PHARMACOLOGY: DRUGS ACTING ON GIT

DIGESTIVE ENZYMES
SALIVA SUBSTITUTE PANCREATIN PANCRELIPASE
Used in conditions that result in Used to aid in digestion and absorption of fats, proteins and An enriched preparation of lipase and proteolytic enzymes
dry mouth carbohydrates Has 12 times the lipolytic activity and 4 times the proteolytic activity of pancreatin
Not absorbed systemically Contains low concentrations of lipase and proteolytic Rapidly and permanently inactivated by gastric acid should be given with PPI
enzymes Of value in:
Not recommended for children Pancreatic insufficiency due to cystic fibrosis
Pancreatitis
Pancreatectomy
Taken with every meal
May increase incidence of gout

DRUGS USED IN PEPTIC ULCER DISEASE

A. ANTACIDS
Mechanism Include
They are weak bases that react with gastric acid to form a salt and water Magnesium hydroxide
They reduce gastric acidity Aluminum hydroxide
They provide mucosal protection by stimulating PG production, or by binding of Unabsorbed magnesium salts may cause osmotic diarrhea
injurious substance Aluminum salts may cause constipation
However, may stimulate production of PGE2 stimulate gastric secretion To minimize impacts on bowel function, MgOH & AlOh are commonly administered together
Gelusil
Maalox
Mylanta
Patient with renal insufficiency should not take these agents on long term basis

B. GASTRIC ANTISECRETORY DRUGS

H2 RECEPTOR ANTAGONISTS
Members Cimetidine Famotidine
Ranitidine Nizatidine
PK All are rapidly absorbed from
intestine
Cimetidine, ranitidine & famotidine
undergo hepatic first pass, &
bioavailability is only 50%
Nizatidine has almost 100%
bioavailability
PD Exhibit competitive inhibition at the
parietal cell H2 receptor and
suppress basal and meal stimulated
acid secretion
Highly selective and do not affect H1
or H3 receptors
Reduce volume of gastric secretion
and pepsin
ANTI-MUSCARINIC AGENTS
Pirenzepine
Telenzepine
Act by selective blockade
of presynaptic excitatory
muscarinic receptors on
vagal nerve endings
Gastric acid secretion is
reduced with fewer
adverse effects than
atropine (blockade is
selective)
SOMATOSTATIN ANALOG PROTON PUMP INHIBITORS
Octreotide Omeprazole Lansoprazole
Rabeprazole Pantoprazole
Esomeprazole
Bioavailability is 50% by food
Undergo rapid hepatic first pass
Negligible renal clearance
Should be given 1 hr before meals
IV preparations have short half-lives and should
be given as a continuous infusion or as repeated
bolus injections
Inhibits gastrin production Inhibit acid secretion by inhibition of hydrogen ion
Inhibits antral motility & colon tone secretion
Accelerates gastric emptying Inhibit both fasting and meal-stimulated acid
Induces phase III migrating motor complex secretion
activity (sweep away contents) in the small bowel
Reduces portal blood flow and variceal pressures
Used to treat variceal hemorrhage
It may reduce endocrine & exocrine pancreatic
activity
Uses GERD GERD
PUD PUD
Non-ulcer dyspepsia (NUD) NUD
Prevention of bleeding from stress- Prevention of stress-related mucosal bleeding
related gastritis Gastrinoma & other hypersecretory conditions
AE CNS General
Mental status changes Extremely safe
(hallucinations, confusion, 1-5% - diarrhea, headache, abdominal pain
agitation) w/ IV administration Nutrition
Endocrine effects (Cimetidine) May potentially lead to subnormal Vitamin
Inhibits binding of DHT to B12 levels
androgen receptors Respiratory and Enteric Infections
Inhibits metabolism of estradiol Increased gastric bacterial concentration
Increases serum prolactin Small increased risk of enteric infections
Can lead to impotence & (Clostridium difficile)
gynecomastia Potential Problems d/t Increased Serum Gastrin
Pregnancy & Nursing mothers May stimulate hyperplasia of ECL cells
They pass the placenta gastric carcinoid tumors
They are secreted in breast milk May potentially promote carcinogenesis
Other effects
Blood dyscrasias
Bradycardia and hypotension

C. MUCOSAL PROTECTIVE AGENTS

SUCRALFATE COLLOIDAL BISMUTH COMPOUNDS CARBENOXOLONE MISOPROSTOL
MOA Selective binding to necrotic tissue Same mechanism as sucralfate A steroid congener Inhibits gastric secretion
Acts as a barrier to acid, pepsin and bile Effects: Increases production, secretion and
Stimulates endogenous prostaglandin Inhibits pepsin activity viscosity of intestinal mucus
synthesis Stimulates mucus production
PK Activated by acid May have antimicrobial activity Taken on an empty stomach 1 hr before meals
Should be taken on empty stomach 1 hr against H. pylori
before meals Used usually with an H2 blocker
AE Most common is constipation Limited use because of its Most frequent side effect is diarrhea
mineralocorticoid (aldosterone) effect
CI During pregnancy (abortifacient):
D/t production of uterine contractions
TREATMENT OF PEPTIC ULCER DISEASE (PUD)
Goals of therapy: (1-2 weeks)
Empiric therapy for H. pylori Acid-reducing medication FDA has approved a new 10-day regimen for triple therapy w/ combination of:
Eradication of H. pylori
Bismuth 2 tab qid Omeprazole 20 mg bid Omeprazole 20 mg bid
Discontinuation of NSAID
Metronidazole 250 mg qid Clarithromycin 250 mg bid
intake
Tetracycline 500 mg qid Amoxicillin 1 g bid
Use of PPI
 In patients with active duodenal ulcers, Omeprazole is continued at a dose of 20 mg daily ulcers to exclude the possibility of a malignant ulcer
for an added 18 days
After successful H. pylori eradication, continued maintenance therapy with anti-ulcer GASTROESOPHAGEAL REFLUX DISEASE (GERD)
medication is unnecessary Basis:
Maintenance anti-ulcer therapy will only be approved after consultation and approval by a Burning sub-sternal pain
gastroenterologist and would involve Cimetidine 400 mg at HS as DOC (to reduce basal Worst at night
acid secretion) After a heavy meal
Evaluate after 6 months Evidence-Based Diagnosis
Levofloxacin-based sequential or triple therapy may be superior to standard triple therapy Should be included in the diagnosis of chest pain when heartburn, regurgitation or
(Clarithromycin, Amoxicillin and PPI) dysphagia is present
Newer regimens under study include: Factors that exacerbate include ingestion of large (especially fatty meal), lying down
LOAD (Levofloxacin, Omeprazole, NitAzoxamide, & Doxycycline) for 7-10 days after a meal, using tobacco and eating any of the following foods which relax the
Ofloxacin, Azithromycin, Omeprazole, and Bismuth for 14 days lower esophageal sphincter (chocolate, alcohol, coffee, peppermint)
Patients previously exposed to Macrolide antibiotic should be treated with a regimen that Treatment
does not include Clarithromycin Non- Elevate the entire HOB; adding extra pillows may actually worsen reflux
This macrolide may be replaced by Furazolidone pharmacologic Avoid lying down for 3 hrs after meals
NSAIDs especially Aspirin should be avoided when possible Stop smoking
If not possible, maintenance PPI therapy or a mucosal protective agent are Stop ingesting foods that relax the LES
recommended Pharmacologic Antacids
NON- Smoking cessation H2 blockers
PHARMACOLOGIC Alcohol in high concentration can damage the gastric mucosal PPI (first line therapy)
barrier, but no evidence exists to link alcohol with ulcer recurrence Motility agents in patients who need adjuvant therapy
MONITORING EGD or upper GI series should be performed 8-12 weeks after initial Surgery
diagnosis of all gastric ulcers to document healing
Repeat endoscopic biopsy should be considered for non-healing

DRUGS PROMOTING INTESTINAL MOTILITY

CHOLINOMIMETIC DRUGS DOPAMINE D2 RECEPTOR ANTAGONISTS MACROLIDES CHLORIDE CHANNEL ACTIVATOR
Members Bethanechol Metoclopramide Domperidone Lubiprostone
MOA Stimulates muscarinic M3 receptors on Increase esophageal peristaltic amplitude Directly stimulate motilin receptors on Stimulates chloride channel opening in
muscle cells & at myenteric plexus Increase LES pressure GIT smooth muscle the intestine increases liquid
synapses Enhance gastric emptying Promote the onset of a migrating secretion into the intestine & shortens
Seldom used at present Block D2 receptors at Chemoreceptor Trigger Zone (CTZ) motor complex (MMC) intestinal transit time
Delays gastric emptying
Uses GERD May be used in pxs w/ acute upper GIT Used in chronic constipation
Impaired gastric emptying hemorrhage to promote gastric
NUD emptying of blood before endoscopy
Prevention of vomiting
Post-partum lactation stimulation
AE CNS (more of Metoclopramide)
In 10-20% of patients In 25% of pxs (w/ high
Restlessness doses)
Drowsiness Extrapyramidal
Insomnia effects
Anxiety
Agitation
 ANTI-EMETIC AGENTS
SEROTONIN 5-HT3 ANTAGONISTS CORTICOSTEROID NEUROKININ PHENOTHIAZINES BUTYROPHENONES SUBSTITUTED
RECEPTOR BENZAMIDES
ANTAGONIST
Members Ondansetron Granisetron Dexamethasone Aprepitant Prochlorperazine Droperidol Metoclopramide
Dolasetron Palonsetron Methylprednisolone Promethazine Trimethobenzamide
Thiethylperazine
PD Central 5-HT3 receptor blockade in Appear to enhance the Anti-emetic effect Extremely sedating Anti-emetic action is due
vomiting center & CTZ efficacy of 5-HT3 receptor mediated through to dopamine receptor
Blockade of 5-HT3 receptors on antagonists for inhibition of dopamine & blockade
extrinsic intestinal vagal & spinal prevention of acute & muscarinic receptors
afferents delayed N & V
Of value ONLY in emesis due to vagal
stimulation
PK Ondansetron, granisetron & Anti-emetic property
dolasetron have serum HL: 4-9 hrs is d/t blockade at area
Given OD orally or IV postrema
All 3 have comparable efficacy & Oral bioavailability is
tolerability 65%
Palonsetron has greater affinity for 5- Serum HL: 12 hours
HT3 receptor & longer serum HL Used in combination
All 4 undergo extensive hepatic with 5-HT3 receptor
metabolism antagonists &
Elimination is both renal & hepatic corticosteroids
Uses Chemotherapy-induced N & V
Post-operative & post-radiation N & V
AE Generally well-tolerated Fatigue May produce Extrapyramidal effects
Headache, dizziness & constipation Dizziness extrapyramidal effects &
Cause small but significant Diarrhea hypotension
prolongation of QT interval (esp. May inhibit
Dolasetron, EXCEPT Palonsetron) metabolism of other
drugs metabolized by
CYP3A4

H1 ANTIHISTAMINES ANTICHOLINERGICS BENZODIAZEPINES CANNABINOIDS

Members Diphenhydramine Hyoscine Lorazepam Dronabinol
Dimenhydrinate Diazepam Nabilone
Meclizine
PD Weak anti-emetic activity A muscarinic receptor antagonist Used prior to initiation of chemotherapy Psychoactive agents used as anti-emetic
Significant anticholinergic properties Better tolerated as a transdermal to: Dronabinol is uncommonly used because of
patch Reduce anticipatory vomiting availability of better agents
Reduce vomiting caused by anxiety Nabilone is approved for use in USA
Uses Useful for prevention or treatment of One of the best agents for prevention
motion sickness of motion sickness
COMBINATION REGIMENS: Purposes:
To increase anti-emetic activity Corticosteroids and Metoclopramide
To decrease toxicity Anti-histamine and Metoclopramide

LAXATIVES
Laxatives Evacuation of formed fecal material from the rectum
Cathartic Evacuation of unformed, watery fecal material from the entire colon

GENERAL MECHANISM OF ACTION

Retention of intraluminal fluid by hydrophilic or osmotic mechanism
net absorption of fluid by effects on small & large bowel fluid & electrolyte transport
Effects on motility by inhibiting segmenting contractions (mixing movement) or stimulating propulsive contractions (evacuation)

BULK-FORMING LAXATIVES OSMOTIC LAXATIVES STIMULANT LAXATIVES STOOL SOFTENERS

(Stool Surfactants)
Members Psyllium Magnesium oxide Anthroquinone derivatives Docusate sodium /
Methylcellulose Magnesium citrate Aloe Docusate calcium
Polycarbophil Sodium phosphate Senna Glycerin
Bran (fiber) Sorbitol Cascara suppository
Lactulose Phenolphthalein Mineral oil
Polyethylene glycol Castor oil
Bisacodyl (Dulcolax)
PD Indigestible, hydrophilic Soluble but non-absorbable Direct stimulation of enteric Soften stool
colloids that absorb water, compounds that increase stool NS material permitting
forming a bulky emollient gel liquidity due to an obligate Colonic electrolyte and fluid water and lipids to
that distends the colon and increase in fecal fluid secretion penetrate
promotes peristalsis

CHLORIDE CHANNEL ACTIVATOR

Includes Lubiprostone
Dynamics Activates chloride channels to increase fluid secretion in the intestinal lumen causing ease of passage of stools with little
change in electrolyte balance

ANTI-DIARRHEAL AGENTS
OPIOID AGONISTS COLLOIDAL BISMUTH ADSORBENTS BILE SALT-BINDING
COMPOUNDS RESINS
Members Loperamide Bismuth subsalicylate Kaolin Cholestyramine
Diphenoxylate Pectin Colestipol
PD Inhibit presynaptic cholinergic nerves Reduces stool frequency Kaolin is a naturally Decrease diarrhea
Increase colonic transit time & fecal and liquidity in acute occurring hydrated caused by excess
water absorption infectious diarrhea d/t magnesium aluminum fecal bile acids
Decrease mass movements of colon salicylate inhibition of silicate (Attapulgite)
Decrease gastrocolic reflex (after meals) intestinal prostaglandin Pectin is an indigestible
& chloride secretion carbohydrate derived from
AE Diphenoxylate Loperamide
Causes blackening of apples Bloating
(Lomotil) (Imodium)
stools or tongue Both decrease stool liquidity Flatulence
Anorexia Transient ileus Used for short periods & number by adsorbent Constipation
N&V Toxic megacolon only action on bacteria, toxins & Fecal impaction
Gum swelling Necrotizing fluid Malabsorption
Abdominal enterocolitis
May be useful in acute
distension Drowsiness
diarrhea but seldom used
Paralytic ileus N&V
on a chronic basis
Toxic megacolon Dizziness
May aggravate electrolyte
Headache Depression
disorders in children w/
Drowsiness Blurred vision
diarrhea because of
Confusion Abdominal pain
exaggerated loss of Na & K
Dizziness
Increased losses of fat &
nitrogen in stools
 DRUGS USED IN IRRITABLE BOWEL SYNDROME
ANTI-SPASMODICS SEROTONIN 5-HT3 RECEPTOR ANTAGONIST SEROTONIN 5-HT4 RECEPTOR
AGONIST
Members Dicyclomine Alosetron Tegaserod
Hyoscyamine
PD Inhibit muscarinic cholinergic Highly potent and selective antagonist Potent agonist at serotonin
receptors in the enteric plexus & on Rapidly absorbed from the GIT receptors
smooth muscle Bioavailability of 50-60% Protokinetic effects on the colon
Plasma half-life: 1.5 hrs Reduces pain and bloating in IBS
Undergoes hepatic metabolism Increases the number of bowel
Excretion is renal movements and reduces the
Used for tx of women w/ severe IBS in whom hardness of stools
diarrhea is predominant symptom Used in women with IBS w/
constipation
AE Dry mouth Assoc. w/ rare but serious GIT toxicity
Urinary retention Constipation
Ischemic colitis

DRUGS IN INFLAMMATORY BOWEL DISEASE

Diseases include:
Ulcerative colitis (UC)
Crohns disease (CD)
Both can present with:
Diarrhea
Weight loss
Abdominal pain

MILD TO MODERATE DISEASE MODERATE TO SEVERE DISEASE SEVERE TO FULMINANT DISEASE

5-aminosalicylates Glucocorticoids Supportive therapy
Decrease production of leukotrienes Prednisone NPO with NG suction
Include: Immunosuppressive agents Vigorous treatment of dehydration and
Sulfasalazine 6-mercaptopurine electrolyte disturbances
Mesalamine Methotrexate Evaluate for intra-abdominal abscess
Few side effects but more expensive Anti-TNF alpha monoclonal antibody Intensive therapy with IV corticosteroids
Antibiotic Infliximab Nutritional support
Metronidazole Adalimumab
Ciprofloxacin Certolizumab
Budesonide

RISK MODIFICATION
Low roughage/fiber diet
Vitamin B12 supplement
Oral replacement of:
Ca
Mg
Folate
Fe
Vitamins A & D
Avoid highly indigestible foods such as:
Nuts
Pits
Skins
Seeds
Pulps