Dm.ppt

INSULIN and ORAL ANTI DIABETICS

Hernita Taurustya, MD Atas izin: Vivian Soetikno, MD., Sp.FK Department of Pharmacology and Therapeutic 1

DIABETES MELLITUS • A disorder of CHO metabolism associated with insulin deficiency or resistance • Characterized by hyperglycemia: • > 126 mg/dl after > 8 hrs fasting, or • > 200 mg/dl, 2 hour after 75 g oral glucose, or • Random blood glucose > 200 mg/dl 2

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Type I DM (IDDM) • Absolut deficiency of insulin • Destruction of pancreatic islets

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Type II DM (NIDDM) • Insulin deficiency/insulin exhaustion • Insulin resistance

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Type III (other type) • Drugs (corticosteroid), endocrinopathy,

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Gestational DM 3

Pancreas Pancreatic cell types

Approximate percent mass

Products

A cell (alpha)

20

Glucagon

B cell (beta)

75

Insulin

D cell (delta)

3-5

Somatostatin

F cell (PP <2 Pancreatic cell) polypeptide Pancreas contains up to 8 mg of insulin (200 Unit) Basal secretion: 5-15 mUnit/ml After meal : 60-90 mUnit/ml 4

Regulation of insulin secretion

• Stimulants of insulin release:

– Glucose, mannose, secretin, gastrin – Leucine, arginine, fatty acids, amino acids, keton bodies – Vagal stimulation, b2-agonist – Sulfonylureas • Inhibitors of insulin release: – Neural: a-adrenergic agonist – Humoral: somatostatin, glucagon – Drugs: diazoxide, phenytoin, colchicin, 5

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Diet

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Physical exercise

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Drugs: – Oral anti diabetics – Insulin

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Proinsulin: – A chain, B chain, and C peptide: – Proteolytic enzyme cleaves proinsulin  insulin

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Insulin: 51 amino acids – A chain: 21 AA – B chain: 30 AA – Linked by 2 disulphide bridges (A7-B7 and A20-B19) – and another disulphide bridge (A6-A11)

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C peptide: – No clear physiological function – Used as a marker of insulin secretion 8

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Regulation of Glucose Transport by Insulin • Glucose enter cells by diffusion through glucose transporter (GLUT) • Without insulin, the GLUT are retained in vesicles within the cytosol • Insulin facilitates translocation of GLUT to cell membrane, thus allowing the passage of glucose into the cells • Disturbance of glucose transport may lead to type II diabetes.

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Preparations

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•Rapid-acting – aspart, glulisine, lispro, human insulin recombinant inhaled •Short-acting insulin – regular •Intermediate-acting – NPH [neutral protamine Hagedorn] & lente insulin •Long-acting – glargine, detemir 12

Indications of insulin therapy  All T1DM T2DM uncontrolled by diet and/or hypoglycemic agents  Postpancreatectomy diabetes  Gestational diabetes  Diabetic ketoacidosis & hyperglycemic nonketotic

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Goals of insulin therapy  fasting blood glucose conc. 90-120 mg/dL  two-hour postprandial < 150 mg/dL  HbA1c < 7% Factors that determine insulin SC absorption: 1.Site of injection – abdominal wall >> 2.Subcutaneous blood flow – to ↑: massage, hot baths, exercise 3.Volume & concentration of the injected insulin 4.Depth of injection (IM more rapid onset of action) 14

Adverse reactions  Hypoglycemia – counter-regulatory hormones (epinephrine, norepinephrine, cortisol, growth hormone, GLUCAGON)  Insulin allergy  Lipoatrophy & lipohypertrophy

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Drugs that cause hypoglycemia

Drugs that cause hyperglycemia 

Epinephrine

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Ethanol

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Glucocorticoids

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Beta blockers –

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Atypical antipsychotic

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Phenytoin

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Calcium channel

mask effect 

Salicylates

blockers 

Diuretics 16

1. Insulin secretagogues a. Sufonylurea b. Meglitinide: c. D-phenylalanine derivatives 2. Biguanide – decrease hepatic glucose production 3. Thiazolidinediones – reduce insulin resistance 4. α-glucosidase inhibitor – slow digestion & absorption of starch & disaccharides 5. Increatin-based therapies –control post-meal glucose excursions by ↑ insulin release & ↓ glucagon secretion 6. Amylin analog – control post-meal glucose levels & reduces appetite 17

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First generation • Chlorpropamide • Tolbutamide • Tolazamide • Acetoheximide

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Second generation • Glybenclamide (glyburide) • Glypizide • Glyclazide • Glymepiride • Gliquidone

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↑ insulin release from the pancreas

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Reduction of serum glucagon levels by stimulate release of somatostatin

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Closure of potassium channels in extrahepatic tissues 19

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ADVERSE EFFECTS – Hypoglycemia – Allergic reaction – GI disturbances – Cholestatic jaudice

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INTERACTION – Sulfonamides, clofibrate, dicumarol, salicylates

displace the SU from protein binding  increase hypoglycemic effect

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INDICATION – Type 2 DM which fail with diet therapy

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Contraindications: – Type 1 DM, – Type 2 DM with metabolic complication – pregnancy, lactation, – Severe hepatic or renal insufficiency

Secondary failure –failure to maintain a good response over the long-term  additional oral agents or insulin 21

Meglitinides Repaglinide • Mechanism of action  SU • Metabolism: liver & kidney  used cautiously in hepatic & renal insuff.

• Absorbed rapidly from GIT

Allow for multiple

• Half-life 1 hour

preprandial use

• To be taken just before meal • Major SE: hypoglycemia 22

Meglitinides Nateglinide – D-phenylalanine • stimulate very rapid & transient release of insulin from β-cell derivative pancreas & restores initial insulin release in response to GTT IV • major therapeutic effect – reduce post-prandial glycemic elevations in T2DM • take 1-10 min. before meals • metabolized in liver (CYP2C9 & CYP3A4)  used cautiously in hepatic insuff. • excreted unchanged in urine  dosage adjustment in renal insuff. Unnecessasry • fewer episodes of hypoglycemia 23

BIGUANIDES  metformin, phenformin, buformin  metformin alone or in combination with a SU  improves glycemic control & lipid conc.  EUGLYCEMIC  Reduce glucose levels by: 1. ↓ hepatic glucose production 2. ↑ insulin action in muscle & fat (AMPK) 3. slowing glucose absorption from GIT; ↑ glucoselactate 4. reduction of plasma glucagon levels 24

BIGUANIDES • Contraindications – renal disease, alcoholism, hepatic disese, chronic cardiopulmonary dysfunction, past history of lactic acidosis

• Preparation: Tablet 500 and 850 mg to be taken 2-3 times daily; maximum daily dose: 2.5 g

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THIAZOLIDINEDIONES • Increase sensitivity to insulin in peripheral tissue – Increase glucose transport into muscle & adipose tissue by enhancing the synthesis & translocation of glucose transporters – Can activate genes that regulate fatty acid metabolism

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THIAZOLIDINEDIONES PREPARATIONS – Pioglitazone (Actos®)

• Tablet: 15, 30, 45 mg • Dose: 15-45 mg once daily – Rosiglitazone (Avandia®)

• Tablet 2, 4, 8 mg • Dose 2-8 mg once daily

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THIAZOLIDINEDIONES • Might be benefit to prevent development of type 2 DM • EUGLYCEMIC • Slow onset and offset of action (over weeks – months) • Long-term use - decrease of triglyceride and increase of HDL (piogllitazone > rosiglitazone) • ADR: fluid retention [presents as a mild anemia & peripheral edema), weight gain • Contraindications:

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Amylin analog • Pramlintide – synthetic analog of amylin • suppresses glucagon release, delays gastric emptying, has CNS- mediated anorectic effects • Pharmacokinetics: - rapidly absorbed after SC, peak 20 min., duration of action 150 min. - metabolized & excreted in renal • injected immediately before eating • dose: 15 mcg-120 mcg  titrated upward • SE: hypoglycemia & GI symptoms

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Secreted by  pancreatic cells • Derived from a precursor of 69 AA (called

glycentin) • Proteolytic enzyme  Glucagon with 29 AA

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Mechanism of Action

• Activates protein Gs in the receptors  adenylyl

cyclase  cAMP 

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Matabolic effects

• Increases blood glucose by facilitating

gluconeogenesis and glycogenolysis in the liver (No effect on muscle glycogen) • Increases insulin secretion from the pancreas 31

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Cardiac effects: • Inotropic and chronotropic effects (similar to b-

agonist)

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Other effects: • relaxation of intestine

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Clinical uses

• Severe hypoglycemia • Endocrine diagnosis • Beta blocker poisoning

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Rapid degradation in the liver, kidney, plasma, and tissues Plasma T1/2: 3-6 minutes  need continous iv infusion. 32

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An antihypertensive agent Potent hyperglycemic action when given orally Mechanism: • Potassium channel opener (opposite to SU) • Inhibits insulin secretion • Modest capacity to inhibit peripheral

glucose utilization

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Indications • Treatment of hypoglycemia due to hyper

insulinemia (such as in insulinoma), and other form of hypoglycemia • Hypertension 

Side effects • Nausea, vomiting • Hypertrichosis • Na and fluid retention, hyperuricemia,

thrombocytopenia, and leukopenia

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American Diabetes Association Standards of Medical Care in Diabetes2014 Pharmakology Katzung Phatofisiology Sylvia

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