Gi Pharm

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antacids

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all OTC, short-acting but rapid relief;
NaHCO3, CaCO3, Mg(OH)2 or Al(OH)3
some used with simethicone to reduce foaming (good in GERD)
Do not give w/in 2 hrs of tetracycline, fluoroquinolones, itraconazole, and Fe!

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H2 Receptor Antagonists

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prevent parietal cell activation by blocking histamine binding and attenuate responsiveness of cell to other stimuli via decrease in cAMP
Good for nocturnal acid secretion - duodenal ulcers
All available OTC
Cimetidine
Ranitidine
Famotidine
Nizatidine
Clinical use (less often now due to advent of PPIs):
1. Peptic ulcers
2. GERD
3. Dyspepsia
4. Bleeding from stress-related gastritis (parenteral for ICU pts)
5. Warts (Cimetidine)
Tolerance can develop causing rebound increase in acidity
AE: confusion, hallucinations, agitation in the elderly, impotence, gynecomastia, galactorrhea, arrhythmias, bradycardia, hypotension

Rx Interactions: antacids block absorption, Cimetidine decreases P450 interactions decreasing metabolism of some drugs (warfarin, benzodiazepines, CCB, metro, etOH)

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PPIs

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prodrugs converted in the canaliculus and irreversibly inhibit H/K ATPase of active parietal cell --> long reduction of resting and active acid secretion
1. Omeprazole (OTC and generic formulation)
2. Lansoprazole
3. Rabeprazole
4. Pantoprazole
5. Esomeprazole

contrast to H2 blockers they inhibit both fasting and active secretion; short half life but long duration, specific to these proton pumps

Clinical use: agents of choice for most peptic ulcer disorders:
1. GERD
2. PUD - H. pylori increased clearance and healing of ulcers secondary to H. pylori; NSAID ulcers
3. Nonulcer dyspepsia - OTHER AGENTS USED FOR THIS
4. Stress Gastritis in ICU pts
5. ZE or other gastrinomas

AE: very safe drugs, diarrhea, headache, abd pain, increased serum gastrin may cause Colon CA or gastric CA

Rx Interactions:
decrease absorption of Ketoconazole and Digoxin, metabolized by P450 so interference can occur

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Mucosal Protective Agents

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1. Prostaglandin analogs:
prostaglandin binding to parietal cells reduces acid secretion; binding to epithelial cells stimulates mucus/HCO3 production and increase mucosal blood flow; main PG are PGE2 & PGI2 that bind to EP3 on parietal cells
Misoprostol:
Clinical uses:
1. can stimulate uterine contractions and given with mifepristone to terminate pregnancy
2. not widely used b/c of AE but can prevent NSAID induced gastric ulcers
AE: CI in pregnancy, can worsen IBD symptoms

2. Sucralfate:
used for active DU, can be useful to reduce risk of nosocomial pneumonia b/c doesn't increase gastric pH
AE: minimal since no systemic absorption

3. Colloidal Bismuth compounds:
Bismuth subsalicylate: reduces stool frequency and liquidity in acute diarrhea by inhibiting prostaglandins and Cl secretion in intestine; has direct antimicrobial effects useful for H. pylori Tx; binds enterotoxins for traveler's diarrhea
AE: very safe, blackening of stool, prolonged use (encephalopathy ataxia), overdose (salicylate toxicity)

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Therapeutic Approaches for PUD & H. pylori

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PUD: in acute bleeding ulcers give i.v. pantoprazole or lansoprazole for rapid healing
-GERD = stage 1: <2-3 episodes/wk, lifestyle mods w/antacids or H2 antagonists
stage 2: >2-3 episodes/wk, PPI
stage 3: chronic, unrelenting, complications, PPI
therapy should elevate gastric pH to greater than 4

H. pylori: two 14 day therapies
Triple = Amoxicillin or Metro, Clarithromycink and PPI or ranitidine
Quadruple (higher success) = PPI, bismuth subsalicylate, metro, tetracycline

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Bulk Forming Laxatives

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indigestible, hydrophilic colloids that absorb water, distend colon, stimulate peristalsis
lignin very popular and effective
take 1-3d for effect
1st line since they mimic normal evacuation
Natural:
Dietary Bran
Psyllium preparations
Synthetic:
methylcullulose
polycarbophil

CI and AE:
obstructions or megacolon/megarectum, fecal impaction, don't use if n/v

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Stool Surfactants/Softeners

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decrease surface tension of stool to allow water and lipids to enter stools
take 1-3d to work

Docusate: marginally effective for constipation but highly used
Mineral oil: approved for fecal impaction
AE = anal leakage, pneumonitis (do not take before bed)

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Osmotic laxatives

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increase fecal fluidity by retaining water in colon increasing peristalsis from luminal distention

1. Saline laxatives:
rapid acting cathartics, 1-3h
Mg can stimulate CCK release causing fluid retention and increased motility

Common agents:
Mag Sulfate, Mag hydroxide, Mag citrate, Sodium phosphate
AE: well tolerated but long-term can cause hypermagnesemia

2. Non-digestible sugars and alcohols:
Glycerin: bowel movement in less than an hour!
Lactulose, Sorbitol, Mannitol: hydrolyzed in colon to organic acids which acidify lumen and draw in water
used in constipation due to opioids, vincristine, and old age
Lactulose treats hepatic encephalopathy via increasing ammonia excretion

3. Polyethylene Glycol:
cathartic prior to bowel procedures, given with an isotonic ion mixture

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Stimulant laxatives

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rapidly acting cathartics that increase fluidity of stool and stimulate intestinal motility due to low grade inflammation
THESE ARE MOST COMMONLY ABUSED and can lead to myenteric plexus dmg

Agents:
Diphenylmethanes:
1. Bisacodyl - works in minutes to hours, used prior to procedures or constipation

Anthraquinones:
these are plant based irritants that cause colonic contractions
1. Aloe vera
2. Senna
3. Cascara sagrada
4. Rhubarb
AE: long term can cause melanosis coli
5. Ricinoleic Acid: stimulates secretion of fluid and electrolytes
works in 1-3h

Other agents: have limited use w/different mechanisms
1. Lubiprostone - stimulates chloride channel, used for chronic constipation and IBS-C
2. Methylnaltrexone & Alvimopan - opioid receptor blocker that doesn't cross BBB so they are good for opioid constipation

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Antidiarrheals

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should not be used in bloody diarrhea, high fever, or systemic toxicity
can be used in IBS or IBD

Opioid agonists:
inhibit ACh release in enteric plexuses causing decreased motility and increased transit time
1. Loperamide - OTC
doesn't cross BBB
traveler's diarrhea and chronic diarrheal dz
AE: caution to not develop toxic megacolon
2. Diphenoxylate hydrochloride and Difenoxin hydrochloride - piperidine derivatives
cross BBB
Atropine added to discourage abuse

A2 agonists:
1. Clonidine - diabetics w/chronic diarrhea from autonomic neuropathy
drug/etOH withdrawal pts

Bile salt binding resins:
1. Cholestyramine & Colestipol - stop diarrhea from bile malabsorption
AE: worsens diarrhea in bile salt depleted pts and decreases pathogen clearance

Bismuth subsalicylate:
antisecretory, anti-inflammatory, antimicrobial

Octreotide:
peptide analog of Somatostatin
used for metastatic carcinoid tumors or VIPomas

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Antiemetics

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5-HT3 antagonists:
block stimuli from intestinal vagal nerves
1. Ondansetron
2. Granisteron
3. Dolasetron
first line for chemo-induced n/v prophylaxis
very safe and effective

DA receptor antagonists:
block D2 in the CTZ
Agents:
Phenothiazines:
antipsychotics w/antiemetic and sedative properties/general purpose Rx's
1. Prochlorperazine
2. Promethazine - best for vestibular, drug-induced, post-op vomiting
Butyrophenones:
antipsychotics
1. Droperidol - postop n/v and anesthesia induction/maintenance/sedation
AE: extrapyramidal effects, hypotension, prolonged QT interval
2. Haloperidol
Substituted Benzamides:
1. Metoclopramide - agonist of 5HT4 receptors and prokinetic agent also, used in n/v post-chemo
AE: Parkinsonism, dystonias, tardive dyskinesias
2. Trimethobenzamide - less AE

Benzodiazepines:
antianxiety drugs - Lorazepam & Diazepam

Antihistamines and Anticholinergics:
motion sickness
1. Diphenhydramine
2. Dimenhydrinate
3. Cyclizine
4. Meclizine
5. Hyoscine - best for motion sickness
AE: normal Anti-Ch effects
antispasmodic agents for IBS are:
Dicyclomine and Hyoscyamine (cross BBB); Glycopyrrolate and Methscopolamine (don't cross BBB)

Cannabinoids:
Dronabinol & Nabilone

Corticosteroids:
Dexamethasone & Methylprednisolone

Pro-emetic:
Ipecac - induces vomiting in poisoning and oral drug OD

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Prokinetic agents

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stimulate motor fxn in gastroparesis and GERD (LES pressure increase)
Cholinomimetics:
ineffective b/c they start uncoordinated contractions
1. Bethanechol - cholinergic agonist
2. Neostigmine - anti-AChE used for Ogilvie's syndrome

Serotonin Receptor Modulators:
1. Metoclopramide - largely works on Upper GI; blocks 5HT3 and stimulates 5HT4
used for GERD, gastroparesis, hiccups
AE: Tardive dyskinesias

Motilin like agents:
macrolide ABx - Erythromycin, Azithromycin, Clarithromycin

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Drugs for IBD

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inflammatory response from T-cells and TNF-a w/proinflammatory interleukins

anti-inflammatories:
Aminosalicylates: 1st line
1. Sulfasalazine
2. Olsalazine
3. Mesalamine

Glucocorticoids:
1. Prednisone
2. Hydrocortisone
3. Methylprednisolone
AE: typical of steroids (Cushing's syndrome, insomnia, etc.)

ABx:
treat fulminant dz
Metro & Cipro

Immunosuppressants:
1. Azathioprine - blocks DNA/RNA synthesis

Biologics:
Anti-TNF:
increased risk of lymphoma, ATA which can attenuate the response
1. Infliximab - refractive Tx, chimeric mab
2. Adalimumab - Crohn's Tx, all human origin just recombinant
3. Certolizumab - Crohn's Tx, no Fx portion so no C' activation or cellular cytotoxicity

Anti-Integrin:
Natalizumab - IgG4 mab against a4 integrins subunit, high risk of leukoencephalopathy