Pharm 6 Diabetes Flashcards
2 methods of insulin secretion
- Pulsatile pacemaker B cells open Ca channels
- Glucose through GLUT2 -> ATP -> block KIR channel -> Ca opens
Insulin molecule
A + B chain, C-peptide is cleaved
Insulin metabolism
50% degraded in liver, 50% in other target tissues
Insulin receptor MOA (GLUT4)
Tetramer
-Insulin binds to a-subunits -> b-subunits autophosphorylate -> tyrosine kinase
Insulin receptor MOA (mitogen)
MAP-kinase phosphorylation
Insulin in liver
- Glycogen/triglyceride synthesis
- Inhibit glycogenolysis/gluconeogenesis
Insulin in fat
- Glucose uptake, triglyceride storage
- Inhibit lipolysis
Insulin in general
Promote anabolism, inhibit catabolism
Insulin deficiency acidosis mechanism
Increase lipolysis -> ketoacids -> acidosis
Glucose intolerance with onset during pregnancy
GDM - Gestational Diabetes Mellitus
Instant type I diabetes cause
Total pancreatectomy
Drug therapy provoking chronic hyperglycemia
Steroid therapy
Rate limiting step for insulin absorption
Subcutaneous dissociation from hexamers into dimers and then monomers
-Lispro-
Lysine-Proline switched, can’t form aggregates
- Ultra fast
- Take after starting meal
-Aspart-
Proline replaced with aspartic acid, can’t form aggregates
-Ultra fast
-Insulin-
Can be given IV
-Fast
-NPH insulin-
Regular plus protamine zinc insulin (positively charged)
-Intermediate
-Glargine-
Ultra slow, peakless
-Single bedtime dose
-Determir-
Binds to albumin
-Ultra slow
Insulin pump benefit
Controls “dawn phenomenon”
Injection to accelerate insulin absorption
- Intramuscular
- Heat (exercise)
- Abdomen or buttock (blood flow)
Compromised renal function effect on insulin
Reduced clearance, prolonged effectiveness
-Pramlintide-
Amylin analog
- Slows postprandial glucose levels
- Slow stomach, inhibit glucagon
-Pramlintide-
Contraindications
Adverse Effects
- Gastroparesis
- Delayed onset of action of oral drugs
-Exenatide-
MOA
indication
Incretin mimetic
- Stimulate Insulin, inhibit Glucagon
- Suppress postprandial hyperglycemia
- From lizard
GLUT4 recruiting without insulin
5’AMP-K
-From exercise
Sulfonylurea MOA
Directly inhibit KIR -> Insulin secretion
-(normally inhibited by GLUT2 glucose)
2 Sulfonylurea drugs
Glipizide
Glyburide
Sulfonylurea binding site
SUR1 on inwardly-rectifying potassium channel
Sulfonylurea effect
Raise insulin secretion -> correct hyperglycemia
- Increase insulin sensitivity
- Improve B-cell responsiveness
Exenetide, Pramlintide main purpose
Suppress postprandial hyperglycemia
-Glipizide-
Fastish Sulfonylurea
-Bind KIR
-Glyburide-
Slower Sulfonylurea
- Bind KIR
- Doesn’t cross placenta
Glipizide, Glyburide
-Preferred drugs for what
Renal dysfunction
-(2nd gen are fecal excretion)
Glipizide, Glyburide
-Bad drugs for what
Type I DM
Drug for pregnancy
Glyburide
Sulfonylurea Adverse effects
- Severe Hypoglycemia (overdose)
- Weight gain
Drug to use for surgery, severe infections, severe stress or trauma, severe hepatic or renal failure
Insulin ONLY
The Glinides
Repa and Nate
Repaglinide, Nateglinide class
Meglitinides
Repaglinide, Nateglinide MOA
Inhibit KIR, rapid insulin release
Repaglinide, Nateglinide indication
Tx postprandial hyperglycemia
-Reduced risk of long-lasting hypoglycemia
Biguanide drug
Metformin
-Metformin- good for
Rarely produces lactic acidosis
-Metformin-
MOA
Induces 5’AMPK
- no effect on insulin
- no hypoglycemia
-Metformin-
indication
Obese diabetics, prediabetics
-(weight loss, beneficial effect on lipids)
-Metformin-
also good for
Polycystic ovarian syndrome
-Hyperandrogenism insulin resistance
Thiazolidinedione drugs
Glitazone
- Pioglitazone
- Rosiglitazone
-Pioglitazone, Rosiglitazone-
MOA
PPARy ligand
-(peroxisome proliferator-activated receptor) nuclear hormone
-Pioglitazone, Rosiglitazone-
target genes
GLUT4 and GLUT1 increase
-Increase insulin sensitivity
-Rosiglitazone, Pioglitazone-
AE
Black Box for heart failure
-Rosiglitazone - angina, MI
-Acarbose, Miglitol-
MOA
a glucosidase inhibitors
-Delay carb digestion, absorption
-Acarbose, Miglitol-
administration
taken with first bite of meal
-SitaGLIPTIN, SaxaGLIPTIN-
MOA
DPP-4 inhibitors
-slow stomach emptying
-Diazoxide-
MOA
Hyperglycemic agent
- opposite effect of sulfonylureas (KIR)
- inhibits insulin release, not synthesis
Sulfonylurea drugs
Glipizide
Glyburide
-Diazoxide-
indication
Insulinomas
-Glucagon-
MOA
G-protein -> liver glycogenolysis, gluconeogenesis
-Glucagon-
indication
Severe hypoglycemia due to DM Tx
-Orlistat-
MOA
Inhibit GI lipases and TG hydrolysis
-inhibit fat absorption
-Pramlintine, Exenetide-
MOA
Slow gastric emptying