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Med Chem Diabetes Drug Therapies


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What preservatives are used for Regualr and Ultralente Insulins?
Phenol or m-cresol, typically 6 molecules of preservative/hexamer of insulin
NPH and 70/30 Insulins - What is the role of protamine?
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
What does the addition of protamine do for the duration of action?
What insulin preparations are Ultra-short acting?
Lispro, Aspart, Apidra
What insulin preparations are Short-acting?
Insulin R
What insulin preparations are Intermediate acting?
Insulin N(NPH)
What insulin preparations are long-acting?
Lantus, Levemir
What insulin preparations have modifying proteins?
Insulin N(NPH) = Protamine

Insulin 70/30 = Protamine
How is Insulin metabolized/degraded?
Reductive cleavage of disulfide bond catalyzed by glutathione-insulin transhydrogenase
What are short-term adverse effects of Insulin therapy?
a)NE and Epi are released in response to falling blood glucose levels
b)hepatic glucose production stimulated (glycogenolysis and gluconeogenesis)

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
What are long-term adverse effects of Insulin therapy?
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
What are some additional long-term adverse effects of Insulin therapy?
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)
What is the MOA of Insulin Secretagogues (Sulfonylureas)?
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
What is the SAR of Sulfonylureas?
Position 1: Arylsulfonyl group
Position 3/4: Aliphatic group
How is duration of action determined in sulfonylureas?
If aryl cannot undergo benzylic oxidation it prolongs duration of action
What is the SAR of the second generation sulfonylureas?
Aliphatic groups with an extended aromatic ring

More potent, same MOA as first generation
What are the indications of Sulfonylureas?
Type II Diabetes - adjunct to diet therapy
What are the causes of secondary failure in patients taking sulfonylureas?
Decrease Beta-cell function

Beta-cell exhaustion
What is the SAR of the Meglitinide Family of Insulin Secretagogues?
-Look for free carboxylic group
-Typically see quite a bit of bulk
What is the MOA of Meglitinides?
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
What is the key therapeutic advantage of Meglitinides?
Does not stimulate insulin release when there is low blood glucose present (glucose dependent)
What is the indication for Meglitinides?
Treatment of Type II diabetes
What is the MOA of the Biguanides?
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)
What are the indications for Biguanide therapy?
Combo therapy with sulfonylureas or insulin
What is the most important issue with Biguanides?
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.
What is the SAR for the Insulin sensitivity enhancers (Glitazones)?
Contains a Thiazolidinedione
What is the MOA of the Glitazones?
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
What the are indications for Glitazones?
Monotherapy and combination therapy
What are the adverse effects of Glitazones?
Cardiac and liver issues
What is the MOA of alpha-Glycosidase inhibitors?
Inhibits the enzyme alpha-glycosidase which degrade CH2Os (oligosaccharaides and polysaccharides) into smaller CH2O units which slows the absorption of the smaller CH2O units.
What enzymes does Acarbose inhibit?
Both pancreatic alpha-amylases and intestinal alpha-glucosidase hydrolase
What enzymes does Miglitol inhibit?
Only alpha-glucosidase hydrolase
What enzymes does Vogilbose inhibit?
alpha-amylase, maltase, and sucrase
What are the indications for alpha-glycosidase inhibitors?
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 (?)
What are the side effects of alpha-glycosidase inhibitors?
Abdominal fullness, borboygmi, increased intestinal flatulence, and diarrhea
What is the MOA of Aldose Reductase Inhibitors?
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

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