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65 Cards in this Set
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approaches to tx of DMII
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-lifestyle changes
-stimulate insulin secretion(secretagogue) -stimulate insulin secretion(sensitizer) -decrease glucose absorption(alpha-glucosidase inhibitors) |
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secretagogues (stimulate insulin secretion)
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sulfonylureas, repaglinide
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sensitizers (stimulate insulin action)
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metformin, thiazolidinediones
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relation of weight control with management of diabetes
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-obesity is a major cause of insulin resistance; decreased amount of adipose tissue helps to restore insulin sensitivity
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contraindications for the use of sulfonylureas
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-DM type 1
-preganant or lactating -severe, acute, concurrent illness, surgery, or other stress during which glycemic control fluctuates |
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MOA of sulfonylureas
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-pancreatic effects:: secretagogue
-stimulate insulin release and increase beta cell sensitivity to glucose -bind to specific beta cellreceptor(SUR) linked to the potassium ion channel; binding of the sulfonylurea closes the potassium channel preventing K+ efflux -makes membrane potential more positive resulting in depolarization to open Ca2+ channels stimulating insulin release -completely ineffective in pts with no pancreatic fx |
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second generation sulfonylureas
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glyburide, glipizide, and glimepiride
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comparison of first generation and second generation sulfonylureas
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-2nd generation have greater potency, shorter halflife, and longer duration of action
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characteristics of glyburide compared with other sulfonylureas
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-12-24 hr duration of action(dosed once daily)
-most effective in pts with fasting hyperglycemia -less effective in pts with postprandial hyperglycemia -high incidence of severe prolonged hypoglycemia |
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characteristics of glimepiride with other sulfonylureas
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-more potent than glyburide, but actsmore like glipizide
-more effective for postprandial hyperglycemia, with less incidence of hypoglycemia |
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ADR of sulfonylureas
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-most common and severe is hypoglycemia(esp with glyburide)
-2nd most common ADR is weight gain |
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Repaglinide MOA
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-secretagogue
-binds to beta cell membranes and closes ATP-dependent K+ channels; depolarizes cell to open Ca2+ channels; induces insulin secretion -insulin secretion is glucose-dependent and diminishes at low glucose concentrations |
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indications of Repaglinide in DM type 2
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- adjunct to diet and exercise in pts whose hyperglycemia cannot be controlled satisfactorily by diet and exercise alone
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contraindications of Repaglinide
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DM type 1 or DKA
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ADR of Repaglinide
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-hypoglycemia
-weight gain |
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dosing of Repaglinide
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-15-30min before meals 2-4x daily based on blood glucose response
-taken before meals to stimulate insulin release and reduce postprandial hyperglycemia -must eat within 30 min; hypoglycemia is a risk of meal is delayed or inadequate carbs are eaten |
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Metformin MOA
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-insulin sensitizer:
-increased peripheral glucose utilization; direct stimulation of tissue glycolysis, with increased glucose uptake from blood into tissue -decreases hepatic glucose production: inhibition of gluconeogenesis -decreases GI glucose absorption; achieves high concentration of GI epithelium after po dosing, with increased glucose conversion to lactate in enterocytes |
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Actions of Metformin
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-lowers both preprandial and postprandial blood glucose
-euglycemic drug(no reports of hypoglycemia or weight gain) -insulin sparing::insulin secretion remains unchanged while fasting and plasma insulin response may actually decrease -stabilization or decrease in body weight |
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Metformin is the DOC for ?
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obese, dyslipidemic type 2 diabetics
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indications for metformin
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-should be used in all type 2 pts since it is the only oral antihyperglycemic drug that may reduce the risk of total mortality and CV death
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contraindications of metformin
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-renal dysfunction
-pts prone to metabolic acidosis or hypoxic states -temporarily withhold in pts undergoing radiologic studies with iodinated contrast agents |
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Boxed warning for metformin
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very rarely associated with lactic acidosis
-predisposing risk factors include decreased renal function and advanced age |
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Due to the DI between iodinated parenteral contrast agents and metformin you should?
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-withhold metformin 48hrs prior and 48hrs subsequent to the procedure and restart only after renal function is normal
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Thiazolidiones (TZD, "glitazones")
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rosiglitazone and pioglitazone
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pharmacological actions of TZD agents
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"insulin sensitizers"-increase insulin sensitivity through activation of PPARgamma
-lowers blood glucose by improving cell response to insulin without increasing pancreatic insulin secretion -decreases insulin resistance; stimulates glucose uptake into skeletal muscle and fat -decreases hepatic gluconeogenesis |
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net effects of PPARgammma agonists (TZD agents)
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- lowers blood glucose (fasting and postprandial), without causing hypoglycemia when used alone
-enhance insulin sensitivity in metabolic tissues |
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PPARgamma stands for?
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peroxisome proliferation-activated receptor gamma; nuclear transcription factor
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rosiglitazone in tx of DM2
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-as adjunct to diet and exercise when used as monotherapy
-used in combo with sulfonylurea or metformin when diet, exercise, or rosiglitazone, or the single agent alone insuficient to control blood glucose |
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risk of hepatotoxicity with rosiglitazone
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-do not initiate therapy in hepatocellular dz
-some cases of hepatic failure have been reported from Phase IV postmarketing surveillance |
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rosiglitazone warning
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increased risk of heart attacks and possibly death
-may be associated with myocardial ischemic events such as angina or MI |
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pioglitazone indication for DM2
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-use alone as monotherapy or
-use in combo with sulfonylureas, metformin, or insulin when diet plus single agent is inadequate for glycemic control |
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ADR of TZDs
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-weight gain/contribution of fluid retention
-increased CV risk:fluid retentionand edema-->HF -increased CV risk::MI -increased risk of fractures |
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TZD CV risks-HF
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-fluid retention and edema increase risk for HF
-both meds double the risk of HF or worsen existing HF -TZD-induced cardiomyopathy probable -TZDs are contraindicated in stage III and IV HF |
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TZD CV risks-MI
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-increased risk limited to rosiglitazone
-rosiglitazone no longer recommended for use in DM2 |
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TZD risks of fractures
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-1 of 2 studies showed increased fx in men, but both showed increased fx in women
-mechanism: activation of nuclear hormone(PPARgamma)may affect differentiation of stem cells to adipocytes and osteoblasts in bone marrow -increased adipocytes and decreased osteoblasts--decreasd bone formation/mass |
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Acarbose pharmacologic effects
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-complex oligosaccharide that reduces the increase in peak postprandial blood glucose
-most useful in pts with exagerrated postprndial increase in blood glucose -slight improvement of FBG with absence of weight gain |
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Acarbose MOA
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-competitive reversible inhibitor of intestinal brush border alpha-glucosidases, pancreatic alpha-amylase, and sucrase which are responsible for digestion of complex carbohydrates
-results in smaller rise in blood glucose and insulin following meals |
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Why is acarbose the DOC for elderly DM2 pts with postprandial hyperglycemia?
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-does not cause hypoglycemia in the fasting or postprandial state
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ADR of acarbose
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abd pain, diarrhea, flatulence
--60%d/c rate in trials |
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Step 1 of ADA guidelines for tx of DM2
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-lifestyle changes: diet, exercise
-metformin: Tier 1 drug (only drug that has shown mortality benefit) |
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Step 2 of the ADA guidelines for tx of DM2
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-add a sulfonylurea or basal insulin:other Tier 1 drugs
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What are now considered the core therapies for DM2?
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-metformin, sulfonylureas, and insulin
-they lower A1C to a greater extent, cost less, and have longer safety hx |
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Step 3 of the ADA guidelines for tx of DM2
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-intensify insulin therapy
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Analternative therapy for tx of DM2
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-Step 1 plus a Tier 2 drug (pioglitazone or exenatide)
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insulin therapy in tx of DM2 is most commonly started with?
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-basal insulin added to oral therapy
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insulin glargine was originally approved for use at bedtime, but is now approved for?
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use any time of day as long as same time everyday is used
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if A1C goal is not met with insulin glargine in tx of DM2, then?
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add a rapid-acting insulin analog just before meals PRN
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If hyperglycemia continues (A1C>7) in DM2 with use of basal and rapid acting insulin, then
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-d/c basal insulin and use a premixed insulin containing either a rapid or short-acting insulin
-twice daily admin gives better BG control and lower A1C than daily regimen |
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physiologic actions of endogenous incretins and exogenous GLP1
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-normalizes fasting and postprandial glucose by enhancing glucose-mediated insulin secretion; very little effect in normoglycemicso not much tendency to cause hypoglycemia
-suppress glucagon secretion in glucose-dependent manner; no suppression during hypoglycemia -slows gastric emptying and delays nutrient absorption -reduces appetite and food intake |
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Incretin enhancers
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exenatide (Byetta) and sitagliptin (Januvia)
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exenatide (Byetta) interacts with human GLP1 receptors to cause WHAT ACTIONS?
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-restores 1st phase fast insulin response
-increases 2nd phase slow insulin response -lowers serum glucagon during hyperglycemia resulting in decreased hepatic glucose output -slows gastric emptying and reduces rate of glucose absorption -reduces food intake |
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indications for use of exenatide (Byetta)
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-adjunct therapy to improve glycemic control in DM2 in pts who are taking metformin, a sulfonylurea, or a combo of the two, but have not yet achieved glycemic control
-tx of DM2 in adults as monotherapy along with diet and exercise |
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dosing of exenatide (Byetta)
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-initiate at any time within 60 min period before the am and pm meals; do not admin after meals
-SC injections |
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precaution/ADR for exenatide (Byetta)
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-not for use in DM1, pts using insulin, pts with DKA,orin pts with severe renal dysfunction or ESRD
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sitagliptin (Januvia) indications
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-DM2 as monotherapy or in combo with metformin or a TZD
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labeling on sitaglipitin (Januvia) updated to warn of?
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-anaphylaxis, angioedema, andexfoliative skin conditions; frequency unknown and causal relationship uncertain
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sitagliptin/metformin (Janumet)
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combo drug with the advantage of lack of weight gain, edema, or hypoglycemia
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Amylinomimetics MOA
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-mimic effects of endogenous hormone amylin which is secreted by beta cellswith insulin postprandially
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effects of amylinomimetics
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-reduces postprandial glucose levels
-slows/delays gastric emptying -induces satiety and regulates food intake -suppresses postprandial glucagon secretion to decrease hepatic glucose production |
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Pramlintide
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amylinomimetic agent
-slows gastric emptying, decreasespostprandial elevation in BG, decreases glucagon secretion postprandial, and induces satiety leading to decreased appetite and caloric intake/weight loss |
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indications for use of Pramlintide
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DM1 and DM2
-as adjunct tx in pts who use mealtime insulin therapy |
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dosing for Pramlintide
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-when initiating therapy, initial insulin dose reduction required to reduce risk of insulin-induced hpoglycemia
-reduce all insulin by 50% -a 0.3 mL U-100 insulin syrince is used -increase dosage to next increment when no significant nausea has occured -if nausea persists, decrease dose and if still presists d/c -admin SC immediately prior to meals |
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reasons to d/c Pramlintide therapy?
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-recurrent unexplained hypoglycemia requiring medical assistance
-persistent clinically significant nausea -pt noncompliance |
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what types of pts should not be considered for Pramlintide therapy?
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-recurrent or severehypoglycemia requiring medical assistance during past 6mo or hypoglycemic unawareness
-confirmed gastroparesis or tequire GI motility stimulating agents -pediatric pts |
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Colesevelam (Welchol)
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combo agent of antidiabetic and antihyperlipidemic meds
-FDA approved to decrease both A1C and LDL used as adjunct to other therapy |