Med chem lecture on Anti ulcer drugs

• Give the structure and uses of ranitidine.(2013,2.5)

• How omeprazole inhibit acid secretion? (2010,2.5)

• Write in short about the chemistry of prostaglandin. (2010,2.5)

• How proton pump inhibitors heal ulcers? (2009,2.5)

• Classify Anti-ulcer drugs (2008,5)

Anti-ulcer drugs

Ulcer is a very much a treatable disease

Ulcer• An ulcer is a kind of open wound accompanied by

inflammation. It can occur both on outer skin and internal epithelium such as surface of the stomach or inside the mouth.

• Ulcers start when the top layer (surface) of skinor mucous membrane is hurt. This top layer dies. When it dies, the skin or mucous membrane and opens. This leaves an open sore called an ulcer.

• Ulcers can be from – infection with H.pylori (responsible 90% 0f petide

ulcers)– substances that will burn skin or mucous membranes,

such as stomach acid– from pressure on a part of the skin. – from cancer to diseases of blood vessels.

Foot Ulcer

Mouth ulcer

Tongue Ulcer

Foot Ulcer

Duodenal Ulcer Gastric Ulcer

Peptide ulcer

Acid secretion in stomach

• Within the gastric mucosa lies the oxystic glands those parietal cells secrete about 2-3 litre of HCl of pH 1 into the stomach

• The cells don’t store a reservoir of HCl acid. H+ and Cl-

are secreted separately into the stomach;H+ by proton pumps and Cl- by chlorine ion channels

• The working of proton pump is controlled by various regulators and drugs for ulcers have effect on them– Histamine at H2 receptors– Gastrin at G receptors – Acetylcholine at M2 receptors– Prostaglandin (PgE2)– Somatostatin (SST)

Promote acid secretion

Inhibit acid secretion

Gastric Glands and their cell types,secretion and functions

Proton pump stimulated by His, Ach and Gastrin and inhibited by PgE2

Anti-ulcer Drugs classes1) Reduction of gastric acid secretion

• H2 antihistamine: Cimetidine, ranitidine, famotidine,roxantidine

• Proton Pump Inhibitors (PPTs): Omeprazole, Pantoprazole, rabeprazole, esmoprazole

• Anticholinergics: Pirenzepine,Propantheline,Oxyphenonium

• Prostaglandin analogues: Misoprostol, enprostil, rioprostil

2) Neutralization of gastric acid (Antacids)

• Systemic: Sodium bicarbonate, Sodium citrate

• Non-systemic (Local): MgOH, Al(OH)3, CaCO3

3) Ulcer protectives: Sucralfate, CBS (Colloidal Bismuth Subcitrate)

4) Ulcer healing Drugs: Carbenoxolone sodium

5) Anti-H. pyloric drugs: Amoxicillin, clarithromycin, metronidazole, tinidazole, tetracycline

How H. Pylori causes ulcer?

• This bacteria burrows through the protective 1mm thick mucus layer and attaches itself to the epithelial of stomach walls to avoid acidic conditions. Furthermore it also produces large amounts of urease, which breaks down the urea present in the stomach to carbon dioxide and ammonia. The ammonia protects it from stomach acidity and is toxic to epithelial cells which secrete mucus. It also produces cell damaging chemicals such as proteases and vacuolating cytotoxinA (VacA). All together the mucus barrier is damaged and made thinner than 0.5 mm and in this state the stomach becomes more susceptible to attack by acid and pepsin

H2 Histamine antagonists

• Histamine is released from mast cell in gastric mucosa by gastrin and acetylcholine

• MOA- Histamine acts on H2 receptor and stimulates proton pump through the cAMPpathway which leads to acid secretion. These drug antagonize H2 receptor and block Histamine mediated acid secretion

• They are associated with libido loss or erectile dysfunction

SAR of H2 Histamine antagonists

• 1) Need an aromatic/hetero-aromatic ring. The imidazole ring isnot required but if it is present there must be electron donors atposition 5 to promote t tautomer .

• 2) The terminal nitrogen group should be polar but not basic formaximal potency

• 3) Separation of the ring from the nitrogen group by 4 atomsgives maximal potency

Normally both tautomers are equally favored

If at position 5 R’ = electron donating group

eg CH3, OH,NH3, then τ tautomer is favored

Imidazole

H2 anti-histamine

drugs

Note• All these contain the NHCH3 or NH2 group at

right terminal which are very basic. But the SAR demands that this Nitrogen not be basic. So how is it achieved?

• Same way the N in amide is not basic. The presence of electron withdrawing group next to the terminal nitrogen, in form of C=O as in amide or CN, SO2NH2 and NO2 as in this case, attracts N’s lone pair electron and can no longer share it to act like a base. The C=N and C=C along with the withdrawing groups that is attached to terminal N account for polarity.

Cimetidine• It is a imidazole derivative H2-antagonist

• It inhibits CYP, which leads to many drug–drug interactions.

• It exhibits antiandrogenic action and can cause gynecomastia if used for more than 1 month.

• It has 63-78% bioavailability

• Uses– Peptide Ulcer, heartburn, Zollinger–Ellison syndrome,GERD

• MOA -Histamine acts on H2 receptor and stimulates proton pump through the cAMP pathway which leads to acid secretion. These drug antagonize H2 receptor and block Histamine mediated acid secretion

•It is a furan derivative H2-antagonist, which is anisostere of the imidazole ring.•It is a weaker CYP inhibitor than cimetidine and has noantiadrogenic effect•It is about 6 times more potent than Cimetidine with alonger Duration of action.•It’s bioavailability is 52%.•UsesPeptide Ulcer, heartburn

•MOA -Histamine acts on H2 receptor and stimulates proton pump through the cAMP pathway which leads to acid secretion. These drug antagonize H2 receptor and block Histamine mediated acid secretion

Ranitidine

Famotidine• It is a thiazole derivative H2-anatgonist.

• It does not cause gynecomastia and is a weakinhibitor of CYP.

• It is 40 times more potent than Cimetidine but it has only 37 to 45% bioavailability.

• Uses

– Peptide Ulcer, heartburn,GERD

• MOA -Histamine acts on H2 receptor and stimulates proton pump through the cAMP pathway which leads to acid secretion. These drug antagonize H2 receptor and block Histamine mediated acid secretion

Nizatidine• It is a thiazole derivative similar to Ranitidine.

• It does not inhibit CYP and has no antiandrogenic effect.

• It is 10 times more potent than Cimetidine. and it has more than 98% bioavailability

• Uses

– Peptide Ulcer, heartburn,GERD

• MOA -Histamine acts on H2 receptor and stimulates proton pump through the cAMP pathway which leads to acid secretion. These drug antagonize H2 receptor and block Histamine mediated acid secretion

Ranitidine ‘s Furan ring vs Nizatidine’s Thiazole ringNote how only the rings are different in these 2 drugs

Ranitidine Nizatidine

6 X potent than cimetidine

10 X potent than cimetidine

52% bioavailability > 98% bioavailability

Bioisoterism has powerful effect on drug efficacy and biocompatibility!

Proton Pump Inhibitors (PPI)

Omeprazole Lansoprazole

Pantoprazole Rabeprazole

Proton Pump Inhibitors (PPI)• Inhibition of Histamine receptor does not fully prevent acid

secretion because Ach and gastrin also separately promote acid secretion.

• But all these 3 regulators ultimately act on proton pump. The pump can also be independently inhibited which fully inhibits acid secretion.

• Hence, PPI have stronger acid suppression and are thus favored over H2-antagonists.

• PPI are irreversible antagonists too, which means once they bind to a pump it cannot regain it’s function anymore and is thus destroyed and replaced by a new one which takes time. This makes their effect stronger and longer (drug action persists even after it disappears from blood!)

• Also they have demonstrated antibacterial activity which is an advantage against H.pylori infection.

• Because they prevent acid secretion very strongly than H2 anatgonists, they interfere absroption of drugs needing acidic condition like antifungals, Iron salts, Digoxin, Ampicillin.

How PPI’s work?1) Benzimidazole PPI’s are prodrug that are converted into

sulphenamide within the acidic environment of parietal cells in stomach.

2) The sulfonamide then covalently and irreversibly interacts with sulphahydryl groups in cysteine amino acid of the binding site of the proton pump to create a disulphide bond.

• The disulphide bond between drug and pump is not completely irreversible. There are enzymes capable of reactivating the pump by breaking this disulphide bond. But if this bond is made with a particular cysteine in the binding sire, cysteine 822, then is ensures maximum resistance to such reduction thus incurring longer duration of action.

• They are made into delayed release or enteric coated formulation which prevents their release in the stomach. This is done because if they are activated in the stomach then the charged sulphonamide form won’t be easily absorbded.

Acidic stomach protonatesprodrug

Prodrugconverts intoactive form

Benzimidazole Sulfenamide

Sulfenamidebound to Sulfhydryl of proton pump

HS-Proton pump

Omeprazole• It is an benzimidazole prodrug proton pump inhibitor• It’s acid inhibition activity is far stronger than H2 antagonists

such that it is incompatible with drugs needing acidic condition for absorption

• It duration of action is 24-72 hrs, even after it has cleared from plasma due to its irreversible

• It’s S enantiomer is called esomeprazole and has more potency and 3 times lower clearance than the R isomer. Esomeprazole can be used against NSAIDS induced ulcer.

• Uses– Peptide ulcer, GERD, heart burn, Zollinger-Ellision syndrome

MOA- It activates into sulphamide form in the acid environment and bonds to sulphahydryl groups of cysteineamino acids in the binding site of the proton pump

Lansoprazole• It is an benzimidazole prodrug proton pump inhibitor

• It’s acid inhibition activity is far stronger than H2 antagonists such that it is incompatible with drugs needing acidic condition for absorption

• It is highly plasma bound but bioavailability is double than omeprazole

• Uses– Peptide ulcer, GERD, heart burn, Zollinger-Ellision

syndrome, NSAIDS induced ulcers

MOA- It activates into sulphamide form in the acid environment and bonds to sulphahydryl groups of cysteine amino acids in the binding site of the proton pump

Prantoprazole• It is an benzimidazole prodrug proton pump inhibitor• It’s acid inhibition activity is far stronger than H2

antagonists such that it is incompatible with drugs needing acidic condition for absorption

• It is highly plasma bound and has better bioavailability than omeprazole and is also extensively liver metabolized

• Uses– Peptide ulcer, GERD, heart burn, Zollinger-Ellision

syndrome

MOA- It activates into sulphamide form in the acid environment and bonds to sulphahydryl groups of cysteine amino acids in the binding site of the proton pump

Rabeprazole

• It is an benzimidazole prodrug proton pump inhibitor• It’s acid inhibition activity is far stronger than H2

antagonists such that it is incompatible with drugs needing acidic condition for absorption

• It is highly plasma bound and has better bioavailability than omeprazole and is also extensively liver metabolized

• Uses– Peptide ulcer, GERD, heart burn, Zollinger-Ellision syndrome

MOA- It activates into sulphamide form in the acid environment and bonds to sulphahydryl groups of cysteine amino acids in the binding site of the proton pump

Try associating PK differences as a result of structural variability (just note that any pattern u may find is only valid in PPI, not other drug category)

Prostaglandins

• The prostaglandins are group of hormone like lipid compounds containing 20-carbon unsaturated fatty acids which is biosynthetically derived from metabolism of arachidonic acid.

• They have a wide pharmacological actions on the cardiovascular system, GI smooth muscle, the reproductive system, the nervous system, platelets, kidney, the eye, etc.

• They are of interest as anti ulcer drugs because they can not only inhibit acid secretion completely like PPI’s but also suppress pepsin which prevents autodigestion of exposed epithelial cells. On top of that, it also has maintains the integrity of mucus layer, termed cytoprotection.

Misoprostal• It is a prostaglandin based antiulcer drug• It is semi-synthetic derivative of PgE1• It has both anti-secretory and cytoprotective effect• It is also a prodrug that after being quickly absorbed gets

deesterified rapidly into it’s active acid form• It has 90% chance of inducing abortion• Uses

– NSAIDS causes gastric ulcer– Doudenal ulcer unresponsive to H2-antagonists– In Arthritis in combination with diclofenac– Off- label use to end pregnancy (before 12 weeks) with or

without mifepristone (anti-progesterone)

• MOA: It agonizes PgE receptors and mediates inhibition of proton pump and also cytpprotective action is based on increases in GI mucus an bicarbonate secretion

Future- Target H.Pylori

• Prevent Adhesion into stomach cells

• Inhibit urease breakdown

Thank You