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Diabetes mellitus - Pharmacology

This document discusses diabetes mellitus and its treatment. It describes the four main types of diabetes: type 1, type 2, gestational diabetes, and other causes. It discusses the pathophysiology, clinical features, diagnosis, and management of the different types. The document also describes various insulin preparations including rapid-acting, short-acting, intermediate-acting, and long-acting insulins. It discusses oral hypoglycemic agents that increase insulin secretion like sulfonylureas.

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Diabetes Mellitus-1 By Dr. Tehreem Zulfiqar Assistant Professor Pharmacology Nishtar Medical University
Learning Outcomes By the end of this session you will be able to: •Describe pathophysiology of diabetes along with its important types •Enumerate different types of insulin •Classify oral hypoglycemic agents.
Diabetes Mellitus • “Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.” • The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
Criteria for Diagnosing Diabetes According to WHO diabetes is if : •Fasting Glucose =>7mmol or 126mg/dl •Random Glucose =>11.1mmol or 200mg/dl
Clinical Classification of Diabetes There are four clinical classifications of diabetes: •◦Type 1 diabetes (insulin dependent diabetes mellitus) •◦Type 2 diabetes (non-insulin dependent diabetes mellitus) •◦Gestational diabetes •◦Diabetes due to other causes (genetic defects or medications, etc)
Type 1 Diabetes Mellitus •Also known as Juvenile Onset Diabetes •Complete or near-total insulin deficiency •Occurs <30 years of age •Underweight patient
Etiology •T cell mediated autoimmune destruction of beta cells /glutamic acid decarboxylase antibodies (GAD Abs) •Genetic predisposition (HLA- DR3 DR4 genes) •30-50% concordance in identical twins •May be triggered by an invasion of viruses or the action of chemical toxins •Due to β-cell destruction pancreas fails to respond to glucose
Type 1 Diabetes Mellitus
Type 1 Diabetes Mellitus •Shows classic symptoms of insulin deficiency (polydipsia, polyphagia, polyuria, and weight loss) •Require exogenous (injected) insulin to control hyperglycemia and maintain blood glucose concentrations as close to normal as possible
Type 2 Diabetes Mellitus •Most common •• >40 years of age •• Normal or overweight •• Genetic factor •– Strongly positive
Type 2 Diabetes Mellitus Etiology Insulin resistance •Initially normal or increased insulin secretion or but later decreases. •β-cells are usually normal but disturbance is •*less active insulin production •*less cellular response to insulin due to deficiency of GLUT 4 transporter in insulin sensitive cells •*presence of antibodies against insulin
Type 2 Diabetes Mellitus •The goal in treating T2DM is to maintain blood glucose concentrations within normal limits and to prevent the development of long-term complications of the disease •◦Weight reduction, exercise, and dietary modification decrease insulin resistance and correct the hyperglycemia of type 2 diabetes in some patients
Type 2 Diabetes Mellitus •Most patients are dependent on pharmacologic intervention with oral glucose-lowering agents •As the disease progresses, β-cell function declines and insulin therapy is often required
Comparison of Type 1 and Type 2 Diabetes
Gestational Diabetes Mellitus •Gestational diabetes is defined as carbohydrate intolerance due to Insulin resistance with onset or first recognition during late pregnancy •It is important to maintain adequate glycemic control during pregnancy •Uncontrolled gestational diabetes can lead to fetal macrosomia(abnormally large body), shoulder dystocia(difficult delivery), and neonatal hypoglycemia
Gestational Diabetes Mellitus •Diet, exercise, and or insulin administration are effective in this condition •Glibenclamide (glyburide)and metformin may be safe alternatives to insulin therapy for gestational diabetes
Clinical Features of Diabetes Mellitus •Hyperglycemia •Glycosuria •Polyuria •Polydipsia •Polyphagia •Dehydration •Loss of weight •Poor resistance to infections due to protein depletion
Dietary modifications in diabetes Low fat and/or high fiber foods, which are generally encouraged for people with diabetes
Role of Exercise in Diabetes
Insulin Insulin is a storage hormone: •It promotes anabolism •Inhibits catabolism of carbohydrates, fatty acids and protein In the absence of insulin: •Most tissues cannot use glucose •Fats/proteins are broken down to provide energy
Insulin •Insulin is a polypeptide hormone consisting of two peptide chains connected by disulfide bonds •Synthesized as a precursor (proinsulin) that undergoes proteolytic cleavage to form insulin and C-peptide, both of which are secreted by the β cells of the pancreas
Insulin- Mechanism of Action •Insulin binds to insulin receptors on the plasma membrane and activates tyrosine kinase –primarily in adipose tissue, liver and skeletal muscle
Secretion of Insulin
Actions of Insulin
Actions of Insulin
Sources of Insulin •Human insulin is produced by recombinant DNA technology using E. coli or yeast altered genetically to contain the human insulin gene •Modifications of the amino acid sequence of human insulin have produced insulins with different PK properties
Types of Insulin Rapid acting and short acting insulin •Regular insulin (Humulin-R®, Actrapid®) •Insulin lispro(Humalog®) •Insulin aspart (Novorapid®) •Insulin glulisine Intermediate acting insulin •Neutral protamine Hagedorn(NPH) insulin suspension of crystalline zinc insulin combined at neutral pH with the positively charged polypeptide protamine •Insulin NPH is also called insulin isophane (HumulinN NPH®)
Types of Insulin Long acting insulin •Insulin glargine(Lantus®) •Insulin detemir Insulin combinations •70% NPH insulin plus 30% regular insulin (Humulin70/30®) •◦50% NPH insulin plus 50% regular insulin •◦75% NPL insulin plus 25% insulin lispro (HumalogMix®)
Oral hypoglycemic Agents
Introduction • These drugs lower blood glucose levels and are effective orally. • The chief drawback of insulin is—it must be given by injection.
Classification • Enhance Insulin secretion • 1.Sulfonylureas • First generation: Tolbutamide • Second generation: Glibenclamide, Glipizide, • 2.Meglitinide analogues • Repaglinide, Nateglinide • 3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs) • Exenatide, Liraglutide • 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors • Sitagliptin, Vildagliptin.
Classification • Overcome Insulin resistance • 1. Biguanide • Metformin • 2. Thiazolidinediones (PPAR activator) • Pioglitazone • Rosiglitazone
Miscellaneous antidiabetic drugs • α-Glucosidase inhibitors • Acarbose, Miglitol, Voglibose • Sodium-glucose cotransport-2 (SGLT-2) Inhibitor: Dapagliflozin
Summary
Diabetes Mellitus-2 By Dr. Tehreem Zulfiqar Assistant Professor Pharmacology Nishtar Medical University
Learning Outcomes By the end of this session you will be able to: •Describe different types of insulin in detail •Discuss important adverse effects associated with the use of insulin
Insulin Preparations •Rapidly acting insulin •Short acting insulin •Intermediate acting insulin •Long acting insulin •Insulin combinations
 These include following preparations: • Insulin lispro (Humalog®) • Insulin aspart • Insulin Glulisine (Novorapid®) Rapidly Acting Insulin Preparations
Rapidly Acting Insulin Preparations • Lispro, aspart and glulisine forms are classified as rapid-acting insulins because of their rapid onset and short duration of action •Rapid acting insulins offer more flexible treatment regimens and may lower the risk of hypoglycemia
Rapidly Acting Insulin Preparations • Insulin aspart and insulin glulisine have pharmacokinetic and pharmacodynamic properties similar to those of insulin lispro • Administered to mimic the prandial (mealtime) release of insulin •Usually not used alone but with a longer-acting insulin to ensure proper glucose control •Administered SC
• Insulin lispro is usually administered 15 minutes prior to a meal or immediately following a meal • Insulin glulisine can be taken either 15 minutes before a meal or within 20 minutes after starting a meal • Insulin aspart should be administered just prior to the meal or up to 15 minutes following the meal Rapidly Acting Insulin Preparations
Short Acting Insulin- Regular Insulin •A short-acting, soluble, crystalline zinc insulin; now made by recombinant DNA techniques. •Given subcutaneously •Given IV in emergencies •Rapidly lowers blood glucose levels
Short Acting Insulin- Regular Insulin •In high concentrations, eg, in the vial, regular insulin molecules self-aggregate in antiparallel fashion to form dimers that stabilize around zinc ions to create insulin hexamers. • The hexameric nature of regular insulin causes a delayed onset and prolongs the time to peak action.
• All of the rapid-acting formulations are suitable for IV administration, although regular insulin is most commonly used when the IV route is needed • Insulin lispro, insulin aspart, and insulin glulisine may also be used in external insulin pumps Rapidly Acting and Short Acting Insulin Preparations
• Neutral protamine Hagedorn (NPH) insulin suspension • Its duration of action is intermediate because of the delayed absorption from its conjugation with protamine forming a less-soluble complex • NPH insulin should only be given subcutaneously (never IV) Intermediately Acting Insulin
• Useful in treating all forms of diabetes except diabetic ketoacidosis and emergency hyperglycemia • Used for basal control and is usually given along with rapid- or short-acting insulin for mealtime control Intermediately Acting Insulin
 Insulin Glargine (Lantus®) •Insulin glargine is a soluble, “peakless” long-acting insulin analog. •The attachment of two arginine molecules to the B- chain carboxyl terminal and substitution of a glycine for asparagine at the A21 position created an analog •Given SC Long Acting Insulin Preparations
Long Acting Insulin Preparations •Insulin detemir •Most recently developed long-acting insulin analog. •Terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the terminal B29 lysine. •Insulin detemir and insulin glargine should not be mixed in the same syringe with other insulins
• Various premixed combinations of human insulins are available • 70% NPH insulin plus 30% (70/30®) regular insulin (Humulin • 50% NPH insulin plus 50% regular insulin • 75% NPL insulin plus 25% insulin lispro (Humalog Mix®)
• Standard treatment involves injection of insulin twice daily • Intensive treatment seeks to normalize blood glucose through more frequent injections of insulin (three or more times daily in response to monitoring blood glucose levels) Standard Treatment Versus Invasive Treatment
• The frequency of hypoglycemic episodes, coma, and seizures is higher with intensive treatment • Patients on intensive therapy show a significant reduction in long-term complications of diabetes as retinopathy, nephropathy, and neuropathy • Intensive therapy is not recommended for patients with longstanding diabetes, significant microvascular complications, advanced age, and hypoglycemic unawareness Standard Treatment Versus Invasive Treatment
• Insulin is degraded in the GIT if taken orally • Insulin is administered by subcutaneous injection • In a hyperglycemic emergency, regular insulin is injected IV • Continuous subcutaneous insulin infusion (insulin pump) does not require multiple daily injections Insulin Administration
• Dose, site of injection, blood supply, temperature, and physical activity can affect the duration of action of the various preparations • Insulin is inactivated by insulin-degrading enzyme (insulin protease) which is found mainly in the liver and kidney Insulin Administration
Insulin injection sites
• Symptoms of hypoglycemia in excessive dose • Lipodystrophy • Allergic reactions • Local injection site reactions • Diabetics with renal insufficiency may require adjustment of the insulin dose Adverse Effects of Insulin
Management of Hypoglycemia 1. Give simple sugar orally if pt. is conscious and can swallow – orange juice, candy, glucose tablets, lump of sugar 2. Give Glucagon (SC or IM) if pt. is unconscious or cannot take sugar by mouth 3. As soon as pt. regains consciousness, he should be given carbohydrate by mouth 4. If pt. does not respond to the above measures, he is given 50 ml of 50% glucose I.V. or 1000 ml of 5%-10% glucose in water I.V.
Preventing Hypoglycemic Reactions Due to Insulin Instruct the pt. as follows: 1. Hypoglycemia may be prevented by maintaining regular exercise, diet and insulin 2. Early symptoms of hypoglycemia should by recognized and treated 3. Carry at all times some form of simple carbohydrate (orange juice, sugar, candy) 4. Extra food should be taken before unusual physical activity or prolonged periods of exercise 5. Between-meal and bedtime snacks may be necessary to maintain a normal glucose level.
Exercise •A 13-year-old boy with type 1 diabetes is brought to the hospital complaining of dizziness. Laboratory findings include severe hyperglycemia, ketoacidosis, and a blood pH of 7.15. A rapidly acting insulin preparation is being used for the management. •Which of the following is the most likely complication of insulin therapy in this patient? •(A) Dilutional hyponatremia •(B) Hypoglycemia •(C) Increased bleeding tendency •(D) Pancreatitis •(E) Severe hypertension
Key •Answer is B
Summary
INSULIN ROUTE Ultra rapid acting Insulin analog/ Short- Acting (Humalog) IV/SC PRANDIAL/ SUPPLEMENTAL Rapid acting: Regular (Semilente) IV/SC PRANDIAL/ SUPPLEMENTAL Intermediate: NPH (Lente) SC BASAL Long acting: Protamine Zinc (Ultralente) SC BASAL
Diabetes Mellitus-3 By Dr. Tehreem Zulfiqar Assistant Professor Pharmacology Nishtar Medical University
Learning Outcomes By the end of this session you will be able to: •Describe oral hypoglycemic agents in detail •Discuss newer parenteral agents used for type 2 diabetes
• Useful in the treatment of patients who have type 2 diabetes and cannot be managed by diet alone • Patients who have developed diabetes after age 40 and have had diabetes less than 5 years are most likely to respond well to oral glucose-lowering agents • Oral glucose-lowering agents should not be given to patients with type 1 diabetes Oral Hypoglycemic agents
Agents that Increase Insulin Secretion
Sulfonylureas • First generation : Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide • Second generation : Glipizide, Glyburide • more potent, more efficacious and fewer adverse effects. • Third generation : Glimiperide
• Promote insulin release from the β cells of the pancreas Mechanism of action: • Stimulation of insulin release from the β cells of the pancreas by blocking the ATP-sensitive K+ channels, resulting in depolarization and Ca2+ influx • Reduction in hepatic glucose production • Increase in peripheral insulin sensitivity Sulfonylureas
Adverse effects: • Weight gain • Hyperinsulinemia • Hypoglycemia • Should be used with caution in patients with hepatic or renal insufficiency, because drug accumulation may cause hypoglycemia • Glibenclamide has minimal transfer across the placenta and may be a safe alternative to insulin therapy in pregnancy Sulfonylureas
• Repaglinide • Nateglinide Mechanism of action: • Like the sulfonylureas, their action is dependent on functioning pancreatic β cells • Same mechanism of action as sulfonylureas • Categorized as postprandial glucose regulators; they are particularly effective in early release of insulin after a meal Glinides
• The glinides have a rapid onset and a short duration of action • Combined therapy of these agents with metformin or the glitazones is better than monotherapy in improving glycemic control • Glinides should not be used in combination with sulfonylureas (overlapping MOA) • Well absorbed orally • Excreted in bile Glinides
• Hypoglycemia (lower incidence than sulfonylureas) • Weight gain (less than with sulfonylureas) • Must be used with caution in patients with hepatic impairment Glinides- Adverse effects
• Amylin is a hormone produced by beta cells of pancrease that works by delaying gastric emptying, decreasing postprandial glucagon secretion, and improving satiety • Administered SC and should be injected immediately prior to meals • Pramlintide may not be mixed in the same syringe with any insulin preparation • Used as an adjunct to mealtime insulin therapy in patients with type 1 and type 2 diabetes Synthetic Amylin Analog: Pramlintide
Incretin Modulators These include: 1. Glucagon-like peptide-1 (GLP-1) analogs: Exanatide 2. DPP-4 inhibitor: Sitagliptin
• Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones, which are released from endocrine cells in the epithelium of the bowel in response to food. • The incretins augment glucose-stimulated insulin release from pancreatic B cells, retard gastric emptying, inhibit glucagon secretion, and produce a feeling of satiety. Glucagon-like peptide-1 (GLP-1) analogs: Exanatide
• These agents may be used as adjunct therapy in patients who have failed to achieve adequate glycemic control on a sulfonylurea, metformin, a glitazone, or a combination of them • Administered subcutaneously • Exenatide should be injected twice daily within 60 minutes prior to morning and evening meals • Exenatide should be avoided in patients with severe renal impairment Glucagon-like peptide-1 (GLP-1) analogs: Exanatide
•Sitagliptin (Januvia®) • Vildagliptin (Galvus®) • Orally active DPP-4 inhibitors used for the treatment of patients with type 2 diabetes • Combinations with metformin are available Dipeptidyl peptidase-IV (DPP-4) Inhibitors
Mechanism of action • Inhibit the enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as GLP-1 • Prolonging the activity of incretin hormones results in increased insulin release in response to meals and reduction in glucagon secretion Dipeptidyl peptidase-IV (DPP-4) Inhibitors
• Majority of DPP-4 inhibitors are excreted in urine therefore dosage adjustment is required in renal impairment • Adverse effects • Nasopharyngitis • Headache • Pancreatitis has occurred with sitagliptin Dipeptidyl peptidase-IV (DPP-4) Inhibitors
• Insulin sensitizers improve insulin action • Lower blood sugar by improving target-cell response to insulin without increasing pancreatic insulin secretion. These include: • Biguanides • Thiazolidinediones Insulin Sensitizers
• Metformin (Glucophage®) • Increases glucose uptake and use by target tissues, decreasing insulin resistance • Does not promote insulin secretion (hyperinsulinemia is not a problem) • The risk of hypoglycemia is less than with sulfonylureas Biguanides- Metformin
Mechanism of action: • Reduces hepatic glucose output by inhibiting hepatic gluconeogenesis • Slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization • The patient commonly loses weight because of loss of appetite Biguanides- Metformin
• The ADA recommends metformin as the drug of choice for newly diagnosed type 2 diabetics • Well absorbed orally • Metformin may be used alone or in combination with one of the other agents as well as with insulin • Hpoglycemia may occur when metformin is taken in combination with insulin • Excreted in urine Biguanides- Metformin
• GI adverse effects • Metformin is contraindicated in diabetic patients with renal and/or hepatic disease and in those with diabetic ketoacidosis • Rarely fatal lactic acidosis has occurred • Long-term use may interfere with vitamin B12 absorption Metformin Adverse effects