Gastrointestinal Pharmacology (BMS150) PDF

Gastrointestinal Pharmacology Acid suppressors BMS150 Objectives With respect to acid suppressors: Relate their mechanism of action to their therapeutic effects Discuss any relevant adverse effects or contraindications Recognize given generic names or suffixes  Stomach acid review...

Gastrointestinal Pharmacology Acid suppressors BMS150 Objectives With respect to acid suppressors: Relate their mechanism of action to their therapeutic effects Discuss any relevant adverse effects or contraindications Recognize given generic names or suffixes  Stomach acid review Select points (relevant to GI pharmacology): Acetylcholine Histamine M3-R H2-R Gastrin CCK-R Inhibitory PGE-R Prostaglandins Stimulatory G-protein G-protein Signalling Signalling K+ H+ Parietal cell K+ H+ Overview H2 Blockers Anticholinergic Drugs PPI’s Prostaglandin analogues H2-Blockers Mechanism of action Competitive block of H2-R on parietal cells Specific Agents Cimetidine (Tagametâ), Ranitidine ((Zantacâ), Famotidine (Pepcidâ) Note “tidine” endings Therapeutic uses: Ulcers Peptic ulcers Often associated with what type of infection? Common: “triple therapy” Also non-malignant gastric and duodenal ulcers H2-Blockers Therapeutic Uses continued Management of Zollinger-Ellison syndrome (?) What category of drug do you think would be even more effective for this, and why? Gastroesophageal reflux disease Antacids usually more effective for acute use – why? Anticholinergics Mechanism of action Block of ?-receptors on parietal cells Review: What NT normally acts on these receptors? Which nerve releases this NT at the level of the viscera? Specific agent FYI - Pirenzipine Therapeutic uses: ulcers Peptic, non-malignant gastric, duodenal PPI’s (proton pump inhibitors) Mechanism of action H+, K+-ATPase inhibition Specific agents Omeprazole, esomeprazole Note “prazole” endings PPI’s (proton pump inhibitors) Therapeutic uses As for H2-blockers Ulcers Common for first line use in peptic ulcer triple therapy GERD Management of Zollinger-Ellison syndrome Which do you think would be more effective, H2-blockers or PPI’s? Why? Prostaglandins: PGE1 analogues Prostaglandins (PGs) review (FYI this term except for “new” part): PG’s are considered eicosanoids. What are the two structural categories of lipids, and which one are eicosanoids based on? What specific lipid are most eicosanoids derived from? What are some physiological functions of PG’s you learned last term? New: Some PG’s can cause uterine contractions Prostaglandins: PGE1 analogues Mechanism of action: 2 parts 1) Decreased proton pump activity 2) Increased bicarbonate and mucous secretion Protective effect against acidity Specific PGE1 analogue Misoprostal Prostaglandins: PGE1 analogues Therapeutic use Most common = prevention of NSAID-induced ulcer/GI bleed Review: What is the connection between NSAID’s and PG’s, including the enzyme involved? Therefore, PGE1 analogues replace the gastro-protective PG’s that are decreased during NSAID use Contraindication: pregnant women Why? Gastrointestinal Pharmacology Motility and antinausea agents BMS150 Objectives With respect to motility and anti-nausea agents: Relate their mechanism of action to their therapeutic effects Discuss any relevant adverse effects or contraindications Recognize given generic names or suffixes Overview Agents that decrease motility Diphenoxylate-atropine (Lomotilâ) Loperamide (Imodiumâ) Agents that increase motility Laxatives Metoclopramide (Maxeranâ, Reglanâ) Domperidone (Motiliumâ) Overview Antinausea agents Anticholinergics Scopolamine Promethazine Dopamine-R blockers Metoclopramide Domperidone Decreased motility Diphenoxylate-atropine § Mechanism of action: diphenoxylate Opioid receptor agonist § Inhibits ACH release in enteric system at low doses What does ACH normally do to gut motility? Since opioids inhibit this effect, what do you think is a common adverse effect if someone takes an opioid for pain relief? Decreased motility Diphenoxylate-atropine § Mechanism of action: Atropine M-blocker - why is it part of the formulation? § 1) Synergistic effect with diphenoxylate to decrease effects of ACH on the gut § 2) Anticholinergic side effects discourage abuse potential Why does this drug have abuse potential? Anticholinergic side effects occur before euphoric opioid effects are felt Choose the correct common and annoying anticholinergic side effect: A – Dry mouth B – Excessive salivation Decreased motility Loperamide § Similar to diphenoxylate-atropine, but without the atropine Does not cross BBB, so general lack of CNS effects and therefore extremely low abuse potential § Note: Both these drugs are also relatively insoluble to prevent self-injection Increased motility Laxatives § Can be considered milder forms of cathartics, which are agents that cause evacuation of the bowels § Usually a secondary constipation treatment What might be a primary diet-based treatment? Increased motility Laxatives § Mechanisms fall into 4 main categories Bulking agents Osmotic laxatives Chemical stimulants Stool softeners Increased motility Laxatives: Bulking agents § Ex: Bran, psyllium § Non-absorbed agents that create bulkier stools and draw water into stools Bulkier stool: stimulates the bowel Softer stool: easier to move Increased motility Laxatives: Osmotics § Ex: Magnesium sulfate, magnesium hydroxide (“milk of magnesia”), lactulose § Not well-absorbed from the intestinal tract Results in an increase in osmotic pressure leading to retention of water in intestine, lumen extension, and increased bowel action Increased motility Laxatives: Osmotics § More on magnesium hydroxide Low doses: can neutralize stomach acid (antacid) High doses: too much bowel movement can cause diarrhea § Danger with too high dose of any laxative Increased motility Laxatives: Osmotics § More on lactulose Disaccharide (FYI galactose and fructose) that is not broken down well in the SI § Reaches colon, where it is broken down by bacteria to produce lactic acid Acidic conditions ionize ammonia to NH4+ Will this increase or decrease excretion of ammonia? Why? Remember, ammonia is neurotoxic Increased motility Laxatives: Chemical stimulants § Ex: Emodin (active ingredient found in Senna, aloe, cascara) § Irritate the gut to induce peristalsis and increase mucous production Increased motility Laxatives: Stool Softeners § Use water or oil to soften stools § Ex: Mineral oil, sodium docusate Mineral oil § Lubricates stools for easier passage § Do you think olive oil would work too? Sodium docusate § Detergent that allows water to penetrate stools Prevents hard, dry stools and allows for easier passage Increased motility Metoclopramide § Mechanism of action for increased motility: Block of peripheral D-receptors § Dopamine is inhibitory in the GIT, ACH is stimulatory Blocking dopamine effects allows ACH effects to predominate Increased peristalsis Increased tone of lower esophageal sphincter Increased motility Metoclopramide § Mechanism of action for anti-nausea/vomiting: Block of central D-receptors § Antiemetic action comes from block of D2-receptors in medulla § Therapeutic uses GERD (via peripheral D-receptor block) Diabetic gastric stasis (via peripheral D-receptor block) Prevention of nausea and vomiting with chemotherapy (via central D-receptor block) Increased motility Metoclopramide § Select adverse effects 1) What happens when you take the peripheral effects too far? 2) Hyperprolactinemia § Dopamine is also know as PIH = prolactin inhibitory hormone Blocking dopamine therefore causes increased prolactin Increased motility Domperidone § Similar to metoclopramide, but less likely to cross BBB or into breast milk § Off-label use: stimulation of milk production in lactating mothers Due to what action? Antinausea Anticholinergics § Block cholinergic transmissions between vestibular and vomiting centers in the CNS § Specific agents Scopolamine: M-blocker Promethazine: M-blocker and H1-blocker § Also used as an antihistamine and sedative due to the H1-block Antinausea D2-blockers (review from earlier today) § Antiemetic action from D2-block where? § Specific agents Metoclopramide, domperidone § Also used for?