insulin pharm

7/29/2019 Insulin Pharm

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Pharmacology of insulin

By

Dr. Amina Unis


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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.


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The American

Diabetes Association (ADA)

recognizes four clinicalclassifications 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 othercauses (e.g., genetic

4. defects or medication

induced)


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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)


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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.


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hyperglycaemia results in

increased intracellular ATP levels

which close the ATP-dependent Kchannels.

Decreased outward K current

through this channel results in

depolarization of the cell and

opening voltagedependent Ca

channels.

The resultant influx of Ca triggersthe release of insulin.

Secretion of insulin occurs by

exocytosis.


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Insulin receptorsare 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 aninitiation of a cascade of events of

phosphorylation takes place..


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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.


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C. Insulin administration

Because insulin is a polypeptide, it is degraded in the

gastrointestinal tract if taken orally.

It therefore is generally administered bysubcutaneous 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


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Insulin Preparations

Onset and duration of action of human insul in and insu l in analogs.

NPH = Neutral Protam ine Hagedo rn

A.Rapid-acting and short-acting insulin

B. Intermediate acting insulin

C.Long acting insulin


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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 ofregular insulin is 50 to 120 minutes.


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Insu l in l isprodiffers 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 ofinsul in l isproare seen at 30 to 90 minutes

after injection.Insulin aspart and insulin glulisine have pharmacokinetic

and pharmacodynamic properties similar to those of insulin

lispro


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B. Intermediate-acting insulin-

insulin 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.


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C. Long -act ing insu l in preparat ions

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 otherinsulins, it must be given subcutaneously.

Insulin detemir:

Insul in detemir has a fatty-acid side chain. The addit ion

of th e fatty-acid side chain enhances assoc iat ionto

albumin. Slow dissociation from albumin results in long-

acting properties similar to those ofinsulin glargine.


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Duration Insulin Peak (hr)

Duration

(hr)

Forms and

Modifiers

Variability

in

Absorption

Rapid Lispro,aspart,

glulisine

1 3-4 Analogue,monomeric

Minimal

Short Regular 2-4 6-8 None Moderate

Intermediate

NPH 4-8 12-16 Protamine High

Long Glargine No distinct

peak

24 Analogue,

precipitate

s at neutral

pH

Moderate

Detemir No distinct

peak

24 (less

at doses


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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.


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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.


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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 pen-

sized injectors have been developed. These contain

cartridges of insulin and replaceable needles


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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 deliversindividualized basal and bolus insulin replacement doses

based on blood glucose self-monitoring results


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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

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