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Insulin Mechanism of Action
- Activates insulin receptors
- Tyrosin Kinase 2ndary messenger
- increases cellular glucose uptake via GLUT4 in muscle and adipose tissue
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Rapid Onset Insulins
- Lispro (2-4 hr duration)
- Glulisine (2-5 hr duration)
- Aspart (4-6 hr duration)
15min onset for all
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Short acting insulin
- structure
- onset
- duration
- crystalline - identical to human insulin
- 30-45 min onset SC
- 5-7 hrs duration
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Only insulin available for IV administration?
Short acting insulin
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Short acting insulin approved for pump use
velosulin
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1st line for Ketoacidosis or severe hyperglycemia?
- IV regular insulin
- * may also use rapid onset insulins (lispro, aspart, glulisine) to reduce KA but give SC
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Name an intermediate-acting insulin
- onset
- peak time
- NPH - protamine insulin
- onset - 1-2 hrs
- peaks at 4-8 hrs
- * usu mixed with rapid onset insulin to provide postprandial control
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long-acting insulins
- onset
- duration
- glargine
- onset - slow, peakless
- duration 24hr
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What is Pramlitide
fxn in Type I
fxn in Type II
- Injectable analog of amylin - used in conjunction with insulin in type I and II
- In type I - stabilizes postprandialglucose peaks and valleys
- In type II - suppresses postprandial glucagon secretion and reduces food intake
Slows gastric emptying – may alter absorption of other medications/ nausea adverse effect
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Tx for hypoglycemia
- juice, candy or high glucose food if conscious
- Unconscious or vomiting: IV glucose or IM glucagon as soon as possible
- * glucagon onset is not immediate
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Mechanism of Action of glucagon
onset
- Gs-cAMP activation: phosphorylates enzymes that catalyze gluconeogenesis.
- onset - may take up to 30 mins to increase BG
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List some complications of insulin use
- Hypersensitivity - IgE mediated
- Immune insulin resistance - anti-insulin IgGs. More common in obese diabetics
- Lipodystrophy - body fat redistribution. rotate injection site or use highly puriifed preps.
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How do you prevent insulin allergy?
Use recombinant therapy
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What is the first line tx for Type II diabetes?
Metformin
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Effects of Metformin?
- Decreases hyperglycemia w/o hypoglycemia
- Stimulates glycolysis and inhibits gluconeogenesis
- reduces plasma glucagon
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Benefits of Metformin use?
- May promote weight loss.
- PO, inexpensive
- Lowers A1c 1-2%
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Concerns while using metformin?
- Nausea, diarrhea
- Renal elimination (contraindicated in pts with renal dysfunction)
- Potentially fatal lactic acidosis if renal impairment also
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Name some conditions that increase the risk of metformin-induced lactic acidosis
- Kidney dysfuntion
- alcohol abuse
- Dehydration
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Mechanism of Action of Rosiglitazone? Alt: pioglitazone
- A TZD. Activates peroxisome proliferator-activated receptor gamma (PPARg).
- This increases GLUT1 and GLUT4 gene expression
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Beneficial effects of Rosiglitazone?
- Increases muscle glucose uptake and redistributes fat to decrease insulin resistance - "insulin sensitizer"
- Drops A1c 1%
- rarely causes hypoglycemia
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Concerns while using Rosiglitazone?
- Increased risk of CHF and MI (esp in combo w/insulin)
- Increased risk of fractures in postmenopausal women
- Does not act rapidly - delay in decreasing BG
- Weight gain and edema
- metabolized by liver enzymes?? - drug interaction issues.
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What is the mechanism of action of exanatide?
- GLP-1 receptor agonist. Adjunct in metformin/SUR therapy
- Potentiates insulin release when BG rises
- Decreases glucagon levels
- Promotes weight loss in obese
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Pharm benefits of Exenatide?
- hypoglycemia is rare when used w/metformin
- Potentiates insulin release when BG rises
- Decreases glucagon levels
- Promotes weight loss in obese
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Concerns with exenatide use
- expensive, injection
- nausea, diarrhea
- Can cause serious renal dysfunction if there's HPN, renal impairment, dehydrated or elderly
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What is Sitaglipitin? What is its mechanism of action?
- Orally available GLP-1 therapeutic. Like exenatide.
- inhibits DPP-4 to block GLP-1 breakdown increasing its levels
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What is the mechanism of action of Glimepiride?
a 2G SUR. Closes K+ channels and potentiates insulin release in response to glucose uptake
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Name other SURs
glipizide and glyburide
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Name some beneficial chx of glimepiride
- PO, low cost
- rapid onset
- long duration
- drops A1c 1-3%
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Some concerns while usuing glimepiride?
- CYP2C9 metabolism.
- Some renal elimination - adjust dose.for mild renal impairment.
- Hemolytic anemia risk in pts with G6PD deficiency - avoid SURs
- Hypoglycemia
- Weight gain
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Name some insulin secretagogue alternatives for pts with a G6PD deficiency?
- nateglinide and repaglinide - non-sulfonamide.
- Also appropriate for pts with sulfur allergies
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Nateglinide action?
- transient, very rapid but short-acting effect to close K+ channel to increase insulin release.
- appro for postprandial use
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Repaglinide action?
- Closes K+ channels, more similar to sulfonylureas.
- Also rapid - appropriate for postprandial surge in BG
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Benefits of non-sulfonamide insulin secretagogues?
- ideal for post-prandial BG surges
- Nateglinide considered OK if renal impairment
- Drops A1c 0.5-1.5% , >>> A1c drop if given w/ metformin
- Generally adjunct if post-prandial glucose surges
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Concerns with the use of repa~ and nateglinide?
Hepatic CYP3A4 (also 2C9 for nateglinide) metabolism
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