GI Tract - Prescription

University of Hawai‘i Hilo Pre-Nursing Program NURS 203 – General Pharmacology Danita Narciso Pharm D

Learning Objectives

• Know what each is indicated to treat • Know drug mechanisms of action • Know major adverse drug effects (will be discussed) Drugs to Treat Upset (/GERD)/Prevent Ulcers

• • Proton Pump Inhibitors • H2 Receptor Antagonists • Sucralfate Analog - MOA

• Misoprostol (Cytotec®) Synthetic prostaglandin E1 analog which places the protective that are consumed by prostaglandin inhibiting

Mucus M M Parietal Cell EP3 EP4

Parietal Cell ATP Prostaglandin Analog

• Kinetics • ADRs • Absorption – rapid & extensive • Diarrhea, abdominal pain, dyspepsia, , nausea, & vomiting • Metabolized – • • binding - >90% • Half life – 20-40 minutes • Dosing for protection of NSAID induced gastric ulcers • Time to peak – 6-22 minutes (fasting) • 200 mcg 4 times daily with food • – urine 80% • Interactions • Antacids • category X Sucralfate - MOA

• Sucralfate (Carafate®) Forms a viscous paste-like adhesive substance by binding with positively charges . Selectively forms a protective coating along the gastric lining against , peptic acid, and salts

SUCROSE – ALUMINUM - SULFATE Sucralfate

• Kinetics • Dosing • Absorption – oral is minimal • Initial treatment – 1 g, 4 times per day on an empty stomach for 4-8 weeks • Distribution – acts locally at ulcer site • Maintenance – 1 g BID • Duration – up to 6 hours • Metabolism – none • ADRs • Excretion – small amounts in urine as • unchanged drug • Interactions • Can decrease the absorption & concentration of many drugs • Pregnancy category B Proton Pump Inhibitors - MOA

• (Prilosec®) Inhibit the hydrogen/potassium adenosine triphosphatase (ATPase) enzyme of the secretory surface of the gastric • (Nexium®) parietal cells. Proton • (Prevacid®) Potassium • (Dexilant®) Proton Pump • (Aciphex®) PPI PPI Proton Pump Inhibitor • (Protonix®) Parietal Parietal Chloride ion Cell Cell

Proton Pump Inhibitors - Omeprazole • Kinetics • Absorption – rapid • Dosing • Protein binding - ~95% • 40 mg daily for gastric ulcer for 4-8 weeks • Onset – 1 hour, peak (2 hours) • ADRs • Duration – 72 hours, 50% max @ 24 hrs, • with d/c take 3-5 days for normal return to Headache & dizziness baseline • Abdominal pain, diarrhea, & flatulence • Metabolism – hepatic CYP2C19 • Interactions – 30-40%, 100% in poor hepatic function, Asians 4fold AUC as • Inducers & inhibitors of CYP enzymes compared to Caucasians • Clopidogrel (Plavix) – Risk X • Half life – 0.5-1 hr, hepatic impairment =3 • Pregnancy category C • Excretion – urine 77%,

H2 Receptor Antagonists - MOA

• (Tagamet®) Competitive inhibitor of the H2 receptor of the gastric parietal cell. Inhibits secretion, gastric volume, & proton • (Zantac®) availability • (Pepcid®)

• (Axid®) Stomach lumen

H Histamine Parietal H Cells G Gastrin G A Acetylcholine A H2 Receptor Antagonists - Ranitidine

• Kinetics • Dosing • Absorption – 50% oral, IM – rapid • 150 mg BID or 300 mg daily with evening meal • Distribution Increased with reduced • ADRs • Half life kidney function • Metabolism – hepatic (minor) • AV block with rapid IV administration • Time to peak – oral 2-3 hrs, IM < 15 mins • Abdominal pain, constipation, diarrhea, nausea, & vomiting

• Interactions • May decrease the concentrations of other through drug effect or enzyme interactions Drugs to Treat Nausea & Vomiting

• 5HT3 Antagonists • Dopamine Antagonists • Antihistamines/Anticholinergics • Substance P Antagonists

5HT3 Antagonists - MOA

• Ondansetron (Zofran®) 5 HT3 antagonist peripherally at vagal nerve terminals and • Dolasetron (Anzemet®) centrally at chemoreceptor trigger zone • Granisetron (Kytril®) S • Palonosetron (Aloxi®) S

S Serotonin 5HT3 5HT3 Receptor Sodium Receptor 5HT3 Antagonist - Ondansetron

• Kinetics • Dosing • Absorption – Well absorbed from GI tract • Varies depending on indication • Onset – 30 minutes • Dose adjust in severe hepatic impairment • Protein binding – 70-76% • ADRs • Metabolism – extensive hepatic w/ CYP • Headache, fatigue, & drowsiness involvement • Constipation • Half life – considerable increase in hepatic impairment, (3hr, 12hr, 20hr) • Hypoxia • Excretion – mostly urine as metabolites • Interactions • May increase or decrease concentrations of other drugs Dopamine Antagonists - MOA

• Prochlorperazine Blocks dopamine receptors in chemoreceptor trigger zone & (Compazine®) anticholinergic effect blocking the release of hypothalamic hypophyseal hormones • Chlorpromazine (Thorazine®)

Blocks Blocks H1 Decrease in Decrease D2 M1 nausea & in CTZ Inner ear vertigo vomiting Dopamine Antagonist - Prochlorperazine

• Kinetics • Dosing • Absorption – Rapid • 10-25 mg every 4-6 hours • Onset – IM 15 mins, oral 30-60 mins • IM and IV dosing available • Protein binding – 92-97% • ADRs • Metabolism – extensive hepatic • Parkinsonian-like syndrome, tartive dyskinesia • Half life – 2 hours, 30 hours (biphasic) • Dizziness, drowsiness • Excretion – urine • Constipation, nausea • Breast enlargement • Interactions • Many – avoid with anticholinergics MOA Antihistamines Anticholinergics • Cyclizine (Marezine®) OTC • Scopolamine (Hyoscine) • Hydroxyzine (Vistaril®) Antagonizes histamine & serotonin • Promethazine (Phenergan®) • Diphenhydramine (Benadryl®)

Competes with histamine for H1 receptor site on effector cells Additional Information

Antihistamines - Promethazine Anticholinergics • Dosing • Dosing • 12.5-25 mg Q 4-6 hours PRN • 1 patch Q 72 hours • ADRs • ADRs • Bradycardia • Dry mouth • Bradycardia • Agitation, akathisia, tartive dyskinesia • Constipation • Constipation • Blurred vision • Blurred vision • Interactions • Interactions • CNS depressants, other anticholinergics • Other anticholinergics, CNS depressants • Pregnancy category C • Pregnancy category C

Substance P Antagonists - MOA

• Aprepitant (Emend®) Inhibits the substance P/neurokinin 1 (NK1) receptor; augments the antiemetic activity of 5-HT3 receptor • Fosaprepitant (Emend antagonists and corticosteroids to inhibit acute and delayed Inject®) phases of -induced emesis

Substance P Antagonist

• Kinetics • Dosing • Distribution – Vd ~70 L, crosses BBB • 125 mg 1 hour prior to chemo, 80 mg daily on days 2&3 • Protein binding – 95% • Metabolism – Extensively hepatic CYP3A4 • ADRs (major) & other CYP enzymes • Fatigue • Half life – 9-13 hours • Nausea, constipation, hiccups • Time to peak – 3 hrs adults, 4 hours children • Weakness – muscular • Interactions • Inhibitors/inducers/substrates of CYP enzymes Drugs to Treat Slowed Gastric Motility

• Prokinetic Agents

Prokinetic Agents - MOA

• Metoclopramide (Reglan®) Blocks dopamine receptors and (when given in higher doses) also blocks serotonin receptors in chemoreceptor trigger zone of the CNS. Enhances response to acetylcholine

Decrease nausea Increase GI & vomiting motility 5HT3 antagonist D2 antagonist 5HT4 agonist Cholinergic D2 receptor agonist antagonist Prokinetic Agents - Metoclopramide

• Kinetics • Dosing • Onset – 30-60 mins • Varies depending on indication • Absorption – oral, rapid • DM gut – 10 mg 4 times per day prior to meals & bed for 2-8 weeks • Bioavailability – 65-95% • GERD – 10-15 mg 4 times per day prior to meals & • Half life – 5-6 hrs adults, 4 hrs children bed • Time to peak 1-2 hrs • > 12 weeks not recommended • Excretion – urine 85% • ADRs • Drowsiness & dystonic reaction • Interactions • Other dopaminergic drugs & anticholinergic drugs Questions