ANTI-DIABETIC AGENTS •

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Insulin• Proinsulin is converted to insulin and C

peptide.• Insulin is referred as the storage

hormone as it promotes anabolism and inhibits catabolism of carbohydrates, fatty acids and protein.

• In the absence of insulin, most tissues cannot use glucose and fats/proteins are broken down to provide energy.

InsulinMechanism of action :• Insulin binds to insulin receptors on

the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle.

• The Nerves, RBC’s, Kidney, and Lens of the eye do not require insulin for glucose transport.

Insulin Liver : • Insulin increase the storage of glucose

as glycogen in the liver. • It inserts the GLUT-2 glucose transport

molecule in the cell membrane. • It inhibits gluconeogenesis – thus

significantly ↓ glucose output by the liver.

• It decrease the protein catabolism.

Insulin Muscle : • Insulin stimulates the glycogen

synthesis and protein synthesis.• Glucose transport into the cells is

facilitated by GLUT-4 into the cell membrane.

• It inhibits the protein catabolism.

Insulin Adipose tissue :• Insulin facilitates the storage of

triglyceride by activating plasma lipoprotein lipase and inhibiting intracellular lipolysis.

• It increase the glucose uptake by GLUT-4 insertion into the cell membrane.

Insulin

Insulin• Insulin is a 51 AA peptide• Not active orally.• Insulin is inactivated by insulinase

found mainly in liver and kidney.• Dose reduced in renal insufficiency• Sources of Insulin :

– Beef pancreas / Pork pancreas – Human insulin: recombinant DNA origin

InsulinHuman Insulin : • Do not contain measurable

amounts of proinsulin or contaminants.

• Diminished antibody• Less allergic reactions• Less lipodystrophy• Preferred in gestational diabetes

• Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on:

• Nature of the diabetes• Age and situation of the person• Other factors.

Diabetes Mellitus Type I• Type 1 diabetes most commonly afflicts individuals

in puberty or early adulthood, but some latent forms can occur later in life. The disease is characterized by an absolute deficiency of insulin caused by massive β-cell necrosis. Loss of β-cell function is usually ascribed to autoimmune-mediated processes directed against the β-cell, and it may be triggered by an invasion of viruses or the action of chemical toxins. As a result of the destruction of these cells, the pancreas fails to respond to glucose, and the Type 1 diabetic shows classic symptoms of insulin deficiency (polydipsia, polyphagia, polyuria, and weight loss). Type 1 diabetics require exogenous insulin to avoid the catabolic state that results from and is characterized by hyperglycemia and life-threatening ketoacidosis.

Diabetes Mellitus Type II• Most diabetics are Type 2. The disease is

influenced by genetic factors, aging, obesity, and peripheral insulin resistance rather than by autoimmune processes or viruses. The metabolic alterations observed are milder than those described for Type 1 (for example, Type 2 patients typically are not ketotic), but the long-term clinical consequences can be just as devastating (for example, vascular complications and subsequent infection can lead to amputation of the lower limbs).

Types of DM• Diabetes mellitus type 1 is a disease caused

by the lack of insulin. Insulin must be used in Type I, which must be injected.

• Diabetes mellitus type 2 is a disease of insulin resistance by cells. Treatments include:– agents that increase the amount of insulin

secreted by the pancreas– agents that increase the sensitivity of target

organs to insulin– agents that decrease the rate at which glucose

is absorbed from the gastrointestinal tract.

Types of DM

Type 1 Type 2Age of onset Usually during

childhood or pubertyFrequently over age 35

Nutritional status at time of onset

Frequently undernourished

Obesity usually present

Prevalence 5 to 10 % of diagnosed diabetics

90 to 95 % of diagnosed diabetics

Genetic predisposition

Moderate Very strong

Defect or deficiency

B cells are destroyed, eliminating the production of insulin

Inability of B cells to produce appropriate quantities of insulin; insulin resistance; other defects

Symptoms of Hypoglycemia

DRUG GROUPS

Adverse effects of OHAsMeglitinideSulfonylureas

Hypoglycemia

Biguanidesα-Glucosidase inhibitors

GI disturbance

Biguanides

Nausea

Thiazolidinediones

Risk of hepatotoxicity

SulfonylureasMeglitinidesThiazolidinediones

Weight gain

1) Insulin secretagogues• Useful in the treatment of patients who

have Type 2 diabetes but who cannot be managed by diet alone.

• Best response to OHA is seen in one who develops diabetes after age 40 and has had diabetes less than 5 years.

• Patients with long-standing disease may require a combination of hypoglycemic drugs with or without insulin to control their hyperglycemia.

• Oral hypoglycemic agents should NOT be given to patients with Type 1 diabetes.

A. Sulfonylureas• These agents are classified as

insulin secretagogues, because they promote insulin release from the β cells of the pancreas. The primary drugs used today are tolbutamide and the second-generation derivatives, glyburide, glipizide, and glimepiride.

Sulfonylureas :• First generation : Acetohexamide,

Chlorpropamide, Tolbutamide, Tolazamide

• Second generation : Glipizide, Glyburide – more potent, more efficacious and fewer adverse effects.

• Third generation : Glimiperide

A. Sulfonylureas• Mechanism of action:1)stimulation of insulin release from the

β cells of the pancreas by blocking the ATP-dependent K+ channels, resulting in depolarization and Ca2+ influx

2)reduction in hepatic glucose production

3)increase in peripheral insulin sensitivity.

A. Sulfonylureas• Pharmacokinetics:• Given orally, these drugs bind to

serum proteins• Metabolized by the liver• Excreted by the liver or kidney• Tolbutamide has the shortest

duration of action (6-12 hours), whereas the second-generation agents last about 24 hours

A. Sulfonylureas• Adverse Effects:• Weight gain• Hyperinsulinemia• Hypoglycemia• These drugs should be used with caution in

patients with hepatic or renal insufficiency, because delayed excretion of the drug-resulting in its accumulation-may cause hypoglycemia.

• Renal impairment is a particular problem in the case of those agents that are metabolized to active compounds, such as glyburide.

• Glyburide has minimal transfer across the placenta and may be a reasonably safe alternative to insulin therapy for diabetes in pregnancy.

2) Insulin sensitizers• Two classes of oral agents-the

biguanides and thiazolidinediones improve insulin action. These agents lower blood sugar by improving target-cell response to insulin without increasing pancreatic insulin secretion.

• They address the core problem in Type II diabetes—insulin resistance.

A. Biguanides• Metformin (glucophage), the only

currently available biguanide• it increases glucose uptake and

utilization by target tissues, thereby decreasing insulin resistance.

• Requires insulin for its action, but it does not promote insulin secretion.

• Hyperinsulinemia is not a problem. Thus, the risk of hypoglycemia is far less than that with sulfonylureas

A. Biguanides• Mechanism of action:• reduction of hepatic glucose output, largely

by inhibiting hepatic gluconeogenesis.• Slowing intestinal absorption of sugars• Improves peripheral glucose uptake and

utilization.• Metformin may be used alone or in

combination with one of the other agents, as well as with insulin.

• Hypoglycemia has occurred when metformin was taken in combination.

A. Biguanides• Pharmacokinetics:• Metformin is well absorbed orally,

is not bound to serum proteins• It is not metabolized• Excretion is via the urine.

A. Biguanides• Adverse effects:• These are largely gastrointestinal. • Contraindicated in diabetics with renal

and/or hepatic disease, acute myocardial infarction, severe infection, or diabetic ketoacidosis.

• It should be used with caution in patients greater than 80 years of age or in those with a history of congestive heart failure or alcohol abuse.

• Long-term use may interfere with vitamin B12 absorption.

B. Thiazolidinediones• Another group of agents that are insulin

sensitizers are the thiazolidinediones (TZDs) or, more familiarly the glitazones.

• Although insulin is required for their action, these drugs do not promote its release from the pancreatic β cells; thus, hyperinsulinemia does not result.

• Troglitazone was the first of these to be approved for the treatment of Type 2 diabetic, but was withdrawn after a number of deaths due to hepatotoxicity were reported. Presently, two members of this class are available, pioglitazone and rosiglitazone.

B. Thiazolidinediones• Mechanism of action:• Exact mechanism by which the TZDs

lower insulin resistance remains to be elucidated

• They are known to target the peroxisome proliferator-activated receptor-γ (PPARγ)-α nuclear hormone receptor. Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.

B. Thiazolidinediones• Pharmacokinetics:• Both pioglitazone and rosiglitazone are

absorbed very well after oral administration and are extensively bound to serum albumin.

• Both undergo extensive metabolism by different cytochrome P450 isozymes.

• Pioglitazone:• Renal elimination is negligible, with the

majority of the active drug and metabolites excreted in the bile and eliminated in the feces.

• Rosiglitazone:• The metabolites are primarily excreted in the

urine.

Oral Anti-diabetic drugsMechanisms to reduce blood sugar :• Stimulation of pancreatic insulin

release – Sulfonylureas, Meglitinide• Reduce the bio-synthesis of glucose

in liver – Biguanides (Metformin)• Increase the sensitivity of target

cells to insulin -- Thiazolidinediones• Retard the absorption of sugars

from the GI tract – Acarbose, Miglitol

B. Thiazolidinediones

• Adverse Effects:• Very few cases of liver toxicity have been

reported with rosiglitazone or pioglitazone.

• Weight increase can occur, possibly through the ability of TZDs to increase subcutaneous fat or due to fluid retention.

• Glitazones have been associated with osteopenia and increased fracture risk.

• Other adverse effects include headache and anemia.

3) α-glucosidase inhibitors• Alpha-glucosidase inhibitors are oral

anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.

α-glucosidase inhibitors• Acarbose and miglitol are orally

active drugs used for the treatment of patients with Type 2 diabetes.

α-glucosidase inhibitors• Mechanism of action:• These drugs are taken at the beginning of meals.

They act by delaying the digestion of carbohydrates, thereby resulting in lower postprandial glucose levels. Both drugs exert their effects by reversibly inhibiting membrane-bound α-glucosidase in the intestinal brush border. This enzyme is responsible for the hydrolysis of oligosaccharides to glucose and other sugars. Consequently, the postprandial rise of blood glucose is blunted. Unlike the other oral hypoglycemic agents, these drugs do not stimulate insulin release, nor do they increase insulin action in target tissues. Thus, as monotherapy, they do not cause hypoglycemia. However, when used in combination with the sulfonylureas or with insulin, hypoglycemia may develop.

α-glucosidase inhibitors• Pharmacokinetics:• Acarbose is poorly absorbed. It is

metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine. On the other hand, miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney.

α-glucosidase inhibitors• Adverse effects:• The major side effects are

flatulence, diarrhea, and abdominal cramping. Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs.

4) Dipeptidyl peptidase-4 inhibitor• DPP-4 inhibitors or gliptins, are a class of oral

hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2.

• The first agent of the class - sitagliptin - was approved by the FDA in 2006.

• Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.

Dipeptidyl peptidase-4 inhibitor• Sitagliptin is an orally active

dipeptidyl peptidase-IV (DPP-IV) inhibitor used for the treatment of patients with Type 2 diabetes. Other agents in this category are currently in development.

Sitagliptin• Mechanism of action:• Sitagliptin inhibits the enzyme DPP-IV,

which is responsible for the inactivation of incretin hormones, such as glucagon-like peptide-1 (GLP-1). Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in inappropriate secretion of glucagon. Sitagliptin may be used as monotherapy or in combination with a sulfonylurea, metformin or a glitazone.

Sitagliptin• Pharmacokinetics:• Sitagliptin is well absorbed after

oral administration. Food does not affect the extent of absorption. The majority of sitagliptin is excreted unchanged in the urine. Dosage adjustments are recommended for patients with renal dysfunction.

Sitagliptin• Adverse Effects:• In general, sitagliptin is well

tolerated, with the most common adverse effects being nasopharyngitis and headache. Rates of hypoglycemia are comparable to those with placebo when sitagliptin is used as monotherapy or in combination with metformin or pioglitazone.

Anti-diabetic drugsGlucagon like Peptide : GLP-1

analog : Xenatide : (Byetta) :• GLP is an incretin released from the

small intestine which increase the glucose dependent insulin secretion.

• Xenatide suppress glucagon release and reduce appetite

• It is administered by SC injection.

Anti-diabetic drugsGlucagon like Peptide : GLP-1 analog : Xenatide : (Byetta) :

Endocrine pancreasGlucagon :• It has positive inotropic action and

chronotropic action on the heart.• It acts by stimulation of glucagon

receptors and not through beta 1 receptors.

• This is the basis for using glucagon in beta blocker overdose.