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Endo-Repro Exam 2 > Lecture 1: Drugs for Diabetes > Flashcards

Lecture 1: Drugs for Diabetes Flashcards

1
Q

List the 3 rapid-acting insulin agents

A
  • Aspart
  • Lispro
  • Glusine
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2
Q

What is the drug that is an intermediate-acting insulin called?

A

Neutral Protamine Hagerdorn (NPH)

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3
Q

What are the 2 long-acting insulins?

A
  • Detemir
  • Glargine
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4
Q

Which mutations from the human sequence of insulin allow for fast absorption of the rapid-acting insulin drugs?

A

Block assembly of dimers and hexamers

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5
Q

What is the clinical use for the rapid-acting insulin drugs, aspart, lispro, and glulisine; how are they administered?

A

Post-prandial hyperglcemia - take before meal via SQ injections

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6
Q

What makes the absorption rate of short-acting, regular insulin, slower and less predictable?

A

Form hexamers, which are too bulky to be transported via endothelium into the blood stream

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7
Q

List 4 clinical uses for using short-acting, regular insulin?

A
  • Basal insulin maintenance
  • Overnight coverage
  • Postprandial hyperglycemia - but must inject 45 min before meal
  • Can be given IV in urgent situations
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8
Q

What is the composition of the intermediate-acting insulin, neutral protamine hagerdon, and how does this relate to its pharmacokinetics?

A
  • Complex of protamine w/ zinc insulin
  • Protamine has to be digested by tissue proteolytic enzymes before insulin can be absorbed
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9
Q

What is the clinical use of the intermediate-acting insulin, neutral protamine hagerdon (NPH)?

A
  • Basal insulin maintenance and/or overnight coverage
  • Use is declining due to being replaced by long-acting insulins
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10
Q

What is the molecular composition of the long-acting insulin, Detemir, and how is this related to its pharmacokinetics?

A
  • Lys 29 in B chain is myristoylated (lipid)
  • Rapid absorbed into blood but binds strongly to albumin
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11
Q

What is the molecular composition of the long-acting insulin, Glargine, and how is this related to its pharmacokinetics?

A
  • AA substitution in both A and B chains enhance crystal stability, change pKA of insulin
  • Soluble at low pH (4) but precipitates at pH 7
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12
Q

What is the clinical use of the long-acting insulins, Detemir and Glargine; how are they administered?

A
  • Basal insulin maintenance
  • 1-2 SQ injections daily
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13
Q

How does the peak of actions differ between the long-acting insulin Detmir and Glargine?

A
  • Detemir peaks from 3-9 hours
  • Glargine is peakless!
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14
Q

Which drugs are given for severe hyperkalemia and explain why each is given?

A
  • Insulin (IV) + glucose (to prevent hypoglycemic shock) + furosemide
  • Insulin (IV) rapidly activates Na/K-ATPase to shift K+ into cells
  • K+ is eliminated from the body using the loop diuretic, furosemide
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15
Q

List some potential AE’s of using insulin drugs.

A
  • Hypoglycemia = most common
  • Lipodystrophy
  • Resistance
  • Allergic rxns —> immediate type hypersensitivity = rare
  • Hypokalemia
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16
Q

How can resistance to exogenous insulin develop?

A
  • Pt’s commonly develop insulin binding antibodies
  • IgG antibodies can neutralize the action of insulin
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17
Q

What are 3 common causes of hypoglycemia as an AE in patient on insulin therapy?

A
  • Delayed of meal or a missed meal
  • Exercise —> ↑ consumption of glucose by muscle + hyperemic skin has ↑ rate of insulin absorption
  • Overdose of insulin
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18
Q

What is used in the tx of hypoglycemia as a complication of insulin therapy?

A
  • Glucose: juice or candy if conscious; IV glucose if unconscious
  • Diazoxide: inhibits release of insulin by beta cells
  • Glucagon (SQ)
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19
Q

What is the MOA of diazoxide and why is it used for hypoglycemia induced by insulin therapy?

A
  • Strong hyperglycemic agent –> K+-ATPchannelopener
  • Inhibits release of insulin by beta cells
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20
Q

Where is amylin secreted from and what is the amylin analog used for diabetics?

A
  • Pancreatic β-cells
  • Amylin analong drug = Pramlintide
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21
Q

List 4 actions of amylin secreted by pancreatic β-cells

A
  • Inhibits glucagon secretion
  • Enhances insulin sensitivity
  • ↓ gastric emptying (slows rate of intestinal glucose absorption)
  • Causes satiety
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22
Q

What are the clinical uses for the amylin analog, Pramlintide; how is it administered?

A
  • T1DM
  • T2DM pt’s who take mealtime insulin therapy
  • Injected SQ before mals as an ajunct to insulin therapy
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23
Q

What are some of the AE’s associated w/ the amylin analog, Pramlintide?

A
  • GI: nausea, vomiting, diarrhea, anorexia
  • Severe hypoglycemia: especially if used together w/ insulin (↓ dose of insulin)
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24
Q

What is a drug interaction you must be aware of when using the amylin analog, Pramlintide?

A

Enhances effects of anticholinergic drugs in GI tract –> Constipation

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25
Q

What are 2 ligands for GPCR-Gs which enhance the secretion of insulin?

A
  • β2-AR agonists
  • GLP-1 receptor agonists (incretins)
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26
Q

What are 2 ligands for GPCR-Gi which inhibit the secretion of insulin?

A
  • Somatostatin
  • α2-AR agonists (remember α2 uses a Gi)
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27
Q

Which cells synthesize and secrete GLP-1?

A

Intestinal L-cells

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28
Q

What are 5 actions of the incretin, GLP-1?

A
  • Promotes β-cell proliferation + insulin gene expression + glucose-dependent insulin secretion
  • Inhibits glucagon secretion
  • Causes satiety, by inhibiting gastric emptying
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29
Q

What are the 2 long-acting GLP-1 receptor agonists used for diabetes?

A
  • Exenatide
  • Liraglutide
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30
Q

Which long-acting GLP-1 receptor agonist has the longest half-life?

A
  • Liraglutide = 11-15 hrs ***
  • Exenatide = 2.4 hrs
31
Q

How was the long-acting GLP-1 receptor agonist, Exendatide made less susceptible to the hydrolysis by DPP-4?

A

Glycine substitution

32
Q

Which property of the long-acting GLP-1 agonist, Liraglutide, makes it have such a long half-life?

A

Lipid-modified - so is rapidly absorbed, but binds to albumin

33
Q

What is the clinical use of the long-acting GLP-1 receptor agonists?

A

Approved for T2DM pt’s who are NOT adequately controlled by metformin/sulfonylureas/thiazolidinediones

34
Q

What are some of the immediate and long-term AE’s of the long-acting GLP-1 receptor agonists?

A
  • GI: nausea, vomiting, diarrhea, and anorexia
  • Linked to cases of acute pancreatitis and pancreatic cancer!!!
35
Q

Why is there a lower risk of hypoglycemia when using long-acting GLP-1 receptor agonists vs. pramlintide (amylin analog)?

A
  • Exhibits glucose-DEPENDENT insulinotropism
  • GLP-1 receptor agonists stimulate insulin secretion during hyperglycemia but NOT during hypoglycemia
36
Q

What are the four DPP-4 inhibitors used in the tx of diabetes?

A
  • Sitagliptin
  • Alogliptin
  • Linagliptin
  • Saxagliptin

**The -gliptins

37
Q

What is the MOA of the DPP-4 inhibitors (-gliptins) used in diabetes?

A
  • Prevent the degradation of GLP-1 and other incretins
  • Leads to ↓ glucagon release, gastric emptying
  • ↑ glucose-dependent insulin release, satiety
38
Q

What is the clinical use for the DPP-4 inhibitors (-gliptins); how are they administered?

A
  • Adjunctive therapy to diet + exercise in pt’s w/ T2DM
  • Used as monotherapy and in combo w/ metformin/sulfonylureas/TZDs
  • Taken orally
39
Q

What are 3 AE’s associated with the DPP-4 inhibitors (-gliptins)?

A
  • Upper respiratory infections and nasopharyngitis
  • Linked to acute pancreatitis
  • Hypoglycemia (if combined w/ insulin secretagogues - their doses have to be adjusted)
40
Q

What are the three, 1st generation Sulfonylureas used for diabetes?

A
  • Chlorpropamide
  • Tolbutamide
  • Tolazamide
41
Q

What are the three, 2nd generation Sulfonylureas used for diabetes?

A
  • Glipizide
  • Glyburide
  • Glimepiride
42
Q

What is the MOA of the Sulfonylureas used for tx of diabetes?

A
  • Bind to sulfonylurea receptor (SUR) of pancreatic β-cells

- Block K+ current through Kir6.2 inwardly rectifying potassium channel

  • Cell depolarizes –> insulin release via ↑ Ca2+ influx
43
Q

What is the clinical use of Sulfonylureas for diabetes?

A

T2DM as a monotherapy or in combo w/ insulin or other anti-diabtetics

44
Q

List 4 of the AE’s assoc. with the Sulfonylureas used for diabetes

A
  • Hypoglycemia
  • Weight gain (↑ insulin release)
  • Secondary failure = pt’s who respond initially later cease to respond to sulfonylureas and develop unacceptable hyperglycemia
  • Dermatologic and general hypersensitivity rxns –> SULFA drugs!!!
45
Q

List 3 cross-reactivity drug interactions associated with the Sulfonylureas used for diabetes.

A
  • Sulfonamide antibiotics
  • Carbonic anhydrase inhibitors
  • Diuretics (thiazides, furosemide)
46
Q

List 3 drug interactions which enhance the hypoglycemic effect of Sulfonylureas.

A
  • Displaced from binding with plasma proteins by other highly protein bound drugs: sulfonamides, clofibrate, salicylates
  • Enhancing the effect on KATP channel: ethanol
  • Inhibition of CYP enzymes: azole antifungals, gemfibrozil, cimetidine, etc.
47
Q

List 3 drug interactions which decrease the glucose lowering effect of Sulfonylureas.

A
  • Inhibiting insulin secretion: beta-blockers and CCBs
  • Antagonizing their effect on KATP channel: diazoxide

- Inducing hepatic CYP enzymes: phenytoin, griseofulvin, rifampin, etc.

48
Q

What are the 2 non-sulfonylureas (meglitinides) used for tx of diabetes?

A
  • Nateglinide
  • Repaglinide
49
Q

What is the clinical use for the non-sulfonylureas (meglitinides); how are they administered route and timing?

A
  • Control of postprandial hyperglycemia in pt’s w/ T2DM
  • Taken orally BEFORE meal
  • Can be used either alone (isolated postprandial hyperglycemia) or in combo w/ other antidiabetic drugs
50
Q

List 3 AE’s associated with the non-sulfonylureas (meglitinides)?

A
  • Hypoglycemia
  • Secondary failure
  • Weight gain
51
Q

What is the MOA of the biguanide, Metformin?

A
  • Activation of AMP-dependent protein kinase, leading to:
  • Inhibition of lipogenesis and gluconeogenesis
  • ↑ in glucose uptake + glycolysis + FA oxidation + insulin sensitivity
  • Lowers glucose levels in hyperglycemic state (but not normoglycemic)
52
Q

What is the clinical use of Metformin?

A

Most commonly used oral agent for T2DM and is generally accepted as the FIRST-LINE tx

53
Q

List some of the advantages of using Metformin as a first-line agent for T2DM

A
  • Superior or equivalent glucose-lowering efficacy compared to other oral meds
  • Does not cause hypoglycemia or weight gain
  • Can be taken orally and used alone or in combo w/ other oral agents
  • Clinical trials show a ↓ risk of both macro- and microvascular complications
54
Q

What are the AE’s associated with Metformin?

A
  • Most common = GI = anorexia, N/V, diarrhea, abdominal discomfort
  • ↓ absorption of vit B12

- Lactic acidosis, especially under conditions of hypoxia, renal and hepatic insufficiency

55
Q

The use of Metformin is contraindicated in which patients?

A
  • Pt’s w/ conditions predisposing to tissue hypoxia (HF, COPD), renal failure, chronic alcoholism and cirrhosis
  • May cause lactic acidosis as AE, which can worsen hypoxia
56
Q

What are the 2 thiazolidinediones used for diabetes?

A
  • Pioglitazone
  • Rosiglitazone
57
Q

What is the MOA of the thiazolidinediones, pioglitazone and rosiglitazone?

A
  • Activate PPAR-γ (a nuclear receptor) expressed in fat, muscle, liver, and endothelium
  • ↑ insulin sensitivity and levels of adiponectin + ↑ GLUT4
58
Q

How are the thiazolidinediones, pioglitazone and rosiglitazone administered and what is significant about their pharmacokinetics?

A
  • Orally once daily
  • Onset is delayed –> full effect develops after 1-3 months
  • Effect persists after drugs are eliminated for weeks-months
59
Q

How are thiazolidinediones, pioglitazone and rosiglitazone metabolized and how does this effect the pt populations who can take the drugs?

A
  • Metabolized by the liver; so half-life can be reduced by CYP-inducer (rifampin) or prolonged by CYP-inhibitors (gemfibrosil)
  • Safe to administer to pt’s with renal failure
60
Q

What are the clinical uses for the thiazolidinediones, pioglitazone and rosiglitazone?

A
  • Use in T2DM, alone or in combo w/ other antidiabetics
  • Shown to delay progression from prediabetes to T2DM***
  • Euglycemic drugs (no hypoglycemia when used alone)
61
Q

What are some of the AE’s associated with thiazolidinediones, pioglitazone and rosiglitazone?

A
  • Weight gain and Edema (incidence doubled if administered w/ insulin)
  • Exacerbation of HF
  • ↑ total cholesterol and LDL-C (rosiglitazone)
  • ↑ risk of fracture –> osteoporosis (especially postmenopausal women)
62
Q

Which patients are the thiazolidinediones, pioglitazone and rosiglitazone contraindicated in?

A

Pt’s w/ NYHA class III or IV heart failure

63
Q

By which mechanism are the thiazolidinediones, pioglitazone and rosiglitazone associated with edema as an AE?

A
  • ↑ vascular permeability
  • ↑ expressio of ENaC –> ↑ Na+ and H2O reabsorption in collecting duct
64
Q

What are the 3 SGLT2 inhibitors used for diabetes?

A
  • Canagliflozin
  • Dapagliflozin
  • Empagliflozin
65
Q

What is the MOA of the SGLT2 inhibitors?

A
  • Block reabsorption of glucose in proximal convoluted tubule
  • ↑ glucose excretion and reduced hyperglycemia
66
Q

Other than ↑ excretion of glucose in the urine, what are 5 other effects of SGLT2 inhibitors?

A
  • Cause osmotic diuresis
  • Induce weight loss
  • ↓ BP
  • ↓ plasma levels of uric acid
  • Do not cause hypoglycemia when used alone
67
Q

What is the clinical use, route of administration, and timing for the SGLT2 inhibitors (-gliflozins)?

A
  • Taken orally before the first meal 1x/day
  • Used as adjunct to diet + exercise in adults w/ T2DM
68
Q

Which underlying condition should be corrected before using SGLT2 inhibitors (-gliflozins)?

A

Hypovolemia

69
Q

List 6 AE’s associated with the SGLT2 inhibitors (-gliflozins).

A
  • Hypotension
  • Hypovolemia
  • Hypoglycemia if combo w/ insulin or insulin secretagogues
  • Genital (mycotic) and UTI’s
  • Renal function impairment due to ↓ GFR
  • Hyperkalemia –> esp. in pt’s w/ impaired renal function and those on ACEIs, ARBs, and K+-sparing diuretics
70
Q

What are the 2 α-glycosidase inhibitors used for diabetes?

A
  • Acarbose
  • Miglitol
71
Q

What is the MOA of the α-glycosidase inhibitors, acarbose and miglitol?

A
  • Competitively inhibit intestinal brush border α-glycosidases —> delayed CHO hydrolysis and glucose absorption
  • ↓ postprandial hyperglycemia to create insulin-sparing effect
72
Q

What is the clinical use for the α-glycosidase inhibitors, acarbose and miglitol, how and when are they administered, and what are their benefits?

A
  • Use in T2DM as monotherapy or in combo w/ other oral antidiabetics or insulin
  • Taken orally at mealtime
  • Do not cause hypoglycemia when used alone
  • Do not cause weight gain
73
Q

What are the AE’s of the α-glycosidase inhibitors, acarbose and miglitol?

A
  • Most common = malabsorption, flatulence, diarrhea, and bloating
  • Hypoglycemia when used in combo with insulin or insulin secretagogues
  • Not recommended if kidney function impaired
74
Q

What are drug-drug interactions specific to the α-glycosidase inhibitor acarbose and to miglitol?

A
  • ↓ absorption of digoxin (acarbose)
  • ↓ absorption of propranolol and ranitidine (miglitol)

Endo-Repro Exam 2 (11 decks)

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