Pharmacology Learning Outcomes

By
 After the end of this lecture YOU will be able to
Dr. Muneeb  Describe what is Ulcer?
 What are the types of Ulcer?
 Describe the pathophysiology of the disease
 Describe principles of gastric and duodenal ulcers

Drugs acting on GIT 


Entail the drug therapy needed to treat gastric ulcers
Describe the common side effects of drugs used to manage ulcer disease

Peptic and dudonal

Ulcer
Dr. Syed Muneeb Anjum (Ph.D.)
IPS, UVAS University of Veterinary and
Animal Sciences 1 2

Normal defence mechanisms Physiology of Gastric Secretion

 If we have acids in our stomach how are we protected?  Fundus
 Protection from gastric acid and Pepsin  Mucosa
 Mucosal defences  Parietal cells
 Local Prostaglandins (PGs) and Nitric Oxide (NO) production  Secrete HCl and intrinsic factor
 Chief cells
 Why do we suffer from ulcers then?
 Secrete pepsinogen
 Failure of defence mechanism
 GASTRIC or DUDODINAL ULCER
 Antrum and pylorus
 G cells
 What shall we do for Treatment and prevention of this disease?
 Secrete hormone gastrin
 Decreasing gastric acidity

 Enhancing mucosal defence
 Role of Bacteria
 Helicobacter pylori
 Aggressive approach
 Antibiotic therapy included

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 Regulation of Gastric Secretion

By Adam L. VanWert, Pharm.D., Ph.D. - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=12677508 5 6

HCl secretion by Gastric Parietal cell Gastric acid secretion and its regulation
 Factors and their receptors regulating gastric acid secretion
 Neuronal
 Ach (M3), GRP (BB2) (gastrin-releasing peptide)
 Paracrine
 Histamine (H2)
 Endocrine
 Gastrin (CCK2)
 Location of receptors
 Basolateral membrane of parietal cells
 ECL (Enterochromafin cells)
 H2 Receptors
 The H2 receptor is a GPCR that activates the Gs–adenylyl cyclase–cyclic AMP–PKA pathway
 ACh and gastrin
 Signal through GPCRs that couple to the Gq-PLC-IP3-Ca2+ pathway in parietal cells
 GRP
 Uses the Gq-PLC-IP3-Ca2+ signaling pathway to activate gastrin secretion from G cells

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 Gastric acid secretion and its regulation Gastric acid secretion and its regulation
 Parietal cells  H+,K+-ATPase (the proton pump)  Role of ECL cells
 Activation by Cyclic AMP and the Ca2+-dependent pathways  Usually present in close proximity to parietal cells  Source of gastric histamine
 Causes exchange of H+ / K+ across parietal cell membrane  Histamine acts as a paracrine mediator, diffusing from its site of release to nearby parietal cells, where it activates H2
 Generates largest ion gradient in vertebrates receptors to stimulate gastric acid secretion
 Intracellular pH of about 7.3 and an intra-canalicular pH of about 0.8  Role of G cells
 Regulation from CNS  Antral G cells produce Gastrin  most potent inducer of acid secretion  multiple pathways stimulate its release
 Dorsal motor nucleus of the vagal nerve, the hypothalamus, and the solitary tract nucleus  e.g. CNS activation, local distention, and chemical components of the gastric contents
 Dorsal motor nuclei efferent fibers  Vagus nerve  Ganglia of ENS  Postganglionic vagal fibers  Ach  M3  Mechanism of release
receptors  Basolateral membrane of parietal cells  Some vagal fibers to the stomach also release GRP (a peptide of 27 amino acids)
 CNS regulates gastric acid secretion in response to the sight, smell, taste, or anticipation of food (the “cephalic” phase of  GRP activates the BB2 bombesin receptor on G cells
acid secretion)  Activates the Gq-PLC-IP3-Ca2+ pathway and causing secretion of gastrin
 ACh also indirectly affects parietal cells by increasing the release of histamine from the ECL cells in the fundus of the  Gastrin stimulates acid secretion indirectly by inducing the release of histamine by ECL cells, direct effect as well but lesser
stomach and of gastrin from G cells in the gastric antrum
 Role of D cells
 Role of ECL cells  Antral D cells produce Somatostatin  Inhibits gastric acid secretion
 Usually present in close proximity to parietal cells  Source of gastric histamine  Acidification of the gastric luminal pH to less than 3 stimulates somatostatin release
 Histamine acts as a paracrine mediator, diffusing from its site of release to nearby parietal cells, where it activates H2  Somatostatin suppresses gastrin release in a negative feedback loop
receptors to stimulate gastric acid secretion
 D cells are decreased in patients with H. pylori infection,  may contribute to excess gastrin production
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Parietal Cell H+,K+-ATPase Gastric acid secretion: A pharmacologist’s view

 H+/ K+-ATPase (proton pump)
 Enzyme responsible for secreting protons into the lumen of the gastric gland
 Chemical structure & genetic regulation
 A heterodimeric protein  composed of two subunits  products of two genes
 ATP4A gene  encodes the α subunit  contains the catalytic sites of the enzyme  forms the membrane pore
 ATP4B encodes the β subunit
 N-terminal cytoplasmic domain
 Transmembrane domain
 Highly glycosylated extracellular domain
 Working of H+/ K+-ATPase
 Hydronium ions bind to three active sites present in the α subunit
 Secretion involves conformational change allowing the movement of protons
 Movement is balanced by the transport of K+
 The stoichiometry of transport is pH dependent, varying between two H+ and two K+ per molecule of ATP to one of each
under more acidic conditions.
 Inhibiting the H+,K+-ATPase (or proton pump) is the mainstay of modern pharmacotherapy for acid-related disorders.

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 Gastric acid secretion: A pharmacologist’s view

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Proton Pump Inhibitors (PPIs) H2 Receptor Antagonists

 As discussed on board  H2 Receptor Antagonists
 Landmark in the treatment of acid-peptic disease
 Available as OTC drugs  Considered safe?
 Mechanism of Action and Pharmacology
 H2 receptor antagonists inhibit acid production by reversibly competing
with histamine for binding to H2 receptors on the basolateral membrane
of parietal cells
 Less potent than PPIs but still suppress 24-hour gastric acid secretion by
about 70%
 Suppression of basal and nocturnal acid secretion is about 70%
 Evening dosing of an H2 receptor antagonist is adequate therapy for
suppression of nocturnal acid secretion
 Important in the healing of duodenal ulcers
 Not recommended for bleeding ulcers  no evidence of improvements
 Don’t have any effects on H1 receptors

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 H2 Receptor Antagonists H2 Receptor Antagonists
 Pharmacokinetics
 After oral administration
 Distributed widely throughout the body
 Including into breast milk and across the placenta
 A small fraction is protein bound
 Patient with renal dysfunction  dosage adjustments are needed
 All except Nizatidine also available in IV formulations Indications Contra-indications Adverse Effects

 Adverse Effects ! Bismuth Subsalisylate

 Ranitidine • Peptic Ulcers Cimetidine • CNS effects
• Acute stress inhibits P-450 • Diarrhoea
 Has been called off due to presence of N-nitrosodimethylamine (NDMA) ulcers enzyme • Headache
 Hepatotoxic and a known carcinogen in lab Animals • GERD systems  • Drowsiness
• Fatigue
 Cimetidine • Muscular pain
• Constipation
 Acts as nonsteroidal antiandrogen
 Displaces dihydrotestosterone from its cytoplasmic receptor, increases plasma prolactin and inhibits degradation of estradiol by liver
 Long term use may cause Gynecomastia and galactorrhoea in male
 High doses given for long periods have produced, loss of libido, impotence and short-lasting decrease in sperm count
 Tolerance may develop within 3 days of starting treatment
 May be resistant to increased doses of the medications 17 18

Agents That Enhance Mucosal Defence Agents That Enhance Mucosal Defence
 Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1)  ADME
 Synthetic analogue of PGE1 that is FDA approved to prevent  Rapidly absorbed after oral administration
NSAID-induced mucosal injury  Rapidly and extensively de-esterified to form misoprostol acid, (principal and active metabolite of the drug)
 Mechanism of Action and Pharmacology  A single dose inhibits acid production within 30 min
 Major prostaglandins synthesized by gastric mucosa  Therapeutic effect peaks at 60–90 min and lasts for up to 3 h
 Prostaglandin E2 and prostacyclin (PGI2)  major PGs  Food and antacids decrease the rate of misoprostol absorption
synthesized by the gastric mucosa  Free acid is excreted mainly in the urine, with an elimination t1/2 of 20 – 40 min
 Bind to EP3 receptors on gastric mucosal cells and parietal cells  Adverse Effects
 Stimulate the Gi pathway, thereby decreasing intracellular cyclic  Dose related Diarrhoea
AMP and gastric acid secretion
 Up to 30% patients  with or without abdominal pain and cramps  Self limiting in 2 weeks
 can prevent gastric injury by cytoprotective effects that include
stimulation of mucin and bicarbonate secretion and increased  More severe cases may necessitate drug discontinuation
mucosal blood flow  IBS
 Therapeutics uses  Misoprostol can cause clinical exacerbations of inflammatory bowel disease
 Rarely used  Contraindications
 Basal acid secretion inhibition  85 -95% @ 100-200 ug/day  Contraindicated for reducing the risk of NSAID-induced ulcer in women of childbearing potential
 Counter the effects of NSAIDs  Completely contraindicated during pregnancy
 It can increase uterine contractility
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 Agents That Enhance Mucosal Defence Sucralfate
 Pepsin-mediated hydrolysis of mucosal proteins  mucosal erosion and ulceration  Dose
 Prevention  Sulphated polysaccharides e.g. Sufralfate  1 g four times daily (for active duodenal ulcer) or 1 g twice daily (for maintenance therapy)
 Sucralfate  For children, it is given 40–80 mg/kg/d in divided doses every 6 h
 Consists of the octasulfate of sucrose to which Al(OH)3 has been added  Administration
 In pH < 4  sucralfate undergoes extensive cross-linking to produce a viscous, sticky polymer  sucralfate should be taken on an empty stomach 1 h before meals  activation by acid
 Adheres to epithelial cells and ulcer craters for up to 6 h after a single dose
 Use of antacids within 30 min of a dose of sucralfate should be avoided
 Inhibits hydrolysis of mucosal proteins by pepsin
 Adverse effects
 other cytoprotective effects
 Most common  Constipation (about 2%)
 Stimulation of local production of PGs and epidermal growth factor
 Should be avoided in patients with renal failure who are at risk for aluminium overload
 Sucralfate also binds bile salts  biliary esophagitis or gastritis
 Aluminium-containing antacids should not be combined with sucralfate in renal failure patients
 Therapeutic Uses
 Inhibition of Drug absorption
 Diminished used to treat peptic acid disease
 Sucralfate forms a viscous layer in the stomach that may inhibit absorption of other drugs
 Prophylaxis of nosocomial pneumonia induced stress ulcers
 E.g. phenytoin, digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics
 mucosal inflammation/ulceration  not responding to acid suppression
 Sucralfate therefore should be taken at least 2 h after the administration of other drugs
 Oral mucositis (radiation and aphthous ulcers) and bile reflux gastropathy
 The “sticky” nature of the viscous gel produced by sucralfate in the stomach  development of bezoars in some patients
 Rectal enema for radiation proctitis and solitary rectal ulcers

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Antacids Antacids
 NaHCO3, CaCO3, Mg2+ & Al3+ salts  Simethicone
 Cost effective, easily available and rapidly action  acute management of acid reflux (Heartburn) & esophagitis  A surfactant  may decrease foaming and hence oesophageal reflux  included in many antacid preparations.

 Mechanism of Action and Pharmacology  Therapeutic uses

 NaHCO3  effective neutralization of acid  Antacids are given orally 1 and 3 h after meals and at bedtime
 Very water soluble  Rapidly absorbed from stomach  Can be given as often as every 30–60 min in sever cases
 Alkali and Sodium  risk for patients with cardiac or renal failure  Should be administered in suspension form because this probably has greater neutralizing capacity
 Most antacids can elevate urinary pH by about 1 pH unit
 CaCO3  rapid action to neutralize gastric H+
 Releases CO2  Can cause belching, nausea, abdominal distention and flatulence  Adverse effects
 May also induce rebound acid secretion  With renal insufficiency, absorbed Al3+ can contribute to
 Combinations of Mg2+ (rapidly reacting) and Al3+ (slowly reacting) hydroxides  Osteoporosis, encephalopathy, and proximal myopathy.
 Provide a relatively balanced and sustained neutralizing capacity  preferred by most experts  About 15% of orally administered Ca2+ is absorbed, causing transient hypercalcemia
 Fixed combinations of Mg2+ and Al3+ theoretically counteract the adverse effects of each other on the bowel  The hypercalcemia from as little as 3 – 4 g of CaCO3 per day can be problematic in patients with uremia
 Al3+ can relax gastric smooth muscle, producing delayed gastric emptying and constipation  Milk-alkali syndrome (alkalosis, hypercalcemia, and renal insufficiency)
 Mg2+ exerts the opposite effects  when large doses of NaHCO3 and CaCO3 were administered commonly with milk or cream
 Magaldrate, a hydroxymagnesium aluminate complex,
 Converted rapidly in gastric acid to Mg(OH)2 and Al(OH)3
 Absorbed poorly and thus provides a sustained antacid effect
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 Other Acid Suppressants and Cytoprotectants Therapeutic Strategies for Specific Acid-Peptic Disorders
 The M1 muscarinic receptor antagonists  Gastroesophageal Reflux Disease (GERD)
 Pirenzepine and Telenzepine  Acid reflux or gastroesophageal regurgitation
 Suppress neural stimulation of acid production  Mild  non erosive esophagitis
 Act on M1 receptors of intramural ganglia  Severe  Erosive esophagitis
 Can reduce basal acid production by 40%–50  Characterized by endoscopically visible mucosal damage 
 Rarely used today can lead to adenocarcinoma
  poor efficacy, significant and undesirable anticholinergic side effects, and risk of blood disorders (pirenzepine)  Treatment goals
 Rebamipide (india, asia)  Complete resolution of symptoms and healing of esophagitis
 Cytoprotective  increasing PG generation in gastric mucosa and by scavenging reactive oxygen species  PPIs clearly are more effective than H2 receptor antagonists
in achieving these goals
 Ecabet (Japan)
 Increases the formation of PGE 2 and PGI2
 Carbenoxolone (Europe)
 Derivative of glycyrrhizic acid found in licorice root
 Cause hypokalaemia and hypertensionexcessive mineralocorticoid receptor activation
 Bismuth compounds
 Frequently prescribed in combination with antibiotics to eradicate H. pylori and prevent ulcer recurrence
 Bind to the base of the ulcer, promote mucin and bicarbonate production, and have significant antibacterial effects

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Gastroesophageal Reflux Disease (GERD) Gastroesophageal Reflux Disease (GERD)

 Mild GERD  GERD in pregnancy
 Some benefit form nocturnal doses of H2 receptor antagonists, but many need twice per day  Occurs in 30%–50% of pregnancies
 Sever GERD  Most drugs used to treat GERD fall in FDA category B, except Omeprazole  category C
 Twice-daily dosing with a PPI may be needed  Antacids or sucralfate are considered the first-line drugs
 Nocturnal acid breakthrough  PPIs  Twice daily + H2 receptor antagonist at night  Mild cases
 H2 receptor antagonists can be used, with ranitidine having the most established safety track record
 Sever Cases
 Omeprazole, lansoprazole, and pantoprazole are considered safe

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Common GI problems and management in Pregnancy

H+ / K+
ATPase

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