Endocrine: DM Pharmacology

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Author:
jcbarbery
ID:
212085
Filename:
Endocrine: DM Pharmacology
Updated:
2013-04-11 14:34:59
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DM diabetes pharmacotherapy endocrine
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Description:
Pharmacotherapy of diabetes mellitus
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  1. 1st Gen Sulfonylureas
    Ex: Tolbutamide, Tolazamide, Chlorpropamide

    • Rarely used today
    • More SEs in elderly and renally impaired
    • Less potent than 2nd gens
    • Active metabolites -> var Glu control
    • Other drugs inhib metabolism or excretion
  2. 2nd Gen Sulfonylureas
    • 100-150 x more potent than 1st Gens

    • Glyburide (Micronase / Glynase / DiaBeta)
    • Glipizide (Glucotrol)
    • Glimepiride (Amaryl)
  3. Sulfonylurea MOA
    Increase pancreatic secretion of insulin

    Dec hepatic clearance of insulin

    Bind to sulfonylurea receptor (ATP-sensitive K+ channel) on β cells

    • -> dec K+ efflux
    • ->> cell membrane depolarization
    • -> Ca++ influx
    • -> translocation of secretory granules
    • -> exocytosis releasing insulin
  4. Sulfonylurea AEs
    Hypoglycemia

    Weight gain

    HA

    Dizziness

    Mild GI discomfort

    Rash
  5. Sulfonylurea CIs
    Absolute: Previous hypersensitivity

    Relative: Hepatic or Renal insufficiency
  6. Sulfonylurea Response Failure
    • Primary Failure:
    •      No initial response

    • Secondary Failure:
    •      5-7% of patients per year
    •      Beta-cell desensitization
    •      Pancreas burn out
  7. Sulfonylurea Efficacy
    60-70 mg/dl decrease in FBG levels

    1.5-2.0% decrease in A1c
  8. Best Sulfonylurea Patient Characteristics
    • Age > 40
    • DM < 5 years    
    • Mild-moderate hyperglycemia    
    • No previous insulin use    
    • Not morbidly obese
  9. Sulfonylurea Monitoring
    FBG & A1c

    Baseline and yearly ALT/AST and Cr
  10. Meglitinide MOA
    Repaglinide & Nateglinide

    • Glu dep. insulin release (unlike sulfonylureas)
    • Best for postprandial (Rapid onset & elim.)

    Reduces K+ efflux -> Depolarization -> Ca++ influx -> insulin granule exocytosis
  11. Meglitinide CIs
    • Hypersensitivity
    • Severe liver insufficiency
  12. Meglitinide AEs
    Same as sulfonylureas w/less hypoglycemia
  13. Meglitinide Efficacy
    • Dec FBG: 10-30 mg/dl
    • Dec in Post-prandial glucose: 30-60 mg/dl
    • Dec HbgA1c: 0.5-1.5%
  14. Best Meglitinide Patient Characteristics
    • Post-prandial Glu 1o disorder / concern
    • Mild hyperglycemia
    • Cost not an issue
  15. Meglitinide Monitoring
    Same as with sulfonylureas

    +

    Postprandial glucose levels
  16. Biguanide MOA
    Dec hepatic Glu prod (gluconeogenesis)

    • Imp insulin sens. in muscle & fat
    •    
    • Slightly dec. Glu absorb from intestine & inc. carb -> lactate conversion (cause of GI AE)

    Antihyperglycemic, not hypoglycemic
  17. Metformin Immediate Release
    • Init @ 850 mg QD or 500 mg BID
    • Max 2550 mg per day
    • Adj @ 500 mg/day @ 1-2 week increments

    • Outside of initial dosing, split daily dose to bid
    • CI w/ renal/hepatic dysfunction
  18. Metformin Sustained Release
    • Init @ 500 mg once daily
    • Max 2000 mg per day

    Can be dosed BID w/ daily dosages >1000 mg
  19. Biguanide CIs
    • Absolute = Renal Insufficiency
    •      Scr > 1.4 in females
    •      Scr > 1.5 in males
    •      Inc risk lactic acidosis (50% mortality)
    •      Monitor Cr throughout therapy

    • Hepatic Dysfunction
    • Elderly (>80 yo) w/o renal dysfunction
    • CHF
    • Respiratory insufficiency
    • Severe infections

    • Concomitant iodinated contrast media
    •      kidney damage
    •      hold metformin dose prior & 48 hrs after
  20. Biguanide AEs
    • GI (discomfort / diarrhea / nausea)
    •      20-30% of patients
    •      Minimized w/ slow titration and food

    • Hypoglycemia w/ monotherapy not common (d/t MOA)

    Diminished B12 levels (significance?)

    Lactic acidosis  (3 cases/100,000 pt yrs)
  21. Biguanide Efficacy
    • Dec HgA1c 1.5-2.0%
    • Dec FPG 60-70 mg/dL

    Modest imp in lipids and weight
  22. Best Biguanide Patient Characteristics
    • Central obesity (may reduce CV outcomes)
    • Mild-moderate hyperglycemia
    • 2o sulfonylurea failure
  23. Biguanide Monitoring
    FBG & A1c
    Creatinine at baseline and yearly
  24. TZD MOA
    Lower insulin resistance in peripheral tissue

    Lower glucose production by the liver

    Binds to PPAR gamma which regs genes for carb and lipid metabolism

    May increase insulin receptor binding

    • Inc # of Glu transporters (GLUT 1 & 4)     
    •      -> inc Glu transport into muscle/adipose

    • Require insulin to be present
  25. TZD CIs
    Hepatic Insufficiency

    HF
  26. TZD AEs
    • Edema (~ 4-5% experience some swelling)
    •      Usu. in combo w/sulfonylureas or insulin

    • Mild weight gain (worse with combo Tx)
    •      Probably from edema

    • Hepatotoxicity (now rare)
    •      Troglitazone (Rezulin) pulled in 2000
  27. TZD Efficacy
    Dependent on level of insulin resistance

    • Dec FBG: 30-55 mg/dl
    • Dec A1c 0.3-0.9% in “general” diabetics
    •      1.2-2.6% in “suspected” insulin resistance

    • Some beneficial effects on lipids
    •     Pioglitazone mildly lowers TG levels
    •     Both shown to inc HDL (15-20% !!)
    •     Both change LDL from dense to "fluffy"
  28. Appropriate TZD Candidates
    Mild Hyperglycemia w/ mild insulin resistance

    Insulin resistance strongly suspected/proven
  29. TZD Monitoring
    FBG & A1c

    ALT at baseline and periodically thereafter
  30. DPP-4 Inhibitor MOA
    Sitagliptin, Saxagliptin, Linagliptin

    Food in GI stims hormone release from L cells

    GLP-1 & GIP travel to pancreas and bind GLP-1 receptor -> insulin release to prep for incoing Glu as well as dec glucagon release -> dec in hepatic Glu prod.

    t1/2 of GLP-1 & GIP very short (mins or less)

    Inhibition of DPP-4 allows inc t1/2

    Glucose dep; unlikely to cause hypoglycemia
  31. DPP-4 inhibitor CIs
    • Type 1 DM
    • Hypersensitivity
    • DKA
  32. DPP-4 inhibitor AEs
    GI
  33. Sitagliptin Efficacy
    • Dec FBG: 10-15 mg/dL
    • Dec A1c: 0.5-0.6%
    • Dec post-prandial glucose: 50 mg/dL
  34. Saxagliptin Efficacy
    • Dec FBG: 14-25 mg/dL
    • Dec A1c: 0.75%
    • Dec post-prandial glucose: 24-41 mg/dL
  35. Canagliflozin MOA
    SGLT2 Inhibitor

    Blocks Glu binding on Na-Glu transporters in the kidney preventing reabsorption of Glu

    Promotes elim of Glu in the urine
  36. Canagliflozin Warnings
    • Hypotension
    •      Especially in the elderly
    • Hyperkalemia
    • Increased LDL-C
  37. Canagliflozin AEs
    • Genital mycotic infections
    •      Mostly in females and uncircumcised males

    • UTIs
    •      More prevalent in females

    • Increased urination
    •      Caution in elderly (falls, BPH)
  38. Canagliflozin Efficacy
    • Dec FBG: 27-35 mg/dL
    • Dec PPG: 43-60 mg/dL
    • Dec A1c: 0.8-1.1%

    Some benefit on weight (2.8-4kg loss)
  39. Appropriate Canagliflozin Candidates
    • Mild Hyperglycemia
    •  
    • Caution in elderly and women
  40. Canagliflozin Monitoring
    • FBG & A1c
       
    • S/Sx of urinary or genital infections

    BP

    Potassium
  41. Incretin Mimetic MOA
    Exenatide, Liraglutide, Exenatide ER

    A GLP-1 agonist (GLP-1 mimic)

    Inc glucose dep insulin secretion by beta-cells

    Suppresses elevated glucagon secretion

    Slows gastric emptying
  42. Incretin Mimetic Indications
    • Type 2 DM as monotherapy or adjunct w/
    •      metformin
    •      sulfonylurea
    •      TZD
    •      Combination of the three

    Byetta and Victoza may be combined with basal insulin
  43. Incretin Mimetic Dispensation/Storage
    Refrigerate

    Dispensed in pens; Bydureon is a kit for reconstitution

    Discard after 30 days of first use
  44. Incretin Mimetic PK
    Onset 2 hours

    Half-life 2.4 hours
  45. Incretin Mimetic Admin
    BID/QD 0-60 min before meals; ideal time is 30 min

    SQ in thigh, abdomen or upper arm
  46. Incretin Mimetic SEs
    • Pancreatitis: rare, but potentially fatal
    • Hypoglycemia
    •      only w/sulfonylureas
    •      reduce dose w/sulfonylureas

    • Nausea
    •      Dose-dependent
    •      44% of patients experienced
    •      Decreases over time

    Dyspepsia (Small % of patients)
  47. Incretin Mimetic Pt Counseling
    Proper storage

    No adj dose if reduction in food intake

    • Contraindications
    •      Hx of pancreatitis
    •           (can occur spontaneously w/o a Hx)
    •      Thyroid carcinoma
  48. Rapid Acting Insulins
    • Lispro (Humalog)
    • Aspart (Novolog)
    • Glulisine (Apidra)

    More flex than Reg Insulin (15 min pre meal instead of 30)
  49. Lispro
    Humalog

    Proline & lysine transposed on C-peptide -> faster dissociation
  50. Aspart
    Novolog

    Aspartic Acid in place of proline on beta-chain -> fewer hexamers
  51. Glulisine
    Apidra

    Similar to Aspart/NovoLog
  52. Short Acting Insulins
    • Regular Insulin (Humulin R / Novolin R /
    • Velosulin)

    Form hexamers
  53. Intermediate Acting Insulins
    Suspensions

    NPH (Neutral-Protamine-Hagedorn): Humalin N, Novolin N

    Uses protamine and zinc to bind insulin >> slow release of monomers after injection

    Can mix w/reg insulin (70:30 & 50:50 premixed)
  54. Long Acting Insulins
    Suspensions

    • Insulin glargine (Lantus)
    • Insulin detemir (Levemir)
  55. Insulin glargine
    Lantus

    • Glycine sub'd for asparagine @ A21 & 2 arginines added at C-terminus
    •      -> more neutral isoelectric point
    •      -> dec solubility at injection site
    •      -> delayed absorption
  56. Insulin detemir
    Levemir

    • Fatty acid acylated insulin
    •      -> inc albumin affinity
    •      -> 1o reason for inc duration

    • Soluble at neutral pH
    •      -> liquid following SC injection
    •      -> inc surface area
    •      -> dec absorption variablity
  57. Clinical Pearls w/ Insulin
    • Admin SC
    • Reg insulin is only IV formulation

    Human insulin has faster onset/dur than pork

    • Intermed/LA insulins complexed w/zinc
    •      (slows the breakdown)
  58. RA Insulin PK
    • Onset 15-30m
    • Peak 1-2h
    • Dur 3-5h
  59. SA Insulin PK
    • Onset 30-60m
    • Peak 2-3h
    • Dur 3-6h
  60. IA Insulin PK
    • Onset 2-4h
    • Peak 4-6h
    • Dur 8-12h
  61. LA Insulin PK
    • Onset 2-4h
    • Peak ~flat
    • Dur Lantus  22-24h
    •       Levemir 14-24h
  62. Insulin Storage
    • Refrigerate (36-46oF)·        
    • Unopened good until Exp Date·        
    • Opened: room temp x 1month
             
    • Extemporaneous/prefilled pens/syringes
    •      refrigerated x 21-30 days
    •      1 wk out of fridge
  63. Insulin Pens
    Simplifies admin

    • "dial up" the desired number of units
    • Regular and fixed ratios of mixed insulins
  64. Insulin Pumps
    Cont SC insulin infusion (CSII)

    Regular or rapid insulins (NOT suspensions)

    Provides basal insulin + programmable bolus w/meal injections

    • Similar to “normal” pancreatic secretion
    • Use w/ knowledgeable, stable, motivated pts

    Allows great freedom and control

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