oral antidiabetics
DESCRIPTION
Insulinotropic agentOral Hypoglycemic agentAcidic in natureSulfonamide structure analogue but have no antibacterial activityTRANSCRIPT
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Oral Antidiabetics
Sulfonylureas
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Sulfonylureas
• Insulinotropic agent• Oral Hypoglycemic agent• Acidic in nature• Sulfonamide structure analogue but have no
antibacterial activity
SulfonylureaSulfonamide
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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
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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.
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Ref: Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
(often referred as third generation)
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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.
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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
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Biotransformation of tolbutamide
Inactive:Excreted rapidly
Half life: 4 to 7 hours
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Chlorpropamide
• Metabolized slowly• Long duration of action
Half life: 24 to 48 hours
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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
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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
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Mechanism of action:
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ATP – Sensitive K+ Channels
Type of Cell Kir
Pancreatic b, 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)
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Sulfonylurea: Side effects
• Hypoglycemia• Weight gain• Drug interaction (Mainly 1st generation)• Allergic reactions (Sulfa compounds)
- Pruritus- Rash
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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.
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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
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140 kDa
65 kDa
Sulphonylurea receptor (SUR1)
Cell membrane
Glimepiride
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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)
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Oral Antidiabetics
Nonsulfonylureas
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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
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Repaglinide
• This agent is a derivative of benzoic acid • Its structure is unrelated to that of the
sulfonylureas
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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
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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
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Oral Antidiabetics
Biguanide
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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
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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)
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Biguanides
Metformin Phenformin
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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
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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)
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Etoformin
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Oral Antidiabetics
Thiazolidinediones
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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
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Pioglitazone
Rosiglitazone *
*
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Chirality
• Both has one chiral center thus has two isomers
• Compounds are used as racemic mixture• Functionally indistinguishable: due to
interconversion in in vivo
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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.
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Mechanism of action
• Insulin resistance is decreased• Increase the synthesis of certain proteins
involved in glucose metabolism
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Oral Antidiabetics
α-Glucosidase Inhibitors
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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 )
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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
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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.
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(Table sugar)
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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.
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Non-reducing end
Reducing end
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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
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Fig: Structure of Acarbose
4
5
Non-reducing end
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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.
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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
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Miglitol
Glucose
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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.
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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.