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82 terms

drugs for diabetes mellitus

STUDY
PLAY
describe type I diabetes
selective B cell destruction --> severe and absolute insulin def
juvenille onset
- type 1A --> autoimmune
- Type 1B --> non-autoimmune
- insulin therapy necessary
describe type 2 diabetes
tissue resistance to insulin + decreased relative insulin secretion
- usually in adults and obesity is common
- treat with diet, weight reduction, oral hypoglycemics + insulin
describe type 4 gestational diabetes
affects 4% of pregnant women
- glucose intolerance of pregnancy
- requires insulin
MOA of insulin
secreted by B cells in response to increased glucose (member of IGF)
describe insulin receptor
4 subunits --> possess tyrosine kinase activity
- insulin binding leads to autophosphorylation + enhancing kinase activity
describe the actions of insulin
- signaling cascade leads too glucose transporter translocation to membrane (GLUT4),
- glucose uptake
- glycogen synthase
- increased glycogen formation
- increase lipogenesis + protein synthesis
- enhanced DNA synthesis and cell growth (anabolic signals)
tissues affected by insulin - Liver
promotes gluocose storage as glycogen
- increased TG synthesis
- inhibits glyogenolysis, inhibits conversion of Fatty acids and AA to ketoacids
- inhibits conversion of AA to glucose
tissues affected by insulin - muscle
increases AA transport and protein synthesis
- increased glycogen deposits, increased glucose uptake, increased glycogen synthesis
tissues affected by insulin- adipose tissue
synthesis and storage of TGs
induction of lipoprotein lipase
increased glucose transport
decreased intracellular lipase
complications due to diabetes
glycation non enzymatic
formation of sorbitol from aldose reductase --> osmotic cell death
- peripheral nerves --> swelling, osmotic effected, microangiopathy
- GI system --> decreased autonomic activity leads to constipation, gastric stasis
complications of diabetes kidney + retina + skin
thickening + scarring + worsened by hypertension
retina --> blindness, proliferation of capillaries
skin --> slowed mucopolysaccharide turnover leads to impaired wound healing
should intensive insulin therapy be used for type 1 patients?
intensive insulin therapy decreases risk of retinopathy, neuropathy, vascular events, and hypercholestrolemia
- increases risk of hypoglycemia and weight gain
is intensive glycemic control useful for type II diabetes?
decreases micro and macrovascular complications
- BP control also decrease microvascular complications
PHARMACOTHERAPY WITH INSULIN
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properties of endogenous insulin
1/2 life is 3-5 minutes + degraded by liver + kidneys
formulation of insulin
subcu, IV, IM, inhaled
- used in combination with short and long acting to achieve insulin levels
regular insulin (short acting)
soluble crystalline Zn insulin prep tends to hexamerize
- peaks 2-4 and lasts 5-7 hrs
- IV and subcu
- useful for managing DKA or when insulin req change rapidly
ULTRA SHORT ACTING/RAPID ACTING INSULIN ANALOGUES
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lispro
- human insulin analog
- less tendency to aggregate
- peak serum values in 1hr and duration 3-4hrs
- pts can eat 5min after injection
- lowest variability of absorption of all commercial preps
Aspart
extra neg charge means less tendency to aggregate
- similar to lispro
glulisine
absorption + action all similar to other rapid acting insulins
INTERMEDIATE ACTING INSULINS
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isophane NPH insulins
combo insulin (- charge) and protamin (+ charge)
onset 1-2 hrs and duration 13-18hrs
- used alone or in combination with faster acting drugs
Lente
mix of semilente and ultralente
- semilente --> rapid onset and short duration
-ultralente -->delayed onset + prolonged duration
combo --> durations 13-20hrs
used alone or with faster acting insulin
LONG ACTING INSULINS
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describe ultralente
- large particle size so slow release into blood stream
- high variability of absorption
- onet 2-6 and duration 18-30 hrs
- mimics basal insulin release from pancreas + can provide tight control with rapid acting insulin
BASAL INSULIN ANALOGUES (LONG ACTING)
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describe glargine
- human insulin analogue that crystalizes to form slowly dissolving hexamers
- flat peakless profile with duration >24hrs
- mimics basal pancreas release
What are the side effects of glargine
may cause allergies/irritation at the site of injection
describe detemir
basal human insulin analogue
advantages of basal insulin analogues
superior to traditional long lasting insulins but more expensive
PRE-MIXED INSULIN PREPARATIONS
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describe premixed insulin preps
most require short and long term insulins
- regular insulin or insulin lispro can be mixed with NPH, lente, or ultralente
- injected immediately in two doses morning + evening
stable premixed
combinations of NPH/regular or neutral protamine lispro/lispro
describe inhaled insulin
out of market because of inconvenience, inconsistence, high cost + adverse effects
what insulin concentrations are typically used?
100IU/ml is most widely used
- range from U40-U500
- with young children, may require the insulin to be diluted
what are the injection sites for insulin?
abdomen, front/lateral thigh, buttocks, lateral aspect of arm
what are the insulin delivery systems are used
portable pen + continuous subcutaneous infusion devices
describe portable pen injectors
usually use lispro, NPH or NPL
- short + intermediate acting agents
describe the subcutaneous continuous insulin infusion devices
develivers insulin based on blood glucose monitoring
- aspart, lispro and glulisine (short acting insulins)
what are the best insulin regiments
basal bolus concept (pump) or intermediate acting +long acting insulin analogue once or twice daily
what are the indications for insulin treatment?
- B cell failure from type I diabetes, pancreatitis, or post-pancreatectomy
- type 2 diabetes when dietary control, weight reduction + oral anti diabetcs are insufficient
- gestational diabetes
- unstable forms --> DKA, hyperglycemic non-ketotic coma
what are the adverse reactions to insulin
hypoglycemia, weight gain, lipodystrophy , abs to insulin
describe the side effect - hypoglycemia
more common in type 1 with tight control
- see increased sympathetic activity + parasym
- sweating, tachycardia, trembling, coma, confusion
describe the side effect lipodystrophy
hypertrophy of subcu fatty tissue at injection sites
- due to lipogenic action of insulin
- mainly cosmetic problem
- treat by rotating sites of injection
describe the side effect of ab generation
can develop insulin allergy but very rare with purified human insulin
what are some potential drug/drug interactions
glucocorticoids, oral contraceptives, and B-agonists/antagonists can interact
INSULIN SECRETOGOGUES
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what are the insulin secretogogues?
sulfonylureas, meglitinide, nateglinide
- target ATP sensitive K+ channel action in B cells
describe sulfonyl ureas
1st and 2nd generations are substituted arylsulfonylureas
- can develop allergy
describe the 1st generation agents
tolbutamide, chlorporpamide, tolazamide
- have lower potency, higher adverse effects, more drug interactions
- not freq prescribed
describe the 2nd generation agents
glyburide, glipizdie, glimepiride
- increased potency, less Adverse effects
- not more efficacious
describe the MOA of sulfonylureas
lowers blood glucose by stimulating insulin release from B cells
- blocks inward rectifier K+ channel
- chronic therapy results in decreased glucagon secretion
- chronic -->potentiation of insulin action (etiology unknown)
adeverse effects of sulfonylureas
well tolerated
- may cause hypoglycemia and weight gain
- use in caution in elderly and CV disease
describe metabolism of 2nd generation sulfonylureas
glyburide + glipizide --> inactivated by liver + kidney
- not for pts with renal + hepatic insuf.
glimepiride --> inactivated by liver
- not for pts with liver disease
which of the 2nd generation sulfonylureas is prescribed worldwide
glyburide
what are the drug interactions of sulfonylureas
decreased effectiveness by barbiturates, rifampin (induce cyp3a4), glucocorticoids, OCPs, thiazides, phenytoin, B-agonists
do pts develop tolerance to sulfonylureas?
efficacy decreases with chronic use because of tolerance
MEGLITINIDES
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describe repaglinide
newer secretogogues --> structurally different from sulfonylureas but same MOA
- rapid absorption + short 1/2 lives (1hr)
- produces fast + brief insulin secretion
what are the uses of repaglinide
used to reduce postprandial hyperglycemia so taken before each meal
D-PHENYLALANINE DERIVATIVE
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describe nateglinide
even quicker onset + shorter duration
- may cause weight gain, but hypoglycemia unlikely
- inactivated by liver so caution in pts with liver disease
Describe metformin
MOA unknown- major action is to deceases hepatic insulin resistance + decreases glucose production by liver
- does not increase insulin release
- anti-hyperglycemic but not hypoglycemic + may help obese pts lose weight
- first line monotherapys
what are the indications for metformin
- prevention of type 2 diabetes
- monotherapy with lifestyle changes
- combo with secretagogues
what are the adverse effects of metformin
GI disturbances in 20% of pts (diarrhea, discomfort)
- decreases B12 absorption (may require supplementation)
- severe lactic acidosis (decreased uptake of lactic acid)
what are the contraindications for metformin
alcoholism, hepatic disease, or predisposition to tissue anoxia
- cleared by kidney so not for renal insufficiency
THIAZOLIDINEDIONES (GLITAZONES)
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what are the thizolidinediones
rosiglitazone and pioglitazone
what are the proposed mechanisms of thiazolidinediones?
binds PPARgamma ==> increases transcription of genes that mediate insulin action (glucose transporters, FA transporters)
- acts in adipose tissue
- increaeses glucose uptake but not insulin release
- does not come hypoglycemia
- decreased visceral fat deposits and increased FA uptake
- decreases fasting plasma glucose and HBA1C but less then metformin or sulfonylureas
what are the adverse effects of rosiglitazone
increase heart failure, fatal liver damage (LFT tests), modest weight gain, mild anemia
what are the drug interactions
metabolized by p450 system so can induce enzymes that degrade OCPs
ALPHA GLUCOSIDASE INHIBITORS
acarbose and miglitol
describe the alpha glucosidase inhibitors
inhibit intestinal alpha-glucosidase
- enzymes digest complex starches to monosaccharides
- digestion deferred to distal small intestine
- lowers postprandial rise in glucose
- decreases HBA1C but no as effective as sulfonylureas and metformin
side effects of alpha glucosidase inhibitors
Gas from carbohydrate fermentation in colon, diarrhea, and abdominal pain
- contraindicated in presence of GI disease
describe exanatide
synthetic analog of human glucagon like peptide -1
- stimulates insulin secretion + lowers glucagon levels, slows gastric emptying + increases satiety
- alternative to metformin + sulfonylureas
what are the adverse effects of exanatide
weight loss (not real adverse effect), nausea, vomitting, diarrhea
INHIBITORS OF DPP-4 (DIPEPTIDYL PEPTIDASE 4)
sitagliptin and saxagliptin
describe sita and saxagliptin
oral hypoglycemis that inhibit DPP-4 which digests GLP-1
- increases GLP1 + stimulates insulin secretion, suppress glucagon, and slows gastric emptying
describe pramlintide
synthetic analogue of human amylin (islet amyloid polypeptide)
- slow gastric emptying, increase satiety, suppress postprandial glucagon + hepatic output
- type I and II pts
adverse effects of pramlintide
nausea, vomitting, headache, anorexia
summary of pharmacotherpay
1) lifestyle change + metformin
2) addtion of second medication
3) further adjustment + insulin therapy
4) less validate therapies (exenatide. pioglitazone, sulfonylurea)
5) basal insulin