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PHA 223 > PPIs > Flashcards

PPIs Flashcards

1
Q

what does the stomach secrete?

A

HCL/ bicarbonate/ pepsinogen/ intrinsic factor/ mucus / prostaglandins/

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2
Q

what is the role of the intrinsic factor?

A

a glycoprotein that facilitates gastric absorption of vitamin B12

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3
Q

how is the stomach divided?

A

Stomach is divided into three functional areas, each with specific glands
cardiac/ pyloric and gastric area

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4
Q

what is the role of the different areas in the stomach?

A
  • Cardiac–the uppermost area of the stomach by the cardiac sphincter, contains cardiac glands
  • Pyloric–pyloric zone is lowermost part of the stomach, contains the pyloric glands
  • Gastric–fundus is the larger part of the body of the stomach, contains gastric glands–gastric glands play the most significant role in acid-related disorders–cells of gastric gland are the largest in number and of primary importance in acid control
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5
Q

what do different cells regulate in the stomach?

A

•parietal … gastric acid, intrinsic factor
chief … pepsinogen
•mucoid… mucus

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6
Q

what is the role of the parietal cell in the gastric gland?

A
  • Produce and secrete HCl

* Primary site of action for many acid-controller drugs

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7
Q

what does HCL do in the gastric gland?

A 
•Secreted by the parietal cells 
–stimulated by food
–Large fatty meals
–Excessive amounts of alcohol
–Emotional stress
•Maintains stomach at pH of 1 to 4
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8
Q

how is HCL regulated in the stomach?

A

The proton pump H+/K+ATPase
•Pumps protons out of the parietal cell and potassium ions back in
Potassium ions exit the parietal cell as counterionsfor the chloride ions and are then pumped back in

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9
Q

where is HCL formed?

A

canaliculus

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10
Q

what role do the chief cells have in the gastric gland?

A

–Secrete pepsinogen, a proenzyme
–Pepsinogen becomes pepsinwhen activated by exposure to acid
–Pepsin breaks down proteins (proteolytic)

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11
Q

what role do mucoid cells have in the gastric gland?

A

–Mucus-secreting cells (surface epithelial cells)
–Provide a protective mucous coat
–Protect against self-digestion by HCl

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12
Q

what happens if there is an imbalance of the 3 cells of the gastric gland and their secretions?

A

Hyperacidity–most common
–overproduction of HCl by the parietal cells
/ PUD/
h. pylori–Bacterium found in GI tract of 90% of patients with duodenal ulcers, and 70% of those with gastric ulcers
/ GURD

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13
Q

what are some acid controlling agents?

A

antacids
H2antagonists
PPI

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14
Q

what are some examples of antacids?

A
  • any (non-corrosive) alkali could be used
  • sodium (or potassium) bicarbonate
  • calcium (or magnesium) carbonate
  • aluminium hydroxide, magnesium trisilicate
  • may include other agents to help alleviate condition; for example, alginates
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15
Q

give some examples of h2 receptor antagonists?

A

•cimetidine •famotidine •ranitidine

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16
Q

what are some examples of PPIs?

A

•lansoprazole •(es)omeprazole •rabeprazole •pantoprazole

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17
Q

what are Antacids MOA?

A
  • Antacids DO NOT prevent the over-production of acid
  • Antacids DO neutralize the acid once it’s in the stomach
  • Quick onset of relief but last for a short duration
  • Simple acid-base reaction
  • Promote gastric mucosal defense mechanisms
  • Reduction of pain associated with acid-related disorders
18
Q

what effect does raising the ph from 1.3-1.6 have?

A

neutralizes 50% of the gastric acid

19
Q

what effect does rasising the ph to 1.3 to 2.3 have?

A

neutralizes 90% of the gastric acid

20
Q

what is an alginate?

A
  • Polysaccharides derived from seaweeds–Usually used as sodium salt
  • Alginates gel in solution due to cross-linking
  • Especially good in the presence of calcium ions
21
Q

how do alginates work?

A
  • Produces a ‘raft’
  • Bicarbonate produces CO2gas and floats raft
  • Prevents reflux
22
Q

what do h2 antagonists do?

A

reduce acid secretion
•Block histamine (H2) at the receptors of acid-producing parietal cells–production of hydrogen ions is reduced, resulting in decreased secretion from the parietal cells

23
Q

what happens when histamine is blocked?

A

Up to 90% inhibition of vagal and gastrin stimulatedn acid secretion occurs when histamine is blocked
results in increase in ph in the stomach

24
Q

what is a PPI moa?

A

–irreversibly bind to H+/K+ATPase
enzyme–result: achlorhydria
•gastric acid secretion is blocked

25
what are the subunits of a PPI?
``` - a subunit (110 kDa) three lobes in the cytoplasmic domain N (ATP binding) P (phosphorylation) A (activation) domainsten transmembrane segments in the membrane domain gastric ``` b-subunit short cytoplasmic region (~36 residues) one transmembrane segment (core MW 35 kDa) heavily glycosylated extracellular region (~230 residues)involved in correct membrane integration and targeting of the complex to the cell surface
26
how have PPIs developed over time?
* Pyridylthioacetamide–potential antiviral reduced gastric acid secretion, liver toxicity due to thionamide•H77/67 then H 124/26 subsequently developed–timoprazole identified as active, resulting from metabolism–sulfoxide identified as important element in drug action–inhibits iodine uptake in thyroid gland * Picoprazole developed -free of antithyroid effect exhibited by timoprazole
27
how do you get more potent analogies of proton pump inhibitors?
•More potent analogues developed by modulating pyridine basicity
28
ppis are prodrugs, what do they get activated by?
•Activated by strongly acidic conditions found in the canaliculae of parietal cells
29
which of the omeprazoles had the best chirality?
S •S-isomer : 90% gastric acid production inhibition •R-isomer : 25% gastric acid production inhibition -–maintains intragastric pH > 4 for longer–reduced clearance –increased systemic bioavailability –interpatient variation is less
30
what do PPPIs require to transform to an achiral intermediate?
acid-mediated transformation
31
what was seen in the plasma conc when 40mg of esomeprazole was taken and 20mg of esomeprazole was taken?
40 mg of esomeprazole taken orally showed much higher and more prolonged plasma concentration curves than 20 mg esomeprazole.
32
when do you give PPIs?
* GERD maintenance therapy * Erosive esophagitis * Short-term treatment of active duodenal and benign gastric ulcers * Zollinger-Ellison syndrome * Treatment of H. pylori–induced ulcers
33
is PPIs short or long term treatment?
short term
34
what medications should you be cautious of with PPIs?
May increase serum levels of diazepam, phenytoin, and cause increased chance for bleeding with warfarin
35
when is h. pylori prominent in the stomach?
High rate of reappearance of stomach ulcers after PPI treatment with naturally present H. pylori implicated
36
how do h.pylori survive in the stomach?
–survives well at pH close to stomach wall–survives well in oxygen concentrations of ca. 5% –secretes urease which hydrolyses urea, neutralising acid in local environment –secrete proteins and toxins that interact with stomach epithelial cells leading to inflammation and damage
37
what effect do antibiotics have on h.pylori?
–resistance -> eradication can be difficult (resting cocoidforms)•difficulty in delivering antibiotics at therapeutic concentrations –bismuth subcitrate and potassium dicitratobismuthate prevent adherence to mucosa •enhance local prostaglandin synthesis, coat ulcer base, enhance adsorption of pepsin
38
what is the pka of a PPI like?
PPIs are lipophilic, weak bases pka 4,0.8 inactive at neutral ph
39
when are PPIs most active?
Rapidly activated close to the target -once activated, react rapidly with the target H+/K+-ATPase enzyme
40
what is the metabolism of a PPI like?
* Oxidative metabolism overall shows a 3-fold preference for R-isomer; stereoselective(S:R) * Phenotype selectivity / variation due to genetic polymorphism * 18-22% of asian population (poor metabolisers) unable to express functional form of CYP2C19
41
what is the MOA ppi?
–from systemic circulation, crosses membrane of parietal cells –ionised in strongly acidic environment of secretory canaliculusof parietal cells–unable to move back across the membrane resulting in accumulation in canaliculus–protonation triggers an acid-catalysed conversion leading to covalent binding to a cysteine residue in the H+/K+-ATPase enzyme and enzyme inhibition–inhibition is irreversible and duration depends on regeneration of new pumps by parietal cells

PHA 223 (42 decks)

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