1.12 - Pharmacology of GORD (core drugs) Flashcards
What classes of drugs are involved in GORD? (4)
- NSAIDs (increase GORD)
- proton pump inhibitors (PPIs)
- histamine (H2) receptor antagonists
- paracetamol (AKA acetaminophen)
What are some examples of NSAIDs? (3)
And what NSAID can be used for peptic ulcer?
- ibuprofen
- naproxen
- diclofenac
Celecoxib - COX-2 specific
What is the primary mechanism of action of NSAIDs?
- inhibit the enzyme cyclo-oxygenase (COX) which is the rate-limiting step for the production of all prostanoids (prostaglandins and thromboxanes) from arachidonic acid
- prostanoids act through a large number of prostanoid receptors to produce a highly complex array of actions
- COX-2 inhibition leads to anti-inflammatory, analgesic and antipyretic effects
- unwanted side effects due to COX-1 inhibition reducing PGs (PGs increase HCO3-, mucus production, blood flow, inhibit acid production)
What is the drug target for NSAIDs?
Cyclo-oxygenase (COX) enzyme
What are the main side effects of NSAIDs? (8)
- gastric irritation, ulceration, bleeding
- gastric perforation (extreme)
- reduced creatinine clearance and possible nephritis
- chronic renal failure in prolonged analgesic abuse over years
- bronchoconstriction in susceptible individuals (contraindication in asthma)
- skin rashes & allergies, dizziness, tinnitus
- adverse cardiovascular effects (hypertension, stroke, MI) may occur with prolonged use/pre-existing CV risk
- aspirin linked with rare but serious post-viral encephalitis (Reye’s syndrome) in children
What are the main uses of NSAIDs? (4)
- analgesics for relief of mild to moderate pain (e.g. MSK pain - osteoarthritis, headache, dysmenorrhoea)
- antipyretics to reduce fever
- anti-inflammatory drugs for control of chronic inflammatory diseases e.g. RA, OA
- aspirin only: anti-aggregatory agent to inhibit platelet aggregation in stroke/MI risk patients
What are some examples of PPIs? (2)
- omeprazole
- lansoprazole
What is the primary mechanism of action of PPIs?
- 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 is approx. 1hr but single daily dose affects acid secretion for 2-3 days
- PPIs inhibit basal and stimulated gastric acid secretion by >90%
What is the drug target of PPIs?
H+/K+ ATPase (proton pump)
What are the main side effects of PPIs?
- uncommon:
- headache
- diarrhoea
- bloating
- abdominal pain & rashes
- use of PPIs may mask gastric cancer symptoms
- omeprazole is an inhibitor of cytochrome P2C19 and has been reported to reduce the activity of e.g. clopidogrel, when platelet function is monitored
- increased fracture risk
What is some extra information about PPIs? (2)
- 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 given as capsules of enteric-coated granules
What is an example of a histamine (H2) receptor antagonist?
Ranitidine
What is the primary mechanism of action of H2 antagonists?
- competitive antagonists of H2 histamine receptors (structural analogues of histamine)
- inhibit stimulatory action of histamine released from enterochromaffin-like (ECL) cells on gastric parietal cells
- inhibit gastric acid secretion by 60%
What is the drug target of H2 antagonists?
Histamine H2 receptor
What are the main side effects of H2 antagonists?
- side effect incidence is low
- diarrhoea, dizziness, muscle pains and transient rashes have been reported
- cimetidine (not other H2 antagonists) inhibits cytochrome P450 and may retard metabolism and potentiate effects of a range of drugs including oral anticoagulants and TCAs
What is some extra information about H2 antagonists? (3)
- ranitidine plasma half-life is 2-3 hours and well tolerated so 2x daily dose is effective
- undergo 1st pass metabolism (50% bioavailability)
- low dose OTC formulations available from pharmacy for short term use without prescription
What is the main mechanism of action of paracetamol (acetaminophen)?
- still not totally clear
- at peripheral sites, may inhibit a peroxidase enzyme involved in converting arachidonic acids to prostaglandins (involves COX)
- the ability of paracetamol to inhibit peroxidase can be blocked if excessive levels of peroxide build up (common in inflammation)
- activation of descending serotonergic pathways possibly via 5HT3 receptor activation
- inhibits reuptake of endogenous endocannabinoids, which would increase activation of cannabinoid receptors - may contribute to activation of descending pathways
What is the drug target of paracetamol?
- unclear:
- peroxidase
- 5HT3 receptors
- cannabinoid reuptake proteins
What are the main side effects of paracetamol?
- relatively safe drug with few common side effects
- overdose can lead to:
- liver damage and less frequently renal damage
- nausea and vomiting are early features of poisoning (settle in 24h)
- onset of right subcostal pain after 24h indicates hepatic necrosis
What is some extra information about paracetamol? (3)
- anti-pyretic and analgesic
- NOT anti-inflammatory
- many medications contain paracetamol, must be careful not to OD
How do NSAIDs have an analgesic effect?
- NSAIDs inhibit COX, which produces prostaglandins
- PGs do not directly cause pain but sensitise peripheral nociceptor mediators (bradykinin and histamine) which causes pain
- NSAIDs inhibit this
- indirect effect on pain too - PGs mediate inflammation, and hence NSAIDs will reduce inflammation
How do NSAIDs have adverse effect on the stomach?
- non-selective so also target COX 1 (unintended –> side effect)
- acts on gastric mucosal cells to inhibit PG production and hence inhibition of PG-mediated protection of gastric mucosa
- PGs increase HCO3- release, mucus production and blood flow
For patients with osteoarthritis etc and requiring an NSAID for the pain, what can you co-prescribe to reduce risk of GI adverse events?
PPI
How might PPIs increase fracture risk?
Mechanism of action unclear, but 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
