Pharm: Insulin and Oral Hypoglycemic Agents Flashcards
insulin receptor?
tyrosine kinase enzyme activity
Insulin binding to the receptor stimulates autophosphorylation of the receptor Beta subunits and activation of tyrosine kinase activity
Docking proteins bind to the receptor and recruit other mediator proteins to the plasma membrane
GLUT receptors
- glucose transport into the cells
GLUT2 = glucose sensor in the beta cells, liver, pancreas
GLUT 4 = muscle and fat cells
GLUT 3 = brain
binding of insulin –> GLUT transport expression in order for glucose transport into the cell. When insulin signal goes away then GLUT is internalized into the cell
Regulation of glucose metabolism?
- Insulin stimulates glucose uptake
- Insulin stimulates glucose storage and utilization
- Insulin inhibits glycogen breakdown (glycogenolysis)
- Insulin inhibits glucose synthesis (gluconeogenesis)
recommended hemoglobin A1C?
6.5-7%
t1/2 of 120 days - used to measure long term exposure to elevated glucose
metformin**
Biguanide: antihyperglycemic agent (oral)
** recommended starting place for tx of type II DM
Actions:
- NOT hypoglycemic (makes it one of the safest)
- increases insulin action, glycolysis, uptake and utilization by muscle
- ** turns off gluconeogenesis, and decreases hepatic glucose output
Monotherapy can be used
Advantages:
- no weight gain
- no hypoglycemia
- favorable lipid profile
- its a pill, unlike inuslin, there is no injections
Concern: lactic acidosis w/ renal or hepatic insufficeincy (rare)
SE:
GI: anorexia, nausea, abdominal discomfort, diarrhea
Glimepiride**
Sulfonylureas: Stimulates insulin secretion (oral)
MOA:
- Block ATP-sensitive K+ channel
- Leads to depolarization and influx of Ca++
- Results in insulin secretion
- causes less weight gain than other SU’s
Adverse Effects: Weight gain and Hypoglycemia
CI’s: sulfa allergy, pregnancy, type 1 DM, ketoacidosis, renal failure, hepatic failure, and major surgery
Glipizide**
Sulfonylureas: Stimulates insulin secretion (oral)
MOA:
- Block ATP-sensitive K+ channel
- Leads to depolarization and influx of Ca++
- Results in insulin secretion
Adverse Effects: Weight gain and Hypoglycemia
Glyburide**
Sulfonylureas: Stimulates insulin secretion (oral)
MOA:
- Block ATP-sensitive K+ channel
- Leads to depolarization and influx of Ca++
- Results in insulin secretion
Adverse Effects: Weight gain and Hypoglycemia
- greater incidence of prolonged hypoglycemia
- use cautiously in elderly or those predisposed to hypoglycemia
Repaglinide**
Non-sulfonylurea secretagogue (Meglitinide)- Stimulates insulin secretion (oral)
- insulin releasing agents - act same way as sulfonylureas
- Blocks ATP-sensitive K+ channel - Binds at different site than sulfonylureas
Biggest difference from sulfonylureas?
- Short half-life; rapid action
- Taken right before meals (good advantage)
Nateglinide**
Non-sulfonylurea secretagogue (Meglitinide)- Stimulates insulin secretion (oral)
- insulin releasing agents - act same way as sulfonylureas
- Blocks ATP-sensitive K+ channel - Binds at different site than sulfonylureas
Biggest difference from sulfonylureas?
- Short half-life; rapid action
- Taken right before meals (good advantage)
Pioglitazone**
Thiazolidinediones (TZD): Insulin sensitizer (oral)
** use is controversial
MOA: PPAR-gamma agonists
- binds to nuclear txn factors involved in insulin action
- decreased insulin resistance
- increased peripheral action of insulin
- increased glucose uptake via (GLUT1 and GLUT4)
- decreased hepatic glucose output
LONG TERM RISKS!
- risk of MI and weight gain!!
- causes fluid retention –> CHF
Acarbose**
alpha-Glucosidase inhibitor: prevents complex carbohydrates hydrolysis and delays carb abosorption (oral)
MOA:
- inhibits digestion of complex sugars
- Decrease sugar uptake after a meal
- Cause flatulence and GI upset: poor compliance
- Watch out for hypoglycemia when used with insulin or sulfonylurea
Miglitol**
alpha-Glucosidase inhibitor: prevents complex carbohydrates hydrolysis and delays carb abosorption (oral)
MOA:
- inhibits digestion of complex sugars
- Decrease sugar uptake after a meal
- Cause flatulence and GI upset: poor compliance
- Watch out for hypoglycemia when used with insulin or sulfonylurea
Exenatide**
Glucagon-Like Peptide-1 (GLP-1) Agonist: potentiates glucose-dependent insulin secretion, suppress glucagon secretion, slow gastric emptying, promotes satiety
dose: SC injection 1x/week
MOA:
- enhances insulin secretion
- inhibits glucagon secretion
- appetite suppression/satiety
- reduces gastric emptying
- stimulates islet cell growth, differentiation, regeneration
- ** decreased HbA1c, postprandial glucose and weight loss
Advantages: satiety and little hypoglycemia
ddx of diabetes?
Classic signs and symptoms
Unequivocally high FPG >126 mg/dL
Random glucose of >200 mg/dL
FPG of >126 mg/dL on two or more occasions
Failure on Oral Glucose Tolerance Test
Rapidly acting insulin?
- shows one fast rapid peak
Insulin lispro (human) insulin aspart (human) insulin glulisine (human)
short acting insulin
Regular insulin
Intermediate-acting insulin?
NPH (Isophane Insulin Suspension)
Long acting insulin?
Insulin Glargine
Insulin Detemir
Fixed-mix insulin preparation?
NPH/Regular mixture
NPH/Humalog mixture
NPA/aspart
- NPA/NPH are intermediate acting - these are used to sustain insulin, esp. at nighttime
- regular/humalog/aspart are more rapidly acting and will result in short peaks throughout the day
how does metformin differ from sulfonylurea agents?
-
DDP-4 inhibitors
- gliptin
- potentiate glucose-dependent insulin secretion and suppress glucagon secretion (oral)
ex. Alogliptin, linagliptin, saxagliptin, stiagliptin phosphate
MOA: enzyme breaks peptide bonds
- increases insulin secretion, decreases glucagon, decreases hepatic glucose production, increases peripheral glucose uptake and utilization
Advantages: Little hypoglycemia
Amylin analogs
- mimics amylin (SC injection before meals)
- ex: pramlintide acetate
- third of fourth line tx: reqs. SQ injections prior to meals that can’t be mixed with inuslin
MOA:
- synthetic analog of amyln: results in decreased endogenous glucagon production, decreased gastric emptying time, decreased prostprandial glucose levels
** used esp. in pts w/ insulin resistance
SGLT2 inhibitors
- gliflozin
- sodium-glucose co-transporter 2 inhibitors: decreases renal glucose reabsorption and increases urinary glucose excretion
- ex: canagliflozin, dapagliflozin, empagliflozin
MOA:
- oral tx once per day
- SGLT2 is a membrane protein expressed on kidney: it transports filtered glucose from the proximal renal tubule into tubular epithelial cells.
- By inhibiting SGLT2, canagliflozin decreases glucose reabsorption, increases urinary glucose excretion, and lowers blood glucose levels
- Flozins are modestly effective in reducing HbA1c, systolic blood pressure and weight, with a low risk of hypoglycemia.
AE’s:
Genital mycotic infections can occur in both men and women; long-term safety still unknown.
Sulfonylureas
“insulin releasers” (oral)
- glimepiride, glipizide, glyburide
MOA: Lower blood glucose
- Block ATP-sensitive K+ channel
- Leads to depolarization and influx of Ca++
- Results in insulin secretion***
Key points:
- stimulates insulin release –> lowers blood glucose
- indirectly increase tissue sensitivity to insulin
- helps suppress hepatic glucose output
** success depends on functionality of Beta cells!
non-sulfonylurea secreatagogues
- stimulates insulin secretion
- Repaglinide, nateglinide
- insulin releasing agents - act same way as sulfonylureas
- Blocks ATP-sensitive K+ channel - Binds at different site than sulfonylureas
Biggest difference from sulfonylureas?
- Short half-life; rapid action
- Taken right before meals (good advantage)
Thiazolidinediones (TZDs)
Insulin sensitizers (oral) ex. pioglitazone, rosiglitazone
- use is controversial
MOA: PPAR-gamma agonists
- binds to nuclear txn factors involved in insulin action
- decreased insulin resistance
- increased peripheral action of insulin
- increased glucose uptake via (GLUT1 and GLUT4)
- decreased hepatic glucose output
LONG TERM RISKS!
- risk of MI and weight gain!!
- causes fluid retention –> CHF
signs of hypoglycemia?
- need increased glucose - too much insulin (this is a common AE of tx of diabetes)
Signs and Symptoms
- Sweating, hunger, paresthesias, palpitations, tremor, anxiety
- confusion, weakness, drowsiness, blurred vision, loss of consciousness
Treatment:
Glucose
Glucagon
alpha-glucosidase inhibitors
prevents complex carbs hydrolysis and delays carb absorption (oral)
ex. acarbose, miglitol
MOA:
- inhibits digestion of complex sugars
- Decrease sugar uptake after a meal
- Cause flatulence and GI upset: poor compliance
- Watch out for hypoglycemia when used with insulin or sulfonylurea
Glucagon-like peptide-1 analog (GLP-1) agonists
potentiate glucose-dependent insulin secretion, suppress glucagon secretion, slows gastric emptying, and promotes satiety
ex: Exenatide, liraglutide
dose: SC injection 1x/week
MOA:
- enhances insulin secretion
- inhibits glucagon secretion
- appetite suppression/satiety
- reduces gastric emptying
- stimulates islet cell growth, differentiation, regeneration
- ** decreased HbA1c, postprandial (postmeal) glucose and weight loss
Advantages: satiety and little hypoglycemia
SE: not many, just GI
advantages of metformin?
its first choice! and can be used as monotherapy
Advantages:
- no weight gain
- no hypoglycemia
- favorable lipid profile
- its a pill, unlike inuslin, there is no injections
concern for metformin?
its considered quite safe, but lactic acidosis can rarely occur with
- renal or hepatic insufficiency
- CV disease
SE for sulfonylureas?
Adverse Effects: Weight gain and Hypoglycemia
which SU causes most hypoglycemia?
glyburide!
benefits of GLP-1 agonists?
*** decreased HbA1c, postprandial (postmeal) glucose and weight loss
whats big problem with GLP-1 agonist?
its a peptide, has to be injected! (no pill form :/) - though can now be once per week injections
recommended HbA1c target?
below 6.5% for diabetics
signs of hypoglycemia?
autonomic: sweating, hunger, paresthesias, palpitations, tremor anxiety
neuro: difficulty concentrating, confusion, weakness, drowsiness, feeling of warmth, dizziness, blurred vision, loss of consciousness
can be drug induced by: ethanol. beta adrenergic antagonists, salicylates
- ethanol inhibits gluconeogensis
- Beta agonists inhibit the effects of catecholamines on gluconeogensis and can mask the sympathetically mediated sx associated with low blood glucose (tremors, palpitations)
