Pharmacology of GORD

Question 1

What is the mechanism of action of NSAID’s?

Answer 1

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

Question 2

How do Prostanoids act?

Answer 2

Prostanoids act through a large number of prostanoid receptors to produce a highly complex array of actions.

Question 3

What causes the anti-inflammatory actions of NSAID’s?

Answer 3

inhibition of COX-2

Question 4

What causes the unwanted side effects of NSAID’s?

Answer 4

inhibition of COX-1

Question 5

What is the drug target for NSAID’s?

Answer 5

Cyclo-oxygenase (COX) enzyme

Question 6

What are the side effects of NSAID’s?

Answer 6

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.

Question 7

What are the main uses of NSAID’s?

Answer 7

Analgesics - relief of mild to moderate pain.

Antipyretics- reduce fever

Anti inflammatory - RA

Anti-aggregation - aspirin only

Question 8

What is the Mechanism of action of PPI’s (omeprazole, Lansoprazole)?

Answer 8

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%.

Question 9

What are the side effects of PPI’s?

Answer 9

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.



Question 10

Are PPI’s pro-drugs?

Answer 10

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 11

How are PPI’s generally given?

Answer 11

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

Question 12

What is the mechanism of action of Histamine H2 receptor Antagonists e.g. ranitidine?

Answer 12

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%.

Question 13

What is the primary target of H2 Receptor antagonists?

Answer 13

Histamine H2 receptors

Question 14

What are the side effects of H2 Receptor antagonists?

Answer 14

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.

Question 15

What is the plasma half life on Ranitidine?

Answer 15

Ranitidine plasma half-life approx. 2-3 h – well tolerated so twice daily dosing effective.

Question 16

What metabolism does Ranitidine go through?

Answer 16

Undergo 1st pass metabolism (50% bioavailability). Low dose over-the-counter formulations available from pharmacies for short term use without prescription.

Question 17

What is the mechanism of action of Paracetamol?

Answer 17

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.

Question 18

What is the primary target of paractetamol (acetaminophen)?

Answer 18

Unclear.

5HT3 receptors/Cannabinoid reuptake proteins/Peroxidase

Question 19

What happens in Paracetamol overdose?

Answer 19

Liver damage and less frequently renal damage.



Nausea and vomiting early features of poisoning (settle in 24h).



Onset of right subcostal pain after 24hindicates hepatic necrosis.

Question 20

What are the effects of Paracetamol?

Answer 20

Analgesic and anti-pyretic.



Does NOT possess anti-inflammatory activity.



Question 21

Why must care be taken when prescribing paracetamol?

Answer 21

A number of medications contain paracetamol, so care must be taken to avoid accidental overdose. 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.

Question 22

How do NSAID’s target joint pain?

Answer 22

Target COX enzymes at peripheral nociceptive nerve endings.
COX produces Prostaglandins which sensitise peripheral nociceptors mediators (e.g histamine, bradykinin) which causes pain. NSAID’s inhibit COX.

Question 23

What is the indirect effect of Prostoglandins on pain?

Answer 23

Mediate inflammation and so NSAID’s will reduce inflammation

Question 24

How do PPI’s increase risk of fracture?

Answer 24

change in pH induced by PPI’s may affect absorption of calcium salts, less calcium absorbed so less available for bone.