PKPD/Pharmacology of Oral Diabetic Agents

which medications are involved in increased insulin secretion in the ominous octet?

sulfonylureas, meflitinides, incretins

which medications are involved in decreased glucagon secretion in the ominous octet?

incretins and amylin

which medications are involved in appetite control in the ominous octet?

incretins and amylin

which medications are involved in decreased glucose reabsorption in the ominous octet?

SGLT2i

which medications are involved in increased glucose uptake and utilization in the ominous octet?

thiazolidinediones and metformin

which medications are involved in lipotoxicity in the ominous octet?

thiazolidinediones and salicylates

which medications are involved in decreased glucose output in the ominous octet?

metformin and thiazolidinediones

which medications are involved in the GI tract in the ominous octet?

incretin, alpha glucosidase inhibitors, amylin, bile acid sequestrants

primary MOA of sulfonylureas

stimulate insulin release from beta-cells - “insulin secretagogues”

site of action for sulfonylureas

pancreas - beta cells

2nd generation sulfonylurea products:

glyburide, glipizide, and glimepiride

brand of glyburide

DiaBeta, Micronase, Glynase Prestabs

brand of glipizide

Glucotrol, Glucotrol XL

brand of glimepiride

Amaryl

glyburide MDD

20 mg/d

dosing range of Glynase and Glynase Prestab

0.75-12 mg po daily

what CrCl should glyburide NOT be used in?

< 50 mL/min

Glipizide IR MDD

40 mg/d

glipizide XL MDD

20 mg/d

glimepiride MDD

8 mg/d

ADRs of sulfonylureas

hypoglycemia, N/V, weight gain, GI upset, rash, cholestatic jaundice, hemolytic anemia

who should sulfonylureas be used with caution in?

elderly, patients who skip meals, vigorous exercise, significant weight loss

onset of action for glyburide

15-60 minutes

onset of action for glipizide

rapido

onset of action for glimepiride

2-3 hours

duration of action for sulfonylureas

~24 hours

T/F: sulfonylureas are highly protein bound

true

metabolism of sulfonylureas

CYP2C9

half-life of glyburide

~10 hoursh

half-life of glipizide

2-5 hours

half-life of glimepiride

5-9 hours

T/F: G6PD may play a role in glyburide and glimepiride but the evidence is weak and not clinically significant

true

DDI with sulfonylureas

alcohol (flushing, potentiation of hypoglycemia), decreased renal excretion of allopurinol and probenecid, displaced protein binding of salicylates, clofibrate, and other sulfonamides

Contraindications of sulfonylureas

HS, DKA, CrCl < 50 (glyburide only), Pregnancy-near term (glyburide/glipizide only), all are category C for pregnancy, T1DM

Precautions for sulfonylureas

impaired renal function, impaired liver function, elderly, sulfonamide allergy, thyroid dz, adrenal insufficiency, malnutrition, G6PD deficiency

monitoring for sulfonylureas

hypoglycemia, FBG, A1c, weight gain, allergic rxns, sun sensitivity

how long does it take to see the full effect of sulfonylureas?

4-6 weeks

Counseling points for sulfonylureas

best to take 30 minutes before eating first thing in the morning, beware of signs/symptoms of hypoglycemia, avoid alcohol use, ask patient about hypoglycemia and weight gain with every refill

primary MOA of meglitinides

stimulate insulin release from beta cells - insulin secretagogues & short acting

site of action for meglitinides

pancreas, beta cells

meglitinide agents:

repaglinide and nateglinide

brand of repaglinide

Prandin

brand of nateglinide

Starlix

dosing of nateglinide

60-120 mg PO before meals

dose of repaglinide if A1c < 8%

start 0.5 mg PO before meals

dose of repaglinide if A1c >/= 8%

1-2 mg PO before meals

MDD of repaglinide

4 mg/dose or 16 mg/day

ADRs of meglitinides

hypoglycemia, GI disturbances, weight gain, HA, use with caution in kidney/liver impairment

onset of action for nateglinide and repaglinide

~20 minutes

duration of action for nateglinide and repaglinide

4 hours

metabolism of nateglinide

CYP2C9 and CYP3A4

metabolism of repaglinide

CYP3A4 and CYP2C8

DDI with nateglinide

mifepristone (do not use within 14 days) and pazopanib (increased nateglinide levels)

DDI with repaglinide

mifepristone (do not use within 14 days), gemfibrozil (increased repaglinide levels), NPH insulin (increased risk of MI)

Contraindications for meglitinides

HS, T1DM, DKA

Precautions for meglitinides

severe renal disease, impaired liver function, use with insulin

counseling points for meglitinides

administer before meals (repaglinide 15-30 mins & nateglinide 1-30 mins), if you skip a meal you have to skip the dose, short acting form of a sulfonylurea, avoid alcohol use, ask patient about hypoglycemia and weight gain with every refill

monitoring for meglitinides

PPG, hypoglycemia, A1c, weight gain

when are the peak effects of meglitinides seen?

4-6 weeks

primary MOA of biguanides

decreased glucose output from the liver (hepatic glucose production)

secondary MOA of biguanides

increased peripheral muscle glucose sensitivity (glucose uptake and utilization)

site of action for biguanides

liver and peripheral muscle

what products are biguanides?

Metformin IR and Metformin ER

what strengths exist for metformin IR?

500 mg, 850 mg, and 1000 mg

what strengths exist for metformin ER

500 mg, 750 mg, and 1000 mg

initial dosing of metformin:

IR = 500 mg BID or 850 daily

ER = 500-1000 mg with evening meal

what is the minimal effective dose of biguanides?

500 mg PO BID

optimal dosing of metformin:

IR = 850-1000 mg BID

ER = 1000-2000 mg daily

metformin dosing for eGFR > 45 mL/min

no adjustments

metformin dosing for eGFR 30-45 mL/min

half dose, up to 1000 mg/day

metformin dosing for eGFR </= 30 mL/min

Discontinue

metformin dosing for acute renal failure

discontinue until reversed

how should metformin dosing work when patients are initiated on it?

titrate slowly to avoid GI effects

facts regarding Glucophae XR

dual hydrophilic polymer system - outside layer contains no drug, but a gel matrix instead (generic = ‘osmotic’)

facts regarding Glumetza

brand name d/c, gastric-retentive technology that releases in the stomach and not the GI tract (generic = ‘modified release’)

facts regarding Fortamet

brand name d/c, single-composition osmotic technology - semi-permeable outside membrane (generic = ‘osmotic laser drilled’)

facts regarding Riomet

only liquid formulation of metformin - very expensive

ADRs of biguanides

GI (N/V/D, abdominal discomfort, anorexia), weight loss, and lactic acidosis

onset of action for metformin

couple days

metabolism of metformin

no CYP450 activity

half-life of metformin

4-9 hours

time to peak for IR metformin

2-3 hours

time to peak for ER metformin

6-8 hours

DDI with biguanides

dofetilide, dalfampridine, radiopaque contrast dyes, cimetidine, trimethoprim, trospium, corticosteroids, danazol, luteinizing hormones, lamotrigine

Contraindications for metformin

HS, renal disease/dysfunction, metabolic acidosis, DKA, lactic acidosis, iodinated contrast, impaired liver function, hypoxemia, dehydration, sepsis, surgery

Precautions for metformin

elderly, excessive alcohol use, CHF requiring drug therapy

monitoring for metformin

renal function (eGFR), GI intolerance, FBG/PPG, A1c, B12 levels, weight loss, signs/symptoms of lactic acidosis

Signs and symptoms of lactic acidosis:

SOB, muscle cramping, tachycardia.

time to peak effect for metformin

6-8 weeks

counseling points for metformin

take with food to decrease GI effects, start low and go slow, avoid alcohol use, GI upset/diarrhea should decrease over time (contact MD if it doesn’t), ask patient about GI upset, weight loss, and signs/symptoms of lactic acidosis

primary MOA for TZDs

increased peripheral muscle glucose sensitivity (glucose uptake and utilization)

secondary MOA of TZDs

decreased glucose output from the liver (hepatic glucose output)

site of action for TZDs

muscle and adipose tissue

available thiazolidinediones (TZDs)

rosiglitazone and pioglitazonebr

brand of rosiglitazone

Avandia

brand of pioglitazone

Actos

MDD of rosiglitazone

8 mg/day

MDD for pioglitazone

45 mg/day

ADRs of TZDs

edema (may worsen if CHF), weight gain (can be > 10 kg), hepatic toxicity, bladder cancer, fractures

onset of action for TZDs

delayed