Oral antidiabetics

Oral agents:
1. Oral agents: Insulin secretagogues
Useful for:
• Type 2 diabetes that cannot be managed by diet alone.
• Patients who have developed diabetes after age 40 and have had diabetes less than 5 years are those most likely to respond well to oral glucose-lowering agents.
• Patients with long-standing disease may require a combination of glucose-lowering drugs with or without insulin to control their hyperglycemia.
Notes:
1. Insulin is added because of the progressive decline in ? cells that occur due to the disease or aging.
2. Oral glucose-lowering agents should not be given to patients with
type1 diabetes

A. Sulfonylureas (SUs)
These agents are classified as insulin secretagogues, because they promote
insulin release from the ? cells of the pancreas. The primary drugs used today are tolbutamide (1st generation) & the 2nd generation drugs glyburide (glibenclamide), glipizide & glimepiride.

Mechanism of action:
1) Stimulation of insulin release from the ? cells of the pancreas by blocking
the ATP-sensitive K+ channels, resulting in depolarization & Ca2+ influx;
2) Reduction in hepatic glucose production
3) Increase in peripheral insulin sensitivity.

Pharmacokinetics and fate:
• Bind to serum proteins, metabolized by the liver, and excreted by the liver or kidney.
• Duration of action is the shortest for Tolbtamide (6-12 hours), while that of 2nd generation is ranged from 12 to 24 hours.

Adverse effects:
• Propensity to cause weight gain, hyperinsulinemia & hypoglycemia.
• Used with caution in patients with hepatic or renal insufficiency.
• 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 during pregnancy.

Drug interaction:
1- Phenylbutazone, Salicylates & Sulfonamides displace SUs from plasma
Proteins.
2- Allopurinol, Probenecid, Salicylates & Sulfonamides decrease urinary
excretion of SUs or their metabolism.
3- Dicuramol, Chloramphenicol, Monoamine oxidase inhibitors,
Phenylbutazone, reduce hepatic metabolism of SUs.


B. Glinides (Meglitinides)
They include Repaglinide & Nateglinide.
Although they are not SUs, they have common actions.

Mechanism of action:
• Their action is dependent on functioning pancreatic ? cells.
• Bind to a distinct site on the SUs receptor of ATP-sensitive potassium channels
• In contrast to SUs, glinides have a rapid onset & a short duration of action.
• Effective in the early release of insulin that occurs after a meal & are categorized as postprandial glucose regulators.
• Combined therapy of these agents with metformin or the glitazones has been shown to be better than monotherapy with either agent in improving glycemic control.
• Glinides should not be used in combination with SUs due to overlapping mechanisms of action.

Pharmacokinetics and fate:
• Well absorbed orally after being taken 1 to 30 minutes before meals.
• Both glinides are metabolized to inactive products by cytochrome P450 in the liver & are excreted through the bile.

Adverse effects:
• Incidence of hypoglycemia is lower than that with SUs.
• Repaglinide effect may enhance by ketoconazole, itraconazole, fluconazole, erythromycin & clarithromycin, whereas opposed by other drugs, such as barbiturates, carbamazepine & rifampin.
• Repaglinide has been reported to cause severe hypoglycemia when taken concomitantly with gemfibrozil (lipid-lowering drug) & concurrent use is contraindicated.
• Weight gain is less than with the SUs.
• Used with caution in patients with hepatic impairment.

2. Oral agents: Insulin sensitizers
• Two classes biguanides & thiazolidinediones.
• They lower blood sugar by improving target-cell response to insulin without increasing pancreatic insulin secretion.

A. Biguanides: Metformin
• The only currently available biguanide.
• It increases glucose uptake & use by target tissues, thereby decreasing insulin resistance.
• Does not promote insulin secretion thus, the risk of hypoglycemia is far less than that with SUs. .
• Hypoglycemia may only occur if caloric intake is not adequate or exercise is not compensated for calorically.
Mechanism of action:
1. Main mechanism is the reduction of hepatic glucose output, largely by inhibiting hepatic gluconeogenesis.

Note: Excess glucose produced by the liver is a major source of high blood glucose in type 2 diabetes, accounting for the high blood glucose on
waking in the morning.
2. Also it slows intestinal absorption of sugars & improves peripheral glucose uptake & utilization.
3. An important property of this drug is its ability to modestly reduce hyperlipidemia (LDL & VLDL cholesterol concentrations fall & HDL cholesterol rises).
• These effects may not be apparent until 4 to 6 weeks of use.
• The patient commonly loses weight because of loss of appetite.
• It is recommended as the drug of choice for newly diagnosed type 2 diabetics.
• Metformin may be used alone or in combination with one of the other agents as well as with insulin.
• Hypoglycemia may occur when metformin is taken with insulin (dose of insulin may require adjustment because metformin decreases the production of glucose by the liver).

Pharmacokinetics and fate:
• Well absorbed orally, is not bound to serum proteins and is not metabolized.
• Excretion is via the urine.

Adverse effects:
• Largely are gastrointestinal.
• Metformin is contraindicated in presence of renal and/or hepatic disease and diabetic ketoacidosis.
• It should be discontinued in cases of acute MI, exacerbation of CHF & severe infection.
• Used with caution in patients older than age 80 years & in those with a history of CHF or alcohol abuse (note: diabetics being treated with HF medications should not be given metformin because of an increased risk of lactic acidosis).
• Should be temporarily discontinued in patients undergoing diagnosis requiring IV radiographic contrast agents.
• Rarely, potentially fatal lactic acidosis has occurred.
• Long-term use may interfere with vitamin B12 absorption.

Other uses:
Effective in the treatment of polycystic ovary disease. Its ability to lower insulin resistance in these women can result in ovulation and, therefore, possibly pregnancy.

B. Thiazolidinediones (TZDs) (glitazones)
• They do not promote insulin release from the pancreatic ? cells, so hyperinsulinemia is not a risk.
• Troglitazone was the first TZD but was withdrawn after a number of deaths from hepatotoxicity.
• The two members of this class currently available are pioglitazone
& rosiglitazone.

Mechanism of action:
• Exact mechanism by which the TZDs lower insulin resistance remains to be elucidated, but they are known to target the peroxisome proliferator–activated receptor-? (PPAR?), a nuclear hormone receptor.
• Ligands for PPAR? regulate adipocyte production & secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver & skeletal muscle.
• Hyperglycemia, hyperinsulinemia, hypertriglyceridemia & elevated HbA1c levels are improved.
• LDL levels are neither affected by pioglitazone monotherapy nor when the drug is used in combination with other agents, whereas LDL levels have increased with rosiglitazone.
• Both drugs increase HDL levels.
• Pioglitazone & rosiglitazone can be used as monotherapy or in combination with other glucose-lowering agents or insulin (insulin dose should be lowered).
• Pioglitazone is recommends as a 2nd -line alternative for patients who fail or have contraindications to metformin therapy.
• Rosiglitazone is not recommended due to concerns regarding cardiac adverse effects.

Pharmacokinetics and fate:
• Both pioglitazone & rosiglitazone are well absorbed after oral administration & are extensively bound to serum albumin.
• Both undergo extensive metabolism by different CYP450 isozymes.
• Some metabolites of pioglitazone have activity.
• Renal elimination of pioglitazone is negligible, with the majority of the active drug & metabolites excreted in the bile & eliminated in the feces.
• The metabolites of rosiglitazone are primarily excreted in the urine.
• No dosage adjustment is required in renal impairment.
• It is recommended that these agents not be used in nursing mothers.

Adverse effects:
• Due to deaths from hepatotoxicity in patients take troglitazone it is recommended that liver enzyme levels of patients on these medications be measured initially and periodically thereafter.
• Very few cases of liver toxicity have been reported with rosiglitazone or pioglitazone.
• Weight increase can occur, possibly because TZDs may increase SC fat or cause fluid retention(can lead to or worsen heart failure).
• TZDs have been associated with osteopenia & increased fracture risk.
• Increased risk of MI & death from CV causes with rosiglitazone has been identified.
• Other adverse effects of the TZDs include headache & anemia.
• TZDs reduce plasma concentration of the estrogen-containing contraceptives & pregnancy may occur.

Other uses:
Relief of insulin resistance with the TZDs can cause ovulation to resume in premenopausal women with polycystic ovary syndrome.

3. Oral agents: ?- Glucosidase inhibitors
Acarbose & miglitol
Orally active drugs used for the treatment of patients with type 2 diabetes.

Mechanism of action
• Taken at the beginning of meals.
• Act by delaying the digestion of carbohydrates, thereby resulting in lower postprandial glucose levels.
• They reversibly inhibit membrane-bound ?- glucosidase in the intestinal brush border (an enzyme responsible for the hydrolysis of oligosaccharides to glucose & other sugars).
• Acarbose also inhibits pancreatic ?- amylase, thereby interfering with the breakdown of starch to oligosaccharides.
• Consequently, the postprandial rise of blood glucose is blunted.
• They neither stimulate insulin release nor increase insulin action in target tissues. Thus, as monotherapy, they do not cause hypoglycemia.
• However, when used in combination with the SUs or with insulin, hypoglycemia may develop.
Note: It is important that the hypoglycemic patient be treated with glucose rather than sucrose, because sucrase is also inhibited by these drugs.

Pharmacokinetics and fate
• Acarbose is poorly absorbed, metabolized primarily by intestinal bacteria, & some of the metabolites are absorbed & excreted into the urine.
• Miglitol is very well absorbed but has no systemic effects, excreted unchanged by the kidney.

Adverse effects
• The major side effects are flatulence, diarrhea & abdominal cramping.
• Patients with inflammatory bowel disease, colonic ulceration, or
intestinal obstruction should not use these drugs.

4. Oral agents: Dipeptidyl peptidase - IV inhibitors
Sitagliptin
• Orally active dipeptidyl peptidase-IV (DPP-IV) inhibitors used for the treatment of patients with type 2 diabetes.
• Other agents in this category are currently in development.

Mechanism of action
• Inhibits the enzyme DPP-IV, which is responsible for the inactivation of incretin hormones such as glucagon-like peptide-1 (GLP-1).
• Incretin hormones in turn, increase insulin release in response to meals & reduce inappropriate secretion of glucagon.
• DPP-IV inhibitors may be used as monotherapy or in combination with a SU, metformin, glitazones or insulin.

Pharmacokinetics and fate
• Well absorbed after oral administration.
• Absorption does not affect by food.
• Majority of sitagliptin is excreted unchanged in the urine.
• Dosage adjustments is recommended for patients with renal dysfunction.

Adverse effects
• Well tolerated, with the most common adverse effects being nasopharyngitis & headache.
• As monotherapy or in combination with metformin or pioglitazone, the rates of hypoglycemia are comparable to those with placebo.

Incretin mimetics
• Oral glucose results in a higher secretion of insulin than occurs when an
equal load of glucose is given IV.
• This effect is referred to as the “incretin effect” & is markedly reduced in type 2 diabetes.
• The incretin effect occurs because the gut releases incretin hormones, notably GLP-1 & gastric inhibitory polypeptide, in response to a meal.
• Incretin hormones are responsible for 60 - 70 % of postprandial insulin secretion.

Exenatide
• Injectable (SC) incretin mimetics used for the treatment of patients with type 2 diabetes.
• Used as adjunct therapy in patients who have failed to achieve adequate glycemic control on SU, metformin, glitazone or their combination.

Mechanism of action
• Analogs of GLP-1, acting as GLP-1 receptor agonists & thus it
1. Improves glucose- dependent insulin secretion.
2. Slows gastric emptying time, decrease food intake.
3. Decreases postprandial glucagon secretion.
4. Promotes ?-cell proliferation.
• Consequently, weight gain & postprandial hyperglycemia are reduced & HbA1c levels decline.

Pharmacokinetics and fate
• Being polypeptide, exenatide must be administered
SC.
• Because of its short duration of action, exenatide should be injected
twice daily within 60 minutes prior to morning & evening meals.
• A once-weekly preparation is under investigation.
• Should be avoided in patients with severe renal impairment.


Adverse effects
• Similar to pramlintide, they consist of nausea, vomiting, diarrhea.