What are the Sulfonylureas?
Generic - Brand
Acetohexamide - Dymelor
CHlorproamide - Diabinese
Tolazamide - Tolinase
Tolbutamide - Orinase
Glipizide - Gluctrol
Glipizide - Glucotrol XL
Glyburide micronized - DiaBeta Micronase Glynase
Glimepiride - Amaryl
What are the short acting insulin secretagogues?
Generic - Brand
Nateglinide - Starlix
Repaglinide - Prandin
What are the Biguanides?
Biguanides - Glucophage
Metformin Extended- Release -- Glucophage XR
What are the Thiazolidinediones?
Generic - Brand
Pioglitazone - Actos
Rosiglitazone - Avandia
WHat are the Alpha- FLucose inhibitors?
Generic - Brand
Acarbose - precose
Miglitol - Glyset
What are the Dipeptidyl peptidase-IV inhibitors (DDPIV inhibitors)?
Generic - Brand
Sitagliptin - Januvia
What are the combination products?
What are the Agents of Sulfonylurea?
What is the MOA of Sulfonylurea?
interact with ATP-sensitive K channels in beta cell membrane to increase insulin secretion.
Binds to receptor associated with ATP-sensitive K+ channel; dec K+ conductance; membrane depolarization inc Ca influx; inc insulin release
extrapancreatic mechanism: inc insulin receptor number; dec hepatic gluconeogenesis stimulate synthesis of glucose transporter proteins
What are the characteristics of Sulfonylurea?
need functioning beta cells ---> less effective with time as beta cells decrease in number
advantage: less expensive than newer agents
1st and 2nd generation agents: equal efficacy, differ duation and dosage
What are the unwanted effects of Sulfonylurea?
hypoglycemia (esp. elderly with impaired renal or hepatic function): glyburide, chlorpropramide >> glipizide, glimepiride >> tolbutamide
CV complications (tolbutamide)
Inc CV death: 1st generation
> glyburide > metformin
What are the Non-Sulfonylurea secretagogue? (meglitinides)
What is the PK/PD of Non-Sulfonylurea Secretagogue?
peak insulin at 30-60 minutes
faster acting than SU
duration : 4-6 hours
administer before meals only: need to eat soon after
What is the MOA of non-sulfonylurea?
same as SU but no sulfur structure - block SU receptor on K ATP channels in pancreatic beta cells (somwewhat selective for beta cells vs. vascular smooth msucle and heart)
inc glycogen, fat and protein formation
What are the side effects of Non-Sulfonylurea?
less hypoglycemia than SU
also have initial weight gain
What is the drug of Biguainde?
What is the PK/PD of Metformin?
excreted unchanged in urine ---> so good renal function is needed
half life ~ 3 hours
available as extended release from glucophage XR; glumetza
1/3 patients experience treatment failure after average time of 1.5 years
What is the MOA of biguanide?
dec hepatic glucose production
improves insulin's ability to move glucose into cells
dec instetinal glucose absorption - minot
inc peripheral glucose utilization - minor
reduce blood glucose levels by 20% alone and boost glucose - lowering effects of SU, etc by additional 25%
What is unique of Metformin
no increased insulin secretion
do not require beta cell function but require insulin for effectiveness ---> no risk for hypoglycemia (sometimes referred to as a euglycemic agent or an antihyperglyemic agent or an antihyperglycemic agent
no weight gain (may with weight loss)
advantage in obese patients
as effective as SUs; inexpensive
recommended first line therapy by ADA
What are the side effects of Metformin?
rare: lactic acidosis
CI: renal-impaired patients
use with caution in elderly over 80 years; conditions predisposing to tissue anoxia
What are the drugs of the Thiazolidinediones (insulin sensitizer)?
What is the PK/PD of Thiazolidinediones?
reduce insulin resistance (often used in obsese patients); no increased insulin release: increase cell sensitivity to insulin; activate nuclear protein in adipose tissue (mainly, but also in muscle and liver)
TZDs are ligands of PPAR gamma (peroxisome proliferator-activator receptor gamma) - inc expression of genes for transporter proteins that move glucose into cells inresposne to insulin and also inc fatty acid uptake
-PPARgamma: predominantly in adipose tissue, kidney, liver, and small intestine (limited expression in muscle) ---> regulate adipocyte differentiation and insulin sensitization
What are the side effects of Thiazolidinediones?
fluid retention may lead to adverse CV events such as HF ---> CI in HF
edema seen in 4-6%: more frequent when combined with insulin or insulin secretatgogues
Weight gain: 2-10 pounds in 6-12 months; perhaps from fluid retention; due to sodium ion reabsorption in renal collecting ducts
low risk for heaptoxicity but FDA requires liver function blood testing for year
absorption inhibited by colestipol ---> so do not take at the same time
What are alpha-glucosidase inhibitors?
What is the PK/pD of Acarbose?
binding affinity for the alpha-glucosidase enzymes is: glycoamylase > sucrase > maltase > dextraase
no affinity for the beta-glucosidase enzymes, such as lactase
What is PK/PD of Miglitol?
more potent inhibitor of sucrase and maltase than acarbose
smaller molecule than acarbose
What is the MOA of PK/PD of Miglitol?
comeptitive and reversible inhibitor
inhibit alpha glucosidase enzymes, lining border of small intestine
interfere with hydrolysis/digestion of complex polysaccharides and sucrose
inhibits glucoamulase, sucrase, and maltase
delays digestion and absoprtion of sucrose and complex carbohydrates ---> results in dec glucose absorption
Main effect: dec postprandial hyperglycemia ---> must be taken with each meal; not effective at other times
What is the combination therapy?
TZD and SU - direclty improve in insulin sensitivity (muscle and adipose tissue) and improved estimation of beta-cell function (pancreas beta cells) + inc insulin secretion from functioning pancreatic beta cells to increase plasma insulin levels (pancrease) ---> dec plasma glucose
TZD and metformin: direct improve in insulin sensitivity (muscle and adipose tissue) and improved estimation of beta cell function (pancrease beta cells) and dec hepatic glucose and output and dec intestinal absorption of gluocse and increase peripheral glucose uptake and utilization (liver) ---> dec plasma glucose
What is the drug for amylin analgoues?
What is the clincial use of Pramlintide?
...subQ administration, onlu used with insulin, inject immediately before eating
administered in addition to insulin for better glucose control
used in type 1 and in insulin-requiring type 2 diabetes
What is the mecahsnim of action of Pramlintide
bind to amylin receptors
suppresses glucagon release
delays gastric emptying
suppress appetitive via CNS
induces weight loss
dec postprandial glucose level
What are the side effects of Pramlintide?
hypoglycemia -- significant --> should dec rapi/short- acitng insulin doses by 30 -50 %
GI: N/V and anorexia
What is the drug of GLIP-1 analog class?
What is the PK/PD of Exenatide (Byetta)?
injectable, adjunctive therapy to improve glycemic control in type 2 diabetes taking TZDs, metformin, a SU or met/SU
Administer within 60 minutes before am and pm meals
absorbedly quickly from injection site, reach peak at 2 hours, duration for 10 hours
longer duration of action and same effects as GLP-1; same affinity for GLP-1 receptor sites
eliminated by renal excretion
What is the MOA of Exenatide (Byetta)?
inc glucose dependent insulin secretion, acts only in the presence of hyperglycemia
As blood glucose approaches normal, insulin secretion decreases ---> low risk of hypoglycemia
inc insulin release: inc cAMP and Ca_@ influx into beta cell ---> trigger insulin granule exocytosis
suppress glucagon secretion ---> dec hepatic glucose putput inc glucose tolerance, dec A1c
slow gastric emptying _--> dec food intake
dec body weight (lose average of 5 pounds in 26 week study)
What are the characteristics of Exenatide (Byetta)?
made from saliva of glial monster
may prserve some beta cell function and increase beta cell mass
What are the SI of Exenatide (Byetta)/
GI - nauseau
new FDA warning - acute pancreatitis...
What are the drugs of the Dipeptidyl peptidase inhibitors (DDP-4)?
What is the use of PK/PD of DDP-4 inhibitors?
clinical use: monotherapy or in combination with metformin or TZDs in type 2 diabetes; not sued in type 1 diabetes
Saxagliptin: same mechanism as sitagliptin: metabolzied by CYP3A4
side effects: URI
What is the MOA of DDP-4 inhibitors?
competitive, reversible DPP-4 inhibitor
blocks degradation of GLP-1, inc GLP-1 levels
DDP-4 : proline peptidase
Sitaglipitn binds pocket of active sites
inc insulin production/release; dec glucagon in a glucose dependent way ---> No hypoglycemia
may improve beta cell function (cell mass)
What are the characteristics of DDP-4 inhibitors?
DDP-4 activity inhibited by > 80% for 24 hours with 100 mg dose by oral: DDP-4 inhibits 50% of GLP-1 within 2 minutesl GLP-1 plasma levels increased 2-fold
What are the SE of DDP-4 (Sitaglipitn/Saxagliptin)?
mostly well tolerated
no effect on food intake
body weight neutral
minimal GI problems
New FDA warning: severe allergic and dermatologic /hypersensitivity reactions;
ananphylaxis; angioedema; exfoliative skin conditions including SJS; onset within 3 months; some after first dose; Merck indicates no known frequency
What are Incretins?
INtestinal seCRETion of INsulin hormones.
INcretins : naturally occurring gut hormones secreted rapidly from intestines in response to food in a glucose-dependent manner
What is GLP-1?
glucose like peptide 1 secreted from L cells in small intestein/colon
GIP -glucose dependent insulinotropic polypeptide secreted from K cells in small intestine.
What is the effect of GIP/GLP-1?
stimulate insulin synthesis and release, help modulate pancreatic islet cell secretions
glucose dependent insulin release - higher glucose ---> more insulin release
elicitis greater insulin release when glucose is administered orally vs intravenously
rapidly degraded by DDP-IV (>80% of pool)
require continuous subcutaneous infusion ---> limited used.