Pharmacotherapy of Diabetes Mellitus and Drug interaction Amoxicillin and Clavulonic Acif

Pharmacotherapy of Diabetes Mellitus and Drug Interaction

1. Pharmacotherapy of Diabetes Mellitus and Drug interaction: Amoxicillin + Clavulanic acid Dr. Snehashis Singha Junior Resident 2 nd Year Department of Pharmacology & Therapeutics King George’s Medical University, Lucknow, U.P. INDIA Email [email protected]

2. Contents Introduction Classification of antidiabetic drugs Criteria for diagnosis of diabetes Pharmacotherapy of diabetes mellitus Insulin therapy Oral antidiabetic drugs Management approach in diabetes mellitus Drug interaction : Amoxicillin and Clavulanic acid

3. Learning objectives: At the end of this teaching-learning session, the audience will be able to understand : Diabetes Mellitus, criteria for its diagnosis & classification of antidiabetic drugs What are the key features of insulin therapy & oral antidiabetic drugs ? What is the management approach for diabetes mellitus ? How does the interaction between amoxicillin and clavulanic acid work ?

4. Introduction Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia , caused by complex interaction of genetics and environmental factors. Depending on the etiology of DM, factors contributing to hyperglycemia include: Reduced insulin secretion Decreased glucose utilization Increased glucose production

5. Types of diabetes mellitus

6. Source : Goodman and Gilman, 14 th Edition, Page 1027 Adapted from American Diabetes Association 2022a Criteria for the diagnosis of diabetes

7. Approach Type 1 DM Type 2 DM Lifestyle & Diet (Requires strict adherence) Carbohydrate and calorie counting, low glycemic index foods, exercise Low glycemic index foods , low calorie and high fiber diet, exercise Improve Insulin Availability Exogenous insulin (Basal-bolus, pump) Insulin, Sulfonylurea, Meglitinide , DPP-4 inhibtors , GLP-1 RA Overcome Insulin Resistance — Metformin, Thiazolidinedione, α- Glucosidase inhibitor Pharmacotherapy of Diabetes Mellitus

8. Insulin therapy Discovered in 1921 by Banting and Best Structure of Insulin: Insulin is a two chain polypeptide A-chain: 21 amino acids B-chain: 30 amino acids Preproinsulin synthesized in β cells as 110 amino acids. Processed into proinsulin (86 amino acids), cleaved into insulin (51 amino acids) & C-peptide (35 amino acids) Insulin and C-peptide are stored in granules and released into the bloodstream Basal Secretion: 1 unit/hour having 51 amino acids , disulphide bonds connect A and B chains

9. Neural Regulation : Adrenergic α2 receptors inhibit insulin. Cholinergic vagus nerve stimulation promotes insulin secretion. Chemical Regulation : Glucose stimulates insulin via GLUT1, ATP, and K+ channel inhibition; Incretins (GLP-1, GIP) enhance release of insulin Hormonal Regulation of insulin : GH, thyroxine corticosteroid promote & somatostatin inhibits Insulin binds Receptor tyrosine kinase, activating GLUT4 translocation, PI 3 Kinase, and signaling cascades Fig. Neural regulation of insulin

10. Actions of insulin : Tissue Effects of Insulin LIVER Increases glucose uptake & glycogen synthesis Inhibits glycogenolysis & glucose output Inhibits gluconeogenesis from protein, pyruvate, FFA, glycerol SKELETAL MUSCLE Increases glucose uptake & utilization Inhibits proteolysis & release of amino acids, pyruvate, lactate into blood (reducing gluconeogenic substrates) ADIPOSE TISSUE Increases glucose uptake & storage as fat and glycogen Inhibits lipolysis & release of FFA + glycerol (reducing gluconeogenic precursors)

11. Type Appearance Onset (hr) Peak (hr) Duration (hr) Can be mixed with Rapid acting Insulin lispro Clear 0.2–0.3 1–1.5 3–5 Regular, NPH Insulin aspart Clear 0.2–0.3 1–1.5 3–5 Regular, NPH Insulin glulisine Clear 0.2–0.4 1–2 3–5 Regular, NPH Short acting Regular (soluble) insulin Clear 0.5–1 2–3 6–8 All preparations (except insulin glargine/ detemir ) Intermediate acting Insulin zinc suspension or Lente Cloudy 1–2 8–10 12–20 Regular Neutral protamine hagedorn (NPH) or isophane insulin Cloudy 1–2 8–10 12–20 Regular Long acting Insulin glargine Clear 2–4 — 24 None Insulin detemir Clear 1–4 — 20–24 None Types of insulin preparations and insulin analogues

12. Rapid-acting insulin Lispro : Proline -lysine swap at B28-B29 Aspart : Proline replaced by aspartic acid Glulisine : Lysine replaces asparagine at B23 Onset: Begins working within 15 minutes of injection Duration: Lasts for about 3-4 hours, making it ideal for meal-time blood glucose control

13. Short-acting insulin Example: Regular insulin Regular insulin is a neutral pH solution, stabilized with zinc, forming hexamers for slow absorption after s.c. inj. Peak action occurs in 2–3 hours, lasting 6–8 hours. Best injected 30 minutes - 1 hour before meals Intravenous ( i.v. ) injection ensures rapid dissociation and immediate action

14. Intermediate-acting insulin Example: Lente , Isophane (Neutral Protamine Hagedorn ) insulin
Suspension of insulin with protamine and zinc in a neutral pH solution. Zinc in insulin stabilizes hexamers, prolongs its action, and regulates its release from subcutaneous depots Peak Action: 6–12 hours; Duration: 18–24 hours, administered twice daily
Inject 1–2 hours before meals

15. Human insulin Produced via recombinant DNA (E. coli/yeast) technology in Escherichia coli—‘proinsulin recombinant bacteria’ ( prb ) and in yeast—‘precursor yeast recombinant’ ( pyr ), or by ‘enzymatic modification of porcine insulin’ ( emp ). Better solubility; faster s.c. absorption Includes Actrapid , Insulatard , Mixtard

16. Long-acting insulin Glargine : Arg-gly modification, forms a slow-release depot Detemir : Binds albumin; slower, stable release Degludec : Ultra-long-acting ( ~ 40 hours); less hypoglycemia Onset: Takes about 1 hour to start working Providing a steady insulin level throughout the day Used for basal insulin requirements in Type 1 & 2 DM

17. Insulin regimens in diabetes Type 1 DM : 0.4–0.8 U/kg/day and in Type 2 DM : 0.2–1.6 U/kg/da Split-Mixed Regimen 30:70 or 50:50 mix of Regular and NPH insulin Administered before breakfast and dinner Only two injections needed but may not cover post-lunch glucose adequately Basal-Bolus Regimen Long-acting insulin (e.g., Glargine) for basal coverage & Rapid-acting insulin (e.g., Lispro ) Achieves round-the-clock euglycemia but multiple doses are required

18. Insulin side effects Hypoglycemia : Most common side effect, particularly with rapid-acting insulins Weight Gain : Insulin therapy often causes weight gain due to increased glucose storage in cells Lipohypertrophy : Fat accumulation at injection sites Allergic Reactions : Localized redness, swelling, or itching at the injection site

19. Metformin ( Biguanide ) Mechanism of Action: Activates AMP-activated protein kinase (AMPK) As 1 st choice drug for T2DM if not tolerated or c/ i , HbA1c reduction by (0.8–1.2%) Advantages: Doesn’t cause hypoglycaemia, promotes weight loss, prevents β - cell exhaustion/failure in T2DM, prevents micro-macro vascular complications Adverse effects: Gastrointestinal intolerance , lactic acidosis , Vit B 12 deficiency

20. Source: Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther . 2023;17:1907-1932. Mechanisms of action of Metformin

21. Source: Tripathi , K. D. 8th ed Essentials of medical pharmacology, Page – 297 Sulfonylureas (SU), meglitinide analogues ( Megli ), sulfonylurea receptor 1 (SUR1), ATP-sensitive potassium (KATP), glucagon-like peptide 1 (GLP1), glucose-dependent insulinotropic polypeptide (GIP), exenatide (Exe), liraglutide (Lira), dipeptidyl peptidase-4 (DPP-4), sitagliptin ( Sita ), vildagliptin ( Vilda ). Mechanisms of action of antidiabetic drugs

22. Sulfonylureas 1 st gen. ( tolbutamide , chlorpropamide ) are less potent with higher hypoglycemia risk, while 2 nd gen. (glimepiride, glibenclamide ) are more potent Sulfonylureas bind to sulfonylurea receptor (SUR1) on pancreatic β- cells Adverse Effects: Hypoglycemia , weight gain, hypersensitivity and s hould not be given to nursing mothers Drugs like phenylbutazone , salicylate enhance SU action, increasing hypoglycemia risk. Phenobarbitone , phenytoin, corticosteroids, and OCPs reduce its efficacy

23. GLP-1 receptor agonists ( Liraglutide , Semaglutide , Exenatide ) Mechanism of Action: GLP-1 receptor agonists stimulate insulin release , inhibit glucagon secretion Uses: Used in type 2 diabetes to improve glycemic control. Lowers HbA1c & both postprandial & fasting blood glucose Advantages: Improves glycemic control, promotes weight loss, and preserves β-cell function. Rare risk of hypoglycemia unless combined with other medications. Adverse Effects: Acute pancreatitis is a rare but serious risk factor

24. DPP-4 inhibitors ( Sitagliptin , Vildagliptin , Saxagliptin , Linagliptin ) Mechanism of Action: DPP-4 inhibitors prevent the breakdown of GLP-1 and GIP Used as adjunct therapy in T2DM, particularly when metformin, SU or insulin alone are insufficient. Suitable for patients with low hypoglycemia risk Advantages: Low risk of hypoglycemia , body weight-neutral Adverse Effects: Nausea, loose stools, headache, rash, and angioedema. Rarely, pancreatitis, hepatotoxicity, and QT prolongation (with teneligliptin) may occur

25. Thiazolidinediones (TZDs) Mechanism of Action: Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPAR γ ) agonist that enhances GLUT-4 expression and insulin sensitivity. It also suppresses hepatic gluconeogenesis and improves lipid metabolism via PPAR α activation Reduces HbA1c (0.5–1.2% ). Improves insulin sensitivity, lowers TG & raises HDL Adverse Effects: Fluid retention, edema , weight gain, CHF risk, fractures in elderly women & hepatic dysfunction. Long-term use may increase bladder cancer risk

26. Source : PharmaWiki . Thiazolidinediones [Internet]. PharmaWiki ; Available from: https ://tmedweb.tulane.edu/pharmwiki/doku.php/thiazolidinediones Mechanism of action of Thiazolidinedione

27. SGLT-2 inhibitors ( Empagliflozin , Canagliflozin , Dapagliflozin ) Mechanism of Action: Blocks the sodium-glucose co-transporter 2 in the proximal renal tubules Approved for use in type 2 diabetes, either alone or in combination with other antidiabetic drugs. Reduces HbA1c by (0.5–1.0%) Advantages: Promotes weight loss, and does not cause hypoglycemia Adverse Effects: May cause glycosuria, increasing the risk of urinary and genital infections , electrolyte imbalances , ketoacidosis, and frequent urination

28. Source : PharmaWiki . SGLT-2 inhibitors [Internet]. PharmaWiki ; Available from: https://tmedweb.tulane.edu/pharmwiki/doku.php/sglt-2_inhibitors Mechanism of action of SGLT-2 inhibitors

29. α- Glucosidase inhibitors ( Acarbose , Miglitol , Voglibose ) Mechanism: Inhibit α- glucosidases in the small intestine, slowing carbohydrate digestion and absorption & promoting GLP-1 release, reducing postprandial glycaemia without raising insulin levels Indications: Type 2 diabetes (adjunct to other drugs) Benefits: Modestly lowers HbA1c (0.4–0.8%) , reduces postprandial blood sugar levels Side Effects: GI discomfort (flatulence, loose stools)

30. Pramlintide : A synthetic amylin analog used in T1DM & T2DM. Delays gastric emptying, reduces postprandial glucagon, promotes satiety, lowers HbA1c & supports weight loss Colesevelam : A bile acid sequestrant for T2DM, offering mild blood glucose reduction and weight neutrality Bromocriptine : A dopamine agonist reducing insulin resistance with modest HbA1c reduction Emerging adjunct therapies in diabetes

31. Simplified flow chart of management approaches in diabetes mellitus (Met—Metformin; SU—Sulfonylurea; Megli — Meglitinide /d-phenylalanine analogue; DPP-4i—Dipeptidyl peptidase-4 inhibitor; α Gli — α Glucosidase inhibitor; Pio —Pioglitazone; GLP-1 Ago—GLP-1 receptor agonist ) Source: Tripathi , K. D. 8th ed Essentials of medical pharmacology, Page - 304

32. Factors in therapeutic decision for diabetes treatment Based on the 2018 recommendations of the consensus panel of the American Diabetes Association/ European Association for the Study of Diabetes Source: Current Medical Diagnosis and Treatment (CMDT) 2024, Page 1224

33. Major side effects and cost considerations: Based on the 2018 recommendations of the consensus panel of the American Diabetes Association/ European Association for the Study of Diabetes Source: Current Medical Diagnosis and Treatment (CMDT) 2024, Page 1224

34. Amoxicillin and Clavulanic acid combination Amoxicillin: Broad-spectrum beta-lactam antibiotic. Inhibits bacterial cell wall synthesis Clavulanic Acid: Beta-lactamase inhibitor, progressive inhibitor , suicide inhibitor but has no/weak antibacterial activity on its own. Commonly used sinusitis, otitis media, respiratory & skin infections

35. Drug interaction Mechanism of Action : Amoxicillin alone is degraded by beta-lactamase -producing bacteria. Clavulanic acid binds irreversibly to beta-lactamase enzymes , preventing them from destroying amoxicillin Synergistic Effect : Protects amoxicillin from degradation by beta-lactamase enzymes produced by resistant bacteria, such as Staphylococcus aureus and Klebsiella pneumoniae . By neutralizing beta-lactamase, it helps prevent resistance & reduces treatment failure in beta-lactamase-producing organisms

36. Summary T1DM: A bsolute insulin deficiency, requiring lifelong insulin therapy T2DM: Initially managed with Metformin (reduces hepatic glucose production, improves insulin sensitivity). Sulfonylureas (increase insulin secretion), Thiazolidinediones (enhance insulin action), DPP-4 inhibitors (prolong incretin effects) & SGLT2 inhibitors (increase glucose excretion) Clavulanic acid irreversibly binds β- lactamase, protecting amoxicillin from degradation

37. References Brunton LL, Hilal-Dandan R, Knollmann BC, editors. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14 th ed. New York: McGraw Hill; 2022. p.1023–45 Tripathi KD. Essentials of medical pharmacology. 8 th edition. New Delhi: Jaypee Brothers Medical Publishers; 2019. p.280-305 Papadakis MA, McPhee SJ, Rabow MW, editors. Current Medical Diagnosis & Treatment 2024. 63 rd ed. New York: McGraw Hill; 2024. p.1201–44. Fauci AS, Kasper DL, Longo DL, et al., editors. Harrison's principles of internal medicine. 20th ed. New York: McGraw-Hill Education; 2018. p. 3094-3136.