Drugs for Diabetes Flashcards
what is diabetes mellitus?
insufficiency of insulin signalling relative to the requirements of the tissues for this hormone
what are some symptoms of DM?
polyuria (sweet urine) polydipsia (excessive thirst) polyphagia (excessive hunger) elevated fasting blood sugar ketosis weight loss
What are the normal fasting blood glucose levels?
4.4-6.1mmol/L
what fasting blood glucose level indicates DM?
7 mmol/L or over
what is type 1 DM? type 2 DM?
type 1 - autoimmune destruction of beta cells in pancreas
type 2 - insulin resistance; insulin secretion is present but inappropriate in requirement and timing
what are some differences between T1DM and T2DM?
1) T1DM onset primarily in childhood; T2DM onset primarily after 40y.o
2) T1DM are often normal weight; T2DM typically obese
3) T1DM prone to ketoacidosis, not T2DM
4) T1DM requires insulin admin, T2DM does not require it
5) T1DM tx = insulin; T2DM tx = healthy diet/exercise, hypoglycemic tabs, insulin
what is the relative prevalence of T1DM and T2DM?
1 - 10-20%
2 - 80%
what is preproinsulin?
a very large peptide that is cleaved to produce proinsulin?
what is proinsulin?
the precursor to insulin. it is cleaved to produce insulin and C-peptide
where is insulin secreted from?
pancreatic beta cells
what is the potential function of C peptide?
has a role in rate of endogenous insulin release
what does insulin consist of?
A chain (21 AA) B chain (30 AA) these are attached in parallel by two disulfide links
what stimulates insulin secretion?
elevated blood glucose
also by physiological levels of AAs, FAs, and ketone bodies
what signals an increase in insulin secretion? decrease?
incr - parasym
decr - sym
what inhibits insulin/glucagon secretion?
somatostatin (product of pancreatic D cells)
describe the PK for insulin
largely unbound distributed in ECF volume first pass metabolism also degraded by kidney t1/2 = 9min
what are some results of lack of insulin in the body?
1) hyperglycemia (underutilization of glucose by muslce and fat; overproduction of glc in liver)
2) reduced glycogen/protein synthesis
increased lipolysis
what is the difference between the different insulin preparations?
duration of action - depending on rate of absorption after SC injection
what are the four kinds of insulin preparations?
rapid acting
short acting
intermediate acting
long acting
what are some examples of a rapid acting insulin preparation?
insulin Lispro (Humalog) insulin aspart (Novolog) insulin glulisine (Apidra)
what are rapid acting insulin preparations?
insulin where the 28th and 29th AA are reversed on the B chain, resulting in rapid absorption
what is the benefit of using rapid acting insulin preparations?
better post-prandial glucose control with reduced risk for hypoglycemia
what is an example of a short acting insulin preparation?
regular novolin R (Novo Nordisk)
what is a short acting insulin preparation?
has rapid onset and short duration
peak effect in 5h, duration up to 12h
what is an example of an intermediate acting insulin preparation?
humulin N (Lilly)
what is found in intermediate acting insulin preparation?
protamine
suspension is at neutral pH in phosphate buffer
what is the peak level and DoA for intermediate acting insulin preparation?
duration = 10-20h peak = 4-8h
what are three examples of long acting insulin preparation? what is the downside to one of the preparations?
insulin glargine (LantusR) insulin detemir (LevemirR) - requires BID dosing rather than OD dosing with LantusR Novolin 70/30%(NPH)
what is long acting insulin preparation?
insulin with 3 altered AAs in B chain (Asparagine replaces glycine, 2 arginines added at C-terminus)
what is the benefit to using long acting insulin preparations?
useful for providing basal insulin concentration overnight
what is the DoA for long acting insulin preparations?
22-24h
what are some SE’s related to insulin preparation use?
hypoglycemia (with insulin overdose) - sweating, tachycardia, trembling, confusion, unconsciousness, coma local reactions at injection site (rare) allergic reactions (Rare)
what is an insulin pump?
what is a downside to using the insulin pump?
delivers insulin at a constant slow rate, plus a bolus when desired (ex: before meals)
con: requires frequent self-monitoring of blood glucose and dosage adjustment
what are two drug classes of insulin releasing agents?
sulfonyureas
meglitinide analogs
what are some examples of sulfonylureas?
glimepiride
glipizide
glyburide
what is the MoA for sulfonylureas?
1) stimulate pancreatic insulin secretion and sensitize beta cells to glucose
2) increase insulin sensitivity of target tissues
what causes insulin secretion?
due to inhibition of ATP sensitive K+. High glc increases ATP, which inhibits K+ channels, leading to depolarization and opening of Ca2+ channels with influx of Ca2+
briefly describe the PK for sulfonylureas?
absorbed from GI tract
considerable protein binding
what are some potential SE’s of sulfonylureas?
hypoglycemia (overdose) - worst with those taking glyburide
weight gain
aggravation of myocardial ischemia
when is sulfonylurea use contraindicated?
in patients with CV disease or liver/kidney insufficiencies
what are the indications of sulfonylureas?
mild T2DM when diet alone is not sufficient and insulin injection is not practical
Not proven to be of benefit in preventing long-term complications of diabetes
what are some examples of meglitinide analogs?
repaglinide
nateglinide
what is the MoA for meglitinide analogs?
increases insulin secretion by binding to the ATP-sensitive K+ channels
briefly describe the PK for meglitinide analogs
rapidly absorbed with short half life and fast onset
must be taken 15-30 min prior to meals
what is a side effect of meglitinide analogs?
may cause weight gain
what is a drug class of weight reducing agents?
biguanides
what is the first line treatment for T2DM?
metformin
give an example of a biguanide
metformin
what is the MoA for biguanides?
activates AMP-activated protein kinase (AMPK), triggering decreased gluconeogenesis in liver/skeletal muscle and increased peripheral insulin response.
Does not effect insulin secretion
briefly describe the PK for biguanides
not metabolized or protein bound
no drug interactions
renal impairment reduces excretion
what is a major concern of using biguanides?
increased risk of fatal lactic acidosis
note: risk of this with metformin is reduced compared to other biguanides
what is a benefit to using metformin?
associated with mild weight loss
lowers parandial glucose but does not produce hypoglycemia
what is a drug class for insulin sensitivity enhancers?
thiazolidinedione derivates
what are two examples of thiazolidinedione derivates?
rosiglitazone
pioglitazone
what is the MoA of thiazolidinedione derivates?
decreases insulin resistance by binding to insulin-responsive genes
decreases gluconeogenesis and glucose output; increases glc uptake and utilization in skeletal muscle
decreases insulin requirement
no effect on insulin secretion
what is the difference between rosiglitazone and pioglitazone?
rosiglitazone does not interfere with CYP3A4 activity, so there is less chance for side effects
what are some side effects to using pioglitazone?
edema macula edema loss of bone density weight gain concerns with bladder cancer
what are two examples of alpha-glucosidase inhibitors?
acarbose
miglitol
what is the MoA of alpha-glucosidase inhibitors? what is one benefit of this drug class?
slows the break down and absorption of starch and complex carbohydrates
pro: does not cause hypoglycemia
what is the indication for alpha-glucosidase inhibitors?
type 2 diabetes
what is a side effect to alpha-glucosidase inhibitors?
abdominal discomfort
when is the use of alpha-glucosidase inhibitors contraindicated?
chronic intestinal diseases
what are two classes of drugs under incretins?
DPP-4 inhibitors
GLP-1 analogs
what are two examples of DPP-4 inhibitors?
sitagliptin-PO4 (Januvia)
saxagliptin (Onglyza)
what is the MoA of DPP-4 inhibitors?
ingesting a meal leads to secretions of GLP-1 from gut, which is insulinotropic and are decreased in T2DM. DDP-4 inhibitors inhibit dipeptidyl peptidase-4, an enzyme that degrades GLP-1
increase insulin synthesis and release; decrease glucagon levels
name two examples of GLP-1 analogs. what is the difference between the two?
exenatide (Byetta) - BID SC injection
liraglutide (Victoza) - OD SC injection
what is a benefit to using GLP-1 analogs?
reduced weight and blood glucose
what is an example of an amylin?
pramlintide (Symlin)
what is the MoA of pramlintide?
amylin is a hormone co-secreted with insulin from beta cells in response to glc
Pramlintide is a synthetic analog of amylin, which is more soluble and does not readily aggregate like amyline
Decreaes glucagon secretion and glc absorption
what is the indication of pramlintide?
type 1 and type 2 diabetes
what can cause complications of diabetes?
periods of less severe hyperglycemia result in glycosylation of various proteins and accumulation of sorbitol in non-insulin dependent cells
what are some complications of diabetes?
micro: neuropathy nephropathy retinopathy macro: CV disease
