ENDOCRINE PHARM Flashcards

Question

Mention Intermediate Acting Insulin Preparations

Answer 1

**Long Acting Insulin** * Onset → 1–4 hours * Peak → flat; not defined * Duration → ∼ 24-36 hours * More consistent effect and longer duration of action compared to NPH insulin * Often used in combination with rapid or short-actinginsulin * Administered once or twice daily * Subcutaneous injection * Sustain a plateau efficacy to maintain more stable insulin levels * Has a pH of 4 and forms a microprecipitate at the injection site, resulting in delayed absorption. Mechanism: * Bind insulin receptor (tyrosine kinase activity). * Liver → increase glucose stored as glycogen. * Muscle → increase glycogen, protein synthesis. * Fat → TG storage. * Cell membrane → K+ uptake. Clinical Use: * Type 1 DM, type 2 DM, GDM (basal glucose control) Side Effects: 1. Hypoglycemia (the required dose of insulin depends on individual levels of physical activity, alcohol consumption, and stress (stress increases the dose of insulin required)) 2. Weight gain (due to the anabolic effect of insulin) 3. Lipodystrophy at the injection site (patients should regularly change injection sites to avoid lipodystrophies) 4. Hypokalemia (due to activation of the Na+/K+ ATPase) 5. Allergic or hypersensitivity reactions 6. Edema (extremely rare side effect and mainly occurs after starting intensive insulin therapy in patients with longstanding hyperglycemia and/or newly diagnosed diabetes mellitus) 7. Pain and erythema at the injection site

Answer 2

**Long Acting Insulin** * Onset → 1–4 hours * Peak → flat; not defined * Duration → ∼ 24-36 hours * More consistent effect and longer duration of action compared to NPH insulin * Often used in combination with rapid or short-actinginsulin * Administered once or twice daily * Subcutaneous injection * Sustain a plateau efficacy to maintain more stable insulin levels * Has a pH of 4 and forms a microprecipitate at the injection site, resulting in delayed absorption. Mechanism: * Bind insulin receptor (tyrosine kinase activity). * Liver → increase glucose stored as glycogen. * Muscle → increase glycogen, protein synthesis. * Fat → TG storage. * Cell membrane → K+ uptake. Clinical Use: * Type 1 DM, type 2 DM, GDM (basal glucose control) Side Effects: 1. Hypoglycemia (the required dose of insulin depends on individual levels of physical activity, alcohol consumption, and stress (stress increases the dose of insulin required)) 2. Weight gain (due to the anabolic effect of insulin) 3. Lipodystrophy at the injection site (patients should regularly change injection sites to avoid lipodystrophies) 4. Hypokalemia (due to activation of the Na+/K+ ATPase) 5. Allergic or hypersensitivity reactions 6. Edema (extremely rare side effect and mainly occurs after starting intensive insulin therapy in patients with longstanding hyperglycemia and/or newly diagnosed diabetes mellitus) 7. Pain and erythema at the injection site

Answer 3

**Long Acting Insulin** * Onset → 1–4 hours * Peak → flat; not defined * Duration → ∼ 24-36 hours * More consistent effect and longer duration of action compared to NPH insulin * Often used in combination with rapid or short-actinginsulin * Administered once or twice daily * Subcutaneous injection * Sustain a plateau efficacy to maintain more stable insulin levels * Has a pH of 4 and forms a microprecipitate at the injection site, resulting in delayed absorption. Mechanism: * Bind insulin receptor (tyrosine kinase activity). * Liver → increase glucose stored as glycogen. * Muscle → increase glycogen, protein synthesis. * Fat → TG storage. * Cell membrane → K+ uptake Clinical Use: * Type 1 DM, type 2 DM, GDM (basal glucose control) Side Effects: 1. Hypoglycemia (the required dose of insulin depends on individual levels of physical activity, alcohol consumption, and stress (stress increases the dose of insulin required)) 2. Weight gain (due to the anabolic effect of insulin) 3. Lipodystrophy at the injection site (patients should regularly change injection sites to avoid lipodystrophies) 4. Hypokalemia (due to activation of the Na+/K+ ATPase) 5. Allergic or hypersensitivity reactions 6. Edema (extremely rare side effect and mainly occurs after starting intensive insulin therapy in patients with longstanding hyperglycemia and/or newly diagnosed diabetes mellitus) 7. Pain and erythema at the injection site

Answer 4

1. Detemir 2. Glargine 3. Degludec

Answer 5

**Biguanides** * Glycemic efficacy → lowers HbA1c by 1.2–2% over 3 months * Weight loss (often desired) or weight stabilization * No risk of hypoglycemia * Beneficial effect on dyslipidemia * Reduces the risk of macroangiopathic complications in patients with diabetes * Must be paused prior to surgery * Cost-effective * Inhibit hepatic gluconeogenesis and the action of glucagon via inhibition of the mitochondrial isoform of glycerophosphate dehydrogenase in the liver * Increase glycolysis, peripheral glucose uptake (increase insulin sensitivity). * Enhances the effect of insulin * Reduction in insulin resistance via modification of glucose metabolic pathways * Inhibits mitochondrial glycerophosphate dehydrogenase (mGPD) → ↓ hepatic gluconeogenesis and intestinal glucose absorption and the action of the glucagon * Increases peripheral insulin sensitivity → ↑ peripheral glucose uptake and glycolysis * Lowers postprandial and fasting blood glucose levels * Reduces LDL, increases HDL

Answer 6

**Biguanides** * Do not cause hypoglycemia * GI upset * Promote weight loss (often desired) * Vitamin B12 deficiency (impairs the enteral absorption of vitamin B12) * Metallic taste in the mouth (dysgeusia) * Metformin-associated lactic acidosis * High-risk groups 1. Elderly individuals (existing dehydration may be sufficient to trigger metabolic decompensation with subsequent lactic acidosis) 2. Patients with renal insufficiency or CHF

Answer 7

**Biguanides** * Renal failure (if creatinine clearance \< 30 mL/min) * Intravenous iodinated contrast medium (the elimination of metformin is reduced by the administration of iodinated contrast medium, even if overt renal failure does not develop (contrast-induced nephropathy)) * Heart failure, respiratory failure, shock, sepsis (processes associated with hypoperfusion and hypoxemia) * Alcoholism * Severe liver failure (impaired clearance of lactate increases the risk of lactic acidosis) * Chronic pancreatitis, starvation ketosis, ketoacidosis, sepsis (conditions involving the production of acidic metabolites)

Answer 8

**Biguanides** * Sulfonylureas (the simultaneous administration of metformin and sulfonylurea may be associated with an increase in cardiovascular mortality)

Answer 9

**Glitazones/Thiazolidinediones** * Safe to use in renal impairment * Glycemic efficacy → lowers HbA1c by 1% in 3 months * Favorable effect on lipid metabolism → ↓ triglyceride, ↓ LDL, ↑ HDL * No risk of hypoglycemia * Onset of action is delayed by several weeks (this delay results from the slow upregulation of proteins involved in increasing insulin sensitivity (e.g., adipokine, GLUT4)) * Activation of the transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type in the nucleus) → ↑ transcription of genes involved in glucose and lipid metabolism → ↑ levels of adipokines such as adiponectin and insulin sensitivity → ↑ storage of fatty acids in adipocytes, ↓ products of lipid metabolism (e.g.,free fatty acids) → ↓ free fatty acids in circulation → ↑ glucose utilization and ↓ hepatic glucose production * Decrease insulin resistance * Increase GLUT 4 expression

Answer 10

**Glitazones/Thiazolidinediones** * Safe to use in renal impairment * Glycemic efficacy → lowers HbA1c by 1% in 3 months * Favorable effect on lipid metabolism → ↓ triglyceride, ↓ LDL, ↑ HDL * No risk of hypoglycemia * Onset of action is delayed by several weeks (this delay results from the slow upregulation of proteins involved in increasing insulin sensitivity (e.g., adipokine, GLUT4)) * Activation of the transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type in the nucleus) → ↑ transcription of genes involved in glucose and lipid metabolism → ↑ levels of adipokines such as adiponectin and insulin sensitivity → ↑ storage of fatty acids in adipocytes, ↓ products of lipid metabolism (e.g.,free fatty acids) → ↓ free fatty acids in circulation → ↑ glucose utilization and ↓ hepatic glucose production * Decrease insulin resistance * Increase GLUT 4 expression

Answer 11

1. Pioglitazone 2. Rosiglitazone

Answer 12

**Glitazones/Thiazolidinediones** May be considered as monotherapy in patients with severe renal failure and/or contraindications for insulin therapy

Answer 13

**Glitazones/ thiazolidinediones** * ↑ Risk of heart failure * ↑ Risk of bone fractures (osteoporosis) (take vitamin D) * Fluid retention and edema * Weight gain * Hepatotoxicity * Myalgia * Rosiglitazone → ↑ risk of cardiovascular complications like cardiac infarction or death

Answer 14

**Glitazones/ thiazolidinediones** 1. Congestive heart failure (NYHA III or IV) 2. Liver failure

Answer 15

**Glitazones/ thiazolidinediones** * ↑ Risk of heart failure * ↑ Risk of bone fractures (osteoporosis) (take vitamin D) * Fluid retention and edema * Weight gain * Hepatotoxicity * Myalgia

Answer 16

**Glitazones/Thiazolidinediones** May be considered as monotherapy in patients with severe renal failure and/or contraindications for insulin therapy

Answer 17

**Glitazones/ thiazolidinediones** 1. Congestive heart failure (NYHA III or IV) 2. Liver failure 3. Pioglitazone → history of bladder cancer or active bladder cancer; macrohematuria of unknown origin

Answer 18

1. Chlorpropamide 2. Tolbutamide

Answer 19

**First Generation Sulfonylurea** Mechanism: * Block ATP-sensitive potassium channels of the pancreatic β cells → depolarization of the cell membrane → calcium influx → insulin secretion (the use of sulfonylureas in early stages of disease can lead to a premature loss of β-cell function, potentially impairing the effectiveness of antidiabetic treatment) * Extrapancreatic effect → ↓ hepatic gluconeogenesis, ↑ peripheral insulin sensitivity Clinical Use: * Patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine * Generally not frequently used Adverse Effects: 1. Life-threatening hypoglycemia; increased risk under the following circumstances: * Simultaneous intake of CYP2C9 inhibitors (e.g., amiodarone, trimethoprim, fluconazole) * Patients with renal failure (because sulfonylureas are excreted via the kidneys, renal failure can result in accumulation. Hypoglycemia due to accumulation of long-acting glyburide may persist for several days, requiring extensive glucose substitution. Short-acting agents have a lower risk of accumulation and hypoglycemia) * Decreased carbohydrate intake (diets or periods of fasting) * Elevated glucose utilization (e.g., unaccustomed physical activity) * Sulfonylurea overdose 2. Alcohol intolerance (first-generation agents): disulfiram-like reaction 3. Weight gain 4. Hematological changes → granulocytopenia, hemolytic anemia 5. Allergic skin reactions 6. Sulfonylureas are associated with more cardiovascular (macrovascular) complications than metformin. 7. β-cell apoptosis → studies suggest that sulfonylureas induce β-cell apoptosis in human islet cells. Contraindications 1. Severe cardiovascular comorbidity (there is evidence that cardiovascular diseases may be exacerbated by sulfonylurea exposure during the course of disease) 2. Obesity 3. Sulfonamide allergy (particularly long-acting substances) 4. Severe liver and kidney failure 5. Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided!

Answer 20

**Second Generation Sulfonylurea** Mechanism: * Block ATP-sensitive potassium channels of the pancreatic β cells → depolarization of the cell membrane → calcium influx → insulin secretion (the use of sulfonylureas in early stages of disease can lead to a premature loss of β-cell function, potentially impairing the effectiveness of antidiabetic treatment) * Extrapancreatic effect → ↓ hepatic gluconeogenesis, ↑ peripheral insulin sensitivity Clinical Use: * Patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine * Generally not frequently used Adverse Effects: 1. Life-threatening hypoglycemia; increased risk under the following circumstances: * Simultaneous intake of CYP2C9 inhibitors (e.g., amiodarone, trimethoprim, fluconazole) * Patients with renal failure (because sulfonylureas are excreted via the kidneys, renal failure can result in accumulation. Hypoglycemia due to accumulation of long-acting glyburide may persist for several days, requiring extensive glucose substitution. Short-acting agents have a lower risk of accumulation and hypoglycemia) * Decreased carbohydrate intake (diets or periods of fasting) * Elevated glucose utilization (e.g., unaccustomed physical activity) * Sulfonylurea overdose 2. Alcohol intolerance (first-generation agents): disulfiram-like reaction 3. Weight gain 4. Hematological changes → granulocytopenia, hemolytic anemia 5. Allergic skin reactions 6. Sulfonylureas are associated with more cardiovascular (macrovascular) complications than metformin. 7. β-cell apoptosis → studies suggest that sulfonylureas induce β-cell apoptosis in human islet cells. Contraindications 1. Severe cardiovascular comorbidity (there is evidence that cardiovascular diseases may be exacerbated by sulfonylurea exposure during the course of disease) 2. Obesity 3. Sulfonamide allergy (particularly long-acting substances) 4. Severe liver and kidney failure 5. Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided!

Answer 21

**Short-acting second Generation Sulfonylurea** Mechanism: * Block ATP-sensitive potassium channels of the pancreatic β cells → depolarization of the cell membrane → calcium influx → insulin secretion (the use of sulfonylureas in early stages of disease can lead to a premature loss of β-cell function, potentially impairing the effectiveness of antidiabetic treatment) * Extrapancreatic effect → ↓ hepatic gluconeogenesis, ↑ peripheral insulin sensitivity Clinical Use: * Patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine * Generally not frequently used Adverse Effects: 1. Life-threatening hypoglycemia; increased risk under the following circumstances: * Simultaneous intake of CYP2C9 inhibitors (e.g., amiodarone, trimethoprim, fluconazole) * Patients with renal failure (because sulfonylureas are excreted via the kidneys, renal failure can result in accumulation. Hypoglycemia due to accumulation of long-acting glyburide may persist for several days, requiring extensive glucose substitution. Short-acting agents have a lower risk of accumulation and hypoglycemia) * Decreased carbohydrate intake (diets or periods of fasting) * Elevated glucose utilization (e.g., unaccustomed physical activity) * Sulfonylurea overdose 2. Alcohol intolerance (first-generation agents): disulfiram-like reaction 3. Weight gain 4. Hematological changes → granulocytopenia, hemolytic anemia 5. Allergic skin reactions 6. Sulfonylureas are associated with more cardiovascular (macrovascular) complications than metformin. 7. β-cell apoptosis → studies suggest that sulfonylureas induce β-cell apoptosis in human islet cells. Contraindications 1. Severe cardiovascular comorbidity (there is evidence that cardiovascular diseases may be exacerbated by sulfonylurea exposure during the course of disease) 2. Obesity 3. Sulfonamide allergy (particularly long-acting substances) 4. Severe liver and kidney failure 5. Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided!

Answer 22

**Long-acting second Generation Sulfonylurea** Mechanism: * Block ATP-sensitive potassium channels of the pancreatic β cells → depolarization of the cell membrane → calcium influx → insulin secretion (the use of sulfonylureas in early stages of disease can lead to a premature loss of β-cell function, potentially impairing the effectiveness of antidiabetic treatment) * Extrapancreatic effect → ↓ hepatic gluconeogenesis, ↑ peripheral insulin sensitivity Clinical Use: * Patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine * Generally not frequently used Adverse Effects: 1. Life-threatening hypoglycemia; increased risk under the following circumstances: * Simultaneous intake of CYP2C9 inhibitors (e.g., amiodarone, trimethoprim, fluconazole) * Patients with renal failure (because sulfonylureas are excreted via the kidneys, renal failure can result in accumulation. Hypoglycemia due to accumulation of long-acting glyburide may persist for several days, requiring extensive glucose substitution. Short-acting agents have a lower risk of accumulation and hypoglycemia) * Decreased carbohydrate intake (diets or periods of fasting) * Elevated glucose utilization (e.g., unaccustomed physical activity) * Sulfonylurea overdose 2. Alcohol intolerance (first-generation agents): disulfiram-like reaction 3. Weight gain 4. Hematological changes → granulocytopenia, hemolytic anemia 5. Allergic skin reactions 6. Sulfonylureas are associated with more cardiovascular (macrovascular) complications than metformin. 7. β-cell apoptosis → studies suggest that sulfonylureas induce β-cell apoptosis in human islet cells. Contraindications 1. Severe cardiovascular comorbidity (there is evidence that cardiovascular diseases may be exacerbated by sulfonylurea exposure during the course of disease) 2. Obesity 3. Sulfonamide allergy (particularly long-acting substances) 4. Severe liver and kidney failure 5. Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided!

Answer 23

**First Generation Sulfonylurea** Mechanism: * Block ATP-sensitive potassium channels of the pancreatic β cells → depolarization of the cell membrane → calcium influx → insulin secretion (the use of sulfonylureas in early stages of disease can lead to a premature loss of β-cell function, potentially impairing the effectiveness of antidiabetic treatment) * Extrapancreatic effect → ↓ hepatic gluconeogenesis, ↑ peripheral insulin sensitivity Clinical Use: * Patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine * Generally not frequently used Adverse Effects: 1. Life-threatening hypoglycemia; increased risk under the following circumstances: * Simultaneous intake of CYP2C9 inhibitors (e.g., amiodarone, trimethoprim, fluconazole) * Patients with renal failure (because sulfonylureas are excreted via the kidneys, renal failure can result in accumulation. Hypoglycemia due to accumulation of long-acting glyburide may persist for several days, requiring extensive glucose substitution. Short-acting agents have a lower risk of accumulation and hypoglycemia) * Decreased carbohydrate intake (diets or periods of fasting) * Elevated glucose utilization (e.g., unaccustomed physical activity) * Sulfonylurea overdose 2. Alcohol intolerance (first-generation agents): disulfiram-like reaction 3. Weight gain 4. Hematological changes → granulocytopenia, hemolytic anemia 5. Allergic skin reactions 6. Sulfonylureas are associated with more cardiovascular (macrovascular) complications than metformin. 7. β-cell apoptosis → studies suggest that sulfonylureas induce β-cell apoptosis in human islet cells. Contraindications 1. Severe cardiovascular comorbidity (there is evidence that cardiovascular diseases may be exacerbated by sulfonylurea exposure during the course of disease) 2. Obesity 3. Sulfonamide allergy (particularly long-acting substances) 4. Severe liver and kidney failure 5. Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided!

Answer 24

1. Glyburide (long-acting agent) 2. Glipizide (short-acting agent) 3. Glimepiride

Answer 25

**Meglitinide (sulfonylurea analogue)** Tolerated well by patients with chronic kidney disease (especially repaglinide) More expensive than sulfonylureas Mechanism * Similar mechanism of action to that of sulfonylureas) * Blockage of ATP-sensitive potassium channels of the pancreatic beta cells → depolarization of the cell membrane → calcium influx → insulin secretion * Meglitinides should be taken shortly before meals (in contrast to (long-acting) sulfonylureas, meglitinides are short-acting agents (half-life of ∼ 30–60 min) that primarily affect blood glucose levels shortly after intake) Clinical Use: * Particularly suitable for patients with postprandial peaks in blood glucose levels, but overall rarely prescribed Adverse Effects: 1. Life-threatening hypoglycemia, especially in patients with renal failure (less of a risk than with sulfonylureas) 2. Weight gain 3. Hepatotoxicity (rare) Contraindications → severe liver failure Interactions → sulfonylureas

Answer 26

**Meglitinide (sulfonylurea analogue)** Tolerated well by patients with chronic kidney disease (especially repaglinide) More expensive than sulfonylureas Mechanism * Similar mechanism of action to that of sulfonylureas) * Blockage of ATP-sensitive potassium channels of the pancreatic beta cells → depolarization of the cell membrane → calcium influx → insulin secretion * Meglitinides should be taken shortly before meals (in contrast to (long-acting) sulfonylureas, meglitinides are short-acting agents (half-life of ∼ 30–60 min) that primarily affect blood glucose levels shortly after intake) Clinical Use: * Particularly suitable for patients with postprandial peaks in blood glucose levels, but overall rarely prescribed Adverse Effects: 1. Life-threatening hypoglycemia, especially in patients with renal failure (less of a risk than with sulfonylureas) 2. Weight gain 3. Hepatotoxicity (rare) Contraindications → severe liver failure Interactions → sulfonylureas

Answer 27

**Glucagon-like Peptide Receptor-1 Agonists (incretin mimetics)** Subcutaneous injection Mechanism: * GLP-1 agonists directly enhance the effect of incretin via exogenous "incretin” intake. As with all agonist drugs that enhance the effect of an endogenous substance, the effects and side effects are particularly pronounced when increasing the dose. * Incretin effect → food intake → activation of enteroendocrine cells in the gastrointestinal tract → release of GLP-1 → GLP-1 degradation via the enzyme DPP-4 → end of the GLP-1 effect * Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to degradation by DPP-4 enzyme → ↑ insulin secretion, ↓ glucagon secretion, slow gastric emptying (↑ feeling of satiety, ↓ weight) Side effects 1. Weight loss (may be wanted) 2. No risk of hypoglycemia 3. Gastrointestinal symptoms * Nausea, vomiting * Strong feeling of satiety (often desired) * Pancreatitis and potentially pancreatic cancer 4. Potential risk of medullary thyroid cancer (MTC) (further investigation required) Contraindications 1. Preexisting symptomatic gastrointestinal motility disorders 2. Chronic pancreatitis or a family history of pancreatic tumors 3. Personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2)

Answer 28

**Glucagon-like Peptide Receptor-1 Agonists (incretin mimetics)** Subcutaneous injection A rapid-release formula that is administered daily, liraglutide is also approved for the treatment of severe obesity with secondary complications. Mechanism: * GLP-1 agonists directly enhance the effect of incretin via exogenous "incretin” intake. As with all agonist drugs that enhance the effect of an endogenous substance, the effects and side effects are particularly pronounced when increasing the dose. * Incretin effect → food intake → activation of enteroendocrine cells in the gastrointestinal tract → release of GLP-1 → GLP-1 degradation via the enzyme DPP-4 → end of the GLP-1 effect * Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to degradation by DPP-4 enzyme → ↑ insulin secretion, ↓ glucagon secretion, slow gastric emptying (↑ feeling of satiety, ↓ weight) Side effects 1. Weight loss (may be wanted) 2. No risk of hypoglycemia 3. Gastrointestinal symptoms * Nausea, vomiting * Strong feeling of satiety (often desired) * Pancreatitis and potentially pancreatic cancer 4. Potential risk of medullary thyroid cancer (MTC) (further investigation required) Contraindications 1. Preexisting symptomatic gastrointestinal motility disorders 2. Chronic pancreatitis or a family history of pancreatic tumors 3. Personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2)

Answer 29

**Glucagon-like Peptide Receptor-1 Agonists (incretin mimetics)** Subcutaneous injection An extended-release formula that is administered once a week Mechanism: * GLP-1 agonists directly enhance the effect of incretin via exogenous "incretin” intake. As with all agonist drugs that enhance the effect of an endogenous substance, the effects and side effects are particularly pronounced when increasing the dose. * Incretin effect → food intake → activation of enteroendocrine cells in the gastrointestinal tract → release of GLP-1 → GLP-1 degradation via the enzyme DPP-4 → end of the GLP-1 effect * Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to degradation by DPP-4 enzyme → ↑ insulin secretion, ↓ glucagon secretion, slow gastric emptying (↑ feeling of satiety, ↓ weight) Side effects 1. Weight loss (may be wanted) 2. No risk of hypoglycemia 3. Gastrointestinal symptoms * Nausea, vomiting * Strong feeling of satiety (often desired) * Pancreatitis and potentially pancreatic cancer 4. Potential risk of medullary thyroid cancer (MTC) (further investigation required) Contraindications 1. Preexisting symptomatic gastrointestinal motility disorders 2. Chronic pancreatitis or a family history of pancreatic tumors 3. Personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2)

Answer 30

**Glucagon-like Peptide Receptor-1 Agonists (incretin mimetics)** Subcutaneous injection Mechanism: * GLP-1 agonists directly enhance the effect of incretin via exogenous "incretin” intake. As with all agonist drugs that enhance the effect of an endogenous substance, the effects and side effects are particularly pronounced when increasing the dose. * Incretin effect → food intake → activation of enteroendocrine cells in the gastrointestinal tract → release of GLP-1 → GLP-1 degradation via the enzyme DPP-4 → end of the GLP-1 effect * Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to degradation by DPP-4 enzyme → ↑ insulin secretion, ↓ glucagon secretion, slow gastric emptying (↑ feeling of satiety, ↓ weight) Side effects 1. Weight loss (may be wanted) 2. No risk of hypoglycemia 3. Gastrointestinal symptoms * Nausea, vomiting * Strong feeling of satiety (often desired) * Pancreatitis and potentially pancreatic cancer 4. Potential risk of medullary thyroid cancer (MTC) (further investigation required) Contraindications 1. Preexisting symptomatic gastrointestinal motility disorders 2. Chronic pancreatitis or a family history of pancreatic tumors 3. Personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2)

Answer 31

1. Exenatide 2. Liraglutide 3. Albiglutide 4. Dulaglutide

Answer 32

**Dipeptidyl peptidase-4 inhibitors (gliptins)** Mechanism: * Indirectly increase the endogenous incretin effect by inhibiting the DPP-4 that breaks down GLP-1 → ↑ insulin secretion, ↓ glucagon secretion, delayed gastric emptying Adverse Effects: 1. No risk of hypoglycemia unless insulin and/or insulinotropic drugs are used simultaneously because insulin release is glucose-dependent 2. Usually no weight changes 3. Gastrointestinal symptoms → diarrhea, constipation (milder than in GLP-1 agonist exposure) 4. Arthralgia 5. ↑ Feeling of satiety (often favorable) due to delayed gastric emptying 6. Nasopharyngitis and upper respiratory tract infection 7. Urinary infections (mild) 8. ↑ Risk of pancreatitis 9. Worsening renal function, acute renal failure 10. Headaches, dizziness Contraindications 1. Liver failure 2. Renal failure 3. Hypersensitivity

Answer 33

**Dipeptidyl peptidase-4 inhibitors (gliptins)** Mechanism: * Indirectly increase the endogenous incretin effect by inhibiting the DPP-4 that breaks down GLP-1 → ↑ insulin secretion, ↓ glucagon secretion, delayed gastric emptying Adverse Effects: 1. No risk of hypoglycemia unless insulin and/or insulinotropic drugs are used simultaneously because insulin release is glucose-dependent 2. Usually no weight changes 3. Gastrointestinal symptoms → diarrhea, constipation (milder than in GLP-1 agonist exposure) 4. Arthralgia 5. ↑ Feeling of satiety (often favorable) due to delayed gastric emptying 6. Nasopharyngitis and upper respiratory tract infection 7. Urinary infections (mild) 8. ↑ Risk of pancreatitis 9. Worsening renal function, acute renal failure 10. Headaches, dizziness Contraindications 1. Liver failure 2. Renal failure 3. Hypersensitivity

Answer 34

**Dipeptidyl peptidase-4 inhibitors (gliptins)** Mechanism: * Indirectly increase the endogenous incretin effect by inhibiting the DPP-4 that breaks down GLP-1 → ↑ insulin secretion, ↓ glucagon secretion, delayed gastric emptying Adverse Effects: 1. No risk of hypoglycemia unless insulin and/or insulinotropic drugs are used simultaneously because insulin release is glucose-dependent 2. Usually no weight changes 3. Gastrointestinal symptoms → diarrhea, constipation (milder than in GLP-1 agonist exposure) 4. Arthralgia 5. ↑ Feeling of satiety (often favorable) due to delayed gastric emptying 6. Nasopharyngitis and upper respiratory tract infection 7. Urinary infections (mild) 8. ↑ Risk of pancreatitis 9. Worsening renal function, acute renal failure 10. Headaches, dizziness Contraindications 1. Liver failure 2. Renal failure 3. Hypersensitivity

Answer 35

1. Sitagliptin 2. Saxagliptin 3. Linagliptin

Answer 36

**α-glucosidase inhibitors** Mechanism: * Inhibit alpha-glucosidase (a brush border enzyme expressed by intestinal epithelial cells) → delayed and ↓ intestinalglucose absorption and ↓ carbohydrate breakdown, resulting in ↓ hyperglycemia after food ingestion * Particularly effective in controlling postprandial blood glucose levels * The undigested carbohydrates reach the colon, where they are degraded by intestinal bacteria, resulting in the production of intestinal gas. Adverse Effects: 1. No risk of hypoglycemia 2. Gastrointestinal symptoms (flatulence, bloating, abdominal discomfort, diarrhea) (because of reduced digestion of complex carbohydrates in the gastrointestinal tract, carbohydrates are digested by intestinal bacteria in the colon. This results in gastrointestinal side effects. Gradually titrating the dose normally minimizes these side effects) Contraindications 1. Severe renal failure 2. Inflammatory bowel disease 3. Conditions associated with malabsorption

Answer 37

**α-glucosidase inhibitors** Mechanism: * Inhibit alpha-glucosidase (a brush border enzyme expressed by intestinal epithelial cells) → delayed and ↓ intestinalglucose absorption and ↓ carbohydrate breakdown, resulting in ↓ hyperglycemia after food ingestion * Particularly effective in controlling postprandial blood glucose levels * The undigested carbohydrates reach the colon, where they are degraded by intestinal bacteria, resulting in the production of intestinal gas. Adverse Effects: 1. No risk of hypoglycemia 2. Gastrointestinal symptoms (flatulence, bloating, abdominal discomfort, diarrhea) (because of reduced digestion of complex carbohydrates in the gastrointestinal tract, carbohydrates are digested by intestinal bacteria in the colon. This results in gastrointestinal side effects. Gradually titrating the dose normally minimizes these side effects) Contraindications 1. Severe renal failure 2. Inflammatory bowel disease 3. Conditions associated with malabsorption

Answer 38

1. Acarbose 2. Miglitol

Answer 39

1. Pramlintide

Answer 40

**Amylin analog** Should be administered at least 1 hour after others medication because decrease the gastric emptying Never after a meal Mechanism: * Work on pancreas * Decrease postprandial glucose * Slow blood glucose uptake * Decrease glucagon release Decrease gastric emptying * Increase satiety Side Effects: 1. Hypoglycemia (in setting of misstimed prandial insulin) 2. Nausea 3. Diarrhea Contraindications: 1. Gastroparesis

Answer 41

1. Metformin 2. GLP-1 agonist 3. SGLT-2 inhibitors 4. Orlistat 5. Pramlintide

Answer 42

1. GLP-1 analogs (exenatide, liraglutide) 2. Biguanides (metformin) 3. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) 4. Amylin analog (pramlintide)

Answer 43

1. Sulfonylureas * 1st generation → chlorpropamide, tolbutamide * 2nd generation → glimepiride, glipizide, glyburide 2. Meglitinides (ateglinide, repaglinide) 3. Glitazones/thiazolidinediones (pioglitazone, rosiglitazone)

Answer 44

**Thionamide** Slow onset of action (3–4 weeks) (onset after T4 stores are depleted) Mechanism: * Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling of iodine → inhibition of thyroid hormone synthesis. Clinical Use: * Hyperthyroidism * PTU used in first trimester of pregnancy (due to methimazole teratogenicity) * Methimazole used in second and third trimesters of pregnancy (due to risk of PTU-induced hepatotoxicity). * Not used to treat Graves ophthalmopathy (treated with corticosteroids). * After radioactive iodine treatment * Before radioactive iodine treatment or thyroidectomy (normal/near-normal thyroid function needs to be achieved before either radioactive iodine treatment or surgery in order to minimize the risk of thyroid storm) * Thyroid storm Adverse Effect: 1. Allergy/hypersensitivity * The most common side effect is a pruritic rash (particularly with methimazole) * Rarely, severe effects such as exfoliative dermatitis, polyserositis, and acute arthralgia occur * If mild, switch to propylthiouracil; if severe, avoid thioamides because of the risk of cross-sensitivities 2. Hematologic side effects * Agranulocytosis * Rare but dangerous (affects ∼ 0.5% of patients; more common in elderly and those taking high doses) * Rapidly reversible with discontinuation of treatment * Recurrent URI and chronic cough after starting methimazole suspect agranulocytosis (leukopenia) * Aplastic anemia * Thrombocytopenia 3. Hepatotoxicity (seen with propylthiouracil use) * Hepatitis * Cholestatic jaundice * Liver failure 4. Teratogenicity → increased risk of congenital malformations with carbimazole and methimazole (e.g., aplasia cutis) 5. Other * Diffuse goiter * Impaired sense of taste (dysgeusia)

Answer 45

**Thionamide** Onset after T4 stores are depleted Methimazole has a faster onset of action and fewer side effects than propylthiouracil Mechanism: * Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling of iodine → inhibition of thyroid hormone synthesis. Clinical Use: * Hyperthyroidism * PTU used in first trimester of pregnancy (due to methimazole teratogenicity) * Methimazole used in second and third trimesters of pregnancy (due to risk of PTU-induced hepatotoxicity). * Not used to treat Graves ophthalmopathy (treated with corticosteroids). * After radioactive iodine treatment * Before radioactive iodine treatment or thyroidectomy (normal/near-normal thyroid function needs to be achieved before either radioactive iodine treatment or surgery in order to minimize the risk of thyroid storm) * Thyroid storm Adverse Effect: 1. Allergy/hypersensitivity * The most common side effect is a pruritic rash (particularly with methimazole) * Rarely, severe effects such as exfoliative dermatitis, polyserositis, and acute arthralgia occur * If mild, switch to propylthiouracil; if severe, avoid thioamides because of the risk of cross-sensitivities 2. Hematologic side effects * Agranulocytosis * Rare but dangerous (affects ∼ 0.5% of patients; more common in elderly and those taking high doses) * Rapidly reversible with discontinuation of treatment * Recurrent URI and chronic cough after starting methimazole suspect agranulocytosis (leukopenia) * Aplastic anemia * Thrombocytopenia 3. Hepatotoxicity (seen with propylthiouracil use) * Hepatitis * Cholestatic jaundice * Liver failure 4. Teratogenicity → increased risk of congenital malformations with carbimazole and methimazole (e.g., aplasia cutis) 5. Other * Diffuse goiter * Impaired sense of taste (dysgeusia)

Answer 46

**Thionamide** Slow onset of action (3–4 weeks) (onset after T4 stores are depleted) Mechanism: * Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling of iodine → inhibition of thyroid hormone synthesis. * Blocks 5′-deiodinase → decrease peripheral conversion of T4 to T3. * Blocks Peripheral conversion. Clinical Use: * Hyperthyroidism * PTU used in first trimester of pregnancy (due to methimazole teratogenicity) * Methimazole used in second and third trimesters of pregnancy (due to risk of PTU-induced hepatotoxicity). * Not used to treat Graves ophthalmopathy (treated with corticosteroids). * After radioactive iodine treatment * Before radioactive iodine treatment or thyroidectomy (normal/near-normal thyroid function needs to be achieved before either radioactive iodine treatment or surgery in order to minimize the risk of thyroid storm) * Thyroid storm Adverse Effect: 1. Allergy/hypersensitivity * The most common side effect is a pruritic rash (particularly with methimazole) * Rarely, severe effects such as exfoliative dermatitis, ANCA-associated vasculitis (propylthiouracil), polyserositis, and acute arthralgia occur * If mild, switch to propylthiouracil; if severe, avoid thioamides because of the risk of cross-sensitivities 2. Hematologic side effects * Agranulocytosis * Rare but dangerous (affects ∼ 0.5% of patients; more common in elderly and those taking high doses) * Rapidly reversible with discontinuation of treatment * Recurrent URI and chronic cough after starting methimazole suspect agranulocytosis (leukopenia) * Aplastic anemia * Thrombocytopenia 3. Hepatotoxicity (seen with propylthiouracil use) * Hepatitis * Cholestatic jaundice * Liver failure 4. Teratogenicity → increased risk of congenital malformations with carbimazole and methimazole (e.g., aplasia cutis) 5. Other * Diffuse goiter * Impaired sense of taste (dysgeusia)

Answer 47

**Lugol's iodine (oral potassium iodide)** **Saturated solution of potassium iodide (SSKI)** Rapid onset of action (within a week) Mechanism: * Inhibit proteolytic cleavage of T3 and T4 from thyroglobulin → inhibits thyroid hormone release * Also decrease thyroid vascularity and decrease the size of the gland Clinical Use: 1. Pretreatment before thyroid surgery (decreases vascularity → less operative blood loss; decreases thyroid hormone release → reduced risk of thyroid storm) 2. Adjunctive therapy in thyroid storm (iodides must be given at least an hour after antithyroid drug administration to prevent the iodide from being used as a substrate for new hormone synthesis and possible worsening of the thyroid storm) 3. Adjunctive therapy in hyperthyroidism (rarely used as a sole therapy in hyperthyroidismsince the thyroid overcomes the iodide block within a few weeks) 4. Used as prophylaxis to decrease radioactive iodine uptake in the thyroid gland (e.g., after a nuclear accident or I₁₃₁ overdose in patients undergoing radioactive iodine ablation) Adverse Effects: * Side-effects are rare and often mild. * Oral/gastric mucosal irritation (e.g., aphthous ulcers, metallic taste) → to avoid mucosal irritation, iodides should be consumed with food or diluted with fluids. * Allergy/hypersensitivity → rash, angioedema; rarely, severe anaphylactic reactions can occur * Teratogenicity → contraindicated in pregnancy because they can cross the placental barrier and cause fetal goiter * Iodides delay and decrease the effects of radioactive iodine. They must be stopped at least a week before radioactive iodine ablation. Contraindication 1. Pregnancy

Answer 48

**Long Acting Somatostatin Analog** Mechanism: * ↓ Insulin and glucagon secretion * ↓ Growth hormonesecretion * ↓ Gastric acid and pepsinogen secretion * ↓ Pancreatic and small bowel fluid secretion * ↓ Gallbladdercontraction → ↓ biliary drainage * Splanchnic vasoconstriction (inhibits secretion of various splanchnic vasodilatory hormones) Clinical Use: 1. Acute esophageal varices bleeding (not in prevention) 2. Acromegaly 3. Carcinoid syndrome 4. VIPoma 5. Acromegaly 6. Gastrinoma 7. Glucagonoma Adverse Effects: * Nausea * Cramps * Steatorrhea * Increase risk of cholelithiasis due to CCK inhibition.

Answer 49

1. Octreotide 2. Lanreotide

Answer 50

**Long Acting Somatostatin Analog** Mechanism: * ↓ Insulin and glucagon secretion * ↓ Growth hormonesecretion * ↓ Gastric acid and pepsinogen secretion * ↓ Pancreatic and small bowel fluid secretion * ↓ Gallbladdercontraction → ↓ biliary drainage * Splanchnic vasoconstriction (inhibits secretion of various splanchnic vasodilatory hormones) Clinical Use: 1. Acute esophageal varices bleeding (not in prevention) 2. Acromegaly 3. Carcinoid syndrome 4. VIPoma 5. Acromegaly 6. Gastrinoma 7. Glucagonoma Adverse Effects: * Nausea * Cramps * Steatorrhea * Increase risk of cholelithiasis due to CCK inhibition.

Answer 51

Fludrocortisone

Answer 52

Mechanism: * Synthetic analog of aldosterone (predominantly mineralocorticoid activity) with little glucocorticoid effects. * Mineralocorticoid and glucocorticoid activity Clinical Use: * Mineralocorticoid replacement in 1° adrenal insufficiency. Adverse Effects: * Similar to glucocorticoids * Also edema, exacerbation of heart failure, hyperpigmentation.

Answer 53

**Calcimimetic** Mechanism: * Modulation of calcium-sensitive receptor (CaSR) in parathyroid glands → ↑ sensibility of the receptor to circulating Ca2+ → inhibition of PTH release * Increase the calcium sensitivity of parathyroid chief cells and therefore modulate unregulated and excessive PTH secretion in response to the moderate serum calcium changes observed in pHTP Clinical Use: 1. Primary hyperparathyroidism after failed parathyroidectomy 2. Hypercalcemia in hemodialysis patients with secondary hypoparathyroidism due to CKD 3. Parathyroid carcinoma with hypercalcemia Adverse Effects: 1. Gastrointestinal → nausea, vomiting, diarrhea 2. Hypocalcemia Contraindications 1. Hypocalcemia 2. In patients with osteoporosis → bisphosphonates 3. Avoid lithium and thiazide diuretics. Interactions: strong inhibition of CYP2A6

Answer 54

1. Sevelamer 2. Calcium acetate 3. Calcium carbonate 4. Lanthanum

Answer 55

**Phosphate binder** Mechanism: * Binds phosphate in the gut (sevelamer is nonabsorbable) → ↓ phosphate absorption → ↓ serum phosphate → ↓ PTH Clinical Use: * Hyperphosphatemia caused by chronic kidney disease Adverse Effects 1. Gastrointestinal → nausea, vomiting, diarrhea, constipation, pain 2. Hypophosphatemia 3. Fatigue 4. Joint pain

Answer 56

**Phosphate binder** Mechanism: * Binds phosphate in the gut (nonabsorbable) → ↓ phosphate absorption → ↓ serum phosphate → ↓ PTH Clinical Use: * Hyperphosphatemia caused by chronic kidney disease Adverse Effects 1. Gastrointestinal → nausea, vomiting, diarrhea, constipation, pain 2. Hypophosphatemia 3. Fatigue 4. Joint pain

Answer 57

**Phosphate binder** Mechanism: * Binds phosphate in the gut (nonabsorbable) → ↓ phosphate absorption → ↓ serum phosphate → ↓ PTH Clinical Use: * Hyperphosphatemia caused by chronic kidney disease Adverse Effects 1. Gastrointestinal → nausea, vomiting, diarrhea, constipation, pain 2. Hypophosphatemia 3. Fatigue 4. Joint pain

Answer 58

**Phosphate binder** Mechanism: * Binds phosphate in the gut (nonabsorbable) → ↓ phosphate absorption → ↓ serum phosphate → ↓ PTH Clinical Use: * Hyperphosphatemia caused by chronic kidney disease Adverse Effects 1. Gastrointestinal → nausea, vomiting, diarrhea, constipation, pain 2. Hypophosphatemia 3. Fatigue 4. Joint pain

Answer 59

1. Sodium polystyrene sulfonate (falling out of favor due to adverse effects) 2. Sodium zirconium cyclosilicate 3. Patiromer (cation-exchange polymer)

Answer 60

**Cation-exchange resins** Falling out of favor due to adverse effects Mechanism: * These drugs release Na+ or Ca2+ ions in the gut, which are exchanged for K+, thereby enhancing enteral K+ elimination. Clinical Use: * Nonurgent lowering of K+ * Often used for treatment of chronic hyperkalemia. * Onset of action takes several hours, so it is not recommended as monotherapy in acute hyperkalemia Adverse Effects: 1. Gastrointestinal upset (eg, diarrhea) 2. Hypokalemia 3. Hypercalcemia (due to luminal exchange of calcium) 4. Hypomagnesemia (due to off-target binding of other positive ions) 5. Sodium polystyrene sulfonate carries a risk of intestinal necrosis (especially if combined with the laxativesorbitol) and should be avoided in patients with abnormal bowel function. Interactions: * Bind to certain medications (eg, ciprofloxacin, levothyroxine)

Answer 61

**Cation-exchange resins** Mechanism: * These drugs release Na+ or Ca2+ ions in the gut, which are exchanged for K+, thereby enhancing enteral K+ elimination. Clinical Use: * Nonurgent lowering of K+ * Often used for treatment of chronic hyperkalemia. * Onset of action takes several hours, so it is not recommended as monotherapy in acute hyperkalemia Adverse Effects: 1. Gastrointestinal upset (eg, diarrhea) 2. Hypokalemia 3. Hypercalcemia (due to luminal exchange of calcium) 4. Hypomagnesemia (due to off-target binding of other positive ions) Interactions: * Bind to certain medications (eg, ciprofloxacin, levothyroxine)

Answer 62

**Cation-exchange polymer** Mechanism: * These drugs release Na+ or Ca2+ ions in the gut, which are exchanged for K+, thereby enhancing enteral K+ elimination. Clinical Use: * Nonurgent lowering of K+ * Often used for treatment of chronic hyperkalemia. * Onset of action takes several hours, so it is not recommended as monotherapy in acute hyperkalemia Adverse Effects: 1. Gastrointestinal upset (eg, diarrhea) 2. Hypokalemia 3. Hypercalcemia (due to luminal exchange of calcium) 4. Hypomagnesemia (due to off-target binding of other positive ions) Interactions: * Bind to certain medications (eg, ciprofloxacin, levothyroxine)

Answer 63

Mechanism: * Inhibit tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis. Clinical Use: * Reduce peripheral serotonin production in patients with carcinoid syndrome to treat diarrhea.

Answer 64

**Vitamin D analog** * Mechanism: * Activates the vitamin D receptor, a nuclear transcription factor * Acts by inhibiting T cell and keratinocyte proliferation and stimulating keratinocyte differentiation * Clinical Use: * Plaque psoriasis

ENDOCRINE PHARM Flashcards

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