Antidiabetic Drugs

Dr Naser Ashraf Tadvi

Associate Professor, Pharmacology
Ayaan Institute of Medical Sciences
 Objectives
• Recall the synthesis,secretion and structure of Insulin
• Describe the Mechanism of Action, Pharmacological actions,
ADRs of Insulin and precautions taken to prevent those ADRs
• Enlist Insulin preparations and analogs
• Outline the management of Diabetic Ketoacidosis
• Enlist non-insulin parenteral drugs used in DM
• Classify the oral antidiabetic drugs
• Discuss the pharmacology of the Oral Antidiabetic drugs
 What Is diabetes mellitus?
• A group of metabolic disorders
characterized by chronic hyperglycemia
associated with disturbances of
carbohydrate, fat and protein
metabolism due to absolute or relative
deficiency in insulin secretion and/or
action
Classification of Diabetes Mellitus
• Type I:
• Type II:
• Type III:
• Type IV:
Biosynthesis of insulin

Preproinsulin

Proinsulin

Insulin
 Structure of insulin

21 amino acids

30 AA
Difference between human, pork, beef
insulin

Species A-chain B-chain

8th AA 10th AA 30th AA

Human THR 1LEU- THR

Pork THR ILEU ALA

Beef ALA VAL ALA

Secretion of insulin
> 70 mg/ml

GLUT 2
 Regulation of insulin secretion

• Direct stimulation
• Plasma glucose or Amino Acids , ketones
• Hormonal regulation
•Neural regulation
• Parasympathetic stimulates insulin release
through IP3/ DAG
• Sympathetic inhibits insulin release through
2 receptor activation
 Pharmacological Actions of insulin
• Metabolic:
– carbohydrate, lipid , protein, electrolyte
• Vascular
• Anti-inflammatory
• Fibrinolytic
• Growth
 Pharmacological Actions of insulin

Rapid actions Intermediary actions Long term

Sec / min Few hours > 24 hrs

E.g Through DNA •↑ multiplication

Metabolic e.g •↑ differentiation
actions • ↑ GLUT synthesis of cells
• Synthesis of • Imp role in
enzymes for AA intrauterine &
metabolism extrauterine
growth
 Carbohydrate metabolism
• Over all action of insulin is to ↓ glucose level
in blood
– ↑ Transport of glucose inside the cell
– ↑ Peripheral utilization of glucose
– ↑ Glycogen synthesis
– ↓ Glycogenolysis
– ↓ Neoglucogenesis
 Lipid metabolism
• ↓ Lipolysis
• ↑ Lipogenesis
• ↑ Glycerogenesis
• ↓ Ketogenesis
• ↑ Clearance of VLDL & chylomicrons from
blood through enzyme Vascular Endothelial
Lipoprotein Lipase
 Protein metabolism
• Protein synthesis
• ↑ entry of amino acids in cells

Electrolyte metabolism
• ↑ transport of K+, Ca++, inorganic phosphates
 Other actions
• Vascular actions:
– Vasodilation ? Activation of endothelial NO
production
• Anti-inflammatory action
– Especially in vasculature
• Decreased fibrinolysis
• Growth
Mechanism of action of insulin
 INS Insulin molecule

Insulin Mediated Glucose Transport

Insulin  subunit
Receptor
 Complex  Tyrosine Kinase Activation
b subunit
b b
Metabolised Stored as Glycogen

Glucose
INS
b  b
G

Storage vesicle
containing
GLUT 4
 Fate of insulin
• Distributed only extracellularly
• Must be given parenterally
• Addition of zinc or protein decreases its
absorption & prolongs the DOA
• Insulin released from pancreas is in
monomeric form
• Half life of insulin = 5 -9 minutes
Different types of insulin preparations

• Conventional preparations of insulin

– Produced from beef or pork pancreas
– 1 % of other proteins, Potentially antigenic
• Highly purified insulin preparations
– Gel filtration reduces proinsulin (50-200PPM)
• Human insulins (Recombinant)
• Newer insulin analogs
 Conventional insulin preparations
Type Onset Peak DOA
(Hr) (Hr) (Hr)
Regular insulin 0.5 -1 2-4 6-8
Short acting
Semilente 1 3-6 12-16
Intermediate Lente
1-2 8-10 20-24
acting Isophane(NPH)
Long acting Ultra lente
Protamine Zinc 4-6 14-18 24-36
Insulin (PZI)
Highly purified insulin preparations
• Single peak insulins
– Purified by gel filtration contain 50 -200 PPM
proinsulin
– Actrapid: purified pork regular insulin
– Monotard: purified pork lente
– Mixtard: purified pork regular(30%) + isophane(70%)
• Mono component insulins
– After gel filtration purified by ion exchange
chromatography contain 20 PPM proinsulin
– Actrapid MC, Monotard MC
 Human insulins
• Human (Actrapid, monotard, insulatard, mixtard)
• Obtained by recombinant DNA technology
• Advantages
– More rapid SC absorption , earlier & more defined
peak
– Less allergy
• Disadvantages
– Costly
– Slightly shorter DOA
 Indications of human insulin
• Insulin resistance
• Allergy to conventional preparations
• Injection site lipodystrophy
• During pregnancy
• Short term use of insulin
 Newer Insulin analogs

Type Onset Peak DOA

(Hr) (Hr)
Lispro 5-15 min 1 3-5
Rapid acting Aspart 10-15 min 1 3-5
Glulisine 5-15 min 1 5-6
Long acting Glargine 1-2 hrs No peak 24 hr
Detemir 2-3 hrs 6-8 hr 24 hr
 Advantages of Insulin analogs over
conventional insulins
• Less nocturnal hypoglycemia
• Less weight gain
• More physiological action profiles
• Less premeal lag time (0-15 mts)
• Lispro & Glulisine even after meals
• Better PP glucose control
• Less intra-patient/inter-patient variability
 Adverse effects of insulin
• Hypoglycemia
• Local reactions
– Lipodystrophy
– Lipoatrophy
• Allergy
• Obesity
• Insulin induced edema
 Uses of insulin
• Diabetes mellitus
– Must for type I diabetics
– Can be used in type II diabetics
• Diabetic ketoacidosis
• Hyperosmolar non ketotic hyperglycemic
coma
 Indications of insulin in type II DM
• Primary or secondary oral antidiabetic failure
• Pregnancy
• Perioperative period
• CKD
• Fasting > 300 mgms HbA1c > 10
• Diabetic Ketoacidosis in Type 2 DM
 Diabetic Ketoacidosis
Insulin deficiency Absolute / relative
+
Counter hormone excess
↓ Anabolism ↑ catabolism
↑ Glycogenolysis
↓Peripheral ↑ Glycolysis
utilization of Glucose ↑Gluconeogenesis

Hyperglycemia Dehydration
↓ Fluid intake
Heavy Glucosuria Loss of water
(osmotic diuresis) & electrolytes Hyperosmolarity
 Pathogenesis of DKA
(How ketoacidosis occurs)
↑ Lipolysis Hyperketonemia

↑ FFA to liver ↓ Alkali reserve

↑ Acetyl coA
Acidosis

↑ Acetoacetyl coA

Acetoacetate b-Hydroxy
butrate Acetone
 Treatment of DKA
• Fluid therapy
• Rapid acting regular insulin
• Potassium
• Bicarbonate
• Phosphate
• Antibiotics
 Fluid therapy
• Adequate tissue perfusion is necessary insulin
action
• Normal saline is fluid of choice for initial
rehydration
– 1 litre in first hour then reduced progressively to 0.5
L/ 4 hours (4 to 6 litres in 24 hours)
• When BSL reaches 300 mg% fluid should be
changed to 5 % dextrose with concurrent insulin
 Insulin in DKA
• Regular/ short acting insulin IV treatment of
choice
• Loading dose = 0.1-0.2 U/kg IV bolus
• Then 0.1 U /kg/hr IV by continuous infusion
• Rate doubled if no significant fall in BSL in 2 hr
• 2-3 U/hr after BSL reaches 300mg%
• If patient becomes fully conscious encouraged
to take oral food & SC insulin started
 Potassium replacement
• 10 mEq/L potassium can be added with 3rd
bottle of normal saline
• Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr
 Bicarbonates & phosphates
• Bicarbonates
– If blood pH > 7.1 no need of sodium bicarbonate
– In presence of severe acidosis 50 mEq of sodium
bicarbonate added to IV fluid
• Phosphates
– Non availability of ideal preparation
– Replacement not very essential unless < 1 mEq/L
– potassium phosphate 5-10 m mol/hr
 Newer insulin delivery devices
• Prefilled insulin syringes
• Pen devices
• Jet injectors
• Inhaled insulin (Affreza)
• Insulin pumps
• Insulin complexed with liposomes:
intraperitoneal, rectal, oral
 Non Insulin Parenteral drugs used in
DM
• Glucagon like Peptide 1 Analogs
– Exenatide
– Liraglutide

• Amylin Mimetic Drugs

– Pramlintide
Classification of Oral Antidiabetic drugs
 Sulfonylureas
• Mechanism of action
– Release of insulin by acting on SUR1 receptors
Daily dose & Duration of action

Sulfonylureas Doses No of DOA

doses/day (hrs )
1 Tolbutamide 0.5 – 2 g 2-3 6-8
2 Chlorpropramide 0.1 to 0.5 g 1 36 -48
3 Glibenclamide 5 to 15 mg 1-2 18-24
4 Gliclazide 40- 240 mg 1-2 12-24
5 Glipizide 5 to 40 mg 1-2 12-18
6 Glimepiride 1 to 6 mg 1 Upto 24
 Individual Sulfonylurea
Sulfonylureas Special points
1 Tolbutamide Short acting, low potency , hypoglycemia
least likely
2 Chlorpropramide ↑Hypoglycemia, ↑ADH , Disulfiram Like
Reaction, Cholestatic jaundice , longest
acting
3 Glibenclamide Potent but slow acting
4 Gliclazide Antiplatelet, antioxidant action, may delay
Retinopathy, less weight gain
5 Glipizide Fast acting, hypoglycemia & weight gain less
likely
6 Glimepiride Long acting
 Adverse effects
• Hypoglycemia:
• GI disturbances: Nausea, vomiting, metallic
taste, diarrhoea & flatulence
• Weight gain
• Hypersensitivity
• Chlorpropamide:
– cholestatic jaundice, dilutional hyponatremia,
disulfiram like reaction
 Meglitinide analogs(repaglinide, nateglinide )

• Quick & short acting insulin releasers

• MOA: same as Sulfonylureas but act through
different receptor SUR2
• Mainly used to control Post prandial
hyperglycemia
• Cause less hypoglycemia
 Biguanides
• Metformin & phenformin
• Little or no hypoglycemia
• Also improves the lipid profile in type II
diabetic patients
• Metformin dose = 0.5 to 2.5 g/day in 2-3
divided doses
Mechanism of action of metformin
• Suppress hepatic & renal gluconeogenesis
– Inhibits AMP activated protein kinase enzyme
• ↑ uptake & utilization of glucose by skeletal
muscles which reduces insulin resistance
• Inhibit alimentary absorption of glucose
• Promotion of insulin binding to its receptors
 METFORMIN - INDICATIONS
• First line drug in Type 2 Diabetes
• Obesity
• Insulin resistance
• Along with other antidiabetic drugs
Sulfonylureas, Thiazolidinediones,
Insulin.
 Adverse effects
• Anorexia, nausea, vomiting, diarrhoea
• Metallic taste
• Loss of weight
• Skin rashes
• Lactic acidosis: rare
• Vitamin B12 deficiency: due to malabsorption
Usually does not cause hypoglycemia even in
large doses (Euglycemic drug)
Thiazolidinediones (Glitazones)
Rosiglitazone & pioglitazone Selective agonists of PPAR

Bind to nuclear PPAR

Activate insulin responsive genes - regulate

carbohydrate & lipid metabolism

Sensitize the peripheral tissues to insulin

↓blood glucose by

Inhibit hepatic Promote

↑ Glucose transport into
gluconeogenesis lipogenesis
muscle & adipose tissue
• Pioglitazone:
– 15 to 45 mg once daily orally
• Rosiglitazone:
– 4 to 8 mg once daily orally
• Monotherapy – Hypoglycemia
rare
 Adverse effects
• Weight gain: due to fluid retention & edema
• Worsening of CHF
• Mild anemia
• Hepatotoxicity : rare
• Pioglitazone: bladder cancer
 Alpha glucosidase inhibitors
• Acarbose
• Miglitol
• Voglibose
 Mechanism of action

Dietary Carbohydrates (Starch)

Glucosidase
Pancreatic amylase
inhibitors
Oligosaccharides/ Maltose,
Disaccharides Isomaltose, Sucrose

X
 glucosidase enzymes (in
the lining of cells of
intestinal villi)

Monosaccharides (Glucose, fructose)

Absorbed in lower part of intestine

 Adverse effects
• Flatulence, diarrhoea, abdominal pain
• Do not cause hypoglycemia by themselves but
may cause if used with Sulfonylureas
• If hypoglycemia occurs should not be treated
with routine sugar (sucrose) but glucose
• Contraindicated in inflammatory bowel
disease & intestinal obstruction
 DPP-IV Inhibitors
• Dipeptidyl peptidase- 4 inhibitors
– Sitagliptin : 100 mg OD before meals
– Vidagliptin : 50 mg OD before meals
• Adverse effects
– Nasopharyngitis
– Acute pancreatitis
– Joint pain
 Sodium Glucose cotransporter-2
(SGLT2 Inhibitors)
• Canagliflozin:
• Dapagliflozin:
• Empaglifozin (180 g/day)

90%
(180 10%
g/da
y)

(0
g/day)
 SGLT-2 inhibitors
• Advantages
– Cause weight loss
– No hypoglycemia
– Improve insulin resistance
– Diuretic effect beneficial in hypertension
• Disadvantages: (Adverse effects)
– Polyuria
– Increased urinary infections
– Risk of sodium loss
 Effects of Diabetes Drugs
Hypoglycemia
Drug BW Dys- lipidemia
Risk
-glucosidase
Neutral Improved Low
inhibitors
DPP-4 inhibitors Loss Improved Low
GLP-1 agonists Loss Improved Low
Insulin Gain Improved High
Meglitinides Gain Not improved Moderate
Metformin Loss Improved Low
SGLT2 inhibitors Loss ? Low
Sulfonylureas Gain Variable Moderate
TZD Gain Improved Low

Basile JN. J Diabetes Complications. 2013;27(3):280-286.

 References
• Essentials of Medical Pharmacology KD
Tripathi
• Basic and Clinical Pharmacology Katzung
• ADA , STANDARDS OF MEDICAL CARE IN
DIABETES—2020