ANTI-DIABETIC DRUGS Assoc. Prof. Iv. Lambev E-mail: email@example.com www.medpharm-sofia.eu
Glucose occupies a central position in metabolism as the predominant substrate for energy production. NORMOGLYCEMIA (WHO) Fasting glucose: 3.8-6.1 mmol/l HbA1C: 4.7–6.0%
Suspected diabetes mellitus 75 g glucose p.o.: 2 h later
HbA1C is a lab test that shows • the average amount of sugar • in blood over 2–3 months. It shows • how well you are controlling DM. • An HbA1C of 6% or less is normal. • The following are the results • when the HbA1C is being used • to diagnose diabetes: • Normal: Less than 5.7% • Pre-diabetes: 5.7% to 6.4% • DM: 6.5% or higher Values of HbA1C ≥ 7% are a signal for emergency change in treatment.
Diabetes mellitus (DM) Type 1 DM (beta-cell destruction) – about 10% of all patients. a) Autoimmune DM (the so called insulin-dependent DM – IDDM or juvenile-onset diabetes). It results from autoimmune mediated destruction of the beta cells of the pancreas. The rate of destruction is quite variable (and may reach 80% of the beta- cells of the Langerhans islets), being rapid in some individuals and slow in others. The rapidly progressive form is commonly observed in children, but also may occur in adults. The slowly progressive form generally occurs in adults and is sometimes referred to as latent autoimmune DM in adults (LADA). b) Idiopathic type 1 DM, which has no known etiology (has no evidence of autoimmunity). This form is more common among individuals of African and Asian origin. Patients periodically develop ketoacidosis.
Type 2 DM (predominantly insulin resistance with relative insulin deficiency or predominantly an insulin secretory defect with/without insulin resistance). DM of this type previously encompassed non- insulin-dependent diabetes (NIDDM), or adult-onset diabetes. It is a term used for individuals who have relative (rather than absolute) insulin deficiency. People with this type of diabetes (> 80% of patients with DM) frequently are resistant to the action of insulin. • Other specific types of DM • Genetic defects of beta-cell function (mutations on chromo- • some 12 in a hepatic nuclear transcription factor referred to as • HNF13. A second form is associated with mutations in • the glucokinase gene on chromosome 7p.
Genetic defects in insulin action (It is connected with • some pediatric syndromes that have mutations in the insulin • receptor gene with subsequent alterations in the insulin receptor • function and extreme insulin resistance). • Diseases of the exocrine pancreas (pancreatitis, trauma, cancer) • Endocrinopathies(acromegaly, Cushing’s syndrome, • glucagonoma, and pheochromocytoma). • Drug- or chemical-induced (pentamidine, glucocorticoids, etc.). • Viral infections may cause beta-cell destruction (e.g. mumps, • adenovirus, cytomegalovirus, Coxsackie B, congenital rubella). • Other genetic syndromes sometimes associated with • DM (Down’s, Klinefelter’s and Turner’s syndromes, etc.). • Gestational diabetes includes the former categories • of gestational impaired glucose tolerance.
> 520 000 patients with DM
DM – complications: • large blood vessel atherosclerosis • coronary heart disease (CHD) • limb ischaemia (diabetic foot!) • stroke • small blood vessel atherosclerosis • retinopathy • neuropathy • nephropathy • skin ulceration • infection (mycoses, etc.)
Diabetic retinopathy results in scattered haemorrhages, yellow exudates, and neovascularization Diabetic nephropathy
Management goals • Normoglycemia • avoiding hypoglycemia • or ketosis • HbA1C < 6.5% • (glycosylated hemoglobin) • Reduce • - nephropathy • - neuropathy • - retinopathy • - infections (mycoses, etc)
Control blood • pressure (120/80 mm) • Diet • – weight control • – low fat intake • – normal protein intake • – carbohydrates ~ 50% of total energy BMI 18.5–24.9 ! • Motor activity and compliance!
t1/2: 5–6 min molecule mass: 5734 Da I. Insulin Insulin is a protein, secreted from the β-cells of the islets of Langerhans in the pancreas in response to a rise in blood glucose, and inhibited by a fall.
Glucagon Cortisol Adrenaline Somatotrophin (GH) hyper- glyce- mia Insulin Amylin hypoglycemia
Amylin(Islet Amyloid Polypeptide – IAPP) reperesents a 37-residue peptide hormone. It is cosecreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
Mechanism of action • Insulin acts via receptors that • are transmembrane • glycoproteins. • Each receptors has two binding • sites. Receptor occupancy • results in:
1. Activation of insulin-dependent glucose transport processes in adipose tissue and muscle. 2. Inhibition of adenylyl cyclase- dependent processes (lipolysis, proteolysis, glycogenolysis).
Insulin (-) AC PD cAMP ATP 3’,5’-AMP (+) Lipolysis in adipose tissue (hypercholesterolemia)
4. Intracellular accumulation of potassium and phosphate (which are linked to glucose transport in some tissue). 5. Increased cellular amino acid uptake, DNA and RNA synthesis. 6. Increased oxidative phosphorylation.
Insulinis extracted either from cattle or pig pancreas. Bovine (B) insulin differs from human insulin in three amino acid residues, and porcine (S) insulin in one, but their action is very similar to human. Nobel prize (1923)
More recently, recombinant DNA technology has allowed in vitro manufacturing of insulin with the same structure as human (H) insulin. All current insulin preparations have a low content of impurities.
Insulin is initially purified by protein extraction to form a crystalline product. It may then undergo either gel filtration to produce a single peak (SP) insulin or gel filtration and ion exchange chromatography which generates:
monocomponent (MC), • single component (SC) and • rarely immunogenic (RI) insulin. • Other abbreviations • which are used for insulins are: • Hum- and -man (for human ), • PP(purified preparation)
MAIN TYPES OF • INSULIN PREPARATIONS • Short-acting • Intermediate-acting • (they contain protamin or Zn) • Long-acting • (they contain both protamin & Zn) • Injectors (with cartridge): • OptiPen, OptiSet, Penfill, etc.
Comparisons among insulins Type Onset of Peak Duration action activity Short- acting 10–20 min 1–2 h 5–7 h Interme- diate-act. 1–2 h 5–7 h 13–18 h Long-act. 2–4 h 8–14 h 18–36 h
Insulins are used mainly in type 1 DM. Patients with type 2 DM use insulins in the following cases too: • acute infections • pregnancy • surgical operations • burn • myocardial infarction • ketoacidosis
Therapy of DM with insulin is a replacement therapy. High compliance! s.c.: 6 sec
Insulin pumps: They infuse subcutaneously fast-acting insulin through small catheter (very handy and very expensive).
Short-acting insulins • and analogues a) Insulins: Actrapid, Humulin R b) Analogues: Insulin aspart, Insulin lispro s.c. 15 min before meal 4 times daily chronobiologically (4:3:2:1) c) Per inhalation: Exubera
Ketoacidosis Short-acting insulin (i.v. or i.v. infusion) with physiological saline and potassium chloride
2. Intermediate-acting insulins and analogues • Humulin M • Humulin N • Insulatard • Mixtard s.c. 20 min before meal 2 times daily Chronobiologically
3. Long-acting insulins • Insulin detemir • (Levemir) • Insulin glargine • (Lantus) s.c. 20 min before meal once daily
Adverse effects of insulins • hypoglycemia/coma • allergic reactions • insulin resistance • lipodystrophia of subcutane- • ous fat at or near injection • local fibrosis
II. Oral hypoglycemic and other drugs, used in DM type 2
1. Biguanides: Metformin • usually first line drug for type 2 DM • reduces intestinal glucose absorption • stimulates anaerobic glycolysis • stimulates glucose uptake • enhances insulin receptor binding
Metformin • excreted exclusively • by the kidney • does not increase weight • and preferable in the obese • GI side effects • rarely • lactic acidosis
2. Sulfonylureas • I generation: • Chlorpropamide and Tolbutamide (Out) • II generation: • Glibenclamide (Maninil: tab. 5 mg) • Gliclazide (Diaprel MR) • Glipizide • Gliquidone
Mechanism of action • promote enhanced insulin release • from the pancreas • leads to a reduction in hepatic • glucose production • Unwanted effects • Hypoglycemia, weight gain • facial flushing following • alcohol ingestion
Sulfonylureas – important drug interactions: • displacement from protein binding sites • – salicylates and sulphonamides • interference with hepatic metabolism • – inducers: rifampicin, phenytoin • – inhibitors: cimetidine • reduction of renal elimination • – allopurinol, salicylates
3. Meglitinides: stimulate the release of insulin • from pancreas by closing ATP-dependent • potassium channels. • - Nateglinide • - Repaglinide 4. Glucosidase inhibitors - Acarbose (Gluco Bay): p.o. • Inhibits intestinal alpha-glucosidase • Decreases intestinal absorption • of the mono- and polysaccharides. • Produces flatulence and diarrhoea.
5. Thiazolidinediones (TZDs) They increase tissue insulin sensitivity but have serious ADRs and the EMA recommended in Sept (2010) that they be suspended from the EU market: - Rosiglitazone (Avandia) hashigh cardiovascular risks. - Pioglitazonecausesbladder tumors. - Troglitazone causeshepatitis.
6. Glucagon-like peptide-1 (GLP-1) agonists (in type 2 DM):increase pancreatic secretion of insulin: Exenatide Bydureon (s.c./7 days): $323/4 doses, resp. $4200 per year
Liraglutid is a GPL-1 agonist, which reduces, BM, HbA1C, andsystolic blood pressure, and improves beta cell function of the pancreas (s.c. once a day) Liraglutid