Most Peptic Ulcer Disease Results from:

1)     infection with H. pylori

2)     use of aspirin, NSAIDS

3)     gastrin-secreting tumors

Antacids – Sodium Bicarbonate, Calcium Carbonate, Magnesium Hydroxide, Aluminum Hydroxide

Sodium Bicarbonate

• systemic
• do not use long term
• can change pH of blood and urine (alkalosis)
• Contraindications – HTN

Calcium Carbonate

• partially systemic
• do not use long term
• prolonged neutralizing capacity
• can lead to acid rebound by stimulating Gastrin release
• Contraindications – renal impairment

Magnesium Hydroxide

• Non-systemic
• Is a LAXATIVE and can cause diarrhea –know for test

Aluminum Hydroxide

• non-systemic
• CONSTIPATES —- know for test!!!
• Can cause phosphate depletion and resorption of bone

Drug Interactions of all antacids

1)     increased stomach pH

2)     can chelate tetracyclines or digoxin

3)     the systemic antacids can alter urinary pH

Ø  leads to increased excretion of acidic drugs (aspirin)

Ø  decreased excretion of basic drugs (quinidine)

4)     reduces the oral bioavailability of cimetidine or ranitidine if administered concomitantly

5)     impairs the binding of sucralfate to the ulcerated mucosa

Inhibitors of Acid Secretion

Antimuscarinics – Atropine, Propantheline Isopropamide, Pirenzepine

• block the cholinergic stimulation of motility and secretions throughout the entire GI tract.
• Intolerable to most patients because the dose required has anti-cholinergic effects
• Pirenzapine is a selective M₁ antagonist used in Europe which has fewer anticholinergic effects.

H₂ Antagonists – Cimetidine, Ranitidine, Famotidine

• block histamine stimulation of parietal cell and secretion of H⁺
• results in decreased acid secretion after all known stimuli
• heal 80-90% of peptic ulcers after one year of therapoy
• high relapse rates of recurrence of peptic ulcer after cessation of treatment

Cimetidine -Tagamet

• 1^st H₂ antagonist
• Side effects

1)     mild GI, headache, rash

2)     anti-androgen effects in high doses

3)     mental confusion, elevated serum creatinine, hematologic disturbances in certain people.

• inhibitor of cyt P450 mixed function oxidase system

Ø  causes increased plasma concentrations of many drugs metabolized by the same system

-        warfarin, BZDs, theophylline, phenytoi, lidocaine, Beta-blockers, phenobarbital, Ca channel blockers, carbamazepine

Ranitidine – Zantac

• most popular H₂ antagonist
• Side effects

1)     diarrhea, headache, rash

2)     far less inhibition of hepatic drug metabolism than cimetidine

• DOES NOT BIND TO THE ANDROGEN RECEPTOR

Famotidine – Pepcid

• more potent and has slightly longer duration than ranitidine
• Side effects

1)     infrequent diarrhea, headaches

2)     no drug interactions yet.

• DOES NOT INHIBIT HEPATIC DRUG METABOLISM
• DOES NOT BIND TO THE ANDROGEN RECEPTOR

What to use H₂ antagonists for

1)     healing gastric or duodenal ulcer

2)     prophylaxis against recurrent ulcers

3)     Zollinger-Ellison Syndrome

4)     GERD

Prostaglandins – Misoprostol- PGE₁ receptor agonist

Misoprostol

• derivative of PGE₁ that is resistant to the principal catabolizing enzyme
• acts on oxyntic cell to inhibit acid secretion by opposing histamine stimulation of adenylate cyclase
• stimulates the gastric mucosa to produce bicarb and mucus
• increases mucosal blood flow
• Side effects

1)     GI tract hypermotility and diarrhea – 15%

2)     Uterine contraction and maybe abortion

• Used for prevention of peptic ulcers in high risk patients taking NSAIDS
• Contraindications: Pregnancy

Proton Pump Inhibitors – Omeprazole, Lansoprazole

• inhibition of the H⁺, K⁺-ATPase pump located in the apical membrane of the parietal cell along the secretory canaliculi

Omeprazole (Lansoprazole is similar)

• Mechanism

Ø  trapped and activated in the oxyntic gland secretory canaliculi (weak base trapped in a highly acidic place)

Ø  At low pH, a molecular rearrangement causes activation of a sulfur group that form a stable bond at a critical site of the H⁺,K⁺- ATPase.

Ø  Irreversible

• Produces LONG LASTING effects (3-5 days); still given daily to block the newly formed ATPases.
• Used for: Peptic Ulcer, reflux esophagitis, GERD
• Side Effects

1)     very few

2)     hypergastrinemia with unknown consequences

3)     viable bacteria in stomach

Protective Agents – Sulcrafate

• prevents mucosal damage
• enhances healing of the lesions by reinforcement of adaptive defense mechanisms

Sulcrafate

• composed of a complex of sulfated sucrose and Aluminum Hydroxide
• Mechanism

Ø  at low pH, it undergoes polymerization and crosslinking

Ø  binds to exposed protein in the base of the ulcer crater

Ø  creates a relatively persistent barrier

Ø  H. pylori suppressive

• Side Effects

Ø  NONE systemically; because not absorbed

Ø  2% constipation probably due to the AL(OH)₃

Agents to treat H. pylori infection – Bismuth Subsalicylate, bismuthate, Antibiotics

• H. pylori is a spiral-shaped, Gram (-), urease-priducing bacterium
• Inhabits the area between the mucus and the underlying epithelium
• Bismuth salt and one or two antibiotic for weveral weeks = successful treatment
• Tetracyclin, amoxicillin, metronidazole, clarithromycin, clindamycin
• Use oneprazole or lansoprazole also – efficacy is fine

Prokinetic Agents – Neostigmine, Metoclopramide, Cisapride, Erythromycin

• The Ach release by the enteric nervous system binds to M₂ and M₃ receptors on the GI tract smooth muscle and timulates GI contractions and propulsions.
• REMEMBER THAT THE M₃ receptors are most important
• Different ways to activate the smooth muscle contraction

1)     inhibit acetylcholinesterase – neostigmine

2)     block D₂ receptors responsible for inhibition of acetylcholine release – Metoclopramide

3)     activate the excitatory 5HT₄ receptors on the cholinergic neuron – Cisapride

4)     Motilin

Neostigmine – AchE inhibitor

• activates the smooth muscle M₃ receptors to increase the frequency and amplitude of the contractions
• stomach empties faster
• SIDE EFFECTS: cholinergic crisis – SLUDS
• Rarely used as a prokinetic drug

Metoclopramide (Reglan) – D₂ antagonist

• blocks the inhibitory Dopamine receptor on the cholinergic neuron
• Actions

1)     increased LES tone

2)     increases esophageal clearance

3)     stimulates gastric emptying

4)     decreased small bowel transit time by stimulating peristalsis

• Used for

1)     GERD

2)     Gastric Stasis

3)     Diabetic gastroparesis

4)     To do X-Ray of GI track

• Side Effects

1)     Somnolence

2)     Nervousness

3)     EPS

4)     Increased Serum Prolactin

Cisapride – 5HT₄ agonist

• important to REMEMBER the 4
• Actions

1)     stimulates the motility of the upper GI tract

2)     improves the antroduodenal coordination to promote gastric emptying

3)     increases LES tone

4)     enhances esophageal acid clearance

• Uses

1)     reflux esophagitis

2)     diabetic gastroparesis

3)     intestinal pseudo-obstruction

• Side Effects

1)     increased # of bowel movements

2)     rare: fetal cardiac arrhythmias

• CONTRAINDICATIONS

Ø  DO NOT GIVE W/ MACROLIDE ANTIBIOTICS

Erythromycin – in this case… Motilin receptor agonist

• enhances GI contractions, induces migrating motor complexes, increases the rate of gastric emptying
• uses

1)     diabetic gastroparesis

• MAJOR SIDE EFFECT – abdominal Cramps

Gallstone Dissolution – Chenodeoxycholic Acid, Ursodiol

Chenodeoxycholic acid

• Mechanism

Ø  a natural bile acid, given orally

Ø  decreases the secretion of cholesterol in bile

Ø  increases the secretion of bile acids

• Use

Ø  requires long term therapy (3mths to 2 years)

Ø  requires functioning gallbladder

• Side effects

1)     diarrhea (41%)

2)     liver dysfunction

3)     INCREASES LDL cholesterol by about 10%

Ursodiol

• Mechanism

Ø  modified bile acid (bears), given orally

Ø  decreases the secretion of cholesterol in bile

Ø  inhibits the absorption of cholesterol

• Also takes 3 mths to 2 years
• Side effects

1)     Seldom causes diarrhea or liver dysfunction

2)     NO CHANGE IN SERUM LIPIDS

• Contraindications

Ø  chronic liver disease or allergy to bile acids

Methyl tert-butyl ether (MTBE)

• infused directly into the gallbladdre or bile duct lumen
• ether acts as a solvent for the lipid in the stone

Monoctanoin

• semi-synthetic vegetable oil
• infused into the common bile duct for 7 to 21 days

Laxatives – Psyllium, Bran, Bisacodyl, Docusate, Lactulose, Mineral Oil

Bulk Forming Laxatives – Psyllium (Metamucil), Methyl and Carboxy-methylcellulose, Bran

• Mechanism

Ø  poorly digested polysaccharides not absorbed

Ø  Hydrophilic – absorb H₂O and swell in mass and distend the intestine

Ø  Increased bulk stimulates peristalsis

• Onset: take 2-4 days for effect
• Requires adequate hydration
• TREATMENT OF CHOICE FOR CHRONIC CONSTIPATION

Saline, osmotic laxatives – Magnesium Salts, Sodium phosphates, mineral waters

• Mechanism

Ø  poorly absorbed inorganic salts

Ø  retain H₂O in the lumen oy the osmotic gradient

Ø  distension of the lumen leads to peristalsis

• QUICK ONSET: oral – 2-6 hrs, rectal – 5-15 minutes
• Used in hospital for this reason
• Used for:

1)     before diagnostic procedures or surgery

2)     to eliminate parasites after administration of an antihelminthic

3)     infrequently for acute constipation

• Cautions

Ø  toxic accumulation of magnesium can occur in renal dysfunction

Ø  phosphate salts may provide excessive Na to certain patients that don’t need it (ex. CHF)

Secretory Laxatives – Bisacodyl, Sennosides, Castor Oil

• Mechanism

Ø  stimulate the formation of NO in the mucosa and thus stimulate the secretion of fluid into the lumen

• requires 6-12 hrs – orally
• Bisacodyl is 2^nd line laxative
• Castor Oil is hydrolyzed in the upper GI tract to ricinoleic acid, the active compound

Wetting Agents, Emollients – Docusate (Colace, TIDE)

• Mechanism

Ø  surfactant lowers the surface tension of the stool which facilitates the mixing of H₂O and fatty substances into the fecal mass to increase and soften the fecal mass

Ø  may act also as a stimulant of secretion

• used to PREVENT constipation

Hyperosmotic Agents – Lactulose

• Mechanism

Ø  osmotic properties retain H₂O in the lumen and distension

• Especially useful in the elderly or in severe drug induced constipation
• Lactulose – oral
• Glycerin – rectally

Mineral Oil

• coats the fecal contents thereby decreasing the colonic absorption of H₂O
• Can cause lipoid pneumonia if aspirated
• If used chronically, decreases the absorption of the fat soluble vitamins (ADEK)

Specific Anti-Diarrheal Drug:

Octreotide – somatostatin analogue

• relieves severe secretory diarrhea in a variety of disorders because it inhibits the release of several gastroenteropancreatic peptide hormones.

1)     gastrin

2)     gastric inhibitory peptide

3)     motilin

4)     neurotensin

5)     secretin

6)     vasoactive intestinal peptide

7)     insulin

8)     glucagon

9)     pancreatic polypeptides

• also decreases splanchnic blood flow, reduces intestinal motility, and increased H₂O and electrolyte absorption from the gut.
• Effective in VIPomas and effectivein treatment of AIDS diarrhea
• Cannot be given orally because it is a polypeptide; given chronically by SubQ injection or in emergency, IV bolus

Nonspecific Diarrhea

Opioids – Diphenoxylate, Loperamide

• most effective and prompt-acting nonspecific antidiarrheal agents
• Mechanism

1)     inhibition of intestinal propulsion

-        induces segmenting contractions that retard propulsion

-        increases mixing contractions

2)     inhibition of secretion into the lumen

3)     stimulation of H₂O and electrolyte absorption

• REMEMBER that Meperidine (Demerol) is only one not used for diarrhea

Diphenoxylate – (lomotil)

• cross BBB poorly, so little abuse liability; also combined with atropine to further offset abuse risks
• produces constipation

Loperamide – (Imodium)

• no abuse liability, does not cross BBB
• also produces constipation

Anticholinergics – Atropine

• block the response of intestinal smooth muscle to cholinergic activity
• reduce intestinal secretion
• atropine, scopolamine, methantheline, propantheline
• Primary effect is to REDUCE CRAMPING, not to reduce diarrhea
• Usual anti-muscarinic side-effects

Gel forming  Substances – hydrated aluminum silicate clays

• Kaopectate
• Mechanism

Ø  absorbents and protectants, Promotes formed stool

Ø  essentially useless

Bismuth Subsalicylate, bismuthate (Pepto-Bismol)

• binds to bacterial toxins
• the subsalicylate prevents the production of PGs responsible for intestinal inflammation and secretion
• some anti-bacterial activity
• useful for prevention and treatment of traveler’s diarrhea
• Contraindications

Ø  do not administer with other salicylate containing compound to prevent salicylate toxicity

• REMEMBER, turns the tongue and stool black.

Corticosteroids – Dexamethasone

• Mechanism

Ø  stimulates active Na absorption by increasing the amount of Na⁺-K⁺ ATPase in jejunum, ileum, and colon

• takes 16-36 hrs
• used to treat

1)     chronic refractory diarrhea

2)     chronic inflammatory diarrhea

a₂-agonists – Clonidine

• decrease secretion and inhibit diarrhea; Major side effect is hypotension

Oral Rehydration Solutions

• increase absorption via the dextrose-NA cotransport system of the apical membrane of the intestinal epithelial cell
• Home remedy if oral electrolyte solution is not available

1 teaspoon of table salt

10 teaspoons of sugar

1 quart of H₂O

Inflammatory Bowel Disease – Sulfasalazine, Mesalamine, Olsalazine, Corticosteroids

Sulfasalazine

• metabolized in the gut by bacteria to sulfapyridine and 5-ASA
• 5-ASA

Ø  active agent

Ø  inhibits COX – decreased PGs

Ø  lipooxygenase inhibitor – decreased leukotrienes

Ø  free radical scavenger – decreases cytotoxicity

Ø  blocks formation of bacterial paptides – decreases neutrophil chemotaxis

• Sulfapyridine

Ø  completely absorbed and high blood levels thought to account for most of the side effects of sulfasalazine

• Side effects

1)     N&V

2)     headache

3)     abdominal discomfort

4)     malaise

5)     arthralgia

6)     anorexia

7)     FOLATE DEFICIENCY is common

• Used for: acute exacerbations of mild to moderate ulcerative colitis

Mesalamine (5-ASA)

• just composed of the 5-ASA
• given as a retention enema to treat ulcerative colitis

Ø  can’t give it orally because of rapid proximal absorption

Olsalazine

• covalent dimer of mesalamine – 2X-[5-ASA]
• slow release polymer; covalent bond split by bacteria in the gut
• orally active
• few side effects

Corticosteroids

• oral or parenteral – hydrocortisone, prednisone, prednisolone, and methyl prednisolone most commonly used.
• Used for both Chrohn’s disease and ulcerative colitis
• Enema prep useful in distal ulcerative colitis or proctitis (50% is absorbed so be careful for systemic side effects)
• Decrease transcription of inflammatory mediators

Tags: Aluminum Hydroxide, Antibiotics, Bismuth Subsalicylate, bismuthate, Calcium Carbonate, Cimetidine, Cisapride, Drug Interactions of antacids, erythromycin, Famotidine, Magnesium Hydroxide, Metoclopramide, Misoprostol, Neostigmine, Omeprazole, Peptic Ulcer Disease, prostaglandins, Proton Pump Inhibitors, Ranitidine, secreting tumors, Sodium Bicarbonate, Sulcrafate

This entry was posted on Wednesday, August 5th, 2009 at 5:00 am and is filed under Pharmacology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.