Lecture 4. Oral Hypoglycemic Agents PDF

Pharmacology I – Dentistry (D2) Anti-Diabetic agents Presented by: Dr Mohammad Jaffar Department of Pharmacology Pharmacy Program, BMC, Jeddah  INSULIN Insulin is a two chain polypeptide having 51 amino acids and MW about 6000. The A-chain has 21 while...

Pharmacology I – Dentistry (D2) Anti-Diabetic agents Presented by: Dr Mohammad Jaffar Department of Pharmacology Pharmacy Program, BMC, Jeddah  INSULIN Insulin is a two chain polypeptide having 51 amino acids and MW about 6000. The A-chain has 21 while B-chain has 30 amino acids. There are minor differences between human and beef insulins: Insulin is synthesized in the β cells of pancreatic islets as a single chain peptide Insulin is Stored in the form of granules and secreted in the blood stream Under basal condition ~1U insulin is secreted per hour by human pancreas. Much larger quantity is secreted after every meal. Mechanism of Insulin Release in the body: a) Chemical The β cells have a glucose sensing mechanism dependent on entry of glucose into β cells. More glucose – More insulin release and vice versa (positive feedback mechanism) b) Hormonal A number of hormones modify insulin release in response to glucose (positive feedback mechanism) c) Chemical Adrenergic α2 receptor activation decreases insulin release (negative feedback mechanism) Adrenergic β2 stimulation increases insulin release (positive feedback mechanism) Cholinergic—muscarinic activation causes insulin secretion (positive feedback mechanism) Mechanism of action Insulin acts on specific receptors The insulin receptor is a receptor tyrosine kinase (RTK) which is glycoprotein Insulin triggers the uptake of glucose by every cell and production of energy takes place IRS: Insulin receptor substrate; MAPK; Mitogen activiated protein kinase; GLUT: glucose transporter; PK;Protein Kinase; GSK: glycogen synthase kinase;  Insulin & glucose metabolism Muscle Uptake of glucose and immediate use (exercise) or storage as glycogen (Exercising muscles can take up glucose without insulin) Liver Uptake of glucose and storage as glycogen Adipose Tissue Promotes glucose uptake and conversion to glycerol for fat production  Insulin and Fat Metabolism Liver cells store glycogen only up to 5-6% Remaining glucose triglycerides are synthesized and release into blood Adipose cells store fat Inhibits breakdown of triglycerides Insulin and protein Metabolism Inhibits protein degradation Lack of insulin causes elimination of protein stores Fate of insulin Insulin is distributed only extracellularly. It is a peptide; gets degraded in the g.i.t. if given orally. Injected insulin or that released from pancreas is metabolized primarily in liver and to a smaller extent in kidney and muscles. Half life of Insulin: 5 – 9 mins Type of Insulin:  Types of Insulin: Regular (soluble) insulin unmodified insulin stabilized by a small amount of zinc. Lente insulin (Insulin-zinc suspension): Types of insulin-zinc suspensions have been produced to form suspension The 7:3 ratio mixture of Insulin :Zinc is called ‘Lente insulin’ and is intermediate-acting. Isophane (Neutral Protamine Hagedorn or NPH) insulin: - Protamine is added in a quantity just sufficient to complex all insulin molecules - It is mostly combined with regular insulin (70:30 or 50:50) and injected s.c. twice daily before breakfast and before dinner (split-mixed regimen). Insulin lispro: - Produced by adding proline and lysine. - After s.c. injection resulting in a quick and shorter duration of action. Insulin aspart: - The proline of human insulin is replaced by aspartic acid. - It more closely mimics the physiological insulin release pattern after a meal Insulin glulisine: Insulin analogue with lysine replacing asparagine and glutamic acid replacing lysine. It has been particularly used for continuous subcutaneous insulin infusion (CSII) by a pump. Insulin glargine: This long-acting biosynthetic insulin has 2 additional arginine residues. Onset of action is delayed, but maintained for upto 24 hours. Insulin detemir Myristoyl (a fatty acid) radical is attached to the amino group of lysine of insulin chain. After s.c. injection from which the free form becomes available slowly, but twice daily dosing may be needed. Reaction of Insulin 1. Local reactions: Swelling, erythema and stinging 2. Allergy: This is due to contaminating proteins 3. Edema: Some patients develop, short-lived reaction 4. Hypoglycaemia is seen with insulin used in large dose and with vigorous exercise Management of severe hypoglycemia: Glucose must be given orally or i.v. (for severe cases)—reverses the symptoms rapidly. Glucagon 0.5–1 mg i.v. or Adr 0.2 mg s.c. (less desirable) may be given as an expedient measure in patients who are not able to take sugar orally and injectable glucose is not available.  Pharmacokinetics: Not active orally Must be administered subcutaneously or transdermal The duration of action ranges from 5 – 8 hours for short duration insulin, 18 – 24 hours for intermediate insulin and 24 – 36 hours for long duration acting insulin The degradation occurs in the liver or in the vascular endothelium The byproducts of insulin metabolism are re utilized again by the body  Drug Interactions: Insulin + beta blockers → Prolong hypoglycaemia Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine + Insulin Tends to raise blood sugar and reduce effectiveness of insulin. Insulin + Lithium, high dose aspirin, theophylline & Alcohol → hypoglycaemia  ORAL HYPOGLYCAEMIC DRUGS: CLASSIFICATION A. Enhance Insulin secretion 1. Sulfonylureas (KATP Channel blockers) First generation: Tolbutamide Second generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride 2. Meglitinide/phenylalanine analogues: Repaglinide, Nateglinide 3. Glucagon-like peptide-1 (GLP-1) receptor agonists: (Injectable drugs) Exenatide, Liraglutide 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin B. Overcome Insulin resistance 1. Biguanide (AMPK activator): Metformin 2. Thiazolidinediones (PPARγ activator): Pioglitazone C. Miscellaneous antidiabetic drugs 1. α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose 2. Amylin analogue: Pramlintide 3. Dopamine-D2 receptor agonist: Bromocriptin 4. Sodium-glucose cotransport-2 (SGLT-2) inhibitor: Dapagliflozin Sulfonylureas (KATP Channel blockers): Used in type 2 diabetics, but not in type 1 diabetics. Mechanism of action: Sulfonylureas provoke a release of insulin from pancreas, by blocking the ATP based K – Channels Pharmacokinetics All SUs are well absorbed: Orally active, and are 90% or more bound to plasma proteins: They are primarily metabolized in liver— may produce active metabolite. The metabolites (active/inactive) are excreted in urine. Drug interaction: Sulfonamides, warfarin + Sulfonylurea → enhance action of Sulfonylurea Phenobarbitone, Corticosteroids + Sulfonylurea → Decrease action of Sulfonylurea Adverse Drug Reactions: Nausea, Vomiting, Diarrhoea, Hypoglycemia, Hypersensitivity Note: Sulfonylureas are secreted in milk: should not be given to nursing mothers. Meglitinide / D-phenylalanine analogues: (KATP Channel blockers): Repaglinide Mechanism of action: provoke a brisk release of insulin from pancreas, by blocking the ATP based K – Channels Repaglinide is quickly absorbed and rapidly metabolized. Because of this characteristic its pattern of use is different from that of SUs. It is administered before each major meal to control postprandial hyperglycaemia. Side effects are mild headache, dyspepsia, arthralgia and weight gain ********** Glucagon-like peptide-1 (GLP-1) receptor agonists: (Exenatide) GLP-1 is an important incretin released from the gut in response to ingested glucose. It induces insulin release from pancreatic β cells, inhibits glucagon release from α cells, slows gastric emptying and suppresses appetite by activating specific GLP-1 receptors, Metabolised by dipeptidyl peptidase-4 (DPP-4) which is expressed on the kidney, liver gut mucosa and immune cells. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin Mechanism of action: It is a competitive and selective DPP-4 inhibitor which potentiates the action of GLP-1 receptor agonists. Side effects: It is body weight neutral and carries low risk of hypoglycaemia unless combined with SUs or insulin. The HbA1c lowering caused by Sitagliptin is equivalent to that with metformin. Use: Sitagliptin monotherapy is recommended only when metformin cannot be used Biguanides (AMPK activator): Metformin Mechanism of action: Biguanides do not cause insulin release, but presence of insulin is essential for their action. Activation of AMP dependent protein kinase (AMPK) to play a crucial role in mediating the actions of metformin Suppresses hepatic gluconeogenesis and glucose output from liver* Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat* Adverse effects Side effects with metformin: not serious. Abdominal pain, anorexia, bloating, nausea, metallic taste, mild diarrhoea and tiredness are the usual complaints, which tend to subside with time. Metformin does not cause hypoglycaemia except in overdose. Uses: Metformin is now established as a first choice drug for all type 2 DM patients, except when not tolerated or contraindicated  Thiazolidinedione (PPARγ agonist): Pioglitazone This class of oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator-activated receptor γ (PPARγ) which is expressed mainly in fat cells. Glitazones tend to reverse insulin resistance by enhancing GLUT4 expression and translocation. Plasma fatty acid levels are reduced. Adipocyte turnover and differentiation is accelerated by glitazones. Thus, fatty tissue is a major site of their action.* Lowers HbA1C and insulin levels in type 2 DM patients.*  α Glucosidase inhibitors: Acarbose It is a complex oligosaccharide which reversibly inhibits α-glucosidases, The final enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa. Slows down and decreases digestion and absorption of polysaccharides (starch) and sucrose. Postprandial glycaemia is reduced without significant increase in insulin levels. Acarbose is a mild anti hyperglycaemic and not a hypoglycaemic; may be used as an adjuvant to diet. Thank You