Comprehensive Overview of Anti-Diabetic Drugs and Insulin Therapies

Comprehensive Overview of Anti-Diabetic Drugs and Insulin Therapies

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  ANTI-DIABETIC DRUGS Professor G. Gurgenidze
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  CLASSIFICATION
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  INSULIN PREPARATIONS Pharmaceutical InsulinPreparations Human insulin is manufactured by bacterial recombinant DNA technology. The available forms provide 4 rates of onset and durations of effect that range from rapid-acting to long-acting. The goals of insulin therapy are to control both basal and postprandial (after a meal) glucose levels while minimizing the risk of hypoglycemia. Insulin formulations with different rates of onset and effect are often combined to achieve these goals.
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  1. RAPID-ACTING Three insulinanalogs:  insulin lispro,  insulin aspart,  insulin glulisine have rapid onsets and early peaks of activity that permit control of postprandial glucose levels. The 3 rapid-acting insulins have small alterations in their primary amino acid sequences that speed their entry into the circulation without affecting their interaction with the insulin receptor. The rapid-acting insulins are injected immediately before a meal and are the preferred insulin for continuous subcutaneous infusion devices. They also can be used for emergency treatment of uncomplicated diabetic ketoacidosis. Adverse effects:  Hypoglycemia: dizziness, headache, hunger, sweating, weakness, irritability, tremors, increased heart rate, rapid breathing, blurred vision, trouble concentrating, and loss of consciousness.  Inflammation at the site of injection  Increased appetite Dosage: With meals: The dosage for rapid- acting insulin taken with a meal typically is based on a ration of insulin to carbohydrates in that meal—most commonly, one unit of insulin per 12 to 15 grams of carbs. To bring down overly high glucose levels: In general, one unit of rapid- acting insulin is needed to lower blood sugar by 50 mg/dl.
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  2. SHORT-ACTING Regular insulinis used intravenously in emergencies (eg, diabetic ketoacidosis) or administered subcutaneously in ordinary maintenance regimens, alone or mixed with intermediate- or long-acting preparations. Before the development of rapid-acting insulins, it was the primary form of insulin used for controlling postprandial glucose concentrations, but it requires administration 1 h or more before a meal. Adverse effects common  Bumps, pits, swelling, redness or itching at the injection site.  Muscle pain.  Weight gain.  Swelling of your arms and legs  Low blood sugar (hypoglycemia)  Injection site reactions: redness, swelling, itching Serious  Severe low blood sugar.  Low blood potassium (hypokalemia)  Serious allergic reaction  Heart failure Dosage: Child dosage (ages 0–17 years) - between 0.7 and 1 unit/kg per day. Adult dosage (ages 18–64 years) - between 0.2 and 0.4 unit/kg per day. Senior dosage (ages 65 years and older) - lower dosage so that too much of this drug doesn’t build up in the body
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  3. INTERMEDIATE-ACTING Neutral protamineHagedorn insulin (NPH insulin) is a combination of regular insulin, protamine (a highly basic protein also used to reverse the action of unfractionated heparin) and zinc, that exhibits a delayed onset and peak of action. NPH insulin is often combined with regular and rapid- acting insulins. NPH insulin has a peak effect that occurs between 4 - 10 hours after dosing. Because of this, NPH carries a higher risk of hypoglycemia. In addition, NPH's duration of effect is around 16 - 20 hours, which is shorter than the 24+ hours seen with long-acting insulins. This means NPH often has to be dosed twice daily to achieve sustained control over 24 hours.. Adverse effects: Common: - low blood sugar, - weight gain, - swelling in the hands or feet, - itching, - mild skin rash, - thickening or hollowing of the skin at the injection site - redness or swelling at the injection site Dosage: - Nonobese may require 0.4-0.6 unit/kg/day - Obese may require 0.8-1.2 units/kg/day Serious: - itchy skin rash over the entire body, - trouble breathing, - chest tightness, - lightheadedness, - swelling of the tongue or throat,
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  4. LONG-ACTING  Insulinglargine,  insulin detemir,  insulin degludec modified forms of human insulin that provide a peakless basal insulin level lasting more than 20 h, which helps control basal glucose levels without producing hypoglycemia. Adverse Effects:  low blood sugar (hypoglycemia): dizziness, Chills, blurred vision, Weakness, Headache, fainting  pain, redness, or swelling at the injection site  insulin with thiazolidinediones increases the risk of fluid retention and heart failure.  Degludec: precautions may be necessary because of its long effect in the body Dosage: 0.5 to 1.0 unit per kg per day. It can be administered once daily at bedtime or, ideally, twice daily in addition to another type of insulin
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  5. INSULIN DELIVERYSYSTEMS The standard mode of insulin therapy is subcutaneous injection with conventional disposable needles and syringes. More convenient means of administration are also available, such as inhaled insulin. Portable pen-sized injectors are used to facilitate subcutaneous injection. Some contain replaceable cartridges, whereas others are disposable. Continuous subcutaneous insulin infusion devices avoid the need for multiple daily injections and provide flexibility in the scheduling of patients’ daily activities. Programmable pumps deliver a constant 24-h basal rate, and manual adjustments in the rate of delivery can be made to accommodate changes in insulin requirements (eg, before meals or exercise). An artificial pancreas system that measures glucose and adjusts insulin pump delivery was approved in 2017.
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  NON-INSULIN ANTIDIABETIC DRUGS Severalgroups of oral antidiabetic drugs are used most commonly to treat type 2 diabetes. These include 1. insulin secretagogues, (1*) 2. the biguanide metformin, 3. thiazolidinediones, 4. Incretins, 5. Alpha glucosidase inhibitors (2*) 6. renal glucose reuptake inhibitors (2*) Control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. When the extracellular glucose concentration increases, more glucose enters the cell via the GLUT2 glucose transporter and leads, through metabolism, to increased intracellular ATP production with subsequent closure of ATP-dependent K+ channels, membrane depolarization, opening of voltage-gated Ca2+ channels, increased intracellular Ca2+, and insulin secretion. Sulfonylurea and other insulin secretagogues enhance insulin release by blocking ATP-dependent K+ channels and thereby triggering the events subsequent to reduced K+ influx. 1* 2*
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  SECRETAGOGUES Mechanism and effects—Insulinsecretagogues stimulate the release of endogenous insulin by promoting closure of potassium channels in the pancreatic B-cell membrane . Channel closure depolarizes the cell and triggers insulin release. Insulin secretagogues are not effective in patients who lack functional pancreatic B cells (type 1 diabetes). Most insulin secretagogues are in the chemical class known as sulfonylureas. The second-generation sulfonylureas (glyburide, glipizide, glimepiride) are considerably more potent and used more commonly than the older agents (tolbutamide, chlorpropamide, others). Repaglinide, a meglitinide, and nateglinide, a d-phenylalanine derivative, are also insulin secretagogues. Both have a rapid onset and short duration of action that make them useful for administration just before a meal to control postprandial glucose levels. Toxicities—The insulin secretagogues, especially those with a high potency (eg, glyburide and glipizide), can precipitate hypoglycemia, although the risk is less than that associated with the insulins. The older sulfonylureas (tolbutamide and chlorpropamide) are extensively bound to serum proteins, and drugs that compete for protein binding may enhance their hypoglycemic effects. Occasionally these drugs cause rash or other allergic reactions. Weight gain is common and is especially undesirable in the large fraction of patients with type 2 diabetes who already are overweight.
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  BIGUANIDES 1. Mechanism andeffects Metformin, the primary member of the biguanide group, reduces postprandial and fasting glucose levels. Biguanides inhibit hepatic and renal gluconeogenesis . Other effects include: - stimulation of glucose uptake and glycolysis in peripheral tissues, - slowing of glucose absorption from the gastrointestinal tract, - reduction of plasma glucagon levels. The molecular mechanism of biguanide reduction in hepatic glucose production appears to involve activation of an AMP- stimulated protein kinase. In patients with insulin resistance, metformin reduces endogenous insulin production presumably through enhanced insulin sensitivity. Because of this insulin-sparing effect and because it does not increase weight—unlike insulin, secretagogues, or the thiazolidinediones—metformin is increasingly the drug of first choice in overweight patients with type 2 diabetes. Recent clinical trials suggest that metformin reduces the risk of diabetes in high- risk patients. Metformin is also used to restore fertility in anovulatory women with polycystic ovary disease (PCOD) and evidence of insulin resistance. 2. Toxicities—Unlike the sulfonylureas, the biguanides do not cause hypoglycemia. Their most common toxicity is gastrointestinal distress (nausea, diarrhea), and they can cause lactic acidosis, especially in patients with renal or liver disease, alcoholism, or conditions that predispose to tissue anoxia and lactic acid production (eg, chronic cardiopulmonary dysfunction).
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  THIAZOLIDINEDIONES Mechanism and effects— Thethiazolidinediones, rosiglitazone and pioglitazone, increase target tissue sensitivity to insulin by activating the peroxisome proliferator- activated receptor-gamma nuclear receptor (PPAR-γ receptor). This nuclear receptor regulates the transcription of genes encoding proteins involved in carbohydrate and lipid metabolism. A primary effect of the thiazolidinediones is increasing glucose uptake in muscle and adipose tissue. They also inhibit hepatic gluconeogenesis and have effects on lipid metabolism and the distribution of body fat. Thiazolidinediones reduce both fasting and postprandial hyperglycemia. They are used as monotherapy or in combination with insulin or other oral antidiabetic drugs. Like metformin, the thiazolidinediones have been shown to reduce the risk of diabetes in high-risk patients. Pioglitazone also lowers triglycerides and increases HDL. Toxicities When these drugs are used alone, hypoglycemia is extremely rare. Thiazolidinediones can cause fluid retention, which presents as mild anemia and edema and may increase the risk of heart failure. Recent data have linked rosiglitazone to increased risk of myocardial infarction. The original thiazolidinedione (troglitazone) was removed from the market in several countries because of hepatotoxicity. Rosiglitazone and pioglitazone have not been linked to serious liver dysfunction but still require routine monitoring of liver function. Female patients taking thiazolidinediones appear to have an increased risk of bone fractures. Pioglitazone and troglitazone induce cytochrome P450 activity (especially the CYP3A4 isozyme) and can reduce the serum concentrations of drugs that are metabolized by these enzymes (eg, oral contraceptives, cyclosporine).