Tx of Diabetes Flashcards
Type 1 DM
AI disease
Lack of endogenous insulin
replace insulin
Type 2 DM
Noninsulin dependent diabetes
b cells desensitized to glucose challenge
peripheral tissues resistant to insulin actions
improve insulin sensitivity at early stages and replace insulin in later stages
Type 3 DM
non pancreatic causes
Drugs impair glucose tolerance- corticosteroids, thiazides, oral contraceptives
Type 4 DM
gestational
Goals of treatment of DM
Treat hyperglycemia to avoid long term complications
-fasting glucose 90-120 mg/dl
2 hr post prandial- below 150 mg/dl
HbA1c- below 7%
Insulin
51 AA peptide
Two peptide chains linked by disulfied bond
Preproinsulin>proinsulin> insulin + free C peptide
Acts in liver, muscle, and adipose tissues to decrease blood glucose levels and shift from energy use to storage
-Acts through stimulation of tyrosine kinase receptor
Insulin secretion and effects
Stimulated by increase ATP/ADP ratio which is modulated by glucose, AA, FA, parasympathetic activity
Glucose causes Increase in ATP which closes the K+ channel in the islet cell, stopping K efflux and depolarizing the cell (glucose is low, cell is hyperpolarized). Depolarizing cell will signal Ca++ influx which causes exocytosis of insulin
Sulfonyl urea drugs
Block K+ channels and depolarize islet cells, causing Ca++ influx and insulin vesicle release
Exogenous insulin
Subq administration- allowing for slower absorption
Tailored to pts activity and diet
AE: hypoglycemia, insulin allergy, lipoatrophy, weight gain, insulin edema
Rapid acting insulin
insulin lispro, insulin aspart, insulin glulisine
Short acting insulin
novolin R, humulin R
regular length insulin
-8 hrs
Intmdt acting insulin
Humulin N
Novolin N
Long acting insulin
insulin detemir, insulin glargine (levemir and lantus)
lasts 24 hrs
Tx of DKA
IV infusion of regular insulin at low rate
-administer glucose along to prevent hypoglycemia and fluid and electrolytes
Sulfonylureas
secretagogues
- inhibit activity of K+ channel on islet cell
- activate residual b cells to release insulin by binding to and activating SUR1 (subunit of the K/ATP channel)
- some pts may be allergic
- decrease hepatic clerance of insulin and decrease serum glucagon by stimulating somatostatin release
- can cause weight gain because using more glucose, hypoglycemia
- orally available, metabolized by liver, metabolites excreted in urine
First generation sulfonylureas
Tolbutamide, tolazamide, chlorpropamide
for those prone to hypoglycemic episodes
Second gen sulfonylureas
binds to SUR1 with higher affinity, lower dose req’d
Glyburide, glipizide, glimepiride
Contraindications of sulfonylureas
type 1 DM
pregnancy
lactation
significant hepatic or renal insufficiency
Meglitinides
Secretagogues
- similar MOA to sulfonylurea
- Repaglinide, nateglinide (more rapid)
- cleared by liver (not for those with hepatic insufficiency)
- hypoglycemia AE
Biguanides
Metformin
Insulin sensitizers
Euglycemic effect- helps maintain normal blood glucose levels without producing hypoglycemia
MOA of Metformin
- inhibits gluconeogenesis in the liver, helpful in maintaining normal blood glucose level
- inc peripheral insulin sensitivity
- actings AMP-activated protein kinase
- Inhibits mTOR-C1
Clinical use of metformin
1st line for type 2 DM
Taken with food
also used for PCOS or fatty liver disease
Metformin toxicity
Lactic acidosis- impair hepatic metabolism of lactic acid, but rare
Most AE are GI related- diarrhea, abd discomfort, nausea, metabollic taste, reduced B12 absorption
Thiazolidinediones (TZDs)
Rosiglitazone and Pioglitazone
-PPARy agonists with PPARa agonist activity
(rosiglitazine 10x ppary affinity than pioglitazone)
MOA of TZD
IN adipose tissue, PPARy activators promote transport of serum lipids to adipose tissue
- may activate ppary in other tissues to promote insulin sensitivity- dec hepatic gluconeogenesis, enhance uptake of glucose by skeletal muscle cells
- reduce glucose and triglycerides
metabolized by liver, so can cause hepatic toxicity
chf, weight gain
alpha-glucosidase inhibitors
Inhibitor of intestinal glucose absorption
-competitive and reversible inhibitors of pancreatic alpha-amylase and intestinal alpha-glucosidase enzymes
Acarbose and miglitol
a-glucosidase inhibitors
-inhibits intestinal glucose absorption
-reduces fasting glucose, a1c and post prandial glucose
no risk for hypoglycemia
can cause flatulence, bloating, diarrhea
not recommended for pts with ibd
Incretins
glucagon like peptide1 (GLP1) and glucose dependent insulinotropic peptide (GIP)
Released by cells in ileum, which is stimulated by nutrients entering the gut
-increase insulin secretion, decrease glucagon secretion, delay gastric emptying, decrease appetite
GLP1
Exenatide, liraglutide (victoza), albiglutide, duraglutide
(tide ending)
-increase insulin secretion, decrease glucagon secretion, delay gastric emptying, decrease appetite
- low risk of hypoglycemia, AE- nausea, vomiting, diarrhea
- promote weight loss
DDP4- Inhibitors of Dipeptidyl peptidase 4
Inhibitor of enzyme that degrades endogenous incretins (GLP-1 and GIP)
- increase level of endogenous incretins
- Sitagliptin, Saxagliptin, Linagliptin, Alogliptin
- Monotherapy or in combo with metformin (not with GLP1 analogs)
SGLT2 inhibitors
-Canagliflozin, dapagliflozin, empagliflozin
- Glucose reabsorbed in proximal tubules by sodium glucose transporter (SGLTs)
- Inhibition causes glycosuria and lowers glucose levels
- Efficacy reduced in chronic kidney disease
Side effects- inc incidence of genital infections and UTI
- manageable with better hygiene
- can also lead to intravascular volume contraction and hypotension
-SGLT2 inhibition promotes weight loss
Pramlintide
Amylin analog
- increase insulin secretion, decrease glucagon secretion, delay gastric emptying, decrease appetite, decreases appetite (hypothalamus)
- preprandial as adjunct to insulin improves post prandial glucose control
AE: hypoglycemia and GI symptoms
Covesevalam
Bile acid sequestrant, cholesterol lowering drug
-Can reduce glucose absorption via decreasing FXR nuclear receptor activation
may exacerbate hypertriglyceridemia
Bromocriptine
Dopamine agonist
-lowers glucose levels
AE- nausea, fatigue, dizziness, vomiting, headache
Combo therapy of diabetes
different MOA
target diff proteins
Begin with monotherapy with metformin, GLP1 mimic, SGLT2 inh, GPP-4 inh
Sulfonylureas and TZDs are second choice
Add additional agents as needed
Add insulin therapy to other agents
