INSULIN AND ANTI DIABETIC DRUGS

LEARNING OUTCOMES
At the end of the lecture you should be able to:
Define diabetes mellitus and its types.
Classify various insulin preparation.
Explain pharmacological actions of insulin on
carbohydrate, fat and protein metabolism.
Know the pharmacokinetic, adverse effect and drug
interaction of insulin.
Classify oral hypoglycemic agents and pharmacology of
oral hypoglycemic agents.
 Diabetes Mellitus
Chronic metabolic disease associated with deficiency or
impaired insulin secretion.

Insulin is a hormone that is needed to convert sugar

(glucose), starches and other food into energy needed for
daily life.

The symptoms of DM are poly uria, poly dipsia, and poly

phagia.

Un controlled DM results in Ketoacidosis.

 Diabetes Mellitus
Two types:
(Type 1)- Insulin dependent diabetes (IDDM)

(Type 2) - Non-insulin dependent diabetes (NIDDM)

 Human blood glucose ranges (mg/dL)

Normal blood glucose levels in people who do not

have diabetes
Fasting 70 to 110
Postprandial (After meals) 70 to 140
Target blood glucose levels in people who have
diabetes
Before meals 90 to 130
1 to 2 hours after the start of a meal less than 180
Hypoglycemia (low blood glucose) 70 or below
 Diabetes - Diagnosis
Diabetes mellitus diagnosed by demonstrating any one of
the following:

Fasting plasma glucose level at or above 126 mg/dL (7.0

mmol/l).

Plasma glucose at or above 200 mg/dL or 11.1 mmol/l

two hours after a 75 g oral glucose load as in a glucose
tolerance test.

Random plasma glucose at or above 200 mg/dL or 11.1

mmol/l.
 Classification of Insulin Preparation
Type Onset Peak Duration Comments

Rapid acting 5 – 15 min 30 -60 min 2-5 hr Injected with

meal.

Short acting 30 min 1-3 hr 4-8 hr Injected 15- 30

min before the
meal
Intermediate 1-2 hr 8-12 hr Used to control
acting or Long 4-8 hr between meals.
acting 2- 3 hr
8 -24 hr

Long acting 30 -60 min No peak 16 -24 hr Once daily.

Flat
 CLASSIFICATION OF INSULIN PREPARATION
Type Example
Rapid acting
Lispro/ Aspart/ Glulisine

Short acting Regular

Intermediate acting Isophane NPH insulin preparation

Long acting Insulin glargine

Protamine zinc suspension

 Insulin and Carbohydrate
Metabolism
Glucose is liberated from dietary carbohydrate such as
starch or sucrose by hydrolysis within the small
intestine, then absorbed into the blood.
Elevated concentrations of glucose in blood

Stimulate release of insulin

Insulin acts on cells throughout the body to stimulate

uptake, utilization and storage of glucose.
 Insulin and Carbohydrate
Metabolism
Insulin facilitates entry of glucose into muscle and adipose
tissue via Glut 4 transporter.

Mechanism by which cells can take up glucose is by

facilitated diffusion through a family of hexose
transporters.
 Insulin and Carbohydrate
Metabolism
Insulin stimulates the liver to store glucose in the form of
glycogen.
Insulin activates phosphofructokinase and glycogen
synthase.

These enzymes are involved in glycogen synthesis.

A well-known effect of insulin is to decrease the
concentration of glucose in blood
MECHANISM OF INSULIN - LIVER
 Insulin and Lipid
Metabolism

Insulin promotes synthesis of fatty acids in the liver.

Insulin inhibits breakdown of fat in adipose

tissue by inhibiting the intracellular lipase that
hydrolyzes triglycerides to release fatty acids.
 Insulin and Lipid
Metabolism
Within adipocytes glucose can be used to synthesize
glycerol.

This glycerol, along with the fatty acids delivered from

the liver, are used to synthesize triglyceride within the
adipocyte.

insulin indirectly stimulates accumulation of fat in

adipose tissue
 Insulin and Protein
Metabolism
Insulin stimulates protein synthesis and decrease protein
brake down in the liver.

It increases synthesis of messenger RNA and decreases

gluconeogenesis

Increases amino acid uptake in the muscle

 Pharmacokinetic aspect

• Insulin destroyed in GIT, so must be given in parentally.

• I.V and i.M route preferred incase of emergency – sever
ketoacidosis.
• I.P route – ESRF.
• Onset, peak and duration vary from preparation to
preparation (refer table).
• Metabolized in liver and excreted through urine.
 Insulin side effects

Insulin allergy due to Ig E medicated local cutaneous reaction

and resistance. Rarely cause anaphylactic shock, loss of
consciousness, labored breathing, swelling of the tongue and
breathing tubes, blueness of the skin, low BP.

Hypoglycemia

Nervous disorders due to rapid administration to control acute

diabetes
 Insulin side effects

Lipoatrophy and lipohypertrophy.

Insulin induced presbiopia (reduced ability to focus)

Obesity due to increased appetite.

 Insulin + Drug interaction

• Counter action of insulin cause Hyperglycemia.

• Epinephrine, glucocorticoids.
• Clozapine and olanzapine.
• Phenytoin.
• Calcium channel blockers.
 Classification of Oral Hypoglycemic Agents
First Generation Second Generation

Sulphonyl Urea Tolbutamide Glyburide

Chlorpropamide Glipizide (Glix,
Tolazamide Glipizide DHA)
Acetohexamide Glimepiride
(Amaryl)
Glibenclamide
(Daonil)

Biguanides Metformin (Glucophage)

Meglitinides Nateglinide (Starlix)

Repaglinide (NovoNorm)
 Classification of Oral Hypoglycemic Agents

Thiazolidinediones Rosiglitazone (Avandamet, Avandia)

Pioglitazone (Actos)

α-Glucosidase Acarbose (Glucobay)

inhibitors Miglitol

Dipeptidyl peptidase- Sitagliptin

4 (DPP4) inhibitors Vildagliptin
Saxagliptin
Sulfonylureas first generation Vs second
Generation
First generation Second generation

Less potent. Tolbutamide 100 times more potent than

Relative potency is 1. first generation
Glibenclamide (Relative potency
-150)and Glipizide (Rel.
Potency100)
Duration of action and half life Long Duration and Half life.
is short. Glibenclamide : 18-24 hr
Tolbutamide:6-12 (t1/2 – 4hr) t1/2 : 10 hr

More frequent administration. Less frequent administration

Sulfonylureas Mechanism of Action
 Sulfonylureas Mechanism of Action

Pancreatic effect:
• Sulfonylureas bind to the SUR1 subunits and block the ATP-
sensitive K+ channel
• Reduced K+ conductance causes membrane depolarization
and Ca2+ influx through voltage sensitive Ca2+ channel.
• The above cell signaling stimulates Insulin release.
Extra pancreatic effect:
• Increasing binding capacity of insulin to target tissues and
receptors through extra pancreatic effect.
 Sulfonylureas - Pharmacokinetics

• Absorbed from gastrointestinal tract.

• Food - reduce the absorption.
• Protein binding (albumin): 90-99%
• Metabolized by liver enzymes.
• Elimination through renal route and biliary
route.
 Sulfonylureas-Adverse effects

o Weight gain - Stimulate the appetite.

o Hypoglycemia
o Hyperinsulinemia.
o Nausea, Vomiting.
o Aplastic and hemolytic anemias.
o Agranulocytic jaundice.
o Cholestatic jaundice.
 Sulfonylureas-
Contraindications
vPregnancy - Metabolites cross Blood Placental
Barrier (BPB).
vLactation – Metabolites secreted in milk.
vSignificant hepatic malfunction.
vHepatic and Renal insufficiency..
 Biguanide-Metformin Mechanism of Action

• Reduces blood glucose levels by

à decreasing hepatic glucose production – Decrease
Gluconeogenesis and Glyconeogenesis.
à increasing insulin action in muscle and fat – Increase
Insulin mediated glucose uptake, Glycogenesis.
• It also may decrease plasma glucose by reducing the absorption of
glucose from the intestine, but this action has not been shown to
have clinical relevance.
• Reduced circulating LDL (Low density lipoprotein) and VLDL (Very
low density lipoprotein).
 Metformin Pharmacokinetics

vWell absorbed from small intestine.

v Does not bind with plasma protein.

vEliminated through renal route in unchanged

form.
vThe maximum recommended dose is 2.5 g given
in three divided dose.
 Metformin – Adverse Effect

vDiarrhea, abdominal discomfort, metallic

taste.
vAnorexia.
vPotentially fatal lactic acidosis.
vLong-term use interfere with Vitamin B12
absorption.
v Calcium supplements can reverse
metformin effects on vitamin B12
absorption.
 Metformin – Contra indications
v Renal disease
v Hepatic disease
v Cardiac or respiratory insufficiency.
v Alcohol abuse.
v Pregnancy.
 α-glucosidase inhibitors Mechanism of Action

vInhibit the membrane bound enzyme α-glucosidase

in the intestinal boarder
vDelays the digestion of carbohydrates
vDecreases the glucose absorption
vAlso inhibits pancreatic α-amylase enzyme
vInhibits breakdown of starch to oligosaccharides
 α-glucosidase inhibitors - Pharmacokinetics

vAcarbose is poorly absorbed

vMetabolized by intestinal bacteria
vMeglitol is very well absorbed.
vIt is eliminated unchanged through renal route
 α-glucosidase inhibitors – Adverse
effects

vFlatulence (Excess gas in the intestinal tract)

vDiarrhea
vAbdominal cramps.
 α-glucosidase inhibitors
Contraindications:
vInflammatory bowel disease
vColonic ulceration
vIntestinal obstruction
Dipeptidyl peptidase-4 (DPP4) inhibitors
Competitively inhibits activity of the enzyme DPP-4.

Hence prolong the actions of endogenous Glucagon

Like Peptide 1 (GLP-1) which stimulate insulin
secretion.

They do not cause weight gain or loss.