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Therapeutics 2 Exam 2 -Diabetes > Type 2 Diabetes and Drugs > Flashcards

Type 2 Diabetes and Drugs Flashcards

1
Q

Which tissues/organs are affected in Type 2 diabetes?

A

Liver
—Hepatic glucose production increases

Pancreas
—Plasma glucagon secretion increases

Skeletal muscle
—Glucose utilization decreases

Adipose Tissue
—Lipolysis increases

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2
Q

What is Type 2 diabetes a combination of?

A

Insulin Secretion + Insulin Resistance

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3
Q

Which agents enhance insulin secretion?
(used for hypoglycemia)

A

-Sulfonylureas
(tolbutamide, tolazamide, chlorpropamide, glyburide, glipizide, glimepiride)

-Meglitinides
(nateglinide, repaglinide)

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4
Q

What is required for Type 2 diabetics to be able to use sulfonylureas?

A

-Must have functioning beta cells

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5
Q

What effects do sulfonylureas have on patients with Type 2 diabetes?

A

-Restore first phase insulin release
-Increase beta cell sensitivity to glucose
-Increase glucose stimulated insulin release

*Overall: increase insulin release

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6
Q

What needs to happen for insulin to be released from pancreatic beta cells? (High Glucose levels)

A
  1. Glucose is taken up into the cell by GLUT2 transporters
  2. Glucokinase phosphorylates glucose to G6P
  3. G6P is metabolized and ATP is created
  4. ATP binds to the K+ channel which CLOSES it
  5. This depolarizes the membrane and opens Ca2+ channels
  6. These Ca2+ channels release insulin
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7
Q

How do sulfonylureas work?

A

They bind to the sulfonylurea receptor found on K+ channels
–this inhibits the K+ channel from opening, ultimately depolarizing the membrane and opening Ca2+ channels so that insulin can be released

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8
Q

What happens to insulin release when there are LOW levels of glucose present?

A

No insulin is secreted

-Glucose is not brought into the pancreatic beta cells so there is more ADP than ATP

-ADP binds to the K+ channel and OPENS it

-This stabilizes the negative resting membrane potential and prevents Ca2+ channels from opening

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9
Q

Which is faster: Glucose or Tolbutamide?

A

Tolbutamide
-able to immediately bind to the K+ channel and depolarize the membrane

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10
Q

What are the first generation sulfonylureas?

A

Tolbutamide
Tolazamide
Chloropropamide

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11
Q

What are the second generation sulfonylureas?

A

Glipizide
Glyburide
Glimepiride

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12
Q

What is the most potent 1st generation sulfonylurea?

A

Chlorpropamide

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13
Q

What is the least potent 1st generation sulfonylurea?

A

Tolbutamide

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14
Q

How does the potency of first generation sulfonylureas compare to the potency of second generation sulfonylureas?

A

2nd generations are much more potent!

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15
Q

What are the two more potent 2nd generation sulfonylureas?

A

Glyburide and Glimepiride

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16
Q

What word-endings indicate that a drug is a sulfonylurea?

A

“amide” and “ide”

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17
Q

What form of insulin are 2nd generation sulfonylureas comparable to in terms of the duration they work in the body?

A

Long-lasting insulins

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18
Q

How do Meglitinides work?

A

Have the same mechanism of action as sulfonylureas
-Bind the K+ channel and prevent it from opening

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19
Q

What is the onset/duration of action of Meglitinides?

A

-Quick onset
-Short duration of action

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20
Q

When should Meglitinides be taken?

A

Before each meal

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21
Q

What form of insulin are Meglitinides comparable to?

A

Fast-Acting Insulins

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22
Q

How does the half-life of Nateglinide (Starlix) compare to that of Repaglinide (Prandin) and how does this affect the risk for hypoglycemia?

A

Nateglinide (Starlix) has a shorter half-life
*Less risk of hypoglycemia

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23
Q

Can Nateglinide (Starlix) be used with Metformin?

A

Yes

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24
Q

What are the possible adverse effects of sulfonylureas?

A

-Hypoglycemia
-Cardiovascular events + Mortality (some evidence)
-G.I. problems
-Weight Gain
-Secondary failures

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25
Q

Why are sulfonylureas prone to causing hypoglycemia?

A

They have a long half-life

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26
Q

Which sulfonylurea is most likely to cause hypoglycemia?

A

Glyburide

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27
Q

What are secondary failures and why can these occur with sulfonylureas?

A

When patients are on sulfonylureas for a long time, they can experience a decreasing ability to secrete insulin
*Patient will likely have to eventually go on insulin

-Caused by extra stress on the beta cells that reduces their functioning over time

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28
Q

What two drugs are the biggest concerns when taking sulfonylureas due to an interaction occurring?

A

-Alcohol
-High Dose Salicylates

**The drugs have their own hypoglycemic effects and therefore add onto the hypoglycemic effect of sulfonylureas

(Increase hypoglycemic effect)

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29
Q

Which drugs enhance the incretin effect?

A

GLP-1R Agonists

GLP-1 & GIP Dual Agonists

DPP-IV Inhibitors

Amylin Analogs

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30
Q

What is the incretin effect?

A

Oral glucose stimulates a larger insulin response than IV glucose

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31
Q

Where is GIP excreted from?

A

K cells of the duodenum

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32
Q

Where is GLP-1 excreted from?

A

L cells in the ileum

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33
Q

What is the result of GIP and GLP-1 release when they are able to stimulate beta cells in the pancreas?

A

-Increase insulin secretion
-Increase beta cell proliferation and protection from apoptosis

Demonstrate the incretin effect

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34
Q

What is the role of DPP-IV protease?

A

Degrades GIP and GLP-1

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35
Q

When are GIP and GLP-1 released from the intestines?

A

When blood glucose is elevated after a meal

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36
Q

Is the release of GLP-1 (stimulated insulin secretion) glucose dependent?

A

YES

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37
Q

What affect does GLP-1 have on the beta cells?

A

Increases their mass AND maintains their function

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38
Q

Does GLP-1 stimulate insulin secretion by itself?

A

NO
-amplifies the ability of glucose to stimulate insulin secretion

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39
Q

How does Type 2 Diabetes affect the Incretin Effect?

A

Incretin Effect is diminished

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40
Q

How does Type 2 diabetes affect GLP-1 levels?

A

GLP-1 levels are decreased

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41
Q

What are the two strategies to providing GLP-1 treatment in Type 2 diabetes?

A

1) Provide a long-lasting GLP-1 analog
2) Prevent degradation of endogenous GLP-1

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42
Q

What are the benefits of GLP-1 treatment?

A

-Reduce hyperglycemia (low risk of hypo)
-Weight loss
-Increase beta cell mass

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43
Q

What are the GLP-1R Agonists? (AKA GLP-1 Analogs)

A

-Exenatide
-Liraglutide
-Lixisenatide
-Dulaglutide
-Semaglutide

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44
Q

What word-ending indicates that a drug is a GLP-1R agonist?

A

“tide” some exceptions

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45
Q

What warnings are associated with ALL GLP-1R Agonists (GLP-1 Analogs)?

A

-Nausea and Vomiting
-Pancreatitis
-Risk of thyroid c-cell tumors (monitor calcitonin levels)

Contraindicated in patients with family history of medullary thyroid cancer

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46
Q

What is Exenatide and how does it work?

A

GLP-1R Agonist (GLP-1 Analog)
-Is a 39 amino acid peptide originating from Gila Monster saliva

*Activates GLP-1 Receptor
*Enhances 1st phase secretion
*Has a longer half-life than GLP-1 (resistant to degredation)

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47
Q

How often is Exenatide admistered?

A

-Twice daily injection
-Once weekly injection

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48
Q

Can Exenatide be co-administered with other medications?

A

YES:
-Metformin
-TzDs
-Sulfonylureas

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49
Q

What is Liraglutide (Victoza) and what is its structure?

A

GLP-1R Agonist (GLP-1 Analog)

*Most other GLP-1 analog drugs have an alanine that is changed so that they cannot be cleaved by DPP-IV

*Liraglutide does not have this change!!!!!
**Instead: has a fatty acid bound to it to enhance its duration of action by binding to serum albumin

50
Q

How often is Liraglutide injected?

A

daily

51
Q

Can Liraglutide (Victoza) be co-administered with other medications?

A

YES:
-Metformin
-TzDs
-Sulfonylureas

52
Q

What is Dulaglutide (Trulicity) and what is its structure?

A

GLP-1R Agonist (GLP-1 Analog)

-The Alanines(A) in the molecule are changed to Valines(V) to prevent inactivation by DPP-IV

53
Q

How often is Dulaglutide (Trulicity) injected?

A

Once weekly
Very potent

54
Q

How are GLP-1 agonist peptides released from the IgG Fc domain?

A

They are released slowly by the reduction of disulfide bonds in their linker region

55
Q

What is Lixisenatide (Adlyxin) and what is its structure?

A

GLP-1R Agonist (GLP-1 Analog)

Has the structure of exenatide but with a polylysine tail!
*IS NOT A GLP-1 SEQUENCE DERIVATIVE

56
Q

How often is Lixisenatide (Adlyxin) injected?

A

Once daily before breakfast

57
Q

What is Soliqua?

A

A combination product with Glargine and Lixisenatide

(Basal Insulin and GLP-1 Receptor Agonist)

58
Q

What is Semaglutide (Ozempic) and what is its structure?

A

GLP-1R Agonist (GLP-1 Analog)

-The alanine in the molecule is replaced with a 2-Aminoisobutyrate (a non-natural amino acid)
–This helps the molecule to not be cleaved by DPP-IV

59
Q

How often is Semaglutide (Ozempic) injected?

A

Once weekly
*Very potent

–Bound to serum albumin so it has a long half-life

60
Q

What is the FIRST AND ONLY orally available GLP-1 Receptor Agonist?

A

Rybelsus (oral semaglutide)

61
Q

What is Xultophy?

A

A combination product with Degludec and Liraglutide

(Insulin and GLP-1 Receptor Agonist)

62
Q

What two pathways do GIP and GLP-1 stimulate?

A

cAMP Pathway

ERK1/2 Pathway

63
Q

What is Mounjaro (Tirzepatide)?

A

Full GIP Receptor Agonist
+
Biased GLP-1 Receptor

**Dual agonist, activates both receptors!

64
Q

Does Mounjaro (Tirzepatide) prefer to couple to cAMP or Beta-arrestin?

A

cAMP

**preferring beta-arrestin would lead to desensitization of GLP-1 receptors

65
Q

How does Mounjaro (Tirzepatide) work?

A

Reduces internalization (desensitization) of GLP-1 receptors to maintain the GLP-1 effect

66
Q

How often is Mounjaro (tirzepatide) injected?

A

Once weekly

67
Q

How does Mounjaro (Tirzepatide) effect A1C and Body Weight in comparison to GLP-1 receptor agonists?

A

Mounjaro lowers A1C and bodyweight MORE EFFECTIVELY than GLP-1 receptor agonists

68
Q

What effect does inhibition of DPP-4 have on release of the incretin hormones?

A

Both GLP-1 and GIP have a GREATER release

69
Q

What are the 4 Inhibitors of DPP-4?

A

-Sitagliptin (Januvia)
-Saxagliptin (Onglyza)
-Linagliptin (Tradjenta)
-Alogliptin (Nesina)

70
Q

What word ending indicates that a drug is a DPP-4 Inhibitor?

A

“gliptin”

71
Q

What is the mechanism of action of DPP-4 inhibitors?

A

Enhance the actions of endogenous GLP-1

-Reduce hyperglycemia
-Reduce A1C

72
Q

How do DDP-4 inhibitors work?

A

They bind in the active site of DDP-4 and block the incretins from being able to access it

73
Q

How often are DDP-4 inhibitors dosed?

A

Once daily
**orally

74
Q

What treatment is available for people who are NOT OPEN TO INJECTIONS?

A

DDP-4 inhibitors
(oral)

75
Q

Why is there a low risk of hypoglycemia associated with DDP-4 Inhibitors?

A

They work through the incretin effect and do not directly stimulate insulin secretion

76
Q

Are DDP-4 inhibitors affected by weight?

A

NO, they are weight-neutral

77
Q

Which DPP-4 Inhibitors are Not Extensively Metabolized, and Excreted in the Urine (by the kidney)?

A

Januvia
Nesina

78
Q

Which DPP-4 Inhibitor is Not Extensively Metabolized, and Excreted in Feces (by the liver)?

A

Tradjenta

79
Q

Which DPP-4 Inhibitor is a CYP3A4/5 substrate and has a major metabolite that is active?
(also secreted in the urine by the kidney)

A

Onglyza

80
Q

What are the 3 severe side effects associated with DPP-4 Inhibitors?

A

-Pancreatitis
-Joint Pain
-Heart Failure

*also associated with GLP-1 agonists

81
Q

What alternative cell is DPP-4 found on besides endothelial cells, and what side effect can this cause?

A

Immune Cells
-Can cause reduced white blood cell counts which can lead to infections
-Potential risk of cancer

82
Q

What is an alternative strategy to using DPP-4 inhibitors?

A

Positive Allosteric Modulators
–Make the low concentrations of incretins present more effective

83
Q

What is the one Amylin Analog available?

A

Pramlinitide (Symlin)

84
Q

What are the effects of Pramlinitide (Symlin)?

A

-Slows gastric emptying
-Decreases food intake
-Inhibits glucagon secretion

85
Q

What effect does Pramlinitide (Symlin) have on postprandial blood glucose levels?

A

It blunts these levels

86
Q

How is Pramlinitide (Symlin) administered?

A

In conjunction with insulin
*For use in both Type 1 and Type 2 diabetes

87
Q

Which agents can reduce glucose absorption or increase glucose excretion?

A

alpha-glucosidase inhibitors

SGLT2 inhibitors

88
Q

What are the alpha-glucosidase inhibitors?

A

Acarbose
Miglitol

89
Q

What is the mechanism of action of alpha-glucosidase inhibitors?

A

Inhibit alpha-glucosidase which cleaves disaccharides into monosaccharides so that they are absorbed better (do not want this)

*decreases carbohydrate absorption from the intestine

90
Q

How does the absorption of the two alpha-glucosidase inhibitors differ?

A

Acarbose: minimally absorbed (stays in GI tract)

Miglitol: completely absorbed (gets into bloodstream)

91
Q

What are the adverse affects of alpha-Glucosidase Inhibitors?

A

GI affects (diarrhea, nausea, flatulence)
Acarbose: liver damage

92
Q

Why are alpha-glucosidase inhibitors not the 1st choice of drug to use?

A

They can raise the A1C

93
Q

What are the SGLT2 Inhibitors?

A

Canagliflozin
Empagliflozin
Dapagliflozin
Ertugliflozin

94
Q

What word ending indicated that a drug s an SGLT2 Inhibitor?

A

“gliflozin”

95
Q

How do SGLT2 inhibitors work?

A

Inhibit the Sodium Glucose coTransporter 2

–Decreases the threshold for glucose excretion in urine to reduce blood glucose levels
(more glucose excreted through urine)

96
Q

What other substance besides glucose has increased excreted in the presence of SGLT2 Inhibitors?

A

Sodium

97
Q

How are SGLT Inhibitors given?

A

Orally!

*Adjunct to diet + exercise

98
Q

What are some benefits of using SGLT2 Inhibitors?

A

-Lower A1C
-Produce weight loss

99
Q

What are some adverse effects of SGLT2 inhibitors?

A

-UTI’s and genital infections
-Increased urine flow depletion/hypotension
-Diabetic ketoacidosis (DKA)

Increased risk of lower limb amputation –Canagliflozin

100
Q

When are SGLT2 Inhibitors Contraindicated?

A

-In patients with renal impairment
(this drug requires renal activity to work)

101
Q

What agents reduce insulin resistance/lipotoxicity?

A

Biguanides

Thiazoladinediones

102
Q

What is Metformin (Glucophage)?

A

Biguanide
-Antihyperglycemic agent
-Oral antidiabetic drug
*Does not stimulate insulin secretion, just targets the tissues that respond to insulin and increases their responsiveness

103
Q

What is a benefit to using Metformin instead of older biguanides?

A

Lower risk for lactic acidosis

104
Q

What are the advantages of using a biguanide instead of sulfonylureas?

A

-Rarely causes hypoglycemia
-Rarely causes weight gain

105
Q

What is the mechanism of action for Metformin (Glucophage)?

A

Activates AMP-activated kinase (AMPK)
-increases sensitivity to insulin in liver, fat, and muscle

106
Q

How is metformin dosed?

A

Three-times daily
**not very potent

107
Q

How does metformin work in the liver?

A

-Works on complex 1 of the electron transport chain

-Inhibits ATP production and increases AMP

-AMP accumulates and inhibits Fructose- 1,6-bisphosphate in gluconeogenesis

-This reduces export of glucose by the liver

108
Q

How does metformin work in the skeletal muscle?

A

-AMP accumulates during exercise and activates AMPK

-AMPK phosphorylates TBC1D1/4 which promotes GTPase activity of Rab

-Rab dissociates from GLUT4

-GLUT4 is translocated to the membrane

-GLUT 4 takes glucose out of the blood and brings it into the skeletal muscle

109
Q

When is metformin contraindicated?

A

In disorders that increase the tendency for lactic acidosis

110
Q

What vitamin has decreased absorption when a patient is taking metformin?

A

B-12

111
Q

What effects does metformin have on the blood-lipid profile?

A

-Decreased serum triglycerides
-Decreased serum LDL

*reduces risk of cardiovascular effects

112
Q

What is the first drug given to a patient diagnosed with Type 2 diabetes?

A

Metformin

113
Q

What is the mechanism of action of thiazolidinediones?

A

Activate peroxisome proliferator-activated receptor gamma (PPARy)
–a transcription factor

-Decrease insulin resistance or improve target cell response

114
Q

What is the main target of thiazolidinediones?

A

Adipocytes
-enhances free fatty uptake into fat to reduce serum levels

115
Q

What are the two thiazolidinediones?

A

Rosiglitazone (Avandia) and Pioglitazone (Actos)

116
Q

What word ending indicates that a drug is a thiazolidinedione?

A

“glitazone”

117
Q

Why is thiazolidinedione prescribing limited?

A

They cause cardiovascular toxicities

118
Q

What are the contraindications for thiazolidinediones?

A

Contraindicated in:
NYHA (advanced stage heart failure) Class III or IV

119
Q

What is the function of Resistin, what are its levels in Type 2 diabetes, and what are its mRNA levels in response to thiazolidinediones?

A

Function: Stimulates glucose export by liver + causes insulin resistance

Levels in Type 2 Diabetics are: Elevated

mRNA levels in response to thiazolidinediones are: Decreased

120
Q

What is the function of Adiponectin, what are its levels in Type 2 diabetes, and what are its mRNA levels in response to thiazolidinediones?

A

Function: Reduces blood glucose and insulin resistance

Levels in Type 2 Diabetics are: Decreased

mRNA levels in response to thiazolidinediones are: Increased

121
Q

What is the function of TNFa, what are its levels in Type 2 diabetes, and what are its mRNA levels in response to thiazolidinediones?

A

Function: Stimulates lipolysis, stimulates insulin resistance

Levels in Type 2 Diabetics are: Increased

mRNA levels in response to thiazolidinediones are: Decreased

Therapeutics 2 Exam 2 -Diabetes (4 decks)

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