Tutorial For Mbbs Insulin 6w2652

Pharmacotherapy of Diabetes Mellitus Insulin 15 June 2010

THE ENDOCRINE PANCREAS 1 million islets of Langerhans 4 hormone-producing cells

Cell type

Hormone

Function

Alpha [A] cells

Glucagon

Hyperglycemic factor

Beta [B] Cells

Insulin, Pro insulin, Amylin

Anabolic hormone

Delta[D] Cells

Somatostatin

Universal inhibitor of secretion

G Cells

Gastrin

Stim.Gastric secretion

F cell[PP cell]

Panc.Polypeptide

Digestion

What is DM?

Diabetes mellitus

Elevated blood glucose Associated with absent or inadequate pancreatic insulin secretion With or without concurrent impairment of insulin action.

Expert Committee, 2003

Type 4

Type 3

Diabetes mellitus -TYPES TYPE 1

• IDDM • Loss of beta cells → deficiency of insulin “Juvenile diabetes” majority cases in children.

TYPE 2

• NIDDM • Due to insulin resistance • [or reduced insulin sensitivity] • Combined with reduced insulin secretion • TYPE 3 • Drug induced or other causes • TYPE 4 • Gestational diabetes mellitus

INSULIN

Proinsulin

Two peptide chains A & B of 21 and 30 amino acids linked by disulfide bridges

Insulin Biosynthesis [110AA] Preproinsulin (in RER) ↓ [110-24AA] Proinsulin (Golgi Apparatus) ↓ [51AA] Insulin + C Peptide[-35AA] ↓ Stored in granules of  cells

Basal rate: 1U/h,  during meals

Control:Insulin Release

Counter regulatory

• Chemical Glucose Incretins • Hormonal GH Corticosteroids, Thyroxine Glucagon ↑ Somatostatin ↓

• Neural Adrenergic-a2↓ Adrenergic-b2↑ Muscarinic [Vagal] ↑

Insulin release from the pancreatic Beta cell by Glucose

First phase- Within 2 minutes Delayed phase

Role of ATP sensitive K+ channels (KATP) Hyperglycemia ↓  Intracellular ATP ↓ Blockade of KATP ↓  Outflow of K+ ↓ Depolarization of β cells ↓ Ca2+ influx ↓ Insulin Release

Degradation of Insulin • Endogenous: – Liver – 60%, Kidney: 35-40%

• Exogenous: – Liver – 40%, Kidney- 60%

• Plasma half-life: 5-6 min.

Insulin receptor 2 covalently linked heterodimers

The binding of an insulin molecule Mutual phosphorylation of tyrosin recidues

Activated Tyrosin kinases Further phosphorylates down stream proteins [IRS]

Insulin receptor substrate

•Translocation of glucose transporters (especially GLUT 4) to the cell membrane with increase in glucose uptake; •Increased glycogen synthase activity and increased glycogen formation; •Multiple effects on protein synthesis, lipolysis, and lipogenesis; and •Activation of transcription factors that enhance DNA synthesis and cell growth and division.

Insulin receptors • Glucocorticoids lower the affinity of insulin receptors for insulin; • Growth hormone in excess increases this affinity slightly. • Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance

Glucose transporters [GLUT]

Gluconeogenesis IN LIVER

Absorption

Glycogenolysis Insulin

[-]

[-] Processes add glucose [Hyperglycemia]

Blood

Processes utilize glucose [Hypoglycemia]

[+] Insulin [+]

Protein Synth. In Muscles

Peripheral utilization Lipogenesis

Endocrine effects of Insulin

Endocrine effects of Insulin….

Endocrine effects of Insulin….

Over view of Insulin action

Source and insulin preperations Species

A Chain

B Chain

8th AA

10th AA

30th AA

Human

THR

ILEU

THR

Pork

THR

ILEU

ALA

Beef

ALA

VAL

ALA

Analogs 1.

•

Highly purified pork Insulins Monocomponent insulins

2. Human insulins • Recombninant DNA Technology[E.Coli, Yeast]

3. Insulin analogues Changing or replacing AA sequences 1. Lispro 2. Aspart 3. Glulisine 4. Glargine 5. Detemir

Conventional prep. •Impurities •Antigenic •Less expensive •Replaced by 1. Highly purified pork Insulins 2. Human insulins 3. Insulin analogues

Genetic engineering to produce human insulin

Insulin preparations • Rapid acting insulins: – Insulin lispro – Insulin aspart – Insulin glulisine

Analogues

• *Short acting insulins: – Regular insulin

• *Intermediate acting insulins: – Lente insulin[Insulin Zinc suspension – NPH insulin [Isophane Insulin suspension]

*Long-acting insulins: – – – –

Ultralente insulin Protamine Zinc Insulin (PZI) Insulin Glargine Analogues Insulin detemir

*Premixed insulins: – 70% NPH + 30% Regular – 50% NPH + 50% Regular – 75% NPH + 25% Lispro

*Animal or human

Insulin preparations Rapid acting • More physiologic prandial insulin replacement - their rapid onset and early peak action - closely mimic normal endogenous prandial insulin secretion than does regular insulin, • Can be taken immediately before the meal without sacrificing glucose control. • Their duration of action is rarely more than 4–5 hours, which decreases the risk of late postmeal hypoglycemia. • Lowest variability of absorption [Monomers] • Preferred insulins for use in continuous subcutaneous insulin infusion [CSII] devices.

Insulin preparations Rapid acting

Lispro

Insulin preparations Rapid acting

Aspart

Insulin preparations Rapid acting

Glulysine

Insulin preparations Short acting • Recombinant DNA techniques, purified porcine • Effect appears within 30 minutes - peaks between 2 and 3 hours after s.c injection -lasts 5–8 hours. • Prandial hyperglycemia and risk of late hypoglycemia [30-45 mts before meals] • Only preperation for i.v.use.

Insulin preparations Intermediate acting Lente insulin[Insulin Zinc suspension] NPH insulin [Isophane Insulin suspension]

–Onset-1-2 h –Peak-6-12h –Duration-18-24 –Dose related action profile –Long acting analogs are preferred

Long actingInsulin preparations –Onset-1-2 h –Peak less –Duration-18-24

Detemir

THRThriiii

Glargine

THR Myristic acid

Type

Appearance

Onset

Peak

Duration

Rapid/Short Regular soluble

Clear

0.5–0.7

1.5–4

5–8

Lispro

Clear

0.25

0.5–1.5

2–5

Aspart

Clear

0.25

0.6–0.8

3–5

Glulisine

Clear

---

0.5–1.5

1–2.5

6–12

18–24

6–12

18–24

Intermediate

1–2

NPH (isophane)

Cloudy

Lente

Cloudy

1–2

Long Ultralente

Cloudy

4–6

16–18

20–36

Protamine zinc

Clear

4–6

14–20

24–36

Glargine

Clear

2–5

5–24

18–24

Detemir

Clear

1–2

4–14

6–24

Adverse Effects of Insulin: Hypoglycemia • Results from: – Delay in taking a meal – Inadequate carbohydrate intake – Unusual physical exertion – Too large insulin doses Symptoms

• Autonomic hyperactivity – Sympathetic • Tachycardia, palpitations, sweating, tremulousness

– Parasympathetic: • Nausea, hunger

– Convulsions / Coma

Adverse Effects of Insulin: Hypoglycemia • Hypoglycemia unawareness • Treatment: – Glucose istration: • Fruit juice / Glucose gel / Sugar containing beverage/food to eat at first sign • If severe: 50% dextrose i.v. Carry identity card

Adverse Effects of Insulin Insulin Allergy: • Noninsulin protein contaminants • Less with purified insulin preparations • ? Anaphylaxis

Insulin Resistance [Requirement of > 200U/day] • Acute: – Causes: Infections, trauma, surgery, stress (in stress ↑corticosteroids oppose insulin action) – Treated by regular insulin

• Chronic: – Common in type II – Cause: Antibodies to contaminating proteins which also bind insulin – Treatment- change to human insulin

• Reversible – Pregnancy

Adverse Effects of Insulin Insulin Lipodystrophy • Older insulin preparations → Repeated injections at the same site → Atrophy / Hypertrophy of subcutaneous fat • Atrophy not seen with newer human insulin preparations, hypertrophy still a problem • ? Injection of newer insulin into atrophic area → Restoration of normal contours • Sites of injection: Abdomen best, Keep changing

Insulin Edema • Na+ retention, Weight gain

Unitage of Insulin • 1 U = Amount required to reduce blood glucose by 45 mg% in a fasting rabbit • 1mg=28units

Insulin Delivery Systems • • • •

Disposable needles and syringes: 27 G Portable Pen Injectors Jet injectors Continuous Subcutaneous Insulin Infusion: CSII – Most physiologic insulin replacement – Insulin reservoir/ Program chip/ Keypad/ Display screen – Excellent glycemic control eg, pregnancy

• Inhaled Insulin – Absorbed through alveolar walls – Rapid onset of action / Short duration – ? Pulmonary fibrosis/Pulmonary hypertension

• Oral insulin: Liposome encapsulated

Clinical Uses of Insulin • Type 1 diabetes mellitus • Type 2 diabetes mellitus Not controlled by oral agents  Complications: Diabetic ketoacidosis, Gangrene,  To tide over: Infection, Trauma  Pregnancy [Gestational diabetes not controlled by diet alone] •

Emergency treatment of hyperkalemia: Insulin + glucose

Indications of Human Insulin 1. Insulin resistance 2. Allergy to conventional preparations 3. Injection site lipodystrophy

4. Short term use- surgery, trauma 5. During pregnancy

Insulin regimens • Intensive Insulin therapy-Based on formulaeCSII • Conventional- For type 2 • Spl circumstances • Principle: • Supply postprandial needs • Provide basal control

Glargine + 3 Analogs

2Long acting+2 Rapid or Short acting

CSII

Diabetic Ketoacidocis [Diabetic coma] • Precipitated by infection, trauma, stress in insulin dependent patients • Serious • Hypotension, shock, tachycardia, dehydration, hyperventilation, vomiting, coma

Treatment: 1. Regular insulin-I.V. 2. Bolus followed by infusion 3. i.v fluids. 4. Kcl ??? 5. NaHco3 6. Phosphate 7. Antibiotics

Drug interactions • • • •

Beta blockersInhibit comp mechanisms Warning signs of hypoglycemia are masked Thiazides, Furosemide, Corticosteroids, Os, reduce the effect of insulin • Salicylates, Li, increase insulin secretion

Insulin Delivery Systems

Disposable needles and syringes: 27 G

Portable Pen Injectors

Insulin Delivery Systems

A device that uses high pressure instead of a needle to propel insulin through the skin and into the body.

Inhaled Insulin

Insulin Delivery Systems

Continuous Subcutaneous Insulin Infusion: CSII

Insulin Delivery Systems

‘Artificial pancreas’ Sensor activated pump

1 - Continuous glucose sensor monitors blood sugar level 2 - Data transmitted for the computer program to work out insulin dose 3 - Insulin pump delivers the dose