antidiabetics 59/60 Flashcards
Regular insulin (Humulin R and Novolin R)
Rapid-acting Insulin Preparation (cheap)
clear solution of human sequence insulin
only insulin suitable for intravenous use
works slower than native insulin due to regular insulins forming non-covalent hexamers in solution
breakdown into monomers requires time
Insulin aspart (NovoLog)
Rapid-acting Insulin Preparation
B28 proline is replaced by an aspartic acid residue
works quicker than regular insulin due to forming monomers more quickly
Insulin glulisine (Apidra)
Rapid-acting Insulin Preparation
B3 asparagine is replaced by a lysine residue and the
B29 lysine is replaced by a glutamic acid residue
(“glu and lis” replace)
works quicker than regular insulin due to forming monomers more quickly
Insulin lispro (Humalog)
Rapid-acting Insulin Preparation
normal proline-lysine (“lis for pro”) dipeptide at positions B28 and
B29 are reversed
works quicker than regular insulin due to forming monomers more quickly
NPH Insulin (Humulin N and Novolin N)
Intermediate-acting Insulin Preparation (cheap)
cloudy suspension of human sequence
insulin aggregated with protamine and zinc
unpredictable action due to a variable rate of absorption (still has peak)
mixture of NPH and regular insulin (or other short-acting) in a fixed proportion (70:30) often used
Insulin glargine (Lantus)
Long-acting Insulin Preparation: reproducible and convenient
background insulin replacement (last about 18-20 hours)
aspargine at position A21 is replaced by
glycine and two arginines are added to the C-terminus of the B-chain
soluble at pH 4 but poorly soluble at pH 7
injected subQ, forms fine precipitant in interstitial fluids
Insulin detemir (Levemir)
Long-acting Insulin Preparation: reproducible and convenient
background insulin replacement
threonine at B30 is omitted and a C14 fatty acid chain is attached to amino acid B29
long-acting due to self-association at subQ injection site and by binding to albumin in blood
Metformin (Glucophage, Glucophage XR, Glumetza)
Biguanide
first line for T2 DM
reduces of hepatic gluconeogenesis
through activation of the AMP-activated protein kinase (AMPK) in hepatocytes
euglycemic: prevents hyperglycemia, but does not induce hypoglycemia
Glyburide (Diaβeta, Micronase, Glynase PresTab)
Sulfonylurea
2nd generation
Repaglinide (Prandin)
Meglitinide
hypoglycemia w. skipped meal
Pioglitazone (Actos)
Thiazolidinedione
Rosiglitazone (Avandia)
Thiazolidinedione
Acarbose (Precose)
α-Glucosidase Inhibitor
Pramlitide (symlin)
Amylin Analogue
used for the treatment of type 1 and type 2 diabetes. It primarily acts as an insulin sparing agent, adjunct to insulin therapy
Exenatide (Byetta)
GLP-1 Agonist
synthetic exendin-4, a peptide found in Gila monster venom
monotherapy or as adjunctive therapy for T2 DM, 2x daily, subQ
now extended release 1x weekly
rapidly absorbed from the injection site and reaches a pk conc. in 2 hrs
little metab, excreted by kidney
Sitagliptin (Januvia)
DPP-4 Inhibitor
T2DM
Canagliflozin (Invokana)
SGLT2 inhibitor
Glucagon
29 aa peptide synthesized by the alpha cells in pancreatic islets of Langerhans
used in the emergency treatment of severe hypoglycemia, unconscious pt or glucose not available
also, tx of β–blocker OD
raises blood glucose by stimulating the breakdown of hepatic glycogen stores
binds to a G-protein coupled receptor present in the liver that stimulates adenylate cyclase and an increase in cAMP–>increase in glycogen phosphorylase activity and a decrease in glycogen synthase activity
stimulates gluconeogenesis and ketogenesis in the liver
no effect on glycogen stores in skeletal muscle.
metabolized by liver, kidney and within plasma
Glucose stimulation of insulin
secretion involves the uptake of glucose into the β cell via ??
GLUT-2
transporters
intracellular metabolism of glucose increases the ATP/ADP ratio, which inhibits K(ATP) channels and potassium efflux This inhibition results in ??
Calcium influx does what??
β cell
depolarization and calcium influx
activates recruitment of insulin- containing granules to the cell surface and the release of insulin into the circulation
average individual produces ?? insulin/day
30 units
- half metabolized by liver
- rest by kidney and muscle
insulin is produced as a ??
prepropeptide, starts in RER–>folding, disulfide bonds added–>proinsulin goes to golgi–>packaged in granules (immature)–>proinsulin matured here–>cleaved to insulin and C-peptide (inactive compound)–>granules (in pancreatic B-cells) fuse with plasma membrane and release mature insulin into blood
always basal insulin in circulation
large insulin release after glucose spike in blood
if given bolus of glucose…normal pt would respond with ??
insulin spike from release of pre-formed insulin from B-cells, then depletes
second (more subtle) hump from release of newly created insulin
if given bolus of glucose…Type 2 diabetic pt would respond with ??
delayed and more subtle insulin hump (no spike)
if given bolus of glucose…Type 1 diabetic would respond with ??
no response, unable to produce insulin
insulin has 2 effects ????
that affects what tissues ??
anabolic and anticatabolic
liver, muscle, and
adipose tissue
insulin anticatabolic effects in liver ??
anabolic effects in liver ??
inhibits glycogenolysis, gluconeogenesis, ketogenesis
stimulates glycogen and fatty acid synthesis
insulin anticatabolic effects in muscle ??
anabolic effects in muscle ??
inhibits protein catabolism
stimulates glucose and amino acid uptake
stimulates protein and glycogen synthesis
insulin in adipose tissue:
anticatabolic effects ??
anabolic effects ??
inhibits lipolysis
stimulates glucose uptake
stimulates glycerol synthesis and triglyceride synthesis
“dawn phenomenon” in DM pts
glucose is fine before bed, high in morning
insulin wore off, not enough to inhibit gluconeogenesis in liver
history factoid: started using insulin in humans in ??
1922
before: 0% survival rate
Fredrick Banting “discovered” insulin and began testing injections
initially bovine/porcine
now human via recombinant DNA technology (cleaner prep and less hypersensitivity) since 1982
Type 1 diabetes mellitus
absolute deficiency in insulin due to the
autoimmune destruction of pancreatic β cells
untreated–>ketoacidosis–>coma–>death
insulin replacement therapy is necessary to sustain life
younger than 30 years old when diagnosed
Type 2 diabetes mellitus
90-95% of all diagnosed DM in US
initial development of insulin resistance, followed
by a relative impairment of insulin secretion
Insulin is still produced by β cells in these patients but is not sufficient to overcome the resistance
present in adulthood
dietary intervention is first tx, then oral antiDM drugs
30% benefit from insulin therapy
may need higher units: 40-300 units/day: metabolic syndrome
insulin regimen: give multiple shots combo shots of ???
intermediate-acting (or long-acting): to mimic 24-hour basal insulin secretion
AND
short-acting insulin: to mimic nutrient-stimulated insulin secretion (given preprandial)
The goals for glycemic control are:
Fasting and preprandial blood glucose level of ??
post-prandial blood glucose level two hours after meal of less than ??
Hemoglobin A 1C (HbA 1C ) less than ??
70-130 mg/dL
180 mg/dL
7% (associated with a decreased risk of long-term
complications) (“2 month test”)
(not all patients achieve these goals (hypoglycemia, cognition, age))
inhaled insulin ??
Exubera: pulled from market
Afrezza: now available, same efficacy of injected insulin
Hemoglobin A 1C (HbA 1C ) levels normal ppl and uncontrolled DM
normal 4-5%
uncontrolled: 9-12%
most T1 DM need ?? doses
variable doses (vs. fixed doses)
may be adjusted: how they feel, checking finger-stick glucose
split-mixed regimen
regular and NPH before breakfast
regular and NPH before dinner
problem: NPH at dinner may wear off during night causing “dawn phenomenon” may help to take before bed–>3 shot regimen
basal bolus regimen
insulin aspart before B, L, D
-adjustable
1 injection insulin glargine at bedtime
insulin pump
baseline insulin given over intervals
-adjustable
main adverse effects of insulin therapy
hypoglycemia: not eating enough carbs, too much physical exertion, too large dose of insulin
- ->unconciousness–>brain damage
- give sugar if conscious, IV glucose or glucagon if unconscious
weight gain (good for T1 diabetics: previously thin due to catabolic state)
other adverse effects of insulin therapy
allergic reactions
insulin resistance (neutralizing anti-insulin Abs)
atrophy of subQ fatty tissue (animal preps)
hypertrophy of subQ tissue with using same injection site
increased cancer risk
inhaled insulin adverse effects
throat pain, irritation
cough(most common reason to stop)
altered pulmonary function: dec. FEV1 (do PFTs before prescribing and 4 mos later)
Metformin SEs
GI disturbances in 20% pts
(transient, dose-related)
lactic acidosis (rare but fatal, adhere to contraindications: reduced drug elimination, reduce tissue oxygenation (i.e. )
2 factors that predispose patients to lactic
acidosis ??
contraindications ??
reduced drug elimination reduced tissue oxygenation
alcoholism
renal insufficiency
hepatic disease
hypoxic pulmonary disease
also CI with contrast formulations
or hospitalization for acute illness
metformin benefits
metformin typically taken ?? daily
if mild DM can use
does not cause weight gain (actually causes mild weight loss) or hypoglycemia
2x
metformin monotherapy
if monotherapy of metformin not sufficient, may be used with
sulfonylureas, thiazolidinediones, or insulin
other benefits of metformin
reduce circulating LDL and VLDL
reduce BP
decrease risk of macrovascular and microvascular disease
may reduce risk of certain cancers (via lowering insulin release)
sulfonylureas
only for T2 DM
insulin secretagogues; their mechanism of action requires functioning pancreatic β cells
increased insulin release from pancreatic β cells
bind to the K-ATP channel complex on β cell plasma membranes and inhibit their activity. This inhibition leads to depolarization of β cells, influx of calcium, and insulin release
metabolized by liver
1st gen sulfonylureas
2nd gen sulfonylureas
less potent, have longer half-lives, and are more likely to cause adverse effects (not covered)
glyburide, glipizide, and glimepiride.
Sulfonylureas SEs
Hypoglycemia
Weight gain (inc. appetite)
sulfur allergy
Increased cardiovascular mortality has been associated with long-term sulfonyluea tx
Sulfonylurea CIs
Hepatic impairment
Renal insufficiency
Pregnant and breastfeeding women—sulfonylureas cross the placenta and enter breast milk
caution in susceptible patients to whom hypoglycemia could be particularly dangerous (e.g. elderly patients or patients with acute CV disease)
Sulfonylurea uses
taken how often?
reduced efficacy when?
combo tx??
type 2 diabetes
1x or 2x daily
As β cell function declines, this class of drugs loses efficacy
can be combined with metformin or thiazolidinediones.
MEGLITINIDES
insulin secretagogues with a similar mechanism of action to sulfonylureas: increase insulin release from pancreatic β cells through inhibition of β cell KATP channels
repaglinide and nateglinide
1 hr half life, metabolized by liver
meglitinide SEs
Hypoglycemia may occur with repaglinide if taken before a meal that is subsequently
delayed or skipped. Hypoglycemia is less frequent with nateglinide.
meglitinide CIs
caution when prescribing repaglinide with hepatic impairment
or renal insufficiency
Nateglinide is generally safer in patients with reduced renal function, though the dose may need to be adjusted in such cases
Meglitinide uses
type 2 diabetes
more rapid
pharmacokinetics as compared to sulfonylureas
more frequent preprandial dosing of meglitinides is possible
may be used in patients with sulfur allergies
monotherapy or in conjunction with metformin.
THIAZOLIDINEDIONES
type 2 diabetes
“glitazones” or “Tzds” increase insulin sensitivity in target tissues.
peroxisome proliferator-activated receptor gamma (PPARγ) agonists
PPARγ receptors are nuclear hormone receptors that modulate the expression of genes involved in lipid and glucose metabolism. These receptors are highly expressed in adipose tissue, which is the primary site of action
principal effect: differentiation of adipocytes, resulting in the increased sensitivity to insulin-stimulated uptake of glucose and fatty acids, as well as altered adipokine production (e.g. leptin, adiponectin)
metabolized by liver
effects of thiazolidinediones
Increased insulin sensitivity in skeletal muscle and liver also occurs
Long term effects: lowering of triglyceride levels and a slight rise in HDL and LDL cholesterol levels
thiazolidinedione SEs
*Weight gain and edema* Osteoporosis and bone fracture (women) CHF CV events (see later) For pioglitazone, an additional risk of bladder cancer occurs with higher doses
Black box warning w. thiazolidinedione: rosiglitazone
black box warning for an increased risk in CV events
(MI or stroke) has been observed. This observation is controversial and additional monitoring and evaluation is ongoing. Currently, rosiglitazone carries a black box warning for such adverse effects and can only be prescribed for patients whose blood sugar cannot be controlled with other antidiabetic agents. The future availability of rosiglitazone is uncertain.
This restriction has been removed due to reevaluation of clinical trial data
thiazolidinedione CIs
Pregnancy
Hepatic impairment
Heart failure
Due to the hepatic toxicity of troglitazone, liver function tests are periodically required while taking other thiazolidinediones
thiazolidinedione uses taken how often? monotx or combo? why do the effects take so long? future use?
T2 DM
taken 1x/day
They may be used as a monotherapy, or in conjunction with metformin, sulfonylureas, or
insulin.
Since the effects of thiazolidinediones are mediated by altered gene expression and cell differentiation, maximal effect on glucose homeostasis takes 1-3 months to be seen.
While very effective in the treatment of type 2 diabetes, the adverse risks of this class will likely limit their future use.
α-GLUCOSIDASE INHIBITORS
competitive inhibitors of enteric α-glucosidases, enzymes that break down complex carbohydrates and oligosaccharides
only monosaccharides can be absorbed from the intestinal tract, α-glucosidase inhibitors delay postprandial absorption of glucose
results in attenuation of postprandial increases in plasma glucose, which creates an insulin-sparing effect
Acarbose is minimally absorbed.
a-glucosidase inhibitor SEs
GI disturbances (flatulence, diarrhea, abdominal pain)
from bacterial metabolism of undigested carbohydrates in the colon-diminishes over time due to upregulation of α-glucosidases in the distal small intestine
a-glucosidase inhibitor CIs
inflammatory bowel disease
Renal impairment
Any GI conditions worsened by gas or distension
a-glucosidase inhibitor uses
taken when?
mono or combo?
T2 DM
immediately before each meal
monotherapy, or in conjunction with other oral antidiabetic agents
or insulin
slowly titrated upward to minimize GI disturbances
used in prediabetic patients to prevent the progression to T2 DM
in mild to moderate cases of hypoglycemia, patients taking an α-glucosidase
inhibitor should be given a source of ??
glucose (e.g. Dex Tabs) not sucrose, as sucrose metabolism into the monosaccharides glucose and fructose is impaired in these patients
Bile acid sequestrants
proposed mechanisms:
reduction in intestinal glucose absorption
signaling through nuclear receptors, such as farnesoid X receptor
lower LDL cholesterol
only Colesevelam for T2 DM tx
(not the greatest)
adverse effects: GI disturbances, inc. plasma TGs, interfere with absorption of meds
CI:
hypertriglyceridemia
hx of pancreatitis
esophogeal/GI disorders
taken 2x/day
AMYLIN ANALOGUES
peptide secreted with insulin from pancreatic β cells, which acts on the amylin receptor in the hindbrain
(like amylin) suppresses glucagon release, delays gastric emptying, and promotes satiety.
subQ
not plasma protein bound, met/exc by kidney
amylin analogue SEs
Hypoglycemia
GI disturbances, particularly nausea
Weight loss
amylin analogue CIs
Gastroparesis or other GI motility disorders
amylin analogue uses
T1 and T2 DM
adjunct to insulin therapy
administered separately, diff. syringes
subQ, preprandially
lowers amount of insulin needed to regulate glucose: to avoid hypoglycemia, mealtime insulin doses should be reduced by ~50%
GLP-1 AGONISTS
Incretins: class of GI hormones secreted after meals and augment insulin released from pancreatic β-cells. Glucagon-like polypeptide-1 (GLP-1) is one type of incretin
activate GLP-1 receptor (esp. pancreatic β-cells)
increased insulin synthesis and secretion in a glucose-dependent manner
delayed gastric emptying and decreased appetite (GLP-1 rec in PNS, CNS, GIT)
suppress the release of postprandial glucagon (better insulin effect)
GLP-1 agonist SEs
GI disturbances, (esp. nausea at beginning)
Weight loss
Hypoglycemia, when combined with a sulfonylurea
Pancreatitis, rare but serious
Due to delayed gastric emptying, can alter the pharmacokinetics of drugs that require rapid GI absorption (i.e. OCTs and abx)
GLP-1 agonist CIs
History of pancreatitis
For liraglutide, an increase in thyroid C-cell cancer was observed in rodents. Currently,
liraglutide carries a black box warning that contraindicates its use in patients with family history of medullary cancer or multiple endocrine neoplasia type 2.
DPP-4 INHIBITORS
inhibit enzyme that degrades incretin hormones
- ->increase circulating levels of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)
- ->resulting in increase in postprandial insulin secretion and a decrease in glucagon levels
monotherapy or as adjunctive therapy, T2DM
taken 1x day
high oral availability and achieve >95% inhibition of DPP-4 for 12
hours
remain unbound in the circulation and are excreted renally
DPP-4 inhibitor SEs
Increased rate of infections (DPP-4 is expressed in lymphocytes)
Headache
Hypoglycemia, when combined with a sulfonylurea
Hypersensitivity reactions
Pancreatitis
DPP-4 inhibitor CIs: Saxagliptin dose should be decreased when administered with ??
CYP3A4/5 inhibitors
antiviral, antifungal, and antibacterial agents
SGLT2 INHIBITORS
Sodium-glucose co- transporter 2 (SGLT2) transports filtered glucose from the proximal renal tubule into tubular epithelial cells. Thus, inhibition of SGLT2 reduces glucose reabsorption
new drugs, monotherapy or as adjunctive therapy T2DM, 1x daily
inhibits SGLT2 activity in the kidney, resulting in decreased glucose reabsorption, increased urinary glucose excretion, and lowering of blood glucose levels
SGLT2 inhibitor SEs
Genital mycotic infections (inc. glucose in urine)
UTIs
Can have a diuretic effect
Canagliflozin can increase serum concentrations of digoxin
Dapagliflozin may increase the risk of bladder cancer
Long term safety unknown (i.e. ketoacidosis, fx risk under investigation)
SGLT2 inhibitor CIs
Severe renal impairment
DOPAMINE AGONISTS
not used much, Kopf doesn’t want to spend time on
Bromocriptine: ergonline derivative approved for type 2DM (also hyperprolactinaemia, galactorrhea, Parkinsonism)
increases insulin sensitivity
Table 3
relative efficacy of drugs to lower HbA1c levels
glucagon SEs
Transient N/V
inotropic and chronotropic effects in the heart (similar to β–adrenergic agonists)–>transient tachycardia and HTN may also occur
