Endocrine Pharm Flashcards
What are the two forms of insulin that can be given IV?
Lispro and regular - these are the only solution-form of insulin (others are suspension)
Which insulins have the fastest onset?
Lispro and regular, when given IV work within 2-4 min
What is unique about glargine?
It has no peak activity → used for basal glucose control & no risk of hypoglycemia
What kind of receptor does insulin bind? What happens next?
Tyrosine kinase → autophosphorylation of receptor → allows binding of IRS-1, which becomes phosphorylated → allows binding of SH2 domain proteins, which become phosphorylated → lots of enzyme activity, especially phosphatases → enzymes dephosphorylated to be activated/inactivated, some changes in gene expression (lipoprotein lipase, FA synthase, glucokinase) – SEE BIOCHEM SECTION
What are 3 ketoacids in DKA?
- acetoacetate
- β-hydroxybutyrate
- acetone → fruity breath (no E-delivering activity)
What energetic molecules can β-OHbutyrate give rise to? Where are these molecules used?
1x NADH
2x Acetyl-CoA
- used mainly by muscle tissue (e.g. heart), renal cortex, brain (only if period of prolonged starvation)
What energetic molecules can acetoacetate give rise to?
2x Acetyl-CoA
What is the treatment for DKA?
- regular insulin
- glucose
- fluid and electrolytes (esp. watch for hypokalemia)
What is the effect of insulin on K+ in the body?
insulin drives K+ into cells
What type of glucose transporters are on β cells in the pancreas? What is significant about the pharmacodynamics of this receptor?
GLUT 2 - has very high Km (thus low affinity for glucose) so it is only active when high glucose in blood (e.g. after meals)
How does elevated glucose → insulin release in β cells?
Glucose → gets in cell through GLUT 2 → ↑ ATP → closes K+ channel → depolarization → open voltage-gated Ca2+ channel → ↑ Ca2+ in cell → exocytosis of insulin
What do sulfonureas do? Do they work in T1DM?
block the K+ channel in β cells, mimicking the effect of ↑ ATP; don’t work in T1DM b/c these patients don’t have β cells
What drugs work oppositely to sulfonureas?
diazoxide and minoxidil: direct acting vasodilators that open ATP-dependent K+ channels → hyperpolarization → ↓ insulin release → drug-induced diabetes
What is acetohexamide? What is unique about it?
A first generation sulfonurea; it has an active metabolite → very long duration of action → be careful with renal function
What is tobutamide? What is unique about it?
A first generation sulfonurea; can use in kidney patients b/c no renal tox
What is chlorpropamide? What is unique about it?
A first generation sulfonurea; causes disulfaram-like reaction and SIADH (like carbamazepine)
What are the second generation sulfonureas and their side effects?
GLYburide - ↓ dose in renal pt. or will cause hypoglycemia
gLIPizide - ↓ dose in hepatic pt.
What are the general side effects for sulfonureas?
- hypoglycemia in fasting state (e.g. at 2-3 AM)
- weight gain
- hypersensitivity (SULFONureas have a sulfur group)
- drug interactions (highly plasma protein bound, p450 processed)
What drugs would interact with sulfonureas?
- p450: cimetidine
- hypoglycemia: insulin
- compete for protein binding sites → hypoglycemia: salicylates, sulfonamides
What drug is thought to bypass insulin receptors in cells? How? What are the side effects? What is a notable exception?
Metformin - thought to stimulate PPAR transcription factors directly; since it burns glucose can cause lactic acidosis (rare; contraindicated in renal failure for this reason), GI distress is most common side effect; does not cause hypoglycemia
What is the mechanism of action of acarbose and miglitol?
inhibit α-glucosidase → ↓ breakdown of sugars → ↓ absorption → ↓ post-prandial hyperglycemia and ↓ demand for insulin (may improve insulin sensitivity)
What are the side effects of thiazolidinediones?
- thia = hypersensitivity, lipid sol → hepatotox
- azol = potentiate effects of EtOH
- weight gain
- edema
- heart failure
What do the thiazolidinediones (glitazones) do?
bind to PPAR-gamma → mimic actions of insulin:
- ↓ gluconeogenesis via: ↑ PFK2 → ↑ fructose 2,6- bisphosphate → dephosphorylation/inactivation of fructose-1,6-bisphosphatase (rate limiting step)
- ↑ insulin receptors
What are 2 ways glitazones and metformin ↓ blood glucose?
- enhance uptake in skeletal mm. through ↑ GLUT 4 receptors
2. inhibit glucose production by liver (↓ gluconeogenesis)