Pantoprazole

An informative but short explanation of one of the important PPI pantoprazole. I hope it will help you to make enough sense about pantoprazole. Be connected with me. Thank you .

1. Abir Hasan S ajid Student Dept of Pharmacy Jashore university of science and technology By… Pantoprazole

2. Molecular Machanism Side effects Introduction Drug Interaction Pharmacokinetics Metabolism Dose,dosage form ,strength Contents Indication Precaution, contraindication 02 Indications 02

3. Introduction Inhibits H+/K+ ATPase enzyme(proton pump) Prodrug (requires activation) Reduce Gastric acid secretion Chemical structure of Pantoprazole P antoprazole is a proton pump inhibitor that suppresses the final step in gastric acid production by covalently binding to the H + /K + ATPase enzyme system at the surface of the gastric parietal cell. H+/K+ ATPase is nothing but proton pump. Treat Ulcer,GERD Known as Proton pump inhibitor (PPI)

4. P y r idine ring Benzimid azole ring Structure of panto pr azole P y r idine - pr azole Benzimid azole T wo types of heterocylic ring connected with alkyle sulphoxide bridge in the Structure of Pantprazole. The suffix –prazole is derived from that two ring name. Benzimidazole (Indicates azole of the suffix prazole) Pyridine (Indicates pr of the suffix prazole) Introduction

5. Molecular mechanism ◾Mechanism of acid secretion in stomach H 2 O+CO 2 CA H 2 CO 2 HCO 3 - H + K + PP Cl - Cl - H + HCO 3 - HCl Within the gastric parietal cells, water and CO2 combine and produce the carbonic acid by carbonic anhydrase enzyme. Then carbonic acid split into carbonate ion and proton Bicarbonate exchange outside with Chloride ion by another pump The chloride ion directly secrete into lumen Proton secrete into lumen by proton pump exchange of potassium ion Poton and chloride combines and produce HCl acid

6. P antoprazole is a pro-drug. So it requires bioactivation. After adminstration, it Converted into a active Metabolite. It is actually responsible for the inhibiting proton pump. NB: Prodrug is a biological inactive compound which need to be metabolized in the body to form a active drug. 2H + Process of bioactivation Step 1: Two nitrogen of the two ring of Pantoprazole are attacked by the proton. Pantoprazole Molecular mechanism Protonated Pantoprazole

7. Step 2: The protonated Pantoprazole loses proton and one nitrogen form a bond with carbon of benzimidazole ring. Sulfer breaks the bond with the same carbon and form –S–OH group. -H + Molecular mechanism Amide linkage -SH Proton pump -SH Step 3: This –S-OH complex of Pantoprazole loses water and form a amide bond with benzimidazole‘s Nitrogen and make Sulfenamide (Active metabolite of Pantoprazole). Sulfenamide(active drug) -H 2

8. Molecular mechanism ◾How Acid secretion inhibited by pantoprazole Pantoprazole enters into gastric parietal cell Convert into active metabolite (Sulfenamide) Sulfenamide interact with proton pump Sulfenamide bind to proton pump at thial group Proton pump cant pass proton to the lumen HCl formation inhibited in Gastric environment Inactive Pantoprazole Active drug -

9. The active form of pantoprazole(sulfenamide) binds covalently to the gastric H + / K + -ATPase enzyme via disulfide bond. Reaction occurs with Cys813 and Cys822 Site of H+/K+ ATPase enzyme at thial group(-SH) and form stable disulfides. Sulfenamide reaction with the ATPase e nzyme inhibited the enzyme and it can’t pass proton and potassium betweens lumen and cell.Thus HCl cant be formed in lumen. Molecular mechanism Sulfenamide The reaction with Cys822 confers a rather special property to the covalently inhibited enzyme, namely irreversibility to reducing agents in vitro and in vivo due to the lack of accessibility of Cys822 ◾How pantoprazole reacts with H+/K+ ATPase enzyme Proton pump Cysteine S Sulfenamide – proton pump complex H+/K+ ATPase(proton pump)

10. Indications The main indication of Pantoprazole is Gastric ulcer. It reduce gastric acid secretion and protects the gastric wall from being wounded. It can treat gastro esophagus reflux disorder by reducing gastric acid secretion. Where gastric acid reflux into esophagus. It is prescribed with NSAIDs. Because NSAIDs increase gastric acid secretion. In triple and quadrupole therapy, It can treat infection in the gastric wall caused by a gram –ve bacteria named Helicobacter pylori. It reduced acid secretion caused by zollinger addisons sundrome in which tumor cause stomach to produce more acid. It can be used as prophylactic after anesthesia. It can be used in the treatment of dyspepsia.

11. Indications Gastric Ulcer Gastro esophagus reflux disorder With NSAIDs Helicobacter- pylori eradication Zollinger ellison syndrome Pantoprazole

12. Drug Interaction PPI‘s are generally inhibit the CYP450 enzyms and one of the important CYP450 enzyme on which PPI’s act is CYP2C19. Some drugs are activated by this enzyme. Such as Clopidogrel,Nelfinavin,Rilpirivine. So when these drugs are adminstrated with PPI’s,these drug‘s metabolism can be inhibited by the PPI’s that is mainly for the inhibition of enzyme CYP2C19. Though pantoprazole is less inhibitory among the other PPI’s Drugs that affect by the alteration of pH of upper GI tract should be contraindicated. Pantoprazole may alter the solubility and absorption by altering pH. Example : Erlotinib, Nelfinavir. Pantoprazole CYP2C19 Inhibited CYP2C19 Nelfinavir Inhibited CYP2C19 Reduced Nelfinavir effect Active M8 metabolite

13. Half-life : 1 hr; increased to 3.5-10 hr with CYP2C19 deficiency Dialyzable : No Renal clearance : 0.1 L/hr/kg Total body clearance : 7.6-14 L/hr Excretion : Urine (71%); feces (18%) Pharmacokinetics(ADME) Absorption Bioavailability : 77% (PO; neither food nor antacid alters bioavailability) Onset (PO PUD): 24 hr (initial response) Duration (PO at steady state) : 7 days (PUD) Peak plasma time: 2.8 hr (PO); at end of infusion Protein bound : 98% Vd: 11-24 L Metabolized extensively by hepatic P450 enzyme CYP2C19 . Plasma concentration can increase by 5-fold or more in comparison with that found in persons who have the enzyme. Metabolites : Desmethylpantoprazole sulfate conjugate (activity unknown) Absorption Distribution Metabolism Excretion

14. Pantoprazole sulfone Pantoprazol sulfide 5-hydroxy pantoprazole Pantoprazole sulphate sulfone Pantoprazole sulphate sulfide (M3) CYP3A4 CYP2C19 CYP3A4 Sulfo- transferase Metabolism PPIs are enzymatically cleared in the liver by demethylation reaction primarily by the cytochrome P450 2C19 (CYP2C19) enzyme, and to a lesser extent by CYP3A4(oxidation). Metabolites : 5-hydroxy pantoprazole, Pantoprazole sulphate, pantoprazole sulfone, pantoprazole sulphate sulfone, pantoprazole sulphide,pantoprazole sulphate sulphide. It is documented that CYP2C19 is responsible for > 80% of the metabolism of pantoprazole metabolism. Pantoprazole CYP3A4 Pantoprazole sulphate (M2) CYP3A4

15. Dose,Dosage form and Strength O ral suspension 40mg/packet P owder for injection 40mg/vial T ablet(delayed-release) 20mg / 40mg Tablet(Immediate release) 40mg Indications Dose(Tabletl Time Dose (Iv injection) Time GaStric Ulcer 40 mg(Daily morning) For 4 weeks / 8 weeks (if not healed) 40mg once daily For 7-10 days GERD 20-40 mg (daily morning) For 4 weeks /8 weeks (if not healed) 40mg once daily For 7-10 days Zollinger ellison syndrome 80 mg daily (adjusted) Variable 80 mg every 12 hours (Variable) Variable Prophylaxis for NSAID 20 mg daily According to NSAID 80mg every 12 hours For 24 hours H-pylori ulcer 40 mg twice daily associated with antimicrobials According to antimicrobials - -

16. Side effects Side effects Vomiting Headache Nausea Abdom-inal pain Vit-B12 deficiency Allergic reaction Diarrhoea Bone fracture Long term uses (over 3 years) can cause vit-B12 deficiency(Numbness, weakness) and also has probability of bone fracture. Headache Main side effects of Pantoprazole is nausea,vomiting(4%), Headache(12%) Diarrhoea(9%), dizziness(3%), abdominal pain(6%), joint pain(3%) Abdominal pain

17. Precaution and warnings ! Contraindication Patients should be cautioned that Pantoprazole tablet should not be split, chewed or crushed. Long-term therapy of Pantoprazole may lead to malabsorption of cyanocobalamin (Vitamin B12) Long -term therapy may increase the risk of osteoporosis related disorders. Pantoprazole is contraindicated in patients with known hypersensitivity to any of the components of the formulation. It is also contraindicated when given with the pH sensitive drugs. ◾Erlotinib ◾Nelfenavir

18. Reference https://reference.medscape.com/drug/protonix-pantoprazole-342001#10 https://www.sciencedirect.com/topics/chemistry/pantoprazole https://www.pediatriconcall.com/drugs/pantoprazole/850 https://youtu.be/V0HR-ojkURw https://medex.com.bd/generics/859/pantoprazole/brand-names https://en.m.wikipedia.org/wiki/Pantoprazole