Pharmacology of insulin

By Dr. Amina Unis

Learning Objectives: At the end of the lecture you should be able to: Identify sources insulin and available preparations Describe its endocrine effect on certain tissues & its major hazards. Factors affecting insulin release.

The American Diabetes Association (ADA) recognizes four clinical classifications of diabetes: 1. Type 1 diabetes (formerly insulin-dependent diabetes mellitus), 2. Type 2 diabetes (formerly non-insulin dependent diabetes mellitus), gestational diabetes, 3. and diabetes due to other causes (e.g., genetic 4. defects or medication induced)

Insulin is a hormone produced by the cells of the pancreas,

in response to changes in blood glucose level. It is a polypeptide containing 51 amino acids arranged in two chains (A and B) linked by disulphide bridge. There is species difference in amino acids of both chains (figure)

Pharmacodynamics: Mechanism of Release

The specific stimulus for insulin secretion involves elevations

in circulatory levels of glucose and to a much less extent other substrates. Glucose enters the b cell by facilitated transport, which is mediated by (Glut 2), a specific subtype of glucose transporter.

hyperglycaemia results in increased intracellular ATP levels which close the ATP-dependent K channels. Decreased outward K current through this channel results in depolarization of the cell and

opening voltagedependent Ca
channels. The resultant influx of Ca triggers

the release of insulin.

Secretion of insulin occurs by exocytosis.

Insulin receptors
are found on the membranes of most tissues. It consists of two heterodimers, containing an subunit, which is entirely extracellular and constitutes the recognition site, and a subunit that spans the membrane. The subunit contains a tyrosine kinase. When insulin binds to the portion, at the outside surface of the cell, tyrosine activity is stimulated in the portion and an initiation of a cascade of events of phosphorylation takes place..

In clinical situations associated by elevated blood insulin levels, such as obesity or insulinoma, the concentration of insulin receptors is reduced. This down regulation of insulin receptors seems to provide an intrinsic mechanism whereby target cells limit their response

to excessive hormone concentrations (insulin resistance).

obese type II diabetics may recover insulin responsiveness as a result of dieting so that the insulin secretion diminishes, cellular receptors increase and insulin sensitivity is restored.

C. Insulin administration Because insulin is a polypeptide, it is degraded in the gastrointestinal tract if taken orally.

It therefore is generally administered by subcutaneous injection.

Insulin preparations vary primarily in their times of onset of activity and in their durations of activity. This is due to differences

in the amino acid sequences of the polypeptides.

Insulin is inactivated by insulin degrading enzyme (also called insulin protease), which is found mainly in the liver and kidney

Insulin Preparations
A. Rapid-acting and short-acting insulin B. Intermediate acting insulin C. Long acting insulin

Onset and duration of action of human insulin and insulin analogs. NPH = Neutral Protamine Hagedorn

A. Rapid-acting and short-acting insulin preparations Four insulin preparations fall into this category: 1. regular insulin

2.insulin lispro
3. insulin aspart 4. and insulin glulisine. Regular insulin is a short acting, soluble, crystalline zinc insulin. It is usually given subcutaneously (or intravenously in emergencies). Peak level of regular insulin is 50 to 120 minutes.

Insulin lispro differs from regular insulin in that lysine and

proline at positions 28 and 29 in the B chain are reversed. Insulin lispro Being monomeric, it has the advantage of being mixed with lente or ultralente zinc insulin to possess the virtue of an ultra quick effect and long duration without being precipitated by the zinc, as does the short acting regular Peak levels of insulin lispro are seen at 30 to 90 minutes after injection.

Insulin aspart and insulin glulisine have pharmacokinetic

and pharmacodynamic properties similar to those of insulin lispro

B. Intermediate-acting insulininsulin isophane or Neutral protamine Hagedorn (NPH) insulin is a suspension of crystalline zinc insulin combined

with protamine
Its duration of action is intermediate this is due to delayed absorption of the insulin because of its conjugation with

protamine, forming a less-soluble complex.

It is only be given subcutaneously It is used for basal control and is usually given along with rapid- or short- acting insulin for mealtime control.

C. Long-acting insulin preparations Insulin glargine: It is slower in onset than NPH insulin and has a flat,

prolonged hypoglycemic effect that is, it has no peak.

Like the other insulins, it must be given subcutaneously. Insulin detemir: Insulin detemir has a fatty-acid side chain. The addition of the fatty-acid side chain enhances association to albumin. Slow dissociation from albumin results in longacting properties similar to those of insulin glargine.

Duration Rapid

Insulin Lispro, aspart, glulisine Short Regular Intermedia NPH te Long Glargine

Peak (hr) 1

Duration (hr) 3-4

Variability Forms and in Modifiers Absorption Analogue, Minimal monomeric None Moderate Protamine High

2-4 4-8

6-8 12-16

No distinct 24 peak

Detemir

Analogue, Moderate precipitate s at neutral pH No distinct 24 (less Analogue Minimal peak at doses with fatty<20-30 acid side units) chain

Therapeutic Uses of Insulin: 1. Insulin-dependent diabetes mellitus (Type I). 2. Non-insulin dependent diabetes mellitus not controlled by

diet and oral hypoglycaemics.

3. Diabetic ketoacidosis, (soluble insulin). 4. Control of diabetes in pregnancy (soluble insulin).

5. During and after surgery in diabetic patients (soluble insulin

6. During infection and severe illness in diabetic patients controlled bydiet or oral hypoglycaemics (soluble insulin). 7. To control symptoms in patients with diabetes secondary to pancreatectomy and chronic pancreatitis.

Adverse reactions to insulin 1- hypoglycemia are the most serious and common . 2-weight gain, 3-lipodystrophy (less common

with human insulin),

4-allergic reactions, and local injection site reactions.

Insulin Delivery Systems The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes. During the last three decades, much effort has gone into exploration of other means of administration, and inhaled insulin is now available

A.PORTABLE PEN INJECTORS

To facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pensized injectors have been developed. These contain cartridges of insulin and replaceable needles

B. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION

DEVICES (CSII, INSULIN PUMPS) Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery. The devices have a user-programmable pump that delivers

individualized basal and bolus insulin replacement doses

based on blood glucose self-monitoring results

C. INHALED INSULIN The FDA has approved an inhaled insulin preparation of finely

powdered and aerosolized human insulin. Insulin is readily

absorbed into the bloodstream through alveolar walls, but the challenge has been to create particles that are small enough to pass through the bronchial tree without being trapped and still enter the alveoli in sufficient amounts to have a clinical effect