gastrointestinal drugs

Drugs Affecting GI Function

Abigail Mata | Phar 141 Page 1

1) ACh release (Enteric NS) binds to M1 and M3 receptors 2) Gastrin release - CNS activation, GI wall distention, chemicals in food 3) Gastrin activates ECL Histamine release

-Histamine binds to H2 in parietal cells stimulate Gs protein adenylyl cyclase activated CAMP protein kinase activation proton pump activation H+/K+/ATPase (resp. for exchange of K+ for H+) Acid production

4) Gastric mucosa acidified to pH



Drugs used to treat Gastric Acidity, PUD and GERD

Physiology of Gastric Acid Secretion

HCl and pepsinogen: principal gastric secretory products

capable of inducing mucosal injury

Basal acid production (circadian rhythm)

*highest in the evening, lowest in the morning

Cholinergic input via vagus nerve

Histaminergic input from local gastric sources

Stimulated conditions

Cephalic phase: sight, smell, taste of food

-release of Ach (1 stimulant) from CNS

Gastric phase: food enters stomach distention of GI

walls gastrin release from G cells direct/indirect

promotion of secretion of digestive juices

*direct- parietal cells induced

Intestinal phase: nutrient assimilation; antral D cells in

gastric mucosa (somatostatin) inhibits gastric

secretion

Regulatory Mechanisms of Gastric Acid Secretion

Acetylcholine (neuronal): M3 receptors (basolateral

membrane of parietal cells)

Histamine (paracrine-neighboring): H2 receptors

-Enterochromaffin-like cells adjacent to parietal cells

has H2 receptors

Gastrin (endocrine) : CCK2 (cholecystokinin)or CCK-B/G

receptors

*Parts of stomach: cardiac, fundus, body, pylorus

Regulatory Hormones

Receptors Description

Acetylcholine M3 on basolateral membrane of parietal cells M1 on ECL cells

Released from postganglionic vagal fibers Stimulates "cephalic" phase of acid secretion Indirectly affects parietal cells by increasing release of histamine from ECL cells in the fundus of the stomach and of gastrin from G cells in the gastric antrum

Histamine H2 on parietal cells

Released by ECL cells (in close proximity to parietal

cells) Acts as a paracrine mediator by diffusion

Gastrin G or Cholecystokinin-B (CCK-B or CCK2)

Most potent inducer of acid secretion: indirectly by inducing release of histamine by ECL cells Produced by antral G cells Stimulated by CNS activation, local distention, & chemical components of gastric contents

Somatostatin (SST)

ST2 Produced by antral D cells Inhibits gastric acid secretion Stimulated by acidification of gastric luminal pH to



Proton Pump Inhibitors DRUG PROPERTIES AND

INDICATIONS PHARMACOLOGIC

EFFECT/MOA PHARMACOKINETICS SIDE EFFECTS/CI/DI

OMEPRAZOLE

Prilosec Losec

Hovizol Omepron Protonix

Risek

ESOMEPRAZOLE Nexium

LANSOPRAZOLE Prevacid Prevacid

FDT

DEXLANSOPRAZOLE Dexilant

RABEPRAZOLE Pariet Aciphex

PANTOPRAZOLE Protonix Pantoloc

Enteric-coated contained inside gelatin capsules

Omeprazole Esomeprazole Lansoprazole

Enteric-coated granules as powder for suspension

Lansoprazole

Enteric-coated tablets

Pantoprazole Rabeprazole Omeprazole

Powdered drug combined with sodium bicarbonate

Omeprazole

IV formulations

Pantoprazole Lansoprazole

Most potent suppressors of gastric acid secretion All have equivalent efficacy at comparable doses Promote healing of gastric and duodenal ulcers Treat GERD, including erosive esophagitis (either complicated or unresponsive to tx w/ H2-receptor antagonists) Mainstay in the treatment of pathological hypersecretory conditions, including the Zollinger- Ellison syndrome (tumors in pancreas or SI gastrinoma) FDA approved for reducing risk of duodenal ulcer recurrence associated with H. pylori infections ( D cells low somatostatin- acid) Lansoprazole: FDA approved for treatment and prevention of recurrence of

Prodrugs that require activation in an acid environment Effective in acid suppression regardless of other stimulating factors (targets final step) *80-95% diminished daily gastric acid secretion SULFENAMIDE -active metabolite -targets secretory canaliculi inside parietal cells -site of accumulation of prodrug (cannot escape cell) -binds to SH groups of Cys of protein pump (covalent) inactivate PP *irreversible inhibition causes prolonged action bec. it takes time before new PP are synthesized

Should be given ~30 to 60 minutes before breakfast or the largest meal of the day Small intestine: rapidly absorbed, highly protein bound, and extensively metabolized by hepatic CYP2C19 and CYP3A4 Maximal suppression of acid secretion requires several doses of PPIs -not all PP are simultaneously activated Provide a prolonged (up to 24-to 48-hour) suppression of acid secretion, despite the much shorter plasma half-lives (0.5 to 2 hours) of parent compounds

Nausea, diarrhea, headache, GI disturbance, bone fractures (increased w/ long-term use: hip, wrist, spine) Decreased effectiveness of clopidogrel with omeprazole Low vitamin B12 levels *Vit B12 + intrinsic factor complex requires acid pH for absorption Incomplete absorption of CaCO3 products *alternative: Ca citrate



NSAID-associated gastric ulcers in patients who continue NSAID use

H2-Receptor Antagonists CIMETIDINE

Tagamet

RANITIDINE Zantac

FAMOTIDINE Pepcid H2 Bloc

NIZATIDINE Axid (no

longer marketed

)

Promote healing of gastric and duodenal ulcers Treat uncomplicated GERD Prevent occurrence of stress ulcers *less potent that PPIs (70%) -usually given at night -PPI (morning)

Inhibit acid production by reversibly competing with histamine for binding selectively to H2-receptors on the basolateral membrane of parietal cells, BVs, and other sites Predominantly inhibit basal acid secretion, which accounts for

their efficacy in suppressing

nocturnal acid secretion

Rapidly absorbed after oral administration Peak serum concentrations within 1 to 3 hours Absorption may be enhanced by food or decreased by antacids Only small % is protein-bound Cimetidine Short serum half-life; inhibits CYP450 (enzyme inhibitor) resp for many side effects Ranitidine Longer-acting and 5-10x more potent vs. cimetidine Famotidine 20-50x more potent vs. cimetidine, 3-20x vs. ranitidine Nizatidine Similar potency to ranitidine; eliminated principally by kidneys (bioavailability ~100%)

Diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation Confusion, delirium, hallucinations, slurred speech, and headaches Cimetidine (long-term, high doses): Women: galactorrhea -inhibits CYP enzymes that hydroxylates estradiol) Men: gynecomastia, reduced sperm count, and impotence (due to reduction of testosterone binding to androgen receptor)

Agents that Enhance Mucosal Defense: Prostaglandin Analogs Prostaglandin E2 (PGE2) and prostacyclin (PGI2) Major PGs synthesized by the gastric mucosa Bind to EP3 receptor on parietal cells and stimulate the Gi pathway decreased intracellular cAMP and gastric acid secretion PGE2: cytoprotective effects (stimulation of mucin and bicarbonate secretion; increased mucosal blood flow)

DRUG PROPERTIES AND INDICATIONS

PHARMACOLOGIC EFFECT/MOA

PHARMACOKINETICS SIDE EFFECTS/CI/DI

MISOPROSTOL Cytotec

Synthetic analog of PG E1 FDA approved to

Degree of inhibition of gastric acid secretion is directly related to dose

Rapidly absorbed after oral administration Rapidly and extensively

Diarrhea, with or without abdominal pain and cramps



prevent NSAID-induced mucosal injury

de-esterified to form misoprostol acid Single dose inhibits acid production within 30 minutes Therapeutic effect peaks at 60-90 minutes and lasts for up to 3 hours Food and antacids decrease the rate of absorption Free acid is excreted mainly in the urine Elimination half-life of ~20 to 40 minutes

(30%) *dose-related, begins w/in first 2 wks after initiation of therapy & often resolves spontaneously w/in a week CI: IBD-misoprostol exacerbates IBD -Pregnancy: uterine contractility -taken 4x daily: limits its use

SUCRALFATE Iselpin, Carafate

Complex of aluminum hydroxide and sulfated sucrose Epidermal growth factor (EGF) Effectively heals duodenal ulcers and is used in long-term maintenance therapy to prevent their recurrence

Inhibits pepsin-mediated hydrolysis of mucosal proteins pH



bicarbonate the stomach

loads may pose a risk for patients with cardiac or renal failure Systemic alkalosis, belching and flatulence (NaHCO3) Na content for hypertensive or HF patients

Calcium carbonate Tums, Calsan, Calci-Aid

Also used as calcium supplements for treatment of osteoporosis

Calcium may induce rebound acid secretion, necessitating more frequent administration

Release of CO2 from bicarbonate-and carbonate- containing antacids can cause belching, nausea, abdominal distention, and flatulence

Combination of Mg2+ and Al3+ hydroxides

Magaldrate, Maalox

Symptomatic relief of peptic ulcer disease and GERD Promote healing of duodenal ulcers Used as last-line therapy for acute gastric ulcers -Provides a relatively balanced and sustained neutralizing capacity

Magaldrate: hydroxymagnesium aluminate complex converted rapidly in gastric acid to Mg(OH)2 and Al(OH)3

-Mg (fast acting) -Al (slow acting)

-Poorly absorbed (sustained antacid effect)

Constipation (Al hydroxide) Diarrhea (Mg hydroxide) Hypophosphatemia (Al-containing) Accumulation of cations in renal insufficiency

Simethicone Disflatyl

+ CaCO3+ Vit D (Esvicalforte) + Al and Mg hydroxides (Mylanta, Maalox plus, Kremil-S)

Surfactant added in antacid preparations that may decrease foaming and hence esophageal reflux

Antimicrobial Agents Optimal therapy for patients with PUD (both duodenal and gastric ulcers) who are infected with Helicobacter pylori

TRIPLE THERAPY PPI + Metronidazole/Amoxicillin + Clarithromycin

QUADRUPLE THERAPY Bismuth Subsalicylate + Metronidazole + Tetracycline + PPI

Other Acid Suppressants and Cytoprotectants DRUG PROPERTIES AND INDICATIONS PHARMACOLOGIC EFFECT/MOA SIDE EFFECTS/CI/DI

M1 Muscarinic Receptor Antagonists PIRENZEPINE

-40-50% suppression -significant undesirable anticholinergic effect -risk of blood disorders -poor efficacy



TELENZEPINE

REBAMIPIDE Mucosta Used for ulcer therapy (100mg)

Appears to exert a cytoprotective effect both by increasing PG generation in gastric mucosa and by scavenging reactive oxygen species

ECABET Gastrom also used for ulcer therapy in Japan

Appears to increase the formation of PGE2and PGI2

CARBENOXOLONE Derivative of glycyrrhizic acid found in licorice root -Used for ulcer therapy in Europe

Unclear mechanism; may alter the composition and quantity of mucin -Inhibits type I isozyme of 11-B hydroxysteroid dehydrogenase protects mineralocorticoid receptor activation by cortisol in the distal nephron

Hypokalemia and hypertension due to excessive mineralocorticoid receptor activation

DRUGS USED FOR BOWEL MOTILITY DISORDERS Drug classes: Prokinetic agents and antiemetics Laxatives Antidiarrheals

Dopamine in GIT Serotonin (5-HT) Present in significant amounts in the GIT Inhibitory effects on motility: reduction of LES and intragastric pressures Mediated by D2-dopaminergicreceptors Result from suppression of Ach release from myenteric motor neurons

>90% of total 5-HT in the body exists in GIT Produced by ECL cells and rapidly released in response to chemical and mechanical stimulation Triggers the peristaltic reflex 5-HT1stimulation of the gastric fundus release of nitric oxide and reduces smooth muscle tone 5-HT4stimulation of excitatory motor neurons enhanced Ach release at the NMJ 5-HT3and 5-HT4receptors facilitate interneuronal signaling

Prokinetic Agents and Antiemetics Medications that enhance coordinated GI motility and transit of material in the GI tract Appear to enhance the release of excitatory neurotransmitter at the nerve-muscle junction without interfering with the normal physiological pattern and rhythm of motility

2 TYPES

DOPAMINE RECEPTOR ANTAGONISTS Metoclopramide, Domperidone, Phenothiazines, Butyrophenones

5-HT3 RECEPTOR BLOCKERS

Ondansetron (Zofran); Granisetron (Kytril); Palonosetron (Aloxi); Dolasetron(Anzemet)

Prokinetic Agents and Antiemetics Substituted benzamides Derivatives of PABA Structurally related to procainamide Additional advantage of relieving nausea and vomiting by antagonism of dopamine receptors in CTZ (high brain center for vomiting)



DRUG PROPERTIES AND INDICATIONS

PHARMACOLOGIC EFFECT/MOA

PHARMACOKINETICS SIDE EFFECTS/CI/DI

I. METOCLOPRAMIDE Reglan, Plasil Domperidone Phenothiazines

Ameliorate nausea and vomiting that often accompany GI dysmotility syndromes Improve gastric emptying in symptomatic patients with gastroparesis (paralysis of GIT) IV: adjunctive measure in medical or diagnostic procedures (e.g., intestinal intubation or contrast radiography of the GIT) Treatment of chemotherapy-induced emesis (as well as prophylaxis of anticipatory vomiting CTZ) OFF-LABEL USE: Treatment of persistent hiccups

5-HT4-receptor agonism, vagal and central 5- HT3-antagonism, and possible sensitization of muscarinic receptors on smooth muscle Increases LES tone and stimulates antral and small intestinal contractions *confined effect in upper digestive tract; no colonic effect

Extrapyramidal effects Dystonias (uncoordinated movement) and parkinsonian-like symptoms (TRAP tremor, rigidity, akinesia, postural instability) Tardive dyskinesia (slow abnormal movement; may be irreversible) Galactorrhea Treatment: Anticholinergics Antihistamines

II. DOMPERIDONE Motilium

Predominantly antagonizes the dopamine D2 receptor without major involvement of other Receptors No significant effects on lower GI motility

Does not readily cross BBB to cause extrapyramidal side effects

III. PHENOTHIAZINES Prochlorperazine Comprazine

Treatment of chemotherapy-induced emesis (i.e., low or moderately emetogenic chemotherapeutic agents

Increasing dose improves antiemetic activity

Hypotension, restlessness, EPS, sedation

IV. BUTYROPHENONES Droperidol Inapsine Haloperidol Haldol Serenace

Moderately effective antiemetics Droperidol: used for sedation in endoscopy and surgery (+ opiates or BZDs); cause QT prolongation

5-HT3 Receptor Blockers DRUG PROPERTIES AND

INDICATIONS PHARMACOLOGIC

EFFECT/MOA PHARMACOKINETICS/DOSING SIDE EFFECTS/CI/DI

ONDANSETRON Zofran

Selectively block 5-HT3 receptors in the

-Can be administered as a single dose prior to

Headache as common SE



GRANISETRON Kytril PALONOSETRON Aloxi DOLASETRON Anzemet

visceral vagal afferent fibers and CTZ in the brain

chemotherapy (IV or PO); efficacious against all grades of emetogenic therapy - Longer duration of action

Substance P/neurokinin-1 Receptor Blocker DRUG PROPERTIES AND INDICATIONS PHARMACOKINETICS/DOSING SIDE EFFECTS/CI/DI

APREPITANT Emend

Only indicated for highly or moderately emetogenic chemotherapy regimens

PO administration with dexamethasone and palonosetron

Constipation and fatigue as major SEs

LAXATIVES Commonly used for constipation to accelerate the movement of food through the GIT May cause electrolyte imbalances when used chronically Increase potential for loss of pharmacologic activity of poorly absorbed, delayed-acting, and ER oral drugs by accelerating intestinal transit time All except lubiprostone have risk of dependency for the user

IRRITANTS and STIMULANTS DRUG PROPERTIES AND INDICATIONS PHARMACOLOGIC EFFECT/MOA SIDE EFFECTS/CI/DI

Senna Active ingredient is a group of sennosides (anthraquinone glycosides) + docusate-containing stool softener: useful in treating opioid-induced constipation

Causes evacuation of the bowels within 8 to 10 hours Causes water and electrolyte secretion into the bowel

Bisacodyl Potent stimulant of the colon available as suppositories and enteric-coated tablets

Acts directly on nerve fibers in the colonic mucosa

Abdominal cramps and potential for atonic colon with prolonged use Food interaction: basic food, milk Causes GI irritation

Castor Oil Abortifacient Broken down in the small intestine to ricinoleic acid (very irritating to the stomach and promptly increases peristalsis)

CI in pregnancy

Hydrophilic colloids from indigestible parts of fruits and vegetables

Form gels in the large intestine, causing water retention and intestinal distension, thereby increasing peristaltic activity

Used cautiously in immobile patients -potential to cause intestinal obstruction

Magnesium citrate Magnesium hydroxide Sodium phosphate

Electrolyte solutions containing PEG: used as colonic lavage solutions to prepare the gut for radiologic or endoscopic procedures *less abdominal cramps and gas

Nonabsorbable salts that hold water in the intestine by osmosis, causing bowel distention which increases intestinal activity and produces defecation in a few hours



Lactulose Duphalac

Semi-synthetic disaccharide sugar that cannot be hydrolyzed by intestinal enzymes

Oral doses are degraded in the colon by colonic bacteria into lactic, formic, and acetic acids increases osmotic pressure fluid accumulation, colon distention, soft stools, and defecation

Docusate sodium Docusate calcium Docusate potassium

Often used for prophylaxis rather than acute treatment

Surface-active agents that become emulsified with stool, producing softer feces and ease of passage

Not to be taken concomitantly with mineral oil

Lubricant Laxatives Mineral oil Glycerin suppositories

Mineral oil to be taken orally in an upright position to prevent aspiration and lipid & lipoid pneumonia

Act by facilitating the passage of hard stools

Chloride Channel Activators Lubiprostone Used in the treatment of chronic

constipation Activates chloride channels to increase fluid secretion in the intestinal lumen Metabolism occurs quickly in the stomach and jejunum

Nausea as common SE

ANTIDIARRHEALS Causes of diarrhea Increased osmotic load within the intestine, resulting in retention of water within the lumen Excessive secretion of electrolytes and water into the intestinal lumen Exudation of protein and fluid from the mucosa Altered intestinal motility resulting in rapid transit and decreased fluid absorption

DRUG PROPERTIES AND INDICATIONS PHARMACOLOGIC EFFECT/MOA

Bulk-forming and Hydroscopic Agents

Methylcellulose Citrucel Aluminum hydroxide Alternagel

Hydrophilic and poorly fermentable colloids or polymers that absorb water and increase stool Bulk

May work as gels to modify stool texture and viscosity and to produce a perception of decreased stool fluidity Adsorb intestinal toxins or microorganisms and/or by coating or protecting the intestinal mucosa

Bile Acid Sequestrants

Cholestyramine Colestipol Colesevalam

Bismuth subsalicylate Pepto-Bismol

Crystal complex consisting of trivalent bismuth and salicylate suspended in a mixture of magnesium aluminum silicate clay Prevention and treatment of traveler's diarrhea; other forms of episodic diarrhea and acute gastroenteritis

Low pH of the stomach: drug reacts with HCl to form bismuth oxychloride and salicylic acid Antisecretory, anti-inflammatory, and antimicrobial effects

Antimotility and Antisecretory Agents



Opioids Loperamide Diphenoxylate and difenoxin Octreotide and somatostatin

Opioids Effects on intestinal motility (receptors), intestinal secretion (dreceptors), or absorption ( and d receptors)

Loperamide Lormide Lomotil Imodium

An orally active antidiarrheal agent with -receptor activity agent and penetrates the CNS poorly Effective against traveler's diarrhea, used either alone or in combination with antimicrobial agents (trimethoprim, cotrimoxazole,or a fluoroquinolone) Used as adjunct treatment in almost all forms of chronic diarrheal disease Lacks significant abuse potential

Increases small intestinal and mouth-to-cecum transit times Increases anal sphincter tone 40 to 50 times more potent than morphine as an antidiarrheal

Usual adult dose: 4 mg initially followed by 2 mg after each subsequent loose stool, up to 16 mg per day Must be discontinued if no clinical improvement in acute diarrhea within 48 h

Overdosagecan result in CNS depression (especially in children) and paralytic ileus less movement of intestines

Diphenoxylate Related structurally to meperidine; more potent than morphine as antidiarrheal

Rapidly deesterified to difenoxin Both can produce CNS effects when used in higher doses (40 to 60 mg per day)

Octreotide & Somatostatin

*see previous handouts (hormones)

gastrointestinal drugs

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