Drugs acting on the gastrointestinal tract 2015

Drugs used to inhibit or neutralise gastric secretion to reduce acid secretion and peptic ulceration (both duodenal and gastric), reflux oesophagitis (in which gastric juice causes damage to the oesophagus) Etiology: - increased mucosal irritation - mucosal-damaging mechanisms - acid, pepsin,stress, alcohol, cigarette smoking…) - decreased mucosal-protecting mechanisms of the stomach - NSAIDs consumption - PGS synthesis is diminished (PGE1-2 stimulates mucus and bicarbonate secretion, decreases acid secretion and causes vasodilation), PGI2 inhibits acid, stimulates mucus and bicarbonate secretion - infection of the stomach mucosa with Helicobacter pylori (chronic gastritis)

Regulation

GASTRIC PARIETAL CELL intersticial fluid bazolaterall membrane apical M - muscarinic receptor PGR - prostaglandin E2 receptor ECHB –enterochromaffin cells Gs a Gi - G-proteins cAMP - cyclic AMP Ac - adenylyl cyclase PK - proteinkinase PGE - prostaglandins E C - synport carrier for Cl- a K+ P = antiport, which exchanges Cl- and HCO-3 PP = proton-pump bazolaterall membrane Regulation of acid secretion by parietal cells is important in peptic ulcer. The secretion is an isotonic solution of HCl (150 mmol/L) with a pH less than 1. The Cl- is actively transported into canaliculi in the cells which communicate with the lumen of the gastric glands and thus with the lumen of the stomach. This Cl- secretion is accompanied by K+, which is than exchanged for H+ from within the cell by a PP. Carbonic anhydrase catalyses the combination of carbon dioxide and water to give carbonic acid, which dissociates into H+ and bicarbonate ions. The latter exchanges across the basal membrane for Cl- Three main stimuli act on the parietal cells: - gastrin (a hormon) - ACH (a neurotransmitter) - histamine (a local hormone) apical membrane

Treatment of peptic ulcers ANTACIDS HISTAMINE H2-RECEPTOR ANTAGONISTS PROTON-PUMP INHIBITORS TREATMENT OF HELICOBACTER PYLORI INFECTION DRUGS THAT PROTECT THE MUCOSA

Drugs used to inhibit or neutralise gastric secretion - ANTACIDS symptomatic relieve in peptic ulcer - act by neutralising gastric acid and thus raising the gastric pH. This has the effect of inhibiting peptic activity, which practically ceases at pH 5. They vary widely in their potency The antacids in common use are salts of magnesium and aluminium - magnesium trisilicate, aluminium hydroxide, alginates given 1 and 3 hours after each meal and at bedtime used in dyspepsia, can be effective in promoting healing of duodenal ulcers, their benefit in gastric ulcers is less clear oesophageal reflux

Histamine H2-antagonists competitively inhibit histamine action at all H2 –receptors - reduce gastric acid secretion. They inhibit histamine - gastrin - and ACH-stimulated acid secretion: both basal and food stimulated by 90% and promote healing of duodenal ulcers Relapses are likely to follow when treatment with H2 –receptors antagonists is stopped (cimetidin - a CYP450 inhibitor) ranitidine famotidine Adverse effects: diarrhea, dizziness, muscle pain, transient rashes

Proton-pump inhibitors Inhibit the terminal step in the acid secretory pathway – the proton pump which results in marked inhibition of both basal and stimulated gastric acid secretion i.v./p.o. - given orally (as capsules containing enteric-coated granules) they are absorbed and distributed into the parietal cells and then accumulate in the canaliculi (a single daily dose affects acid secretion for 2-3 days) weak bases - accumulate in the acid environment of the canaliculi of the stimulated parietal cells where they are activated. This preferential accumulation in areas of very low pH, such as occur uniquely in the secretory canaliculi of gastric parietal cells, results in a specific effect on these cells

Proton-pump inhibitors omeprazole, esomeprazole, lanzoprazole, pantoprazole Adverse effects (not very common) - headache, diarrhea, rashes… used in: peptic ulcer reflux oesophagitis as one component of therapy for Helicobacter pylori infection Zollinger-Ellison syndrome (a rare condition caused by gastrin-secreting tumours)

Treatment of Helicobacter pylori infection H.pylori is implicated in the production of gastric and, more particularly, duodenal ulcers and is a risk factor for gastric cancer Combination therapy with three drugs is employed to eradicate H.pylori like: omeprazole + amoxicillin+ metronidazole or omeprazole + clarithromycin + amoxicillin (tetracycline) + bismuth chelates Elimination of the bacillus can produce long-term remission of ulcers but reinfection can occur

Drugs that protect the mucosa enhance the mucosal protection mechanisms and/or provide a physical barrier over the surface of the ulcer Bismuth chelate - out mucosal-protecting effects - coating the ulcer base, adsorbing pepsin, enhancing local PG synthesis, stimulating bicarbonate secretion Adverse effects - nausea, vomiting, blackening of the tongue and faeces toxic effects on the Hellicobacter - used as one component of therapy for H.pylori infection

Drugs that protect the mucosa Sucralfate a complex of aluminium hydroxide and sulfated sucrose in the presence of acid acquires a strong negative charge and binds to positively charged groups in protein forms complex gels with mucus - decreasing mucus degradation and H+ ions diffusion - stimulates bicarbonate secretion and PGs production Adverse effects - constipation (in 15% of patients treated), less common: dry mouth, headache, rashes Reduces the absorption of a number of other drugs including fluorochinolone antibiotics, theophylline, tetracycline, digoxin…

Drugs that protect the mucosa Misoprostol A stable analogue of PGE1 which inhibits gastric acid secretion, both basal and stimulated by food or histamine by a direct action on the parietal cells. It increases mucosal blood flow and augments the secretion of mucus and bicarbonate Adverse effects - diarrhea, abdominal cramps, uterine contractions used to prevent gastric damage that can occur with chronic use of NSAIDs

PROKINETICS drugs increasing GIT motility These drugs increase: Tonus of the lower oesophageal sphincter (inhibition of gastro-intestinal reflux) Gastric emptying (improve gastroparesis and functional dyspepsia) intestinal motility (increased peristalsis) Mechanisms of Action Antagonism at D2 receptors – desinhibition of myenteric motor neurons leads to the increased ACh release Modulation of 5-HT receptors (5-HT4, 5-HT1) – complex effects resulting in increased ACh release (among others)

Prokinetics Domperidon Mechanism of action: predominantly a D2-antagonist It does not cross the blood-brain barrier ! But it affects those CNS areas which lack the barrier - area postrema (antiemetic action ) - hypophysis ( prolactin secretion ) Adverse reaction: galactorrhea, gynecomastia, amenorrhea Metoclopramide Mechanism of action is more complex: D2-antagonism, 5HT4 receptor agonism, sensitisation of M receptors - antiemetic action - CNS adverse effects: extrapyramidal (parkinsonian-like symptomes)

Prokinetics (Cisaprid) Just for your information: Mechanism of action: an agonist on 5-HT4 receptors It was quite potent and often used drug! It was recently withdrawn in number of countries due to the increased risk of arrhythmias - „torsades de pointes“ It is uncommon polymorphous ventricular tachyarrhythmia with potentially fatal outcomes (associated with long QT-interval) Itopride - D2-antagonist/Acetylcholinesterase inhibitor

ANTISPASMODICS (SPASMOLYTICS) Drugs used to relieve spasms of smooth muscle in the GIT Two main groups of drugs: A) drugs affecting autonomic innervations – (anticholinergics and parasympatolytics) B) drugs directly affecting smooth muscle function Combination with analgesics (pethidine, codeine, tramadol, metamizol) = spasmo-analgesic preparations Indications and therapeutical use: Irritable bowel syndrome, flatulent distension of the abdomen (meteorism), smooth muscle spasms Spasmo-analgesics: in biliary, renal and intestinal colics (also in spastic dysmenorrhoea etc.)

Antispasmodics 1. affecting autonomic innervations Parasympatolytics (antimuscarinics) Antagonists on M – receptors Spasmolytic effect on smooth muscle but they tend to have rather opposite effects on sphincters (e.g. Oddi) Drugs: atropine, trospium, tolterodine Adverse effects (relatively frequent): xerostomia, mydriasis, cycloplegia, increased ocular pressure, urinary retention and Anticholinergics Antagonists on both M and N types of cholinergic receptors Spasmolytic effects on both smooth muscle and sphincters Often in combination with other drugs Quarternary amines – low/slow absorption (low adverse effects on the CNS) Drugs: otilonium, fenpiverine, pitophenone, buthylscopolamine

Antispasmodics 2. directly affecting smooth muscle Different mechanisms of action are involved: inhibition of Ca2+ channels, activation of K+ channels, stimulation of NO synthesis Drugs: papaverine (opiate) and drotaverine, mebeverine, alverine, pinaverine