Pharmacology of GORD Flashcards
1
Q
What is the seven step process when it comes to prescribing drugs?
A
- Identify the patient’s problem
- Specify the therapeutic objective
- Select a drug on the basis of comparative efficacy, safety, cost and suitability
- Discuss choice of medication with patient (and carer) and make a shared decision about treatment
- Write a correct prescription
- Counsel the patient on appropriate use of the medicine
- Make appropriate arrangements for follow up (Monitor/stop the treatment)
2
Q
What are the core drugs for the treatment of GORD?
A
- NSAIDS (Ibuprofen, naproxen, diclofenac)
- Proton pump inhibitors (PPIs): omeprazole, lansoprazole
- Histamine (H2) receptor antagonists: ranitidine
- Paracetamol (aka acetaminophen)
3
Q
What is GORD?
A
- Gastro-oesophageal reflux disease (GORD) is a common condition, where acid from the stomach leaks up into the oesophagus.
- It usually occurs as a result of the ring of muscle at the bottom of the oesophagus becoming weakened.
- GORD causes symptoms such as heartburn and an unpleasant taste in the back of the mouth. It may just be an occasional nuisance for some people, but for others it can be a severe, lifelong problem.
- GORD can often be controlled with self-help measures and medication. Occasionally, surgery to correct the problem may be needed.
4
Q
What is the primary mechanism of action for NSAIDS?
A
- NSAIDS inhibit the enzyme cyclo-oxygenase (COX) which is the rate-limiting step for the production of all prostanoids (prostaglandins & thromboxanes) from the parent arachidonic acid at the peripheral nociceptive nerve endings
- This reduces the products of the reaction (prostaglandins)- sensitise peripheral nociceptor to mediators (bradykinin and histamine) which cause pain (make the nerves much more sensitive to pain but note prostaglandins do not stop pain themselves)
5
Q
What is the target site for NSAIDS?
A
Cyclo-oxygenase (COX 2) enzyme
LOCATION= peripheral nociceptive nerve endings (analgesia)
6
Q
What are the main side effects of NSAIDS?
A
- NSAIDS also unintentionally target COX 1 enzyme at the gastric mucosal cells-inhibits PG mediated protection of gastric mucosa (PGs in gastric mucosal cells increase bicarbonate release, mucus production and increased blood flow/ vasodilation for digestion to protect the mucosa from acid)
- gastric irritation, ulceration and bleeding and, in extreme cases, perforation; reduced creatinine clearance and possible nephritis; and bronchoconstriction in susceptible individuals (contraindicated in asthma).
- Skin rashes & other allergies, dizziness, tinnitus.
- Adverse cardiovascular effects (hypertension, stroke, MI) may occur following prolonged use or in patients with pre-existing CV risk.
- Prolonged analgesic abuse over a period of years is associated with chronic renal failure.
- Aspirin has been linked with a rare but serious post-viral encephalitis (Reye’s syndrome) in children.
7
Q
What are the different/ main uses of NSAIDS?
A
- The main uses of NSAIDs are as analgesics for the relief of mild to moderate pain (e.g. musculoskeletal pain, headache, dysmenorrhoea); as antipyretics to reduce fever; as anti-inflammatory drugs for chronic control of inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis); and (aspirin only) as an anti-aggregatory agent to inhibit platelet aggregation in patients who are at risk of stroke or myocardial infarction.
- In 2020, ibuprofen was the 48th, naproxen the 45th and diclofenac the 92nd most commonly prescribed drugs in the West London area.
8
Q
How would you prevent the negative side affects of NSAIDS in the case of treating GORD?
A
- Stop for a short while to stop damage to mucosa
- Prescribe a PPI (decreases acid production; decreases damage to the mucosa) for people with no risk of GI adverse events this can be co perscribed with a non-selective NSAID
- for people with with high risk of GI adverse effects, perscribe a COX-2 selective NSAID and co perscribe PPI
9
Q
What is the primary mechanism of action of Omeprazole/ Lansoprazole?
A
- They are both proton pump inhibitors
- Irreversible inhibitors of H+/K+ ATPase in gastric parietal cells.
- They reduce the production of acid from parietal cells
- They are also weak bases and accumulate in the acid environment of the canaliculi of the parietal cells. This concentrates their actions there and prolongs their duration of action (omeprazole plasma half-life approx. 1 h but single daily dose affects acid secretion for 2-3 days).
10
Q
Describe the mechanism by which gastric acid is secreted
A
- Hydrogen ions are generated within the parietal cell through the dissociation of carbonic acid into H+ and HCO3- from CO2 + H20 -> H2CO3 reaction catalysed by carbonic anhydrase
- Bicarbonate is transported out of the basolateral membrane in exchange for chloride. The outflow of bicarbonate into blood results in a slight elevation of blood pH known as the “alkaline tide”
- Chlodride and potassium ions are transported into the lumen of the cannaliculus by ion channels.
- K+ enters parietal cells through sodium-potasssium pump (Na+/K+ ATPase)
- Hydrogen ion is pumped out of the cell, into the lumen, in exchange for potassium through the action of the proton pump (H+/K+ATPase); potassium is thus effectively recycled
- Histamine stimulates H2 histamine receptors to stimulate parietal cells to secrete gastric acid
11
Q
What is the target site for Omeprazole and Lansoprazole?
A
Target= H+/K+ ATPase (‘proton pump’)
Location= Parietal cell (secretory membrane)
12
Q
What are the main side effects of Omeprazole/ Lansoprazole?
A
- Unwanted effects are uncommon but may include headache, diarrhoea, bloating, abdominal pain & rashes.
- The use of these drugs may mask the symptoms of gastric cancer.
- Omeprazole is an inhibitor of cytochrome P2C19 and has been reported to reduce the activity of e.g. clopidogrel, when platelet function is monitored.
- Proton pump inhibitors are known to increase the risk of fracture- The mechanism of action is unclear, although absorption of calcium salts is pH dependent, so the change in pH induced by PPIs might be responsible for a reduction in absorption and decrease in calcium available for bone.
13
Q
What are the clinical implications of PPIs being prodrugs?
A
- Pro drugs= a biologically inactive compound which can be metabolized in the body to produce a drug.
- PPIs are pro-drugs which, at low pH, are converted into 2 reactive species which react with sulphydryl groups in the H+/K+ ATPase responsible for transporting H+ ions out of the parietal cells.
- Generally given orally but degrade rapidly at low pH so administered as capsules containing enteric-coated granules.
- In 2020, omeprazole was the 5th and lansoprazole the 10th most commonly prescribed drugs in the West London area.
14
Q
What is the primary mechanism of action of Ranitidine?
A
- It is a Histamine (H2) receptor
- H2 antagonists are competitive antagonists of H2 histamine receptors (structural analogues of histamine).
- They inhibit the stimulatory action of histamine released from enterochromaffin-like (ECL) cells on the gastric parietal cells. They inhibit gastric acid secretion by approximately 60%.
15
Q
What is the target site for Ranitidine?
A
- Histamine recetor antagonist
- Target= Histamine H2 receptors
