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PH2501- pharmacology > Lec 33-Peptic ulcer > Flashcards

Lec 33-Peptic ulcer Flashcards

1
Q

GI anatomy

A
  • Gastrin is a hormone from G cells which stimulate the parietal cells to make acid
  • Parietal cells secrete acid; chief cells make pepsin
  • The surface of the stomach is covered by a layer of mucus
  • The stomach has an epithelium made up of gastric glands
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2
Q

Gastric ulcer (what are they and what can make them worse)

A 
Breakdown of gastric mucosal lining 
-Erosions are superficial damage and can heal easily 
-Ulcers occur during damage to sub-mucosal layer 
Factors can worsen the breakdown 
-Pepsin
-Bile
-Bacteria e.g. H.pylori 
-NSAID's
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3
Q

H.Pylori

A
  • Common precursor of gastric and peptic ulcer
  • Risk factor for gastric carcinoma
  • Curved G.-ve rod bacteria
  • Organism synthesises urease which produces ammonia that damages the gastric mucosa
  • Ammonia also neutralises stomach acid pH, which allows the organism to grow and liver in the stomach
  • The host mounts an immune response but this does not clear the bacterium
  • Restriction to the antrum leads to hypergastrinaemia and sometimes duodenal ulcers
  • Treatment: omeprazole; clarithromycin and amoxicillin
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4
Q

H.Pylori cause 70% of gastric and 92% of duodenal ulcers

A

-Virtually all other duodenal and gastric ulcers are caused by NSAIDs

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5
Q

H.pylori how it causes ulcers

A
  • Produces urease which neutralises the acid around it by producing alkaline ammonia (from urea)
  • The number of organisms then increases
  • Mucosal damage can then occur (via bacterial mucinase, as well as pepsin and H+ etc)
  • The endothelial cells and mucosal cells then get exposed to pepsin and acid which causes inflammation
  • Mucosal cells then die
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6
Q

Detection of H.pylori

A 
Invasive procedures 
Biopsy followed by 
-Histology 
-Urease (CLO) test on biopsy 
NON-invasive procedures 
-Serology (test for IgG antibody to H.pylori)- gives to many false positives 
-ELISA for stool antigens 
-Breath test (CO2 liberation from C-13 or C-14 urea). useful for estabilishing eradication
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7
Q

CLO test Campylobacter-like organism

A
  • Agar gel containing urea and pH indicator
  • If H.pylori present its urease enzyme will degrade the urea increasing the pH
  • If H.pylori is present then they will convert the urea to ammonia which will change the pH of the test caused the colour change (via the indicator) =
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8
Q

Carbon 13 urea breath test

A

-Patient take radiolablled C13 pill
containing urea
-This is converted into ammonia and bicarbonate is produced
-The bicarbonate can then enter the blood stream and so into the lungs and can be found in the breath
-NB this process is relatively inaccurate as it gives a lot of false positive

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9
Q

GORD (Gastro-Oesophageal reflux disease)

A
  • Persistent reflux of gastric contents into the oesophagus
  • Stomach has protective mucus layer but oesophagus doesn’t therefore if acid comes it contact this is painful
  • Main symptom= heartburn
  • Cause may include transient relaxation’s and reduce tone of lower oesophageal sphincter
  • If severe can lead to development of columnar cells (pre-cancerous condition
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10
Q

GORD treatment

A

1) diet
2) OTC medicine: antacid and H2 blocker
3) prescription: PPI
4) surgery
Antacids neutralise the stomach acid H2 blockers and PPI reduce acid production

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11
Q

Definition of dyspepsia

A
  • Discomfort or pain centred on the upper abdomen often accompanied by fullness or bloating
  • If chronic termed functional or non-ulcer dyspepsia and sometimes classified as:
  • Reflux like
  • Ulcer-like
  • Dysmotility-like
  • Most cases not related to infection with H.pylori
  • Very common
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12
Q

Medication that causes dyspepsia include

A

-Nitrates
-Biphosphates
-Ca channel antagonists
-Theophylline
-Steroids
-NSAIDS
Give lifestyle advice e.g. diet and smoking, weight loss, alcohol, not eating 3 hours before bed

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13
Q

Antacid: disadvantages

A

-Na bicarbonate- High Na+ load = increase in BP
-Ca carbonate- Ca2+ stimulates acid secretion
-Mg trisilicate- diarrhoea
-Al OH - constipation
Only neutralising the acid doesn’t stop its production so is not effective over night

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14
Q

Best antacids

A
  • Contain both Mg and Al salt to brocade long duration and without constipation and diarrhoea
  • Include an alginate which forms a raft over the gastric contents thus protecting the oesophagus in reflux occurs
  • Or activated dimethicone to reduce foaming
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15
Q

Control of H+ secretion

A
  • G cells- produce gastrin this enter the circulation and effects ECL (endochromaffin like)cells stimulating the release of histamine which acts on parietal cells to produce HCL. The gastrin from the circulation also acts directly on the parietal cells
  • Vagus neurone also stimulate via the release of ACh the ECL cells thus increasing HCL production. Again vagus nerve can also directly stimulate parietal cells with ACh
  • Parietal cells release the HCL via the H+/K+/ATPase known as the proton pump
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16
Q

Histamine (H2) antagonists

A
  • Inhibit the potentiation by histamine of the response to ACh and gastrin
  • Parietal cells have 3 different receptors which stimulate acid secretion (H2, Muscarinic M3, gastrin receptor CCKb)
  • Ranitidine binds to H2 receptor this means that the signal can not be potentiated even if one of the other receptors are stimulated
  • Histamine is released by ECL cells
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17
Q

Can H2 antagonists be used to treat ulcers caused by H.pylori

A

-They heal ulcers but virtually all patients relapse within one year of cessation of treatment

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18
Q

Current uses of histamine H2 receptors antagonist

A
  • Intermittent dyspepsia (ranitidine and famotidine widely available OTC as low dose forms)
  • Functional dyspepsi : may be helpful at prescription dosage
  • Mild to moderate gastro-oesophageal regular disease
19
Q

PPI

A
  • PPI’s are substituted benzimidazole

- The first to be marketed was omeprazole

20
Q

Mechanism by which omeprazole inhibits acid secretion

A

-Omperazole (sequestration in parietal cell and activation) gets turned into sulphonamide derivative
-It is changed because of the acidic conditions
-The sulphur part reacts with the proton pump making it inactive
-

21
Q

Why are substituted benzimidazole specific of the gastric H/K/ATPase

A
  • K/H/ATPase relatively rare (another site is distal colon)
  • Substituted benzimidazoles are weak bases (pKa approx 4) and accumulate in compartments of low pH
  • Only in secretory canaliculi of parietal cells is pH much less than 4
  • Compounds are pro-drugs only activated at pH <4
  • Covalent bond formation with essential sulphydryl group on K/H/ATPase
22
Q

Nexium (esomeprazole)

A
  • Omeprazole is a mix of 2 isomers esomeprazole (s-isomer) and an r-isomer
  • Esomeprazole launched by astra Zeneca as patent expired on omeprazole
  • Licnedsed for management of gastroesophageal reflux disease, including long term management to prevent relapse and with suitable anti-bacterial regime for eradication of H.pylori
  • Claimed to have improved pharmacokinetic profile compared to omeprazole and to offer improved control and healing of reflux oesophagi’s
  • Doubtful that it represents a major therapeutic advance
23
Q

Use of PPi

A

Ulcers cause by H.pylori
-Heal ulcers faster than histamine H2 receptor antagonists within 2 weeks
-But patients still relapse on withdrawal of treatment
Non-Ulcer dyspepsia
-Now used by most GP’s
Severe reflux oesophagitis
-Clearly superior to histamine H2 receptor antagonists

24
Q

The basis of modern therapy for peptic ulcer disease caused by H.pylori

A

-PPI to inhibit acid secretion and therefore promote ulcer healing
-PPI plus anti-biotics to eradicate H.pylori
NB anti-biotics alone don’t eradicate H.pylori

25
Q

Therapies for H.pylori: some examples

A

1) Denol- 1 tablet; tetracycline 500mg, metronidazole 250mg all 4 times daily for 2/52
2) Breakthrough therapy: amoxicillin 1g, clarythromycin 500mg, omeprazole 20mg all BD for 2/52
3) Current therapy: amoxicillin 1g, clarythromycin 500mg, omeprazole 20mg BD 1/52

26
Q

Therapies for H.pylori: some examples- disadvantages of the examples

A

1) large number of tablets (compliance). Side effects- diarrhoea. Resistance to metronidazole now out of date
2) Variable reports on efficacy
3) Resistance to clarithromycin and metronidazole increasing

27
Q

Is therapy successful

A
  • Relapse after eradication of H.pylori are around 1% per annum
  • This therapy therefore represents a cure
  • However resistance to metronidazole and clarithromycin is increasing
28
Q

NSAID’s and ulcer-nature of the problems

A
  • Ulcer complications increased by Four-fold in the elderly
  • 1200 ulcer deaths per year in UK
  • Analgesic effect of NSAID masks presence of ulcer
  • Delay ulcer healing
  • Anti-platelet activity promotes bleeding
29
Q

COX enzyme

A

COX-1
-Constitutively expressed in many tissues
-Produce PG’s and in platelets, TXA2
-Maintenance of normal gastric function
COX-2
-Induced by cytokines
-Probably responsible for most inflammatory effects and pain cause by PG’s
-NSAIDs are non-selective so inhibit both COX-1&2
COX-3
-Constitutive COX-1 with intron 1 and the signal sequence retained. cerebral Cortex and heart
-Possible target for acetaminophen (paracetamol)

30
Q

Pathogenesis of gastric mucosal injury by NSAID

A
  • Aspirin, ibuprofen, diclofenac
  • Topical action direct damage to cells -Inhibition to COX-!&2
  • Decrease in mucous secretion, bicarbonate secretion and blood flow –> tissue damage
  • Increase of TNF-a: neutrophils adhere to capillaries; reduced blood flow; release of O2 radicals –> tissue damage
  • The inhibition of mucus and bicarbonate secretion and of blood flow is caused by inhibition of COX-1
  • The increased leukocyte adherence is caused by inhibition of COX-2
31
Q

Omeprazole for ulcer healing with continued NSAID use

A
  • Ulcers heal most successfully with omeprazole and ranitidine
  • Consider a COX-2 selective or low dose NSAID add PPI
  • Use PPI instead of H2 due to the fact H2 blocks the signal which still can slightly overcome and produce acid where as when you stop the actual cell producing acid there is a far greater reduction in acid secretion
32
Q

risk factors for NSAID ulcer

A
  • Previous history of GI problems
  • Aged over 65
  • High dose NSAID.
  • Concurrent corticosteroid
  • Type of NSAID
33
Q

Prophylaxis of NSAID ulcers

A

1) patient to substitute paracetamol for NSAID
2) Co-therapy with a gastroprotective agent ||
- Low dose NSAID (1.2g) plus PPI
3) Selective COX-2 inhibitor: Coxibs

34
Q

COX-2 selective inhibitors

A
  • Rofecoxib (Vioxx)- withdrawn 2004 CV risk
  • Etoricoxib (Arcoxia)- Osteoarthritis and RA, acute gout
  • Valdecoxib (Extra)- withdrawn 2005 skin reactions
  • Lumiracoxib (prexige)-withdrawn 2007 hepatotoxicity
  • Celecoxib (Celebrex)- osteoarthritis and RA, ankolsing spondylitis
35
Q

Cumulative incidence of endoscopically identified ulcers in patients taking NSAID

A
  • Ibuprofen v.high
  • Rofecoxib 50mg much low
  • 25mg was lower
  • Placebo being the lowest
36
Q

Current status: COX-2 selective inhibitors

A
  • Required to carry warnings of potential gastro-intestinal toxicity
  • Relieve symptoms of arthritis with significantly less GI ulceration than normal NSAID’s
  • COX-2 inhibitors as a class may be associated with an increased risk of thrombotic events
  • COX-2 selective inhibitors should be used to treat RA or osteoarthritis only in patients at high risk of GI complications
  • In patients with significantly risk of CV disease should avoid these
37
Q

Current status: COX-2 selective inhibitors

A
  • Required to carry warnings of potential gastro-intestinal toxicity
  • Relieve symptoms of arthritis with significantly NSAID’s
  • COX-2 inhibitors as a class may be associated with an increased risk of thrombotic events
  • COX-2 selective inhibitors should be used to treat RA or osteoarthritis only in patients at high risk of GI complications
  • In patients with significantly risk of CV events prescribing of COX-2 inhibitors should generally be avoided
38
Q

GI Motility

A
  • Motility type Non-ulcer dyspepsia

- Use a pro kinetic agent to increase gastric emptying

39
Q

Gastric Acid secretion involves a K+/H+ ATPase proton pump

A
  • In resting parietal cells we have tubovesicles

- Secretory canaliculi with low internal pH (this is were the Proton pump is)- stimulated parietal cell

40
Q

GI motility drugs- metoclopramide; domperidone

A
  • Antagonist at central and peripheral D2 receptors
  • 5HT4 agonist on GI muscle (pro kinetic)
  • Extrapyramidal side effects at central D2 receptors (parkinsonium)
  • Increased serum prolactin due to D2 antagonism in pituitary
41
Q

Constipation

A
  • Infrequent bowel action (twice a week for less) with straining to pass hard faeces
  • > 700 medicinal products have constipation listed as a side effect- take medical history
  • Refer if: blood in stool, >7d with no identifiable cause, pain on dedication, >40 years old with sudden unexplained onset
42
Q

Constipation (what causes constipation)

A 
-Occurs when the stool remains in the large intestine for 2 long 
Factors causing constipation 
-Inadequate diet 
-Infrequent exercise 
-Stress 
-Suppression of urge to poo 
-Pregnancy
43
Q

Drug treatment (for constipation)

A
  • Bluck forming ispahula has- increase faecal mass, bloating and flatuence can occur
  • Stimulants: Senna, bisacsdyl- increase motility, onset 6-12 hrs can cause pain
  • Osmotic laxative- lactulose- retain fluid can cause flatulence and ab pain
  • Stoll softeners: docusate- non ionic surfactant, limit to 7 days

PH2501- pharmacology (47 decks)

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