Oral Antidiabetics

Sulfonylureas

Sulfonylureas
Insulinotropic agent Oral Hypoglycemic agent Acidic in nature Sulfonamide structure analogue but have no antibacterial activity

Sulfonylurea

Sulfonamide

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.

(often referred as third generation)

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

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

General structure

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

Biotransformation of tolbutamide

Half life: 4 to 7 hours

Inactive: Excreted rapidly

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
SUR Receptor
(ATP-Binding Cassette Super family)

Kir
Kir 6.2 Kir 6.2

Pancreatic b, neuronal Cardiac muscle, skeletal muscle Smooth muscle

SUR 1 SUR 2A

SUR 2B

Kir 6.2

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

Cell membrane

65 kDa

Sulphonylurea receptor (SUR1)

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 Guanidine Antihyperglycemic drugs Most common: metformin, phenformin Can produce lactic acidosis Phenformin: 2 cases per 1000 users Metformin: 0-0.084 cases per 1000 users Lactic acidosis is an uncommon but potentially fatal adverse effect.

Lactic acidosis
Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop. (vigorous exercise) Cells are forced to metabolize glucose anaerobically, which leads to lactate formation. (biguanides)

Biguanides

Metformin

Phenformin

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
-Glucosidase Inhibitors

-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 )

-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 glucosidases hydrolyze oligosaccharides (typically four to ten), trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine.

(Table sugar)

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

4 5

Non-reducing end

Fig: Structure of Acarbose

Acarbose: Structural properties

Acarbose is a linear tetrasaccharide of -Dglucose 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 nonmonosaccharides), non-monosaccharide foods may not effectively reverse a hypoglycemic episode in a patient taking an alpha-glucosidase inhibitor.