GORD/ Peptic Ulcer Pharmacology Flashcards
What are the drugs for GORD/ Peptic ulcer?
NSAIDS
Proton pump inhibitors (PPIs)
Histamine (H2) receptor antagonists
Paracetamol (aka acetaminophen)
Give examples of NSAIDs?
ibuprofen, naproxen, diclofenac
Give examples of PPIs?
omeprazole, lansoprazole
Give an example of Histamine (H2) receptor antagonists?
ranitidine
What is the drug target of NSAIDs?
Cyclo-oxygenase (COX) enzyme
What is the mechanism of action of NSAIDs?
- 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.
What are the main side effects of NSAIDs?
Common:
- gastric irritation, ulceration and bleeding (extreme cases= perforation)
- reduced creatinine clearance and possible nephritis
- 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.
What are the main uses of NSAIDs? (4)
- analgesics for the relief of mild to moderate pain (e.g. musculoskeletal pain, headache, dysmenorrhoea);
- antipyretics to reduce fever
- anti-inflammatory drugs for chronic control of inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis)
- (aspirin only) as an anti-aggregatory agent to inhibit platelet aggregation in patients who are at risk of stroke or myocardial infarction
What is the drug target of PPIs?
H+/K+ ATPase (‘proton pump’)
What is the 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 approx. 1 h but single daily dose affects acid secretion for 2-3 days).
Proton pump inhibitors inhibit basal (independent of eating) and stimulated gastric acid secretion by >90%.
What are the side effects of PPIs?
- 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 (anti-platelet medication), when platelet function is monitored
Are PPIs pro-drugs or active drugs? And what happens at low pH? And how are they administered?
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.
What are the drug targets of histamine receptor antagonists?
Histamine H2 receptors
What is the mechanism of action of histamine (H2) receptor antagonists?
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%
What are the side effects of histamine (H2) receptor antagonists?
Incidence of side-effects is low.
- Diarrhoea
- Dizziness
- muscle pains
- transient rashes
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.
What type of drug is ranitidine and what is its half-life?
Histamine receptor antagonist
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.
What is the drug target of paracetamol (acetaminophen)?
Unclear.
5HT3 receptors/Cannabinoid reuptake proteins/Peroxidase
What is the mechanism of action of paracetamol (acetaminophen)?
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.
What are the side effects of paracetamol (acetaminophen)?
Relatively safe drug with few common side effects.
OVERDOSE:
Liver damage and less frequently renal damage.
Nausea and vomiting early features of poisoning (settle in 24h).
Onset of right subcostal pain after 24h indicates hepatic necrosis.
What are the an/ antis of paracetemol?
analgesic and anti-pyretic
Does NOT possess anti-inflammatory activity.
Q3: Explain the mechanism of action of naproxen (non-steroidal anti-inflammatory) in terms of:
a) the analgesic effect at the knee joint and
b) the adverse effect within the stomach.
Also: having prescribed the Naproxen, should the GP make any changes to the prescription?
Joint Pain
* ‘Target’ – COX 2 enzyme (naproxen is non-selective i.e. also inhibits COX1)
* ‘Location’ – Peripheral nociceptive nerve endings (analgesia)
* ‘Effect’ – COX produces prostaglandins (PG). PGs do not directly cause pain themselves, but they sensitise peripheral nociceptors mediators (bradykinin and histamine) which causes pain. NSAIDs inhibit COX.
* Indirect effect on pain – PGs mediate inflammation, and hence NSAIDs will reduce inflammation
Stomach injury
* ‘Target’ – COX I enzyme (unintended leading to side effect)
* ‘Location’ – Gastric mucosal cells
* ‘Effect’ – Inhibition PG production and hence inhibition
of PG mediated protection of gastric mucosa
PGs in gastric mucosal cells protect from acid:
Increase Bicarbonate release
Increase Mucus production
Increase Blood flow
Can a patient be on diclofenac and naproxen?
Naproxen & diclofenac gel:
The patient should not have been on both oral naproxen AND topical diclofenac. Topical drugs can cause systemic side effects. Why would this have happened?
1. GP mistake
2. Communication failure
Possible options:
1. Stop the gel
2. Switch to ibuprofen
3. Stop NSAIDs completely
*Personally, I would stop all NSAIDs and consider re-introducing just oral ibuprofen
What other drug would the GP co-prescribe with naproxen in this case? What are the risk factors for gastrointestinal (GI) adverse effects?
