?????-?????????? (Antidiabetis Drugs-Insulin and Oral Antisiabetis Drugs) - PowerPoint PPT Presentation

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Title: ?????-?????????? (Antidiabetis Drugs-Insulin and Oral Antisiabetis Drugs)


1
?????-??????????(Antidiabetis Drugs-Insulin and
Oral Antisiabetis Drugs)
  • ????????????????
  • ???

2
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.

3
Overview
  • 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

4
Overview
  • 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

5
Overview
  • Diabetes Mellitus ??long-term disease
    ??multisystem damage-?functional defect and
    failure
  • Severe-?diabetic ketoacidosis-?coma
  • Etiopathogenisis ??heredity, autoimmunity,
    environmental factor
  • Diagnosisurine glucose, blood glucose

6
Overview
  • 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)

7
Overview
  • Drink and foodgross calorific value
  • Kgheight-105
  • Daily Kg105125.5K
  • (2530Kcal) (2540Kcal)
  • Therapybefore meals

8
Substance 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

9
Classification of Diabetes Mellitus (WHO 1998)
  • Type?
  • insulin dependent diabetes mellitus,IDDM
  • Type?
  • non-insulin dependent diabetes mellitus,NIDDM
  • Others
  • secondary diabetes

10
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 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
11
Diabetes - Insulin
  • Discovered in 1921 by Banting and Best
  • Consist of A B chains linked by 2 disulfide
    bonds
  • (plus additional disulfide in A)




12
Diabetes 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
13
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)

14
Diabetes Insulin(Mechanism)
15
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.
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.
17
Physiological 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.

18
Types 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.

20
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).

21
Who 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.

22
Preparations and Clinical Use of insulin
  • Short-acting preparations.
  • Intermediate acting preparations.
  • Long acting preparations.
  • New very-short- and very-long-acting insulin
    analogues.

23
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24
Insulin 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.

25
Insulin 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).

26
Insulin 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 .

27
Adverse Effects
  • Hypoglycemia
  • Allergic reaction
  • Insulin resistance
  • Hypokalemia
  • Lipoatrophy

28
Adverse 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.

29
Adverse 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.

30
Adverse 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.

31
Adverse 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.

32
Insulin 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.

33
Diabetes-Insulin Action Enhancers
  • Rosiglitazone(????)
  • Pioglitazone (????)

34
The 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.

35
Diabetes Oral Medications
  • Sulfonylureas
  • Biguanides
  • Sulfonylureas and biguanide combination drugs
  • Thiazolidinediones
  • Alpha-glycosidase inhibitors
  • Meglitinides

36
Oral Autidiabetic Drugs
  • Sulfonylureas (????)
  • ?????(Tolbutamide)
  • ????(Chlorpropamide)
  • ???(Glibouclamide ????)
  • ????( Glipizide ?????)
  • ????(Gliclazipe ???)
  • ???(Glurenorm)

37
Oral Autidiabetic Drugs
  • Biguanides (???)
  • ????(Phenformin ????)
  • ????(Metformin ???)
  • a-glucosidase inhibiors
  • (a-????????)
  • ????(Acarbose)

38
Sulfonylureas
  • 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.

39
The 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.

40
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.

41
The 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

42
Adverse Effects of Sulfonylureas
  • Hypoglycaemia
  • Gastrointestinal upsets
  • Hypersensitivity rashes etc.
  • Weight gain stimulation of appetite can be a
    problem in obese patients.

43
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.

44
Biguanides
  • 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.

45
Mechanisms 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.

46
Adverse 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.

47
Acarbose
  • 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.

48
The 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.

49
Adverse 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.

50
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