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72 Cards in this Set
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effects of insulin on adipose tissue
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increased glucose entry, like muscle
increased fatty acid synthesis increased glycerol phosphate synthesis activation of lipoprotein lipase Inhibition of hormone-sensitive lipase Increased K+ uptake, like muscle |
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effects of insulin on muscle tissues
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Incr glc entry
incr glycogen synth incr a.a. uptake Incr protein synth in ribosomes Decr release of GLNG a.a.s incr ketone uptake Incr K+ uptake |
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effects of insulin on liver
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decr ketogenesis
incr protein synth, Incr lipid synth Decr glc output due to decr GLNG, incr glycogen synth, and incr glycolysis |
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fxn of insulin
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carb metabolism: promotes glycogenesis in liver and muscle; inhibits glycogenolysis & GLNG
Protein metabolism: promotes protein & enzyme synth; inhibits proteolysis Fat metabolism: promotes lipogenesis; inhib lipolysis and ketogenesis. |
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IMPORTANT: when do you start annual screening?
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BMI of 25 or more + risk factors
Patients 45 or more w/o risk factors Children: every 3 years at 10yo or onset of puberty if overweight w/ 2 add'l risk factors |
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IMPORTANT: screening pregnant women for GDM:
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If at low risk, may not need to
If at average risk, screen at wk 24-28 If at high risk, screen at wk 20 *high risk is family hx, GDM hx, obesity, glycosuria, PCOS |
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T2D risk factors:
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BMI 25 or more
Physical inactivity 1st degree relative w/ DM High risk ethnic gp IFG, IGT on previous test HTN: 140/90 or on HTN drug CV disease HDL <35mg/dL TG > 250mg/dL Delivery of >9lb baby Hx of GDM Ins resistance: acanthosis nigricans, severe obesity PCOS |
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what fasting BG means that you have diabetes?
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>126mg/dL
Prediabetes is between 100-126 |
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what casual PBG means that you have diabetes?
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200 or more with symptoms: polyuria, polydipsia, unexplained weight loss.
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what 2-hr postchallenge glc concentration is needed to say that someone has diabetes?
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hardly use this, but would want 200 or more during a 75g oral glc tolerance test.
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Definition of IFG:
IGT: |
100-125mg/dL fasting
2hr gtt 140-199mg/dL |
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T1D (10%)
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HLA gene type: HLA complex on chromosome 6
DR3, DR4, or both alleles may be predisposing Envifonmental factors: virus, chemical, cow's milk, etc. Exposed antigens? Autoimmune islet cell destruction |
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Type 1 onset in adults
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LADA: Latent Autoimmune Diabetes in Adults
Slower onset-develops over years Often oral agents will initially provide some glc ctrl On insulin within mo to yrs Earlier start the insulin, easier the ctrl! *the slow progression mirrors a T2D |
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T2D
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over 90% result from insulin resistance, but that may be combined with relative, not absoute, ins deficiency that may require insulin therapy
Estimated average of 7-10yrs prior to diagnosis: about 50% of beta cells remain at time of diagnosis Strong genetic predisposition! (no single gene defect) Usually obese, h/o obesity, sedentary Often diagnosed after 40yo |
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How to make a T2D not be as scared of progressing to more intensive treatments:
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Tell them that it is a progressive disease that can be controlled but not stopped.
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Pathogenesis of T2D:
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Genes lead to lifestyle changes (genetic predisposition to this as predispositions to obesity). These changes lead to ins resistance which lead to IGT-->T2D-->progressive hyperglycemia and high FFA.
Genes could also lead to impaired insulin secretion and the same cascade thereafter. |
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Progressive nature of T2D:
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Insulin deficiency due to B-cell failure: resistance will plateau above normal resistance. diagnosing earlier could slow the progression. After this plateau the BG values continue to exponentially incr. The average dx is at 9-12 yrs which is right after the levels have already started to dramatically incr.
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metabolic syndrome:
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AKA ins resistance syndrome-need 3 of the 5:
elevated waist circumference Elevated TGs Reduced HDL Elevated BP Elevated fasting glc. "syndrome X" associated with also cholesterol, bp, heart disease. When someone is obese think about these things too. The target is LDL!!! |
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results of ins resistance:
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hyperinsulinemia: appetite stimulation; b-cell destruction: T2D
AE's on lipid metabolism Htn Abnormal clotting Liver: incr glc production Muscle: decr glc uptake. Fat: decr lipid uptake |
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Progression of T2D:
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Peripheral resistance (metabolic syndrome)-->hyperinsulinemia and impaired glc tolerance-->defective glucorecognition and early diabetes-->b-cell failure and late diabetes.
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Early Phase Insulin Needs:
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No acute first phase response as you eat to insulin.
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time of peak insulin reesponse after oral glc load:
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normally peak insulin response at 60min. takes twice as long in the t2d.
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Type one or 2???
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Do NOT assume based on age.
Type 1 will be an autoimmune process, thinner, very high glc levels on order of 500, and ketones Type 2 will have the metabolic syndrome! and eventually lose ins production. |
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More type one vs type 2
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Type 2 will present with complications not things like being thirsty.
Type two will often be asymptomatic Type one will have diabetic ketoacidosis and two will have hyperosmolar hyperglycemic state. Microvascular complications at diagnosis are only seen in type 2 Macrovascular complications at diagnosis are only RARELY seen in type 1. |
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GDM risk factors
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>25yo
overwt or obese family hx of DM (first-degree relative) Hx of: abnormal glc metabolism, poor obestric outcome, delivery of infant >9lb, PCOS Race other than white FPG of >85 (not 100!) or 2-hr post prandial of >140. |
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screening for GDM:
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risk assessment at 1st prenatal visit
Screen high risk women ASAP: family hx, hx of GDM, marked obesity, presence of glycosuria, diagnosis of PCOS. If initial screening is neg, retest high risks at 24-28wks gestation. |
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More about screening for GDM:
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low-risk patients dont require screening: must meet following criteria--<25yo, normal weight, caucasian, no known diabetes in 1st degree relatives, no hx of abnormal glc tolerance, no hx of poor obstetrical outcome. For those at ave risk, screen at 24-28wks gestation.
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diagnosing GDM: One-step approach
Two-step approach |
diagnostic 3 hr 100g OGTT
Initial screen: plasma or serum glc measured 1-hr after 50g glc load: glc threshold: 140 or more (~180% sensitivity); 130 or more (90% sensitivity) diagnostic test: 100g OGTT in women who exceed initial threshold Diagnosis of GDM requires 2 of these: fasting >95, 1-ht postglc of >180, 2-hr of >155. |
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Prevention of T2D
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Ideal way to prevent complications of diabetes
focus on decr risk factors: maintain norm wt and maintain active lifestyle 5 prevention trials used med approaches: metformin, acarbose, troglitazone, rosi or ACE, pio |
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Which drug turned out to be the best at prevention?
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Rosiglitazone: TZDs! But long term undesirable effects? :(
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ADA recommended intervention strategy for PreDiabetes:
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IGT, IFG, A1C 5.7-6.4%
-counsel on 5-10% wt loss -instruct for incr physical activity: 150min wkly -follow-up counseling at regular intervals is important for success Screen for diabetes every year Close attention and treatment provided for htn, dyslipidemia, and tobacco use. Consider metformin for obese, high risk pts <60 |
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AACE recommendations for prevention:
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Lifestyle modifications: wt reduction goal of 5-10% (like ADA)
NUTRITION GOALS: fat<30%, Sat. fat<10%, Fiber 15g/1000kcal. Regular physical activity (150min/wk like ADA) Counsel pts about CV risk facctors such as tobacco use, HTN and HLP Aggressively treat HTN and HLP |
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Goals of therapy for diabetes:
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improve quality of life and reduce mortality
Avoid acute complications such as hypoglycemia and ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome Avoid chronic CV complications such as heart attacks, stroke; avoid microvascular complications such as nephropathy, neuropathy, retinopathy. Acheive these goals through good metabolic ctrl: BG, BP, blood lipids. |
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Why is elevated bg a problem?
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retinopathy, neuropathy, nephropathy, amputation, CV disease such as MI, stroke (CVA), periferal vascular disease (PVD).
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Achieving goals of therapy
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diabetes edu
Meal planning Exercise/activity Meds: orals, non-insulin injectables, ins Stress management MONITORING |
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Treatment goals: IMPORTANT
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Want <7% A1c
70-130 preprandial plasma glc <180 Postprandial plasma glc |
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Monitoring glycemic ctrl
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A1c (glycosylated hg, hgbA1c)
Urine glc testing: no longer recommended Ketone testing: sick days and exercise; not used as frequently as in past. BG testing. |
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A1C test:
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glycosylated hb: measure of risk for long-term complications
Ave glycemic ctrl over past 8-12 wks Normal is typically 4-6% "weighted average": most recent BG levels have more impact; post lunch/supper and overnight glc tests relate best to value. Affected by conditions that change life of RBCs: sickle cell anemia, bleeding. 7% is about 150mg/dL 10% is about 250. |
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metabolic ctrl: IMPORTANT
Total cholesterol, HDL, LDL, Non-HDL cholesterol, TGs, BP |
Total cholesterol: <200
HDL: >40 men >50women LDL: <100 (<70) Non-HDL cholesterol: <130mg/dl TGs: <150, <140 best BP: <130/80 |
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BG monitoring:
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T1D: needs to acieve near-normal BG levels; used to assess for hypo
T2D: frequency unresolved; improves glycemic ctrl when pts are using insulin. |
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BG testing regimen:
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On insulin: at least TID prior to giving shot.
Oral meds only: at goal--QD Above goal--at least BID Consider type of meds pt is taking Above target or frequent hypo--test "more frequently" (pre/post, 2-3AM) Additional monitoring: suspect hyper/hypoglycemia (before driving); exercise; sick day mngmt. |
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T2D pathophysiology:
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impaired insulin secretion (target)
Increased hepatic glc production Decreased periferal glc uptake (target) |
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Key concepts for T2D:
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dual impairment:
ins action: ins resistance B-cell fxn: ins secretion "glc toxicity" aggravates both problems Requires multiple approaches Progressive disease |
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methods of lowering glc:
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stimulate ins secretion
decr glc production incr glc uptake by cells slow CHO absorption Correct ins deficiency (goes with first) Decr appetite |
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ADA algorithm
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lifestyle + metformin-->lifestyle+metformin + sulfonylurea--> lifestyle + metformin + basal insulin -->lifestyle +metformin + intensive ins.
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Tier two of algorithm:
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Lifestyle + metformin--> adding pio or a GLP-1 agonist --> lifestyle + metformin + pio + sulfonylurea OR lifestyle + metformin + basal insulin.
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Metformin MoA:
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not exactly known, but it decreases insulin resistance through decr hepatic glycogenolysis and increased cellular uptake of glc.
Good initial response of 1-2% a1c (decr FPG by 60-70!!) Lipid benefits (decr LDL and TGs) No risk for hypo!! NO wt gn and possible wt loss!! |
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dosing of metformin:
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titrate as tolerated: 500mg or 850mg tabs (and 500XR)
Max dose 2250/day although usually don't see benefit >2000mg IR take with meals: decreases GI se's; actually only 50-60% is absorbed on fasting stomach; once daily at breakfast or BID at breakfast and supper. (if have problems with hypogly, take w/ supper...pt preference) |
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Titrating metformin:
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1st: 500mg with dinner
After 5-7days, if GI SE's have not occurred, advance to 500mg BID w/meals. If GI effects appear as dose advances, decrease to previous lower dose. Pepto bismol may be helpful! |
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Side effects of metformin:
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30%: diarrhea, GI upset, flatulence, nausea, vominting. Manny d/c therapy (4% reported)
Diarrhea most common: minimized by slow titration, dosing w/ meals or decr dose. Metallic or unpleasant taste Decr Vit B12 levels (not a worry) Lactic acidosis: .03/1000pt yrs; 30-50% mortality |
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metformin contraindications:
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Patients with renal disease or impairment: >1.5 Srcr; >1.4 in F...CrCl<60ml/min
CHF requiring pharmacologic treatment Acute or chronic metabolic acidosis D/c in individuals scheduled to receive IV radiocontrast media at the time of procedure and for 48 hrs thereafter, since these agents have been associated w/ acute renal dysfxn. |
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Precautions for metformin:
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ppl over 80 should NOT be titrated to the max dose; monitor renal fxn regularly
Use of concomitant meds that may affect renal fxn or metformin disposition (cationic drugs such as amiloride, digoxin, procainamide, quinidine, ranitidine, triamterene, TMP.) Conditions predisposing pts to renal insufficiency or hypoxia such as CHF, COPD, shock, ACUTE MI. Temporarily suspend prior to surgical procedures (except minor procedures not associated w/ food and water restriction) Liver disease Hx of alcohol abuse. |
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lactic acidosis:
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renal impairment: SCr >1.5, 1.4 in F. CrCl<60.
CHF, liver disease Hx of alcohol abuse Predisposed to tissue hypoxia or renal disfxn. (ie contrast iodine media) SYMPTOMS: N/V, Diarrhea, Somnolence, Anorexia, Epigastric Pain, Hyperpnea, Thirst. Like bad case of the flu. |
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Sulfonylureas=step 2 of algorithm
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secretagogues that incr ins secretion from pancreatic b-cells.
Lowers a1c by 1-2%, decr FPG by 50-60mg/dL) 75-90% of all patients respond initially Factors favoring a + response to therapy: recently diagnosed <5yrs; wt w/in 110-160% IBW; FBG<200; never required insulin or requires <40U. 5-20% of pts will experience secondary failure in 1-2 yrs. |
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sulfonylureas dosing:
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2nd gen: glipizide 5mg (max dose of 40, 20 if XR)
Glimepiride 1mg (max dose 8mg) Glyburide 2.5mg (max of 20mg) Can incr every 1-2wks Most benefit usually seen at 1/2 max dose Glipizide dosed 30min b4 meal unless XR ~2kg ave wt gn. |
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which sulfonylurea?
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Glipizide is preferred: fast onset trumps shorter DOA cuz it helps decr hypo, XL form available; less hypo; inactive metabolite makes is safer in renal impaired.
Glimepiride: compliance (daily dosing) Glyburide: more hepatic glycogenolysis suppression; longer duration, which is nice; not "preferred" due to more hypo. |
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sulfonylureas contraindications:
(as opposed to things that will hurt the kidneys in metformin) |
T1D
Mj surgery Severe infections, stress, trauma Hx of severe ADR Predisposition to severe hypo (pts with severe liver or kidney disease) |
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SEs of sulfonylureas:
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hypo esp in elderly
GI (less than 2%) Dermatologic (2-3%) Renal Disulfiram-like rxns w/ alcohol (not seen w/ 2nd gen) !! :) Hepatic disease (<2%)--more worry in metformin Hematologic disorders (<2%) |
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Glinides
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another secretagogue group with similar action to sulfonylureas but shorter t1/2.
short release of ins from b-cells for 1-2hrs. take at meals - targets postprandial levels similar efficacy to sulfonylureas 2 available: repaglinide (prandin) .5-2mg QAC--more potent Nateglinide (Starlix): 120mg QAC--more rapid and shorter DOA. |
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advantages and disadv of glinides:
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give before meals to ctrl sugars after meal while short DOA decr hypo risk esp for elderly. :)
Can skip dose if skip meal or incr dose compliance issue Metabolized and excreted primarily by liver: OK to use in renal impaired Response seen in 1 wk. Poor resp to sulfonylurea=poor response. |
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TZD's: MoA
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Bind to and activate PPAR gamma nuclear receptors that regulate gene transcription: Incr ins-stimulated glc uptake in skeletal muscles and adipocytes; decr in hepatic glc production.
takes a long time to work: messing with transcription to incr ins sensitivity and decr hepatic glc production. similar mech to metformin> |
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TZD's available:
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PIO: 15-45mg daily
ROSI: 4mg daily to BID. |
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TZD pearls:
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3wk onset, 6-12 wks for full effect
Use 1/2 dose if combinin w/ insulin Beyond diabetes...Prevention: reduction in development of diabetes: 60-80% Favorable lipid effects-esp with pio Known heart failure risk! Don't cause it but potentiate it. Fluid seen in hrt flure is exacerbated. Questionable CV risk-rosi not preferred. |
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TZD precautions:
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TZD + heart failure is a no-no
Patients with edema Liver disease (ALT>1.5x ULN) Resumption of ovulation in premenopausal anovulatory women-incr risk for pregnancy and therefore used in PCOS! Also possible for metformin! Frax risk Bladder CA risk Cardiac status? Less hypoglycemia :) |
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TZD SEs:
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wt gn of 1-6kg, dose dependent, combo tx
Edema: dose dependent; more common if also on ins; may cause dyspnea; may potentiate hrt failure; hgb and Hct decr in 1st 4 wks from changes in fl balance Hepatocellular injury: ALT>3x ULN (0.2% with current approved agents); check serum transaminase levels b4 starting therapy and periodically (twice yrly) |
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a-glucosidase inhibs:
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2 agents: acarbose and miglitol
both start at 25mg TID and titrate to 50-100mg TID. Start w/ smallest dose (25mg) to decr GI problems. Take w/meals: postprandial ctrl by decr absorption of carbs: do not affect the absorption of simple sugars such as glc and lactose. Inhib a-glucosidase enz--not absorbed. Lowers Post prandial sugars 40-50mg/dL (a1c .5-1%) no hypoglycemia or wt gain! |
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disadvantages of a-glucosidase inhibitors:
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GI se's lead to 25-45% not able to tolerate.
Flatulence (60-80%), diarrhea (20-40%), abdominal pain (20%). incr delivery of carbs to colon results in incr gas production and GI sx. Reduce SEs by limiting carbs at meals! Start at low doses Incr serum transaminase levels at high doses Compliance (TID) Contraindications: cirrhosis, inflammatory bowel disease, colonic ulceration, intestine obstructions, hernias; Pregnancy; SrCr GREATER THAN 2 |
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Which drugs inhibit the increased output of hepatic glc?
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Metformin
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Which drugs incr ins sensitivity?
TZD was not on pic |
Metformin, glitazones
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which inhibit carb intake?
TZD was not on pic |
A-glucosidase inhibitors
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which drugs increase ins secretion?
TZD was not on pic |
Sulfonylureas, nateglinide, repaglinide
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Incretins:
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intestinal horm released after meal
play important role in norm glc homeostasis Physiologically help regulate ins release in a glc-dependent manner. |
