Pharmacology of Laxatives
and Antidiarrheals….
…and…. Drugs
used to treat Irritable Bowel
Syndrome (IBS) and
Inflammatory Bowel Disease
(IBD)
Overview
TNFa antagonists;
Infliximab, adalimumab
5-HT3 antagonist;
alosetron used in IBS
Learning Objectives
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Contrast five different classes of laxative drugs with different mechanisms.
Compare loperamide with methylnaltrexone in regard to mechanism of
action and therapeutic use (antidiarrheal drugs).
Contrast the two major classes of drugs used to treat irritable bowel
syndrome in regard to mechanism of action, clinical uses, and adverse
effects.
Compare mechanism of action of the six classes of drugs used in
management of inflammatory bowel disease.
Describe mechanism of action, clinical uses, and adverse effects of
metoclopramide.
Supplemental Reading: G & G Pharmacological Basis of Therapeutics 13th
Chapters 50+51 pg. 921-954; Katzung and Trevor Examination and Board
Review, 11th edition, Chapter 59
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GI Diseases/Conditions
● Irritable bowel syndrome (IBS)
» Abdominal pain associated w/constipation
or diarrhea
● Inflammatory bowel disease (IBD)
» Crohn’s Disease
– Infiltration of lymphocytes, macrophages and
submucosal fibrosis
» Ulcerative colitis
– Lymphocytic and neutrophilic infiltrates
● Diarrhea and constipation
Regulation of volume
Decreased motility = excess fluid removal (constipation)
Increased motility = exceeds capacity to remove fluid (diarrhea)
Laxatives
Bulk-forming
MOA, clinical indication, adverse effects
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Natural plant products - psyllium, methylcellulose,
etc
» Bacterial digestion of plant fibers within the colon may lead
to increased bloating and flatus.
Synthetic fiber – polycarbophil
● Indigestible, hydrophilic colloids that absorb water
and form a bulky and lubricating gel
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Distends the colon and promotes peristalsis, stimulating evacuation
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Initially used to treat intermittent constipation and
in pts. with IBS who have constipation
Osmotic
MOA, clinical indication and adverse effects
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Osmotic agents increase water content of stool
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Usually causes evacuation within 4–6 h, sooner in large doses; used in acute
constipation and cleanse bowel prior to colonoscopy
Nonabsorbable Sugars/Salts
» Magnesium hydroxide (milk of magnesia)
–
Magnesium may be absorbed and cause toxicity in renal impairment
» Others: Sorbitol, Lactulose, Prepopik
–
Bacteria in colon may cause cramps and flatus
–
» Sodium phosphate
may lead to cardiac arrhythmias/renal failure; rarely used
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Balanced Polyethylene Glycol (PEG)
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Bowel prep for colonoscopy
Surfactant Agents
(stool softeners)
MOA, clinical indication and adverse effects
Softens stool by permitting entrance of excess lipids
and water
● Used in children and debilitated adults to treat fecal
impaction
● Docusate (oral or enema)
● Glycerin suppository
● Mineral oil
» Lubricates fecal material, prevents H20
reabsorption
● Long-term use can impair absorption of fat-soluble
vitamins (A, D, E, K).
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Stimulant Laxatives (cathartics)
MOA, clinical indication and adverse effects
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Anthraquinone Derivatives
Increase NO synthase activity and platelet activating factor
(PAF); induce mild inflammatory response
Given PO poorly absorbed; produces bowel mov’t in 6-12 hrs.
Given to neurologically impaired pts.
» Aloe
» Senna
» Cascara
» Chronic use causes melanotic pigmentation of colon mucosa
Diphenylmethane Derivatives
» Bisacodyl; used in conjunction with PEG for colon cleansing
prior to colonoscopy
Opioid Receptor Antagonists
MOA, clinical indication and adverse effects
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Methylnaltrexone
» opioid-induced constipation in patients receiving palliative care for
advanced illness who have had inadequate response to other agents
» It is administered as a subcutaneous injection (0.15 mg/kg) every 2
days
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Alvimopan
» short-term use to shorten the period of postoperative ileus in
hospitalized patients who have undergone small or large bowel
resection
» Alvimopan (12 mg capsule) is administered orally within 5 hours
before surgery and twice daily after surgery until bowel function has
recovered
– no more than 7 days.
» cardiovascular toxicity, restricted to short-term use in hospitalized
patients only
Antidiarrheal
Agents
Opioid Agonists
MOA, clinical indication and adverse effects
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Loperamide – OTC, doesn’t cross the BBB
» No analgesic properties or addiction potential
» Administered 1-4 times daily to relieve diarrhea
» Opioid receptor (e.g mμ) agonists inhibit presynapic
ACh release in submucosal and myenteric plexuses;
increase colonic transit time and fecal H2O absorption
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Diphenoxylate – prescription needed
» No analgesic properties
» Higher doses can produce CNS effects and lead to
opioid dependence
» Commercial preps contain small amounts of atropine to
discourage overdosage
Irritable Bowel Syndrome
(IBS)
Nonorganic functional disturbance; affects 15% of US
population
● Etiology: psychosocial, altered motility (inc gastrocolonic
response), inc GI sensory response (volume/distension)
● Symptomatic treatment: inc dietary fiber, antidiarrheals,
antispasmodics (dicyclomine), avoid drinks/foods known
to activate condition
● Drugs that block serotonin receptor 5-HT3 activity
(alosetron) for diarrhea symptoms
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Drugs that activate Cl- Channel in small intestine for
constipation symptoms (lubiprostone and
linaclotide)
Serotonin 5-HT3 Receptor
GI 5-HT3 receptors
● Activate visceral afferent pain sensation
resulting in unpleasant sensations = nausea,
bloating, and pain
● Increases colonic motility
Alosetron (LOTRONEX)
MOA and clinical indication
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5HT3 receptor (antagonist) blockade of enteric
cholinergic neurons
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Inhibits colonic motility, increasing colonic transit time
» used to treat IBS in women when diarrhea is main complaint
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Rapidly absorbed from GI tract, 50-60% bioavailability,
metabolized by P450 enzymes
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T ½ is 1.5 hours
» Duration of effect longer
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Other “trons” ondansetron, dolesetron, palonosetron are
used as anti-emetic agents
Alosetron Cont’d
clinical indication and adverse effects
● Dose: 1mg once or twice daily
● Leads to reduction in number of bowel
movements/day; improvement in stool
consistency
● ADR – constipation in up to 30% of patients
» Note: can cause ischemic colitis in 0.3% pts
Prokinetic Agent
Mechanism of action & adverse reactions
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Metoclopramide (REGLAN)
» Antagonist (blocks) enteric GI dopamine-D2 receptors
» Increases ACh activity (cholinomimetic) – increase in
upper GI tone/motility; also anti-emetic effects via
CNS activity
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ADRs:
» Inc. GI activity
» Central DA antagonism: sedation, extrapyramidal effects
(think Parkinson’s Disease), seizures, increased:
prolactin, galactorrhea, menstrual irregularities
Inflammatory Bowel Disease
(IBD)
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Crohn’s disease
» Infiltration of lymphocytes, macrophages and submucosal
fibrosis
» Lesions are not confluent and contain “skip areas” of
normal colon
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Ulcerative colitis
» Lymphocytic and neutrophilic infiltrates
» Lesions are confluent
» Always involves rectum
» Bloody diarrhea
Drugs for IBD
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5-aminosalicylic acids (5-ASA drugs; e.g. Mesalamine)
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Antimicrobials: metronidazole, ciprofloxacin for bacterial control
if indicated
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Corticosteroids (prednisone; budesonide) for acute flares
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Immunosuppressives: azathioprine, mercaptopurine;
methotrexate (Crohn’s), cyclosporine (ulcerative colitis)
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anti-Tumor Necrosis Factor receptor antagonists:
adalimumab; infiximab
anti-integrin antagonists: natalizumab
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5-Aminosalicylates
● MOA: anti-inflammatory work topically not
systemically in areas of diseased GI mucosa
» Inhibits activity of nuclear factor-kB (NF-kB);
transcription factor to reduce proinflammatory
cytokine expression
● Many formulations are designed to deliver
5-ASAs to distal segments of small bowel or
colon
Specific 5-ASAs
Sites of Action
Sulfasalazine (AZULFIDINE) – colonic bacteria
break azo bond (azoreductase) to release 5-ASA
● Balsalazide (COLAZAL) – same as above
● Olsalazine (DIPENTUM) – same as above
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Mesalamine
» (ASACOL) -acrylic coated released @ ph7 @ terminal
ileum/colon
» (PENTASA) ethylcellulose coated time-released throughout
GI, more in small intestine
» enema (ROWASA) & (CANASA) rectal suppositories for
distal colitis/proctitis
Metabolism of 5-ASA’s
Specific 5-ASAs
Sites of Action
Adverse Effects of aminosalicylates
●Sulfasalazine – formation & absorption of sulfapyridine
can cause adverse effects of sulfonamides: allergy, rash,
hemolytic anemia; interference with folic acid absorption
(up to 40% of pts.); not so with balsalazide & olsalazine
●GI disturbances/diarrhea in 10-20% pts (olsalazine)
●Other aminosalicylates are well tolerated and minor; skin
rash and headache
●higher doses may cause renal damage
Tumor Necrosis Factor antagonists
MOA, clinical indication and adverse effects
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Indicated for acute/chronic Crohn’s disease in
moderate to severe conditions
» Infliximab (REMICADE) also ulcerative colitis
» Adalimumab (HUMIRA) also ulcerative colitis
» Certolizumab (CIMZIA)
Mechanism: Prevent TNF binding to receptors to
inhibit proinflammatory cytokine expression
Use: remission/maintenance in pts with inadequate
response to mesalamine/steroids
ADRs: infection, antibody development, infusion rxn,
autoimmune rxns
TNF antagonists cont.
MOA, clinical indication, pharmacokinetics
Anti-Integrin Therapy
MOA, clinical indication and adverse effects
● Natalizumab (TYSABRI)
● Monoclonal antibody against α4 subunit of
integrin on the surface of leukocytes
● Prevents leukocyte binding to vascular
endothelium (p-selectins and ICAM-1)
● Used when Crohn’s disease patients are
refractory to TNF-alpha antagonist
● 0.4% Pts. (4 out of 1000) may develop
progressive multi-focal leukoencephalopathy
(PML)
Ulcerative Proctitis/Distal
Colitis < 40 cm
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Mesalamine or steroid suppositories or enemas (topical)
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Patients unwilling to take topical therapy: oral sulfasalazine or
mesalamine
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Oral corticosteroids (prednisone, prednisolone)
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Newer corticosteroid, budesonide (ENTOCORT), formulated
to release steroid in intestines to minimize systemic steroidal
ADRs
» MOA: corticosteroids inhibit production of inflammatory cytokines
(TNF-a, IL-1, IL-8) and cell adhesion molecules
Ulcerative Colitis > 40 cm
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Mild-moderate disease: oral mesalamine or
sulfasalazine +/- topical therapy(also for maintenance
of remission)
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Moderate-severe acute disease: steroids
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Mercaptopurine or azathioprine for
steroid-dependent or cyclosporine-induced remissions
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Cyclosporine for fulminate ulcerative colitis
unresponsive to steroids
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Antibiotics only if acute infection present
Crohn’s Disease
Mesalamine in mild-moderate disease or PO
budesonide (Entocort EC)
● PO steroids for mod-severe disease
● IV steroids for acute severe disease
● Immunomodulators (azathioprine, mercaptopurine)
for refractory or steroid-dependent disease, &
remission maintenance
● anti-TNF drugs; moderate/severe; long-term use for
refractory cases to conventional therapy
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Antibiotics: metronidazole, ciprofloxacin; if needed
Treatment regimen for IBD
Summary
Please review summary tables on pgs. 1115 - 1116
Clinical correlations case 1
A patient who is taking verapamil for
hypertension and angina has become
constipated. Which of the following drugs is an
osmotic laxative that could be used to treat the
patient’s constipation?
A. Aluminum hydroxide
B. Diphenoxylate
C. Magnesium hydroxide
D. Metoclopramide
E. Ranitidine
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Clinical correlations case 2
A 34-year-old woman has irritable bowel syndrome with
diarrhea that is not responsive to conventional therapies.
Despite the small risk of severe constipation and ischemic
colitis, the patient decides to begin therapy with alosetron.
Alosetron has which of the following receptor actions?
A. 5-HT3 receptor antagonist
B. 5-HT4 receptor agonist
C. D2 receptor antagonist
D. TNF receptor antagonist
E. Muscarinic receptor antagonist
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Clinical correlations case 3
On your way to examination, you experience the
vulnerable feeling that an attack of diarrhea is imminent.
If you stopped at the drugstore, which one of the
following antidiarrheal drugs could you buy without a
prescription even though it is related chemically to the
strong opioid analgesic meridipine?
A. Aluminum hydroxide
B. Diphenoxylate
C. Loperamide
D. Magnesium hydroxide
E. Metoclopramide
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Clinical correlations case 4
A patient is receiving highly emetogenic
chemotherapy for metastatic carcinoma. To prevent
chemotherapy-induced nausea and vomiting, she is
likely to be treated with which of the following?
A. Levodopa
B. Methotrexate
C. Misoprostol
D. Ondansetron
E. Sucralfate
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Basic Drug Review
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Which drug is most likely to be useful in the
treatment of inflammatory bowel disease?
Diphenhydramine
B. Diphenoxylate-Anti-diarrheal
C. Mesalamine-this drug is used to Treat
Imflammatory Bowel disease
D. Ondansetron
E. Psyllium-Laxative agent
A.
Featured Case: Chapter 62
A 21-year-old woman comes with her parents to discuss
therapeutic options for her Crohn’s disease. She was
diagnosed with Crohn’s 2 years ago, and it involves her
terminal ileum and proximal colon, as confirmed by
colonoscopy and small bowel radiography. She was
initially treated with mesalamine and budesonide with
good response, but over the last 2 months, she has had
a relapse of her symptoms. She is experiencing fatigue,
cramping, abdominal pains, and non-bloody diarrhea up
to 10x daily, and she has had a 15-lb weight loss.
Featured Case: Chapter 62 cont.
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She has no other significant medical or surgical history. She
appears thin and tired. Abdominal examination reveals
tenderness without guarding in the right lower quadrant; no
masses are palpable. Which of the following agents would be
appropriate to treat this patient at this time?
A.
Mercaptopurine
Magnesium hydroxide-laxative
Alosetron-FOR IBS
Natalizumab
Sulfasalazine-5-ASA agent similar to Mesalamine and not
appropriate
B.
C.
D.
E.
Featured Case: Chapter 62 cont.
● Which is an appropriate long-term
management option for patients with
inadequate response to mesalamine?
A. Prednisone
B. Alosteron
C. Balsalazide
D. Adalimumab-use with inadequate
response to mesalamine
E. Natalizumab
Clinical correlations; Bonus question
overview of GI drugs
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A.
B.
C.
D.
E.
A 55-year-old woman with type 1 diabetes of 40 years’
duration complains of severe bloating and abdominal
distress, especially after meal. Evaluation is
consistent with diabetic gastroparesis. Which of the
following is a prokinetic drug that could be used in this
situation?
Alosetron
Cimetidine
Loperamide
Metoclopramide-THIS IS A PROKINETIC DRUG
Sucralfate
Overview
(cimetidine)
(omeprazole)
(Calcium Carbonate)
(used outside the U.S)
Objectives
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Explain differences in mechanism of action between H2 blockers,
and proton pump inhibitors (PPIs).
Contrast mechanisms of action between antacids and mucosal
protective agents.
Compare pharmacokinetics between H2 blockers, and proton
pump inhibitors (PPIs).
Explain use of antibiotics in peptic ulcer disease.
Explain major adverse effects resulting from chronic use of PPIs.
Reading: Basic & Clinical Pharmacology, Katzung 14th, Chapter 62, pg.
1087-1096
Supplemental Reading: Katzung & Trevor’s Pharmacology Examination &
Board Review (11th), Chapter 59; G&G Pharmacological Basis of
Therapeutics (13th) Chapter 49, pg. 909-944
GI Diseases/Conditions
● Peptic Ulcer Disease
» 1 out of 10 Americans will develop an ulcer
over the course of their lifetime
» Gastric
» Duodenal
» Stress related
● Gastro-Esophageal Reflux Disease
» 1/5 adults display symptoms of GERD at
least once a week
» Heartburn (acid reflux), esophagitis
Antacids
MOA, pharmacokinetics, clinical indications, adverse effects
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Take @ onset of heartburn symptoms; effects last up to 2hrs; onset
of action within minutes
NaHCO3(s) + HCl(aq) 🡪 NaCl(aq) + H2O(l) +
Sodium bicarbonate (Alka-Seltzer) CO2(g)
(s) + 2 HCl(aq) 🡪 CaCl2(aq) + H2O(l) +
3
Calcium carbonate (Tums, Os-Cal) CaCO
CO2(g)
» ADRS (NaHCO3 & CaCO3): Belching, metabolic alkalosis, renal
insufficiency, hypercalcemia (milk-alkali syndrome), chelates
drugs tetracycline, fluoroquinolones, itraconazole
Magnesium + Aluminum hydroxide (Gelusil, Maalox, Mylanta)
Al(OH)3(s) + Mg(OH)2(s) + 5 HCl(aq) 🡪 AlCl3(aq) + MgCl2(aq) + 5 H2O(l)
» Aluminum salts = constipation; Magnesium salts = diarrhea
» Long term use is contraindicated in patients with renal
insufficiency; no belching
Antihistamine H2 Blockers
Mechanism of action & Clinical indication
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Competitive H2 receptor antagonists
» Reversible dec of H+ production by parietal cells
» Inhibit production of cAMP
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Dose-dependent effects
Inhibit basal, nocturnal > food-stimulated acid secretions
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Effective for duodenal > gastric ulcers
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Little effect on GI motility or emptying time
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Healing rate > 70% with 6-8 weeks tx
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Proton Pump Inhibitors (PPI’s)
Mechanism of action & clinical indication
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PPI’s are the most effective reducers of HCl
secretion
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Irreversibly inhibit H+ / K+ ATPase
» 80-95% inhibition of HCL production; lipophilic weak
bases that get protonated and concentrated in parietal
cells and get converted to a sulfenamide to inhibit the
proton pump
Uses: Zollinger-Ellison syndrome (gastrintumors), gastric / duodenal ulcers,
gastroesophageal reflux disease
● May take 2-5 days to reach steady state
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Acid Control – H2 Blockers vs. PPIs
Sucralfate (CARAFATE)
Mechanism of action & adverse effects
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Cytoprotective agent
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Salt of sucrose complexed to sulfated aluminum hydroxide
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Interacts with HCl to form viscous paste that binds to proteins in
ulcers to promote direct healing (a.k.a. Belly Jelly)
Claims to stimulate mucosal PG synthesis
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GI disturbances: n,v / constipation
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Drug interactions: sucrafate my bind to other drugs such as
cimetidine, digoxin, anticoagulants, phenytoin, quinolones and impair
their absorption
» Do not adm simultaneously with antacids/H2 blockers/PPIs,
administer them 2hrs prior to Sucralfate admin
GERD / Prokinetic Drugs
Mechanism of action & adverse reactions
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Metoclopramide (REGLAN)
» Blocks enteric GI presynaptic dopamine-D2 receptors
» Increases ACh activity (cholinomimetic) – increase in
upper GI tone/motility; also anti-emetic effects via CNS
activity
●
ADRs:
» Inc. GI activity
» Central DA antagonism: sedation, extrapyramidal effects
(think Parkinson’s Disease), seizures, increased:
prolactin, galactorrhea, menstrual irregularities
Effect on pH: H2 Blockers vs. PPIs
Summary
proton pump inhibitor (given once
daily) and an H2 receptor antagonist
(given twice daily) in elevating
gastric pH to the target ranges
Basic Drug Review
● Which of the following is used to directly
heal an ulcer lesion?
A. Clarithromycin
B. Sucralfate–CAN BE USED TO
DIRECTLY HEAL an ulcerated lesion
C. Omeprazole
D. Famotidine
E. Aluminum hydroxide
Basic Drug Review
Which drug accumulates in parietal cells and
undergoes conversion to a derivative that
irreversibly inhibits H+/K+ ATPase?
A. Cimetidine
B. Misoprostol
C. Metoclopramide
D. Esomeprazole-proton pump inhibitor
E. Bismuth subsalicylate
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Basic Drug Review
Which drug is most effective to treat a patient with
Zollinger-Ellison syndrome that would reduce GI
acidity?
A. Lansoprazole-proton pump inhibitor that raises the
pH of the stomach and upper intestin (reducing GI
acidity)
B. Metoclopramide
C. Calcium carbonate
D. Misoprostol
E. Ranitidine
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