IUO Diabetes Mellitus yr 5 2022.pptx

IUO Diabetes Mellitus yr 5 2022.pptx

• 1.
  Pharmacotherapeutics of Diabetes Mellitus DrJS SONI Ph D, FPCPharm. Dept. of Clinical Pharmacy & Pharmacy Practice. Igbinedion University Okada. Yr 5, 2022
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  MODES of TREATMENT •All diabetics irrespective of other treatment require some control of their eating and exercise patterns • Dibetics must watch their - total caloric intake -types of nutrients and eating schedule 50% of patients may require only diet Another 25% would need to augment their natural insulin with drugs while the remainder will need insulin.
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  Modes of treatmentThediabetic diet. • Diet recommendations include - discouraging fats - encouraging complex carbohydrate and fibre - The recommended diabetic diet except in a few respects is now similar to the normal healthy diet that everyone should eat. i.e regular meals, low in fats, low simple sugars, low in sodium and high in complex carbohydrate (starch) and fibre
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  Modes of treatmentExercise. • Exercise - Reduces blood glucose and increases high density lipoprotein (HDL) cholesterol levels, - reduces the risk of developing coronary heart disease - decreases stress and makes patients feel better - it also helps prevent weight gain
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  Modes of treatmentExercise • Patients should strive to - exercise everyday - realize that exercise reduces blood glucose levels hence they must either reduce their insulin dosage or consume extra calories before they exercise. They should also be aware that insulin is absorbed and peaks more rapidly during exercise especially when injected into the leg
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  Modes of treatmentInsulin •Human insulin is often preferred in initiating insulin therapy because it is less antigenic than animal derived insulin. Insulin preparation onset of action peak (h) duration (h) Rapid acting insulin 5-15min 1-2 4-5 Lispro (Humalog) Aspart (Novolog) GLulisine (Apidra) Short acting insulin Regular (R) (Humulin, Novolin) 30min-1h 2-4 8-10 Intermediate acting NPH ( Humulin N) 1-2h 5-7 13-18 Long acting Glargine (lanctus) 1-2h Rel. Flat up to 24 Determir (Levemir) 2-4h 8 -12h 6-20
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  Initial Insulin dosagein T1DM • 0.5 U/kg/day with negative to moderate ketones • 0.7 U/kg/day with large ketones
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  Case 1 • 14yrs old, • 3Ps & weight loss – 10 days duration • RBS 418 mg % • 36 kg wt • No marked dehydration • T1DM- No ketoacidosis • Proceed?
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  Case 1 • (0.5U/kg/day with negative to moderate ketones) • 36 kg wt • No ketoacidosis • 36 X 0.5 = 18 U/day
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  18 U/day as“Four-shot-per-day” • Basal-Bolus therapy • Ideal for better control & flexible lifestyle • 50% Basal dose= 9 U at bedtime (NPH,G,D) • 50% Bolus dose = 9 U premeals (R,A,L,Glu) 3U Prebreakfast 3U Prelunch 3U Predinner
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  18 U/day as“Five-shot-per-day” • Basal-Bolus therapy • Ideal for better control & flexible lifestyle but “too many shots” • 50% Basal dose= 9 U divided as 5 U prebreakfast + 4 U at bedtime (G or D) • 50% Bolus dose = 9 U premeals (R,A,L,Glu) 3U Prebreakfast 3U Prelunch 3U Predinner
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  18 U/day as“Two-shot-per-day” Split mixed regimen • 2/3 prebreakfast (12 U) • 1/3 predinner (6 U) • Prebreakfast: 8 U NPH + 4 U Regular (A,L,G) • Predinner: 3 U NPH + 3 U Regular “8 N/4 R - 0 - 3N/3R”
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  18 U/day as“Three-shot-per-day” • 2/3 prebreakfast (12 U) • 8 U NPH + 4 U Regular (A,L,Glu) • 1/3 peridinner (6 U) • 3 U Regular ( or A,L,Glu) Predinner • 3 U NPH at bedtime
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  How to initiateinsulin treatment in type 2 • Start with 0.2 units / kg (or) • Body weight divided by 5 (or) • Dose = FBS-50 (or) 10 • Average fasting blood sugar divided by 18
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  Sites of Injection •Insulin can be given IV, IM or SC. • Into the following sites - the abdomen - Arm - Hip (buttocks) - and thigh. (The rate of absorption is fastest from the abdomen, intermediate from the arm and slowest from the thigh).
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  Rotation of injectionsites. • Previously patients were advised to rotate injection sites between the aforementioned sites but this has been shown to cause altered glucose control due rate of absorption differences. Now it is recommended that insulin injection be rotated within the same anatomical region to avoid this effect
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  Anti diabetic drugs •In Part 2
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  DRUG GROUPS Antidiabetic agents Insulin secretagogues Sulfonylureas Meglitinide analogue Insulinsensitizers Biguanides Thiazolidinediones (TZD) α-glucosidase inhibitors Dipeptidyl Peptidase-IV inhibitors
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  Adverse effects oforal Antidiabetic drugs Meglitinide Sulfonylureas Hypoglycemia Biguanides α-Glucosidase inhibitors GI disturbance Biguanides Nausea Thiazolidinediones Risk of hepatotoxicity Sulfonylureas Meglitinides Thiazolidinediones Weight gain
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  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 antidiabetics 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 antidiabetic drugs with or without insulin to control their hyperglycemia. • Oral antidiabetic agents should NOT be given to patients with Type 1 diabetes.
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  A. Sulfonylureas • Theseagents 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 (glibenclamide), glipizide, and glimepiride.
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  A. Sulfonylureas • Mechanismof 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.
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  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
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  A. Sulfonylureas • AdverseEffects: • 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/ glibenclamide has minimal transfer across the placenta and may be a reasonably safe alternative to insulin therapy for diabetes in pregnancy.
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  B. Meglitinide analogs •This class of agents includes repaglinide and nateglinide. Although they are not sulfonylureas, they have common actions.
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  B. Meglitinide analogs •Mechanism of action: • Their action is dependent on functioning pancreatic β cells. • They bind to a distinct site on the sulfonylurea receptor of ATP- sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin. • However, in contrast to the sulfonylureas, the meglitinides have a rapid onset and a short duration of action. • They are are categorized as postprandial glucose regulators. • Meglitinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action.
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  B. Meglitinide analogs •Pharmacokinetics: • These drugs are well absorbed orally after being taken 1 to 30 minutes before meals. • Both meglitinides are metabolized to inactive products by CYP3A4 in the liver. • Excreted through the bile.
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  B. Meglitinide analogs •Adverse Effects: • Incidence of hypoglycemia is lower than that of the sulfonylureas. • Repaglinide has been reported to cause severe hypoglycemia in patients who are also taking the lipid-lowering drug gemfibrozil. • Weight gain is less of a problem with the meglitinides than with the sulfonylureas. • Must be used with caution in patients with hepatic impairment.
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  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.
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  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
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  A. Biguanides • Mechanismof 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.
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  A. Biguanides • Pharmacokinetics: •Metformin is well absorbed orally, is not bound to serum proteins • It is not metabolized • Excretion is via the urine.
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  A. Biguanides • Adverseeffects: • 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.
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  B. Thiazolidinediones • Anothergroup 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.
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  B. Thiazolidinediones • Mechanismof 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.
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  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.
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  B. Thiazolidinediones • AdverseEffects: • 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.
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  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.
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  α-glucosidase inhibitors • Acarboseand miglitol are orally active drugs used for the treatment of patients with Type 2 diabetes.
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  α-glucosidase inhibitors • Mechanismof 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.
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  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.
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  α-glucosidase inhibitors • Adverseeffects: • 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.
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  4) Dipeptidyl peptidase-4inhibitor • 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.
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  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.
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  Sitagliptin • Mechanism ofaction: • 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.
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  Sitagliptin • Pharmacokinetics: • Sitagliptinis 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.
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  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.
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  • Thank you