4. GI Tract Pharmacology Flashcards
GIT Pharmacology (3)
- 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
Anti-emetics & Emesis (vomiting) (3)
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
Dyspepsia (indigestion)
- 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
Causes & symptoms - dyspepsia
- 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)
Peptic ulcers
- 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
Treatments of dyspepsia
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)
Histamine H2 Receptor Antagonists (cimetidine, ranitidine) - Mechanism
- 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
H2RA Interactions
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
Proton Pump Inhibitors (Omeprazole) - Mechanism
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
PPI interactions (omeprazole)
- 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
Gastric antacids (systemic)
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
Gastric antacids (non-systemic)
- 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
Mucosal protective agents (4)
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
Treatment of IBD
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
Crohn’s disease
- 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
