Gastrointestinal Pharmacology

Gastrointestinal Pharmacology : 

Gastrointestinal Pharmacology Dr Areles Molleman

Gastrointestinal pharmacology : 

Gastrointestinal pharmacology Aims To review gastrointestinal pathophysiology of common gastrointestinal disorders To introduce you to current drug intervention

Study materials : 

Study materials This presentation On-line book (e-book): The Gastrointestinal System at a Glance by S. Keshav Access via Voyager, make sure you are logged into Athens Chapters 26-34, 47 about mechanism and treatment of the most common GI disorders You can print the relevant pages (20) Other text books and reviews

Nausea and vomiting : 

Nausea and vomiting Keshav, ch. 26

Some causes of vomiting : 

Some causes of vomiting Overindulgence Pregnancy Motion sickness Foul smells Horrific sights Radiation Chemotherapy Anxiety Infection Extreme pain Intestinal obstruction Opiate analgesics Surgery Intracranial pressure Pyloric stenosis Tumour lysis syndrome Diabetic gastroparesis Labyrinthisis Vestibular neuronitis Pancreatitis Uraemia Some cancers Addison’s disease Hypercalcaemia Diabetic ketoacidosis Mesenteric ischaemia Anaesthetics Hepatitis

Structures involved in vomiting : 

Structures involved in vomiting

Neural pathways controlling vomiting : 

Neural pathways controlling vomiting

Prolonged vomiting : 

Prolonged vomiting Anorexia Dehydration Electrolyte imbalance Malnutrition Weakness Lethargy Depression Mallory-Weiss tears:

Anti-emetic drugs : 

Anti-emetic drugs Dopamine antagonists substituted benzamides: metoclopramide butyrophenones: haloperidol phenothiazines: chlorpromazine Corticosteroids: prednisolone Benzodiazepines: lorazepam 5HT3 blockers: ondansetron Cannabinoids

Post-operative nausea and vomiting : 

Post-operative nausea and vomiting Vomiting Centre opioids anaesthetics CTZ nitrous oxide gastrointestinal tract psychological hypotension vestibular input pharynx pain

Cannabinoids as anti-emetics : 

Cannabinoids as anti-emetics Natural or synthetic agonists for CB1/2 receptors CB1 receptors in the brain (and testes), CB2 receptors elsewhere G protein-coupled to cAMP (negative), and ion channels In use in some countries as anti-emetics: D9-tetrahydrocannabinol and nabilone

Diarrhea : 

Diarrhea Keshav, ch. 27, 32, 33

Clinical manifestations of diarrhoea : 

Clinical manifestations of diarrhoea Increased frequency of propulsive bowel volume of faeces Na+, K+, and water loss leading to Dehydration Hypovolumenia Shock Cardiovascular collapse If fluid balance is maintained: hypokalemia

Causes of diarrhoea : 

Causes of diarrhoea Osmotic diarrhoea excess of non-absorbable solute in the gut malabsorption of nutrients Secretory diarrhoea infections: most importantly toxins produced by micro-organisms, e.g.Vibrio cholerae or Escherichia coli inflammatory bowel disease Disorder of motility induced by other diseases diabetes parasites, enterotoxins, food allergies

Impact : 

Impact Current deaths ~ 2 million/yr worldwide (WHO) Cholera toxin (ChTX) a prototypic enterotoxin, was rife in London until mid 1850’s Rotavirus kills ~ 500,000 children (<5yr) per year Current management - oral rehydration salts Other proven therapies - vaccines and antibiotics, but both are short-lived and so not cost-effective

Malabsorption syndromes : 

Malabsorption syndromes Glucose/galactase malabsorption Inadequate lipolysis Decreased conjugated bile salts Abnormalities of mucosal cell transport non-specific: tropical sprue/celiacs, surgery specific: disaccharidase deficiency

Malabsorption effects : 

Malabsorption effects Decreased aminoacid uptake: wasting, hypoproteinema, oedema Decreased fat absorption: insufficient uptake of fat soluble vitamins A, D, K, and E Decreased uptake of bile salts: increased adenylyl cyclase activity in colon

Celiac disease (sprue) : 

Celiac disease (sprue) Intolerance of gluten Due to absence of gluten hydrolase Gliadin formation: stops formation of microvilli Leads to thinning of mucosa, general malabsorption, inflammatory response

Lactose intolerance : 

Lactose intolerance lactase deficiency genetic causes: loss of lactase activity in adulthood: Caucasian people : 15% Black and Asian people : 80-90% pathology (CO2 / H2 production, diarrhoea) aggravated by bacterial stimulation

Infectious diarrhoea : 

Infectious diarrhoea Non-inflammatory Mostly in small intestine No faecal WBC Examples: Vibrio cholerae Escherichia coli Giardia lamblia Cryptosporidium Inflammatory Invasive Mostly in colon Faecal WBC Examples: Shigella spp. Campylobacter jejuni Salmonella enteriditis Clostridium difficile

Epithelial transport : 

Epithelial transport Apical villous cells: NaCl co-transport (Na+/H+ and Cl-/HCO3- exchangers) crypt cells: Ca2+ / cAMP / cGMP dependent Cl- channel Basolateral Na/K/Cl co-transporter (entry) Na/K pump K channels

cAMP pathway : 

cAMP pathway ChTx, E.coli LT Monosialoganglioside receptor ADP-ribosylation of adenylyl cyclase Prolonged increase in cyclic AMP Activation of A kinase Increased Cl- secretion / inhibited NaCl absorption

Ribosylisation of Ga : 

Ribosylisation of Ga a -ADP-ribose a ADP-ribose + GTP GDP GTP GDP A1 A2 B B B B B Ganglioside-R A1 A2 A1 A2

Effects of ribosylisation : 

Effects of ribosylisation ChTx: activation of Gas in absence of agonists (bAR, prostaglandins) pertussis toxin (PTx): activation of Gai in absence of agonists (enkephalins, aAR, ACh, somatostatin)

Mechanism of increased Cl- secretion : 

Mechanism of increased Cl- secretion Cl- K+ Cl- Na+ cAMP PKA + + + Apical side Basolateral side

Cholera toxin - indirect pathways : 

Cholera toxin - indirect pathways 5HT epithelia lumen SMP MP cholera toxin or rotavirus sensory neuron secretory neuron Cl-, H20 SP SP ACh ACh VIP muscle muscle Contraction and pain Cox, 2006

Examples of non-bacterial infections : 

Examples of non-bacterial infections Giardiasis protozoan parasite infection most common: G. lamblia, G. intestinalis non-inflammatory (commensal) can attack brush border transmitted through contaminated drinking water or sexually Entamoeba hystolytica many strains are just commensal can destroy mucosa causing amoebic dysentery: haemorraghe, perforation, and peritonitis

Slide 28: 

Cryptosporidium fungal, water-borne/sexually transmitted normally 7-28 days illness, but causes deadly fulminant diarrhoea in AIDS patients Examples of non-bacterial infections

Prevention of acute infectious diarrhoea : 

Prevention of acute infectious diarrhoea Killing/avoiding micropathogens Cooking/peeling of foodstuff Vaccines pathogen specific only against very dangerous diseases not effective against TD

Slide 30: 

Drugs used to treat diarrhoea act by increasing intestinal transit time inhibiting secretion disabling micro-organisms and toxins Oral replacement therapy and rehydration is important Treatment of diarrhoea in general

Treatment of acute infectious diarrhoea I : 

Treatment of acute infectious diarrhoea I First aid oral rehydration therapy (ORT): glucose/salt solution stimulates SGLT1 Ganong, 1997

Treatment of acute infectious diarrhoea II : 

Treatment of acute infectious diarrhoea II Antimotility drugs loperamide (Imodium), diphenoxylate (Lomotil): synthetic opiates Bulk-forming agents polycarbophyl, methylcellulose, psyllium Adsorbents activated attapulgite (MgAl-silicate) activated charcoal

Treatment of acute infectious diarrhoea III : 

Bismuth reduces secretion by inhibiting pumps Pepto-Bismol Antibiotics only effective against bacteria big and increasing danger of resistance Antiprotozoics, antifungals Treatment of acute infectious diarrhoea III

Gastro-oesophageal reflux : 

Gastro-oesophageal reflux Keshav, ch. 30

Gastro-oesophageal reflux : 

Gastro-oesophageal reflux Gastro-oesophageal reflux is a normal occurrence Gastro-oesophageal reflux disease (GORD) occurs only when the normal anti-reflux mechanism fails Persistent reflux of acid gastric contents causes inflammation of the oesophageal mucosa – reflux oesophagitis Pepsin and bile from the duodenum may contribute Symptoms of ‘heart burn’: a burning retrosternal pain after food, hot drinks or alcohol, and made worse by lying down, stooping or bending

Gastric acid production : 

Gastric acid production

Antacids : 

Antacids A drug which neutralises an acid – gastric acid A weak base (B-) that combines with H+ (protons) B- + H+ = BH Consequences removal of H+ from stomach fluid raises the pH pepsin inactive when the pH > 4 Uses Dyspepsia symptomatic relief in peptic ulcer disease

Antacids examples : 

Antacids examples Aluminium hydroxide – a gel adsorbs pepsin, complexes phosphates in the intestine and increases their excretion, decrease excretion via kidney useful in treatment of kidney failure Magnesium carbonate Magnesium trisilicate – insoluble powder, reacts slowly, prolonged action, forms a viscous coating of colloidal silica Adverse effects: aluminium – constipation magnesium – diarrhoea Solution: Mix together and use

Antacids examples (contd.) : 

Antacids examples (contd.) calcium carbonate sodium bicarbonate – rapid, short lived action, CO2 belching Large or repeated doses – some may be absorbed from intestine leading to alkalosis Antacid preparations containing sodium should not be given to patients on a sodium-restricted diet

Alginates : 

Alginates Seaweed derivatives – react with acid to produce a viscous layer may be combined with antacids floats on surface of gastric contents reduces the effects of gastric reflux

Constipation : 

Constipation Keshav, ch. 28

Constipation : 

Constipation Decreased colonic transit is a complex phenomenon and is very common Common causes: Low dietary fibre intake Drugs: diuretics, analgesics and anti-cholinergic drugs Hirschsprung’s Disease Occurs more often in the elderly

Laxatives I : 

Laxatives I Treatment of constipation Need to promote propulsive activity Increasing faecal bulk – acts as stimulus for peristalsis and propulsion of intestinal contents bran ispaghula (plantain seeds) sterculia (karaya gum)

Slide 44: 

Laxatives II Osmotic laxatives – not absorbed, draw water into the small and large intestine eg. Magnesium salts osmotic effect plus release of CCK which stimulates intestinal secretion and motility adverse effects: CNS depression, heart block, neuromuscular block avoid in children and renal patients Lactulose disaccharide broken down by bacteria to galactose and fructose, which are fermented to lactic and acetic acid produces osmotic effect > 24hr

Laxatives III : 

Laxatives III (iii) Stimulant laxatives (purgatives) increase irritability of the intestine by stimulating enteric nerves, increase water and electrolyte secretion and peristalsis Senna: anthraquinone derivatives: emoidin pharmacologically active component, 6-12 hr Danthron – used in elderly and terminally ill (carcinogenic) Bisacodyl, suppository – stimulates rectal mucosa, 15 min Sodium picosulphate – oral use, clear intestine for surgery

Lubricants and stool softeners : 

Lubricants and stool softeners Dioctyl sodium succinate – detergent action, lowers surface tension, breaks up stools, stimulates fluid accumulation, may be combined with stimulant laxatives such as danthron Glycerol suppository stimulates colonic activity Liquid paraffin not recommended – impairs uptake of fat soluble vitamins

Site of action of laxatives : 

Site of action of laxatives 353-35.1

Ulcers : 

Ulcers Keshav, ch. 31

Mucosal protection : 

Mucosal protection pH 7 pH 2 Mucous layer Epithelial cells HCO3- HCO3-

Peptic ulceration : 

Peptic ulceration Gastric and duodenal ulcers Erosion of the mucosal surface Due to one of the following: Weak mucosal barrier- reduced HCO3_ and mucus secretion Excessive acid secretion – Zollinger-Ellison Helicobacter pylori infection

Chronic protection/aggression imbalance : 

Chronic protection/aggression imbalance Acid, proteolytic enzymes (e.g. pepsin), and bile digest the mucosal layer infection with Helicobacter pylori - production of ulcerogens Non-steroidal anti-inflammatory drugs, NSAID e.g. aspirin or indomethacin inhibits production of cytoprotective prostaglandins Trauma and disease - vasoconstriction and mucosal ischaemia Cigarette smoking

Peptic ulcer pathology : 

Peptic ulcer pathology

Clinical manifestations : 

Clinical manifestations Increased post-prandial and bombesin-stimulated plasma gastrin concentrations Increased parietal cell mass, evidenced by increased pentagastrin-stimulated maximal or peak acid output (about twice normal level) Increased basal, meal, and bombesin- or GRP-stimulated acid output Defective inhibitory control of acid secretion: meal stimulated secretion less inhibited by low intra-gastric pH, intraduodenal fat, or gastric antral distension

Factors in gastric acid secretion : 

Factors in gastric acid secretion Gastrin peptide released by G cells Stimulates parietal cell secretion, probably indirectly via histamine Trophic action on mucosa cells G cells are stimulated by increase in pH Somatostatin released by D cells Tonically inhibits all gastric secretion Gastrin releasing peptide (GRP) release by gastric nerves upon vagal stimulation Stimulates both D and G cells (eating signal)

H. pylori mechanism of increase in acid secretion : 

H. pylori mechanism of increase in acid secretion D cell G cell Parietal cell H+ somatostatin gastrin GRP Vagal nerve H. pylori

Eradication of Helicobacter pylori : 

Eradication of Helicobacter pylori Triple therapy - antibiotics and bismuth Metronidazole and either tetracyclin or amoxycillin with a bismuth preparation Omeprazole and amoxycillin, or clarithromycin Omeprazole, amoxycillin and metronidazole Ranitidine, amoxycillin and metronidazole Disadvantages - resistance of Helicobacter pylori to antibiotics- complicated treatment regimen- diarrhea, abdominal pain, fever, increased white blood cell count, rectal bleeding, pseudomembranous colitis

NSAID mechanism of ulceration: COX inhibition : 

NSAID mechanism of ulceration: COX inhibition PG effects Mucus production Blood vessel dilation HCO3- stimulation

Slide 58: 

Good COX bad COX

There is more to it than that : 

There is more to it than that No clear correlation between inhibition of COX and intestinal damage COX activity has often returned towards normal by the time ulcers are observed COX activity can be inhibited by more than 95% without apparent gastrointestinal damage Small doses of aspirin almost completely inactivate gastric COX, but there is progressive increase in gastric damage with increasing aspirin dose Aspirin causes no small intestinal injury in experimental animals, but it is an effective inhibitor of COX Damage has been observed within five to 10 minutes of oral administration of aspirin; this is too fast for a PG mediated process

2-stage hypothesis : 

2-stage hypothesis NSAIDs first damage cells by attacking their mitochondria (biochemical/ultrastructural damage) NSAIDs uncouple mitochondrial oxidative phosphorylation This leads to loss of cytoskeletal control over tight junctions and increased mucosal permeability. Concomitant leakage of calcium from mitochondria initiates a cascade of free oxygen species damage, further potentiating the permeability changes 2. Then aggravate macroscopic damage in the known ways

Anti-ulcer treatments : 

Anti-ulcer treatments Four approaches: - to reduce acid- to reduce pepsin- to increase mucosal resistance- to eradicate Helicobacter pylori

Control ofgastric acid secretion : 

Control ofgastric acid secretion

Drugs reducing acid secretion : 

Drugs reducing acid secretion Anticholinergic Drugs: Muscarinic receptor antagonists Atropine, propantheline, polidine, pirenzepine Histamine H2 receptor antagonists: Inhibit acid secretion simulated by histamine, gastrin and meals Cimetidine, ranitidine, famotidine, nizatidine 3. H+/K+ ATPase Inhibitor ‘proton pump inhibitor’ Pro-drugs activated by acid at site of production Non reversible proton pump inhibitor - interacts with SH group on the H+/K+ ATPase Omeprazole, pantoprazole, lansoprazole, rabprozole

Drugs which promote the healing of ulcers I : 

Drugs which promote the healing of ulcers I Bismuth Compounds Bismuth salts, e.g. subnitrate, carbonate, dicitrate, tripotassium dicitrato bismuthate - protective coat - complexes with gastric mucus - stimulates prostaglandin synthesis - antipeptic activity - increased formation of mucus and bicarbonate - anti-bacterial action (Helicobacter pylori - eradication 30% of cases) - binding of epidermal growth factor

Drugs which promote the healing of ulcers II : 

Drugs which promote the healing of ulcers II 2. Liquorice Extracts: Carbenoxolone sodium accelerates healing of gastric but not duodenal ulcers - anti-inflammatory properties - promotes mucus secretion, increases life-span of mucosal cells 3. Prostaglandins Misoprostol - PGE1 derivative - increased mucus and bicarbonate secretion - increased blood flow - useful in the treatment of NSAID induced gastric ulcer Adverse effects: diarrhoea, abdominal cramps, uterine contractions

Drugs which promote the healing of ulcers III : 

Drugs which promote the healing of ulcers III 4. Sucralfate: Aluminium salt of sucrose octasulphate - in acid solution - viscous gel - covers ulcer crater - bile and pepsin become adsorbed - pepsin inactivated - increased bicarbonate secretion - mucosa protected - binding of epidermal growth factor

Inflammatory Bowel Disease (IBD) : 

Inflammatory Bowel Disease (IBD) Keshav, ch. 34

Inflammatory Bowel Disease : 

Inflammatory Bowel Disease Two conditions Crohn’s disease - can affect any part of the GI tract Ulcerative colitis - affects only the large intestine Clinical features overlap: Diarrhoea Pain Periodic relapses Leads to nutrient deficiency

Inflammatory Bowel Disease : 

Inflammatory Bowel Disease Aetiology unknown Racial differences and geographical clusters Genetic Familial – conditions more common amongst relatives of a patient than in general population Environmental causes Diet – no evidence Smoking – patients with CD are more likely to be smokers increased risk of UC in non-smokers and ex-smokers (protective effect of smoking ??) 69

Medication for IBD : 

Medication for IBD Aminosalicylates (5-aminosalicytic acid - 5-ASA) Sulfasalazine, mesalazine etc. Reduction of inflammatory cytokines Corticosteroids TNF-a antibody Immunosuppressives (cannabinoids?)