Diabetic Medication

Insulin
Short-acting insulins:
These are used for treatment of DKA
To cover operations and illnesses in patients with diabetes
Sometimes in the long term control of diabetes combined
with longer acting insulin
The are the only insulins suitable for IVI use.
Following subcutaneous injection their action starts after
about 30 minutes and lasts up to 8 hours. After intravenous
injection the onset is much quicker but it only lasts for
about 30 minutes. They include Humulin and Human
Actratpid.
The human insulin is the preferred insulin for a pregnant
lady.

 Insulin Lispro and Insulin Aspart are

modified forms of human insulin, they are
very rapidly mobilized from the
subcutaneous injection site.
They act quicker than the soluble insulin
onset of 15 minutes after subcutaneous
injection and last up to 4 hours.
Their place in management of diabetes are
not settled, they may be useful if given
directly before a meal to control the rise in
blood sugar and thus mimicking more
closely the response of the normal
pancreas.

 Insulin Glulisine is a fast-acting

synthetic recombinant insulin
analogue differing form human
insulin in its amino acid sequence.
It is marketed as Apidra
It is injected subcutaneously
immediately before meals and when
necessary after food.
When given subcutaneously it
appears in the blood earlier than
human insulin and it should be given
15 min before a meal or within 20
minutes after a meal.

Intermediate-acting Insulin
These insulins act for varying periods
depending on the mix of rapid and
slow-acting components.
The blood glucose starts to fall in 1-2
hours after injection and this effect
continues for 16-24 hours. The are
usually given once or twice daily and
may be combined with soluble
insulin.

 Insulin Zinc suspension: It was found

that if insulin was buffered with
acetate its action was prolonged, and
a further tow types of insulin could
be prepared: amorphous, in which
the particles were small, and a
crystaline form with larger particles.
The action of amorphous insulin is
rapid and short-lived, but that of
crystaline insulin is more prolonged.
By using a mixture of theses insulins
a smooth and prolonged effect can
be achieved.

 Among those available are Human

Monotard (30% amorphous, 70%
crystaline and Human Ultratard
(crystaline).
Biphasic Isophane insulins :
Biphasic insulins consist of insulin
complexed with protamine.
This can then be mixed with varying
amounts of soluble insulin to produce and
immediate and longer effect.
These include Human Mixtard 30/70 and
Humulin M1, M2, M3, M4 (varying
proportions of soluble and isophane insulin).

 Insulin Glargine (Lantus)

It is a preparation of insulin as an acidic
solution that is given subcutaneously
once daily at bedtime and forms
microcrystals under the skin.
These microcrystals dissolve slowly and
release insulin into the bloodstream.
The onset of action is 1 hour after
injection, full activity is reached with in
4-5 hours. This activity is maintained at
a constant level for 24 hours.
In contrast to insulin zinc suspension
(Lente) and isophane insulin (NPH),
insulin glargine produces no significant

 Adverse effects of Insulin Glargine:

Similar to those of NPH insulin
Hypoglycaemia
Reactions at the injection site
Rashes
Pruritus and
Allergic reactions
The incidence of hypoglycaemic events
are similar to those of NPH insulin.
Insulin glargine has been claimed that it
causes less nocturnal hypoglycemia
than the once a day dose of NPH insulin.

Long-acting insulin
Protamine zinc insulin
Produced by adding protamine zinc to insulin.
Its action is prolonged, starting after 6 hours and
lasting 24-30 hours.
It is bovine insulin and may give rise to skin rashes
and painful lumps at the site of injection.
If soluble and PZI insulin are mixed in the syringe
before injection, some of the soluble insulin
becomes PZI insulin.
To minimize this, the soluble insulin should be drawn
up first and the mixture of insulins injected
immediately.

 Human Ultratard
Alternatively, the crystalline form of human insulin zinc
suspension (Human Ultratard) also has a prolonged
action and is not immunogenic.

Insulin detemir
A recombinant form of long-acting insulin, marketed as
Levemir.
This is identical to insulin in amino acid sequence and
composition, but has been made more fat-soluble
through addition of a fatty-acid moiety to the last
amino acid on the end of the B chain.
This makes the insulin more slowly absorbed from the
fat stores after subcutaneous injection, thereby making
it more long-lasting.
Also fatty-acid addition causes it to be bound to
circulating albumin, which holds it in the bloodstream
longer.

Injection of Insulin
Patients should be taught how to inject themselves if
possible.
Best sites for injection are the front of the thighs, the
abdomen and the outer sides of the arms and on the
buttocks.
A different site should be used each time, but it must be
remembered that the rate of absorption of insulin into
the circulation varies with different parts of the body.
Therefore it is better to use the same area but not the
same site at the same time of the day.
For example you give the evening dose on the buttocks
and the morning dose on the abdomen.

Oral hypoglycemic agents

The sulphonylureas
Metformin
Thiazolidinediones
Prandial glucose regulators
Acarbose

Sulphonylureas

Chlorpropamide
Glibenclamide
Gliclazide
Glimepiride
Glipizide
Gliquidone
Tolbutimide

Mechanism of Action
This group of drugs are related to the
sulphonamides
They lower blood glucose levels by
increasing insulin production by the
pancreas. They may also increase
the sensitivity of the tissues to
insulin.

Clinical Use
All given orally and differ largely in
their duration of action.
They are used in patients with
NIDDM who are usually middle-aged
or elderly and obese.
They supplement but do not replace,
treatment and diet.
Not used in young people with
diabetes.

 Glyclazide, glipizide, glimeride and

glibenclamide are now most commonly
prescribed.
Gliclazide is the one most used.
Its effects last up to 24 hours and it
rarely causes hypoglycaemic episodes.
It can also be taken once or twice a day.
Takes about 5 hours to achieve peak
response.
This means that it can be taken before
breakfast and gives good cover before
lunch and supper.

 Tolbutamide and Chlorpropamide are not

used now as much as before.
Tolbutamide is very safe if used correctly.
Duration of action is about 6 hours and for this
reason it is particularly recommended in elderly
patients, as the risk of hypoglycaemia is reduced
and it is given orally two or three times daily.

Chlorpropamide
Similar to Tolbutamide
Action lasts a full 24 hours, so once daily dose is
appropriate.
Due to adverse effects it should only be used in
patients who have been successfully treated
with it for some time.

Adverse effects

Gastrointestinal upsets
Blood dyscrasias (abnormalities)
Fluid retention
Hypoglycaemia
Skin rashes

Drug interaction
NSAIDS like aspirin enhance the
effect
Thiazide diuretics reduce the effect
of sulphonylureas.

Metformin
Belongs to a group called biguanides

Mechanism of Action
Reduces glucose absorption from the
gastrointestinal tract
Stimulate uptake of glucose into
muscle
Inhibit gluconeogenesis (biosynthesis
of glucose from non-carbohydrate
sources, e.g. amino acids).
Reduces glucose release from the
liver.

Other effects
Metformin inhibits plasma low-density
lipoproteins (LDL). It may therefore, reduce
the danger of atheroma in some patients.
Metformin does not reduce the production
of ketone bodies
Metformin does not cause hypoglycaemia
Metformin does not cause weight gain,
possibly because it does not stimulate
appetite.

Clinical use
Its main use is combined with one of
the sulphonyureas when the patient
is not responding satisfactorily toe
diet or to these drugs alone.
Metformin is also occasionally used
combined with insulin in patients
with IDDM whose disease is providing
difficult control.

Thiazolidinediones
Pioglitazone
Rosiglitazone
They belong to a group of chemicals
called glitazones. The first such drug
to be marketed in the UK was
troglitazone which was withdrawn
due to liver toxicity.

Machanism of Action
They seem to reduce tissue
resistance to insulin.

Clinical Use
They have been very satisfactory in controlling
NIDDM when combined with other agents.
They can be combined with either Metformin
or Sulphonylureas.
Onset of action is slow, and patients may need
encouragement to persist with treatment.
About 25% of patients do not respond, and
these tend to be more obese patients with
longstanding insulin resistance and lower
pancreatic reserves.

Adverse reactions
Liver toxicity (although not many
reports)
Weight gain
Increase in plasma LDL

Contraindications

Pregnancy
Breastfeeding
Liver disease
History of Heart Failure
Do not give with insulin

Drug Interactions

Calcium channel blockers

Erythromycin
Ciclosporin
Statins
Glucocorticoids (Prednisone)

Prandial Glucose regulators

Nateglinide and repaglinide
Act post prandial, they deal with the rise in
circulating glucose that occurs immediately
after a meal.
They stimulate insulin release from the
pancreas in the same way oral sulphonylureas
do, but in contrast to the latter it does not
promote insulin release in the absence of
glucose.
Nateglinide works by restoring early-phase
insulin release.

 Both drugs are quickly absorbed from

the GIT and both are very short-acting.
Nateglinide synergizes with metformin,
i.e. the drug increases the effects of a
given dose of metformin.
Both drugs are taken before a meal, and
both are omitted if the meal is missed.

Adverse effects

Anorexia
Nausea
Lactic acidosis
Drowsiness
Abdominal pain
Vomiting
Shock

Acarbose
Mechanism of action: Acarbose is an inhibitor of
the enzyme intestinal -glucosidase. This enzyme
is part of the gastrointestinal mechanism for
converting carbohydrate to glucose.
Clinical use: Taken orally before meals, this agent
inhibits the digestion of complex carbohydrates
such as sucrose and starches, thus preventing
their absorption, but it does not interfere with
glucose absorption. The post-prandial rise in the
blood sugar is reduced. However the unabsorbed
carbohydrates may cause flatulence and
diarrhoea.

Glucagon
Glucagon is released in response to high plasma
levels of amino acids, especially arginine, e.g. After
high-protein meal.
It is also released in response to circulating
adrenaline and increased sympathetic or
parasympathetic activity.
Release is inhibited by another hormone,
somatostatin which is released from other cells in
the pancreatic islets, called D cells.
In contrast to insulin, however, plasma
concentrations of glucagon do not fluctuate but
remain fairly steady throughout the day.

Actions of Glucagon
Stimulates glycogen breakdown to glucose in the
liver
Stimulates gluconeogenesis
Inhibits glycogen synthesis
Inhibits glucose oxidation
Causes lipolysis in fat
Increases breakdown of muscle
Increases release of Insulin
Overall result is to increase blood glucose.
Glucagons actions oppose those of insulin. It also
limits its own actions by stimulating insulin release.

Clinical Use
Glucagon is used to raise blood sugar
in patients who are hypoglycaemic,
e.g. after and overdose of insulin. It
can be administered intramuscularly,
subcutaneously or intravenously.