"Pharmacology Oral Glycemics I & II Ruth Weinstock" Flashcards
1
Q
What causes type 1 DM?
A
Autoimmune destruction of insulin- producing pancreatic beta cells
Insulin therapy is required
2
Q
How does a healthy pancreas work in the islets of Langerhans?
A
α-cells secrete glucagon • β-cells secrete insulin
3
Q
How do the islets of Langerhans work in a person with T2DM?
A
α-cells dysfunction: secrete inappropriately high levels of glucagon
Fewer β-cells: secrete insufficient levels of insulin
β-cell mass declines over time
T2DM Is Marked by Blunted Insulin Response and Inadequate Glucagon Suppression After Meals
4
Q
What are the functions of glucagon-like hormone (GLP-1)?
A
- Enhances glucose-dependent insulin secretion
- Slows gastric emptying
- Suppresses glucagon secretion
- Promotes satiety
- Receptors in the islet cells, CNS, elsewhere
- Metabolized rapidly (half-life 2-3 min) by DPP-4 (dipepetidyl peptidase-4)
5
Q
T/F: GLP-1 release is reduced in T2DM?
A
True
Without insulin, effect of eating produces hyperglycemia
6
Q
What is the first line pharmacological therapy for T2DM?
A
At the time of type 2 diabetes diagnosis, initiate metformin therapy along with lifestyle interventions, unless metformin is contraindicated
In newly diagnosed type 2 diabetes patients with markedly symptomatic and/ or elevated blood glucose levels or A1C, consider insulin therapy, with or without additional agents, from the
outset
7
Q
If noninsulin monotherapy is unsuccessful in the treatment of T2DM, what is the next step?
A
add a second oral agent, a GLP-1 receptor agonist, or insulin
8
Q
Class: Metformin
*Tx of Hyperglycemia in T2DM
A
Biguanide
9
Q
MOA: Metformin
*Tx of Hyperglycemia in T2DM
A
Reduces hepatic glucose production by Activating AMP-kinase and inhibits mitochondrial isoform of glycerophosphate dehydrogenase
10
Q
What are the advantages of metformin?
*Tx of Hyperglycemia in T2DM
A
No weight gain (weight neutral)
• No hypoglycemia
• Reduction in cardiovascular events and mortality
• Possibly less cancer
11
Q
What are the disadvantages of metformin?
*Tx of Hyperglycemia in T2DM
A
Gastrointestinal side effects (diarrhea, abdominal cramping, anorexia)
• Lactic acidosis (rare)
• Vitamin B12 deficiency
12
Q
In what patient population is metformin contraindicated?
*Tx of Hyperglycemia in T2DM
A
In patients with reduced kidney function
13
Q
Class: Glibenclamide/Glyburide
*Tx of Hyperglycemia in T2DM
A
Sulfonylureas (2nd generation)
14
Q
Class: Glipizide
*Tx of Hyperglycemia in T2DM
A
Sulfonylureas (2nd generation)
15
Q
Class: Gliclazide
*Tx of Hyperglycemia in T2DM
A
Sulfonylureas (2nd generation)
16
Q
Class: Glimepiride
*Tx of Hyperglycemia in T2DM
A
Sulfonylureas (2nd generation)
17
Q
What is the MOA of the sulfonylureas drugs? • Glibenclamide/Glyburide • Glipizide • Gliclazide • Glimepiride
*Tx of Hyperglycemia in T2DM
A
Closes K-ATP channels on beta cell plasma membranes to increase insulin secretion
18
Q
T/F: The sulfonylureas drugs are well tolerated.
*Tx of Hyperglycemia in T2DM
A
True • Glibenclamide/Glyburide • Glipizide • Gliclazide • Glimepiride
19
Q
What are the disadvantages of the sulfonylureas drugs?
*Tx of Hyperglycemia in T2DM
A
- Relatively glucose-independent stimulation of insulin secretion: Hypoglycemia, including episodes necessitating hospital admission and causing death
- Weight gain
- May blunt myocardial ischemic preconditioning
20
Q
Class: Repaglinide
*Tx of Hyperglycemia in T2DM
A
Meglitinides
21
Q
Class: Nateglinide
*Tx of Hyperglycemia in T2DM
A
Meglitinides
22
Q
MOA: Meglitinides (Repaglinide, Nateglinide)
*Tx of Hyperglycemia in T2DM
A
Same as the sulfonylureas: Closes KATP channels on β-cell plasma membranes to increase insulin secretion
23
Q
What are the advantages of the Meglitinides (Repaglinide and Nateglinide) over the sufonylureas drugs?
*Tx of Hyperglycemia in T2DM
A
Accentuated effects around meal ingestion (short- acting)
24
Q
What are the side effects of the Meglitinides (Repaglinide and Nateglinide)?
*Tx of Hyperglycemia in T2DM
A
- Hypoglycemia
- Weight gain
- May blunt myocardial ischemic preconditioning
- Dosing frequency (before each meal)
25
Class: Pioglitazone
*Tx of Hyperglycemia in T2DM
Thiazolidinediones (Glitazones)
26
MOA: Pioglitazone
*Tx of Hyperglycemia in T2DM
Activates the nuclear transcription factor PPAR-γ to increase peripheral insulin sensitivity
27
What are the advantages of Pioglitazone?
*Tx of Hyperglycemia in T2DM
* No hypoglycemia
* HDL cholesterol ↑
* Triglycerides ↓
* Possible reduction in myocardial infarctions
28
What are the disadvantages of Pioglitazone?
*Tx of Hyperglycemia in T2DM
* Weight gain
* Edema
* Heart failure
* Bone fractures
* Increased bladder cancer risk
29
Class: Rosiglitazone
*Tx of Hyperglycemia in T2DM
Thiazolidinediones (Glitazones)
30
Rosiglitazone is similar to pioglitazone in its MOA, but has different disadvantages. What are they?
*Tx of Hyperglycemia in T2DM
```
• LDL cholesterol ↑
• Weight gain
• Edema
• Heart failure
• Bone fractures
• Increased cardiovascular events (mixed
evidence)
```
31
Rosiglitazone is contraindicated in patients with what condition?
*Tx of Hyperglycemia in T2DM
Heart disease
32
Class: Acarbose
*Tx of Hyperglycemia in T2DM
α-Glucosidase inhibitors
33
Class: Miglitol
*Tx of Hyperglycemia in T2DM
α-Glucosidase inhibitors
34
MOA: α-Glucosidase inhibitors (Acarbose and Miglitol)
*Tx of Hyperglycemia in T2DM
Inhibits intestinal alpha-glucosidase in order to slow intestinal carbohydrate digestion and thus glucose absorption
35
What are the advantages of the α-Glucosidase inhibitors (Acarbose and Miglitol)?
*Tx of Hyperglycemia in T2DM
* Nonsystemic medication
* Postprandial glucose ↓
* Weight neutral
* No hypoglycemia
36
What are the disadvantages of the α-Glucosidase inhibitors (Acarbose and Miglitol)?
*Tx of Hyperglycemia in T2DM
* Gastrointestinal side effects (gas, flatulence, diarrhea, abdominal fullness and discomfort)
* Dosing frequency
* Modest reduction in A1c
37
Class: Exenatide
*Tx of Hyperglycemia in T2DM
GLP-1 receptor agonists (incretin mimetics)
Dose Exenatide twice daily or weekly - injectible
38
Class: Liraglutide
*Tx of Hyperglycemia in T2DM
GLP-1 receptor agonists (incretin mimetics)
Dose Liraglutide daily - injectible
39
Class: Albiglutide
*Tx of Hyperglycemia in T2DM
GLP-1 receptor agonists (incretin mimetics)
Dose Albiglutide weekly - injectible
40
Class: Dulaglutide
*Tx of Hyperglycemia in T2DM
GLP-1 receptor agonists (incretin mimetics)
Dose Dulaglutide weekly - injectible
41
```
MOA: GLP-1 receptor agonists (incretin mimetics):
• Exenatide
• Liraglutide
• Albiglutide
• Dulaglutide
```
*Tx of Hyperglycemia in T2DM
Activates GLP-1 receptors to:
• Insulin secretion ↑ (glucose-dependent)
• Glucagon secretion ↓ (glucose-dependent)
• Slowsgastricemptying
• Satiety ↑
42
```
What are the advantages of the GLP-1 receptor agonists (incretin mimetics)?
• Exenatide
• Liraglutide
• Albiglutide
• Dulaglutide
```
*Tx of Hyperglycemia in T2DM
Weight reduction;
| Potention for improved beta-cell mass/function
43
```
What are the disadtantages of the GLP-1 receptor antagonists (incretin mimetics)?
• Exenatide
• Liraglutide
• Albiglutide
• Dulaglutide
```
*Tx of Hyperglycemia in T2DM
• Gastrointestinal side effects (nausea, vomiting, diarrhea) • Cases of acute pancreatitis observed
• Hypoglycemia(less than sulfonylureas)
• Caution with renal insufficiency
• C-cellhyperplasia/medullary thyroid tumors in animals (liraglutide)
• Injectable
• Long-term safety unknown-
--increased pancreatic cancer
44
Class: Sitagliptin
*Tx of Hyperglycemia in T2DM
DPP-4 inhibitors (incretin enhancers)
45
Class: Alogliptin
*Tx of Hyperglycemia in T2DM
DPP-4 inhibitors (incretin enhancers)
46
Class: Saxagiptin
*Tx of Hyperglycemia in T2DM
DPP-4 inhibitors (incretin enhancers)
47
Class: Linagliptin
*Tx of Hyperglycemia in T2DM
DPP-4 inhibitors (incretin enhancers)
48
MOA: DDP-4 inhibitors (incretin enhancers) (the gliptins)
*Tx of Hyperglycemia in T2DM
```
Inhibit DDP-4 activity to:
• Active GLP-1 concentration ↑ and
Active GIP concentration ↑
• Insulin secretion ↑
• Glucagon secretion ↓
```
49
```
What are the advantages of DDP-4 inhibitors?
• Sitagliptin
• Alogliptin
• Saxagliptin
• Linagliptin
```
*Tx of Hyperglycemia in T2DM
No hypoglycemia;
| Weight neutral
50
```
What are the disadvantages of the DDP-4 inhibitors?
• Sitagliptin
• Alogliptin
• Saxagliptin
• Linagliptin
```
*Tx of Hyperglycemia in T2DM
* Occasional reports of urticaria/angioedema; URIs, headache, arthralgias
* Cases of pancreatitis observed
* Long-term safety unknown
51
Class: Canaglifozin
*Tx of Hyperglycemia in T2DM
SGLT2 (sodium glucose cotransporter 2) inhibitor
52
Class: Dapaglifozin
*Tx of Hyperglycemia in T2DM
SGLT2 (sodium glucose cotransporter 2) inhibitor
53
Class: Empaglifozin
*Tx of Hyperglycemia in T2DM
SGLT2 (sodium glucose cotransporter 2) inhibitor
54
MOA: SGLT2 (sodium glucose cotransporter 2) inhibitor
• Canagliflozin
• Dapagliflozin
• Empagliflozin
*Tx of Hyperglycemia in T2DM
Reduces glucose resorption in the kidney; α cell agonist in order to increase urinary glucos excretion and increase glucagon secretion
55
```
What are the advantages of
• Canagliflozin
• Dapagliflozin
• Empagliflozin
?
```
*Tx of Hyperglycemia in T2DM
Ho hypoglycemia;
| Weight loss possible
56
```
What are the disadvantages of
• Canagliflozin
• Dapagliflozin
• Empagliflozin
?
```
*Tx of Hyperglycemia in T2DM
* Volume depletion (hypotension, renal impairment); hyperkalemia; ketoacidosis
* Genital mycotic infections; UTIs
* Hypersensitivity; increased LDL-chol
* Reduced bone density, increased bone fracture risk
* Long-term safety unknown; avoid in renal insufficiency
57
Class: Colesevelam
*Tx of Hyperglycemia in T2DM
bile acid sequestrant
58
MOA: Colesevelam
*Tx of Hyperglycemia in T2DM
Reduces hepatic glucose production
59
What are the advantages of Colesevelam?
*Tx of Hyperglycemia in T2DM
* No hypoglycemia
| * LDL cholesterol ↓
60
What are the disadvatages of colesevalem?
*Tx of Hyperglycemia in T2DM
```
• Constipation
• Triglycerides ↑
• May interfere with absorption of other
medications
• Modest reduction in A1c
```
61
Hypoglycemia is most common when taking what medication?
* Most common with treatment with sulfonylurea drugs and insulin
* More common in type 1 vs. type 2 diabetes
* Increased risk if over 60 years old, impaired renal function, poor nutrition, liver disease, increased physical activity, longer duration of diabetes
62
What is the preferred treatment for hypoglycemia?
* Glucose (15–20 g) preferred treatment for conscious individual with hypoglycemia
* Glucagon should be prescribed for all individuals at significant risk of severe hypoglycemia and caregivers/family members instructed in administration
63
When is glucagon therapy indicated for hypoglycemia?
* Given only if unconscious or unable to swallow - patient never gives to self
* Turn on side - nausea, vomiting, call 911
* type 1 should always have prescription
* type 2 with previous severe low blood sugar
64
How is severe hypoglycemia treated in a hospital setting?
IV dextrose
65
What are some causes of oral therapy inadequacy in diabetes mgmt?
```
Dietary noncompliance;
Physical inactivity;
Stress;
Insulin resistance;
Simultaneous use of diabetogenic drugs;
Progressive beta-cell dysfunction (insulin deficiency)
```
66
T/F: A1C can still rise 0.2-0.3% yearly with stable oral monotherapy
True
This rate is the same as for diet alone, sulfonylureas, and metformin treatment
67
Amylin is a protein released with insulin from beta cells in response to eating. It is deficient in T1DM with variable levels in T2DM. What is its action?
– Slows gastric emptying
– Suppresses postprandial glucagon secretion
– May reduce appetite
68
Class: Pramlintide
Amylin analog
69
MOA: Pramlintide
* Reduces post-prandial glucose levels (inhibits glucagon production, slows gastric emptying)
* Use with short/rapidly acting insulin
70
In what patient population if Pramlintide indicated?
For use in adults with insulin-requiring diabetes
71
What is a major side effect of Pramlintide?
Significant risk of hypoglycemia
72
What are the side effects of Pramlintide?
GI side effects, especially nausea;
| Significant risk of hypoglycemia
73
What are the advantages of Pramlintide?
May reduce appetite and promote weight loss
74
When is insulin therapy indicated in patients?
All patients with T1DM;
T2DM with:
- Glucose toxicity
- Insufficient endogenous insulin production
- Contraindication to oral therapy
-- Significant hyperglycemia at presentation
-- Hyperglycemia on maximal doses of oral agents
Decompensation ie
– Acute injury, stress, infection, myocardial ischemia
– Severe hyperglycemia with ketonemia and/or ketonuria
– Uncontrolled weight loss
– Use of diabetogenic medications (eg, corticosteroids)
-- Surgery
-- Pregnancy
-- Serious renal or hepatic disease
75
Intermediate-acting insulin is also known as:
– NPH (N= neutral pH, P= protamine zinc,
| H=origin in Hagedorn's laboratory)
76
Class:
Lispro insulin;
Aspart insulin;
Glulisine insulin
rapid-acting insulin analogs
amino acid changes speed absorption
77
Class:
Detemir insulin (rDNA origin);
Neutral protamine insulin (NPL);
Neutral protamine aspart (NPA)
Intermediate-acting insulin analogs
78
Class: Glargine insulin
Long-acting insulin analog (basal insulin)
79
Class: Degludec insulin
Ultra-long acting basal insulin analog
Low 24 hour variability
80
What is an advantage of degludec/aspart 70/30?
Reduced hypoglycemia compared with other premixed insulins
81
What are the advantages of premixed insulin?
– Convenient
– Potentially longer shelf life – avoids problem of protamine-bound insulin exchanged with lispro/aspart/Regular
– Fewer dosing errors
– Simple (pens)
82
T/F: Premixed insulins are rarely used in T1DM.
True
83
What are the disadvantages of premixed insulins?
– Loss of flexibility in matching to
• Carbohydrate intake
• Physical activity
– Harder to treat short-term hi or low blood glucose levels
– Lack of clinical outcome data – Hypoglycemia risk
84
When not in a hospital setting, insulin is typically administered how?
SubQ
85
Inhaled insulin is contraindicated in what patient populations?
COPD and asthma
may cause FEV decrease;
long term risks unknown
86
What are the regional differences in insulin absorption?
– Abdomen > arm > buttocks > thigh
– Rotate sites within region
– Use specific regions for specific times of day
87
What is split-mix insulin therapy?
2x a day at breakfast and dinner, can include bedtime dose
Disadvantages
– Not very physiological
– Greater likelihood of nocturnal hypoglycemia given peak of presupper NPH
– Greater chance of fasting hyperglycemia
88
What is the basal/bolus insulin concept?
• Basal insulin
– Suppresses glucose production between meals and
overnight
– Usually 40% to 50% of daily needs
• Bolus insulin (mealtime)
– Matched to carbohydrate intake, premeal glucose,
anticipated activity
– Limits hyperglycemia after meals
– Usually 10% to 20% of total daily insulin requirement at each meal
89
What are the side effects of insulin therapy?
```
Hypoglycemia;
Weight gain;
Allergic rxn (local or systemic);
Liphypertrophy;
Lipoatrophy (atrophy of subcutaneous fat at the injection site)
```
90
Continuous Subcutaneous Insulin Infusion (CSII) Systems infuse what kind of insulin?
rapid-acting
| in-dwelling catheter
91
What insulin therapy has shown the greatest reduction in A1C levels in those with the highest starting A1C?
Insulin pump therapy
* Glycemic control as good as with multiple daily injections if not better
* ↓ severe hypoglycemia, especially if history of severe hypoglycemia
* Good patient satisfaction
* Greater QOL and lifestyle flexibility
* More expensive than injection therapy
92
What is "IOB?"
• Insulin-on-board (IOB): amount of insulin from last bolus not yet absorbed
93
Define "stacking."
Insulin bolus when there is IOB
94
Define "sensitivity factor."
Correction factor: amount of glucose lowering expected from one unit of insulin
95
What are the major obstacles to optimal insulin therapy?
* Hypoglycemia
* Hyperglycemia
* Glycemic excursions/glucose variability
96
When should patients monitor their glucose?
– Prior to meals and snacks
– Occasionally postprandially
– At bedtime
– Prior to exercise
– When they suspect low blood glucose
– After treating low blood glucose until they are normoglycemic
– Prior to critical tasks such as driving
97
T/F: A normal A1C may be the result of hypoglycemic events in uncontrolled DM patients.
True - emphasizes the need for continuous BG monitoring
98
What patients are candidates for CGM?
* Repeated hypoglycemia
* Hypoglycemic unawareness
* Discrepancies between A1C and SMBG • Pregnancy
* Unable to achieve goals
99
Summarize treatment goals in T1DM.
```
• Diet, physical activity, education
• Basal/bolus insulin therapy with:
– Multiple daily injections or
– Insulin pump therapy
• Sensor-augmented insulin therapy in selected patients
```
100
Summarize treatment goals in T2DM.
1. Diet, exercise and education
2. Unless contraindicated, metformin is the optimal 1st line drug
3. After metformin, combination therapy with 1-2 other oral/injectible agents is reasonable; minimize side effects
4. Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain BG control
