Insulin Pharm
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Transcript of 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