GORD/peptic ulcer disease

Question 1

Give three examples of NSAIDs

Answer 1

• Ibuprofen
• Neproxen
• Diclofenac

Question 2

What is the primary mechanism of action of NSAIDs?

Answer 2

• Inhibit cyclo-oxygenase enzyme (COX) which is rate limiting step for production of all prostanoids (prostaglandins & thromboxanes) from arachidonic acid
• Prostanoids act through large no. of prostanoid receptors to produce a lot of effects
• COX-2 inhibition leads to anti-inflammatory, analgesic and antipyretic effects
• Unwanted effects are due to COX-1 inhibition

Question 3

What is the drug target of NSAIDs?

Answer 3

COX enzyme

Question 4

What are the main side effects of NSAIDs?

Answer 4

• Gastric irritation, ulceration, bleeding
• Gastric perforation in extreme cases
• 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 or with pre-existing CV risk
• Aspirin linked with rare but serious post-viral encephalitis (Reye’s syndrome) in children

Question 5

What are the main uses of NSAIDs?

Answer 5

As:
- analgesics for relief of mild to moderate pain (e.g. MSK pain, headache, dysmenorrhoea)
- antipyretics to reduce fever
- anti-inflammatory drugs for control of chronic inflammatory diseases e.g. RA, OA

For aspirin only: anti-aggregatory agent to inhibit platelet aggregation in stroke/MI risk patient

Question 6

Give two examples of proton pump inhibitors (PPIs)

Answer 6

• Omeprazole
• Lansoprazole

Question 7

What is the primary mechanism of action of PPIs?

Answer 7

• Irreversible inhibitors of H+/K+ ATPase in gastric parietal cells
• They are weak bases and accumulate in acid environment of canaliculi of the parietal cells
• This concentrates their actions there and prolongs their duration of action
• Omeprazole plasma half life is 1 hour but single daily dose affects acid secretion for 2-3 days
• Proton pump inhibitors inhibit basal and stimulated gastric acid secretion by >90%

Question 8

What is the drug target of PPIs?

Answer 8

H+/K+ ATPase (proton pump)

Question 9

What are the main uncommon side effects of PPI?

Answer 9

• Headache
• Diarrhoea
• Bloating
• Abdominal pain & rashes

Question 10

What are some other side effects of PPIs?

Answer 10

• Use of these drugs may mask gastric cancer symptoms
• Omeprazole is inhibitor of cytochrome P2C19 and has been reported to reduce activity of e.g. clopidogrel, when platelet function is monitored

Question 11

Why and how do PPIs get activated?

Answer 11

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

Question 12

How are PPIs given?

Answer 12

Generally given orally but degrade rapidly at low pH so given as capsules of enteric-coated granules

Question 13

Give an example of Histamine (H2) receptor antagonist

Answer 13

Ranitidine

Question 14

What is the primary mechanism of H2 receptor antagonist?

Answer 14

• Competitive H2 receptor antagonists
• Inhibit stimulatory action of histamine released from enterochromaffin-like (ECL) cells on gastric parietal cells
• Inhibit gastric acid secretion by 60%

Question 15

What is the drug target of H2 receptor antagonist?

Answer 15

Histamine H2 receptor

Question 16

What are the main side effects of H2 receptor antagonist?

Answer 16

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

Question 17

Describe the life of ranitidine once taken

Answer 17

• Ranitidine plasma half life is 2-3 hours and well tolerated so 2x daily dose is effective
• Undergo 1st pass metabolism (50% bioavailability)

Question 18

How is ranitidine prescribed?

Answer 18

Low dose over-the-counter formulations available from pharmacy for short term use without prescription

Question 19

What is the primary mechanism of action of paracetamol aka acetaminophen?

Answer 19

• At peripheral sites, may** inhibit a peroxidase enzyme** involved in converting arachidonic acids to prostaglandins
  
  • But paracetamol ability to inhibit peroxidase can be blocked in excess levels of peroxide build up like 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

Question 20

What is the drug target of paracetamol?

Answer 20

Not sure maybe:

• 5HT3 receptors
• Cannabinoid reuptake proteins
• Peroxidase

Question 21

What are the main side effects of paracetamol?

Answer 21

• Relatively safe drug with few common side effects
• Overdose can lead to:
  
  • 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

Question 22

What are the roles of paracetamol?

Answer 22

• Anti-pyretic and analgesic
• NOT anti-inflammatory