H2 Antagonists and PPIs

What is a peptic ulcer?

Sores the develop in the lining of the stomach, lower oesophagus or small intestine. Localised erosion of mucosal membrane. Pain and irritation due to exposed surface by stomach acid. Pre 1960s, intense pain - untreated severe pain even death

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What are the causes of a peptic ulcer?

Stress, alcohol, diet, NSAIDs (aspirin inhibits COX-1 - responsible for the synthesis of PGs that inhibit acid secretion and protect gastric mucosa) H.Pylori

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Excess acid in the stomach can cause what? (1)

Heartburn, indigestion, acid reflux (describes pain and discomfort caused by high levels of acid in the stomach). Burning sensation ranges from discomfort to excruciating unbearable pain which feels like burning a hole in the abdomen

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Excess acid in the stomach can cause what? (2)

Often mistaken for a heart attack

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Describe features of gastric acid secretion (an active transport mechanism) - 1

CO2 and H2O combine to form carbonic acid catalysed by carbonic anhydrase. Bicarbonate is actively excreted at the basal side of the cell and in exchange for Cl ions. At the apical side of the cell K+ ions are exchanged for protons (K-H ATPase)

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Describe features of gastric acid secretion (an active transport mechanism) - 2

Chloride ions and protons made acid. Acid deactivates ingested bacteria and denatures ingested proteins to allow for efficient protease reactions

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Describe features of stomach cells (1)

Walls of stomach lined with millions of gastric glands which secrete 400-800 mL of gastric juice at each meal. Several types of cells found in the gastric glands - parietal cells, Chief cells, mucous secreting cells, hormone secreting cells (gastrin)

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Describe features of stomach cells (2)

Acid deviates ingested bacteria and denatures ingested proteins to allow for efficient protease reactions. Parietal cells contain K-H ATPase. Transmembrane protein secretes protons by active transport through the use of ATP

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Describe features of stomach cells (3)

Concentration of protons in gastric juice can be as high as 0.15 mol/L giving gastric juices a pH of less than 1. In cells the proton concentration is 40 nmol/L. Cells are rich with mitochondria and consume high levels of energy

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What are the targets on the parietal cells for drugs? (1)

(Antacids - alkaline substances used to quickly neutralise acid on the stomach). H2 blockers (reduce production of histamine in the stomach). Gastric proton pump inhibitors (enzyme inhibitors which reduce the secretion of acid). (M3 antagonists)

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What are the targets on the parietal cells for drugs? (2)

Antimicrobial agents to destroy bacteria which may cause ulcers (e.g. H.Pylori)

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Describe features of antacids

Gums, lozenges, tablets, powders, liquids. Effectiveness depends on their form and ability to neutralise acid. Sodium bicarbonate. Calcium carbonate. Al or Mg salts

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What are the common non-prescription antacids?

Alka-Seltzer, aspirin/citric acid, sodium bicarbonate. Gaviscon, sodium alginate (500 mg), sodium bicarbonate (267 mg), calcium carbonate (160 mg/10 mL), paraben, saccharin

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Describe the chemistry of H2 antagonists (1)

Imidazole (pKa of 7.4), N protonated (can pick up or lose a proton). Imidazole group part of histamine structure. At physiological pH histamine exists as protonated at the primary amine

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Describe the chemistry of H2 antagonists (2)

About 80% of histamine mono cation exists in aqueous solution that binds to the receptor. H can be on two possible N positions (tele or pros). Tele tautomer (H in tele N) permits binding with receptor

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Describe the chemistry of H2 antagonists (3)

Tautomerism is important for H2 interaction and not H1 interaction. Able to determine structure e.g. using H-NMR

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Describe the chemistry of H2 antagonists (4)

NH3+ and imidazole (trans or gauche position). The trans conformer has less steric hindrance but the gauche conformer is stabilised by an ion-dipole interaction. Both conforms exist in solution. Both H1 and H2 receptors bind the trans conformer

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Describe the chemistry of H2 antagonists (5)

Based on the observation that alpha and beta methyl histamine are unable to assume the trans conformation and are weak agonists at both H1 and H2 receptors

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Describe the chemistry of H2 antagonists (6)

Experiment to determine conformation of the histamine structure (use methyl groups, work out which conformation interacts with binding site). Observation of alpha and beta methyl histamines – determine better conformer)

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Describe the modifications of the histamine structure to produce a histamine antagonist (1)

Change amino group to guanidine (larger structure, still basic, protonated in water, pKa of 14.5). Extra C in the chain. Guanidine analogue was synthesised and tested as an antagonist (test if it could bind to receptor and prevent histamine binding)

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Describe the modifications of the histamine structure to produce a histamine antagonist (2)

Guanidine analogue of histamine found to be an agonist rather than an antagonist. Stimulates acid secretion rather than blocking acid secretion. Guanidine has a greater pKa (14.5) compared to 10 for histamine side chain (always protonated)

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Describe the modifications of the histamine structure to produce a histamine antagonist (3)

High positive charge makes the compound an agonist. Need to lower pKa of compound. Buriamide (thiourea too far away from ring to influence pKa, alkyl chain is electron donating and raises pKa of ring)

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Describe the modifications of the histamine structure to produce a histamine antagonist (4)

Replacement of C=N in guanidine with C=S to give a thiourea (much less basic, thiourea also produce toxicity/reduces WBCs, gives rise to side effects). Replacing basic guanidino group with neutral thiourea yields effective H2 antagonist

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Describe the modifications of the histamine structure to produce a histamine antagonist (5)

Metiamide, pKa of 6.8 (reduced). Extra methyl group and S atom. Increase in chain length and insertion of S in side chain. Metiamide 10x more effective than buriamide. S/E - decrease in number of WBCs, prone to infection due to thiourea moiety

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Describe the modifications of the histamine structure to produce a histamine antagonist (6)

Neither was as effective as metiamide. Guanidine no longer showed antagonistic effect (guanidine will be fully protonated). Look at pKa of guanidines with different functional groups. Cyano and nitro would not be protonated at all, both synthesised

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Describe features of cimetidine (1)

Initial imidazole , S and methyl groups, guanidine, CN group. pKa of 7.5. Degree of protonation of imidazole ring of buriamide is >10x higher than that of histamine at physiologic pH. Inductive effect on side chain, increase electron density at N3

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Describe features of cimetidine (2)

Favours dissociation of proton from N1 and Nn-H neutral tautomer predominates which is non-optimal for binding to H2 receptor (low potency)

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Describe features of cimetidine (3)

Introduction of S atom into side chain and C5-CH3 of buriamide gave metiamide which showed greater potency and selectivity at H2 receptor antagonist activity. S introduced an inductive effect on side chain and CH3 introduced inductive effect at C5

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Describe features of cimetidine (4)

Results in increase and decrease in electron densities at N1 and N3. Facilitates dissociation of H3-H to predominant desired NT-H tautomer

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Describe features of cimetidine (5)

Need aromatic ring with N electrons next to side chain. Imidazole ring not required (other H2 antagonists don't have it) but if present the T tautomer should predominate. T tautomer is promoted by electron donors at position 5

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Describe features of cimetidine (6)

Electron withdrawers at position 4. Terminal N group should be polar but not basic for maximal potency. Separation of ring from N group by 4 atoms gives maximal potency. Cimetidine - successful drug

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Describe features of cimetidine (7)

Electron donor CH3 at C5 and electron withdrawing side chain at C4. Non-basic cyanoguanidine terminal N group

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Describe features of ranitidine

Furan derivative, isostere of imidazole with electrons on O with 50% bioavailability. 4-10 times more potent than cimetidine with longer duration of action. Weaker CYP inhibitor. Tertiary amine side chain allows formation of salts

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Describe features of famotidine

Thiazole derivative. 40-60 times more potent than cimetidine. Weak CYP inhibitor. Salts easily prepared for compound but absorption is complete with only 40 to 50% bioavailability

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Describe the development of PPIs (1)

CMN 131 thioamide (originally an anti-virus drug, inhibits gastric acid secretion, associated liver toxicity, thiamine group). H124/26 (inhibits acid secretion, pyridine ring and thiomethmylene, important for activity), N replaced with benzimidazole

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Describe the development of PPIs (2)

Timoprazole sulphoxide (formed by metabolism of H126/26, active drug, pyridinylmethylsulfinyl benzamide structure, S/E - inhibits iodine uptake by thyroid gland)

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Describe the development of PPIs (3)

Picoprazole (potent anti-secretory properties over long periods, no toxic S/E on thyroid, no serious S/E)

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Describe the development of PPIs (4)

H159/69 (substituents which increase basicity of pyridine ring show good activity, promotes mechanism of activation, methyl substituents at meta position/inductive effect, methoxy substituent more effective at para than meta positions)

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Describe the development of PPIs (5)

Reasons effect for H159/69 increases electron density on N. H159/69 potent but chemically labile

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Describe features of omeprazole (1)

Substituents varied to balance between potency and stability. Launched by Astra. World's biggest selling drug. Weak bases accumulated in acidic compartment, substituents added to pyridine ring to obtain pKa to maximise accumulation in parietal cell

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Describe features of omeprazole (2)

Lifelong toxicological studies at very high doses in rats revealed development of endocrine tumours in the stomach. Halted clinical studies until it was shown tumours were the result of very high doses causing severe suppression

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Describe features of omeprazole (3)

Restarted, resulted in extreme caution in recommended dose 20 mg

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Describe features of omeprazole (4)

Omeprazole (not active form/pro-drug), administrated, protonation of N, spiro intermediate formed, O (bonded to S) picks up a proton, sulfenic acid formed, OH groups removed/picks up proton as group leaves compound

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Describe features of omeprazole (5)

Sulfenamide (active drug) formed/not chiral. SH-ATPase pump attacks active drug, breaks S-N bond, SH-ATPase pump no longer functional, ATPase doesn’t release protons (reduce acid secretion). Disulphide adduct

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Describe features of omeprazole (6)

Intramolecular transfer of proton occurs prior to nucleophilic attack. Electron donor (OCH3) to pyridine ring enhanced rate of attack of C2, promotes formation of active species (sulfenamide)

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Is S=O chiral?

Yes

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Is omeprazole optically pure?

No (chiral) with 50% metabolism

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Is esomeprazole optically pure?

Optically pure (chiral derivative) with 70% metabolism

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Describe other features of omeprazole (1)

Prodrug, transformed in acidic canaliculi of parietal cells into active form (sulfenamide). Sulfeniamide reacts with thiol groups on enzyme to form disulfide link to inactivate enzyme. High specificity action due to several factors

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Describe other features of omeprazole (2)

Omeprazole is a weak base (pKa 4.0), concentrates in acidic canaliculi of parietal cells. Low pH causes conversion into active species close to target enzyme. Active species is a permanent cation which cannot escape canaliculi

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Describe other features of omeprazole (3)

At higher pHs, omeprazole has good stability. Commercial products are enteric coated to prevent gastric decomposition

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Describe features of other PPIs (1)

pKa and hydrophobicity of PPIs determine the extent to which they accumulate in the canalicular lumen. Rate of enzyme inhibition corresponds to rate of sulfenamide formation

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Describe features of other PPIs (2)

pH at which half of maximum rate of activation occurs is 3.0 for Pantoprazole, 4.0 for Omeprazole and 5.0 for Lansoprazole. Different structures/PK/bioavailability (PO Vd not clinically important). All PPIs are chiral due to S

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Describe features of other PPIs (3)

Isomers converted into non-chidral active species at the same rate. In vivo, S omeprazole (esomeprazole) produced higher plasma concentrations due to undergoing less CYP2C19 metabolism, produces 70% higher AUC than omeprazole

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H2 Antagonists and PPIs

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