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Antidiabetic Drugs

Antidiabetic Drugs. Kaukab Azim, MBBS , PhD. Drug List - INSULINS. Note: A ll are administered subcutaneously ; Regular insulin can be administered I.V. , especially in the management of diabetic ketoacidosis; surgery and during acute infections. Drug List – Oral Antidiabetics.

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Antidiabetic Drugs

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  1. Antidiabetic Drugs Kaukab Azim, MBBS, PhD

  2. Drug List - INSULINS Note: All are administered subcutaneously; Regular insulin can be administered I.V., especially in the management of diabetic ketoacidosis; surgery and during acute infections.

  3. Drug List – Oral Antidiabetics (GLIP ih zyd), (glye-MEP-ir-ide), (met FOR min), (thy-a-zoll-i-deen-dye-ones)

  4. Insulin Synthesis and Secretion Synthesis Golgi apparatus of B cells synthesizes insulin from pro-insulin. Insulin is stored in secretory granules. Secretion • Basal release (in pulses every 15-30 minutes) • Glucose stimulated release: • Early, rapid phase (stored insulin is secreted-old) • Later, slower phase (newly synthesized insulin is secreted).

  5. A Simplified Model of Glucose stimulated release of Insulin 1 2 Metabolism of glucose increases intracellular ATP ATP closes ATP-dependent K+ channels 3 4 Decrease efflux of K+ causes depolarization Depolarization opens voltage-gated Ca++ channels 5 Ca++ triggers insulin release by exocytosis

  6. Factors Regulating Insulin Secretion

  7. Mechanism of Action of Insulin • Insulin binds to a specific transmembranetyrosine-kinase linked receptor located in cell membranes of most tissues. The receptor consists of two alpha subunits linked to two beta subunits. (the affinity of insulin for its receptor is lowered by corticosteroids and increased by growth hormone; at concentration of insulin that produce maximal effects only 10% of the receptors are occupied) • Insulin binding to the alpha subunits causes the activation of the beta receptor subunit, which contain the tyrosine kinase. The enzyme is phosphorylated and this turn leads to the following two cascadepathways: • IRS(Insulin receptor substrate)-1 Pathway • IRS(Insulin receptor substrate)-2 Pathway

  8. Mechanism of Action of Insulin The insulin receptor • A specific transmembranetyrosine-kinase linked receptor located in cell membranes of most tissues. • Activation of this receptor, triggers the phosphorylation of a tyrosine kinase enzyme which in turn leads to the following two cascade pathways: • Insulin receptor substrate-1 (IRS-1) pathway:Leading to • Regulation of proliferation and differentiation of several cell types • Regulation of DNA synthesis • Insulin receptor substrate-2 (IRS-2) pathway:Leading to • Increased glucose uptake by the lipid and muscle cells • Increased glycogen formation • Regulation of gene transcription

  9. Pharmcodynamics of Insulin The general physiological function of insulin is to conserve fuel by facilitating the uptake, utilization and storage of glucose, amino acids and fats after meals. Effects on carbohydrate metabolism • Increased glucose transport into the cells (several glucose transporters are activated). • Increased glycogen synthesis (glycogen synthase is stimulated) • Increased glycolysis (the activity of several key enzymes is stimulated) • Decreased glycogenolysis (glycogen phosphorylase is inhibited). • Decreased gluconeogenesis (many gluconeogenic enzymes are depressed).

  10. Pharmcodynamics of Insulin The ultimate effect of insulin is to control the intracellular utilization of glucose, as follows: • 50% of ingested glucose is converted to energy (glycolysis) • 10% of ingested glucose is converted to glycogen (glycogen synthesis) • 40% of ingested glucose is converted to fat Effects on lipid metabolism • Increased triglyceride formation and storage (lipoprotein lipase is induced and activated to hydrolyze triglycerides from lipoproteins. Glycerol phosphate generated from glucose permits esterification of fatty acids). • Decreased lipolysis (direct inhibition of hormone-sensitive intracellular lipase) • Increased lipogenesis (glucose is converted to fat)

  11. Pharmcodynamics of Insulin Effects on protein metabolism • Increased amino acid transport into the cells. • Increased protein synthesis. Other metabolic effects • Increased transport into cells of K+, Ca++, nucleosides and phosphate. Long-term actions • Stimulation of cell proliferation

  12. Pharmacokinetics of Insulin ABSORPTION • Bioavailability: • NO ORAL BIOAVAILABILITY • SC, IM: good. • Nasal: good (investigational). DISTRIBUTION • Bound in plasma: < 5%. • Vd(70 Kg): . 15 L. BIOTRANSFORMATION • All insulin is metabolized in liver, kidney, and muscle (internalized with insulin receptors and destroyed intracellularly) • (50% of insulin secreted by pancreas into the portal vein does not reach the general circulation). EXCRETION • None • Total Clearance: 800-2500 mL/min (70 Kg) Half-life: 5-10 minutes(L.end)

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