B5.003 - Drugs for Diabetes Flashcards
what is diabetes mellitus
symptoms of hyperglycemia due to inappropriate insulin secretion or function
types 1-4 of DM
1 - autoimmune destruction of beta cells, insulin dependent
2 - noninsulin dependent, associated with diabetes and metabolic syndrome
3 - non pancreatic causes, drugs that impair glucose tolerance
4 - gestational diabetes
what are drugs that can cause T3DM
Corticosteroids
Thiazide diuretics
Combination oral contraceptives
major goals of treatment of diabetes
treat hyperglycemia and improve all aspects of metabolism
fasting glucose 90-120
2 hr post prandial <150
HgA1c <7%
treatment strategy for T1DM
replacement of insulin
treatment strategy for T2DM
improve insulin sensitivity at early stages and replace insulin in later stages
change lifestyle
reduce glucose absorption
increase insulin secretion
what stimulates insulin secretion
increase in ATP/ADP ratio glucose and other sugars AAs FAs PARA GLP-1
what stimulates insulin synthesis
nutrients
insulin acts through stimulation of what
tyrosine kinase receptor
IR autophosphorylation leads to phosphorylation and activation of downstream signaling proteins
where does insulin act
Liver
muscle
adipose tissue
to decrease blood glucose levels and shift from energy use to storage
who gets exogenous insulin
T1DM patients
final drug of choice for T2DM, postpancreatectomy and gestational diabetes
how is insulin given and why
subcutaneous because it slows the rate of absorption, good if you dont want a huge increase of insulin
adverse effects of exogenous insulin
hypoglycemia insulin allergy lipoatrophy weight gain insulin edema
what do insulin regiments tailor to
activity and diet
rapid acting insulins
Lispro
Aspart
Glulisine
given with a meal
short acting insulins
like normal endogenous
regular Novolin
regular Humulin
intermediate acting insulins
NPH humulin
NPH novolin
long acting insulins
detemir, levemir
glargine, lantus
algorithm for adding or intensifying insulin
start with long acting insulin
insulin titration every 2-3 days to reach glycemic goal
if glycemic goal not met add prandial insulin or GLP-1 RA or SGLT-2i or DPP-4i
how is insulin used to treat DKA
IV infusion of regular insulin at low rate (.1 unit/kg body wt/hr)
may need to administer glucose with it to prevent hypoglycemia
add appropriate fluid and electrolytes
drug types to treat T2DM
insulin secretagogues insulin receptor sensitizers inhibitors of glucose absorbance incretins/mimics inhibitors of glucose reuptake in kidney
mechanism of action of sulfonylureas
activate residual beta cells to release insulin by binding to and activation SUR1
what is SUR1
sulfonylurea receptor 1, a subunit of K/ATP channel. Sulfos replace the Mg2+/ADP on SUR1 that activate the channel, similar to the fed state
first generation sulfos
tolbutamide, tolazamide, chlorpropamide
whats the diff between 1st gen and 2nd gen sulfonylureas
second gen binds to SUR1 with higher affinity so lower dose is required
2nd gen sulfos
glyburide, glipizide, glimepiride
pharmacokinetics of sulfonylureas
orally available, bound to plasma albumin; metabolized by the liver; metabolites excreted in urine
AEs of sulfonylureas
hypoglycemia, weight gain
what patient would get first gen solfonylureas
pts with kidney issues or elderly at high risk of hypoglycemia
contraindications of sulfonylureas
T1DM
pregnancy
lactation
significant hepatic or renal insufficiency
MOA of meglitinides
similar to sulfonylureas by binding SUR1 but at a different site to activate K/ATP channel
what are the meglitinides
Repaglinide (Prandin)
Nateglinide (Starlix) - more rapid onset
pharmacokinetics
cleared by liver, so not suitable for patients wiht hepatic insufficiency
major AE of meglitinides
hypoglycemia
what are biguanides
metformin
what is the euglycemic effect and what drug produces it
helps maintain normal blood glucose levels, typically without producing hypoglycemia
MOA of metformin
reduces hepatic gluconeogenesis
increases peripheral glucose uptake
activates AMPK
inhibits mTOR-C1
pharma actions of metformin
inhibits gluconeogensis in liver
does not promote weight gain or hypoglycemia
can reduce plasma TGs by 15-20%
clinical uses of metformin
1st line therapy for T2DM
oral dosage 500mg-2.55g / day taken with or after food
also useful in treating polycystic ovary syndrome and NAFLD
metabolism and excretion of metformin
orally effective, T1/2: 1.5 - 3 hrs
not bound to plasma protein; not metabolized; excreted by kidney as parent compound
metformin toxicity
lactic acidosis, by blocking gluconeogenesis may impair hepatic metabolism of lactic acid
more common in pts with renal insufficiency
dose related complication
GI related
reduced Vitamin B12 absorption
what do thiazolidinediones (TZDs) do
PPAR gamma agonists with PPAR alpha agonist activity
what is the MOA of TZDs
in adipose tissue, PPAR gamma activators promote the transport of serum lipids to adipose tissue
may also activate PPAR gamma in other tissues to promote insulin sensitivity
what are the TZDs
Rosiglitazone 10x affinity
Pioglitazone
whats troglitazone
a TZD that was pulled bc of liver toxicity
TZDs effective at reducing what
glucose and TG levels
where are TZDs metabolized
liver
what are AEs of TZDs
weight gain
hepatic toxicity
CHF
MOA of alpha glucosidase inhibitors
competitive and reversible inhibitors of pancreatic alpha amylase and intestinal alpha glucosidase enzymes
this leads to increased time required to absorb complex carbs and reduces post prandial glucose peak
what are the glucosidase inhibitors
acarbose and miglitol
often used in combination with other hypoglycemic agents
AEs of glucosidase inhibitors
NO risk for hypoglycemia
flatulence, bloating, diarrhea
incretins
GLP-1 and GIP
what does GLP-1 do
stimulates secretion of insulin enteroendocrine cells (L cells) in the ileum, hormonal signal that increases insulin secretion but decreases glucagon secretion in pancreas, delays gastric emptying and decreases appetite in hypothalamus
what is GIP
another hormonal signal that has similar effects to GLP-1
AEs of GLP-1 analogues
nausea, vomiting, diarrhea
LOW risk of hypoglycemia
what are the GLP-1 analogues
exenatide
liraglutide
albigutide
duraglutide
what do DDP-4 inhibitors do
normally DDP-4 degrades endogenous incretids, so inhibitors block that from happening
what are the DDP-4 inhibitors
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
what are DDP-4i not used in combination with
GLP-1 analogs, because they are less susceptible to DPP-4 degradation inherently and it would be redundant
what do SGLT2 inhibitors do
block SGLT2
SGLT2 are located in the proximal tubules and allow glucose reabsorption after its been freely filtered by glomeruli
SGLT2 accounts for 90% of glucose reabsorption
AEs of SGLT2 inhibitors
glycosuria genital infections UTIs hypotension weight loss
what are the SGLT2 inhibitors
canagliflozin
dapagliflozin
empagliflozin
what is pramlintide
amylin analog
mimics high dose pharmacologic effects of amylin
MOA of pramlintide
pancreas - increases insulin secretion and decreases glucagon secretion
delays gastric emptying
decreases appetite
how is pramlintide given
preprandial use as an adjunct to insulin in T1 and T2 DM
pharmacokinetics of pramlintide
renal metabolism and excretion
AEs of pramlintide
hypoglycemia
GI symptoms
colesevalam
bile acid sequestrant, cholseterol lowering drug
MOA not fully understood
MOA of colesevalam
interrupts enterohepatic circulation
decreases farnesoid X receptor nuclear receptor activation
AE of colesevalam
can exacerbate hypertriglyceridemia common in T2D
what does bromocriptine do
dopamine agonist
AEs of bromocriptine
nausea fatigue dizziness vomiting headache
principles of combination therapy
combine different mechanisms
target different proteins
advantage of using lower doses
fewer AEs
combo therapy in treating T2DM
begin with monotherapy Metformin
GLP-1 mimic, SGLT-2 inhibitors, or DDP-4 inhibitor
what are second choice agents for T2DM
sulfonylureas and TZDs
