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Endo II Exam 2 - Pharm and CLMD > 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
What are 2 ligands for GPCR-Gs which enhance the secretion of insulin?
- **β2-AR** agonists - **GLP-1** receptor agonists (incretins)
26
What are 2 ligands for GPCR-Gi which inhibit the secretion of insulin?
- **Somatostatin** - **α2-AR** agonists (remember α2 uses a **Gi**)
27
Which cells synthesize and secrete GLP-1?
**Intestinal L-cells**
28
What are 5 actions of the incretin, GLP-1?
- **Promotes** β-cell proliferation + **insulin gene** expression + glucose-dependent **insulin secretion** - **Inhibits** glucagon secretion - Causes **satiety**, by **inhibiting** gastric emptying
29
What are the 2 long-acting GLP-1 receptor agonists used for diabetes?
- Exena**tide** - Liraglu**tide**
30
Which long-acting GLP-1 receptor agonist has the longest half-life?
- **Liraglutide** = 11-15 hrs **\*\*\*** - **Exenatide** = 2.4 hrs
31
How was the long-acting GLP-1 receptor agonist, Exendatide made less susceptible to the hydrolysis by DPP-4?
**Glycine** substitution
32
Which property of the long-acting GLP-1 agonist, Liraglutide, makes it have such a long half-life?
**Lipid-modified** - so is **rapidly** absorbed, but binds to **albumin**
33
What is the clinical use of the long-acting GLP-1 receptor agonists?
Approved for **T2DM** pt's who are **NOT** adequately controlled by metformin/sulfonylureas/thiazolidinediones
34
What are some of the immediate and long-term AE's of the long-acting GLP-1 receptor agonists?
- **GI:** nausea, vomiting, diarrhea, and anorexia - Linked to cases of **acute pancreatitis** and **pancreatic cancer!!!**
35
Why is there a lower risk of hypoglycemia when using long-acting GLP-1 receptor agonists vs. pramlintide (amylin analog)?
- Exhibits **glucose-DEPENDENT** insulinotropism - GLP-1 receptor agonists stimulate insulin secretion during hyperglycemia but NOT during hypoglycemia
36
What are the four DPP-4 inhibitors used in the tx of diabetes?
- **S**ita**gliptin** - **A**lo**gliptin** - **L**ina**gliptin** - **S**axa**gliptin** \*\*The **-gliptins**
37
What is the MOA of the DPP-4 inhibitors (-gliptins) used in diabetes?
- Prevent the degradation of GLP-1 and other incretins - Leads to ↓ glucagon release, gastric emptying - ↑ glucose-dependent insulin release, satiety
38
What is the clinical use for the DPP-4 inhibitors (-gliptins); how are they administered?
- **Adjunctive** therapy to **diet** + **exercise** in pt's w/ **T2DM** - Used as **monotherapy** and in **combo** w/ metformin/sulfonylureas/TZDs - Taken **orally**
39
What are 3 AE's associated with the DPP-4 inhibitors (-gliptins)?
- **Upper respiratory infections** and **nasopharyngitis** - Linked to **acute pancreatitis** - **Hypo**glycemia (if combined w/ insulin secretagogues - their doses have to be adjusted)
40
What are the three, **1st** **generation** Sulfonylureas used for diabetes?
- Chlorprop**amide** - Tolbut**amide** - Tolaz**amide**
41
What are the three, **2nd generation** Sulfonylureas used for diabetes?
- **Gl**ipiz**ide** - **G****l**ybur**ide** - **Gl**imepir**ide**
42
What is the MOA of the Sulfonylureas used for tx of diabetes?
- 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
What is the clinical use of Sulfonylureas for diabetes?
**T2DM** as a **monotherapy** or in **combo** w/ **insulin** or other **anti-diabtetics**
44
List 4 of the AE's assoc. with the Sulfonylureas used for diabetes
- **Hypo**glycemia - **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
List 3 cross-reactivity drug interactions associated with the Sulfonylureas used for diabetes.
- **Sulf**onamide antibiotics - **Carbonic anhydrase inhibitors** - **Diuretics** (thiazides, furosemide)
46
List 3 drug interactions which enhance the hypoglycemic effect of Sulfonylureas.
- **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
List 3 drug interactions which decrease the glucose lowering effect of Sulfonylureas.
- **Inhibiting** insulin secretion: **beta-blockers** and **CCBs** - **Antagonizing** their effect on **KATP** channel: **diazoxide** **-** **Inducing** hepatic **CYP** enzymes: **phenytoin, griseofulvin, rifampin, etc.**
48
What are the 2 non-sulfonylureas (meglitinides) used for tx of diabetes?
- Nate**glinide** - Repa**glinide**
49
What is the clinical use for the non-sulfonylureas (meglitinides); how are they administered route and timing?
- 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
List 3 AE's associated with the non-sulfonylureas (meglitinides)?
- **Hypo**glycemia - **Secondary failure** - **Weight gain**
51
What is the MOA of the biguanide, Metformin?
- 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 **normo**glycemic)
52
What is the clinical use of Metformin?
**Most commonly** used **oral** agent for **T2DM** and is generally accepted as the **FIRST-LINE tx**
53
List some of the advantages of using Metformin as a first-line agent for T2DM
- **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
What are the AE's associated with Metformin?
- **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
The use of Metformin is contraindicated in which patients?
- 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
What are the 2 thiazolidinediones used for diabetes?
- Pio**glitazone** - Rosi**glitazone**
57
What is the MOA of the thiazolidinediones, pioglitazone and rosiglitazone?
- **Activate PPAR-**γ (a **nuclear receptor**) expressed in **fat**, **muscle**, **liver**, and **endothelium** - ↑ **insulin sensitivity** and **levels of adiponectin +** ↑ **GLUT4**
58
How are the thiazolidinediones, pioglitazone and rosiglitazone administered and what is significant about their pharmacokinetics?
- **Orally** once daily - **Onset is delayed** --\> **full effect** develops after **1-3 months** - Effect **persists** after drugs are eliminated for **weeks-months**
59
How are thiazolidinediones, pioglitazone and rosiglitazone metabolized and how does this effect the pt populations who can take the drugs?
- **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
What are the clinical uses for the thiazolidinediones, pioglitazone and rosiglitazone?
- 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
What are some of the AE's associated with thiazolidinediones, pioglitazone and rosiglitazone?
- **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
Which patients are the thiazolidinediones, pioglitazone and rosiglitazone contraindicated in?
Pt's w/ **NYHA class III** or **IV heart failure**
63
By which mechanism are the thiazolidinediones, pioglitazone and rosiglitazone associated with edema as an AE?
- ↑ vascular **permeability** - ↑ expressio of **ENaC** --\> ↑ **Na+** and **H2O reabsorption** in **collecting duct**
64
What are the 3 SGLT2 inhibitors used for diabetes?
- Cana**gliflozin** - Dapa**gliflozin** - Empa**gliflozin**
65
What is the MOA of the SGLT2 inhibitors?
- Block **reabsorption** of glucose in **proximal convoluted tubule** - ↑ **glucose excretion** and **reduced hyperglycemia**
66
Other than ↑ excretion of glucose in the urine, what are 5 other effects of SGLT2 inhibitors?
- Cause **osmotic diuresis** - Induce **weight loss** - ↓ **BP** - ↓ plasma levels of **uric acid** - Do **not** cause **hypo**glycemia when used alone
67
What is the clinical use, route of administration, and timing for the SGLT2 inhibitors (-gliflozins)?
- Taken **orally** before the **first meal** 1x/day - Used as **adjunct** to **diet** + **exercise** in **adults** w/ **T2DM**
68
Which underlying condition should be corrected before using SGLT2 inhibitors (-gliflozins)?
**Hypovolemia**
69
List 6 AE's associated with the SGLT2 inhibitors (-gliflozins).
- **Hypo**tension - **Hypo**volemia - **Hypo**glycemia if combo w/ insulin or insulin secretagogues - **Genital** (mycotic) and **UTI's** - **Renal function impairment** due to ↓ GFR - **Hyper**kalemia --\> esp. in pt's w/ impaired renal function and those on ACEIs, ARBs, and K+-sparing diuretics
70
What are the 2 α-glycosidase inhibitors used for diabetes?
- Acarbose - Miglitol
71
What is the MOA of the α-glycosidase inhibitors, acarbose and miglitol?
- **Competitively** **inhibit** intestinal brush border α-glycosidases ---\> **delayed** CHO hydrolysis and glucose absorption - ↓ **postprandial hyperglycemia** to create **insulin-sparing effect**
72
What is the clinical use for the α-glycosidase inhibitors, acarbose and miglitol, how and when are they administered, and what are their benefits?
- 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
What are the AE's of the α-glycosidase inhibitors, acarbose and miglitol?
- **Most common** = malabsorption, flatulence, diarrhea, and bloating - **Hypoglycemia** when used in combo with insulin or insulin secretagogues - Not recommended if **kidney function** impaired
74
What are drug-drug interactions specific to the α-glycosidase inhibitor acarbose and to miglitol?
- ↓ absorption of **digoxin** (**acarbose**) - ↓ absorption of **propranolol** and **ranitidine** (**miglitol**)

Endo II Exam 2 - Pharm and CLMD (7 decks)

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