Diabetes Drugs

Question 1

MOA of Metformin?

Answer 1

Decrease hepatic glucose 
production
Activate hepatic AMP-kinase
 and inhibit mitochondrial isoform of glycerophosphate 
dehydrogenase

Question 2

Benefits of Metformin?

Answer 2

Weight neutral
No hypoglycemia
Possibly fewer CVD events and cancer

Question 3

What are the common side effects of Metformin?

Answer 3

GI problems: 
diarrhea (usually but 
not always transient)
abdominal discomfort, 
nausea, vomiting, anorexia

Question 4

What are the rare side effects of Metformin?

Answer 4

lactic acidosis

Vitamin B12 deficiency

Question 5

Glyburide, Glipizide, Glimepiride are what class of drugs?

Answer 5

Oral Sulfonylurea agents (promote insulin secretion)

Question 6

What is the MAO of oral sulfonylurea agents?

Answer 6

Block K(atp) chennels in pancreatic beta-cells which stimulates insulin and C-peptide secretion

(serum glucose enters beta-cells via Glut2 bidirectional glucose transporters. ^[Glucose] increases glycolysis and produces ATP => ATP DEACTIVATES K+ channels, which depolarize beta cell membrane triggering the opening of voltage gated Ca2+ channels, and Ca2+ mediated excocytosis of insulin and C-peptide. (pre-formed pro-insulin is stored in secretory granules - C-peptide is just part of the pro-insulin molecule)

Question 7

What are the side effects of Sulfonylurea drugs?

Answer 7

Hypoglycemia
Weight gain

*May adversely affect
ischemic preconditioning

Question 8

What kind of drugs are Repaglinide and Nateglinide?

Answer 8

Oral meglitinides

Question 9

What is the MOA of Oral meglitinides?

Answer 9

Same as Sulfonylurea drugs - Block K+(ATP) channels to stimulate insulin and C-peptide secretion

Question 10

What are advantages/disadvantages of meglitinides vs Sulfonylurea drugs? (i.e. Side effects / dosing)

Answer 10

Both cause hypoglycemia and weight gain but meglitinides (repaglinide, nateglinide) cause less hypoglycemia than the sulfonylurea drugs (glyburide, glipizide, glimepiride)

Question 11

Drugs that activate PPAR-gamma ?

Answer 11

Thiazolidinediones “-litazone” Pioglitazone Rosiglitazone

PPAR-y = paraxazome proliferator-activated receptor

Question 12

What is the MAO of Pioglitazone?

Answer 12

activates PPAR-gamma

Decreases insulin resistance

Question 13

Why do the Rides, Zides, and Glinides cause weight gain?

Answer 13

All increase insulin secretion and activate its endogenous anabolic responses - increase glycogen and triglyceride sysnthesis, decrease lypolysis/ inhibit glucogon release)

Question 14

What is the consequence activating PPAR-gamma?

Answer 14

decreases insulin resistance

Question 15

What are the specific benefits and disadvantages of pioglitazone?

Answer 15

Possible decrease in
myocardial infarctions

Increase in bladder cancer

Question 16

What are the side effects/disadvantages of Thiazolidinediones?

Answer 16

(Pioglitazone Rosiglitazone) sides effects:

Weight gain
Edema
Congestive heart failure
Bone fractures
Macular edema

EXPENSIVE!

Question 17

What is the shared benefit of Pioglitazone and Rosiglitazone?

Answer 17

No hypoglycemia

Question 18

What is the MOA for Acarbose and Miglitol?

Answer 18

Oral Alpha-Glucosidase (competitive)
Inhibitors

usually oligosaccarides - acarbose may also inhibit pancreatic amylase

Question 19

What does inhibiting Alpha-Glucosidase do?

Answer 19

Delays carbohydrate
absorption which results in
decreased postprandial
glucose levels

Question 20

What are the benefits of acarbose and miglitol?

Answer 20

No hypoglycemia
Weight neutral 
Moderate efficacy in 
lowering 
postprandial glucose 
levels

Question 21

What are the side effects of acarbose and miglitol?

Answer 21

GI symptoms:
flatulence, diarrhea,
abdominal fullness and
discomfort

Dosing issues: Need to take with each
carbohydrate containing
meal

Efficacy issues:
only modest ↓ in A1c

Question 22

What is the MOA?

Exenatide
Liraglutide
Dulaglutide
Albiglutide

Answer 22

GLP-1 Receptor Agonists

Question 23

what does a GLP-1 Receptor Agonist do? (4 functions)

Answer 23

Increases glucose-stimulated insulin
secretion,

decreases glucagon secretion,

slows
gastric motility,

increases
satiety

Question 24

What are the major benefits of GLP-1R agonists?

Answer 24

Promote weight loss

No hypoglycemia

Question 25

Disadvantages of GLP-1R agonists?

Answer 25

Risk of pancreatitis GI side effects (nausea, vomiting, diarrhea) Hypoglycemia (less than sulfonylureas) Caution with renal insufficiency ``` Have to inject subcutaneously (Byetta twice daily, Bydureon Albiglutide, Dulaglutide once weekly, Victoza once daily) ``` C-cell hyperplasia/medullary thyroid tumors in animals Expensive!

Question 26

What drugs inhibit the metabolism of GLP-1 (glucagon-like-peptide 1)?

Answer 26

the DPP-4 inhibitors "-gliptins"

Question 27

What are the benefits of the DDP-4 inhibitors?

Answer 27

Weight neutral No hypoglycemia Well-tolerated

Question 28

What are the side effects of DDP-4 inhibitors?

Answer 28

Risk of pancreatitis Possible runny nose, URIs, headache

Question 29

What is the MOA of these drugs? Canagliflozin Dapagliflozin Empagliflozin

Answer 29

oral SGLT2 Inhibitors ("-gliflozin" - GLucose In FLow cauZes INfections)

Question 30

What is SGLT2?

Answer 30

Sodium/Glucose cotransporter-2 facilitates re-absorption of glucose and sodium Inhibition of SGLT2 reduces glucose reabsorption in the kidney; increases urinary glucose excretion

Question 31

Side effects of canagliflozin, Dapagliflozin, and Empagliflozin?

Answer 31

``` Genital mycotic infections, urinary tract infections, hypotension, impaired renal function, hyperkalemia, hypersensitivity, increased LDL-cholesterol ```

Question 32

Which drugs share increased risk of pancreatitis?

Answer 32

GLP-1 agonists and DPP4 inhibitors ("tides" and "gliptins")--- both function along same pathway leading to endogenous insulin secretion but GLP-1 agonists are upstream so these drugs are more potent stimulators of insulin - GLP1/GIP/Glucagon are agonists for GLP1R increases insulin secretion - DPP4 is enzyme that breaks down GLP1 so blocking DPP4 also increases insulin secretion by activation of GLP1R **Insulin cases the kidney to increase Na+ reabsorption so more insulin (e.g. GLP1R agonists) forces the kidney to work harder**

Question 33

Which class of drugs cases UTI's and gentical mycoses as a side effect? Why doe they do this?

Answer 33

gliflozin drugs (SGLT-2 inhibitors) - Increased urinary exretion of glucose (from blocked reabsorption) acts as a growth medium for fungi and bacteria