msc unit 7 insulin pharmacology 1 & 2 attoub

7/30/2019 MSC Unit 7 Insulin Pharmacology 1 & 2 ATTOUB

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Insulin Pharmacology 1 & 2

Dr. Samir ATTOUB

Department of Pharmacology & Therapeutics

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Insulin Synthesis

Pro-hormone convertases/

Carboxypeptidase ro- ormone conver ases

Carboxypeptidase

InsulinPro-Insulin

Insulin is synthesized as a pro-hormone, pro-insulin, that undergoesroteol tic cleava e to form insulin and e tide C

Mature insulin is composed of two polypeptide chains (- and -, .

contains up to 8 mg of insulin

Circulating C-peptide has no known biological function but serves asa better index of insulin secretion


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Insulin Secretion

Insulin secretion is a tightly regulated process designed to provide

stable concentrations of lucose in blood durin both fastin and

feeding. This regulation is achieved by the coordinated interplay of

various nutrients, gastrointestinal hormones, pancreatic hormones,and autonomic neurotransmitters

.

Glucose enters cell by facilitated transport via Glut 2 transporter

The rise in intracellular Ca2+ tri ers insulin secretion

When evoked by glucose, insulin secretion is biphasic: The firstphase reaches a peak after 1 to 2 minutes and is short-lived; the

second phase has a delayed onset but a longer duration. These phases

insulin, respectively


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Mechanism of Insulin Action

The insulin receptor is a transmembrane receptor tyrosine kinaselocated in the plasma membrane of insulin-sensitive cells (e. g.

adipocytes, myocytes, hepatocytes). It mediates the effect of insulin

on specific cellular responses (e. g. glucose transport, glycogen, ,

Insulin binds to an subunit of the insulin rece tor activatin the

tyrosine kinase domain on its subunits. The major intracellulartarget molecules of the tyrosine kinase activity of the INSR-subunit

are the insulin receptor substrates (IRS). Tyrosine phosphorylated

IRS interacts with and activates phosphatidylinositol 3-kinase (PI 3-

kinase Akt (protein kinase B, PKB). The other major pathway is

Grb2 activation of the mito en activated rotein MAP kinase

cascade, which controls cell growth


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Mechanism of Insulin Action

In adipose and muscle tissue, activation of PKB/Akt triggers thetranslocation of vesicles containing the glucose transporter GLUT4

glucose uptake by these tissues. This effect is reversible, the

transporters return to the intracellular pool on removal of insulin

Release of insulin


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Diabetes Mellitus

Diabetes mellitus is defined as hyperglycemia due to absolute orrelative lack of insulin with various degrees of insulin resistance. By

2010, the number of diabetes persons is expected to approach 220

million

The most common forms are type 1 diabetes, with absolute lack of

insulin and t e 2 diabetes which is due to the combination of

insulin resistance and insufficient insulin secretion

A large number of individuals are asymptomatic and do not know

they have the disease

The chronic hyperglycemia of diabetes is associated with long-term

dama e d sfunction and failure of various or ans es eciall the

eyes, kidneys, nerves, heart and blood vessels


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Type 1 Diabetes

Insulin Dependent Diabetes Mellitus (IDDM) or Type 1 Diabetes,or juvenile diabetes: results from a destruction of insulin-secreting

-ce s y an auto mmune mec an sm ur ng a per o o severa

years leading to absolute insulin deficiency

Loss of-cells may be due to:

- Antibodies a ainst -cell roteins lutamic acid decarbox lase,

tyrosine phosphatase IA-2, insulin)- Viral infection

- ct ons o c em ca tox ns

T e 1 diabetes alwa s re uires treatment with insulin to

maintain blood glucose concentrations close to normal


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Type 2 Diabetes

Non-Insulin Dependent Diabetes Mellitus (NIDDM) or Type 2

(obesity, insulin resistance, dyslipidemia, hypertension)

~ 90% of all patients

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in frequency. The genetic basis for type 2 DM cannot change in sucha short time; thus, other contributing factors, including increasingage, obesity, sedentary lifestyle, and low birth weight, must account

for this dramatic increase. In addition, type 2 DM is being diagnosed

Type 2 diabetes is characterized by tissue resistance to the action

of insulin combined with a relative deficiency in insulin secretion


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Causes of Insulin Resistance

Abnormal -cell secretory productAbnormal insulin molecule

Incomplete conversion of proinsulin to insulin

Target tissue defects

Insulin receptor defects (mutations)

Down-regulation in the number of insulin receptors (Obesity)Post receptor defects

Circulating insulin antagonists, . .,

hormone, cortisol, glucagon, or catecholamines

Anti-insulin and anti-insulin rece tor antibodies


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The birth of an idea

In 1889, Minkowski and Von Mering showed that pancreatectomizeddogs exhibit a syndrome similar to diabetes mellitus in humans

In October, 1920 Frederick Banting, a young surgeon in London,Ontario, Canada, first conceived the idea that led to the discovery of

insulin

Banting and Best thus obtained a pancreatic extract that decreased the

concentrat on o oo g ucose n a et c ogs

e ore nsu nwas scovere ,e ore nsu nwas scovere ,everyonewithtype1diabetesdiedeveryonewithtype1diabetesdied

withinweekstoyearsofitsonsetwithinweekstoyearsofitsonset


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Treatment of Type 2 Diabetes

Weight normalization by hypocaloric, low fat diet and exercisemay normalize glucose homeostasis for a period of several years

More pharmacological control with hypoglycemic agents

Individuals with type 2 diabetes may not require insulin tosurvive, but 30% or more will benefit from insulin therapy to

con ro e oo g ucose


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Treatment of Type 1 Diabetes

Type 1 diabetes always requires treatment with insulin. The goal ofsubcutaneous insulin thera is to re lace the normal basal

(overnight, fasting, and between meal) as well as bolus or prandial

(mealtime) insulin. Current regimens generally use long-actinginsulins to provide basal or background coverage, and rapid-acting

insulin to meet the mealtime requirements

A variety of insulin preparations are available; all have

different times to onset of activity and durations of action


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PRINCIPAL TYPES AND DURATION OF ACTION

OF INSULIN PREPARATIONS

. - ,

and aspart insulin). All of the rapid-acting analogs have a quicker

onset of action when com ared to re ular insulin reach maximalconcentrations faster, and have a shorter duration of action;

2. Short-acting, with rapid onset of action (regular insulin);

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4. Lon -actin with slow onset of action Ultralente and Insulin

glargine)


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Rapid acting Insulins

nsu n spro uma og , a recom nant nsu n ana ogue, s

identical to human insulin except for the transposition of prolineand lysine at positions 28 and 29 in the C-terminus of the B chain

This change reduced the ability to dimerize in solution and translates

into more rapid absorption of insulin lispro than human regularinsulin from subcutaneous sites

When in ected subcutaneousl , the dru is ra idl absorbed with

onset of action within 15-30 minutes and duration more than 3-5hours, which is shorter than regular insulin. It is associated withsi nificantl im roved l cemic control com ared with re ularinsulin, with out increased incidence of hypoglycemia

- Administer 0 - 15 min re-meal vs. 30 - 45 min for re ular insulin


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Rapid acting Insulins

nsu n aspar ovo og s omo ogous w t regu ar uman

insulin with the exception of a single substitution of the amino acidproline by aspartic acid in position B28, and is produced byrecom nant DNA tec no ogy an resu ts n aster a sorpt on ratessimilar to Lispro after subcutaneous injection

Following subcutaneous administration, insulin aspart has an onsetof action of roughly 15 minutes which is quicker than the onset ofre ular insulin

With insulin aspart, patients may start eating within 10 minutesafter dosin . Duration of action no lon er than 3-5 hours


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Short acting Insulins

Regular insulin is a short-acting soluble crystalline insulin madeby recombinant DNA techniques to produce a molecule identical to

between 2 and 3 hours after subcutaneous injection and generally

lasts 6-8 hours. 1 mg = 27.5 units

Regular insulin (soluble insulin) is used subcutaneously in ordinarymaintenance re imens. Subcutaneousl administered re ular

insulin is best given 30-60 minutes before a meal

.intravenously in emergencies


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Rapid-acting and short-acting insulins are often administered two tothree times a day or more


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Intermediate Acting Insulins

NPH insulin and zinc insulin have a more delayed onset of action, butthey act longer. Both preparation are given by subcutaneous injection

once a day before breakfast or twice a day

1. NPH insulin - Neutral Protamine Hagedorn / Isophane insulin

suspension: insulin is conjugated with protamine @ neutral pH (7.2),

e comp ex s ow y sso ve n o y u s. er su cu aneous

injection, proteolytic tissue enzymes degrade the protamine to permit

NPH insulin has an onset of approximately 1-2 hours and duration of

14-18 hours. It is usuall mixed with re ular lis ro or as art insulinand given for insulin replacement in patients with type 1 diabetes. In

patients with type 2 DM, intermediate-acting insulin given at bedtime

may help normalize fasting blood glucose

i i i i


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Intermediate acting insulins

2. Lente insulin - insulin zinc suspension: Lente insulin is anintermediate-acting insulin that is produced by adding zinc ions toregular insulin, which causes a delay in absorption and a prolongationof the duration of action after subcutaneous administration

Lente insulin has an onset of approximately 1-4 hours and duration of-

with a quick-acting insulin (regular insulin, insulin aspart, or insulin

lispro)

L i I li


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Long acting Insulins

1. Ultralente insulin: is the first long-acting prep. 100% crystallineinsulin zinc large particles which are slow to dissolve. They have

slower absorption and a prolonged peak of action

This insulin is used to provide a low basal level of insulin throughout

the day. It is often given in the morning or in the morning and

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L ti I li


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Long acting Insulins

2. Insulin glargine (Lantus) insoluble insulin: is created byrecombinant DNA modification of human insulin. Extension of the C-

-substitution of glycine for asparagine at position A-21, resulting in

precipitation of the insulin at the injection site and a slooowwwre ease over w no pronounce pea . rov es a e er once-daily 24-hour insulin coverage than ultralente or NPH insulin.To maintain solubilit , the formulation is unusuall acidic H 4.0

and insulin glargine should not be mixed with currently availableshort-and rapid- acting insulin preparations (i.e., regular insulin,

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I h l d I li (E b )


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Inhaled Insulin (Exubera)

In 2006 the U.S. FDA approved the use of Exubera, the first inhalableinsulin. Inhaled insulin has similar efficacy to injected insulin

Currently, inhaled insulin is short and rapid acting and is typically

taken before meals; an injection of long-acting insulin at night iso ten st requ re

Used for t e 1 and t e 2 diabetes

Contraindicated for: smokers and patients with unstable or poorly,

chronic obstructive pulmonary disease, or emphysema)

, , ,discomfort, hypoglycemia

n c o er , zer ec e to scont nue xu era n t esecondary to limited use by patients and health care professionals

Ad R ti t I li Th


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Adverse Reactions to Insulins Therapy

Hypoglycemic reactions are the most common complication ofinsulin therapy, which may result in confusion, anxiety, palpitation

inadequate carbohydrate consumed, unusual physical exercise, or a

dose of insulin that is too large for immediate needs

Hypoglycemia that occurs during sleep may be difficult to detect butshould be sus ected from a histor of mornin headaches, ni ht

sweats, or symptoms of hypothermia

administration. To treat mild hypoglycemia in a patient who is

conscious and able to swallow, dextrose tablets, glucose gel, or anysugar-containing beverage or food may be given

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glucose or an injection of glucagon


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Pharmakokinetic characteristics of the most commonly

used insulin preparations and analogs


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Insulin schedule: an example

As a rough guide, patients require a total daily

insulin dose of an unit for each kilogram of their

ideal weight (height 100)

Daytime requirements are 2/3 and night time

requirements 1/3 of the total insulin

= =. .78:2 = 39 units/d (26 u in the morning &


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msc unit 7 insulin pharmacology 1 & 2 attoub

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