Gastric Acid Secretion from Parietal Cells in Fundus of Stomach

stimulated by Acetylcholine Ach (parasympathetic nervous system, muscarinc receptors, increase Ca2+)

and Gastrin (from gastric antrum G cells, Gastrin/CCK receptors, increase Ca2+)

and histamine (from enterochromaffin-like ECL cells stimulated by Ach/gastrin, H2 receptors, increase cAMP)

inhibited by prostaglandins (degrease cAMP)

Somatostatin

released from gastric antrum D cells in response to high HCl levels-->decreases gastrin secretion at G cells-->feedback inhibition of gastric acid secretion

decreases secretion of fluid into GI tract

decreases GI motility

also called growth hormone inhibitory peptide and involved in hypothalamic-pituitary axis

Enterochromaffin-like Cells

receptors for acetylcholine Ach and Gastrin

synthesize and secrete histamine to stimulate parietal cells to make HCl

found in gastric fundus near blood vessels

Gastric Mucosal Defense Mechanisms

(against HCl and pepsin)

1. pre-epithelial defenses: secreted mucus and bicarbonate-->pH 7 at cell surface vs. pH 2 in lumen

2. cellular defenses: mucosal cells migrate and proliferate to fill a gap created by cell damage

3. submucosal defenses: submucosal microcirculatory system supplies nutrients and immune defenses

Prostaglandins stimulate all of these defenses

Lower esophageal sphincter tone normally protects esophagus from gastric contents, defective in GERD

Prostaglandin Effects in Stomach

Inhibit HCl production

Stimulate bicarbonate and mucus secretion

dilate submucosal blood vessels

stimulate mucosal cell proliferation and migration following damage to gastric mucosa

Antacids

Aluminum Hydroxide +/- Magnesium Hydroxide,

Calcium Carbonate, Sodium Bicarbonate

react with HCl to increase gastric pH

original peptic ulcer tx before H. pylori or proton pump inhibitors PPIs

OTC drugs for intermittent heartburn and dyspepsia

Aluminum Hydroxide

Aluminum Hydroxide + Magnesium Hydroxide combo.

OTC antacids

react with HCl to increase gastric pH

used for intermittent heartburn & dyspepsia

Adverse:magnesium OH can cause diarrhea while aluminum OH can cause constipation--this is why they are combined

both metal ions can accumulate-->toxicity in patients with renal failure

may decrease absorption of other drugs (chelatin, pH changes, etc.)

Calcium Carbonate

OTC antacid

reacts with HCl to increase gastric pH

used for occasional heartburn & dyspepsia

Adverse: at high doses and with dairy product consumption may cause milk-alkali syndrome --> hypercalcemia, metabolic alkalosis, and renal insufficiency

Drug Classes Used to Treat Acid-Peptic Diseases

Antacids

H2 receptor blockers

Proton pump inhibitors PPIs

Sucralfate

Prostaglandin analogs

Bismuth compounds

Antimicrobials (if H. Pylori related disease)

H2 receptor blockers

Cimetidine

Ranitidine

competative inhibitors of H2 receptors on parietal cells-->reduction in HCl secretion (fasting>stimulated)

used in GERD, peptic ulcer disease, and to prevent upper GI bleeds in severely ill patients

oral & parenteral

metabolism + renal filtration and secretion

Cimetidine

H2 receptor inhibitor-->reduction in HCl secretion (fasting>stimulated)

used in GERD, peptic ulcer disease, and to prevent upper GI bleeds in severely ill patients

oral & parenteral

metabolism + renal filtration and secretion

Adverse: anti-androgen effects may cause gynecomastia in males and galactorrhea in females, diarrhea or constipation in some, altered mental status in severely ill patients, decreases absorption of other drugs & interferes with their metabolism via various CYP450s

Ranitidine

competative inhibitor of H2 receptors on parietal cells-->reduction in HCl secretion (fasting>stimulated)

used in GERD, peptic ulcer disease, and to prevent upper GI bleeds in severely ill patients

oral & parenteral

metabolism + renal filtration and secretion

Adverse: diarrhea/constipation in some, altered mental status in severely ill patients, decreases absorption of other drugs

Proton Pump Inhibitors

Omeprazole, Esomeprazole, Lansoprazole

relatively new "blockbuster drugs" widely used for GERD and peptic ulcer disease (especially H. pylori associated)

also good for Zollinger-Ellison syndrome

pro-drugs, weak bases concentrated in parietial cell canaliculi by ion-trapping and converted to active metabolites which covalently bind and inhibit H+/K+ pump, decreasing HCl secretion (fasting and stimulated, very effective)

Adverse: increased gastrin production by G cells (carcinoid tumors in rats), drug interactions (due to pH changes and CYP450 metabolism)

Peptic Ulcer Disease

mainly caused by  H. Pylori infection and/or chronic NSAID use

also associated with stress and gastric acid over-production states

H. pylori related disease is commonly treated by triple or quadruple drug therapy involving at least 1 antimicrobial and usually a PPI

Drugs that increase gastric mucosal defenses

Sucralfate (sucrose + aluminum hydroxide)

Misprostil (prostaglandin analog)

Bismuth compounds (peptobismol)

Omeprazole

aka Prilosec, racemic mix

relatively new "blockbuster drug" widely used for GERD and peptic ulcer disease (especially H. pylori associated)

also good for Zollinger-Ellison syndrome

pro-drug, weak base concentrated in parietial cell canaliculi by ion-trapping and converted to active metabolite which covalently binds and inhibits H+/K+ pump, decreasing HCl secretion (fasting and stimulated, very effective)

Adverse: increased gastrin production by G cells (carcinoid tumors in rats), drug interactions (due to pH changes and CYP450 metabolism)

Esomeprazole

aka Nexium, S isomer only

widely used for GERD and peptic ulcer disease (especially H. pylori associated)

also good for Zollinger-Ellison syndrome

pro-drug, weak base concentrated in parietial cell canaliculi by ion-trapping and converted to active metabolite which covalently binds and inhibits H+/K+ pump, decreasing HCl secretion (fasting and stimulated, very effective)

Adverse: increased gastrin production by G cells (carcinoid tumors in rats), drug interactions (due to pH changes)

Lansoprazole

widely used for GERD and peptic ulcer disease (especially H. pylori associated)

also good for Zollinger-Ellison syndrome

pro-drug, weak base concentrated in parietial cell canaliculi by ion-trapping and converted to active metabolite which covalently binds and inhibits H+/K+ pump, decreasing HCl secretion (fasting and stimulated, very effective)

Adverse: increased gastrin production by G cells (carcinoid tumors in rats), drug interactions (due to pH changes)

Sucralfate

oral drug that binds gastric mucosal cells as a thick paste, protective to mucosa in peptic ulcer disease

may form physical barrier

limited use now, mostly to prevent stress ulcers in seriously ill patients

sucrose salt complexed to sulfated aluminum hydroxide

Adverse: constipation in 2% of patients, some aluminum absorbed and may cause problems in patients w/renal insufficiency, may decrease absorption of other drugs

Misoprostil

prostaglandin analog

decreases HCl production, increases mucus and bicarbonate secretion in stomach

increases submucosal bloodflow

protective to gastric mucosa

used to decrease risk of NSAID-induced peptic ulcers in high-risk patients

Adverse: diarrhea, abdominal cramps in a large % of patients, contraindicated in pregnancy b/c it also causes uterine contractions

Bismuth Compounds

i.e. bisumth subsalixylate (peptobismol) and bismuth subcitrate potassium

mechanism unknown

OTC for dyspepsia, diarrhea (especially traveler's diarrhea)

included in some anti-H. Pylori regimens

Adverse: darkening of tongue and stool (may frighten patients)

Pancrelipase

Porcine pacreatic extract containing amylases, lipases, proteases, and purines

pancreatic enzyme supplement for patients with exocrine pancreatic insufficiency (from cystic fibrosis, chronic pancreatitis, pancreatectomy, etc.)

oral drug, coated for release in intestines

Adverse: fibrosing colonopathy which may require surgery, increased uric acid (from purines), allergic rxns.

Ursodiol

Ursodeoxycholic acid

a naturally occuring bile acid (usually a small %)

dissolves small cholesterol gallstones by unknown mechanism

Not for Surgical Patients

Drugs to prevent Variceal Bleeding in advanced liver disease

Octreotide (somatostatin analog)

nonselective Beta blockers (i.e. propanolol)

both decrease variceal pressure, helping prevent rupture

Drugs that increase GI motility

good for diabetic gastropareisis

Metoclopramide (dopamine antagonist)

Erythromycin (macrolide antibiotic)

Metoclopramide

dopamine antagonist

usually D2 dopamine receptors in GI tract inhibit motility, so inhibiting them--> increased GI motility

increases lower esophageal sphincter tone

increases gastric emptying

oral or IV

used to treat diabetic gastropareisis and as an anti-emetic w/cancer chemotherapy

Adverse: extrapyramidal effects (Parinsoninan-like motor problems), tardive dyskinesia (repetiative involuntary movements of face and extremities), restlessness, drowsiness, insomnia, anxiety, agitation

Erythromycin

a macrolide antiobiotic (50S ribosomal subunit binding protein synthesis inhibitor)  which happens to stimulate motilin receptors in the GI tract

increases upper GI contractions

used in diabetic gastropareisis

Types of Laxatives

Bulk forming

Stool surfactant agents  (softeners)

Osmotic

Stimulant

Chloride channel activating

Opiod receptor antagonists

very popular OTC but rarely needed

know cause of constipation and possible side-effects before prescribing these

may be useful in preventing constipation in high risk patients

Bulk forming laxatives

i.e. psyllium (metamucil) or methylcellulose (citrucel) or polycarbophil (FiberCon)

absorb water

distend colon

increase persitalsis

OTC for mild constipation

Docusate

aka Colace

Stool surfactant agent or softener

OTC for mild or transient constipation

decreases surface tension allowing water and lipid to enter stool, stools are then easier to pass

Magnesium Hydroxide

Antacid and Osmotic laxative

aka milk of magnesia

nonabsorbable salt draws fluid into bowel lumen

also interactswith HCl to increase gastric pH

Adverse: risk of hypermagnesemia in renal failure patients

Lactulose

Osmotic laxative

nonabsorbable sugar draws fluid into GI lumen

Balanced polyethylene glycol

"go-litely" bowel prep. for colonscopy patients

osmotic laxative

nonabsorbable

draws fluid into GI lumen but electrolyte balanced to cause minimal dehydration

usually prescribed by the gallon for the night before a screening colonoscopy

Senna

stimulant laxative

anthraquinone (natural product)

mechanism poorly understood: may act directly on enteric nervous system or may act as a mucosal irritant

may cause melanosis coli--brown discoloration of colonic mucosa

Biscodyl

stimulant laxative

a diphenylmethane

aka ducalax

Lubiprostone

Chloride channel activating laxative

increases fluid secretion and GI motility

used in chronic constipation and in women with irritable bowel syndrome with predominnant constipation

Methylnaltrexone

opioid receptor antagonist

blocks peripheral mu receptors without impacting central opioid-mediated analgesic effects

used to treat chronic constipation

Irritable Bowel Syndrome

characterized by abdominal pain, diarrhea or constipation predominates

common pharmaceutical therapies: 1.anticholinergic antispasmodics (i.e.dicyclomine or hyoscyamine with typical side effects like dry mouth, blurred vision, and urinary hesitancy) if diarrhea predominanat, 2. a serotonin 5-HT3 receptor antagonist (alosetron) if diarrhea predominanat, 3. chloride channel activator (lubiprostone) if constipation predominant

Alosetron

Serotonin 5-HT3 receptor antagonist

decreases pain and diarrhea in diarrhea-predominant irritable bowel syndrome

indicated only for women with severe disease

restricted program, special training required to be able to prescribe

infrequent but severe adverse effects: GI toxicity, ischemic colitis, constipation with bowel perforation

Antidiarrheal Drugs

like laxatives these are often unneccessary

opioid agonists

colloidal bismuth compounds

kaolin and pectin

bile-salt binding resins

octreotide (somatostatin analog)

Loperamide

opioid agonist with poor entry into CNS

used as an antidiarrheal drug

does not cause CNS effects or dependance

available OTC

Bile salt diarrhea

some patients with ileal disease or resection can not properly reabsorb their bile salts, this causes osmotic diarrhea

bile salt binding resins like cholestyramine (normally a cholesterol-lowering drug) can help reduce diarrhea in these patients by binding the bile salts in the GI lumen

the bound bile salts are carried out in feces

Octreotide

Somatostatin agonist

synthetic peptide

longer half-life

decreases fluid secretion into GI tract, decreases GI motility, supresses H+ release in stomach, many other effects

used to reduce the effects (diarrhea, flushing) of carcinoid tumors and VIPomas

also used to prevent rupture of varices in late-stage liver disease

Vomiting Triggers

memory, fear, dread, anticipation, pain, smell, sight (cortex, thalamus, hypothalamus, meninges)

inner ear motion, aminoglycosides (vestibular system + cerebellum)

GI irritants--bacteria, viruses, radiation, cytotoxic drugs (vagal and sympathetic afferents)

blood-borne emetics--cytotoxic drugs, opioids, cholinomimetics, Digoxin, L-DOPA, bromocriptine, apomorphine, emetine/ipecac (vagal and sympathetics)

gagging (pharyngeal afferants)

Central Vomiting Centers

Ondansetron

Serotonin 5-HT3 receptor antagonist

blocks peripheral vagal afferents and central vomiting receptors

used to reduce vomiting with certain cancer chemotherapies and after surgical operations

oral or IV

hepatic metabolism

Adverse: headache, constipation, some increase in QT interval

Classes of Anti-Emetic Drugs

often used with highly emetogenic cancer drugs

1. Serotonin 5-HT3 receptor antagonists (---setron suffix)

2. Corticosteroids (dexamethasone)

3. Neurokinin-1 receptor antagonists (aprepitant, fosaprepeitant)

4. Phenothiazines (phrochlorperazine, promethazine)

5. Dopamine receptor blockers (metoclopramide)

6. H1 Antihistamines/Anticholinergics (diphenylhdramine, scopolamine, meclizine)

7. Benzodiazepines

8. Cannabinoids (dronabinol, nabilone)

Aprepitant

Neurokinin-1 NK-1 receptor antagonist/

substance P receptor antagonist

acts solitary tract nucleus to inhibit vomiting

used to prevent chemotherapy-induced emesis

oral drug

hepatic metabolism

also the active metabolite of IV drug fosaprepitant

Adverse: fatigue, dizziness, diarrhea, drug interactions

Prochlorperazine

a phenothiazine 1st gen. antihistamine with anti-muscarinic and anti-dopaminergic action-->anti emesis use

widely used to prevent nausea and vomiting from many sources including motion sickness

Adverse: Sedation

Promethazine

aka Phenergan

a phenothiazine 1st gen. antihistamine with anti-muscarinic and anti-dopaminergic action-->anti emesis use

widely used to prevent nausea and vomiting from many sources including motion sickness

Adverse: Sedation

Diphenylhydramine

aka Benadryl

1st gen. antihistamine with anticholinergic activity

used to prevent motion sickness and allergic rhinitis

main adverse: sedation

Scopolamine

muscarinic antagonist

used to prevent motion sickness

Adverse: dry mouth, blurry vision, urinary retention, etc.

Dronabinol

THC the active component of marijuana

used to control chemotherapy related nausea and vomiting in patients unresponsive to conventional therapy

acts on central CB1 receptors to reduce emesis

Adverse: CNS effects similar to marijuana

Inflammatory Bowel Disease

Ulcerative Colitis and/or Crohn's Disease

mild UC treated with 5-ASA compounds

both treated with glucocorticoids if mild-moderate

moderate-severe disease treated with methotrexate, purine analogs, anti-TNF anitbodies, or an anti-integrin antibody

Sulfasalazine

oral azo compound metabolized by distal GI tract bacteria to active metabolite 5-ASA (5-aminosalicylic acid) and sulfapyramide (which causes many side effects)

5-ASA begins to be released in proximal colon

older drug

used to treat inflammatory bowel disease, especially ulcerative colitis

mechanism unknown

Adverse: GI upset, headaches, hypersensativity rxns, reversible oligospermia, decreased folate absorption

Mesalamine

5-ASA

usually formulated to be slow-release or coated with a pH sensitive capsule to delay release and absorption until the distal bowel (ileum or colon) where the drug may be effective

used in mild ulcerative colitis

mechanism uknown

oral drug

Adverse: diarrhea, interstitial nephritis

Glucocorticoids used to treat Inflamatory Bowel Disease

for Crohns and Ulcerative Colitis

prednisone

prednisolone

budesonide-newer, less systemic bioavailability

Adverse: immunosuppressive

Azathioprine and 6-Mercaptopurine

purine analogs

used to treat leukemias and moderate-severe ulcerative colitis and Crohn's disease

azathioprine-->6-MP-->active nucleotides

interfere with DNA and RNA synthesis and other rxns.

TMPT polymorphisms influence rate of metabolism and toxicity (pharmacogenetics)

6-MP may be metabolized by TMPT, HGPRT, or xanthine oxidase (6-MP interacts with gout drug allopurinol)

Adverse: bone marrow suppression, liver toxicity, immunosuppression

Methotrexate

an immunosuppresive anti-cancer drug sometimes used to treat moderate-severe ulcerative colitis and Crohn's disease

inhibits dihydrofolate reductase-->decreased dTMP-->decreased DNA synthesis

Infliximab

immunomodulatory chimeric anti-TNF monoclonal antibody

IV drug used to treat moderate-severe Crohn's disease or ulcerative colitis in patients not responding to glucorticoids, purine analogs, or methotrexate

Adverse: increased infection risk (and re-infection/activation of TB), infusion rxns (anaphylaxis-like) which may be severe, serum sickness-like illness (fever, rash, arthralgia, myalgia), development of antibodies against drug, lymphoma

Adalimumab

human monoclonal anti-TNF antibody

approved for Crohn's disease patients unresponsive to traditional therapy

administered subcutaneously

Certolizumab

Fab fragment with anti-TNF action conjugated with polyethylene glycol

administered subcutaneously

for Crohn's disease refractory to conventional treatment

Natalizumab

aka Tysarbi

humanized Mab that binds alpha4-integrin (a cell adhesion molecule involved in leukocyte extravasion in inflammation)

for patients with Crohn's disease resistant to glucocorticoids, purine analogs, methotrexate, and anti-TNF antibodies (last resort dangerous drug)

restricted distribution program (must get certified to prescribe it like dofetalide, thalidomide, and alosetron)

Adverse: increased risk of progressive multifocal leukoencephalopathy (often fatal opportunistic viral brain infection)