Download 抗糖尿病药－胰岛素与口服降血糖药 (Antidiabetis Drugs－Insulin and

Antidiabetis Drugs－Insulin
and Oral Antisiabetis Drugs
Department of Pharmacology,
Peking Union Medical College
Caiying Ye
Overview

diabetes mellitus
A chronic condition associated with
abnormally high blood sugar.
Results from either deficiency of or a
resistance to insulin- a hormone
produced by the pancreas whose function
is to lower blood sugar.
Overview
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morbidity：
300,000 people－→>0.67％
40 years old―→2.53％
1994 25~64 years old－→2.51％
1996 20~75 years old－→3.21％
1997―→13,500,000 people
(all over the word)
Prediction:2025―→>30,000,000 people
Overview
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Cause
by
many
of
reasons
――chronic
hyperglycemia－→metabolic disorder
Hyperglycemia ―― a group of diseases
characterized by high levels of blood glucose
resulting from defects in insulin production,
insulin action, or both.
Insulin: B cells ――synthesis － → secretion
――blood circulation － → target cells － → binding
with insulin receptor －→intracellular substance
metabolism
any link going wrong －→diabetes mellitus
Overview
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Diabetes Mellitus ――long-term disease
――multisystem damage－→functional
defect and failure
Severe－→diabetic ketoacidosis－→coma
Etiopathogenisis ――heredity,
autoimmunity, environmental factor
Diagnosis：urine glucose, blood glucose
Overview
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Therapy: early treatment, long term therapy,
combined therapy and therapeutic measure
individualization
Purpose：blood glucose－→normal, to correct
metabolic disorder, increase in life span,
decrease death
Principle：persevere (cannot cure)
Overview

Drink and food：gross calorific value
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Kg＝height－105
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Daily Kg＝105～125.5K
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（25～30Kcal） (25～40Kcal)
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Therapy：before meals
Substance Metabolic Disorder
and Clinical Situation of Diabetic
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glucose utilization disorder→glucose decomposition
decrease→energy insufficient→starvation condition
→polyphagia
hyperglycemia →glucosuria →hypertonicity
diuresis →polyuria
protein degradation
accentuation┤
↓
athrepsy dehydration thirst→polydipsia
↓
lipolysis excessive hyperosmolar nonketotic diabetic
coma ketonuria
lipolysis excessive →ketoplasia
excessive→Ketonemia→acidosis
coma
Classification of Diabetes Mellitus
(WHO 1998)

TypeⅠ:
insulin dependent diabetes mellitus，IDDM
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TypeⅡ:
non-insulin dependent diabetes mellitus，
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NIDDM
Others：
secondary diabetes
Diabetes Mellitus

Type 1 Diabetes
- cells that produce insulin are
destroyed
- results in insulin dependence
- commonly detected before 30

Type 2 Diabetes
- blood glucose levels rise
due to
1) Lack of insulin
production
2) Insufficient insulin
action (resistant cells)
- commonly detected after
40
- effects > 90%
- eventually leads to β-cell
failure
(resulting in insulin dependence)
Gestational Diabetes
3-5% of pregnant women in the US
develop gestational diabetes
Diabetes - Insulin
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~
~
Discovered in 1921 by Banting
and Best
Consist of A & B chains linked
by 2 disulfide bonds
(plus additional disulfide in A)
A = 21amino acids B = 30 amino acids
Diabetes – Insulin
(synthesis, storage, secretion)
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Produced within the
pancreas by β cells  islets
of Langerhans
insulin mRNA is translated
as a single chain precursor
called preproinsulin
removal of signal peptide
during insertion into the
endoplasmic reticulum
generates proinsulin
Within the endoplasmic
reticulum, proinsulin is
exposed to several specific
endopeptidases which excise
the C peptide, thereby
generating the mature form
of insulin
Stored as β granules
Zn
Diabetes – Insulin
(Biochemical Role)
-Tyrosine Kinase
receptors are the
locks
in which the insulin
key fits
- Involved in signal
transduction
(insulin hormone being 1st
messenger)
Diabetes – Insulin
(Mechanism)
Insulin drug evolution
Stage 1 Insulin was extracted from the
glands of cows and pigs. (1920s)
Stage 2 Convert pig insulin into human insulin
by removing the one amino acid that
distinguishes them and replacing it with the
human version.

Stage 3 Insert the
human insulin gene into E.
coli and culture the
recombinant E.coli to
produce in sul in (trade
name = Humulin®). Yeast
is also used to produce
insulin (trade name
=Novolin®) (1987).
Recombinant DNA technology has also made it possible
to manufacture slightly-modified forms of human
insulin that work faster (Humalog® and NovoLog®) or
slower (Lantus®) than regular human insulin.
Physiological disposition of insulin
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Insulin must be administered parenterally,
usually by s.c. injection.
It is metabolised by the liver and the
kidney and has a half-life of 9-10
minutes.
To extend its period of action, show
release preparations have been developed.
Types of insulin
 Regular insulin
 Insulin analogs
 Pre-mixed insulin
 Short peptide mimics
Insulin affects many organs:
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It stimulates skeletal muscle
fibers.
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It stimulates liver cells.
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It acts on fat cells
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It inhibits production of
certain enzyme.
In each case, insulin triggers
these effects by binding to
the insulin receptor.
amino acids
uptake
glucose
uptake
protein
synthesis
glycogen
synthesis
fat
synthesis
enzyme
production
glycogen
breaking
The Pharmacological Action of Insulin
It allows the active uptake of glucose and its
utilisation in muscle and fat cells.
It stimulates synthesis of glycogen in the liver.
It inhibits formation of glucose (gluconeogensis)
in the liver.
It inhibits breakdown of lipids.
It stimulates protein synthesis.
It stimulates some cell ion transport
mechanisms (e.g. Na+/K+-ATPase).
Who need insulin medicine?
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Type I (insulin dependent) diabetes patients whose
body produces no insulin.
Type 2 diabetes patients that do not always
produce enough insulin.
diabetic ketoacidosis, hypertonicity hyperglycemia
coma and lactic acidosis accompany with
hyperglycemia
diabetes mellitus accompany with severe infection,
wasting disease, hyperpyrexia, pregnancy, wound
and operation.
secondary diabetes is caused by pancreatectomy.
Preparations and Clinical Use of insulin
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Short-acting preparations.
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Intermediate acting preparations.
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Long acting preparations.
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New very-short- and very-long-acting
insulin analogues.
Insulin Regimens
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Dose and choice of preparations must be
determined for each patient individually.
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Many patients will monitor their blood
glucose at home and make minor
adjustments in dose accordingly.
Insulin Regimens
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Diabetic Ketoacidosis and diabetic coma:
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Insulin (S.C. Injection) will be given to lower
blood sugar and to prevent further ketone
formation. Once blood glucose levels have fallen
to 250 mg, additional glucose may be given to
allow continued insulin administration without
hypoglycemia (low blood sugar).
Insulin Regimens
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Hyperpotassaemia:
Insulin coadminidtrate with glucose（help K＋get
into cell）
(1)
Prevention
and
Treatment
of
arrhythmia
caused by myocardial infarction.
the combination treatment of insulin, glucose
and KCl
(2) Insulin shock therapy has been used to treat
schizophrenia .
Adverse Effects
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Hypoglycemia
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Allergic reaction
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Insulin resistance
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Hypokalemia
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Lipoatrophy
Adverse Effects
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1. Allergic reaction: foreign protein enter into
human body
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Insulin
has
antigenicity,
the
slight
reaction
includes local swelling, itch, ache. It rarely
occurs urticaria, angioedema and anaphylactic
shock.
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It often uses antihistamine drug and adrenal
cortex hormone to treat with severe allergic
reaction ， and these patients should change to
use high purity insulin or human insulin.
Adverse Effects
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2. Hypoglycemia
（the most common and serious adverse）
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It is the result of an imbalance between
glucose intake (e.g. missing a meal),
glucose utilisation (e.g. unusual exercise)
and insulin dose.
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The result is sympathetic activation and
neuroglycopenia.
Adverse Effects
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Patients and their families should be
trained to spot the warning signs and how
to treat hypoglycaemia, including possibly
administration of glucagon if the patient
loses consciousness.
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Treatment is by administration of
carbohydrate orally to a conscious patient,
or i.v. glucose or i.m. glucagon.
Adverse Effects
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4.Hypokalemia: may occur in the acidosis
patients who use a lot of insulin and
glucose, it can lead to the patient death
with abnormal heart beat.
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5.Lipoatrophy: is the atrophy or
hypertrophy of fat at the site of
injection.
Insulin Resistance (INR)
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Insulin resistance is a prominent feature in
obese individuals and in non-insulindependent diabetes.
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Some resistance may be caused by defects
in binding of insulin. Other possible
mechanisms include secretion of an abnormal
B-cell secretory product or the presence of
circulation insulin antagonists.
Diabetes-Insulin Action Enhancers
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Rosiglitazone
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Pioglitazone
The Action of Insulin Action Enhancers
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Improve insulin resistance，decrease
hyperglycemia.
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Improve fat metabolism disorder.
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Prevent and treat the blood vessel
complication of type II diabetes mellitus.
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Improve pancreatic B cell function.
Diabetes – Oral Medications
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Sulfonylureas
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Biguanides
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Sulfonylureas and biguanide combination
drugs
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Thiazolidinediones
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Alpha-glycosidase inhibitors
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Meglitinides
Oral Autidiabetic Drugs
Sulfonylureas
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Tolbutamide
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Chlorpropamide
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Glibouclamide
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Glipizide
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Gliclazipe
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Glurenorm
Oral Autidiabetic Drugs
Biguanides
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Phenformin
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Metformin
α-glucosidase inhibiors
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Acarbose
Sulfonylureas
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[physiological disposition]
The sulfonyureas are administered orally
and undergo varying degrees of hepatic
metabolism and renal elimination of the
parent compound and metabolites. Most
of the sulfonylureas are metabolized to
inactive or less active compounds in the
liver.
The Mechanism of Action
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Sulfonylureas interact with receptors on
pancreatic b-cells to block ATP-sensitive
potassium channels.
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This, in turn, leads to opening of calcium
channels.
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Which leads to the production of insulin.
The Pharmacological Effect of Sulfonylureas
1. Hypoglycemic Activity
Sulfonylureas act primarily by increasing
the secretion of insulin and secondarily
by decreasing the secretion of glucagon.
2. Antidiuresis effect: treat with diabetes
insipidus.
3. Decrease platelet adhesion reaction,
stimulate plasminogen synthesis.
The Clinical Application of Sulfonylureas
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Diabetes Mellitus：A sulfonylurea
drug is often used to treat type II
DM that cannot be controlled with
dietary restrictions.
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Diabetes Insipidus：coadministrating
with Hydrochlorothiazide can
improve the effect
Adverse Effects of Sulfonylureas
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Hypoglycaemia
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Gastrointestinal upsets
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Hypersensitivity: rashes etc.
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Weight gain: stimulation of appetite
can be a problem in obese patients.
Drug Interactions

Sulfonylureas are heavily protein bound
and their actions may be increased by
other drugs (e.g. sulfonamides) that
compete for the binding sites.
Biguanides
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[Physiological Disposition]
Metformin is administered orally from
two to four times a day and is eliminated
by
renal
excretion
of
the
parent
compound. Its duration of action is about
18 hours.
Mechanisms and
Pharmacological Effects

Metformin is now considered a first-line drug for
the treatment of type II DM.
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In patients with type II DM, it alleviates
hyperglycemia primarily by decreasing the hepatic
glucose output.
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It also appears to decrease glucose absorption
from the gut and increase insulin sensitivity in
skeletal muscle and adipose tissue.
Adverse Effects of Biguanides
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The most common adverse effects of
metformin are gastrointestinal disturbances.
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Patients with renal or hepatic disease,
alcoholism, or a predisposition to metabolic
acidosis should not be treated with
metformin, because they are at increased
risk of lactic acidosis.
Acarbose
[Mechanisms and Pharmacological Effects]
 The digestion of dietary starch and
disaccharides such as sucrose is dependent on
the action of α-glucosidase, an enzyme
located in the brush border of the intestinal
tract.
 It thereby slows the digestion of starch and
disaccharides, decreases the rate of glucose
absorption, and lowers the postprandial blood
glucose concentration.
The Indications of Acarbose

Acarbose is used in the treatment of
type II DM.
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It is administered with each meal and
is particularly effective when given
with meals containing large amounts of
starch.
Adverse effects of Acarbose
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The most common side effect of
acarbose are increased flatulence and
abdominal bloating.
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Acarbose may increase the oral
bioavailability of metformin and cause a
decrease in iron absorption.
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