MSC Unit 7 Insulin Pharmacology 1 & 2 ATTOUB
Transcript of 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
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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
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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
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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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