncotic pressure (low albumin)
2. high plasma hydrostatic pressure (Na H2O retention)
3. increased capillary permeability
--> movement of fluid out of vasculature into peritoneal cavity
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Treatment of new-onset ascites
Goals of therapy: control ascites accumulation, relieve symptoms, prevent complications
sodium restriction to 2000mg/day
fluid restriction not necessary unless severe hyponatremia (Na < 120-125 mEq/L)
Diuretic therapy:
Spironolactone (aldosterone antagonist)
Furosemide (loop diuretic)
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Spironolactone
for new-onset ascites
aldosterone antagonist
acts by inhibiting aldosterone's effects on the distal tubule/cortical collecting duct of the kidneys decreasing Na+ and H2O retention.
should be used alone only in the mgmt of mild ascites w/no peripheral edema
dosing: 100 mg po daily in the morning titrated every 3-5 days to a max dose of 400 mg daily
adverse effects include gynecomastia & hyperkalemia (increased potassium in blood)
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Furosemide
for new-onset ascites treatment
loop diuretic
acts on the ascending limb of hence in the kidneys to decrease Na+ and H2O retention
never used alone for ascites mgmt. - always w/spironolactone
dosing: 40 mg po daily in morning titrated every 3-5 days w/the spironolactone to max daily dose of 160mg po
adverse effects: hypokalemia, hypomagnesemia, hypocalcemia, polyuria, and possibly tinnitus
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Ascites treatment
spironolactone + furosemide combination recommended 1st line --> more effective & w/less hyperkalemia.
maintain ideal ratio of 100:40
titrate therapy every 3-5 days
goal fluid/wt loss = 0.5 kg/day (can increase to 1-2 kg/day if significant peripheral edema)
Goal: random spot urinary Na > urinary K
Hold therapy if recurrent or uncontrolled HE or suspected HRS
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Paracentesis
Ascites treatment
abdominal fluid tap
to relieve abdominal pain or respiratory difficulties when tense ascites is present
prior to diuretics of tense ascites is present
chronically for diuretic-resistant (refractory) ascites
if > 5L fluid removed - consider giving IV albumin
can be used to diagnose spontaneous peritonitis (SBP)
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Complications of Ascites
Spontaneous Bacterial Peritonitis (SBP)
infection in the peritoneal cavity
fever, abdominal pain, 13% of patients are asymptomatic
fluid should be tested in patients admitted to hospital with ascites or ascites + symptoms or worsening kidney function
Treat with PO or IV antibiotics for 5 days, tun consider long-term PO antibiotic prophylaxis
certain patients w/SBP will need IV albumin therapy to prevent hepatorenal syndrome
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Other complications of cirrhosis
Hepatorenal syndreom (HRS)
functional acute renal failure in the setting of cirrhosis. No structural kidney damage
due to intense renal vasoconstriction, which results from extreme systemic vasodilation & drop in effective circulating volume
only effective treatment for HRS is liver transplant
drug therapies are used as bridges to transplant.
Wernicke Encephalopathy (WE): typically reversible, acute/subacute confusional state that includes symptoms of impaired muscle coordination (ataxia) & vision changes such as nystagmus
Korsakoff Dementia (KD): irreversible psychosis/dementia after WE, anterograde/retrograde amnesia, confabulation, hallucinations
Due to thiamine (vitamine B1) deficiency
Prevention: thiamine 100 mg po once daily
treatment: high dose IV thiamine for 3-5 days
