Pharm of Drugs in Upper GI Disease Flashcards
How is H+ secreted into the lumen of the stomach?
Via a H/K ATPase (H out, K in)
Constitutive activation via histamine release from enterochromaffin-like cells
Prostaglandin E2
Mediates mucus and bicarb secretion from mucus cells
Via EP receptors
2 general ways to treat acid-related disorders
Neutralize or reduce gastric levels of H+/ H pylori
Strengthen/enhance protective factors
5 options for acid neutralizing/lowering drugs
3 main ones, 2 others
Antacids Histamine H2 receptor antagonists Proton pump inhibitors Antimuscarinics Gastrin receptor antagonists
Antacids
3 examples and MOA
Al(OH)3, Mg(OH)2, CaCO3
Direct neutralization of already secreted stomach acid
Increased gastric pH
No receptor interaction (direct chemical interaction)
Pharmacokinetics of antacids
Counter ions (Al, Ca, Mg) are poorly absorbed
They may chelate other drugs, affecting their absorption
Altered pH may affect drug absorption
Indications for antacids
Heartburn/mild GERD
Dyspepsia
Side effects from antacids
Carbonate based salts: belching (CO2 is produced)
Ca: hypercalcemia
Al: constipation, hypophosphatemia (impaired absorption)
Mg: diarrhea
H2 receptor antagonists
Competitive, selective block of histamine H2 receptors
The -tidine drugs (ranitidine)
Reduced (but not eliminated) acid secretion
ACh and gastrin pathways in response to a meal are still active
Most effective in reduction of nocturnal acid secretion
Pharmacokinetics in H2 receptor antagonists
Oral, intramuscular, and intravenous formulations
Bioavailability is 50%, need a twice daily administration (except nizatidine - oral, minimal 1st pass metabolism)
Renal elimination
Indications for H2 receptor antagonists
GERD
Peptic ulcer disease
Dyspepsia
Prevention of bleeding from stress-related gastritis
Some common and some rare side effects from H2 receptor antagonists
Common: diarrhea (or constipation), headache, drowsiness/fatigue, muscle pain
Rare: confusion/agitation, delirum/hallucinations, slurred speech
Proton pump inhibitors
The -prazole drugs (ex: omeprazole)
Irreversible inactivation of proton pump common to ALL triggers of gastric acid secretion (inhibits the H/K ATPase)
Restoration of function requires new proton pump synthesis (takes 18-24 hours)
Relatively selective for parietal cell proton pumps
Pharmacokinetics of PPIs
Parietal cell access requires systemic absorption (oral formulations require enteric coating)
Prodrug molecules activated by acid (best if taken within 30-60 mins of meal)
Drug interactions: altered pH (reduced absorption of some drugs), competition for certain cytochrom P450 enzymes
Indications for a PPI
Gastric/duodenal ulcer (H pylori associated or NSAID induced)
GERD
Prevention of bleeding from stress-related gastritis
Gastric hypersecretory conditions
Common side effects of PPIs
Generally well-tolerated Nausea Diarrhea (or constipation) Abdominal pain Flatulence
Antimuscarinics
Work on food induced pathways
Ex: pirenzipine
Utile and effective, but side effects!
Gastrin receptor antagonists
Ex: proglumide
Work on food induced pathways
Pathway inhibited at pH < 2.5 (won’t give you tangible benefits)
Blocks the CCK2/B receptor
Treatment for H pylori
PPI and two antibiotics and 14 days (triple therapy)
Clarithromycin and amoxicillin or metronsazole
Or PPI alone for 6 weeks
Misoprostol
Prostaglandin E1 analogue (emulates endogenous PGE2)
Direct effects on parietal cells (inhibitory) or mucus cells (stimulatory)
Pharmacokinetics of misoprostol
Short half-life
Frequent dosing
No impact on cytochrome P450
Indication for misoprostol
NSAID-induced ulcers
Contraindication of misoprostol
Pregnancy
Its a strong uterine stimulant so there is a huge uterine stimulant
Side effects from misoprostol
Diarrhea
Abdominal cramping
Uterine contraction
All because prostaglandin E1/E2 to stimulate GI/uterine smooth muscle
Sucralfate
Al(OH)3-sucrose sulfate complex Acid release anionic sulfated sucrose Binds to charged proteins in ulcer Viscous, sticky, protective barrier Indirect stimulation of PGE2 production
Pharmacokinetics of sucralfate
Localized action, minimal systemic absorption
Short effect (6 hours)
Take on empty stomach
Indications for sucralfate
Gastric and duodenal ulcer
Side effects of sucralfate
Al-induced constipation
May reduce absorption of some other drugs (Direct binding, or impaired membrane crossing)
Bismuth subsalicylate
Coat ulcers to form a physical protective barrier
Increased PGE2, HCO3 and mucus production
Antimicrobial against H pylori
Reduces stool frequency
Pharmacokinetics of bismuth subsalicylate
Dissociated in stomach, acts locally
Only salicylate substantially absorbed
Indications for bismuth subsalicylate
Adjuvant to triple therapy for H pylori-induced ulcers
Acute diarrhea
Contraindications of bismuth subsalicylate
Children with viral infections (Reye’s syndrome)
Allergies to ASA
Side effects as bismuth subsalicylate
Black stool (reaction with hydrogen sulfide in colon, may be confused with GI bleeding)
Blackening of tongue
Constipation
Prokinetic drugs
Ex: metoclopramide and domperidone
Both dopamine D2 receptor antagonists
Metoclopromaide has additional activity as agonist of serotonin receptors
Relieve basal dopamine inhibition of upper GI tract, stimulating peristalsis and facilitating gastric emptying
Move things along the tract faster (less material in the GI tract that can splash up into the esophagus)
Pharmacokinetics of prokinetics drugs
Metoclopromide is available in oral and parenteral formulations
Domperiodone has greater first-pass metabolism
Short duration of action
Hepatic metabolism
Indications of prokinetic drugs
GERD
Impaired gastric emptying
Nausea and vomiting
Postpartum lactation stimulation
Contraindications of prokinetic drugs
Situations where GI motility is harmful
Side effects of prokinetic drugs
GI crampings
Diarrhea
Hyperprolactinemia
Metoclopromide (not domperidone) crosses BBB
Anti-emetic pharmacology
Based on receptor expression in brainstem vomiting center and/or chemoreceptor trigger zone
Ex: Ondansetron, Dimenhydrinate, Scopolamine
Ondansetron
Antagonist of serotonin 5-HT3 receptors
Vomiting center, chemoreceptor trigger zone, vagal afferents
Indications for ondansetron
Chemotherapy-induced nausea and vomiting
Postoperative and postradiation nausea and vomiting
Side effects for Ondansetron
Headache
Dizziness
Constipation
Dimenhydrinate
Antagonist of histamine H1 receptors (some anticholinergic activity)
Relatively weak anti-emetic activity (can be used as adjuvant)
Indications for dimenhydrinate
Motion sickness (prevention or treatment)
Side effects of dimenhydrinate
Dizziness
Sedation/drowsiness
Dry mouth
Urinary retention
Scopolamine
Antagonist of muscarinic receptors
Comparable efficacy to dimenhydrinate
Best administered as transdermal patch
Indication for scopolamine
Motion sickness (prevention and treatments)
Side effects of scopolamine
Antagonist of muscarinic receptors when given orally
Comparable efficacy to dimenhydrinate
Best administered as transdermal patch
