ANTIDIABETIC DRUGS

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ANTIDIABETIC DRUGS
Prof.MUDr Jirina Martínková CSc
2006/2007
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ANTIDIABETIC DRUGS
Classification and the nomenclature of diabetes
mellitus (DM) DM is a chronic metabolic disorder
characterised by a high blood glucose
concentration-hyperglycemia (fasting plasma
glucose gt 7.0 mmol//L or plasma glucose gt 11.1
mmol/L 2hr after a meal) - caused by insulin
deficiency often combined with insulin
resistance. Hyperglycemia occurs because of
uncontrolled hepatic glucose output and reduced
uptake of glucose by skeletal muscle with reduced
glycogen synthesis. When the renal threshold for
glucose reabsorption is exceeded glucose spills
over into the urine -glycosuria and causes an
osmotic diuresis - polyuria which in turn
results in dehydration thirst and increased
drinking polydipsia. Diabetic ketoacidosis
is an acute emergency- it develops because of
accelerated fat breakdown to acetyl-CoA which
in the absence of aerobic carbohydrate
metabolism is converted to acetoacetate and
beta-hydroxybutyrate (which cause acidosis) and
acetone (a ketone)
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ANTIDIABETIC DRUGS
Various complications develop as a consequence
of the metabolic derangements in DM often over
many years Many of these are the results of
disease of blood vessels either large
(macrovascular disease) of small
(microangiopathy). Macrovascular disease
consists of acclerated atheroma which is much
more common and severe in diabetic patients.
Microangiopathy particularly affects the retina
(blindness) kidney (chronic renal failure) and
peripheral nerves (diabetic neuropathywhich is
associated with accumulation of osmotically
active metabolites of glucose. Coexisting
hypertension promotes progressive renal damage.
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ANTIDIABETIC DRUGS
Classification and the nomenclature of diabetes
mellitus (DM) Type 1 diabetes encompasses cases
resulting from pancreatic B cell destruction
(immune-mediated in most cases). Type 2 diabetes
consists of combined defects of insulin secretion
and action ranging from predominantly insulin
resistance with relative insulin deficiency to a
predominantly secretory defect with insulin
resistance.
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ANTIDIABETIC DRUGS
Type 1 diabetes (DM1) is a severe form associated
with ketosis in the untreated state. It occurs
most commonly in juveniles but occasionaly in
adults the nonobese. It is a catabolic disorder
form in which circulating insulin is virtually
absent plasma glucagon elevated and the
pancreatic B cells fail to respond to
insulinogenic stimuli (Fig.1).
Type 2 diabetes (DM2) represents a heterogenous
group comprising milder forms of DM that occur
predominantly in adults. Circulating endogenous
insulin is often subnormal or relatively
inadequate because of tissue insensitivity.
Obesity which generally results in impaired
insulin action is a common risk factor and most
patients with DM2 are obese. In addition to
tissue insensitivity to insulin there is an
accompanying deficiency of the pancreatic B
cellss response to glucose (Fig.2).
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Fig. 1. Schematic diagram of two-phase release of
insulin in response to a constant glucose infusion
glucose
prediabetes/diabetes Type 2
Arb. units
Basal level
normal
Type 1
early phase late phase
permitted
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ANTIDIABETIC DRUGS
INSULIN (I) is a small protein which contains two
chains (A and B) linked by disulfide bridges. I
is released from pancreatic B cells at a low
basal rate and at much higher stimulated rate in
response to a variety of stimuli especially
glucose.
Degradation The liver and kidney are the two
main organs that remove I from the circulation
presumably by hydrolysis of the disulfide
connection between the A and B chains through
insulinase. Further degradation by proteolysis
occurs. The liver normally clears the blood of
approximately 60 of the insulin released from
the pancreas as the terminal of portal vein blood
flow with the kidney removing 35-40 of the
endogenous hormone. In contrast in
insulin-treated diabetics receiving s.c. I this
ratio is reversed.
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ANTIDIABETIC DRUGS
The insulin receptor Once I has entered the
circulation it is bound by specialised receptors
identified in only a few target tissues (e.g.
liver muscle and adipose tissue (Fig. 1) The
full insulin receptor consists of two
heterodimers each containing an alpha subunit
which is entirely extracellular and constitues
the recongition site and a beta subunit which
spans the membrane.The beta subunit contains a
tyrosine kinase. When insulin binds to alpha
subunit at the outside surface of the cells
tyrosine kinase activity is stimulated in the
beta portion (nine substances have been
identified for the activated insulin receptors to
be phosphorylated). Self-phosphorylation of the
beta portion results in translocation of certain
proteins such as glucose transporter from
sequestered sites within adipocytes and muscle
cells to exposed locations on the cell surface.
Finally the insulin-receptor complex is
internalised.
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Fig. 2.
Schematic diagram of the two-phase release of
insulin in response to a constant
glucose infusion.
INSULIN RECEPTOR Binding sites
Cell membrane
Intracellular space
Tyrosin kinase
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ANTIDIABETIC DRUGS
Downregulation of insulin receptors appears in
clinical situation associated with elevated blood
levels such as obesity of insulinoma.
Schematic diagram of the two-phase release of
insulin in response to a constant glucose
infusion (Fig. 2). The first phase is missing in
DM2 and both are missing in DM1. In contrast it
is produced by aminoacids glucagon
gastrointestinal tract hormones (gastrin
secretin) which are released by eating. Other
stimuli include fatty acids the parasympathetic
nervous system stimulation and drugs that act on
sulfonylurea receptors.
Insulin release is inhibited by the sympathetic
nervous system (the role of alpha2adrenoceptors)
and several peptides (somatostatin)
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ANTIDIABETIC DRUGS
Effects of insulin (I) on its targets I promotes
the storage of fat as well as glucose (both
sources of energy) within specialised target
cells and influences cell growth and metabolic
functions of a wide variety of tissues.
1.Action of insulin on glucose transporters I
has an important effect on several transport
molecules that facilitate glucose movement
across cell membranes (GLUT 1-GLUT 4) GLUT-4
(inserted into the membranes of muscle and
adipose cells) is responsible for
insulin-mediated uptake of glucose GLUT-2
(B-cells of pancreas) mediates transport of
glucose into pancreatic B-cells. Its defects may
contribute to the reduced insulin secretion that
characterizes DM2
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ANTIDIABETIC DRUGS
2. Action of insulin on liver The first major
organ reached by endogenous insulin via portal
circulation in the liver where it acts
to increase storage of glucose and to reset the
liver to the fed state by reversing a number of
catabolic mechanisms associated with the
postabsorptive stateglycogenolysis ketogenesis
and gluconeogenesis These effects are brought
about directly through activation or repression
of selective enzymes or indirectly by reducing
fatty acids flux to the liver via antilipolytic
action on adipocytes. In addition I
decreases urea production protein catabolism
promotes triglycerides synthesis and increases
potassium and phosphate uptake by the organ.
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ANTIDIABETIC DRUGS
3. Effect of insulin on muscle promotes protein
synthesis by increasing amino acid transport and
by stimulating ribosomal activity. It also
promotes glycogen synthesis to replace glycogen
stores expended by muscle activity.
4. Effect of insulin on adipose tissue I acts to
reduce circulating free fatty acids and to
promote triglyceride storage in adipocytes (the
most efficient means of storing energy).
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Treatment of DM
Diet is the cornestone combined with increased
exercise
Insulin is essential for the treatment of DM1
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Pharmacokinetics Insulin is destroyed in the
GIT and must be given parenterally (s.c. i.v.
i.m.). Pulmonary absorption occurs and inhalation
of an aerosol is a new route of administration.
Once absorbed insulin has an elimination
half-life of approximately 10 min it is
inactivated enzymatically in the liver and kidney

Species of insulin Beef (slightly more antigenic)
and purified monospecies pork insulin. Declining
costs for biosynthesis of human insulin
generally supplanted purified pork insulins. H u
m a n i n s u l i n s are produced by
recombinant DNA techniques by inserting the
human proinsulin gene into E. coli or yeast and
treating the extracted proinsulin to form the
human insulin molecule. Human insulin from E.coli
is available for clinical use as Humulin and
dispensed as either regular NPH lente or
ultralente Humulin.
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Insulin
Insulin analogues - alteration of the insulin
peptide provides an opportunity to change the
absorption rate of the molecule. Insulin lispro
(ultra-short acting insulin) and
glargine ultra-long acting insulin are the first
to use.

Various formulations of insulin are available
varying in the timing of their peak affect and
duration of action (Fig. 3).
ultra-short acting insulin- Insulin
lispro monomeric insulin produced by recombinant
technology in which two aminoacids (proline and
lysine) have been reversed in their position
without any influence on receptor binding. The
advantage is quick dissociation into monomers and
rapid absorption. Peak serum value is reached in
1 hr. Its use is associated with significantly
improved glycemic control (without increasee
incidence of hypoglycemia). Used for emergency
(ketoacidosis) for rapid response (surgery).
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Insulin
short - acting insulin regular
insulin (HM-R) soluble crystalline zinc insulin
the only type of insulin that should be
administered i.v. intermediate - acting
and long- acting insulin are made by
precipitating insulin with protamine or zink
thus forming finely divided amorphous solid or
relatively insoluble crystals which are injected
as a suspension from which insulin is slowly
absorbed. These preparations include isophane
insulin and amorphous or crystalline insulin zinc
suspension. NEPHAN INSULIN (NPH neutral
protamine or isophane insulin) is an intermediate
insulin with the delayed onset of action achieved
by combining appropriate amount of insulin and
protamine.

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Insulin
LENTE INSULIN is a mixture of 30 semilente - an
amorphous precipitate of insulin with zinc ions
in acetate buffer that has a relatively rapid
onset of action 70 of ultralente insulin.
ULTRALENTE INSULIN HUMULIN ULTRALENTE a
poorly soluble crystal zinc insulin that has a
delayed onset and prolonged duration of action.
This is needed in type1 patients to achieve
basal insulin concentratin throughout the 24 hrs
that are comparable to those achieved in normal
subjects by basal endogenous secretion.
GLARGINE soluble peakless ultra-long acting
insulin. The attachment of two arginine
molecules to the chain B and substitution of a
glycine for asparagine created an analogue which
precipitates after s.c. injection
the crystalline depot to
provide a peakless basal insulin replacement that
can last more than 24 hours.


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Insulin
Tab. 1 HUMAN INSULINS and ANALOGUES


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Fig. 3
lispro
arbitrary units
permitted
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Insulin

INSULIN DELIVERY SYSTEMS Insulin pen
injectors to facilitate multiple s.c. injections
of insulin portable pen-sized injectors have
been developed. These contain replaceable
cartridges of U100 human insulin and retractable
needles. Disponsable insulin pens are also
available for regular insulin insulin lispro
NPH insulin. Pens eliminate the need to carry
syringes and bottles of insulin to the workplace
and while traveling. Continuous subcutaneous
insulin infusion device (insulin pumps) the
devices have a manually programmable pump that
delivers individualized basal and bolus insulin
replacement based on blood glucose
self-monitoring results.Normally the 24hours
basal rates are relatively constant from day to
day though temporarily altered rates can be
superimposed to adjust for a short-term change in
requirement. It is usually placed on a belt or in
a pocket and the insulin is infused through
thin plastic tubing that is connected

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Insulin

INSULIN DELIVERY SYSTEMS (to continue) to the
subcutaneously inserted infusion set. The insulin
reservoir tubing and infusion set need to be
changed using sterile techiques every 2 or 3
days. The use is encouraged for individuals who
are unable to obtain target control while on
multiple injection regimens and in circumstances
where excellent glycemic control is desired
(pregnancy). A regular insulin is the only
insulin specifically approved for pump use.
Inhaled insulin has a rapid onset and a
relatively short duration of action. It should be
used to cover mealtime insulin requirements or to
correct high glucose levels.

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Fig. 4. Portable pen injectors
permitted
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Insulin

• Adverse effects
• - hypoglycemia
• common and if severe can cause brain damage.
  Warning signals of more rapid development due to
  regular insulintachycardia palpitations
  sweating tremulousness (the sympathetic nerv
  syst. hyperactivity)
• nauzea hunger --convulsions coma
  (parasympathetic hyperactivity).
• In older diabetics in those taking
  longer-acting insulins are mainly symptoms of
  impaired function of the CNS mental confusion
  bizarre behavior ultimately coma
• The treatment is to take a sweet drink or
  snack or if the patient is unconscious to give
  i.v. glucose or i.m. glucagon.
• allergy is unusual but can occur as local or
  systemic reactions

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Insulin

• Clinical uses of insulin
• patients with DM1 require long-term maintenance
  treatment with
• insulin. An intermediate-acting preparation
  is often combined
• with a short-acting preparations taken
  before meals
• soluble insulin is used (i.v.) in emergency
  treatment of
• hyperglycemic diabetic emergencies
  (ketoacidosis)
• many patients with DM2 ultimately require
  insulin treatement
• short-term treatment of patients with DM2 or
  impaired glucose
• tolerance during intercurrent events
  (operations infections
• myocardial infarction)
• emergency treatment of hyperkalemia insulin is
  given with
• glucose to lower extracellular K via
  redistribution into cells

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Oral hypoglycemic agents
Biguanides Sulfonylureas Meglitidines Thiazolidine
diones Alpha-glucosidase inhibitors
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Oral hypoglycemic agents
Biguanides -Metformin Lowers blood glucose-
increases glucose uptake and utilisation in
muscle reduces hepatic glucose production
(gluconeogenesis) Adverse effects - GIT
disturbancies (anorexia weight loss diarrhea)
transient - lactic acidosis rare but
potencially fatal Metformin should be avoided in
patients who predispose to lactic acidosis (renal
and hepatic disease heart failure) Use DM2
patients obese and who fail treatment with diet
alone. It does not cause hypoglycemia
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Oral hypoglycemic agents
Sulfonylureas stimulate insulin secretion by
B-cells (the equivalent of phase 1-
secretagogues) and thus reducing plasma
glucose. Pharmacokinetics . well absorbed
orally . all bind strongly to plasma albumin
and compete for these binding
sites with salicylates and sulfonamides . most
are excreted in the urine their
action is increased in the
elderly and in patients with renal disease .
cross the placenta severe
hypoglycemia at birth s. are generally
contraindicated in pregnancy
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Oral hypoglycemic agents
First generation Tolbutamide Second
generation glibenclamide glipizide
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Oral hypoglycemic agents
Meglitidines A new class of insulin secretagogues
modulates B cell insulin release by regulating
potassium efflux through the potassium
channels repaglinid has a very fast onset of
action with a peak concentration and peak effect
within approximately 1 hour after digestion.
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Oral hypoglycemic agents
Thiazolidinediones a recently introduced class of
drugs that enhance target tissue insulin
sensitivity- rosiglitazone pioglitazone Their
main action is to diminish insulin resistance by
increasing glucose uptake and metabolism in
muscle and adipose tissues. Alpha-glucosidase
inhibitors Acarbose and miglitol are competitive
inhibitors of the intestinal enzymes and modulate
the postprandial digestion and absorption of
starch and disacharides.
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Oral hypoglycemic agents

• Clinical uses of oral hypoglycemic drugs
• DM2 as a supplement to diet and excercise to
  reduce
• symptoms from hyperglycemia
• metformin is preferred for obese patients unless
  
• contraindicated by factors that predispose
  to lactic
• acidosis
• drugs that act on the sulfonylurea receptors are
  well
• tolerated but often promote weight gain.