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Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 1 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby
GI Pharmacology Part 2
GI Water Flux and Motility
 Key thing with drug action is transit time through the GI
 In a normal diet 9 liters of fluid enter small intestine, only 0.1 liters pass with
the stool, most is absorbed
 Small intestine absorbs 8 liters.
 It’s up to the colon to resorb the rest of that. And the colon has the capacity
to resorb a lot of that.
 The presence of non-absorbable solutes will increase the passage of fluid
and produce diarrhea.
 Excessive reabsorption of water causes constipation
 Intestinal motility dictates the time available for reabsorption of water and
solutes.
 Increased motility leads to diarrhea; decreased motility can cause
constipation.
 Decreased motility is an important component of nausea and vomiting and
increased GI motility is a significant property of some antiemetic agents.
Laxatives
 Laxative Abuse – d/t all the OTC remedies available
o This is very common, especially in elderly
o Overuse of laxative leads to thorough evacuation
o Requires several days to accumulate bulk
o Lag in defecation is interpreted as continued constipation
o Take more laxative - vicious cycle
o If continued, bowel becomes unresponsive due to smooth muscle of GI
tract loses it’s sensitivity, also leads to electrolyte imbalances
 The most satisfactory prophylactic and treatment for functional constipation is
a diet rich in fiber coupled with proper daily exercise and bowel training
Laxative Drugs – 3 classes: Fiber, Saline laxatives, and osmotic laxatives
 Dietary fiber and bulk-forming laxatives – this means a change in diet
o bran, psyllium, methylcellulose – these can be available as meds if a
diet change is not possible
 Saline laxatives (Milk of Magnesia, Fleet, etc.) – stimulate fluid accumulation
in GI tract
 Osmotic laxatives – nonabsorbable solutes that draw water from tissues and
increase more bulk fluid  laxative effect
o Polyethylene glycol-electrolyte solutions (Colyte, Golytely) are the drug
of choice for bowel preparation for colonoscopy, barium enema, or
colorectal surgery.
o Lactulose = nonabsorbable sugar for hepatic encephalopathy; helps
clear excess ammonia (eg/ for pt with bleeding varices and cirrhosis of
liver – all the protein from bleeding is being broken down and causing
a protein load  excessive N and NH3 compounds  leading to
encephalopathy
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Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 2 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby
Stimulant laxatives (Ex-Lax, etc.) – variety of stimulants that stimulate motility
of GI tract
o Not recommended for routine use
; short term only
Surfactant Stool Softeners: Docusates – used in nursing homes and elderly
patients
Some laxatives are dose dependent
o Low doses – mild effect
o Higher doses – cathartic effect = fast, rapid action (for surgery or
endoscopy)
Treatment of Diarrhea
 change motility in GI tract so there is more time for absorption of fluid and
electrolytes
Opioids – of morphine/codeine class
o Loperamide (Imodium)
o Diphenoxylate (Lomotil) + atropine – gives a nasty atropine side effect, so
drug abusers won’t use it
o Diphenoxin (Motofen) + atropine
o Codeine, morphine, and paregoric (tincture of opium)
 Change motility of GI tract by slowing it down
 agonists at opiate receptors in smooth muscle receptors in GI tract
 These poorly penetrate the CNS compared to the psychoactive opioids
 Opioids are the mainstay of nonspecific treatment of diarrhea
 Act at mu and delta receptor in GI tract to decrease motility, poor CNS
penetration
 Uncomplicated infectious diarrhea is usually self limited - treat with fluid
replacement and bed rest.
Pepto Bismol – effective especially for Traveller’s diarrhea
 Made up of clay, bismuth, and a salicylate compound
 Salicylate is an anti-inflammatory and bismuth increases GI motility and
the clay absorbs bacterial toxins
 One of the first things to recommend to a patient with routine diarrhea
Octreotide
 somatostatin analog
 for severe diarrhea associated with tumors and AIDs
 IV or SQ – because it’s a peptide
 Expensive and not routine
 Also used to treat patients with esophageal varices and have rupture of
the varices – it stops the bleeding (vasopressin can also be used)
Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 3 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby
Antiemetic Agents – treatment of nausea and vomiting
 See figure in powerpoints – shows variety of pathways that lead to the
complex reflex of vomiting
o Do not memorize chart, but know that the stimuli of nausea and vomiting
come from lots of different places
o Eg/ toxic substances – sensed in chemosensor areas of brain where there
is poor blood brain barrier and then triggers a feeling of nausea
o Eg/ obstruction of GI tract can be stimulus of vomiting
 There are many different neural pathways and thus different neural
transmitters and receptors (eg/ dopamine, ACh, histamine, serotonin)  thus
lots of different drugs and drug classes can be effective as antiemetics
 Many of these drugs have been created due to the emetic side effects of
cancer chemotherapy
Antiemetic Drug Classes
5-HT3 Antagonists (serotonin type 3 receptor blocker)
o Ondansetron (Zofran) – KNOW THIS ONE!!!
o Granisetron (Kytril)
o Dolasetron (Anzemet)
 serotonin is major neurotransmitter in PNS and CNS and has 17 different
receptor subtypes
 these are the most efficacious antiemetic agents so far
 5-HT3 receptors are located at several sites involved in the vomiting reflex
including the chemoreceptor trigger zone.
 Antagonists of these receptors are very effective inhibitors of emesis even to
chemotherapeutic agents. Drawback = very expensive (5 pills for $2500),
thus not for routine Rx
 Primarily used for cancer chemo-induced emesis – due to cost
D2 Dopamine Receptor Antagonists – lots of these drugs
(aka. Neuroleptics, psychotics, benzoamides)
o Metoclopramide (Reglan) – KNOW THIS ONE!!!
o Trimethobenzamide (Tigan) – similar, but less efficacious
 Important prokinetic effects = increases gastric emptying and motility of GI
tract
 Blocks both D2 and 5-HT3 receptors, 5-HT4 agonist
o Serotonin blockade is more important than dopamine blocking activity
 Useful in diabetic neuropathy/gastroparesis, cancer chemo, postoperative
N&V, GERD, migraine
 Can be given PO, IV, IM
 Serious side effects possible include sedation and extrapyramidal reactions,
hyperprolactinemia
 There use to be another agent called propulside that was major agent for
promotility, but it caused fatal cardiac arrhythmias in some patients (those
with drug-drug interaction)
Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 4 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby

“General Purpose Antiemetics” – D2 receptor blockers for short term
treatments
 Chlorpromazine (Thorazine)
 Prochlorperazine (Compazine)
 Triethylperazine (Torecan)
o These are antipsychotic agents
o Antiemetic effect at low doses
o Also sedating, (can be helpful in some patients)
o Side effects increase with dose (related to D2 blockade) –
hypotension, sedation, hyperprolactinemia, extrapyramidal
movement disorders
H1 Antihistamines agents
 Mentioned earlier about H2 blockers – but all they do is block acid secretion
o Promethazine (Phenergan) – used a lot in hospitals
o Dimenhydrinate (Dramamine) – used for car sickness
o Diphenhydramine (Benadryl)
o Meclizine (Antivert)
 For motion sickness, postoperative N&V, and inner ear problems
 Have prominent antimuscarinic activity also  produces sedation
Antimuscarinic Agent
 Scopolomine - patch for motion sickness, lasts for one week
 Also get antimuscarinic side effects (dry mouth, etc..)
Antiemetics – Indications
 Motion sickness and vertigo
o Scopolamine & Antihistamines (Dimenhydrinate, Promethazine,
Meclizine)
 Postoperative recovery – D2 blockers
o Prochlorperazine, chlorpromazine, thiethylperazine
 Pregnancy (fluids, PPI or H2 blocker) – avoid meds
 Cancer Chemotherapy – use whatever it takes
o Combinations w/ Ondansetron, antihistamine, steroid
 Migraine and gastric stasis – metaclopramide
Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 5 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby
Promotility Agents
 (see diagram in ppts)
 main motor fiber is cholinergic with muscarinic cholinergic receptors
 agents that stimulates motility would be an agonist at muscarinic receptors –
use Bethanechol
 several other fibers modulate the activity
 nonadrenergic, noncholinergic serotoninergic neuron  releases ATP and
peptides and is inhibitory on cholinergic neuron – regulated by stimulation of a
5HT3 receptor
 these drugs can work as D2 blockers, 5HT3 blockers, or 5HT4 agonists
Metoclopramide (Reglan) – KNOW THIS ONE
o D2 Dopamine antagonist, 5-HT3 antagonist, and 5-HT4 agonist
o Facilitates Ach release
o Antiemetic – used in cancer chemo and migraine
o Treat gastroparesis and GERD
Motilin & Macrolide Antibiotics
o Motilin = hormone that stimulates motility in GI tract
o Erythromycin, Clarithromycin, Azithromycin stimulate the motilin
receptor
Tegaserod (Zelnorm)
o A 5-HT4 partial agonist approved for treatment of IBS (modestly
effective)
Cisapride (Propulsid) -- Taken off market in 2000 due to cardiac arrhythmias
o improves gastric emptying
o 5HT4 agonist
o improves lower esophageal sphincter tone
o stimulates esophageal peristalsis
o stimulates colonic motility
o useful in GERD and cases of gastric stasis
o Available through special program if no other drug helps
Inflammatory Bowel Disease
 Dr Aziz went through these drugs yesterday in his lecture
5-ASA compounds (5-aminosalicylic acid)
o All derivatives of 5-ASA
o Anti-inflammatory effects
o Inhibits COX and 5-lipoxygenase pathways, i.e., prostaglandins and
leukotrienes
o Drugs are formulated to only be released in lower GI tract so that GI
aspirin-like toxicity is diminished
o In lower GI tract the drug is split by bacteria and then it starts to have
its anti-inflammatory effect
 5-ASA (Mesalamine)
o Pentasa, Asacol, Rowasa – formulated in a resin to be released only
when it reaches terminal ileum and colon
Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 6 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby
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Salfasalazine
o A 5-ASA molecule linked to an antibiotic
o 5-ASA split off in lower GI
Olsalazine
o Two 5-ASA molecules linked together
Balsalazide
o 5-ASA linked an inert carrier
Corticosteroids – suppress immune and inflammatory system at multiple sites
o Prednisone
o Budesonide – PO and suppository (discussed earlier as inhalation Tx)
o Methylprednisolone – IV
o Hydrocortisone – IV
 To induce remission in moderate to severe disease flare-ups – ulcerative
colitis and Crohn’s disease
 Serious side effects
 Must be slowly tapered off of drug
Immunosuppressants
 Azathioprine (converts into mercaptopurine) and 6-mercaptopurine
o Analogs of purines that inhibit ribonucleotide synthesis and cell
proliferation
 Methotrexate
o Inhibitor of dihydrofolate reductase, purine and pyrimidine base
synthesis, DNA synthesis
 Cyclosporine
o Inhibitor of cell-mediated immune responses
o Use reserved for severe disease
 Infliximab
o Monoclonal antibody against tumor necrosis factoralpha)
o Blocks TNF-alpha
-producing
macrophages and T cells
o Extremely effective in remitting Crohn’s disease, but very expensive
o Must be given by IV infusion
 Antibiotics
o Metronidazole (Flagyl) – effective when there is bacterial involvement
o Ciprofloxacin (Cipro) – effective when there is bacterial involvement
o For active inflammatory, fistulous and perianal Crohn’s disease
o Treatment of infections after ileal or colonic resections
Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 7 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby
Antibiotic-associated Colitis
 Antibiotic treatment can disrupt balance of GI flora and lead to overgrowth by
Clostridium difficile – classic example
 C. difficile produces toxin that causes local inflammation and diarrhea.
 Local areas of necrosis – exudative coating formed =pseudomembrane.
 Nearly any antibiotic cause pseudomembranous colitis but prototype is
clindamycin
 Currently, amoxicillin-ampicillin, cephalosporins, and clindamycin most
commonly associated – because these are used more often
 Treatment metronidazole, vancomycin, or bacitracin
Irritable Bowel Syndrome
 Patient counseling – key treatment
 Laxative or antidiarrheal – can be associated with diarrhea or constipation
Tagaserod (Zelnorm)
o 5-HT4 partial agonist, increases motility, decreases abdominal pain
Antidepressants
o Tricyclics, e.g., imipramine, desipramine – long history of success
with these, but has potential problems
o SSRIs, e.g., fluoxetine – used more often now
Viral Hepatitis
Interferon-alpha
o Recombinant cytokine
o Stimulates synthesis of antiviral proteins
o Must be given parenterally
o For hepatitis B and C
Lamivudine
o Inhibits viral reverse transcriptase (NRTI)
o For chronic hepatitis B or HIV
o Requires long-term therapy
o Well tolerated
Interferon-alpha + ribavirin
o For chronic hepatitis C
o Ribavirin inhibits replication of virus
o Ribavirin also used as aerosol for RSV
Drugs and Liver Toxicity
 Many drugs are biotransformed by liver
 Many drugs can cause idiosyncratic liver damage or cytotoxicity in overdose
Tylenol (acetaminophen) toxicity
 Minor metabolite normally detoxified by glutathione
 In overdose, glutathione levels depleted – potentially fatal liver toxicity
 Toxic ROS is produced by Tylenol, but this is cleaned up by glutathione  too
Wednesday 2/26/04, 11 A.M.
GI-2 #17 Page 8 of 8
Dr. Martin
Eric Lawrence for Jennifer Derby
much aspirin overwhelms the glutathion  toxic necrosis of liver cells