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Antidiabetic drugs

Antidiabetic drugs



Antidiabetic drugs

Antidiabetic drugs



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    Antidiabetic drugs Antidiabetic drugs Presentation Transcript

    • AETIOLOGY AND CLASSIFICATION OF DM • TYPE -1 Immune mediated Idiopathic • TYPE-2 • OTHER- genetic defects of insulin action, pancreatic disease, hormonal antagonist to insulin, drug induced, viral infections etc • GESTATIONAL
    • TYPE -1 • <40yrs • Duration of symptoms over weeks • Body wt- normal –low • Ketonuria- + • Autoantibodies + • Family history - TYPE-2 • > 50yrs • Duration of symptoms over months • Obese • • • +
    • ACTIONS OF INSULIN ANABOLIC • Carbohydrate metabolismGlucose transport, metabolism,glyconeogenisis ,glycolysis. • Lipid metabolismtriglyceride , fatty acids synthesis • Protein metabolismAA transport, protein synthesis. CATABOLIC • Gluconeogenisis • Glycogenolysis. • Lipolysis • Fatty acid oxidation • Protein degradation
    • HOW TO DIAGNOSE DM • • • • • Test for urine- glucose, ketones, proteins Blood glucose- fasting and random FBS- >7mmol/l (126mg/dl) RBS->11.1mmol/l(200mg/dl) Glycosylated Hb- provides an accurate measure of glycemic control over weeks to month.
    • STRUCTURE OF INSULIN A • It comprises of 2 chains B • Joined by disulfide bonds. • Porcine insulin resembles human insulin except that is contains alanine residue on B chains. • Proinsulin has only mild biological activity • Separate A & B chains are inactive.
    • structure
    • PHARMACOKINETICS • Elimination ½ - 5-10min ( iv adm) • Metabolised into liver & kidneys by proteolytic enzyme. • 50% of insulin reaching liver is metabolized by its single pass through liver. • Renal dysfunctions prolongs its elimination. • Its effect after iv adm- 30-60min • Sc adm- released slowly as it tightly bound to receptors so has a prolong effect.
    • • Insulin is secreted into the portal veins @ 1U/h. • Food intake increases the rate by 5-10 folds. • Total daily secretion of insulin is 40U. • Sympathetic and parasympathetic system influence the secretion of insulin • Ex: a-adrenergic stimulation-decreases • b-adrenergic / parasym- increases.
    • RECEPTORS • Receptors are characterized as insulin binding proteins. • Contain 2 subunits( a & b) joined by disulfide bonds. • Insulin & ATP( in vitro) receptors to become phosphorylated on tyrosine residues of b subunits. • The number of insulin receptors is inversely proportional to its plasma conc. • Insulin has an ability to regulate its receptorsobesity and IDDM – decrease in the receptors.
    • PREPARATION • • • • • Source- bovine, porcine, human Most common commercial preparation- 100U Daily dose in DM- 20-60 U * Biosynthetic and semisynthetic insulin Semisynthetic(porcine) produced by enzymatic process. • Biosynthetic- recombinant DNA tec.
    • CLASSIFICATION hours after sc adm ONSET PEAK DURATION 0.5-1.0 2-3 6-8 2-4 4-10 10-20 8-14 minimal 24-36 FAST ACTING Regular(CZI) INTERMEDIATE Isophane(NPH) LONG ACTING ultralente
    • REGULAR INSULIN • Fast acting preparation • Can be given iv/sc • It can be mixed with other insulin preparation in same syringe. • t/t of abrupt onset hyperglycemia and ketoacidosis • Single iv-(5-10 U) OR infusion(0.5-2.0 U/h).
    • Regular insulin
    • ISOPHANE INSULIN • It is intermediate acting • Its duration of action is prolonged because it is conjugated with protamine. • It contains 0.005mg/U of protamine. • NPH- neutral sol, protamine, origin in Hagedorns lab.
    • ULTRALENTE • Long acting • Larger particle size and crystalline form of insulin. • Slow onset and prolonged duration of action lacks its usefulness.
    • SIDE EFFECTS a) b) c) d) e) Hypoglycemia Allergic reaction Lipodystrophy Insulin resistance Drug interactions.
    • hypoglycemia • Most serious side effect • Pts vulnerable- receive insulin in absence of carbohydrate intake • Symptoms-diaphoresis, taccy, hypertension, mental confusion, seizures and coma. • Rebound hyperglycemia can occur due to sympath stimulation in response to hypoglycemia ( somogyi effect). • The diagnosis of hypoglycemia is difficult during GA, ANS neuropathy, non selective b blockers- signs are masked.
    • t/t of hypoglycemia • • • • 50-100 ml of 50% glucose solution-iv Glucagon-0.5-1.0mg iv/sc s/e- nausea vomiting carbohydrates p/o.
    • Allergic reactions • Local or systemic • Local-erythematous indurated area, non insulin materials in insulin prepations. • Systemic-antibody mediated & can range from urticaria to life threatening CVS collapse. • Chronic exposure to NPH insulin may produce antibodies against protamine
    • lipodystrophy • Atrophy of fat at the sites of sc injections of insulin. • t/t- frequently changing the site
    • Resistance to insulin • It occurs in patients requiring > 100U of insulin. • Acute or chronic • Acute- trauma, surgery and infection • Chronic –antibodies to insulin.
    • Drug interactions • ACTH, estrogens , glucagon • Epinephrine inhibits insulin secretion and promotes glycogenolysis • Guanethidine- reduces insulin requirements . • Antibioticstetracyclines,choramphenicol,salicylates, phenylbutazone,MAO-I increase the duration of action of insulin.
    • Sulfonylurea • MOA- site of action is the receptors on islet of pancreas(Bcells) • Inhibit ATP –sensitive K channels depolarization of the cell membrane and release of endogenous insulin.  Pharmacokinectics1. absorbed orally from GIT 2. Weakly acidic and bound to albumin(90-98%) 3. Metabolized in liver-active & inactive metabolites 4. Eliminated by kidneys- urine/feces
    • First generation Tolbutamide1. shortest acting(6-12h) 2. Dose-500-3000mg 3. El ½ -4-8h 4. causes fewest side effect Acetohexamide1. 2. 3. 4. 5. Duration-12-18h, el ½ -1.3-6h Dose-250-1500mg Principle metabolite is hydroxyhexamide it is 2.5 times potent. Not used in pts with renal dysfunctions Uricosuric actions and its used in pts with DM & gout
    • Tolazamide 1. Duration-12-24h, el ½ -48h. 2. Dose-100-1000mg 3. Highly absorb after oral adm. 4. It produced active as well as inactive products excreted by kidneys Chlorpropamide • Longest acting • DOA-36h, el ½- 30-36h • Dose-100-750mg • It produces disulfiram like reactions & can cause severe hyponatremia.
    • Second generation Glyburide • DOA- 18-24h, el ½- 4-12 h • Dose-2.5-20mg • Increases insulin sensitivity and inhibit glucose production. • Produces active and inactive metabolites. • It has mild diuretic effect. glipizide • DOA-12-24h, el ½ - 4-7h • Dose-5-40mg • It increases the glucose uptake and inhibits its production. • Produces inactive metabolites. • Mild diuretic effects.
    • Side effects • Most common- hypoglycemia but it is lesser with 2nd generation. • Renal dysfunction impair the elimination and prolongs the effect- hypoglycemia • Cross the placenta- fetal hypoglycemia
    • BIGUANIDES • Decrease blood glucose and produce low risk of hypoglycemia. • They decrease the lipid conc and can lead to mild wt reduction in obese pts. • PK- not bound to proteins and does not undergo metabolism. • Excreted by kidneys (90%)
    • Metformin • It is used in cases when sulfonylureas have failed • Peak plasma conc- 2, el ½- 2-4h • It requires TDS administration • MOA- stimulation of endogenous insulin secretion • Inhibits gluconeogenesis in kidneys and liver and promotes uptake of glucose by skeletal muscles. • it also decreases plasma conc of triglycerides and cholesterol.
    • Side effects • Anorexia • Nausea ,diarrhea • Lactic acidosis- binds to mitochondria decrease ATP metabolises glucose anerobically converts pyruvate to lactate • Hypoxia and sepsis increase LA
    • INTESTINAL GLYCOSIDASE INHIBITORS • Acarbose• Decreases carbohydrate digestion and absorption of disaccharides. • Used alone does not cause hypoglycemia • It increases the effectiveness of injected insulin (IDDM) • Its main effect is on postprandial glucose so it is suited only as a adjunctive therapy • High doses- hepatotoxicity.
    • THIAZOLIDINEDIONES • Bind to ppar (peroxisome proliferator activated receptor) which regulates the expression of several genes. • Enhance the endogenous insulin secretion. • Drugs –rosiglitazone and pioglitazone • Used as a 2nd line therapy for pts not responding to metformin or sulponylurea. • Also used in sever form of DM with obesity as they redistribute abdominal fat to SC tissues • S/E- hepatotoxicity and Na & water retention
    • MEGLITINIDES AND A.A DERIVATIVES • • • • • They are called as prandial glucose regulators Drugs- repaglinide & nateglinide Stimulates the endogenous insulin secretion Adm immediately before meals. Cause less hypoglycemia than sulfonylureas.
    • other forms of insulin • Rapid acting insulin analogues1. Lispro 2. Aspart 3. Glulisine • Long acting insulin analogues1. Glargline 2. detemir
    • references • Davidsons- medicine • Stoelting pharmacology