Pharmacology week 21 - Gastrointestinal

Antacids Uses – heartburn/dyspepsia Mechanism of action – weak bases that react with acid to form salt and water - raise luminal pH of stomach, increase rate of emptying - may promote mucosal defense mechanisms through stim mucosal prostaglandin production - BUT gastrin release – stimulates acid release, need larger amounts for some effect – “acid rebound” NaHCO3 + HCL → CO2 + NaCl (baking soda) - belching/bloating/distension, unreacted alkali absorbed – causes metabolic alkalosis in high doses or in CRF - Na+ worsens CHF/HTN/CRF CaCO3 + HCL → CO2 + CaCL2 - reacts slower/less soluble, belching - excess causes hypercalcaemia or metabolic alkalosis (milk alkali syndrome) Mg(OH)2 or Al(OH)3 + HCL → MgCl2 or AlCl3 + H2O - unabsorbed Mg can cause osmotic diarrhoea - unabsorbed Al can cause constipation - therefore use together eg Mylanta - Mg and Al both filtered by kidneys so don’t use long term in CRF May alter absorption or bind to other drugs - not within 2 hours of tetracyclines, quinolones, itraconazole, iron)

H2 receptor antagonists Agents: Cimetidine, ranitidine, famotidine (all 50% bioavailability, famotidine longer t1/2) PK: - A: orally active - D: t1/2 1-4 hrs, Vd 1L/kg, 70% PB - M: hepatic - E: glomerular filtration, renal tubular secretion PD: o reversible blockade histamine H2 receptors mainly in parietal cells, also cardiac, mast cells, brain o no significant H1 action o decreases basal and meal-stimulated acid production and reduces volume of gastric secretion o also binds to androgen receptors therefore anti-androgen effects - potencies: vary 50 fold between agents; inhibit 60-70% of 24hr acid (especially nocturnal acid secretion) Uses: GORD, PUD, stress related gastritis, hypersecretory conditions - Zollinger-Ellison syndrome Adverse effects: - cimetidine >> ranitidine, famotidine has none of effects - CNS: dizziness, headache, confusion - endocrine: impotence and gynaecomastia (men), galactorrhoea (men and women) - blood dyscrasias (granulocytopenia, thrombocytopenia, neutropenia), bradycardia with rapid iv infusion, rash - gastro: diarrhoea, constipation, reversible cholestasis and hepatitis Contraindications: hypersensitivity Precautions: CRF, lactation and pregnancy Interactions: - cimetidine inhibits CYP450 1A2, 2C9, 2D6, 3A4 so extends half life of drugs metabolized by P450 - decreased renal clearance of basic drugs secreted in renal tubule - ↓ hepatic blood flow - may ↓ clearance of other drugs - increases levels of: theophylline, warfarin, phenytoin, cbz, TCA, beta block, calcium blockers, diazepam Dose: Cimetidine po 400mg BD; Ranitidine po 150mg BD (50mg Q6H slowly)

Proton Pump Inhibitors Agents: omeprazole, lansoprazole, pantoprazole PD: inhibits 90-98% of daily acid secretion PK: - A: well absorbed orally 40-80% bioavailability, bioavailability decreased by food - Prodrug; delivery: enteric coated, absorbed in alkali intestine, activated in parietal cell canaliculi o activation: active, reactive thiophilic cation, covalent bond to H/K ATPase - D: short serum t1/2 1-2hrs, long duration of action, 3-4 days for full effect, high PB - M: 1 st pass/systemic hepatic metabolism, CYP450 metabolism

1 - E: renal Uses: GORD, PUD: NSAID associated, H pylori associated; nonulcer dyspepsia - prevention of stress related mucosal bleeding - gastrinoma (60-120mg/day) Interactions: - decreased acidity → decreased bioavailability: ketoconazole, digoxin - metabolised by CYP450 enzymes – short t1/2 so interaction rare - omeprazole inhibits metabolism warfarin, diazepam, phenytoin Contraindications: severe hepatic impairment Adverse effects: - diarrhoea, headache, abdo pain - infections: ?incr risk resp infection, ?incr risk C diff in hospital patients - increased gastrin and decr acidity ?? incr risk cancer - may mask symptoms of malignancy Dose: 10-40mg/day

Mucosal protective agents Misoprostol - methyl analog of PGE PK: rapidly absorbed, metabolized to active free acid, t1/2 <30 mins PD: acid inhibitor: binds PG receptor on parietal cells, decreases H2 stimulated cAMP – decreases acid production - protective: stimulates bicarb/mucous production, increases mucosal blood flow Uses: decreases incidence of NSAID ulcers and complications Adverse effects: diarrhoea/cramping, stimulates uterus contractions; no drug interactions

Sucralfate - salt of sucrose with sulfated aluminium chloride - forms viscous paste in water, binds to ulcers and erosions Uses: reduce incidence of upper GI bleeding in critically ill No systemic adverse effects, <3% absorption May bind to other drugs decreasing absorption

Colloidal bismuth - non-specific treatment of diarrhoea or non-ulcer dyspepsia

Antiemetics Metoclopramide/Domperidone MOA: central and peripheral D2 receptor antagonist - prokinetic agents - blockade D2 inhibits gastric smooth muscle contraction
causes increased oesophageal peristalsis, increased LES pressure, increased gastric emptying - central blockade of D2 receptors at chemoreceptor trigger zone PK: - A: well absorbed orally, onset 30-60mins po/1-3mins iv - D: Vd 2-3 L/kg, t1/2 4 hrs - M: hepatic metabolism to inactive metabolites - E: renal Uses: GORD, impaired gastric emptying, diabetic gastroparesis, dyspepsia, vomiting, migraine Adverse effects: - metoclopromide: o restlessness, drowsiness, insomnia, agitation o dystonic reactions, NMS o extrapyramidal symptoms (parkinsonism, akathisia, tardive dyskinesia if long term) o elevated prolactin (galactorrhoea, gynaecomastia, impotence, menstrual disorders) - domperidone: does not cross BBB, neuropsych/extrapyramidal effects rare Contraindications: phaeochromocytoma – hypertensive crises, previous extrapyramidal reaction, porphyria, parkinsons Precautions: children, MAOIs Interaction: additive with other CNS depressants; increased motility may affect absorption other drugs Dose: 10mg po/im/iv TDS slow push (rapid injection – anxiety), 20mg migraine

Butyrophenones Droperidol, haloperidol - Central D2 blockade: extremely sedating Adverse effects: extrapyramidal effects; droperidol - QT prolongation – associated with arrhythmias

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Phenothiazines Prochlorperazine MOA: central blockade at CTZ - M1 receptor, D2 receptor - sedation mediated by H1 blockade, cardiovascular effects due to alpha-adrenergic blockade PK: - A: 25% po bioavailability - D: Vd 20L/kg, t1/2 7 hrs - M: liver - E: faeces and urine Indications: antiemetic, vertigo, psychosis Contraindications: severe cardiovascular disease, hypotension Adverse effects: sedation, anticholinergic effects (dry mouth, blurred vision), hypotension, tachycardia, prolonged PR and QT intervals, decreases seizure threshold, hyperprolactinaemia, extrapyramidal signs/dystonic reactions, hypo/hyperthermia Dose: 5mg tds po, 12.5mg im/iv (iv not licensed)

5HT3 Antagonists Ondansetron MOA: central 5HT3A blockade; peripheral 5HT3A blockade – CTZ, extrinsic intestinal vagal and spinal afferents - no effect on D2/M1 receptors – no effect on gastric/oesophageal motility PK: - A: orally active, 60% oral bioavailability - D: Vd 2L/kg, PB 70% - M: hepatic - E: renal, t1.2 3 hrs iv, 4-11hrs po Uses: N/V especially post op or chemo Adverse effects: headache, dizziness, constipation, muscle pain, seizures, CP, prolonged QT but no reported arrhythmias Contraindications: severe hepatic impairment Dose: 4-8mg po/iv BD

Antihistamines - physiological antagonists (adrenaline opp action to histamine but act via different receptors) - histamine release inhibitors (sodium cromoglycate, beta blockers) - histamine receptor antagonists

Promethazine 1st generation antihistamine MOA: competitive H1 antagonist - action on vomiting centre, also acts on vestibular apparatus - some cardiovascular effects due to H2 effects, also antimuscarinic, anti-adrenergic and antiserotonergic effects PK: - A: orally active - D: widely distributed, crosses BBB - M: extensive hepatic - E: renal Uses: Anaphylaxis, allergic reactions, motion sickness, vestibular dysfunction, nausea; also LA due to Na blocking action Adverse reactions: Sedation, anticholinergic effects, orthostatic hypotension, excitation and convulsions in children Dose: 10-25mg po,im,iv

Loratidine 2nd generation antihistamine Other agents: Cetirizine, terfenadine, fexofenadine MOA: competitive H1 antagonist, some cvs effects due to H2, also antimuscarinic, anti-adrenergic, antiserotonergic effects PK: - A: orally active - D: widely distributed except CNS - M: extensive hepatic - E: renal Uses: Anaphylaxis, allergic reactions, motion sickness and vestibular dysfunction, nausea, also LA due to Na blocking

3 Adverse reactions: mild compared to first generation Interactions: terfenadine metabolised by CYP3A4 which is inhibited by grapefruit, ketoconazole and macrolides o assoc with QT prolongation and potentially toxic arrhythmias - fexofenadine the metabolite of terfenadine, lacks the cardiotoxic effects

Hyoscine (Scopolamine) Stereoisomer of atropine, anticholinergic MOA: direct antagonist effect on muscurinic cholinergic receptors; also acts at vomiting centre and vestibular apparatus - relaxation of smooth muscle of bowel, stimulates sphincters, decrease secretions and saliva - tachycardia, euphoria, drowsiness, amnesia, delirium PK: - A: well absorbed po, 1 st pass effect so only moderate bioavailability - D: Vd 1.2 L/kg - M: almost completely metabolised - E: t1/2 redistribution 5mins/elimination 2 hrs Uses: pre-op (sedation, decrease secretions), motion sickness, PONV, decrease secretions in terminally ill Contraindications: narrow-angle glaucoma, intestinal and bladder neck obstruction, children, Down syndrome Adverse effects: anticholinergic effects, may cause bradycardia in low doses Interactions: additive with other anticholinergics Dose: im 0.3-0.6mcg, transdermal patch 0.5 mg over 72 hrs

Other antiemetics Benzodiazepines - act on cerebral cortex, used to control anticipatory nausea and vomiting Marijuana and derivatives (tetrahydrocannabinol) - unknown MOA, may involved CTZ Corticosteroids - unknown MOA

Tegaserod Specific 5HT4 agonist Uses: chronic constipation, irritable bowel Mechanism of action: increases cAMP dependent Cl secretion → increases stool liquidity; increases gastric emptying

Octreotide Synthetic octapeptide analog of somatostatin. Uses: inhibition of endocrine tumour effects, diarrhoea, variceal haemorrhage - reducing portal pressure PK: iv t1/2 1.5 hrs; sc t1/2 6-12 hrs Effects: - inhibits gastrin, CCK, glucagon, insulin, 5HT - decreases gastric/pancreatic fluid secretion/GI motility/inhibits gallbladder contractility - decreases portal and splanchnic blood flow, inhibits secretion of some anterior pituitary hormones

Laxatives Stool softeners - mineral oil, docusate, glycerin supp - Osmotic laxatives: non absorbable sugars (is lactulose) - metabolized by bowel bacteria - flatus, cramps - polyethylene glycol: colonic cleansing; no intravasc fluid or electrolyte shifts; does not cause cramps/bloating - Bulk-forming laxatives: indigestible, hydrophilic colloids; absorb water forming bulky gel – incr peristalsis - flatulence - Stimulant laxatives: anthraquinone derivatives: aloe, senna (chronic use causes melanosis coli)

Antidiarrhoeal agents - not for bloody diarrhoea, high fever or systemic toxicity; can be used to mild diarrhoea, IBS, IBD, stomas - Opioid agonists: incr colonic segmenting activity through inhibit presynaptic cholinergic nerves in submucosal/myenteric plexuses, leads to increased colonic transit time and faecal water absorption - Loperamide: doesn’t cross BBB, no analgesic properties or addiction potential or tolerance; dose: 2mg, 2 with first BM - Diphenoxylate: higher doses have CNS effects and dependence, preparations contain atropine to discourage overdose - Other antidiarrhoeals: colloidal bismuth, kaolin and pectin, bile-salt binding resins (cholestyramine), octreotide(carcinoid)

Antispasmodics - via anticholinergic activity - dicyclomine and hyoscine (buscopan) 10-20mg po/iv tds - inhibit muscurinic cholinergic receptors in the enteric plexus and on smooth muscle

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