PHA401 ANTIDIABETIC DRUGS ANONYMOUS.pdf

ANTIDIABETIC DRUGS BY DR. EMORDI What is diabetes mellitus? Diabetes mellitus is a chronic metabolic disorder characterized by sustained chronic hyperglycemia due to disturbance in carbohydrates, fat and protein metabolism, resulting from defects in insulin secretion and or action....

ANTIDIABETIC DRUGS BY DR. EMORDI What is diabetes mellitus? Diabetes mellitus is a chronic metabolic disorder characterized by sustained chronic hyperglycemia due to disturbance in carbohydrates, fat and protein metabolism, resulting from defects in insulin secretion and or action. CLASSIFICATION OF DIABETES MELLITUS 1. Type 1 DM (Insulin dependent Diabetes Mellitus) insulin is absent and must be given. 2. Type 2 DM (Non-insulin dependent diabetes mellitus) insulin is present but unable to act in type 2 DM, it could be; a. predominantly insulin resistance cells are resistance to insulin entry. b. Predominantly insulin secretory defects 3. Gestational diabetes mellitus- diabetes mellitus occurring for the first time in pregnancy 4. Other specific types E.g. I. MODY 1-6 II. Fibrocaculus pancreatic diabetes mellitus – due to drugs eg. THIAZIDE, DIURETICS, STEROID. III. Endocrinopathies. Eg. Acromegaly, cashing syndrome CLINICAL SIGNIFICANCE OF DIABETES MELLITUS 1. Polyuria (increase urine production) 2. Polydipsia (increase thirst) 3. Polyphagia (increase in food intake) 4. Weight loss 5. Blurred vision 6. Tingling sensation 7. Burning sensation 8. Recurrent infection eg. Boil DIAGONOSIS 1. Fasting plasma glycose greater than 7.0mmol/L (126mg/dl), this patient is diabetic 2. Random plasma glucose greater than 11.1mmol/L/ (200mg/dl) Note:  One abnormal laboratory value is diagnostic in symptomatic individuals  Two values are needed in asymptomatic patient MANAGEMENT 1. Education 2. Diet 3. Drug therapy 4. Rehabilitation DRUG THERAPY TYPE 1: All type 1 diabetes mellitus require insulin for survival INSULIN Insulin is a small protein with a molecular weight of 5808 Daltons (Da). It contains 51 amino acids arrange in two chains (A$B) linked by disulfide bridges. Proinsulin, a long single-chain protein molecule, processed within the golgi apparatus and packed into granules where it is hydrolyzed into insulin and C- peptide. Granules within the B-cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin INSULIN SECRETION Insulin is released from pancreatic B-cells at a low basal rate and at a much higher stimulate rate in response to a variety of stimulus especially glucose. Other stimulants include; other sugars e.g. Mannose, certain amino acids e.g. Leucine, arginine and vagal activity. If glucose concentration rises, ATP production increase, potassium channels close and depolarization of the cell results. Voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. That is, intracellular calcium results in increased insulin secretion. NOTE: Insulin secretagogues close the ATP dependent potassium channel, thereby depolarizing the membrane and causing the insulin relilable. INSULIN DEGRATION The liver and kidney are the two main organs that remove insulin from the circulation NOTE: Half-life of insulin is 3-5mins EFFECTS OF INSULIN Insulin is the main hormone controlling intermediate metabolism having actions on liver, muscle and fat. Its overall effect is to conserve fuel by facilitating the uptake and storage of glucose, amino acids and fats after a meal. Actively, it reduces blood sugar. EFFECT OF INSULIN ON CARBOHYDRATE METABOLISM Insulin influences glucose metabolism in most tissues, especially the liver where it inhibits glycogenolysis and gluconeogenesis. While stimulating glycogen synthesis. It also increases glucose utilization (glycolysis) but the overall effect is to increase hepatic glycogen stores. EFFECT OF INSULIN ON FAT METABOLISM Insulin increases fatty acid as well as Tri-glycerol synthesis in adipose tissue and livers. It inhibits lipolysis via EU-phosphorylation and hence inactivation of lipases. Also inhibits the lipolytic actions of adrenaline growth hormone and glucagon by opposing their actions on other actions on adenylate cyclase. EFFECT OF INSULIN ON PROTEIN METABOLISM Insulin stimulates uptake of amino acids into muscle and increases protein synthesis. Also decreases protein catabolism and inhibit oxidation of amino acids in the liver OTHER METABOLIC EFFECT OF INSULIN Include transport into cells of K+, Ca2+, nucleotides and inorganic phosphate. LONG-TERM EFFECTS OF INSULIN It is an important anabolic hormone, especially during fetal development. It stimulates cell proliferation and is implicated in somatic and visceral growth and development. INSULIN PREPARATIONS Commercial insulin preparations differ in a number of ways, including differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and time of onset and duration of their biologic action. Four principal types of insulins are available; 1. Rapid acting: with very fast onset and short duration 2. Short acting: with rapid onset of action 3. Intermediate acting 4. Long acting 1. RAPID ACTING INSULIN 21 analogs are commercially available, e.g. insulin lispro and insulin abpart. Rapidly absorbed with onset of action within 5-15 minutes and reaching peak activity as early as 1hr Time duration of action is 3-5hrs 2. SHORT ACTING INSULIN Regular insulin is a short acting soluble crystalline zinc insulin made by recombinant DNA technique to produce a molecule identical to human insulin. Its effect appears within 30mins and peaks between 2-3hrs after SC infection and generally lasts 5-8hrs. it is the only type that should be administered intravenously. Also referred to as soluble insulin. Analogs are: (VAR)  VELOSULIN  ACTRAPID  REGULAR 3. INTERMIADIATE ACTING INSULIN  LENTE HUMULIN  LENTE  NPH (NEUTRAL PROTAMINE HAEDORN) INSULIN 4. LONG-ACTING INSULIN  SULTRALETE INSULIN- HUMULIN U  INSULIN GLORGINE. (Note, it should not be mixed with another insulin) SPECIES OF INSULIN 1. Beef and pork insulins: beef insulin differs by 3 amino acids from human insulin, where as only a single amino acid distinguishes pork and human insulins 2. Human insulin: mass production of human insulin by recombinant DNA techniques is now carried out by observing the human, proinsulin opens into Escherichia coli or yeast and treating the extracted proinsulin to form the human insulin molecule. Human insulin from E. coli is available for clinical use as HUMULIN. INSULIN DELIVERY SYSTEM The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes. However, other means of administration include; 1. Portable pen injectors: contain cartridges of insulin and replaceable need facilitate multiple subcutaneous injections of insulin particularly during intensive insulin therapy. 2. Continuous subcutaneous insulin infusion devices (CSH, insulin pumps): are external open-loop pumps for insulin delivery. The devices have a used programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results. The pump is about the size of a pager usually place on a belt or in a pocket and the insulin is infused through thin plastic tubing that is connected to the subcutaneously inserted infusion set. The abdomen is the favored site for the infusion sets although flantes and thighs are also used 3. Inhaled insulin: clinical trials are still in progress to evaluate the safety COMPLICATIONS OF INSULIN THERAPY 1. Hypoglycemia 2. Insulin allergy: an immediate type hypersensitivity 3. Immune insulin resistance: a low titre of circulating IgG anti-insulin antibodies neutralizes the action of insulin to a negligible extent. Insulin antibodies will lead to insulin resistance and may be associated with other autoimmune processes such as LUPUS ERYTHEMATOSIS. 4. Lipodystrophy at injection sites: atrophy of subcutaneous fatty tissue at the site of injection. REFERENCE OF TYPE 2 DIABETES  Oral hypoglycemic agents 1. Insulin secretagogues a. Sulfonylureas b. Meglitinides- Repaglinide c. D- phenylalanine derivatives- Natozamide  Sulfonylureas e.g.  Tolbutamide  Tolazamide  Chlorpropamide  Glyburide (glibenclamide)  Glipizide  Glimepiride 2. Biguanides  Metformin  Phenformin 3. Thiazolidinediones  Pioglitazone  Rosiglitazone 4. Alpha glucosidase inhibitors  Acarbose  Mioglitol SULFONYLUREAS MECHANISM OF ACTION The major action of sulfonylureas is to increase insulin release from the pancreas. Sulfonylureas bind to other receptors that are associated with a B-cell initiated rectifier ATP sensitive potassium channel. Binding of a sulfonylurea inhibit the efflux of potassium ions through the channel and results in a polarization. Depolarization in turn, opens a voltage gated calcium channel and result in calcium influx and the release of preformed insulin. Other mechanism of action of sulfonylureas includes; 1. Reduction of serum glucagon concentrations: Mechanism is not clear but appears to involve indirect inhibition due to enhanced release both insulin and somatostatin, which inhibit A-cell secretion. 2. Potassium channel closure in extra-pancreatic tissue PHARMACOKINETICS Sulfonylureas are well absorbed after oral administration and most reach peak plasma concentrations within 2-4hrs. the duration of action varies; all bind strongly to plasm albumin and are implicated in interaction other drugs e.g. SELICYLATES AND SULFONAMIDES. Most sulfonylureas are excreted in the urine, most sulfonylureas cross the placenta and stimulate fetal B-cells to release insulin causing severe hypoglycemia at birth (GLIBENCLAMIDE is an exception) Recent use of sulfonylureas is generally contraindicated in pregnancy.  SIDE EFFECTS 1. Hypoglycemia 2. Weight gain 3. Gastrointestinal upsets 4. Allergic skin rashes 5. Bone marrow damage DRUG INTERACTIONS Agents that augment the hypoglycemic effects include; 1. NSAID 2. COUMARINS 3. ALCOHOL 4. SULFONAMIDES 5. PRIMETHROPRIMIN 6. CHLORAMPHENICOL 7. IMIDAZOLE 8. ANTIFUNGAL DRUGS NOTE: First generation of sulfonylureas  Tolbutamide  Chlorpropamide  Tolazainide Second generation of sulfonylureas, and they have fewer adverse effects and drugs interactions  Glyburides  Glipizide  Glimepiride BIGUANIDES  Metformin  Phenformin Note: Phenformin was discontinued because of its association with lactic acidosis. MECHANISM OF ACTION 1. Direct stimulation of glycolysis in tissue with increased glucose removal from blood 2. Reduced hepatic and renal gluconeogenesis 3. Slowing of glucose absorption from the GIT with.. glucose to lactate conversion by enterocytes. 4. Reduction of plasm glucagon levels MEFTORMIN It has a half life of 1.5-3hrs not bound to plasma proteins, it is not metabolized and is excreted by the kidneys SIDE EFFECTS 1. Gastrointestinal upset:  Anorexia  Nausea  Vomiting  Diarrhea  Abdominal discomfort 2. Lactic acidosis is a rare but potentially fatal toxic effect. NOTE: Metformin should not be given to persons with;  Renal or hepatic disease  Hypoxic, pulmonary disease  Heart failure CLINICAL USE Type 2 diabetes THIAZOLIDINEDIONES (GLIAZONES) Mechanism of action: They bind to a nuclear receptor called peroxisome proliferator-activated receptor- gamma (PPARY) which is completed with retinoid X receptors (RXR) PPARY occurs mainly in adipose tissue, but also in muscle and liver. It mediates differentiation of adipocytes, increase lipogenesis and enhances uptake of fatty acids and glycose. PHARMACOKINETICS Both rosiglitazone and pioglitazone are rapid nearly completely absorbed, reaches peak concentration in less than 2hrs, highly protein bound. Both have a short less than 7hrs elimination half life for the parent drugs but longer for the metabolites. NOTE: It is metabolized in the liver. SIDE EFFECTS 1. Weight gain 2. Fluid retention 3. Headache 4. Fatigue 5. GI upset 6. Maybe hepatotoxic BILE ACID SEQUESTRANTS  Initially developed as a bile acid. Sequestrant and cholesterol lowering drugs  Colesevelam. MOA- interaction of the enterohepatic circulation and a decreased in fornesoid X receptor activation. GLP-1 Glucagon-like, polypeptide-1 receptor agonist. - It is referred to as incretins - Amplifies postprandial secretion or insulin in a glucose dependent manner. - Inhibits inappropriate elevation of glucagon - Reduces appetite - Increases safety EXAMPLES - Exenatide - Liraglutide DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS - Sitagliptin - Saxagliptin - Linagliptin INCREASED NATURE GLP-1 - These drugs elevate circulating level of natural GLP-1 and glucose dependent insulinotropic polypeptide @ ultimately reduce S postprandial glucose excursions by increasing glucose mediated insulin secretion and lowering glucagon level. GLP-1 RECEPTOR AGONIST Amplific post prandial secretion of insulin in a glucose dependent manner, inhibits inappropriate elevation of glucagon, reduced appetite, lengthens the gastric emptying time and increases safety. BROUGHT TO YOU BY ANONYMOUS 08160094565