4. GI Tract Pharmacology Flashcards
1
Q
GIT Pharmacology (3)
A
- Emesis (vomiting) & anti-emetics
- Dopamine receptor antagonists (metoclopramide, domperidone)
- Serotonin 3 receptor antagonists (ondansetron) - Indigestion (dyspepsia)
- Treatment of peptic ulcers
- Treatment of inflammatory bowel diseases
+ Crohn’s disease
+ Ulcerative colitis - Disorders of gastric motility & their treatment
- Constipation
- Diarrhoea
2
Q
Anti-emetics & Emesis (vomiting) (3)
A
Domperidone receptor antagonists:
- Metoclopramide:
- DR antagonist at the Chemoreceptor Trigger Zone (CTZ), + 5HTR antagonist in CTZ/GI tract
- Due to also acting on DR in the CNS, extrapyramidal side effects & drowsiness are seen - Domperidone:
- Peripheral selective D2/3R antagonist, doesn’t cross blood-brain barrier (BBB)
- Therefore less prone to central side effects
- May act on the CTZ (which lies outside the BBB) as well as the periphery to inhibit emesis
Serotonin receptor antagonist:
- Ondansetron:
- Selective, potent, 5HT3R antagonist at the CTZ, small bowel, vagus nerve
- Most efficacious for chemotherapy-& radiotherapy- induced nausea & vomiting
- Also used for post-operative nausea
- Fewer side effects – constipation & headaches & some cardiovascular effects
3
Q
Dyspepsia (indigestion)
A
- Dyspepsia is not a diagnosis or distinct condition, but rather a term to describe symptoms that may indicate more serious disease of the upper GI tract
- Described as pain/discomfort, difficult digestion, which may be accompanied by symptoms such as burning sensation, nausea, vomiting, bloating & belching
4
Q
Causes & symptoms - dyspepsia
A
- Non-ulcer dyspepsia (or functional) – no organic cause?
- Ulcers (infection of H. pylori or from medications such as NSAIDs)
- IBD (inflammatory bowel disease)
- Lifestyle – obesity
- Gastritis (inflammation)
- GORD (gastro-oesophageal reflux disease – acid reflux, heartburn)
- Hiatus hernia (top part of stomach pushes into lower chest thorough a defect in the diaphragm)
- Gallbladder disease
- Chronic appendicitis
- Cancer (e.g. Zollinger-Ellison syndrome – gastrin-producing tumour)
5
Q
Peptic ulcers
A
- 20% of patients with dyspepsia may have ulcers
- A benign lesion of gastric or duodenal mucosa
- Occurs at sites where mucosal epithelium is exposed to acid & pepsin
- Caused by increased acid production or intrinsic defect in barrier functions of mucosa
+ Infections of stomach mucosa by H. pylori bacteria
+ NSAIDs
+ Elevated mass of gastric parietal cells resulting in elevated gastric acid secretion
6
Q
Treatments of dyspepsia
A
Depends on symptoms & causative factor – using a combination of medications is common:
- Antibiotics for H. pylori infection +
- Acid suppressing medications:
+ Histamine 2 receptor antagonists (H2RA)
+ Proton pump inhibitors (PPIs) - Antacids (systemic & non-systemic) – reduce acidity of stomach juices (rapid onset of action for acute relief)
+ Mucosal protective agents (gastric cytoprotectants) - Prostaglandin analogues (misoprostol)
- Sucralfate
- Bismuth compounds
- Alginates (Gaviscon)
7
Q
Histamine H2 Receptor Antagonists (cimetidine, ranitidine) - Mechanism
A
- Competitive reversible antagonism of histamine H2 receptors
- Inhibit both basal gastric secretions & gastric acid secretion induced by histamine & other secretagogues
- Reduces gastric acid secretion (60%) – (mostly nocturnal HCl secretion)
- Inhibit the formation of cAMP
- Inhibit activation of H+/K+ ATPase pump
- Fast onset of therapeutic action but short duration
8
Q
H2RA Interactions
A
Cimetidine – metabolised in liver & is a strong inhibitor of many CYP450 isoenzymes
- Clinical importance – can lead to increased plasma levels of theophylline, warfarin, diazepam, phenytoin, nifedipine, propranolol etc
Ranitidine – has much lower affinity for CYP isoenzymes but due to pH changes it can affect absorption of other drugs e.g. midazolam bioavailability
9
Q
Proton Pump Inhibitors (Omeprazole) - Mechanism
A
Omeprazole:
- Weak base (pKa 4) which passes through the bloodstream to the parietal cell (located in gastric mucosa & secrete HCl)
- Accumulates in the acidic canaliculus of the parietal cells & is activated by low pH environment (confers specificity & this high safety profile)
- Irreversible covalent binding to disulphide bonds which directly inhibits the H+/K+ ATPase pump, reducing gastric acid secretion
- Most effective mechanism to inhibit gastric acid secretion (90%+), can raise pH up to pH 6
- Short T1/2 but long duration of action – 2-3 days
10
Q
PPI interactions (omeprazole)
A
- Omeprazole is metabolised by CYP2C19 (primarily) & CYP3A4 (minor pathway) in the liver
- Clinical importance – CYP2C19 polymorphisms exist
- Medicines that induce CYP2C19 or 3A4 (phenytoin, rifampicin & St John’s Wort) may lead to decrease omeprazole serum levels
- Omeprazole in combination with drugs metabolised by some CYPs may cause their elimination to be inhibited, resulting in
+ Increased serum concentration (e.g. diazepam CYP2C19-mediated demethylation
+ CYP3A4-mediated demethylation – carbamazepine - OR their activation can be inhibited – e.g. clopidogrel (activated by CYP2C19
- Increase gastric pH may change the ionisation, dissolution & absorption of some medications
11
Q
Gastric antacids (systemic)
A
Sodium bicarbonate (NaHCO3) – often used for symptomatic relief after meals:
- Acts rapidly
- Can be absorbed into bloodstream
- Neutralises by reacting with stomach acid & releases CO2
NaHCO3 + HCl -> NaCl + H2O + CO2
- Can cause metabolic alkalosis, electrolyte imbalance & belching
- Antacids high in sodium are not suitable for patients with hypertension, heart problems, or liver failure due to water retention
12
Q
Gastric antacids (non-systemic)
A
- Aluminium hydroxide (slow acting)
- Magnesium hydroxide (milk of magnesia – fast acting)
- Mylanta (AlOH + MgOH + Simethicone – antifoaming agent)
+ Symptomatic relief
+ Poorly absorbed in small intestine
+ Shouldn’t change systemic pH
Mechanism of action:
- Antacids are weak bases that react with excess acid in the stomach, neutralising gastric acid
Mg (OH)2 + 2HCl -> MgCl2 + 2 H2O
Side effects:
- Can chelate with medications, folate or iron in the GI tract
- Aluminium can interfere with phosphorus absorption & cause constipation
- Mg (OH)2 at higher doses (2-5g) is a laxative
13
Q
Mucosal protective agents (4)
A
Agents that protect the mucosal layer of the stomach which promote gastroprotection
- Misoprostol – analogue of PGE1 (used for prevention of NSAID ulcers)
Mechanism of action:
- Acts on parietal cells
- Inhibits cAMP
- Inhibits activation of H+ pump
- At lower doses, protective actions via stimulation of mucus production & increase mucosal blood flow
Can induce uterine contraction & diarrhoea – multiple daily dosing is required so not normally 1st line treatment
- Sucralfate (Complex of AlOH & sulphated sucrose) – used for duodenal ulcers
Mechanism of action:
- Reacts with HCl & releases Al – forms a viscous paste like material
- Also directly adsorbs pepsin
- Stimulates mucus & bicarbonate secretion & prostaglandin production
Don’t take with H2A or antacids which reduce acidic environment thus activation
- Bismuth chelate – used in combination regimes to treat H. pylori
- Toxic effect on bacillus & may prevent adherence to mucosa or inhibit its proteolytic enzymes
Mucosal-protecting actions:
- Coats ulcer base
- Adsorbs pepsin
- Enhances local prostaglandin synthesis
- Stimulates bicarbonate secretion
Small amounts absorbed – eliminated in urine
Side effect include Blackening of tongue & faeces (bismuth sulfide)
- Alginates (Gaviscon)
- Alginic acid combined with small doses of antacids
- Used for symptomatic relief of heartburn
- Non systemic
Mechanism of action:
- Forms protective barrier in the stomach to prevent acid entering oesophagus
- Precipitate into a gel in the presence of acid, traps CO2 -> foam that floats
Take 30 minutes after a meal, faster relief than H2RA, longer lasting than traditional antacids
14
Q
Treatment of IBD
A
Crohn’s (GI tract inflammation, swelling & thickening commonly of the small bowel & colon) & Ulcerative Colitis (colon inflammation) are the most common IBDs
2 goals for their medical management:
- To bring active disease into remission
- To keep the disease in remission
Drug treatments include:
- Corticosteroids
- Aminosalicylates (e.g. mesalazine / sulphasalazine)
- Immunomodulators e.g. Azathioprine/Infliximab – anti TNF-alpha
15
Q
Crohn’s disease
A
- Inflammation
- Can occur in all layers of the bowel wall
- Abdominal pain, diarrhoea, fever & weight loss
- Bouts of flare-ups & remission
- Bowel obstructions common
+ Increased risk of bowel cancer - Children show inability to maintain growth
- Genetics & environmental factors (smoking)
- Diagnosis is based on biopsy & appearance of bowel wall
- No cure, treatment manages symptoms, maintains remission & prevents relapse
- Antibiotics useful long term, corticosteroids, immunomodulators such as azathioprine & infliximab
16
Q
Azathioprine
A
- Immunosuppressant & anticancer agents – suppresses T cell activity more than B cells
- Azathioprine is converted to active metabolite mercaptopurine
- Purine analogue resembling adenine, imposter purine incorporated into DNA – inhibits nucleic acid & protein synthesis
- Acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes & lymphocytes
17
Q
TNF-alpha
A
- Potent immunosuppressant’s used for severe inflammatory disease
- 3 approved in NZ – adalimumab, etanercept & infliximab
- TNF-alpha is a pro-inflammatory cytokine that when overexpressed mediates chronic inflammation such as Crohn’s disease, Rheumatoid arthritis & ulcerative colitis
18
Q
Infliximab
A
- TNF-alpha chimeric mAb (25% mouse & 75% human)
- Binds to TNF-alpha with high affinity to stop it binding to its receptor on inflammatory cells
Does not affect TNF-beta - Given as a single IV infusions (1-2 hours) every few weeks
Side effects:
- Allergic reactions/rash (infusion related)
- Infections
- Nausea/vomiting/diarrhoea
19
Q
Ulcerative colitis
A
- Also an IBD but 2x as common as Crohn’s disease
- Continuous inflammation of the colon & 95% of cases have rectal involvement
- Affects the inner most lining of the colon
- The mucosa in patients with UC may be dominated by CD4+ non-T helper lymphocytes generating a humoral immune profile
20
Q
Aminosalicylates
A
Mesalazine & sulfasalazine:
- Sulfasalazine is the original
- Mesalazine is the active moiety of sulfasalazine & better tolerated (encapsulated & released when reaches small intestine/colon)
- Used for IBD & mild/moderate Crohn’s disease
- Oral & rectal preps
21
Q
Sulfasalazine & Mesalazine
A
- Act topically on the GI tract, inside the small intestine, decrease synthesis of inflammatory mediators
- Diminishes inflammation by blocking cyclooxygenase & inhibiting prostaglandin (PG) production in the colon
- Inhibits leuokotrienes, NFKB
- Scavenges free radicals
- Can be toxic to the kidneys
22
Q
Disorders of gastric motility
A
- Can be too slow (constipation) or too fast (diarrhoea)
- Depending on cause there are 3 main approaches to the treatment of diarrhoea:
+ Maintenance of fluid & electrolyte balance
+ Use of anti-infectives
+ Use of opiate agonist & muscarinic receptor antagonist
23
Q
Opioid receptors in the gut
A
- 3 classes: µ-,∂-,k- opioid receptors (MOR, DOR & KOR)
- In the GI tract MOR (GI) links to inhibition of Ach release – inhibits gut motility
- MOR also links to inhibition of Cl- secretion & passive water movement
24
Q
Loperamide - Imodium
A
µ opioid receptor agonist – like morphine
- Binds to MOR (relatively selective for the gut wall)
- Opens K+ channels (causing hyperpolarisation)
- This inhibits the opening of Ca channels
- This inhibits Ach release
- Leading to less activation of M3R on smooth muscle cells
- Causes decreased propulsive peristalsis, increased transit time in the intestine
25
Q
Loperamide
A
- Loperamide is given alone, bought OTC, does not cross BBB & causes no addiction nor analgesia
- Increases reabsorption of water & tone of anal sphincter
- Obvious side effect is constipation, cramps & drowsiness
26
Q
Summary: GIT Pharmacology
A
- Emesis (vomiting) & anti-emetics:
- Dopamine receptor antagonists (metoclopramide, domperidone)
- Serotonin 3 receptor antagonists (ondansetron) - Indigestion (dyspepsia):
- Treatment of peptic ulcers:
+ Antibiotics for H. pylori
+ Histamine H2 receptor antagonists – cimetidine, ranitidine
+ Proton pump inhibitors – omeprazole
+ Gastric antacids – sodium bicarbonate, aluminium hydroxide, magnesium hydroxide, Mylanta
+ Mucosal protective agents – misoprostol, sucralfate, bismuth chelate, alginates (Gaviscon)
-Treatment of IBD:
+Crohn’s disease – azathioprine (immunosuppressant), adalimumab, etanercept, infliximab (all TNF-alpha inhibitors)
+ Ulcerative colitis – mesalazine, sulfasalazine
- Disorder of gastric motility & their treatment
- Constipation – laxatives
- Diarrhoea – loperamide (Imodium)
