ANTIDIABETIC

DRUGS

Prof.MUDr Jiřina Martínková, CSc

2006/2007
 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 > 7.0
mmol//L, or plasma glucose > 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)
 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
neuropathy,which is associated with accumulation of osmotically
active metabolites of glucose.
Coexisting hypertension promotes progressive renal damage.
 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.
 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 cells
´s response to glucose (Fig.2).
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 normal
level
Type 1
early phase late phase

permitted
 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.
 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.
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
 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,
stimuli include fatty acids, the
secretin), which are released by eating. Other
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)
 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
 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 state:glycogenolysis, 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.
 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).
 Treatment of DM

Diet is the cornestone, combined with increased exercise

Insulin is essential for the treatment of DM1

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.
 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).
 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.
 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.
 Insulin
Tab. 1 HUMAN INSULINS and ANALOGUES

INSULINS Onset (hr) Maximum (hr) Duration (hr)

NPH 0.5-1 2-3 6-8
Lente 1-2 4-10 12-18
Ultralente 3-4 10-15 18-26

ANALOGUES Onset (min/hr) Maximum (hr) Duration (hr)

Lispro 0.15-15 (min) 0.5-1 3-5

glargine 3-4 (hr) missing 30
Fig. 3

lispro
arbitrary units

permitted
 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
 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.
Fig. 4. Portable pen injectors

permitted
 Insulin
Adverse effects:
- hypoglycemia
common and, if severe, can cause brain damage. Warning signals of
more rapid development due to regular insulin:tachycardia,
insulin
palpitations, sweating, tremulousness (the sympathetic nerv syst. hyperactivity)
+ nauzea, hunger --convulsions + coma (parasympathetic hyperactivity).
In older diabetics, in those taking longer-acting insulins,
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
 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
 Oral hypoglycemic agents

Biguanides
Sulfonylureas
Meglitidines
Thiazolidinediones
Alpha-glucosidase inhibitors
 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
 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
 Oral hypoglycemic agents
First generation:
Tolbutamide
Second generation
glibenclamide, glipizide
 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.
 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.
 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.