(pharm) pharmacology of GORD/PUD Flashcards
what are the four classes of drugs at are commonly prescribed to treat GORD?
non-steroidal anti-inflammatory drugs (NSAIDs)
proton pump inhibitors (PPIs)
histamine (H2) receptor antagonists
paracetamol
give examples of NSAIDs prescribed to treat GORD
ibuprofen, diclofenac and naproxen
explain the primary mechanism of action of NSAIDs
inhibit the enzyme cyclo-oxygenase
= rate-limiting step for all the production of all the prostanoids (prostaglandins, thromboxanes, prostacyclins) from the parent arachidonic acid
what is the drug target for NSAIDs?
cyclo-oxygenase enzyme
what are the side effects of NSAIDs?
gastro
- gastric irritation
- ulceration and bleeding (maybe even perforation)
renal
- reduced creatinine clearance
- nephritis
neurological
- dizziness
- tinnitus (experience ringing or other noises in one or both of your ears)
miscellaneous
- bronchoconstriction in susceptible individuals (contraindicated in asthma)
- skin rashes & other allergies
what do NSAIDs inhibit and what is the impact of this?
inhibit the cyclo-oxygenase enzyme (COX) enzyme
= limit the production of prostanoids (prostacyclin, prostaglandin and thromboxane)
how many COX enzymes are there?
COX-1
COX-2
differentiate between COX-1 and COX-2
both enzymes produce prostaglandins that promote inflammation, pain and fever
COX-1 = produces prostaglandins that activate platelets and protect the stomach and intestinal lining
COX-2 = expressed in inflammatory cells and catalyses the conversion of arachidonic acid to prostaglandins
from which molecule are prostanoids produced?
arachidonic acid
what are prostanoids and what is their function?
subclass of eicosanoids consisting of the prostaglandins, the thromboxanes, and the prostacyclins
= act as inflammatory mediators
what are the gastrointestinal side effects of NSAIDs?
- gastric irritation
- ulceration and bleeding (maybe even perforation)
what are the neurological side effects of NSAIDs?
- dizziness
- tinnitus (experience ringing or other noises in one or both of your ears)
what are the renal side effects of NSAIDs?
- reduced creatinine clearance
- nephritis
what are the cardiac side effects of NSAIDs and when can they occur?
adverse cardiovascular effects (hypertension, stroke, MI)
can occur following prolonged use or in patients with pre-existing cardiovascular risk
who is most at risk of the cardiac side effects of NSAIDs?
patients who have prolonged use of NSAIDs
OR
patients with pre-existing cardiovascular risk
what condition is prolonged analgesic use associated with?
chronic renal failure
which condition has aspirin been linked to within children?
rare but serious condition of viral encephalitis (Reye’s syndrome)
what are the main uses of NSAIDs?
analgesics
antipyretics
anti-inflammatory
anti-aggregatory
what are analgesics?
class of medication designed to relieve pain
how are NSAIDs used as analgesics?
for the relief of mild to moderate pain (e.g. musculoskeletal pain, headache, dysmenorrhoea)
what are antipyretics?
class of medication designed to reduce fever
what are anti-inflammatory drugs?
class of medication designed to reduce inflammation
how are NSAIDs used as anti-inflammatory drugs?
for chronic control of inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis)
what are anti-aggregatory drugs?
class of medication designed to prevent platelet aggregation
(only aspirin is used for this)
how are NSAIDs used as anti-aggregatory drugs?
to inhibit platelet aggregation in patients who are at risk of stroke or myocardial infarction
(only aspirin is used for this)
what are NSAIDs?
non-steroidal anti-inflammatory drugs
what are PPIs?
proton pump inhibitors
give examples of PPIs used to treat GORD
omeprazole, lansoprazole
explain the mechanism of action of PPIs
irreversible inhibitors of H+/K+ ATPase in gastric parietal cells
what is the drug target for PPIs?
H+/K+ ATPase
what are the side effects of PPIs?
gastrointestinal
- diarrhoea
- bloating
- abdominal pain
miscellaneous
- headache
- rashes
which cells are affected by PPI action?
gastric parietal cells
what are PPIs: weak acids or weak bases and what is the implication of this?
weak bases
= accumulate in the acid environment of the gastric parietal cell canaliculi, where their action is concentrated and their effects prolonged
where do PPIs tend to accumulate and why is the important?
tend to accumulate in the acid environment of the gastric parietal cell canaliculi as they are weak bases
= concentrates their activity in the gastric region AND prolongs their duration of action
how long does omeprazole act in the body?
plasma half-life of omerpazole is approximately one hour
(but single daily dose affects acid secretion for 2-3 days)
to what extent do PPIs inhibit acid secretion?
inhibit basal and stimulated gastric acid secretion by >90%
the symptoms of which condition are PPIs likely to mask?
symptoms of gastric cancer can be masked by increased use of PPIs
why drug cannot be taken together with omeprazole and why?
cannot be taken w clopidogrel
= as omeprazole is an inhibitor of cytochrome P2C19
(liver enzyme protein responsible for metabolising clopidogrel and omeprazole among others)
what kind of drugs are PPIs?
pro-drugs
what are pro-drugs?
a pro-drug is a medication or compound that, after administration, is metabolised into a pharmacologically active drug
what happens to the pro-drugs PPIs at low pHs?
converted into two reactive species which react with sulphydryl groups on the H+/K+ ATPase that is responsible for transporting H+ ions out of the parietal cells
= essentially lower H+ ion transport out of the gastric parietal cell
which part of the H+/K+ ATPase is affected by PPI activity?
as PPIs are pro-drugs, they are converted into two reactive species at low pHs
these reactive species react with the sulphydryl groups in the H+/K+ ATPase
what is the normal route of administration for PPIs and why?
generally given orally but degrade rapidly at low pH so administered as capsules containing enteric-coated granules
what are enteric-coated granules and why are they important for PPI administration?
a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment
(to prevent the rapid degradation of PPIs at low pHs when they are administered orally)
how does omeprazole affect CYP2C19?
omeprazole is primarily converted by CYP2C19 to inactive metabolites
however as omeprazole inhibits CYP2C19, it also inhibits its own metabolism
what is the function of cytochrome CYP2C19?
liver enzyme protein responsible for metabolising clopidogrel and omeprazole among others
what are H2 receptor antagonists (H2RAs)?
histamine (H2) receptor antagonists
explain the mechanism of action of H2 receptor antagonists
competitive antagonists of the histamine H2 receptor
= decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting/blocking the binding and stimulatory activity of the endogenous histamine
what is the drug target for H2 receptor antagonists?
H2 histamine receptors
what are the side effects of H2 receptor antagonists?
while the incidence of side effects is low
- diarrhoea
- dizziness
- muscle pains
- transient rashes
(have been reported)
give examples of H2 receptor antagonists that are commonly prescribed
ranitidine
where is the H2 receptor found?
on the acid-secreting gastric parietal cells
what is the normal function of the H2 receptor?
histamine binds to the H2 receptors on the gastric parietal cell surface and stimulates gastric acid secretion
what normally acts on the H2 receptor?
histamine (released by ECL-like cells)
where is the histamine that acts on the H2 receptor normally released from?
enterochromaffin-like (ECL) cells
what is an ECL cell?
enterochromaffin-like cells that secrete histamine in response to activation by gastrin released by neighbouring G cells
to what extent do H2 receptor antagonists inhibit acid secretion?
approx by 60%
which drugs inhibit acid secretion to a greater extent: PPIs or H2 receptor antagonists?
greater extent would be PPI as they reduce acid secretion by 90%
(while H2RAs only reduce acid secretion by 60%)
how common are side effects with H2 receptor antagonists?
not very common = incidence of side effects is low
which H2RA acts on a specific cytohrome and which one?
cimetidine (ut not other H2RAs) act to inhibit cytochrome P450
what is the impact of cimetidine inhibiting P450 action?
may retard the metabolism of and potentiate the effects of a range of drugs including oral anticoagulants and tricyclic antidepressants
what is cytochrome P450 and why is it important?
a group of enzymes that are essential for the metabolism of many medications
how long does ranitidine act in the body?
plasma half-life of approx 2-3 hours
(well tolerated so twice-daily dosing is effective)
what is the bioavailability of H2 receptors antagonists like and why?
approx 50% bioavailability as H2RAs undergo first pass metabolism
can H2 receptor antagonists be used without a prescription?
low dose, over-the-counter formulations available from pharmacies for short term use without a prescription
how is ranitidine tolerated in the body and what does this imply?
well tolerated so twice-daily dosing is effective
which enzyme is affected to cause the desired effects in NSAIDs?
related to inhibition of COX-2
which enzyme is affected to cause the undesired effects in NSAIDs?
unwanted effects are largely a result of inhibition of COX-1
how is ranitidine tolerated in the body and what does this imply?
well tolerated so twice-daily dosing is effective
explain the mechanism of action of paracetamol
(possible proposed mechanisms)
central and peripheral activity
inhibition of prostaglandin synthesis (via COX-3 isoform?)
interaction with cannabinoid receptors or endogenous opioids
interactions with 5HT (serotonin) and adenosine receptors
what is the drug target for paracetamol?
not yet well defined
what are the common side effects of paracetamol?
generally a very safe drug with few side effects at therapeutic doses
what are the unlikely and very rare side effects of paracetamol?
does not cause gastric irritation but in overdose, serious hepatotoxicity may occur
occasional allergic skin reactions
is paracetamol classified as an NSAID and why?
not an NSAID, as it has little anti-inflammatory activity
what are some other common uses of paracetamol?
good analgesic for mild to moderate pain
antipyretic activity
can paracetamol be overdosed on?
ingestion of large amounts of paracetamol remains a common method of suicide in the UK
(even though legal restrictions on sales of paracetamol have reduced the number of overdose fatalities)
explain the mechanism of action of naproxen (NSAID) in terms of the analgesic effect at the knee joint
naproxene inhibits the COX enzyme = rate-limiting step for the production of all prostanoids (prostaglandins & thromboxanes) from the parent arachidonic acid
= so less prostaglandin at peripheral nocireceptive nerve endings
= so reduced sensitisation - and reduced firing rate and the likelihood of firing - to bradykinin and histamines
(prostaglandins normally mediate inflammation so when production is inhibited = inflammation is reduced)
explain the mechanism of action of naproxen (NSAID) in terms of the adverse effect within the stomach
enzyme inhibition of COX-1
= at gastric mucosal cells, inhibition of prostaglandin production
= reduced bicarbonate release, reduced blood flow and reduce mucus production
= inhibition of PG protection of gastric mucosa so it is more sensitive to acid produced by stomach
(protective layer stripped away, increasing risk of erosion and ulceration of gastric mucosa)
why can naproxen lead to peptic ulcers?
naproxene inhibits prostaglandin synthesis
= reduced blood flow, reduced mucus secretion, and reduced bicarbonate release in the gastric environment
= protective layer of the gastric mucosa is stripped away, leaving it exposed to the action of the hydrochloric acid (can lead to ulceration)
why does naproxen have a variety of effects (both on-target and off-target)?
naproxen is non-selective = inhibits BOTH COX-1, as desired, and COX-2, which is not wanted
compare topical drugs to oral drugs
topical drugs = not much drug gets to the target site, few side effects
oral drugs = much better at getting to the site of action, comparatively more side effects
why is it important to stop NSAIDs when prescribing full-dose PPI therapy?
with NSAIDs continually being taken, the ulcer will be very hard to heal as the mucosa doesn’t have a chance to heal properly
= bit aimless giving the full-dose PPI therapy therefore
(so can either stop/reduce the dose of NSAIDs)
why are PPIs prescribed in conjunction with NSAIDs?
NSAIDs leave the gastric wall exposed to the effect of acid = causing pain
and so prescribing PPIs will reduce the acid production and therefore pain
what does the following table suggest?
more than 95% of people on omeprazole are on the highest, maximal dose
= inconsistent with the general guidelines
why is it difficult to wean people off PPIs quickly?
when you begin to wean people off PPIs, can get a temporary rebound of symptoms so you remain on the drug instead
if a patient presenting with abdominal pain has osteoporosis, how would this be managed?
(explain why)
instead of PPIs, give H2 antagonists
= as PPIs can lead to decreased bone density and increase osteoporosis (increased fracture risk), prescribe H2 antagonists instead
= altered pH due to PPIs can affect calcium absorption, decreasing it = decreasing bone density
why do PPIs increase the risk of osteoporosis?
alter pH that can cause a decrease in calcium absorption
= decreasing bone density
= increasing osteoporosis risk
what is the mechanism of action of histamine (H2) receptor antagonists in the treatment of peptic ulcer disease?
competitive antagonists of H2 histamine receptors
= inhibit the stimulatory action of histamine released from enterochromaffin-like (ECL) cells on the gastric parietal cells
= inhibiting gastric acid secretion
why do PPIs increase the risk of fractures?
for healthy bones & a normal bone density, calcium absorption must occur
calcium absorption is pH dependent
= when PPIs are taken, pH of the stomach is altered in a way that reduces pH-dependent calcium absorption
= w less calcium available, reduced bone mineral density
= increased subsequent risk of fractures
explain the mechanism of action of H2 histamine receptor antagonists
target = histamine H2 receptor
location = cell surface of parietal cells
effect = antagonises the histamine H2 receptor so reduced gastric acid secretion due to reduced (cAMP-dependent) activation of the H+/K+ ATPase
what causes the pain experienced in GORD?
corrosive nature of AND repeated exposure to acid can damage the already vulnerable mucosal barrier
= damaged mucosal barrier is further exposed to acid (that is produced normally)
= further damage caused (stuck in vicious cycle)
soo = in people w GORD/PUD, reduce gastric acid production to reduce corrosive nature of environment and therefore further damage to the mucosal barrier
