GORD Flashcards
Drugs
NSAIDS: ibuprofen, naproxen, diclofenac
Proton pump inhibitors (PPIs): omeprazole, lansoprazole
Histamine (H2) receptor antagonists: ranitidine
Paracetamol (aka acetaminophen)
NSAIDS action
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. Prostanoids act through a large number of prostanoid receptors to produce a highly complex array of actions.
It is thought that the anti-inflammatory actions, and probably most of the analgesic & antipyretic actions, of the NSAIDs are related to inhibition of COX-2, while their unwanted effects are largely a result of inhibition of COX-1.
NSAIDS target
Cyclo-oxygenase (COX) enzyme
NSAIDS side effects
Common unwanted effects include 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.
NSAIDS other
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.
PPI action
Irreversible inhibitors of H+/K+ ATPase in gastric parietal cells. They are 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). Proton pump inhibitors inhibit basal and stimulated gastric acid secretion by >90%.
PPI target
H+/K+ ATPase (‘proton pump’)
PPI side effects
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.
PPI other
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.
Histamine receptor antagonist action
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%.
Histamine receptor antagonist target
Histamine H2 receptors
Histamine receptor antagonist side effects
Incidence of side-effects is low. Diarrhoea, dizziness, muscle pains & transient rashes have been reported.
Cimetidine (but not other H2 antagonists) inhibits cytochrome P450 and may retard the metabolism and potentiate the effects of a range of drugs incl. oral anticoagulants and TCAs.
Histamine receptor antagonist other
Ranitidine plasma half-life approx. 2-3 h – well tolerated so twice daily dosing effective. Undergo 1st pass metabolism (50% bioavailability). Low dose over-the-counter formulations available from pharmacies for short term use without prescription.
In 2020, ranitidine was the 37th most commonly prescribed drug in the West London area.
Paracetamol action
Still not totally clear.
At peripheral sites, may inhibit a peroxidase enzyme which is involved in the conversion of arachidonic acid to prostaglandins (1st step in this pathway involves the enzyme, cyclooxygenase). The ability of paracetamol to inhibit peroxidase can be blocked if excessive levels of peroxide build up (as is commonly seen in inflammation)
Activation of descending serotonergic pathways possibly via 5HT3 receptor activation.
Inhibits reuptake of endogenous endocannabinoids, which would increase activation of cannabinoid receptors - this may contribute to activation of descending pathways.
Paracetamol target
Unclear.
5HT3 receptors/Cannabinoid reuptake proteins/Peroxidase
