Title: ?????-?????????? (Antidiabetis Drugs-Insulin and Oral Antisiabetis Drugs)
1?????-??????????(Antidiabetis Drugs-Insulin and
Oral Antisiabetis Drugs)
2Overview
- ???(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.
3Overview
- morbidity
- 300,000 people-?gt0.67
- 40 years old??2.53
- 1994 2564 years old-?2.51
- 1996 2075 years old-?3.21
- 1997??13,500,000 people
- (all over the word)
- Prediction2025??gt30,000,000 people
4Overview
- 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
5Overview
- Diabetes Mellitus ??long-term disease
??multisystem damage-?functional defect and
failure - Severe-?diabetic ketoacidosis-?coma
- Etiopathogenisis ??heredity, autoimmunity,
environmental factor - Diagnosisurine glucose, blood glucose
6Overview
- Therapy early treatment, long term therapy,
combined therapy and therapeutic measure
individualization - Purposeblood glucose-?normal, to correct
metabolic disorder, increase in life span,
decrease death - Principlepersevere (cannot cure)
7Overview
- Drink and foodgross calorific value
- Kgheight-105
- Daily Kg105125.5K
- (2530Kcal) (2540Kcal)
- Therapybefore meals
8Substance Metabolic Disorder and Clinical
Situation of Diabetic
- glucose utilization disorder?glucose
decomposition decrease?energy insufficient?starvat
ion 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
9Classification of Diabetes Mellitus (WHO 1998)
- Type?
- insulin dependent diabetes mellitus,IDDM
- Type?
- non-insulin dependent diabetes mellitus,NIDDM
- Others
- secondary diabetes
10Diabetes 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 gt 90
- - eventually leads to ß-cell failure
- (resulting in insulin dependence)
Gestational Diabetes 3-5 of pregnant women in
the US develop gestational diabetes
11Diabetes - Insulin
- Discovered in 1921 by Banting and Best
- Consist of A B chains linked by 2 disulfide
bonds - (plus additional disulfide in A)
12Diabetes Insulin(synthesis, storage, secretion)
- Produced within the pancreas by ß 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 ß granules
Zn
13Diabetes Insulin(Biochemical Role)
- Tyrosine Kinase
- receptors are the locks
- in which the insulin
- key fits
- - Involved in signal
- transduction
- (insulin hormone being 1st messenger)
14Diabetes Insulin(Mechanism)
15Insulin 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.
16- Stage 3 Insert the human insulin gene into E.
coli and culture the recombinant E.coli to
produce insulin (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.
17Physiological disposition of insulin
- 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.
18Types of insulin
- Regular insulin
- Insulin analogs
- Pre-mixed insulin
- Short peptide mimics
19- Insulin affects many organs
- It stimulates skeletal muscle fibers.
- It stimulates liver cells.
- It acts on fat cells
- It inhibits production of certain enzyme.
- In each case, insulin triggers
- these effects by binding to the insulin
receptor.
20The 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).
21Who need insulin medicine?
- 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.
22Preparations and Clinical Use of insulin
- Short-acting preparations.
- Intermediate acting preparations.
- Long acting preparations.
- New very-short- and very-long-acting insulin
analogues.
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24Insulin Regimens
- Dose and choice of preparations must be
determined for each patient individually. - Many patients will monitor their blood glucose at
home and make minor adjustments in dose
accordingly.
25Insulin Regimens
- Diabetic Ketoacidosis and diabetic coma
- 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).
26Insulin Regimens
- Hyperpotassaemia
- Insulin coadminidtrate with glucose(help Kget
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 .
27Adverse Effects
- Hypoglycemia
- Allergic reaction
- Insulin resistance
- Hypokalemia
- Lipoatrophy
28Adverse Effects
- 1. Allergic reaction foreign protein enter into
human body - Insulin has antigenicity, the slight reaction
includes local swelling, itch, ache. It rarely
occurs urticaria, angioedema and anaphylactic
shock. - 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.
29Adverse Effects
- 2. Hypoglycemia
- (the most common and serious adverse)
- It is the result of an imbalance between glucose
intake (e.g. missing a meal), glucose utilisation
(e.g. unusual exercise) and insulin dose. - The result is sympathetic activation and
neuroglycopenia.
30Adverse Effects
- 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. - Treatment is by administration of carbohydrate
orally to a conscious patient, or i.v. glucose or
i.m. glucagon.
31Adverse Effects
- 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. - 5.Lipoatrophy is the atrophy or hypertrophy of
fat at the site of injection.
32Insulin Resistance (INR)
- Insulin resistance is a prominent feature in
obese individuals and in non-insulin-dependent
diabetes. - 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.
33Diabetes-Insulin Action Enhancers
- Rosiglitazone(????)
- Pioglitazone (????)
34The Action of Insulin Action Enhancers
- Improve insulin resistance,decrease
hyperglycemia. - Improve fat metabolism disorder.
- Prevent and treat the blood vessel complication
of type II diabetes mellitus. - Improve pancreatic B cell function.
-
35Diabetes Oral Medications
- Sulfonylureas
- Biguanides
- Sulfonylureas and biguanide combination drugs
- Thiazolidinediones
- Alpha-glycosidase inhibitors
- Meglitinides
36Oral Autidiabetic Drugs
- Sulfonylureas (????)
- ?????(Tolbutamide)
- ????(Chlorpropamide)
- ???(Glibouclamide ????)
- ????( Glipizide ?????)
- ????(Gliclazipe ???)
- ???(Glurenorm)
37Oral Autidiabetic Drugs
- Biguanides (???)
- ????(Phenformin ????)
- ????(Metformin ???)
- a-glucosidase inhibiors
- (a-????????)
- ????(Acarbose)
38Sulfonylureas
- 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.
39The Mechanism of Action
- Sulfonylureas interact with receptors on
pancreatic b-cells to block ATP-sensitive
potassium channels. - This, in turn, leads to opening of calcium
channels. - Which leads to the production of insulin.
40The 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. -
41The Clinical Application of Sulfonylureas
- Diabetes MellitusA sulfonylurea drug is often
used to treat type II DM that cannot be
controlled with dietary restrictions. - Diabetes Insipiduscoadministrating with
Hydrochlorothiazide can improve the effect
42Adverse Effects of Sulfonylureas
- Hypoglycaemia
- Gastrointestinal upsets
- Hypersensitivity rashes etc.
- Weight gain stimulation of appetite can be a
problem in obese patients.
43Drug Interactions
- Sulfonylureas are heavily protein bound and their
actions may be increased by other drugs (e.g.
sulfonamides) that compete for the binding sites.
44Biguanides
- 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.
45Mechanisms and Pharmacological Effects
- Metformin is now considered a first-line drug for
the treatment of type II DM. - In patients with type II DM, it alleviates
hyperglycemia primarily by decreasing the hepatic
glucose output. - It also appears to decrease glucose absorption
from the gut and increase insulin sensitivity in
skeletal muscle and adipose tissue.
46Adverse Effects of Biguanides
- The most common adverse effects of metformin are
gastrointestinal disturbances. - 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.
47Acarbose
- Mechanisms and Pharmacological Effects
- The digestion of dietary starch and disaccharides
such as sucrose is dependent on the action of
a-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.
48The Indications of Acarbose
- Acarbose is used in the treatment of type II DM.
- It is administered with each meal and is
particularly effective when given with meals
containing large amounts of starch.
49Adverse effects of Acarbose
- The most common side effect of acarbose are
increased flatulence and abdominal bloating. - Acarbose may increase the oral bioavailability of
metformin and cause a decrease in iron absorption.
50Thanks!