Pharmacology of GORD Flashcards
What are the 4 most common main drug classes prescribed for GORD?
- NSAIDs e.g. ibuprofen, naproxen, diclofenac
- Proton pump inhibitors (PPIs) e.g. omeprazole, lansoprazole
3. Histamine (H2) receptor antagonists e.g. ranitidine
- Paracetamol (aka acetaminophen)
What are some examples of NSAIDs?
Ibuprofen
Naproxen
Diclofenac
What is the primary 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 is the drug target site of NSAIDs?
Cyclo-oxygenase (COX) enzyme = both, COX1 and COX2
What are the main side effects of NSAIDs?
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
What is some extra information about NSAIDs?
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
What are some examples of proton pump inhibitors (PPIs)?
Omeprazole
Lansoprazole
What is the primary mechanism of action of proton pump inhibitors (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 and stimulated gastric acid secretion by >90%
What is the drug target site of proton pump inhibitors (PPIs)?
H+/K+ ATPase (‘proton pump’)
What are the main side effects of proton pump inhibitors (PPIs)?
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.
What is some extra information about proton pump inhibitors (PPIs)?
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 some examples of Histamine (H2) receptor antagonists?
Ranitidine
What is the primary 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 is the drug target site of Histamine (H2) receptor antagonists?
Histamine H2 receptors
What are the main side effects of Histamine (H2) receptor antagonists?
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.
What is some extra information about Histamine (H2) receptor antagonists?
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 primary mechanism of action of Paracetamol (aka acetaminophen)?
Its actions appear to be largely restricted to nervous tissue but its mechanism of action is unclear. Current hypotheses suggest both a central and peripheral action possibly involving interaction with a COX-3 isoform (inhibition of PG synthesis), cannabinoid receptors or the endogenous opioids. Interactions at 5HT & adenosine receptors have also been proposed.
What is the drug target site of Paracetamol (aka acetaminophen)?
Not yet well defined. COX-3 isoform?
What are the main side effects of Paracetamol (aka acetaminophen)?
Generally a very safe drug with few side-effects at therapeutic doses. It does not cause gastric irritation but in overdose serious hepatotoxicity may occur. Occasional allergic skin reactions.
What is some extra information about Paracetamol (aka acetaminophen)?
Paracetamol is not an NSAID as it has little anti-inflammatory activity. However, is a good analgesic for mild-to-moderate pain and also has antipyretic activity.
Legal restrictions on sales of paracetamol have significantly reduced the number of fatalities from overdose in the UK although, regrettably, ingestion of large amounts of paracetamol remains a common method of suicide.
What are the 7 steps to prescribe medications to patients in a clinical scenario?
- 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)
71M - Mr Alun Davies
PMH = oesteoarthris, treated with diclofenac gel (1%) and regular paracetamol
Returns to GP 2 months later with bilateral knee pain - medications help reduce but pain there when carrying out strenous activities
Prescribed naproxen (NSAIDS) = additional analgesic
Returns to GP 1 month later = improved osteoarthritis but new PC of intermitted abdominal pain keeping him awake at night for last 2 weeks
SOCRATES = dull, gnawing
What is the patient’s problem?
Osteoarthritis = pain = mobility issues in daily life
Naproxen prescribed = side effects = intermittent, dull, upper abdominal pain = likely to be peptic ulcerations
What is the therapeutic objective for Mr Davies?
Still continue to maintain pain relief for osteoarthritis - ensure it is not interfering majorly with daily life activities (or at least minimising the effect of activities)
Treat new stomach pain, ideally without compromising on pain relief treatment for OA
Prescribe something else to help with peptic ulcerations symptom side effects - e.g. PPI (omeprazole)
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
a) NSAIDs = inhibition of COX enzymes (non-specific)
NSAIDS e.g. naproxen is non selective - so inhibits COX1 and COX2 (both COX enzymes)
Act on peripheral nocioceptive nerve endings (analgesia)
Effects = Reduce COX producing prostaglandins (PG). PGs do not directly cause pain themselves, they just sensitise the pain receptors, so when inflammatory molecules (e.g. bradykinin and histamine) come in contact with the receptors, those are able to signal pain.
COX also has an indirect effect on pain - PGs mediate inflammation, so NSAIDS reduce inflammation
b) Also inhibits COX-1 enzyme
These are found in the gastric mucosal cells
So inhibition of PG = inhibition of PG mediated protection of gastric mucosa
COX-1’s production of PG = PG responsible for stimulation of gastric mucosal cells to produce gastric mucus and bicarb secretion, increased blood flow, and reduction in gastric acid - but if COX-1 is inhibited, these functions are inhibited = decrease in stomach pH = peptic ulcers
Should the GP make changes to the prescription?
Yes - stop naproxen as this is the underlying cause
The patient should not have been on both, oral naproxen and topical diclofenac
Why not should a patient not be on topical and oral NSAIDs?
Why did this happen?
Topical drugs can cause systemic side effects
Oral NSAIDs leave stomach wall exposed to the effect of the acid causing the pain
GP mistake OR communication failure
What solutions should the GP consider?
3 options:
Stop the gel
Switch to ibuprofen
Stop NSAIDs completely
Mr Davies follow up = OGD (oesophageal gastro duodenoscopy) and is diagnosed with peptic ulcer disease - no active bleeding and is negative for H. pylori
Determine what treatment you would initiate for his peptic ulcer disease?
First line treatment = treat underlying cause + PPI therapy
Stop NSAIDS where possible
Offer (full-dose) of PPI therapy for 4-8 weeks
PPIs reduce the acid secretion
Explain the mechanism of action of this drug (PPIs)?
Acts on H+/K+ ATPase (proton pump) in the gastric parietal cells (Secretory membrane)
Inhibit this pump = reduced acid production from parietal cells = fewer H+ pumped out into the stomach = reduces acidity of stomach
What should you do about Mr Davies’ treatment with naproxen?
Stop it completely
Interpret the data in the graph:
What is wrong with it?
100% of all >70y/o continure their PPIs for 3 months, this reduces to 90% at 4 months, 83% at 5 months, 50% at 10 months and 40% at 12 months
Of these, majority (95%) take the 40mg dose, and less than 5% take the 20mg dose
The data, however, accounts for all prescriptions of PPIs - maybe PPI was prescribed or continued for reasons other than peptic ulcer disease
What is the key take home message when comparing the guidance for omeprazole treatment (and PPIs in general) with the data in figure 1?
Massive discrepancy between guidelines and what happens in real life
Guideline = 20mg of 4-8 weeks treatment for peptic ulcer disease
Data suggests that most patients prescribed PPIs are treated for at least 3 months (above the recommended treatment duration 4-8 weeks) and treated at twice the standard treatment dose i.e. 40mg VS 20mg
Nearly 40% are still on 40mg after 12 months
Why is there such a discrepancy between the guidelines and reality?
Difficult to stop taking PPIs
Because once PPIs are stopped, rebound acid secretion = symptoms similar to initial symptoms prior to PPI starting
If Mr Davies suffered from osteoporosis as well, what drug would the GP have chosen to treat his peptic ulcer disease with?
Histamine (H2) receptor antagonist instead of a proton pump inhibitor
Why is a histamine (H2) receptor antagonist preferred over PPIs in those with osteoporosis?
PPI increases risk of osteoporosis fractures
Unknown mechanism - hypothesis = perhaps low absorption of calcium in the gut as Ca2+ absorption is pH dependent
How do H2 receptor antagonists work?
Bind to H2 receptors on cell surface of gastric parietal cells
Effect : Decreases acid production
Histamine acts on H+/K+ ATPase pump and activates it
So reducing histamine production = reduced activation of H+/K+ ATPase pump = reduced acid production
Why are PPIs better at reducing gastric acid that H2 antagonists?
PPIs act directly on H+/K+ ATPase
H2 antagonists act on histamine which activated the H+/K+ pump, but the pump is activated by factors other than histamine
