Dr.

Sara Adil

lecture 3………………………………………………....…..Clinical pharmacology

ANTI DIABETIC DRUGS

Diabetes mellitus (DM) is a It is a metabolic disorder characterized by high blood glucose

concentration (Hyperglycaemia) due to absolute or relative deficiency of insulin

❖ lack of insulin affects the metabolism of carbohydrate, protein and fat

❖ The pancreas has both an endocrine and exocrine function
ž Endocrine: peptide hormones (insulin, amyline, glucagon, somatostatin)
Exocrine digestive enzymes.

❖ Glucose level vary before and after meals and at various times of day
❖ Normal fasting range 80 – 110 mg/dl

❖ A subject with consistent range

>126 mg/dl Hyperglycemia
< 70 mg/dl Hypoglycemia

Types of diabetes mellitus

ž Type I Insulin-dependent diabetes mellitus (IDDM)

ž Type II Non insulin-dependent diabetes mellitus (NIDDM)

Type 1: insulin-dependent diabetes mellitus (IDDM)

• Most commonly afflicts children, adolescents, or young adults, but some latent forms
occur later in life.

• Results from an autoimmune disorder that destroys pancreatic β cells. Loss of β-cell
function in type 1 diabetes results from autoimmune-mediated processes that may be
triggered by viruses or other environmental toxins Sever or absolute insulin
deficiency

• Treatment is dietary modification plus insulin administration.

• 10% of those with diabetes are type I

Type II: Non insulin-dependent diabetes mellitus (NIDDM)

• Result from reduced sensitivity of peripheral tissues to insulin or relative insulin

deficiency
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• generally, has a late onset (past middle age).

• Treatment is dietary modification with or without oral hypoglycemic agents and/or

C-peptide, also known as connecting peptide, is a short peptide chain that connects the A and B chains of
insulin proinsulin, the precursor to insulin. During insulin synthesis, proinsulin is cleaved into insulin and C-peptide.
However, when insulin is synthesized via recombinant DNA technology for therapeutic purposes, C-peptide is
often removed to produce human insulin.

• Over 90% cases of diabetes are type 2 DM. The presence of C-peptide in the insulin molecule can potentially lead to immunogenic reactions. Here’s how:
Structural Differences: C-peptide is not present in the mature insulin molecule found in the bloodstream.

Insulin Therefore, introducing C-peptide along with insulin through exogenous administration might be perceived as
foreign by the immune system, triggering an immune response.

• Insulin is a polypeptide hormone consist of two peptide chains (A and B chains), that
are connected by disulfide bonds C-peptide (connecting peptide) can produce
immunogenic reactions
• insulin consist of 51 amino acid (a.a) chain A (21 a.a ) + chain B (30 a.a )
• Insulin is anabolic hormone class of hormones that primarily promote tissue growth and development in the body.
• Insulin has profound effects on the metabolism of carbohydrate, fat and protein
• Insulin secretion is regulated by blood glucose levels, certain amino acids, other
hormones, and autonomic mediators.
• Other hormones that raise blood glucose levels include: (Cortisol, Glucagon, Growth
hormone, Epinephrine, Estrogen and Progesterone)

Sources of Insulin :
a. Conventional insulin preparations: Bovine (beef) insulin / Porcine (pig) insulin
b. Human insulin: recombinant DNA origin
• Daily secretion is 30-40 units
• Not active orally

Effect of insulin on its targets

ž Liver: glucose storage as glycogen

glycogenolysis

ž Muscle: glucose uptake

glycogen & protein synthesis

ž Adipose tissue: glucose transport to the cell

lipolysis

In diabetes, there is an actual or functional deficiency of insulin; therefore, hyperglycemia

occurs
lecture 3………………………………………………....…..Clinical pharmacology

Mechanism of action

• Insulin binds to specific receptors (receptor tyrosine kinase) present on the cell
membrane of most body cells

• Target tissues are liver, muscle and adipose tissue

• After insulin - receptors binding occurs cell membranes become highly permeable and
allow entry of glucose, amino acids, fatty acids and potassium to inside the cell

Pharmacokinetics

• Insulin is a polypeptide destroyed by proteolytic enzymes in the GIT and, hence, is not
effective orally.

• Insulin is administered usually by subcutaneous (s.c.) route;

• But in emergencies, regular (soluble) insulin is given by i.v. route. After i.v. injection,
soluble insulin is rapidly metabolized by the liver and kidney with a half-life of about
6 min.

• Modification of the amino acid sequence of human insulin produces insulins with
different pharmacokinetic properties

Insulin preparations

insulin preparations are classified according to their duration of action into:

1. Rapid -acting insulins: e.g. insulin lispro, insulin aspart and insulin glulisine.

• Clear solution
• Have rapid onset and short duration
• Onset of action: Very rapid within 5 minutes after subcutaneous injection; need to
be injected immediately before meal to control postprandial hyperglycaemia.
• Duration of action is 3-4 hours. This decreases the risk of late post meal
hypoglycaemia; ie. Those eat late at night

2. Short acting: ex.Regular soluble insulin

• Dispensed as clear solution

• Onset of action is (30min subcutaneous injection), so need to be injected 30minutes

before the main meals to control the early postprandial hyperglycaemia.
lecture 3………………………………………………....…..Clinical pharmacology

• Duration of action is (8 hrs)

• May be given subcutaneous or iv
• Soluble insulin preparations are the only insulin preparations that may be given
Diabetic ketoacidosis (DKA) is a serious complication of diabetes that occurs when your
intravenously body produces high levels of ketones (acids) in the blood. It typically develops in
individuals with type 1 diabetes, but it can also occur in individuals with type 2
Can also be injected IV for: diabetes under certain circumstances, such as severe illness or stress.

a) rapid control of blood glucose levels in typel or type 2 diabetics during diabetic
ketoacidosis, surgery and intercurrent illnesses as acute myocardial infarction or acute
infections. short-acting insulin is effective in the management of hyperkalemia
b) treatment of hyperkalaemia?? due to its ability to promote the cellular uptake of potassium,
leading to a rapid reduction in serum potassium levels

3. Intermediate actin insulins: e.x. NPH (Neutral protamine Hagedorn) ( also called
isophane insulin) Highly basic protein

• Cloudy suspension of insulin formed by the addition of zinc and protamine to regular
insulin.
• The combination with protamine forms a complex that is less soluble, resulting in
delayed absorption and a longer duration of action.
• Onset of action is 1.5 hours and duration of action is 12 hours.
• NPH insulin is used for basal (fasting) control in type 1 or 2 diabetes and is usually
given along with rapid- or short-acting insulin for mealtime control.
• NPH insulin should be given only subcutaneously (never IV), and it should not be
used when rapid glucose lowering is needed (for example, diabetic ketoacidosis).

4. Long acting insulins: e.x. insulin glargine

• Clear solution, has an acidic pH when administered subcutaneously it precipitates at
the more neutral tissue pH at injection site and slowly dissociates to release insulin
providing a low peakless continuous level of circulating insulin.
• Onset of action: (2-5) hrs
• Duration of action: up to 24 hours, allowing once daily administration.
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• Lower risk of nocturnal hypoglycemia than NPH insulin.

• Should not be mixed with other forms of insulins in same syringe to avoid
disturbance of its pH and lose of efficacy
• Should be avoided in pregnant diabetics

5. biphasic (pre-mixed) insulins:

• a mixture of variable proportion of fast and long or intermediate acting insulins

lecture 3………………………………………………....…..Clinical pharmacology

• Intermediate-acting insulin takes several hours to achieve effective plasma

concentration. Hence, they are combined with regular insulin/rapidly acting insulin
analogues.
• For example, NPH (intermediate acting insulin) + regular/rapidly acting insulin
analogues (insulin lispro and aspart) in the ratio of 70:30. They can be mixed in
the same syringe.

Insulin delivery system

1. Subcutaneous injection

2. Portable pen injection

3. Continuous subcutaneous insulin infusion devices (insulin pumps)

4. Inhaled insulin

Indications for insulin

1. Type 1 diabetes mellitus

2. Diabetic ketoacidosis
using a temporary measure or intervention to help cope with the immediate effects of a
3. Diabetes during pregnancy traumatic event or situation until more comprehensive support or treatment can be provided.
4. Stress of surgery, infections and trauma (temporarily to tide over trauma, infection,
surgery, etc.)
5. Patients with type 2 DM unresponsive to oral anti-diabetic drugs.

Drug interactions
1. Blockers X insulin: Nonselective B blockers inhibit glycogenolysis and delay recovery
from hypoglycemia
2. Salicylates X insulin: Salicylates exert hypoglycemic effect by increasing the sensitivity
of pancreatic B cells to glucose and potentiating insulin secretion
Both exacerbate hypoglycemia

Complications of insulin therapy

1. Hypoglycaemia is the most common and dangerous complication. Prolonged
hypoglycaemia may cause permanent brain damage.
2. Allergic reactions are rare; local skin reactions (swelling, redness) at the site of injection
can occur, which may be due to minor contaminants.
3. Lipodystrophy (either atrophy or hypertrophy) may occur at the site of injection. It may
be avoided by using purified insulin preparations and changing the injection site by
rotation.
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4. Insulin resistance: It is a state in which patient requires more than 200 U of insulin/day
and is common among obese type-2 diabetics. It may be acute or chronic. Acute insulin
resistance develops rapidly and is due to stressful conditions like trauma, infection,
surgery, psychological stress, etc. Chronic insulin resistance is common in patients on
prolonged conventional beef or pork insulins. Such patients should be treated with
highly purified insulins. Insulin and Sodium Retention: Insulin has been shown to promote sodium retention by enhancing
the reabsorption of sodium in the kidneys. When insulin levels are elevated, such as during
5. Edema due to salt and water retention insulin therapy or in conditions of insulin resistance, this can lead to increased sodium
reabsorption in the kidneys, contributing to sodium retention in the body.

Sodium and Water Retention: Sodium retention in the body leads to increased extracellular fluid
volume, as water follows sodium via osmosis. This excess fluid can accumulate in tissues, leading
to edema.