Antidiabetis Drugs-Insulin and Oral Antisiabetis Drugs

1
Antidiabetis Drugs-Insulin
and Oral Antisiabetis Drugs

• Department of Pharmacology,
• Peking Union Medical College
• Caiying Ye

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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.

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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

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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

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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

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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)

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Overview

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

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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

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Classification of Diabetes Mellitus (WHO 1998)

• Type?
• insulin dependent diabetes mellitus,IDDM
• Type?
• non-insulin dependent diabetes mellitus,NIDDM
• Others
• secondary diabetes

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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
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Diabetes - Insulin

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

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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
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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)

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Diabetes Insulin(Mechanism)
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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.
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• 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.
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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.

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Types of insulin

• Regular insulin
• Insulin analogs
• Pre-mixed insulin
• Short peptide mimics

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• 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.

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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).

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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.

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Preparations 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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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.

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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).

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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 .

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Adverse Effects

• Hypoglycemia
• Allergic reaction
• Insulin resistance
• Hypokalemia
• Lipoatrophy

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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.

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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.

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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.

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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.

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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.

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Diabetes-Insulin Action Enhancers

• Rosiglitazone
• Pioglitazone

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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.

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Diabetes Oral Medications

• Sulfonylureas
• Biguanides
• Sulfonylureas and biguanide combination drugs
• Thiazolidinediones
• Alpha-glycosidase inhibitors
• Meglitinides

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Oral Autidiabetic Drugs

• Sulfonylureas
• Tolbutamide
• Chlorpropamide
• Glibouclamide
• Glipizide
• Gliclazipe
• Glurenorm

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Oral Autidiabetic Drugs

• Biguanides
• Phenformin
• Metformin
• a-glucosidase inhibiors
• Acarbose

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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.

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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.

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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.

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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

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Adverse Effects of Sulfonylureas

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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Thanks!