:) Gastrointestinal disease Flashcards
1
Q
7 Stool types:
A
Type 1: Severe constipation: Separate hard lumps
Type 2: Mild constipation: Sausage shaped
Type 3: Normal: Cracked sausage
Type 4: Normal: Soft sausage
Type 5: Lacking fibre: Soft blobs
Type 6: Mild diarrhoea: Mushy stool
Type 7: Severe diarrhoea: Watery, liquid
2
Q
Constipation: Definitions – 3
A
- Frequency of bowel movements: < 3 times a week
- Subjective (symptom-based) criteria: Infrequent stools, difficult stool passage, incomplete defecation. Stools dry, hard & abnormally large/small
- Clinical (function-based) criteria:
Primary – without known cause
Secondary – caused by a medical condition or a drug (S/E
3
Q
Primary constipation – 2
A
- The bowel is healthy but not working properly
- Result of lifestyle choices e.g. Social factors, Physical factors, Psychological factors
4
Q
Secondary constipation – 6
A
- Endocrine/metabolic diseases
- Systemic diseases
- Myopathy
- Neurologic disease
- Structural abnormalities
- Iatrogenic (drug-related)
5
Q
Constipation: Pathophysiology - 6
A
- Problems with nerves & muscle problems of lower intestine
- Slow constipation
- Problems with connection between brain & digestive system
- Irritable bowel syndrome with constipation
- Problems with nerves & muscles of rectum
- Dyssynergic defecation
6
Q
Constipation: Causes - 3
A
- Colonobstruction e.g.colorectal cancer
- Obstructed defecation: Alterations of anatomic morphology
- Opioid Induced Constipation
7
Q
Management of Chronic Constipation - 4
A
- Depend on whether primary or secondary
- Focus on underlying cause
- Increased intake of water & fiber
- Laxatives
8
Q
Laxatives: Bulk foring
A
Laxatives: Bulk-forming e.g.ispaghulahusk (Fybogel®)
increase the size & fluid content of stools
causes colonic distension & increased motility
9
Q
Laxatives: Stool softening
A
Laxatives: Stool softening e.g.docusate sodium (Docusol®;Dulcoease®)
reduce surface tension & increase the fluid content of stools
10
Q
Laxatives: Osmotic
A
Laxatives: Osmotic e.g. macrogol ‘3350’ (Movicol®); lactulose (Lactugal®), magnesium oxide
increase the volume & retention of intraluminal fluid
action of lactulose dependant on metabolism by the gut microbiota
11
Q
Laxatives: Stimulant
A
Laxatives: Stimulant e.g., Senna (Senokot®); Bisacodyl (Dulcolax®)
increase peristalsis & water/electrolyte secretion by themucosa
stimulate rectal and/or colonic nerves
actions of dependant on metabolism by the gut microbiota
12
Q
Management of opioid induced constipation: Naloxegol- 4
A
(Moventig®) – a potent, peripheral μ-receptor antagonist
- PEGylation limits ability to cross the blood-brain barrier
- binds to opioid receptors in the myenteric & submucosal plexuses
- blocks adverse actions on motility/secretion & reabsorption
- does not reduce pain relief when co-administered with other opioids
methylnaltrexone & naldemidine also used
13
Q
Management of chronic constipation: ‘Enterokinetics - 2
A
Prucalopride (Resolor™) - a selective 5-HT4 receptor agonist
Promotes motility & mucosal secretion
1. binds 5-HT4 receptors on presynaptic cholinergic neurons
2. increases ACh release by interneurons in the myenteric/submucosal plexus
14
Q
Define: Diarrhoea, Acute, persistent & chronic - 4
A
- Diarrhoea: Abnormal passage of loose or liquid stools more than three times daily &/or a volume of stool greater than 200 g/day’
Episodes of diarrhoea can be classified into 3 categories: - Acute – lasting less than 14 days
- Persistent – lasting longer than 14 days
- Chronic – lasting more than 4 weeks
15
Q
Results from the excessive secretion &/or impaired absorption of fluid & electrolytes across the intestinal epithelium.
A
Results from the excessive secretion &/or impaired absorption of fluid & electrolytes across the intestinal epithelium.
16
Q
Absorption in the Large Intestine - 4
A
Results from the excessive secretion &/or impaired absorption of fluid & electrolytes across the intestinal epithelium.
17
Q
Mechanisms of Diarrhoea - 4
A
- Osmotic
- Secretory
- Inflammatory
- Abnormal motility
18
Q
Mechanisms of Diarrhoea: Osmotic Diarrhoea - 3
A
- Excessive amounts of insoluble material in the lumen, water not reabsorbed
- Ingested solutespoorly absorbed
- Malabsorption e.g. lactose intolerance
19
Q
Mechanisms of Diarrhoea: Secretory diarrhoea - 4
A
- Abnormal ion transport, decrease in electrolyte absorption
- Excessive secretion and/or absorption across the intestinal epithelium
- Exposure to toxins = prolonged opening of Ca
- Other causative agents e.g. drugs
20
Q
Mechanisms of Diarrhoea: Inflammatory disease - 4
A
- Mucosal destruction
- Defective absorption of fluid & electrolytes
- Associated with both fluid & blood loss
- Caused by infection or disease
21
Q
Mechanisms of Diarrhoea: Abnormal motility - 4
A
- Increased motility leads to decreased absorption of fluid/electrolytes
- Increased or decreased contact time between luminalcontents & mucosal surface
- A problem within the muscles that controlsperistalsis
- A problem with the nerves or hormones thatgovern muscle contraction
22
Q
Causes of Diarrhoea - 3
A
- Viruses:Rotavirus and small round structured virus (SRSV; e.g., norovirus)
- Bacteria:Including Campylobacter , E. coli, Salmonella& Shigella
- Antibiotics: Any form of antibiotic treatment, but generally ‘broad-spectrum’
23
Q
Bacterial induced diarrhoea steps - 4
A
- Ingestion of organisms
- Intestinal colonization
- Mucosal invasion to intramucosal multiplication
Or 3. Cytotoxic elaboration - Diarrhoea
24
Q
- Ingestion of organisms
- Intestinal colonization
- Mucosal invasion to intramucosal multiplication
Or 3. Cytotoxic elaboration - Diarrhoea
A
- Ingestion of organisms
- Intestinal colonization
- Mucosal invasion to intramucosal multiplication
Or 3. Cytotoxic elaboration - Diarrhoea
25
Diarrhoea: Treatment & Management - 3
1. Oral rehydration solutions: Prevents dehydration e.g. DioralyteTM
2. Anti-motility drugs: Increase bowel tone & delay intestinal transit time e.g. loperamide
3. Anti-secretory drugs: Agents which reduce secretion e.g. bismuth subsalicylate
26
Oral Rehydration Solutions in the Treatment of Diarrhoea - 3
e.g. DioralyteTM
1. prevents or reverses dehydration
2. combination of sugars and salts, specifically sodium & potassium
3. stimulates water & electrolyte absorption from the GIT
27
Anti-Motility Agents in the Treatment of Diarrhoea - 4
e.g. Loperamide (Imodium®)
1. µ opioid-receptor agonist
2. slows down intestinal transit
3. inhibition of presynaptic cholinergic nerves in the submucosa & myenteric plexus
4. additional effects on absorption & secretion through other opioid receptors
28
Irritable Bowel Syndrome (IBS) Types - 3
IBS with diarrhoea (IBS-D)
IBS with constipation (IBS-C)
Both (IBS-M)
29
Pathophysiology of IBS - 8
1. Gut-brain disorder
2. Food hypersensitivity
3. Genetic disorder
4. Infection & disturbances in microbiota
5. Low-grade mucosal inflammation, immune activation, & altered intestinal permeability
6. Defect in the integrity of the mucosal epithelial barrier
7. Disordered bile acid metabolism
8. Abnormalities in 5-HT metabolism
30
Treatment of IBS - 2
1. Targeted towards symptoms rather than underlying pathophysiology
2. Disease classification defines treatment options
Includes: Antispasmodics, Laxatives, Anti-diarrhoeals, Antidepressants
31
Antispasmodics – 3
1. Smooth muscle relaxants
2. Alverine citrate: 5-HT antagonist: reduces sensitivity of smooth muscle contractile proteins to calcium
3. Hyoscine butylbromide (Buscopan®): Muscarinic antagonist: binds to M3 receptors on the smooth muscle
32
Laxatives e.g. Linaclotide - 5
1. Guanylate cyclase – C agonist
2. Acts on intestinal epithelial cells
3. Increases cGMP in cells
4. Leads to chloride & bicarbonate secretion into lumen
5. Results in increased fluid in lumen & improved transit
33
Anti-Diarrhoeals e.g. Loperamide - 4
1. µ- opioid receptor agonist
2. Slows intestinal motility
3. Increase transit time
4. Results in increase reabsorption of water & electrolytes
34
Antidepressants - 3
1. Tricyclic acid antidepressants (e.g. amitryptiline): Block the reuptake of serotonin (5-HT) & noradrenaline
2. Selective serotonin reuptake inhibitors (SSRIs) (e.g. Fluoxetine): Reduce the reuptake of serotonin (5-HT)
3. Beneficial effect on: Gut motility, Visceral hypersensitivity, GI transit speed
35
IBS Treatment, other approaches - 8
1. Increase soluble fiber in diet
2. Enteric-coated peppermint oil
3. Low FODMAP diet
4. Cognitive behavioral therapy (CBT)
5. Asimadoline and – k-opioid receptor agonist
6. Eluxadoline – a µ and k-opioid receptor agonist
7. Elobixibat – bile acid transport inhibitor
8. Rifaximin - antibiotic
36
Inflammatory Bowel Disease (IBD) - 2
1. Disorders involving chronic inflammation of the GI tract
e.g. Crohn's disease, Ulcerative colitis
2. Symptoms include: Diarrhea, Abdominal pain, Fatigue, Weight loss
37
Differences Between Crohn's Disease & Ulcerative Colitis - 4
1. Crohn’s is anywhere in gut, Ulcerative Colitis is limited to colon & large intestine
2. Crohn’s inflammation occurs in bowel, Ulcerative Colitis in left abdomen
3. Crohn’s ulcer penetrate entire abdominal lining, Ulcer penetrate only inner lining
4. Crohn’s bleeding is uncommon, Ulcerative bleeding is common
38
Inflammatory Response in IBD - 5
1. Genetic defect causes defective barrier clearance
2. Allows bad bacteria to best enter
3. Detected, but immune regulation is defective
4. Results in tissue injury, necrosis & fibrosis
5. Increased T cell presence & promotion of angiogenesis
39
IBD Treatment - 6
1. Aminosalicylates
2. Corticosteroids
3. Immunomodulators
4. Biologic therapies
5. JAK inhibitors
6. Combination therapy
40
IBD Treatment: Amino salicylates - 4
e.g. Mesalamine, Sulfasalazine, Olsalazine, Balsalazide
1. Anti-inflammatory effects through
2. Inhibiting COX
3. Scavenging free radicals
4. Effects on PPAR g
41
IBD Treatment: Corticosteroids - 2
e.g. Prednisolone, Budesonide
1. Alter immune cell function
2. Inhibit inflammation
42
IBD Treatment: Immune Modulators – Triple shared MoA - 6
e.g. Thiopurine drugs, 6-mercaptopurine, Azathioprine
1. pro-drug becomes pharmacologically active as 6-thioguanine nucleotides (6-TGN)
2. 6-TGN inhibits T-lymphocyte proliferation
3. Suppresses genes associated with intestinal inflammation & leukocyte trafficking to the gut including:
4. tumor necrosis factor (TNF)-related apoptosis-inducing ligand
5. TNF receptor superfamily member 7,
6. alpha-4-integrin
43
IBD Treatment: Biologic therapies - 4
1. Monoclonal antibodies that target specific aspects of the immune response
2. Inhibit TNF-α e.g. Adalimumab, Infliximab, Certolizumab, Golimumab
3. Inhibit IL-23 e.g. Risankizumab
4. Inhibit adhesion molecule expression e.g. Vedolizumab
44
IBD Treatment: JAK inhibitors - 5
1. JAK/STAT pathway principal signaling mechanism for a wide array of cytokines & growth factors.
2. JAK activation stimulates cell proliferation, differentiation, cell migration & apoptosis.
3. Tofacitinib approved for IBD
4. Upadactinib approved for IBD and UC
5. Fingotinib approved for UC
45
Coeliac Disease - 4
1. Chronic autoimmune disorder
2. Triggered by gluten ingestion in genetically susceptible individuals
3. Damages the small intestine
4. Diagnosed by blood test to look for presence of antibodies
A) IgA tissue transglutaminase antibody
B) IgA endomysial antibody
C) IgG deamidated gliadin peptide
46
Symptoms of Coeliac Disease - 10
1. Mouth Ulcers
2. Tooth enamel erosion
3. Diarrhea
4. Bloating
5. Constipation
6. Weight loss, malnutrition
7. Joint & muscle pain & swelling
8. Intestinal pain & nausea
9. Skin: brittle nails, acne or eczema
10. In females: infertility, miscarriage, early menopause
47
Autoimmune Response in Coeliac Disease - 7
1. Occurs in individuals expressing HLA-DQ2 or HLA-DQ8
2. Pro-inflammatory & pathogenic immune response towards certain parts of gluten & the intestinal tissue itself, resulting in structural changes
3. Pathogenic CD4+ T-cell response towards post-translationally modified gluten
4. Disease-specific B-cell responses towards deamidated gluten & the self-protein transglutaminase 2
5. Th1 cells that produce high levels of pro-inflammatory cytokines
6. APC cells secrete IL-15
7. Cytotoxic effects on epithelial cells
48
Treatment of Coeliac Disease – 3
1. Gluten free diet
2. ZED1227 tissue transglutaminase inhibitor
3. KAN-101 targets liver pathway to induce immune tolerance
Other Emerging therapies include
Blocking intestinal permeability
Peptidase therapy
Anti- IL-15 treatment
TG2 inhibition
Gluten tolerization
Gluten sequestration
Microbial therapy
49
Gastric acid info - 4
1. Stomach pH between 2 & 3
2. Aid food digestion - optimal for pepsin activity
3. Produced by the parietal cells
4. Defence mechanism against pathogens – bactericidal
50
Mucous neck cell
Mucous neck cell: Secretes:
Mucus (protects lining)
Bicarbonate (for Gastric acid, HCl production)
51
Parietal cells
Parietal cells: Secretes:
Gastric acid (HCl)
Intrinsic factor (Ca absorption)
52
Enterochromaffinc cell
Enterochromaffin cell: Secretes:
Histamine (stimulates stomach acid)
53
Chief cell
Chief cells: Secretes:
Pepsinogen
Gastric lipase
54
D cell
D cells: Secretes;
Somatostatin (inhibits acid)
55
G cell
G cells: Secretes:
Gastrin (stimulates acid)
56
Formation of hydrochloric acid – 8
1. CO2 diffuse from the blood into the stomach cell
2. CO2 combines with H20 to form H2CO3
3. H2CO3 dissociates into bicarbonate and H+
4. H+ is secreted into the lumen in exchange for K+ (by H+/K+ ATPase)
5. Bicarbonate is secreted into the plasma in exchange for Cl-
6. Cl- transported into the lumen through ion channels
7. H+ and Cl- combine to form HCl
8. Na+/K+ balance restored (by Na+/K+ ATPase)
57
Control of gastric secretion - 4
1. Histamine involved in the control of gastric acid secretion
2. Histamine released from enterochromaffin-like cells (ECL)
3. Acid secretion driven by activation of parietal cell H2 receptors by histamine
4. Muscarinic (parasympathetic) pathways act in synergy
58
Control of Gastric Acid Secretion in Parietal Cells - 4
1. ACh from nerves acting on M3 receptors stimulated in response to sight, smell, taste of food
2. Histamine from ECL cells acting on H2 receptors increases H+/K+ ATPase activity
3. Gastrin from G cells acts on cholecystokinin receptors in ECL & acts directly on parietal cell
4. PGE2 inhibits HCl release from parietal cells, stimulates bicarbonate secretion
59
Simulation of Gastric Acid Secretion - 3
1. Initiated by food in stomach
2. Reflex stimulation of enteric nerves
3. G cells directly responsive to foodstuffs
60
Inhibition of Gastric Acid Secretion - 4
1. Somatostatin from D cells
2. Inhibit histamine release from ECL
3. Directly inhibit parietal cells
4. Inhibit gastrin release
61
Stages of Gastric Acid Secretion - 8
1. Sight & thought of food stimulates taste & smell receptors
2. Hypothalamus & oblongata acts on Vagus nerve
3. Stomach distention acts on stretch receptors which acts on Vagovagal reflexes
4.This acts on the Medulla, which acts on Vagus nerve
5. Also acts on local reflexes
6. Food chemical activate chemoreceptors, activating G cells
7. Gastrin releases to blood
8. Local reflexes, Vagus nerve & Gastrin causes stomach secretion activities
62
Mucus Barrier in the Stomach - 5
1. Gel polymer of hydrated mucin glycoproteins
2. Secreted by surface mucous epithelial cells
3. Generates a continuous alkaline mucus barrier
4. Protects stomach lining from acid & pepsin
5. Mucus production under hormonal control
63
Peptic Ulcer - 4
1. Ulceration of stomach or duodenum
2. Symptoms: heartburn, abdominal pain, bloating
3. Associated with: H. pylori infection, Chronic NSAID use, Smoking, Stress
4. Complications – GI bleeding (potentially life-threatening), peritonitis, cancer
64
Gastric Ulcer Pathogenesis: Helicobacter pylori infection
- 3
1. Heliobacter pylori damage protective mucosal layer
2. The bacteria colonizes stomach mucosa
3. Acid passes through weakened mucus layer, causing an ulcer
65
Gastro Oesophageal Reflux Disease - GORD /GERD Symptoms - 5
Symptoms:
1. heartburn, acid reflux
2. Oesophagitis
3. bloating & belching
4. Nausea
5. pain when swallowing
66
Gastro Oesophageal Reflux Disease - GORD /GERD Complications - 4
Complications:
1. ulceration
2. scarring
3. Barrett's oesophagus
4. risk of oesophageal cancer
67
Treatment of Peptic Ulcer – Eradication of Bacteria: Heliobacter pylori
Helicobacter pylori
Thrives in acid environment
Strongly associated with ulceration (& increased stomach cancer risk)
Antibiotic therapy: Amoxicillin, metronidazole, clarithromycin
68
Treatment of Peptic Ulcer – Eradication of Bacteria: Bismuth chelate
Bismuth chelate:
Toxic effect on bacteria
Inhibits bacterial adhesion
Inhibits bacterial proteases
69
Treatment of Peptic Ulcer - Antacids - 5
1. Neutralisation of stomach acid
2. Sodium bicarbonate (Alka Seltzer): HCO3- buffers H+
3. Calcium carbonate (Tums, Rolaids): CO32- buffers H+
4. Aluminium hydroxide (Gaviscon: OH- binds H+
5. Magnesium hydroxide (Milk of Magnesia): OH- binds H+
70
Treatment of Peptic Ulcer – Inhibit Acid Secretion - 3
1. H2 antagonists
2. Cholecystokinin receptor antagonists
3. Proton pump inhibitors
71
Muscarinic Antagonists - 4
1. M1 selective antagonist e.g. pirenzipine
2. Inhibits vagus-induced histamine release
3. Non-selective muscarinic antagonist e.g. atropine
4. Also has direct effects on parietal cells
Parietal cells: Secretes:
Gastric acid (HCl)
Intrinsic factor (Ca absorption)
72
H2 Receptor Antagonists – 2
e.g. cimetidine, famotidine
1. Histamine released from ECL
2. H2 receptors on parietal cells blocked, no HCL secreted
Parietal cells: Secretes:
Gastric acid (HCl)
Intrinsic factor (Ca absorption)
73
Proton Pump Inhibitors (PPI) MoA - 2
1. Irreversibly block H+/K+ ATPase (proton pump) in parietal cell
2. Prevent H+ secretion
e.g. Omeprazole (Prilosec), esomeprazole (Nexium), pantoprazole
74
Proton pump inhibitors- 4
1. Oral dosage in enteric capsules as pro-drugs pass through stomach
2. Absorption in small intestine & into blood
3. Accumulate in acid environment of parietal cell canaliculi:
- selectively activated
- prolonged action
- increasing activity over 5-7 days
4. Irreversibly block the proton pump
75
Potassium-Competitive Acid Blockers (P-CABs) - 5
1. Proton pump inhibitor
2. Binds to potassium (K+ site)
3. Inhibit H+/K+ ATPase
4. Fast onset
5. Stable in acid conditions
e.g. vonoprazan
76
Combination Therapy - 4
1. PPI plus antibacterial therapy
2. Decrease acid secretion
3. Eliminate helicobacter
4. Combination therapy very effective
77
Treatment of Peptic Ulcer: Cytoprotective Drugs
Alginates e.g. Gaviscon
1. increase viscosity & tenacity of mucus
2. keeps the gastric contents in place
Sucralfate
1. reacts with HCl in the stomach to form a viscous paste like material
2. protective barrier at the ulcer surface
3. Also stimulates production of mucus & prostaglandins
4. S/E - reduces absorption of other therapeutic agents
78
Treatment of Peptic Ulcer: Prostaglandin Agonists - 6
1. Prostaglandin analogues – e.g. misoprostol
2. Orally active stable PGE1 analogue
3. Effects via different PG receptor subtypes on different target cells
4. reduces gastric acid & pepsin secretion via inhibition of ECL cell
5. stimulates mucus & bicarbonate secretion by epithelium
6. increases mucosal blood flow by dilator action on arterioles
79
Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) - 2
e.g. aspirin, indomethacin, ibuprofen
1. block production of prostaglandins
2. exacerbate or lead to gastric ulceration
80
Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) - 2
1. Exacerbate or lead to gastric ulceration
Multiple mechanisms
A) Direct irritation of stomach lining
B) Inhibit prostaglandin production via action on COX
2. Removes cytoprotective effects
3. Decreases platelet aggregation – increased bleeding
4. Stomach PG production is mainly by the COX-1 isoform
5. Celecoxib selective COX-2 inhibitors spare stomach
80
Achlorhydria - 3
1. No HCl production in stomach
2. Increased stomach pH
3. Caused by medication, gastric bypass surgery, H. pylori infection, stomach cancer
81
Anti-Ulcer Therapy – H2 Receptor Antagonists - 2
1. Target H2 receptors –discover a specific antagonist that can suppress acid release by histamine
2. Use Cimetidine, similar structure to histamine
82
Structure Activity Relationship (SAR)
Structure Activity Relationship (SAR):
Synthesise a range of compounds related to the lead compound (prototype) to allow one to see how structural variations affect activity
83
Strategies for converting agonists to antagonists
- 5
1. Histamine binding as an agonist.
2. Change of shape is stabilised, “switching on” the H2 receptor.
3. Histamine analogue binding as an antagonist.
4. Add extra structural units/functional groups to find extra binding interactions.
5. Block receptor activation.
84
Strategies for converting agonists to antagonists
- 4
1. Examples: Add extra hydrophobic units to the histamine lead structure
Results
2. Addition of extra hydrophobic groups does not produce antagonist activity.
3. Extra hydrophilic groups added instead.
4. Search for extra polar binding regions
85
Na-Guanylhistamine
- 3
1. A partial agonist - promotes HCl release, but less strongly than the histamine lead.
2. Prevents histamine from fully promoting the release of HCl.
3. Binds H2 receptor, resulting in weak activation, & whilst present, blocks histamine from binding, preventing complete activation.
86
Further development of H2 antagonist SAR
- 2
Strategy:
1. Chain extension – increase the length of flexible chain to push polar group further out & increase interaction with antagonist binding region.
2. Alter the polar group to distinguish between agonist & antagonist regions.
Partial agonist: Antagonist activity increases
No agonist activity: Very weak antagonist
87
Properties - 4
1. Inhibits H2-receptors & lowers levels of gastric acid released
2. Comparable activity to thiourea analogues, but fewer side effects
3. Excreted largely unchanged – forms hydrophilic metabolites
4. Inhibits cytochrome P450 enzymes (DDI with diazepam, lidocaine & warfarin)
88
Hydrophobicity - 3
1. Activity of drugs is often related to their hydrophobicity (changing substituents may have a significant effect). Quantified by log P values
2. Partition coefficient P = [Compound in octanol]/ [Compound in water]
3. High P = High hydrophobicity
89
Ranitidine (Zantac - Glaxo)
- 4
1. Includes the nitroketeneaminal group
2. Different heterocyclic ring (furan)
3. Fewer side effects, longer duration of action, 10 x more active than cimetidine
4. No inhibition of cytochrome P450 system
90
Gastric Acid Release and Anti-Ulcer Therapy - 4
1. HCl generated in parietal cells is exported into stomach by the proton pump (an enzyme complex).
2. Administering H2 antagonists (ranitidine, famotidine) prevents histamine from binding to H2 receptors on parietal cells & stimulating the proton pump to release HCl to the stomach
3. But, secretion of HCl may still be stimulated by gastrin & Ach acting on other parietal cell receptors.
4. To stop secretion of all gastric acid, the proton pump must be inhibited
91
The proton pump - 3
1. A.K.A a H+/K+-ATPase (pumps protons out of the parietal cell at the same time as it pumps potassium ions back in).
2. Energy required for the process is provided by hydrolysis of ATP to ADP, catalysed by ATPase.
3. Controls the final stage of the acid secretion process – inhibition provides a more potent & comprehensive control of gastric acid release (downstream of other targets like H2 receptors).
92
PPI: Mechanism of inhibition - 5
1. PPIs are weak bases (pKa1 = 4) & so are not ionised at pH of the intestinal fluid (6.5), or blood (7.4).
2. After crossing the membrane of parietal cells into acidic conditions of canaliculi (pH < 2), PPIs are ionised & cannot cross back into cell, so accumulate at site of action.
3. PPIs are prodrugs – activated at strongly acidic pH of canaliculi of parietal cells.
4. Specific chemical targets are the Cys residues of the proton pump.
5. Relative reactivity & chemical stability on PPIs depends on how easily the benzimidazole ring is protonated (pKa2).
93
PPIs have very few side effects because - 4
1. Target enzyme (proton pump) is only present in parietal cells.
2. Canaliculi of parietal cells are the only compartments in the body with sufficiently low pH to activate PPIs (inactive at neutral pH).
3. Protonation prevents drugs from returning to general circulation & leads [to] at the target site.
4. Once activated, PPIs react rapidly with the target.
94
PPIs are irreversible inhibitors (unlike H2 antagonists) - 2
1. Inactivation of the proton pump is complete meaning high potency
2. Gastric acid secretion is halted until new pumps are generated by the cell, meaning long duration of action.
95
Further SAR added groups to the benzimidazole ring & varied groups on the pyridine ring - 6
1. Benzimidazole ring shows increased activity:
2. Substituents which increase the basicity of the pyridine ring are good for activity.
3. Promotes the mechanism of activation.
4. Methyl substituents at the meta position have an inductive effect.
5. Methoxy substituent is more effective at para position than meta position.
6. Resonance effect increases electron density on the nitrogen.
96
Final optimisation - 4
1. PPI for clinical use needs to be reactive enough to undergo acid-catalysed activation in canaliculi of parietal cells, BUT stable enough to survive its journey through the bloodstream.
2. H159/69 is potent, but chemically too unstable.
3. Omeprazole as the best balance
4. Effective for eradication of H. pylori as part of triple therapy with at least two antibacterials (e.g. amoxicillin & metronidazole, clarithromycin).
97
Synthesis of Omeprazole
- 5
1. Straightforward synthesis but product is racemic.
2. Sulfur atom is tetrahedral.
3. Racemic product was marketed.
4. Pyridine portion to Benzimidazole portion to Omeprazole
5. Meta-chlorperbenzoic acid to Omeprazole
98
Omeprazole Enantiomer - 4
1. Omeprazole has a chiral centre.
2. The S-enantiomer has better potency and pharmacokinetic profile than R-isomer.
3. Patent on omeprazole expired in 1999, so the S-enantiomer was launched instead an example of chiral switching.
3. Superior performance of S-enantiomer is due to less hydroxylation by cytochrome P450 enzymes & a reduced clearance rate (no difference in mechanism of action
99
Nausea & Vomiting – Causes - 8
1. Ingestion of irritants, toxins, bacteria, virus
2. Motion sickness
3. Distention of stomach (large volumes)
4. Pharyngeal reflex
5. Psychological stress
6. Opioid therapy
7. Early pregnancy
8. Drugs e.g. chemotherapy
100
Nausea - 4
1. Sensation of imminent vomiting
2. Does not always lead to vomiting
3. Unease & discomfort in stomach
4. Less responsive to drug therapy
101
Vomiting (Emesis_ - 2
1. Forceful expulsion of stomach content
2. Preceded by profuse salivation, sweating, elevated heart rate & the sensation of nausea.
101
Emetics Humans - 4
1. NOT recommended in humans
2. Risk of acid aspiration & oesophagitis
3. Increased damage if corrosives ingested
4. Limited effect on poison absorption
101
Vomiting Centre (Emetic centre)
1. Cytotoxic chemotherapies can damage the GIT & activate abdominal vagal afferents.
2. Serotonin, SP & dopamine acting on 5-HT3, NK1 & D2 dopamine receptors respectively are thought to play pivotal roles in the neurotransmission that culminates in emesis.
3. The dorsal vagal complex encompasses the emetic centre, the area postrema & the vagal afferent terminals.
4. Sensory inputs are integrated at the dorsal vagal complex resulting in activation of abdominal muscles, diaphragm, stomach & oesophagus triggering the emetic response.
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Chemotherapy Induced Nausea & Vomiting (CINV) - 5
1. Cytotoxic chemotherapies can damage the GIT & activate abdominal vagal afferents.
2. Serotonin, SP & dopamine acting on 5-HT3, NK1 & D2 dopamine receptors respectively are thought to play pivotal roles in the neurotransmission that culminates in emesis.
3. The dorsal vagal complex encompasses the emetic centre, the area postrema & the vagal afferent terminals.
4. Sensory inputs are integrated at the dorsal vagal complex resulting in activation of abdominal muscles, diaphragm, stomach & oesophagus triggering the emetic response.
103
Post-Operative Nausea & Vomiting (PONV) - 3
1. PONV can be triggered by several perioperative stimuli, including opioids, volatile anaesthetics, anxiety, adverse drug reactions, & motion
2. Secondary to postoperative ileus - inhibition of GI motility following surgery
3. Volatile anesthesia decreases serum levels of anandamide, an endogenous cannabinoid neurotransmitter that suppress nausea & vomiting
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Motion sickness - 6
1. Travelling in a car
2. Inner ear sense motion (due to acceleration & deceleration)
3. Eyes are fixated & find us relatively immobile
4. Brain detects sensory conflict
5. Considers it a result of poison/toxin ingestion
6. Triggers vomiting to flush out toxins
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Morning sickness - 2
Several theories about cause:
1. Increasing levels of HCG or oestrogen overstimulate the Chemotherapy Trigger Zone
2. Increased production of stomach acid & hypoglycaemia may irritate the stomach & trigger vomiting
106
Anti-emetic drugs: Muscarinic receptor antagonist - 6
Muscarinic receptor antagonist – hyoscine (scopolamine)
1. Anti-cholinergic (like Ach)
2. Cross BBB
3. Action in vestibular system (M1 receptors)
4. Blocks parasympathetic nerve transmission
5. Can be administered by transdermal patch
6. S/Es – dry mouth, blurred vision, drowsiness
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Anti-emetics: Anti-histamines (H1 antagonists) - 6
Anti-histamines (H1 antagonists) – cinnarizine, promethazine, cyclizine
1. Act at vestibular nerve
2. Likely some anti-muscarinic activity
3. Useful in motion sickness
4. Limited efficacy against Chemotherapy Trigger Zone mediated vomiting
5. Promethazine sometimes used in severe morning sickness in pregnancy
6. S/Es – drowsiness, sedation
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Anti-emetics: 5-HT3 antagonists - 3
5-HT3 antagonists e.g. ondansetron, granisetron, dolasetron, palonosetron
1. Action in the CTZ & GI tract
2. Useful in PONV, & CINV
3. Not effective for motion sickness
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Anti-emetics: Dopamine receptor antagonists - 5
Dopamine receptor antagonists e.g. amisulphide, domperidone, metoclopramide, olanzapine, prochlorperazine
1. Neuroleptics
2. Many have anti-muscarinic properties
3. Action in the CTZ & GI tract
4. Administered as suppositories
5. Useful in PONV
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Anti-emetics: Neurokinin antagonists
Neurokinin antagonists e.g. aprepitant, tradipitant
1. Antagonism of substance P
2. Target CTZ, emetic centre & GIT
3. Usually as adjunct
4. Treatment of CINV
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Anti-emetics: Corticosteroids
Corticosteroids – dexamethasone
1. Direct action on emetic centre
2. Interaction with 5-HT and NK1 receptors
3. Reduce inflammation & stress
4. Treatment of CINV
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Anti-emetics: Prokinetics
Prokinetics e.g. domperidone, cisparide, mosaphide
1. Promote GI transit
2. Speed up gastric emptying
3. Likely target CB1 in GI tract
4. Used when vomiting induced by gastric stasis
113
Anti-emetics: Phosphorylated carbohydrate solutions
Phosphorylated carbohydrate solutions- emetrol
1. Contain dextrose/fructose
2. Reduce smooth muscle contractions
114
Anti-Emetics: Herbal - 5
1. Ginger may have benefits
2. Mechanisms unclear
3. 5-HT3 antagonist activity (like ‘-setrons’)
4. Ginger generally considered safe
5. Suggested by NICE and NHS in pregnancy & postoperative nausea
115
Non-pharmacological approaches to treating nausea & vomiting - P6 Stimulation - 4
1. P6 Acupoint Stimulation
2. Massage, bands, acupuncture, electrical stimulation
3. Many publications suggesting efficacy
4. In PONV reduced incidence of nausea, vomiting & need for anti-emetics
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Nausea & Vomiting in Pregnancy - 4
1. Drug risk to foetal health
NICE guidance:
2. Ginger
3. P6 pressure
4. Antihistamines – cyclizine, promethazine, prochlorperazine, chlorpromazine
