1. Sulfonylureas
   1. first generation
      1. difficult to procure
      2. Tolazamide (Tolinase)
         1. comparable potency but shorter DOA than Chlorpropamide
         2. slower abs. than other sulfonylureas
         3. half life- 7hrs
         4. active metabolites
         5. >500mg/d --> divided doses given bid
      3. Chlorpropamide (Diabinese)
         1. half life- 32 hrs
         2. MD- 250mg in the morning
         3. slowly metabolized
            1. active metabolites
         4. caution
            1. contraindicated
            2. n hepatic and renal failure
            3. elderly
            4. dosage >500mg increase risk of jaundice
            5. prolonged hypoglycemic rxn more common in elderly
            6. hyperemic flush after alcohol ingestion
            7. genetically predisposed patients
            8. dilutional hyponatremia
            9. hematologic toxicity
            10. thrombocytopenia
      4. Tolbutamide (orinase)
         1. well absorbed
         2. rapidly metabolized by liver
         3. safest in elderly
         4. metabolism inhibited
            1. dicumarol, phenylbutazone, some sulfonamides
         5. elimination half life 4-5hrs
         6. best admin in divided doses
   2. second generation
      1. generic and inexpensive
      2. fewer adverse effects and RX interactions
      3. potent forms used w/ caution in elderly and pt. w/ CV disease
      4. Glyburide ( DiaBeta, Micronase, Glynase presTab)
         1. metabolites have low hypoglycemic activity
         2. dosage
            1. 2.5mg/d or less
            2. avg. MD 5-10mg/d as single morning dose
            3. >20mg/d not recommended
            4. micronized
            5. glynase PresTab
            6. ? bioequivalence to non micronized
            7. caution when switching between micronized & non
         3. caution
            1. few adverse effects
            2. potential for causing hypoglycemia
            3. slight enhance of free water clearance
            4. contraindicated
            5. hepatic impairment
            6. renal insufficiency
      5. Glimepiride (Amaryl)
         1. approved 1x/d mono therapy
            1. can be used in combo w/ insulin
            2. 1mg/d recommended
            3. 8mg daily max
         2. Long DOA
         3. half life 5hrs
         4. completely metabolized by liver to inactive
         5. lowers glucose w/ lowest dose of its class
      6. glipizide (Glucotrol, Glucotrol XL)
         1. shortest half life of the potent
            1. 2-4 hrs
            2. less likely serious hypoglycemia
            3. 10% excreted unchanged
         2. max effect in reducing postprandial hyperglycemia
         3. take 30min before breakfast
            1. abs. delayed by food
         4. contraindicated in significant hepatic and renal impairment
         5. dosage
            1. start w/ 5mg/d and 15mg/d max for single dose
            2. max toatal daily 40mg/d
            3. max therapeutic effect
            4. 15-20mg
            5. glucotrol XL
            6. extended release
            7. 24hr action after 1x/d morning dose
            8. max 20mg/d
   3. MOA
      1. Increase insulin release from pancreas
         1. bind to 140-kDa receptor --> inhibit efflux of potassium ions --> depolarization--> open calcium channel--> calcium efflux and preformed insulin release
         2. long term use --> reduction of glucagon levels
2. Glitinides
   1. Meglitinides
      1. repaglinide (Prandin)
         1. Modulate beta cell insulin release by regulating K efflux
         2. mono therapy or combo w/ biguanides
         3. no sulfur group
         4. very fast onset
            1. control postprandial glucose excursions
            2. tajen just before meal 0.25-4mg (max 16mg/d)
         5. pk conc and effect 1hr after taking
         6. DOA- 5-8hrs
         7. hepatically cleard by CYP3A4
            1. plasma half life - 1hr
         8. caution
            1. hypoglycemia
            2. if meal delayed/ skipped/ inadequate carbs
            3. caution in pts w/ renal and hepatic impairment
      2. two binding sites in common w/ sulfonylureas and 1 unique binding site
   2. MOA
      1. stimulate very rapid transient release of insulin from beta cells through closure of ATP-sensitive K channels--> calcium influx
   3. D-phenylalanine derivative
      1. Nateglinide (Starlix)
         1. latest insulin secretagogue to become clinically available
         2. MOA
            1. stimulate very rapid transient release of insulin from beta cells through closure of ATP-sensitive K channels--> calcium influx
            2. Partially restores initial insulin release response
            3. may suppress glucagon release early in meal --> less hepatic glucose production
            4. amplifies the insulin secretory response to glucose load
            5. diminished in normal glucose levels
         3. TX
            1. special role in isolated postprandial hyperglycemia
            2. min. effect on fasting/ over night glucose level
            3. unlike other secretagogues no titration required
            4. abs within 20min after admin
            5. metab cyp 2C9 and CYP3A4
            6. half life -1.5hr
            7. DOA- <4hrs
         4. Advantages
            1. safe in pts. w/ very reduced renal function
            2. lowest incidence of hypoglycemia of all secretagogues
3. Biguanides
   1. Metformin (Glucophage, glucophage XR)
      1. Combo
         1. glipizide + metformin (metaglip)
         2. glyburide + metformin (glucovance)
         3. rosiglitazone +metformin ( Avandamet)
   2. MOA
      1. reduced hepatic glucose production through activation of enzyme AMPK (major)
      2. (minor) slowing glucose absorption in GI, increased glucose to lactate conversion and removal from blood
      3. Not dependant on pancreatic beta cells
   3. pts. less fasting hyperglycemia & postprandial hyperglycemia
   4. euglycemic
   5. metabolism
      1. half life 1.5-3 hrs
      2. not protein bound
      3. not metabolized
      4. renal excretion active
      5. impair hepatic metabolism of lactic acid
         1. renal insufficiency
            1. accumulate and increase risks of lactic acidosis (dose related complications)
   6. TX
      1. first line therapy
         1. insulin sparing agent
         2. no weight increase
         3. no provoked hypoglycemia
      2. useful in type 2 prevention
         1. middle aged
         2. obese
         3. impaired glucose tolerance
      3. dosage
         1. 500mg-2.55g/d
         2. fasting hyperglycemia
            1. 500mg at bedtime for week
            2. persistent hyperglycemia no GI upset --> 500mg at evening meal
            3. > dose needed --> 500mg at breakfast/lunch or 850mg bid/tid
         3. >1000mg per dose --> significant GI upset
   7. toxicity
      1. GI
         1. anorexia
         2. nausea
         3. abdominal discomfort
         4. diarrhea
         5. dose related
         6. at onset of therapy typically
      2. abs. B12 reduced long term therapy
      3. contraindicated
         1. alcoholism
         2. hepatic disease
         3. renal function decreased
         4. predisposed tissue anoxia (chronic pulmonary dysfunction)
            1. due to increased risk of lactic acidosis
4. Alpha Glucosidase Inhibitors
   1. acarbose (precose)
      1. reversible hepatic enzyme elevation
         1. caution in hepatic disease
   2. miglitol (Glyset)
      1. 6x more potent in inhibiting sucrase
      2. effects isomaltase & beta glucosidases (lactose)
   3. MOA
      1. competitive inhibitors of intestinal alpha glucosidases
      2. reduce post meal glucose excursion
         1. delay digestion / abs. of starch and disaccharides
   4. sucrase,maltase,glucoamylase, dextranase
   5. Adverse RXN
      1. diarrhea
      2. flatulence
      3. abdominal pain
         1. undigested carbs in colon
      4. hypoglycemia
         1. tx w/ glucose not sucrose (may not be broken down)
      5. not used in renal impairment
   6. STOP-NIDDM
      1. trial demonstrated beta cell function restored
      2. reduce CV disease
      3. hypertension reduced
5. Thiazolidinediones (Tzds)
   1. pioglitazone (actos)
      1. alpha and gamma activity
         1. alpha- triglyceride lowering effect
      2. reduce mortality and macrovascular events (stroke)
      3. abs. within 2hrs of taking
      4. food may delay uptake
      5. metab by CYp2C8/ CYP3A4 to active metab
         1. effect effectiveness of contraceptives
      6. dose
         1. 1x/d
            1. 15-30mg/d
            2. max 45mg/d
            3. mono- therapy/ combo w/ metformin/sulfonylureas/insulin
   2. Rosiglitazone (Avandia)
      1. high protein binding
      2. metab by liver
         1. predominantly CYP2C8
      3. dose
         1. 1x/ bid
         2. 4-8mg total dose
      4. caution
         1. increase risk of CV disease
         2. mono therapy/ double combo w/ biguanides/ sulfonylureas / quadruple combo w/ biguadnides, sulfonylurea, insulin
   3. Combo
      1. rosiglitazone +glimepiride (Avandaryl)
   4. decrease insulin resistance
   5. PPAR- gamma ligands
      1. receptors found in muscle/ fat/ liver
      2. modulate expression of genes involved in lipid/glucose metabolism, insulin signal transduction, adipocyte & other tissue differentiation
      3. major site of action
         1. adipose tissue
            1. promote glucose uptake n utilization
            2. modulate synthesis of lipid hormones '
   6. required liver function monitoring
   7. prevention of type 2 diabetes
   8. euglycemic
   9. adverse effects
      1. fluid retention
         1. mild anemia
         2. peripherial edema
      2. increase risk of heart fail
      3. dose related wt gain
      4. decreased osteoblast formation
         1. increase bone fracture in women
      5. drop in triglycerides and slight rise in LDL and HDL
      6. contraindication
         1. liver disease alt >2.5x norm
         2. concurrent diagnosis of heart fail
   10. effective in 70%
   11. moa
       1. involve gene regulation
          1. slow onset /offset
   12. combo w/ sulfonylurea /insulin
       1. hypoglcemia
       2. adjust dosage
6. Incretin based
   1. glucogon like polypeptide 1 analogs
      1. Exenatide (byetta)
         1. Synthetic
         2. 1st incretin therapy for diabetes
         3. injectable adjunct therapy
            1. TX
            2. pts. w/ suboptimal glycemic control
            3. Type 2
            4. tx w/ metformin / metformin + sulfonylureas
            5. Absorption
            6. equally in abdomen, thigh, or arm
            7. pk in 2hrs
            8. DOA 10hrs
         4. glomerular filtration
            1. Adj. dose w/ crcl<30ml/min
         5. Treatment
            1. subQ 1hr before meal
            2. dose
            3. max 10mcg bid
            4. 5mcg bid start
         6. MOA
            1. enhance glucose mediated insulin secretion
            2. ? increase in beta cell mass
            3. ? decrease beta cell apoptosis
            4. ? increase beta cell formation
            5. suppression of postprandial glucagon release
            6. slowed gastric emptying
            7. central loss of appetite
         7. caution
            1. hypoglycemia
            2. when added to existing sulfonylurea therapy
            3. Decrease oral dose
            4. diarrhea
            5. n/v
            6. Nausea decrease w/ use
            7. wt loss
            8. nausea
            9. anorectic effects
            10. necrotizing& hemorrhagic pancreatitis
   2. dipeptideeyl peptidase 4 inhibitor
      1. sitagliptin (januvia)
         1. MOA
            1. inhibits enzyme that degrades incretin & GLP-1 like molecules
            2. increase circulating GLP-1 & GIP
            3. decreases postprandial glucose excursions by increasing glucose mediated insulin secretion and decreasing glucagon levels
         2. half life- 12hrs
         3. dose
            1. 100mg 1x/d
         4. adverse effects
            1. HA
            2. nasopharyngitis
            3. upper respiratory infections
            4. reduce dose in pts. w/ renal impairment
         5. monotherapy/ adjuct w/ metformin or Tzds
7. Amylin Analog
   1. Pramlintide (symlin)
      1. Synthetic analog of amylin
      2. Injectable
         1. pk in 20 mins.
         2. rapid abs.
         3. most reliable abs. from abdomen and thigh
         4. DOA- 150min max
         5. given immediately before eatting
         6. dose
            1. 15-60 mcg subQ
            2. Type 1 diabetes
            3. 60-120mcg subQ
            4. Type 2 diabetes
            5. titrate up starting low
      3. renally metab. and excreted
         1. low crcl doesnt effect bioavailability
      4. used w/ insulin in pts. who cant acheive target postprandial blood sugar
      5. MOA
         1. suppress glucagon release
         2. modulates postprandial glucose levels
            1. approved for preprandial use
            2. type 1 diabetes
            3. Type 2 diabetes
         3. delays gastric emptying
      6. Caution
         1. Hypoglycemia
            1. concurrent rapid/short acting meal time insulin
            2. decrease by 50% > to avoid
            3. insulin secretagogue concurrent use
            4. decrease dose in type 2 diabetes
         2. cant be mixed w/ other insulins
            1. inject alone w/ separate syringe
         3. SE
            1. hypoglycemia
            2. GI symptoms
            3. anorexia
            4. n/v
8. insulin TX of Special circumstances
   1. Hyperosmolar hyperglycemic syndrome (HHS)
      1. profound hypergylcemia
         1. Causes
            1. Phenytoin
            2. steriods
            3. Dialysis
      2. dehydration
         1. causes
            1. Beta blockers
            2. Diuretics
      3. SX
         1. declining mental status
         2. seizure
         3. plasma glucose >600mg/dL
         4. calculated serum osmolality .320mmol
         5. dont have acidosis
      4. Tx
         1. aggressive rehydration
         2. restoration of glucose and electrolyte homeostasis
         3. low dose insulin mayb required
9. relative lack of insulin where the body doesnt produce enough insulin or the body doesnt recognize the insulin thats produced
10. insulin secretagogues