PPIs

Question 1

What is a Prodrug?

Answer 1

Drug which requires biological priming before becoming therapeutically active

Question 2

What is a covalent inhibitor?

Answer 2

one that causes inactivation by covalently binding to an enzyme (irreversible or only slowly reversible)

Question 3

What is a chiral switch?

Answer 3

Marketing a single-enantiomer version of an existing racemic drug

Question 4

Describe the proton pump in parietal cells:

Answer 4

The enzyme H+/K+ ATPase (releases protons in exchange for potassium ions)

Question 5

What are the most common PPIs for gastric ulcers and GORD?

Answer 5

• Omeprazole
• Pantoprazole
• Rabeprazole
• Lansoprazole
• Esomeprazole
• – Drug indications: Duodenal or gastric ulcer, Gord zollinger, ellison syndrome

Question 6

What combination therapy is given to an ulcer caused by H. Pylori?

Answer 6

PPI is combined with antbiotics e.g., clarithromycin/metronidazole and amoxicillin. If patient is penicillin allergic, it is replaced by Tetracycline.

Question 7

What is H. Pylori and how does it act in the body

Answer 7

Spiral bacteria.
- Tunnels into the lower-mucosal layer in the stomach - no other bacteria there to compete with; break down urea in to carbon dioxide and ammonia through a urease enzyme. The ammonia neutralises the acid around it; breath test for ingested urea being broken into ammonia. Goes into growth phase when attacked by antiobiotics (Abx), so killed more easily due to PPI reducing acid levels. PPI reducing acid at ulcerated site reduces damage and makes Abx more effective.

Question 8

H2-RA vs PPI

Answer 8

H2RA - faster relief (in 30-120 mins) for a maximum of 12h. PPIs may take 3-5 days to take full effect.
PPIs - are more effective and long-lasting (maximum 24-48 hours). 70% of ulcers heal with H2RA (>90% with PPI)

Question 9

Omeprazole - adverse interactions and long-term use: (due to lowered acidity or otherwise)

Answer 9

Potential to inhibit Cytochrome P2C19 - which is required to activate clopidogrel (which prevents blood-clotting), as this drug requires activation by oxidation.
Interference with calcium absorption - due to lower stomach acidity; increased risk of hip fractures and osteoporosis.
Hypomagnesemia, also B12 not absorbed.
Community-acquired pneumonia and C. diff

Question 10

The chemistry of omeprazole

Answer 10

• Electric-rich pyridine
• Sulfoxide
• Electron-rich benzimidazole (with electron-withdrawing groups)
  The electron-donating groups (CH3 & OCH3) increase basicity.
  The CH2 holds the N of the pyridine ring close enough to the carbon between the 2 Ns in the benzimidazole so that it can cyclise and form a 5-membered (favourable) ring. When the C=N bond is protonated then the ring will close at the same time; first step of proton activation.
  The methoxy groups on the rings are electron-donating making the rings more electron-rich.
  Has a pKa of (0.79)

Question 11

Chemistry of pantoprazole

Answer 11

The 2 fluorines slow down proton activation. 2 methoxy groups on the ring – better rotation due not being flanked by 2 methyl groups. Better rotation – better electron donation into the ring. However, oxygen next to oxygen is slightly electron withdrawing inductively – due to repulsion. Main thing is difluoro methoxy being less electron donating in pantoprazole.
Permanent, fluorines withdrawing electrons makes drug less electron donating; less electron-rich. Lower pKa (0.11) making it less basic, protonation is much slower. This allows it to get deep within the enzyme and reach cysteine 822, bond to it and permanently inhibit the enzyme. Glutathione cannot restore the Cysteine 822 as disulfide bond is inaccessible due to being so deep inside the enzyme.

Question 12

Chemistry of lansoprazole

Answer 12

Lansoprazole doesn’t have substituents on the benzimidazole ring. But the pyridine ring is different, lansoprazole has trifluoromethoxy group para to the N group, making it slightly electron withdrawing. No flanking from 2 ethyl group though so better rotation to right place and donates electrons into the ring easier.

Question 13

Chemistry of raberprazole

Answer 13

Rabeprazole doesn’t have any substituents on the benzimidazole rings. But the pyridine ring is different. Rabeprazole has much better electron donating group, methoxypropoxy group not flanked by methyl groups so can rotate into right place easier and donate electron into ring well and activate the drug, this makes pyridine ring more basic and nucleophilic – rapid activation of the drug.

Question 14

Omeprazole vs esomeprazole

Answer 14

Omeprazole:
Lone pair of electrons on sulfur in front of plane.
Inhibits gastric acid secretion
Faster metabolism

Esomeprazole:
Lone pair of electrons on sulfur behind the plane
Inhibits gastric acid secretion
Slower metabolism

Therefore (S)-omeprazole (esomeprazole) is superior due to being metabolised more slowly.

Also it’s called esomeprazole because it is the S-enantiomer of omeprazole, that’s where the eso bit comes from.

Question 15

How are PPIs processed upon oral administration?

Answer 15

PPIs are first absorbed in the small intestine (SI), may have an enteric coating to get past the stomach acid, then across the membrane of the SI into the bloodstream, to go back into the lining of the stomach to work.

Question 16

Talk about the detail of PPI mechanism: (better off drawing it or using the slides from the PPIs lecture)

Answer 16

PPIs are more effective than drugs that target the gastrin receptors, or the H2R Receptors, or the N receptors. The drug in its neutral form is lipophilic enough to cross the membrane of the parietal cell.
In acidic environment of parietal cell, the more basic pyridine ring is readily protonated. Once protonated, it cannot leave the cell, as it’s too polar to cross the membrane. Pyridine ring is basic as the Sulphide group is electron-withdrawing. The prodrug can be concentrated in the parietal cells this way. Occasionally a proton is lost from the more basic pyridine and transferred to the benzimidazole. (this is the slow, rate-determining step for prodrug activation.)
The drug is activated when the electrons are pulled from the pyridine rings by the proton, the nitrogen lone pair can attack the C=N bond. The protonation of the benzimidazole C=N leads to cyclisation, giving an unstable spyropyridinium ion.
Forms an unstable tetrahedral intermediate, when there’s more than one heteroatom bonded to a carbon atom, they push each other away.
The acid released by parietal cells in the stomach lining ensures efficient prodrug activation.
The omeprazole molecule and spiropyridinium ion form a conjugate reaction where the lone pair on the nitrogen forms a bond with the carbon double-bonded to the nitrogen and single-bonded to the sulfoxide group.
Then the spiropyridinium ion transfers a proton from N to O resulting in sulfoxide elimination to form a sulfenic acid (also a conjugate reaction).
Intramolecular nucleophilic attack on the sulfenic acid by nitrogen gives a 6-membered cyclic sulfenamide.(this is the active drug which inhibits proton ATPase, both sulfenic acid and sulfenamide are electrophiles)
A nucleophilic thiol on the enzyme attacks the electrophilic sulfenamide to give a long-lived covalent linkage.
The sulfenamide forms a disulfide linkage to deactivate the ATPase enzyme.
pKa for benzimidazole is high, so acid activation is rapid.
The bezimidazole in omeprazole has highest pKa of all PPIs; it is the most basic and protonates rapidly in parietal cells.
Omeprazole - rapid prodrug activation.

Question 17

Why does omeprazole have trouble being active for more than 24 hours?

Answer 17

Glutathione that reactivates the enzyme as omeprazole only reaches the thiol of cysteine 813 which is at the start of the enzyme and can be reversed. The drug would have to go much deeper into the enzyme to be able to irreversible inactive the enzyme, therefore, omeprazole has trouble being active for more than 24 hours.

Question 18

What is a disadvantage of rapid activation of acid?

Answer 18

Omeprazole converts into active drug too soon to reach cysteine822 (this would effectively, permanently inhibit the ATPase enzyme as the the active drug is too far inside the enzyme for it to be removed by GSH.)

Question 19

How is acid secretion gradually restored?

Answer 19

Formation of new proton pump, and reactivation of inhibited PP by glutathione -> done by glutathione (GSH) reduction.

Question 20

Why does it take up to a week to achieve maximum acid suppression?

Answer 20

• Only a few proton pumps are active at a time
• Only active pumps can be inhibited
• Must catch the pumps within 1-1.5h PPI half-life
• Most pumps will activate over a period of 6h.
• Pumps are always synthesised (especially at night)
• Inhibited pumps regenerated by GSH (but not after pantoprazole)
• More pumps are present after fasting: PPI best before meals (breakfast)

Question 21

Which PPIs are oxidised by CYP2C19?

Answer 21

All 4 PPIs except rabeprazole are oxidised by CYP2C19
People who have fewer active variants of CYP2C19 may have unexpectedly high serum levels of PPI (excluding rabeprazole)
Drug may not be effective if you are an ultra-fast metaboliser, slow metabolisers have more of the drug in the body.

Question 22

How is each PPI metabolised? ( recommend drawing or looking at slides)

Answer 22

Omeprazole - CYP2C19 (benzylic oxidation) -> CYP3A4 (sulfoxide oxidised to sulfone)

Pantoprazole - CYP2C19 (para-methoxy demethylation) -> sulfotransferase (sulfation) CYP3A4

Lansoprazole - CYP2C19 (aromatic oxidation) OR CYP3A4 (sulfoxide to sulfone). Note: intestinal CYP3A4 metabolism is inhibited by grapefruit but juice has little effect on lansoprazole as PPI metabolism occurs in liver.

Rabeprazole - non-enzymatic reduction of sulfoxide to sulfide (drug levels will be the same for good or poor CYP2C19 metabolisers)

CYP2C19 oxidises PPIs, and PPIs, especially omeprazole, may compete with other drugs for CYP2C19 (and act as an inhibitor)

Question 23

Why does pantoprazole give longer control of stomach acidity than omeprazole?

Answer 23

Because of its slower activation (this can be helpful for night-time acidity spikes in GORD). However, esomeprazole is similarly long-lasting if taken twice daily because of its formulation and slow clearance by CYP2C19.

Question 24

Why can’t clopidogrel (plavix) be taken with omeprazole?

Answer 24

Clopidogrel is activated by CYP2C19, so if omeprazole competes with it for the enzyme then it won’t be activated hence having a lesser effect in the body; rabeprazole is a good choice as it mainly metabolised non-enzymatically, or one of the other proton pump inhibitors that aren’t metabolised by CYP2C19.

Question 25

Who are generally poor metabolisers/have poor drug clearance in terms of CYP2C19 expression?

Answer 25

East asians and the elderly

PPIs can still be metabolised normally if grapefruit juice is taken. Even in the case of lansoprazole, for which the metabolism is roughly shared between CYP2C19 and CYP3A4 (the cytochrome enzyme inhibited by furanocoumarins) there is no difference in clearance.