Med Chem Diabetes Drug Therapies

Front 1

What preservatives are used for Regualr and Ultralente Insulins?

Back 1

Phenol or m-cresol, typically 6 molecules of preservative/hexamer of insulin

Front 2

NPH and 70/30 Insulins - What is the role of protamine?

Back 2

Protamine is a basic protein that is + charged at physiological pH while insulin is - charged

The additional layer (protamine) must dissociate from the hexamer

Once the protamine has dissociated, then the hexamer can dissociate into dimers

R.L.S.=Protamine dissociating away from hexamer

Front 3

What does the addition of protamine do for the duration of action?

Back 3

Increases

Front 4

What insulin preparations are Ultra-short acting?

Back 4

Lispro, Aspart, Apidra

Front 5

What insulin preparations are Short-acting?

Back 5

Insulin R

Front 6

What insulin preparations are Intermediate acting?

Back 6

Insulin N(NPH)

Front 7

What insulin preparations are long-acting?

Back 7

Lantus, Levemir

Front 8

What insulin preparations have modifying proteins?

Back 8

Insulin N(NPH) = Protamine

Insulin 70/30 = Protamine

Front 9

How is Insulin metabolized/degraded?

Back 9

Reductive cleavage of disulfide bond catalyzed by glutathione-insulin transhydrogenase

Front 10

What are short-term adverse effects of Insulin therapy?

Back 10

Hypoglycemia
a)NE and Epi are released in response to falling blood glucose levels
b)hepatic glucose production stimulated (glycogenolysis and gluconeogenesis)

Symptoms
1)Rapid HR, HA, Cold sweat
2)Abnormal functioning of ANS/CNS = nervousness, convulsions, unconsciousness
3)Impaired neural function = blurred vision, incoherent speech, mental confusion
4)Insulin coma

Front 11

What are long-term adverse effects of Insulin therapy?

Back 11

Hypoglycemic unawarenss

Body eventually gets used to low blood glucose

Adrenergic response stops being noticeable until blood glucose levels are much lower (20-60mg/dl)

Partially reversible if you can decrease the number of hypoglycemic episodes per unit time

Front 12

What are some additional long-term adverse effects of Insulin therapy?

Back 12

1)Insulin resistance: antibodies develop
2)Insulin resistance: receptors become less sensitive
3)Increased rate of degradation/inactivation of insulin (reduction of disulfide linkages, increased proteolysis of hormone, increased immune system inactivation)

Front 13

What is the MOA of Insulin Secretagogues (Sulfonylureas)?

Back 13

Promotes insulinj release from pancreatic Beta-cells (does not require glucose to be present)

Partial= inhibits secretion of glucagon, may enhance insulin receptor sensitivity to insulin

Front 14

What is the SAR of Sulfonylureas?

Back 14

Position 1: Arylsulfonyl group
Position 3/4: Aliphatic group

Front 15

How is duration of action determined in sulfonylureas?

Back 15

If aryl cannot undergo benzylic oxidation it prolongs duration of action

Front 16

What is the SAR of the second generation sulfonylureas?

Back 16

Aliphatic groups with an extended aromatic ring

More potent, same MOA as first generation

Front 17

What are the indications of Sulfonylureas?

Back 17

Type II Diabetes - adjunct to diet therapy

Front 18

What are the causes of secondary failure in patients taking sulfonylureas?

Back 18

Decrease Beta-cell function

Beta-cell exhaustion

Front 19

What is the SAR of the Meglitinide Family of Insulin Secretagogues?

Back 19

-Look for free carboxylic group
-Typically see quite a bit of bulk

Front 20

What is the MOA of Meglitinides?

Back 20

Binds to a receptor site that is distinct from the sylfonylurea binding site on the Beta-cells

Once bound to site, the MOA is same as for sulfonylureas

Front 21

What is the key therapeutic advantage of Meglitinides?

Back 21

Does not stimulate insulin release when there is low blood glucose present (glucose dependent)

Front 22

What is the indication for Meglitinides?

Back 22

Treatment of Type II diabetes

Front 23

What is the MOA of the Biguanides?

Back 23

Inhibits hepatic glucose production (primary)

May increase # of glucose transport units

May potentiate insulin action at cell surface receptors of sensitive tissues

May decrease intestinal absorption of glucose (Minor)

Front 24

What are the indications for Biguanide therapy?

Back 24

Combo therapy with sulfonylureas or insulin

Front 25

What is the most important issue with Biguanides?

Back 25

Risk of lactic acidosis

Less risk when taking metformin since it does not bind as well to mitochondrial membranes and therefore is less likely to inhibit aerobic metabolism.

Front 26

What is the SAR for the Insulin sensitivity enhancers (Glitazones)?

Back 26

Contains a Thiazolidinedione

Front 27

What is the MOA of the Glitazones?

Back 27

Has a post receptor effect after insulin has bound to its receptor

Messenger protein causes GLUT-4 glucose transporters to migrate toward membrane

Glitazones bind to PPAR gamma within the nucleus and turn on the DNA that codes for GLUT-4 transporter biosynthesis

Front 28

What the are indications for Glitazones?

Back 28

Monotherapy and combination therapy

Front 29

What are the adverse effects of Glitazones?

Back 29

Cardiac and liver issues

Front 30

What is the MOA of alpha-Glycosidase inhibitors?

Back 30

Inhibits the enzyme alpha-glycosidase which degrade CH2Os (oligosaccharaides and polysaccharides) into smaller CH2O units which slows the absorption of the smaller CH2O units.

Front 31

What enzymes does Acarbose inhibit?

Back 31

Both pancreatic alpha-amylases and intestinal alpha-glucosidase hydrolase

Front 32

What enzymes does Miglitol inhibit?

Back 32

Only alpha-glucosidase hydrolase

Front 33

What enzymes does Vogilbose inhibit?

Back 33

alpha-amylase, maltase, and sucrase

Front 34

What are the indications for alpha-glycosidase inhibitors?

Back 34

Primary therapy for non-obese type II patients once non-pharm treatment is determined ineffective

Used with insulin in the tx of type I diabetes to perhaps decrease insulin dose (?)

Front 35

What are the side effects of alpha-glycosidase inhibitors?

Back 35

Abdominal fullness, borboygmi, increased intestinal flatulence, and diarrhea

Front 36

What is the MOA of Aldose Reductase Inhibitors?

Back 36

Aldose reductase is found in cornea, kidneys, optic nerve, and in peripheral neurons

Inhibits aldose reductase which catalyzes glucose to sorbitol and subsequently to fructose

Sorbitol accumulates in tissues and draws water into cell