PH1 05: Anti-Diabetic Drugs
Physician Assistant Pa 2013 Session 2 with Tsai at Touro University (NV)
About this deck
By: John Yaw-Jong Tsai
Created: 2011-12-07
Size: 73 flashcards
Views: 63
Created: 2011-12-07
Size: 73 flashcards
Views: 63
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Therapeutic drug overview of the two types of diabetes mellitus
Type I
insulin
with thiazolidinedione for severe insulin resistance
Type II
metformin
other oral hypoglycemic agent
α-glucuronidase inhibitor
combination of metformin and thiazolidinedione or sulfonylurea
insulin
ACEI to reduce HTN (nephroprotective)
insulin
with thiazolidinedione for severe insulin resistance
Type II
metformin
other oral hypoglycemic agent
α-glucuronidase inhibitor
combination of metformin and thiazolidinedione or sulfonylurea
insulin
ACEI to reduce HTN (nephroprotective)
What is the clinical use of glucagon?
catabolism of glycogen stores into glucose
use for severe hypoglycemia and treat or prevent diabetic coma
diagnosis of DM I
beta blocker poisoning (to reverse B1 blockade)
use for severe hypoglycemia and treat or prevent diabetic coma
diagnosis of DM I
beta blocker poisoning (to reverse B1 blockade)
What kind of receptor is the insulin receptor?
tyrosine kinase receptor
upon ligand binding, forms dimers and phosphorylates each other
activates phosphoinositol-3-kinase
which activates PKC and Akt
responsible for glucose transport, glycogen synthesis, lipid synthesis, protein synthesis
upon ligand binding, forms dimers and phosphorylates each other
activates phosphoinositol-3-kinase
which activates PKC and Akt
responsible for glucose transport, glycogen synthesis, lipid synthesis, protein synthesis
What are the target tissues of insulin?
skeletal and cardiac muscles, liver, adipose
stimulates anabolic processes for controlling uptake, use and storage of glucose, amino acids, and fatty acids
inhibits catabolic processes in breakdown of glycogen, protein, and fats
stimulates anabolic processes for controlling uptake, use and storage of glucose, amino acids, and fatty acids
inhibits catabolic processes in breakdown of glycogen, protein, and fats
What chemicals and neuronal stimulation promotes insulin secretion?
glucose, amino acids, ketones
parasympathetic stimulation (vagal)
hormones associated with digestion (gastric inhibitory peptide)
parasympathetic stimulation (vagal)
hormones associated with digestion (gastric inhibitory peptide)
What inhibits insulin secretion?
sympathetic stimulation
How does high glucose activate insulin release?
glucose enters β-cell (GLUT2) → G6P (glucokinase)
TCA cycle increases ATP
↑ ATP/ADP ratio inhibits KIR6.2 (K+ inward rectifier channel)
partial depolarization of cell opens voltage gated Ca2+ channels
↑ Ca2+ causes release of insulin from docked vesicles
TCA cycle increases ATP
↑ ATP/ADP ratio inhibits KIR6.2 (K+ inward rectifier channel)
partial depolarization of cell opens voltage gated Ca2+ channels
↑ Ca2+ causes release of insulin from docked vesicles
Since 2003, how are insulin replacement preparations synthesized?
all insulin made by varying recombinant DNA techniques of human origin stabilized around zinc ions
(Novolin R, Humulin R, Velosulin R)
insulin delivered via subcutaneous injections via insulin pumps
inhalation devices under development
(Novolin R, Humulin R, Velosulin R)
insulin delivered via subcutaneous injections via insulin pumps
inhalation devices under development
What is the physiological state of insulin in the body? (i.e. how normal endogenous insulin exists)
insulin stored as dimers that naturally form hexamers
physiologically active insulin is in monomer form
physiologically active insulin is in monomer form
How does the polymerization of insulin affect its absorption rate?
three rates of absorption based on aggregation state of insulin
- hexamers - slowest rate
- dimers - intermediate rate
- monomers - fastest rate
to replace basal and post-prandial insulin levels
using combination of
using combination of
- rapid acting, rapid onset (short duration) drugs and
- intermediate and long acting drugs
When should sort acting (human recombinant) insulin products be administered?
30 to 40 mins before meal
effective peak action in 2 to 3 hours
duration of action 5 to 8 hours
slower absorption rate than rapid acting short duration modified insulin drugs (lispro, aspart, glulisine)
prevents early post-prandial hyperglycemia
effective peak action in 2 to 3 hours
duration of action 5 to 8 hours
slower absorption rate than rapid acting short duration modified insulin drugs (lispro, aspart, glulisine)
prevents early post-prandial hyperglycemia
What are 2 long acting drugs that replace basal insulin levels?
insulin detemir (Levemir)
insulin glargine (Lantus)
insulin analogues
insulin glargine (Lantus)
insulin analogues
What are some of the rapid acting short duration insulin analogues that most closely mimic endogenous insulin secretion?
insulin lispro (Humalog)
insulin aspart (Novolog)
insulin glulisine (Apidra)
all are modified insulin analogues
onset of action in 10 to 15 minutes
duration of action 3 to 5 hours
insulin aspart (Novolog)
insulin glulisine (Apidra)
all are modified insulin analogues
onset of action in 10 to 15 minutes
duration of action 3 to 5 hours
What changes to function of insulin do the modifications to rapid-acting short duration insulins (lispro, aspart, glulisine) achieve?
modifications in lispro, aspart, glulisine, allow rapid absorption and dissolution into monomers (active form)
faster acting than recombinant insulin
faster acting than recombinant insulin
What are the short acting (human recombinant) insulin products?
Novolin R
Humulin R
Velosulin R
produced by recombinant techniques
stabilized around zinc ions
identical to human insulin
Humulin R
Velosulin R
produced by recombinant techniques
stabilized around zinc ions
identical to human insulin
What are the intermediate acting insulin products?
neutral protamine Hagedorn (NPH)
Humulin N
Novolin N
onset of action in 2 to 5 hours
duration of action 4 to 12 hours
Humulin N
Novolin N
onset of action in 2 to 5 hours
duration of action 4 to 12 hours
What is the mechanism of action of NPH that allows it to be an intermediate acting insulin product?
insulin is complexed with protamine
after injection, subcutaneous proteases degrade protamine to release insulin
after injection, subcutaneous proteases degrade protamine to release insulin
How does detemir (Levemir) achieve its long acting mechanism of action?
detemir (Levemir) prolongs its availability by increasing self-aggregation (into dimers or hexamers) and increasing tissue albumin binding
has the most reproducible effects of intermediate and long acting insulins
has the most reproducible effects of intermediate and long acting insulins
How does glargine (Lantus) behave in acidic pH and in neutral pH?
How is this responsible for its long acting action?
How is this responsible for its long acting action?
glargine (Lantus) is soluble at acidic pH
precipitates at neutral pH (of subcutaneous tissue)
then slowly dissolves into plasma to provide a low continuous level of insulin
precipitates at neutral pH (of subcutaneous tissue)
then slowly dissolves into plasma to provide a low continuous level of insulin
What is the difference in activity between the 2 long acting insulins, detemir (Levemir) and glargine (Lantus)?
detemir (Levemir)
max activity in 1 to 2 hours (low basal level)
maintained for 24 hours or more
glargine (Lantus)
max activity in 4 to 6 hours (low basal level)
maintained for 11 to 24 hours
max activity in 1 to 2 hours (low basal level)
maintained for 24 hours or more
glargine (Lantus)
max activity in 4 to 6 hours (low basal level)
maintained for 11 to 24 hours
How must glargine (Lantus) be stored? Can it be mixed with other insulin preparations?
must be stored in acidic environment
therefore, cannot be mixed with other insulin preparations
therefore, cannot be mixed with other insulin preparations
What are some adverse effects of insulin?
hypoglycemia (most significant effect)
diabetics have decreased ability to compensate for low blood sugar
due to suppressed feedback by glucagon
weight gain (anabolic hormone)
lipodystrophy (must rotate injection sites)
diabetics have decreased ability to compensate for low blood sugar
due to suppressed feedback by glucagon
weight gain (anabolic hormone)
lipodystrophy (must rotate injection sites)
What are the 3 categories oral antidiabetic agents?
insulin secretagogues (promote insulin release)
insulin sensitizers (decrease insulin resistance)
α-glucosidase inhibitors (slows carbohydrate absorption)
insulin sensitizers (decrease insulin resistance)
α-glucosidase inhibitors (slows carbohydrate absorption)
What are the different drugs under category of insulin secretagogues (that promote insulin release)?
sulfonylureas
glipizide
glimepiride
meglitanides
repaglinide (Prandin)
nateglinide (Starlix)
glipizide
glimepiride
meglitanides
repaglinide (Prandin)
nateglinide (Starlix)
What are the 2 sulfonylurea drugs?
glipizide and glimepiride
second generation drugs
more potent with fewer side effects than first generation
second generation drugs
more potent with fewer side effects than first generation
What are the mechanisms of action of the sulfonylureas?
cause hypoglycemic effect
stimulates release of insulin from pancreatic β-cells
by binding to SUR subunit of KIR6.2 causing depolarization and influx of Ca2+
can do this in absence of glucose
increase peripheral insulin sensitivity
stimulates release of insulin from pancreatic β-cells
by binding to SUR subunit of KIR6.2 causing depolarization and influx of Ca2+
can do this in absence of glucose
increase peripheral insulin sensitivity
How do sulfonylureas affect Hb1Ac?
decreases Hb1Ac by 1.5% to 2.0%
e.g. could bring Hb1Ac from 9% down to 7%
e.g. could bring Hb1Ac from 9% down to 7%
What are the therapeutic uses for sulfonylureas and what are its contraindications?
therapeutic uses
control hyperglycemia in DM II
requires dietary restrictions
contraindications
DM I
pregnancy
renal or hepatic insufficiency
control hyperglycemia in DM II
requires dietary restrictions
contraindications
DM I
pregnancy
renal or hepatic insufficiency
What are some adverse effects of sulfonylureas?
hypoglycemic reactions (inc. coma)
esp. in elderly patients, or with renal or hepatic insufficiency
secondary failure - "β-cell burnout" (34% fail after 5 years of therapy)
weight gain (up to 4 kg)
sulfa allergies
esp. in elderly patients, or with renal or hepatic insufficiency
secondary failure - "β-cell burnout" (34% fail after 5 years of therapy)
weight gain (up to 4 kg)
sulfa allergies
What are some possible sulfonylurea drug interactions?
any drug that can displace sulfonylureas from plasma binding proteins
e.g.
sulfonamides
clofibrate (cholesterol lowering)
salicylates (aspirin)
e.g.
sulfonamides
clofibrate (cholesterol lowering)
salicylates (aspirin)
What are the different drugs under category of insulin secretagogues (that promote insulin release)?
sulfonylureas
meglitanides
meglitanides
What are the 2 meglitanide drugs?
repaglinide (Prandin) and nateglinide (Starlix)
structurally unrelated to sulfonylureas
binds to different site on KIR6.2 channel
structurally unrelated to sulfonylureas
binds to different site on KIR6.2 channel
What are the mechanisms of action of the meglitanides?
same as sulfonylureas
cause hypoglycemic effect
stimulates release of insulin from pancreatic β-cells
by binding to SUR subunit of KIR6.2 causing depolarization and influx of Ca2+
glucose must be present for it to work
cause hypoglycemic effect
stimulates release of insulin from pancreatic β-cells
by binding to SUR subunit of KIR6.2 causing depolarization and influx of Ca2+
glucose must be present for it to work
How do meglitanides affect Hb1Ac?
decreases Hb1Ac by 0.6% to 1.0%
(less than sulfonylureas)
e.g. could bring Hb1Ac from 9% down to 8%
(less than sulfonylureas)
e.g. could bring Hb1Ac from 9% down to 8%
What are the therapeutic uses for meglitanides?
pre-prandial use (absorbed rapidly) - peak level in 1 hour
used in combination with insulin sensitizers
never used with sulfonylureas
used in combination with insulin sensitizers
never used with sulfonylureas
What are some adverse effects of meglitanides?
hypoglycemic reactions (inc. coma)
caution in renal or hepatic insufficiency
weight gain (less than sulfonylureas)
caution in renal or hepatic insufficiency
weight gain (less than sulfonylureas)
What are the different drugs under category of insulin sensitizers (that increase insulin sensitivity)?
biguanides
metformin (Glucophage)
thiazolidinediones
pioglitazone (Actos)
metformin (Glucophage)
thiazolidinediones
pioglitazone (Actos)
What is the mechanism of action of metformin (Glucophage)?
antihyperglycemic actions (no hypoglycemia)
does not stimulate insulin secretion (insulin must be present)
increases insulin action in muscle and fat (decreases insulin resistance)
decreases hepatic glycogen breakdown
decreases GI glucose uptake
does not stimulate insulin secretion (insulin must be present)
increases insulin action in muscle and fat (decreases insulin resistance)
decreases hepatic glycogen breakdown
decreases GI glucose uptake
How does metformin affect Hb1Ac?
decreases Hb1Ac by 1.5% to 2.0%
e.g. could bring down HbA1c from 9% down to 7%
same as sulfonylureas
e.g. could bring down HbA1c from 9% down to 7%
same as sulfonylureas
What are the therapeutic uses for metformin?
first line drug for DM II
esp. in overweight patients
causes weight loss instead of weight gain
may be used with insulin or other oral antidiabetic agents
esp. in overweight patients
causes weight loss instead of weight gain
may be used with insulin or other oral antidiabetic agents
What is metformin contraindicated for?
renal or hepatic insufficiency
heart failure patients (lactic acidosis)
other conditions that predispose to lactic acidosis
heart failure patients (lactic acidosis)
other conditions that predispose to lactic acidosis
What are some adverse effects of metformin?
pernicious anemia (vitamin B12 malabsorption)
nausea, vomiting, abdominal pain, flatulence
(dosage should be titrated)
nausea, vomiting, abdominal pain, flatulence
(dosage should be titrated)
What is the mechanism of action of pioglitazone (Actos)?
agonist for nuclear peroxisome proliferator-activated receptor-γ
(PPAR-γ)
increase peripheral insulin sensitivity
activates insulin responsive genes that regulate carbohydrate metabolism
(requires insulin to be present for action)
(PPAR-γ)
increase peripheral insulin sensitivity
activates insulin responsive genes that regulate carbohydrate metabolism
(requires insulin to be present for action)
How does pioglitazone (Actos) affect HbA1c?
decrease HbA1c by 1.0% to 1.5%
e.g. could bring down HbA1c from 9% down to 7.5%
1 to 6 months before max effects are seen
e.g. could bring down HbA1c from 9% down to 7.5%
1 to 6 months before max effects are seen
What are the contraindications for pioglitazone (Actos)?
should not be given to nursing mothers
What are some adverse effects of pioglitazone (Actos)?
liver functions should be monitored
anemia, weight gain, edema, plasma volume expansion (can lead to heart failure)
increased fracture risk after 3 to 4 years of therapy
(rosiglitazone removed from general use due to CV problems)
anemia, weight gain, edema, plasma volume expansion (can lead to heart failure)
increased fracture risk after 3 to 4 years of therapy
(rosiglitazone removed from general use due to CV problems)
What are the α-gluconidase inhibitors?
acarbose (Precose) and miglitol (Glyset)
What are the mechanism of action of α-gluconidase inhibitors?
competitively inhibit enzymes of intestines (α-gluconidase) involved in glucose metabolism
slows absorption of carbohydrates
must be taken before meals
no direct effect on insulin release
(does not cause hypoglycemia)
slows absorption of carbohydrates
must be taken before meals
no direct effect on insulin release
(does not cause hypoglycemia)
What are some adverse effects of α-gluconidase inhibitors?
dose-related malabsorption of carbohydrates
flatulence, diarrhea, abdominal bloating
(slowly increasing dose over several weeks can decrease GI-related adverse effects)
flatulence, diarrhea, abdominal bloating
(slowly increasing dose over several weeks can decrease GI-related adverse effects)
How do α-gluconidase inhibitors affect HbA1c?
minimal effect on HbA1c
only good for elevated post-prandial blood glucose
only good for elevated post-prandial blood glucose
What are some recommended combinations of antidiabetic drugs?
- metformin and sulfonylureas
- sulfonylureas and pioglitazone (a thiazolidinedione)
- metformin and sulfonylureas and pioglitazone
What are some combinations of antidiabetic drugs that are not recommended?
2 types of insulin secretagogues
e.g. sulfonylureas and meglitanides
sulfonylureas for DM I
sulfonylureas with insulin products
e.g. sulfonylureas and meglitanides
sulfonylureas for DM I
sulfonylureas with insulin products
What are some newer antidiabetic agents?
amylin analogues
pramlintide (Symlin)
GLP-1 analogues
exenatide (Byetta)
DPP-IV inhibitors
sitagliptin (Januvia)
pramlintide (Symlin)
GLP-1 analogues
exenatide (Byetta)
DPP-IV inhibitors
sitagliptin (Januvia)
What is amylin?
amylin is endogenous protein co-secreted in vesicles containing insulin
inhibits glucagon secretion
delays gastric emptying
actions synergistic with those of insulin
pramlintide (Symlin) is a synthetic amylin analogue
inhibits glucagon secretion
delays gastric emptying
actions synergistic with those of insulin
pramlintide (Symlin) is a synthetic amylin analogue
What is the mechanism of action of amylin analogue, e.g. pramlintide (Symlin)?
modulates post-prandial glucose levels
injected subcutaneously
inhibits glucagon secretion
delays gastric emptying (feel "full" sooner)
anorexic effects due to effects on CNS
injected subcutaneously
inhibits glucagon secretion
delays gastric emptying (feel "full" sooner)
anorexic effects due to effects on CNS
What are some adverse effects of pramlintide (Symlin)?
hypoglycemia
GI effects: nausea, vomiting, anorexia
GI effects: nausea, vomiting, anorexia
Can amylin analogues like pramlintide (Symlin) be used with insulin?
can be used with insulin
cannot be mixed in same syringe for injection
cannot be mixed in same syringe for injection
What is GLP-1?
glucagon-like peptide 1 - looks like glucagon but acts like insulin
increases glucose-dependent insulin secretion
decreases glucagon secretion
delays gastric emptying
anorexic effects
orally ingested glucose increases GLP-1 levels
increases glucose-dependent insulin secretion
decreases glucagon secretion
delays gastric emptying
anorexic effects
orally ingested glucose increases GLP-1 levels
What is the mechanism of action of GLP-1 analogue, e.g. exenatide (Byetta)?
stimulates GLP-1 receptor (a GPCR)
causes increase insulin gene expression and increased β-cell mass
(opposite to β-cell burnout)
incretin mimetic
glucose dependent, but does not cause hypoglycemia when used alone
causes increase insulin gene expression and increased β-cell mass
(opposite to β-cell burnout)
incretin mimetic
glucose dependent, but does not cause hypoglycemia when used alone
What is the therapeutic use of exenatide (Byetta)?
used for DM II
injected subcutaneously 2 time a day before meals
causes weight loss
injected subcutaneously 2 time a day before meals
causes weight loss
What are adverse effects of GLP-1 analogues?
nausea in 15% to 30% of patients
hypoglycemia can occur if combined with oral insulin secretagogues or exogenous insulin
hypoglycemia can occur if combined with oral insulin secretagogues or exogenous insulin
What is a DPP-IV inhibitor?
dipeptidal peptidase IV (DPP-IV) inhibitor
inhibits DPP-IV from destroying GLP-1
inhibits DPP-IV from destroying GLP-1
What is the mechanism of action of DPP-IV inhibitor, e.g. sitagliptin (Januvia)?
inhibits DPP-IV, prolongs GLP-1 actions
stimulates glucose dependent insulin secretion
stimulates glucose dependent insulin secretion
What is the therapeutic use of DPP-IV inhibitors, e.g. sitagliptin (Januvia)?
DM II
oral delivery
oral delivery
What are some adverse side effects of DPP-IV inhibitors, e.g. sitagliptin (Januvia)?
mild hypoglycemia
dose adjustment needed in renal insufficiency
does not cause GI effects
may have unknown long term adverse effects
(DPP-IV inhibitors affect metabolism of other peptides GHRH, VIP, etc)
dose adjustment needed in renal insufficiency
does not cause GI effects
may have unknown long term adverse effects
(DPP-IV inhibitors affect metabolism of other peptides GHRH, VIP, etc)
What are the antidiabetic agents that are injected?
insulin preparations/analogues
recombinant insulin, lispro, aspart, glulisine, neutral protamine Hagedorn, detemir (Levemir), glargine (Lantus)
amylin analogues
pramlintide (Symlin)
GLP-1 analogues
exenatide (Byetta)
recombinant insulin, lispro, aspart, glulisine, neutral protamine Hagedorn, detemir (Levemir), glargine (Lantus)
amylin analogues
pramlintide (Symlin)
GLP-1 analogues
exenatide (Byetta)
What are the oral antidiabetic agents?
insulin secretagogues (sulfonylureas, meglitanides)
glipizide, glimepiride, repaglinide, nateglinide
insulin sensitizers (biguanides, thiazolidinediones)
metformin, pioglitazone
α-glucosidase inhibitors
acarbose, miglitol
DPP-IV inhibitors
sitagliptin
glipizide, glimepiride, repaglinide, nateglinide
insulin sensitizers (biguanides, thiazolidinediones)
metformin, pioglitazone
α-glucosidase inhibitors
acarbose, miglitol
DPP-IV inhibitors
sitagliptin
Which antidiabetic drugs cause weigh gain?
insulin
sulfonylureas
glipizide, glimepiride
meglitanides
repaglinide, nateglinide
sulfonylureas
glipizide, glimepiride
meglitanides
repaglinide, nateglinide
Which antidiabetic drugs cause weight loss?
metformin (Glucophage)
exenatide (Byetta)
exenatide (Byetta)
Which antidiabetic drugs reduce Hb1Ac?
sulfonylureas (glipizide, glimepiride)
decreases Hb1Ac by 1.5% to 2.0%
meglitanides (repaglinide, nateglinide)
decreases Hb1Ac by 0.6% to 1.0%
metformin
decreases Hb1Ac by 1.5% to 2.0%
pioglitazone
decrease HbA1c by 1.0% to 1.5% (after 6 months)
decreases Hb1Ac by 1.5% to 2.0%
meglitanides (repaglinide, nateglinide)
decreases Hb1Ac by 0.6% to 1.0%
metformin
decreases Hb1Ac by 1.5% to 2.0%
pioglitazone
decrease HbA1c by 1.0% to 1.5% (after 6 months)
Which antidiabetic drugs are contraindicated for pregnant women and nursing mothers?
pregnancy
sulfonylureas
nursing mothers
pioglitazone
sulfonylureas
nursing mothers
pioglitazone
Drug list to know
NPH insulin (Humulin N, Novolin N)
glipizide (Glucotrol), glimepiride (Amaryl)
repaglinide (Prandin)
metformin (Glucophage)
pioglitazone (Actos)
acarbose (Precose), miglitol (Glyset)
pramlinitide (Symlin)
exenatide (Byetta)
sitagliptin (Januvia)
glipizide (Glucotrol), glimepiride (Amaryl)
repaglinide (Prandin)
metformin (Glucophage)
pioglitazone (Actos)
acarbose (Precose), miglitol (Glyset)
pramlinitide (Symlin)
exenatide (Byetta)
sitagliptin (Januvia)
About this deck
By: John Yaw-Jong Tsai
Created: 2011-12-07
Size: 73 flashcards
Views: 63
Created: 2011-12-07
Size: 73 flashcards
Views: 63
About StudyBlue
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Things like online flashcards with photos and audio.
Things like personalized quizzes and friendly reminders about when (and what) to study next.
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