Oral Antidiabetics

Sulfonylureas

Sulfonylureas

• Insulinotropic agent• Oral Hypoglycemic agent• Acidic in nature• Sulfonamide structure analogue but have no

antibacterial activity

SulfonylureaSulfonamide

Sulfonylurea: Generation

• 12,00 sulfonylureas have been synthesized• 10 compounds are used world wide to reduce

blood glucose levels• The sulfonylureas are divided into two groups

or generations of agents• Least expensive class of medication

Sulfonylurea: Generation

• The first group of sulfonylureas includes tolbutamide, acetohexamide, tolazamide, and chlorpropamide.

• A second, more potent generation of hypoglycemic sulfonylureas has emerged, including glyburide (glibenclamide), glipizide, gliclazide, and glimepiride.

Ref: Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

(often referred as third generation)

Sulfonylurea: Generation

• Second (and third generation) sulfonylureas are 100 times more potent than first generation.

• Although their half-lives are short (3 to 5 hours), their hypoglycemic effects are evident for 12 to 24 hours (specific reason unknown).

• Have large side chain in structure.• More lipid soluble.

Sulfonylurea: SAR

• All members of this class of drugs are substituted arylsulfonylureas

• R1 aliphatic group (acetyl, amino, chloro, etc.)• Affect duration of action of drug• It should be in para position

General structure

Biotransformation of tolbutamide

Inactive:Excreted rapidly

Half life: 4 to 7 hours

Chlorpropamide

• Metabolized slowly• Long duration of action

Half life: 24 to 48 hours

Sulfonylurea: SAR

• The second generation agents are more potent than the first generation agents. It is believed that this is because of a specific distance between the nitrogen atom of the substituent (R1) and the sulfonamide nitrogen atom.

Glipizide

Sulfonylurea: SAR

R2 group impart lipophilic properties to the molecule

R2 may be:• Aliphatic moiety (3-6 carbon: max activity) or• An alicyclic or heterocyclic ring (5-7 carbon:

max activity)• Aryl group: toxic compound

Mechanism of action:

ATP – Sensitive K+ Channels

Type of Cell Kir

Pancreatic , neuronal

Cardiac muscle, skeletal muscle

Smooth muscle

SUR Receptor (ATP-Binding

Cassette Super family)

Kir 6.2

Kir 6.2

Kir 6.2

SUR 1

SUR 2A

SUR 2B

Inwardly rectifying potassium channels (Kir, IRK)

Sulfonylurea: Side effects

• Hypoglycemia• Weight gain• Drug interaction (Mainly 1st generation)• Allergic reactions (Sulfa compounds)

- Pruritus- Rash

Sulfonylurea: Cardiac safety

• The prevalence of coronary artery disease (CAD) in the diabetic population is 24 times that observed in the nondiabetic population

• Congestive heart failure, to which CAD and hypertension contribute, is increased three- to four-fold.

Sulfonylurea: Cardiac safety

• In vitro and in vivo evidences suggest that acute or chronic administration of glibenclamide induces potentially harmful cardiovascular effects in both diabetic and nondiabetic patients with IHD, by blocking ATP sensitive potassium channel

Glibenclamide

140 kDa

65 kDa

Sulphonylurea receptor (SUR1)

Cell membrane

Glimepiride

Sulfonylurea: Cardiac safety

• Most Sulphonylureas: 140 kDa

• Glimepiride: 65 kDa

• 65 kDa component absent in cardiovascular system

• Safer to use glimepiride in patients with a higher cardiovascular risk (CAD)

Oral Antidiabetics

Nonsulfonylureas

Meglitinides

• Insulinotropic agent• Acidic compounds• Nonsulfonylurea oral hypoglycemic agent• Commonly used are: Repaglinide, Nateglinide

(known as Metaglinides)• MA similar to sulfonylurea but not clear

whether the drug bind with SUR1

Repaglinide

• This agent is a derivative of benzoic acid • Its structure is unrelated to that of the

sulfonylureas

Nateglinide

• Derived from D-phenylalanine• Its structure is unrelated to that of the

sulfonylureas

• More rapid but less sustained secretion of insulin than other• Produce fewer episodes of hypoglycemia than most other

Meglitinides vs Sulfonylureas

• Causes much faster insulin production than the sulfonylurea

• Short duration of action (Half life: less than an hour) compared to sulfonylureas (several hours)

• Less risk of hypoglycemia and weight gain• Devoid of side effects of sulfa compounds

Oral Antidiabetics

Biguanide

Biguanides

• Guanidine derivatives• Antihyperglycemic drugs• Most common: metformin, phenformin• Can produce lactic acidosis

Phenformin: 2 cases per 1000 usersMetformin: 0-0.084 cases per 1000 users

• Lactic acidosis is an uncommon but potentially fatal adverse effect.

Guanidine

Biguanides

Biguanides: Functions

No effect on pancreatic beta cell.

- glucose uptake and utilization (glycolysis) by muscle cells (peripheral tissue) with lactic acidosis

- glucose production by liver (Gluconeogenesis)

- glucose (+ Vitamin B12) uptake from intestine

Exact mechanism is unknown

Structural properties

• R is aliphatic (Buformin) or aromatic (Phenformin) (exp. metformin)

• R’ usually H, may be alkyl group (etoformin)• R’’ usually H, often large group (phenfosformin)

Etoformin

Oral Antidiabetics

Thiazolidinediones

Thiazolidinediones

• Known as glitazones or insulin resistance reducers

• First drug: Troglitazone (withdrawn due to liver toxicity)

• Two glitazones are available: pioglitazone and rosiglitazone

• Both are acidic compounds

Pioglitazone

Rosiglitazone *

*

Chirality

• Both has one chiral center thus has two isomers

• Compounds are used as racemic mixture• Functionally indistinguishable: due to

interconversion in in vivo

Mechanism of action

• Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor molecules

• Thiazolidinediones are selective agonists for gamma form of PPARs

• When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.

Mechanism of action

• Insulin resistance is decreased• Increase the synthesis of certain proteins

involved in glucose metabolism

Oral Antidiabetics

α-Glucosidase Inhibitors

α-Glucosidase Inhibitors

• Enzyme present in brush border of small intestine

• Split dietary carbohydrate and helps in absorption

• Do not increase insulin secretion, no involvement in hypoglycemia

• No or little effect on fasting blood glucose• Have to use preprandially (as the drugs are

competitive inhibitors )

α-Glucosidase Inhibitors

• Reduce postprandial hyperininsulinemia• Do not promote weight gain• Used as adjunct therapy for obese patient

with diabetes insufficiently controlled by diet and other classical antidiabetic drugs.

• Example: Acarbose, Miglitol and Voglibose

Mechanism of action

• Competitive inhibitor of the enzyme. • This enzyme recognizes specific residues in

the polymeric sugar chain and hydrolyses the interglycoside linkage.

• The membrane-bound intestinal α-glucosidases hydrolyze oligosaccharides (typically four to ten), trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine.

Mechanism of action

• Low dose: Delay absorption• High dose: Inhibit absorption• Inhibition of these enzyme systems reduces

the rate of digestion of carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules.

Non-reducing end

Reducing end

Acarbose

• Naturally occurring oligosaccharide (tetrasaccharide)

• Competitive inhibitor• Enzyme attempts to hydrolyze but failed• Has a 105 fold higher affinity than typical

substrate• Minimally absorb (0.5-1.7%)• Produce flatulence and bloating in 60% cases

Fig: Structure of Acarbose

4

5

Non-reducing end

Acarbose: Structural properties

• Acarbose is a linear tetrasaccharide of -D-glucose residues modified at the non-reducing end.

• The non-reducing end group saccharide residue has a nitrogen atom replacing the interglycosidic oxygen atom and a double bond between C-4 and C-5 positions.

Miglitol

• Has similar structure to a sugar (resembles a monosaccharide)

• Second generation -Glucosidase inhibitor• Competitive inhibitor • Completely absorb at low dose, but not

metabolized and excreted through kidney• Less side effects compared to acarbose

Miglitol

Glucose

Side effects & precautions

• Carbohydrates will remain in the intestine. In the colon, bacteria will digest the complex carbohydrates, thereby causing gastrointestinal side effects such as flatulence and diarrhea.

• Since these effects are dose-related, it is generally advised to start with a low dose and gradually increase the dose to the desired amount.

Side effects & precautions

• If a patient using an alpha-glucosidase inhibitor suffers from an episode of hypoglycemia, the patient should eat something containing monosaccharides, such as glucose tablets. Since the drug will prevent the digestion of polysaccharides (or non-monosaccharides), non-monosaccharide foods may not effectively reverse a hypoglycemic episode in a patient taking an alpha-glucosidase inhibitor.