Endo Outline

Clinical Pharmacology II - Endocrinology

Instructor Information

• Adam Wood, Pharm.D., DABAT

Instructional Objectives

• IO129: Define the basic pharmacokinetic processes of absorption, distribution, metabolism, excretion, and factors that may alter pharmacokinetics for endocrinology medications (B2.02d)

• IO130: Identify the concept of, and potential for, a drug's interaction for endocrinology medications (B2.02d)

• IO131: Interpret the basic principles of rational therapeutics and decision-making for endocrinology medications (B2.02, B2.03, B2.05d)

• IO132: List significant adverse drug reactions and the appropriate intervention for endocrinology medications (B2.02d, B2.05)

• IO133: Describe issues related to bioavailability and bioequivalence for endocrinology medications (B2.02d)

• IO134: Identify the indications, rationale, and mechanisms of action for endocrinology medications (B2.02d, B2.03, B2.05)

• IO135: Analyze the relationship between pharmacodynamic mechanisms and physiologic responses for endocrinology medications (B2.02d, B2.05)

• IO136: Describe essential patient education regarding expected effects, potential adverse effects, proper administration, and costs of medications for endocrinology medications (B2.02d, B2.04, B2.09)

• IO137: Recognize major considerations in selecting the correct dosage, route of administration, and frequency based on relevant patient characteristics, e.g., age, culture, gender, and co-morbid conditions for endocrinology medications (B2.02d, B2.05, B2.06)

• IO138: Identify the components of a correctly written prescription and demonstrate the ability to write a prescription that is compliant with Florida state and federal regulations for endocrinology medications (B2.02d, B2.14)

• IO139: Identify clinically important agents for endocrinology medications (B2.02d)

• IO140: Describe the mechanism of action of each drug and the effects of the drug on the various organ systems for endocrinology medications (B2.02d, B2.03)

• IO141: Describe the clinical applications for endocrinology medications (B2.02d, B2.05)

• IO142: Discuss the routes of absorption, metabolism, and excretion for endocrinology medications (B2.02d)

• IO143: Describe the side effects and toxic manifestations for endocrinology medications (B2.02d)

• IO144: Identify the contraindications for endocrinology medications (B2.02d)

Glucose Homeostasis

• All human cells use glucose for energy.

• Glucose acts as a precursor for the synthesis of lipids, amino acids, and nucleic acids.

• Compounds synthesized from vitamins, essential amino acids, and essential fatty acids cannot be synthesized from glucose in humans.

• The body requires a minimum of 190 mg of glucose/day.

Diabetes Mellitus

• A metabolic syndrome characterized by elevated glucose levels.

• Associated with the following conditions:

  • Cardiovascular disease

  • Neuropathy

  • Nephropathy

  • Retinopathy

  • Hyperlipidemia

  • Peripheral vascular disease

Diagnosis of Diabetes (ADA Guidelines)

• Symptoms: Polyuria, Polydipsia, Weight loss

• Diagnostic Requirements:

  • Random plasma glucose > 200 mg/dL

  • Fasting glucose > 126 mg/dL

  • Glucose tolerance test > 200 mg/dL 2 hrs after ingestion

  • A1C > 6.5%

Classification of Diabetes Mellitus

• Type 1 DM (10% of cases):

  • Requires exogenous insulin for survival.

• Type 1.5 DM: Latent autoimmune diabetes in adults.

• Type 2 DM (90% of cases):

  • Approximately 20-30% may require insulin.

• Gestational DM: Occurs in 4% of pregnancies.

• Impaired fasting glucose (IFG): 110-125 mg/dL.

Morbidity and Mortality Associated with Diabetes Mellitus

• Type 1 Diabetes:

  • Risk of renal failure.

• Type 2 Diabetes:

  • Risk of macrovascular disease.

• Risk Factors:

  • Type 1: genetic factors, viruses, family history.

  • Type 2: family history, ethnicity, obesity, lifestyle choices.

Pancreas Cell Types and Functions

Islet Cell Hormones Regulating Glucose Homeostasis

• Normal conditions involve:

  • α-cells secrete glucagon.

  • β-cells secrete insulin.

• In Type 2 Diabetes Mellitus (T2DM):

  • α-cells dysfunction, secreting inappropriate high levels of glucagon.

  • Depletion of β-cells leading to insufficient insulin secretion.

β-Cell Function in Type 2 Diabetes

• Graph Data:

  • Normal β-cell function at the point of diagnosis can drop significantly below normal levels as diagnosis progresses over time.

• Measurement: HOMA - Homeostasis Model Assessment indicates blending of pancreatic function to 50% of normal.

Type 1 Diabetes Overview

• Characterized by extensive and selective loss of β-cells in the pancreas.

• Recognized as primarily an autoimmune disease (Type 1A, 90%).

• Approximately 80% of patients present with antibodies to islet cell antigens at diagnosis.

• Non-immune or Idiopathic Type 1 (Type 1B, 10%).

Insulin Release Mechanism

• Insulin and C-peptide are released in equal amounts in response to elevated glucose levels.

• C-peptide has no known function but can serve as an index of insulin secretion.

• Degradation occurs via hydrolysis of disulfide bonds followed by proteolysis by insulinase.

• Liver clears approximately 60% of insulin, while the kidney processes about 40%.

• The half-life (T1/2) of insulin is approximately 3-9 minutes.

Mechanism of Insulin Release

1. The pancreas exposed to increased glucose.

2. Glucose binds to GLUT-2 transporter on beta cells, which is subsequently internalized.

3. Internalization leads to glucose oxidation into ATP via the TCA cycle.

4. Increase in ATP levels leads to the closing of ATP-dependent K+ channels.

5. Reduction in outward K+ flow depolarizes the cell.

6. Opening of voltage-gated Ca++ channels leads to increased Ca++ levels which stimulate exocytosis of insulin granules into the bloodstream.

7. Sulfonylureas block ATP-dependent K+ channels on Beta cells, thus stimulating insulin release.

Mechanism of Insulin Action

• Insulin stimulates glucose uptake into target tissues via GLUT 4 transporters.

• Initiates phosphorylation cascades within cells, which translocate glucose transporters from inside the cell to the cell surface.

• Glucose enters cells through facilitated diffusion and can either be used for energy or stored.

Role of Insulin Receptor

• The insulin receptor mediates physiological responses leading to metabolic pathways such as mitogenesis, glycogen synthesis, and various anabolic processes.

Glucose Transporters Overview

Physiological Effects of Insulin

• Liver: Stimulates storage as glycogen; inhibits gluconeogenesis and glycogenolysis.

• Skeletal Muscle: Stimulates glucose uptake and amino acid storage.

• Adipose Tissue: Stimulates conversion of glucose to fatty acids; inhibits the conversion of fatty acids to ketones.

Insulin Release Patterns

• Glucose and insulin levels fluctuate throughout the day, with peaks during breakfast, lunch, and dinner.

• A diagram illustrates the corresponding fluctuations in insulin and glucose levels across specific times of the day.

Insulin Formulations

• Approximately 17 formulations available, differing in onset of activity, duration of action, and solubility characteristics.

• Pharmacokinetic profiles may be altered by varying zinc concentrations or by adding protamine.

• Insulin analogs involve changes in amino acid sequences.

Types and Patterns of Insulin

• Ultra-Short-acting (Lispro, Aspart, Glulisine)

• Short-acting (Regular)

• Intermediate-acting (NPH)

• Long-acting (Ultralente, Glargine, Detemir, Degludec)

• Inhaled (Afrezza®)

Insulin Delivery Systems

• Administration methods include conventional injection, portable pen injector, continuous subcutaneous infusion (insulin pump), and inhaled insulin (Afrezza®).

Insulin Agents and Administration Options

• Rapid-acting Insulins: Humalog, NovoLog, Apidra; administered via pen or vials.

• Short-acting Insulins: Humulin R, Novolin R; also administered via vials.

• Intermediate-acting Insulins: Humulin N, Novolin N.

• Long-acting Insulins: Lantus, Levemir, Tresiba; available via vials and pens.

• Premixed Insulins: Various combinations such as Humalog Mix, Novolog Mix, and NPH-regular combinations.

• Concentrated Insulins: Options like Regular U-500 and Humalog U-200; also includes inhaled insulin Afrezza.

Characteristics of Insulin Types

Complications of Insulin Therapy

• Hypoglycemia: Common side effect; occurs with U-100, U-200, and U-500 formulations.

• Immunological reactions: Insulin allergy (IgE) and immune insulin resistance (IgG) may occur.

• Injection site reactions: Including lipodystrophy; patients should rotate injection sites to minimize risk.

• Weight gain can result from insulin therapy.

Drugs that Influence Insulin Efficacy

• Drugs Decreasing Insulin's Hypoglycemic Effect:

  • Oral contraceptives, corticosteroids, dobutamine, epinephrine, niacin, smoking, thiazides, thyroid hormone.

• Drugs Increasing Insulin's Hypoglycemic Effect:

  • Alcohol, alpha-blockers, anabolic steroids, beta-blockers, MAO inhibitors.

Indications for Insulin Use

• All newly diagnosed Type 1 patients.

• Pregnant women with Type 2 DM or women who develop gestational DM.

• Type 2 DM not controlled by diet, exercise, and oral medications.

• Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome (HHNS).

• Hyperkalemia cases.

Insulin Regimens for Type 1 DM

• Tailored to the patient's lifestyle with basal-bolus regimens based on self-monitored blood glucose readings (SMBG).

• Involves multiple daily injections or continuous subcutaneous insulin infusion.

  • More frequent insulin administration leads to tighter glycemic control but increases treatment complexity.

• Goal: mimic physiological insulin secretion to align with carbohydrate intake and physical activity.

Dosing and Adjustment Strategies in Type 1 DM

• Initial dosage for Type 1 DM is typically 0.5-0.6 units/kg/day, divided equally between basal and bolus.

• Example of an adjustment for a 40 kg female diagnosed with Type 1 DM:

  • Total insulin dose/day = 0.5 * 40 kg = 20 units, with 10 units as basal and 10 units as bolus.

  • Breakdown: 20% at breakfast, 15% at lunch, and 15% at dinner.

Hypoglycemia Education

• Patients need to be educated on recognizing signs/symptoms.

• Hypoglycemic unawareness: Can occur in autonomic neuropathies or frequent hypoglycemic episodes.

• Rules of 15 for treatment:

  • Administer 15g of simple carbohydrates (e.g., 8 oz OJ, 4 glucose tablets).

  • Recheck glucose in 15 minutes; if still low, repeat.

Severe Hypoglycemia Management

• If unconscious, use Glucagon (GlucaGen): Stimulates hepatic glycogenolysis to raise blood glucose.

• Dextrose IV may also be used; doses typically range from 0.5-1 g/kg, advised against using higher concentrations due to thrombophlebitis risk.

Treatment Goals for Diabetes Management

• ADA Recommendations:

  • A1C < 7%

  • Preprandial glucose: 80-130 mg/dL

  • Postprandial glucose: < 180 mg/dL

• AACE/ACE Recommendations:

  • A1C < 6.5%

  • Preprandial glucose: < 110 mg/dL

  • Postprandial glucose: < 140 mg/dL

Treatment Approaches for Type 2 Diabetes

• Initial lifestyle changes followed by monotherapy or combination therapy (oral drugs only or oral drugs with insulin).

Plasma Glucose and Insulin Responses

• Varied responses seen in patients with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and Type 2 Diabetes.

Medications for Type 2 Diabetes

1. 
   

2. Classes of medications:

   • Drugs stimulating insulin production: Sulfonylureas & Meglitinides.

   • Insulin sensitizers and glucose production controllers: Thiazolidinediones & Biguanides.

   • Drugs that slow glucose absorption: Alpha-glucosidase inhibitors.

   • Suppress glucagon and reduce gastric emptying: Incretins.

   • Reduce renal glucose reabsorption: SGLT2 Inhibitors.

3. 
   

4. Efficacy of Monotherapy with Oral Agents: (Fasting Plasma Glucose Reduction and A1C Reduction)
   

   Drug	Fasting Plasma Glucose Reduction (mg/dL)	A1C Reduction (%)
   Thiazolidinedione	35-40	0.5-1.0
   Sulfonylurea	60-70	1.0-2.0
   Biguanide	60-70	1.0-2.0
   Meglitinide	60-70	1.0-2.0
   Alpha-glucosidase	20-30	0.5-1.0
   Sulfonylureas (Oral Hypoglycemics)

   • First Generation Agents:

     • Acetohexamide, Chlorpropamide, Tolazamide, Tolbutamide.

   • Second Generation Agents:

     • Glimepiride, Glipizide, Glyburide (100 times more potent with fewer side effects).

   Mechanism of Action of Sulfonylureas

   • Block ATP-dependent K+ channels in pancreatic beta cells.

   • Induces insulin release via depolarization and subsequent calcium influx.

   • Decreases basal hepatic glucose production and glycogenolysis, increases insulin receptor sensitivity and glucagon suppression.

   Pharmacokinetics of Sulfonylureas

   • Extensive metabolism in the liver with significant protein binding; excreted in urine.

   • Caution with renal or hepatic insufficiency due to powerful effects.

   Adverse Effects of Sulfonylureas

   • Risks include hypoglycemia, weight gain, gastrointestinal disturbances, rash, and potentially serious hematological effects.

   • Resistance may develop over time.

   Contraindications for Sulfonylureas

   • Hypoglycemia, diabetic ketoacidosis, Type 1 diabetes, and use in pregnancy or breastfeeding.

   Meglitinides (Oral Hypoglycemics)

   • Agents: Repaglinide, Nateglinide.

   • Mechanism: Similar to sulfonylureas, block ATP-dependent K+ channels in beta cells.

   • Highly protein-bound and metabolized in the liver.

   Dosing and Effectiveness of Meglitinides

   • Taken before meals to control glucose spikes.

   • Timing is critical—if a meal is missed, skip the dose.

   Biguanides (Oral Antihyperglycemics)

   • Agents: Metformin, Buformin, Phenformin.

   • Mechanism: Decreases hepatic glucose production and increases peripheral glucose uptake, enhancing insulin sensitivity.

   Pharmacokinetics and Effects of Biguanides

   • Not metabolized by the liver; excreted unchanged by the kidneys. Not advised in renal impairment due to lactic acidosis risk.

   • Particularly beneficial for obese patients with insulin resistance.

   Adverse Effects of Biguanides

   • GI disturbances and risk of lactic acidosis, particularly in renal impaired individuals.

   Thiazolidinediones (Oral Antihyperglycemics)

   • Agents: Pioglitazone, Rosiglitazone.

   • Mechanism: Agonists for PPAR-gamma, enhancing insulin sensitivity and glucose utilization in tissues.

   Adverse Effects and Monitoring of Thiazolidinediones

   • Risks include weight gain, heart failure exacerbation, and liver enzyme elevation. Routine monitoring of liver enzymes is recommended.

   Alpha-Glucosidase Inhibitors

   • Agents: Acarbose, Miglitol.

   • Mechanism: Inhibit GI enzymes responsible for carbohydrate digestion, thereby slowing glucose absorption.

   Adverse Effects of Alpha-Glucosidase Inhibitors

   • Gastrointestinal issues including flatulence, diarrhea, and must not be used in patients with inflammatory bowel disease.

   Incretins Overview

   • GLP-1 (Glucagon-like peptide-1): Released in response to food, enhancing insulin secretion and decreasing glucagon release, contributing to satiety.

   • DPP-4 Inhibitors: Protect endogenous incretin activity, enhancing insulin secretion post-meal while suppressing glucagon.

   Medications Targeting Incretin Pathways

   • Agents include: Exenatide, Liraglutide, Dulaglutide.

   • Effects include weight loss and reductions in rates of diabetes complications.

   Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2)

   • Agents: Canagliflozin, Dapagliflozin, Empagliflozin.

   • Mechanism: inhibit renal glucose reabsorption, promoting glucose elimination in urine and aiding in weight loss and glucose control.

   Initial Diabetes Management Strategies

   • Focus on lifestyle modifications, correcting dietary and activity factors, along with pharmacological control as needed.

   Conclusion

   • Understanding the mechanics of diabetes and endocrine medications is critical for effective patient care.

   • Proper dosing, administration, and patient education play vital roles in managing these chronic conditions.

   Questions Section

   • Clarifications pertaining to the pharmacology, mechanisms, and implications of diabetes-related treatments should be raised in this section.

   Hyperprolactinemia

   • Primarily caused by prolactin-secreting tumors (adenomas/microadenomas).

   • Symptoms may include galactorrhea and infertility.

   • Treatment involves the use of dopamine agonists, with options including Bromocriptine and Cabergoline, each having specific monitoring requirements.

   Androgens Overview

   • Discusses the synthesis, function, and therapeutic applications of androgens, including testosterone and its metabolites, as well as side effects and implications for treatment of various conditions, particularly in hormone replacement therapy.

   Corticosteroids Overview

   • Focus on how corticosteroids affect gene transcription and their roles in managing adrenal insufficiency, with indications for specific therapeutics like hydrocortisone for Addison's disease.

   Thyroid Pharmacology Overview

   • Explain thyroid hormone formation, pharmacodynamics, therapeutic agents for hypothyroidism and hyperthyroidism including replacement and antithyroid drugs. Discuss implications of treatment protocols and monitoring strategies.

   Questions Section

   • Any inquiries or uncertainties regarding treatment plans, patient outcomes or drug interactions can be addressed here.