Oral hypoglycemics 2 - slides 18 to 47 Flashcards
(35 cards)
What are biguanides?
AMP dependent protein kinase activators
They decrease hepatic glucose production, increase fatty acid oxidation, and increase peripheral glucose uptake and utilization by increasing tissue insulin sensitivity
They also decrease glucose absorption from the GI tract
(Metformin)
True or False: Biguanides increase insulin release
False, they decrease glucose production in the body and increase glucose uptake
True or False: Biguanides have a high incidence of hypoglycemia
False, they have limited hypoglycemia
Indications for biguanides?
Impaired glucose tolerance (to slow progression to diabetes)
Off label to improve cycling, ovulation, and decrease androgens in PCOS
Also used in T2 diabetes obvi as monotherapy
Pharmacokinetics of metformin?
Not metabolized in the liver
Not bound to proteins
Excreted unchanged by kidneys via renal tubular excretion
Cautions with metformin?
Contraindicated in hepatic disease due to lactic acid formation
Not used in renal impairment bc depends on kidneys for excretion
Side effects of metformin?
Weight loss possible
GI: unpleasant or metallic taste, anorexia, constipation, diarrhea, heartburn
Lactic acidosis: Increased incidence in renal impairment, aging, and after surgery
Rash
Megaloblastic anemia (decreased VB12 absorption)
Contraindications for Metformin?
Heart failure (MI)
Renal disease
Metabolic acidosis or hypoxia
Hepatic disease
Severe pulmonary disease
Cationic drugs compete for tubular excretion
Should be stopped before surgery and radiographic procedures using contrast dies (withhold drug for 48 hours after surgery due to increased lactic acid)
What are Thiazolidinediones?
Pioglitazone
Rosiglitazone (limited by CV toxicity)
Troglitazone (removed bc liver toxicity)
They are peroxisome proliferator activated receptor gamma (PPAR gamma receptor activators)
Mechanism of Thiazolidinediones?
Selective and potent agonists for peroxisome proliferated activated recepotr gamma
PPAR-Y regulates insulin responsive genes
Genes involved in lipid and glucose metabolism
They increase uptake of fatty acids into fat cells and muscle to decrease triglycerides. Also increase tissue sensitivity to insulin
Also increase peripheral glucose uptake and utlization, increasing tissue insulin sensitivity ~60% and decreasing hepatic glucose production
Pharmacokinetics of Thiazolidinediones?
Highly protein bound, metabolized by the liver (Pio CYP2C8 and 3A4, Ros CYP2C8 and 2C9)
Maximal effect requires 6-12 weeks bc you’re depending on gene transcription changes
Adverse effects of Thiazolidinediones?
Weight gain (2-4 kg first year)
Expanded blood volume, edema (10%) - macular edema, yearly retinal exams
Respiratory tract infections
Headache, fatigue, muscle pain
Increased HDL, LDL, decreased TG
Monitor liver enzymes every 2 months for first year, stop drug if ALT is over 3x normal
Increased bone fracture risk
Which thiazolidinediones had to undergo further study? For what? What was the result?
Rosiglitazone further studied for CV effects, end result was it could increase MI risk so it was put under a restricted access program to ensure patients knew the risk of taking the drug
However, further studies showed there was no difference in increased risk of CV event versus other oral diabetes drugs
Cautions with Pioglitazone?
Increased bladder cancer risk
Lots of law suits filed/settled over bladder cancer
What is the “Incretin” effect?
Taking oral glucose vs IV glucose, incretin effect increases glucose levels when taken PO route
What are incretins?
Glucagon-like-peptide-1
GLP is secreted from the L-cells of the intestine
This increases glucose dependent insulin release from the pancreas
Decreases gastric emptying and food intake
What does GLP-1 do?
Stimulates release, biosynthesis, and gene transcription of insulin
In alpha cells: Decreases postprandial glucagon secretion
Liver: Decreased glucagon reduces hepatic glucose output
B cells: Enhances glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
Brain: Promotes satiety and reduces appetite
How is GLP-1 metabolized?
By dipeptidyl peptidase (DPP-IV)
How is GLP-1 release affected in diabetes?
Release of GLP-1 is impaired in pts with T2DM
What is Exenatide?
Isolated from the saliva of gila monster
53% homology with GLP-1
Indications for Exenatide?
Type 2 diabetics taking metformin AND sulfonylureas or combination and not controlled
Adverse effects of exenatide?
Can cause weight loss Nausea and vomiting (decreases over time) Hypoglycemia with sulfonylureas Delays absorption of other oral meds Concern for pancreatitis
How is exenatide administered?
5-10 mcg twice daily 0-60 mins before meals SubQ injection (prefilled pen injectors)
How does exenatide affect insulin response?
It comes the closest to having a biphasic insulin response
