Diabetes Drugs - Part 2 Flashcards
Insulin releasing agents:
Sulfonylureas & meglitinides
Weight reducing agents (AMPK activator):
Biguanides (metformin; 1st line therapy)
Insulin sensitivity enhancers:
Glitazones
- Rosiglitazone; Pioglitazone
Glucosidase inhibitors:
Acarbose
Incretin-related molecules:
GLP-1 analogues
DPP-4 inhibitors
Sodium-glucose transport protein-2 (SGLT2) inhibitors:
Dapaglifozin
Sulfonylureas:
Glimepiride; Glyburide; Glipizide
Sulfonylureas MOA:
- Over 60 yrs of use (1st gen)
- Release insulin form pancreatic beta cells
- Reduce serum glucagon levels
- Potentiate the action of insulin on its target tissues
Target SUR1 to block the KATP channel
- KIR6.2 (4 subuits)
- ATP binding blocks pore
- SUR1 (4 subunits) – binds MgADP/ATP at nucleotide binding sites
- Causes pore opening
- High affinity on SUR1
- Low affinity on KIR6.2 (not relevant in pts)
- Partial antagonists
Sulfonylureas AE’s:
- Glimepiride; Glyburide; Glipizide
- Hypoglycemia (glyburide worse)
- Weight gain
- Aggravation of myocardial ischemia
CI: in pts w/ CV disease & elderly (hypoglycemia more serious) & in pts w/ hepatic impairment &/or renal insufficiency
(not 1st DOC b/c can cause most of these things that come up w/ pts that have diabetes)
Meglitinides MOA:
- Repaglinide; Nateglinide
(Meglitinide analogs)
- Structurally diff from sulfonylureas
- Bind to SUR1 & KIR6.2
- Rapidly absorbed w/ a short half life (4-7 hrs)
- MUST be taken 15-30 mins prior to meals
- Fast onset of action (1 hr peak)
- Can be combined w/ Metformin
- Repaglinide CAN BE USED in pts w/ renal impairment & in the elderly
Biguanides MOA:
- Metformin (GlucophageR) – 1st line therapy
- Not fully understood
- No effect on insulin secretion
- *Activates cyclic AMP-activated protein kinase (AMPK) – regulator of hepatic glucose production & improves insulin resistance
- Dose 1500-2000 mg/day (divided)
- Euglycemic agent (benefit)
Biguanides Benefits:
- Metformin (GlucophageR) – 1st line therapy
- *Euglycemic rather than hypoglycemia – i.e. lowers BG after food, but not fasting levels in steady state
- Increase glycolysis & insulin binding
- Inhibits gluconeogenesis in liver & glucose absorption from the gut
- Reduce plasma glucagon levels
- *Mild weight loss
- METFORMIN is not metabolized
- Excreted by the kidneys in the active form
- Half life 1.5-3 hours
Biguanides AE’s:
- Metformin (GlucophageR) – 1st line therapy
- Lactic acidosis – impaired liver metabolism of lactate
- Range of GI effects
- B12 deficiency
Glitazones – Thiazolidinedione (TZD) compounds MOA:
- Rosiglitazone; Pioglitazone
- Decreases insulin resistance by binding to nuclear r’s which regulate genes responsible for lipid metabolism
- Peroxisome proliferator-activated r. (PPAR)-g agonists
- Decreases gluconeogenesis, glucose output & triglyceride synthesis in the liver
- Increases glucose uptake in skeletal muscle & adipose tissues
- Has no effect on insulin secretion
(by driving expression of these proteins, you turn on these pathways which help to decrease hyperglycemia)
Glitazones – Thiazolidinedione (TZD) compounds Metabolism:
- Rosiglitazone; Pioglitazone
- Absorption better when taken w/ food
- Plasma level peaks in 3 hr, & half-life 16-34 hr
- Metabolized in the liver by CYP3A4
Glitazones – Thiazolidinedione (TZD) compounds Use:
- Rosiglitazone; Pioglitazone
- Used for T2D pts who need more than 30 units of insulin daily & have HbA1C > 8.5%
- Max effect may require 12 wks of tx
- Should be taken orally once a day
Benefits:
- Tighter control of glucose
- HbA1C decreased by 0.6-1.6%
- No lactic acidosis observed
- Pioglitazone – lowers TG’s & raises HDL cholesterol
- Rosiglitazone – raises HDL cholesterol
(therefore both do have some benefits)
Glitazones – Thiazolidinedione (TZD) compounds AE’s:
- Rosiglitazone; Pioglitazone
- Rosiglitazone – myocardial infraction (use stopped in Europe)
CI: in pts w/ renal failure & liver impairment - Edema
- Macular edema
- Loss of bone density
- Weight gain
- Pioglitazone – bladder cancer
*Consequently, these drugs are used less & less
Glucosidase Inhibitors MOA:
- Acarbose; Miglitol
- Acts only in the gut, slows carbohydrate breakdown
- Competitive inhibitors of a-glucosidase enzymes
- Lowers post-prandial rise in BG
- Lowers HbA1C levels
Glucosidase Inhibitors Use:
- Acarbose; Miglitol
Approved for T2D
Glucosidase Inhibitors SE’s:
- Acarbose; Miglitol
Dose dependent abd. bloating, flatulence, which is reduced in 3 months (not really serious)
Incretin-related molecules:
- Meal ingestion leads to secretion of GLP-1 (glucagon-like peptide-1) & gastric inhibitory peptide (GIP) from the gut
- These agents increase insulin synthesis & release, & also decrease glucagon (from a-cells of pancreas)
GLP-1 analogues
DPP-4 inhibitors
Incretins – DPP-4 Inhibitors:
- Sitagliptin-PO4
- Saxagliptin
- Dipeptidyl peptidase-4 inhibitors
- Orally active
- Peak at 1-4 hr – half life of 12 hr (3 hr for sax)
Incretins – DPP-4 Inhibitors: AE’s:
- Sitagliptin-PO4
- Saxagliptin
- Respiratory infections
- May produce pancreatitis (sitagliptin)
- Hypersensitivity rxns – anaphylaxis
GLP-1 Analogues:
- Exenatide
- Liraglutide
GLP-1 Analogues:
- Enhances glucose-dependent insulin secretion from pancreatic b cells
- Restores 1st-phase insulin response
- Suppresses glucagon secretion from pancreatic a cells under conditions of hyperglycemia, which leads to a reduction in glucose output from the liver
- Reduces food intake – weight loss
- Slows gastric emptying, allowing for timely absorption not nutrients
Exenatide:
- Used for T2D w/ either metformin or sulfonylurea
- It is a synthetic version of a intestinal hormone (Extendin-4)
- Euglycemic on its own
- Injected 2x/day*
- Peak at 2hr – lasts 10 hrs
- Consider potential risks of pancreatitis, renal dysfunction
- Nausea
Sodium-glucose transport protein-2 (SGLT2 inhibitors:
Dapagliflozin
- Competitive inhibitor of SGLT2
- Functions in the proximal tubule of kidney (transporter)
- Prevents re-absorption of glucose (glucose is flushed out in urine & therefore decrease BGL’s)
Sodium-glucose transport protein-2 (SGLT2 inhibitors: SE’s
- Excessive glycosuria – hypotension
- Urinary tract & bladder infection
Other drugs – Pramlintide:
- Synthetic analog of Amylin, which is more soluble & dose not readily aggregate like amylin
- Amylin is a hormone co-secreted w/ insulin from b cells in response to glucose
Other drugs – Pramlintide MOA:
- Suppresses glucagon secretion
- Rate of glucose absorption from the gut is slowed down
- Fructosamine is a surrogate marker which reflects average glucose [ ]’s over 2-3 wks prior to testing
- Pramlintide decreased fructosamine by 60%
Other drugs – Pramlintide Use:
- Pramlintide can be mixed w/ regular or NPH insulin just prior to injecting
- Found to be useful for both T1D & T2D
T1D:
control BG w/ insulin & diet as best as possible
T2D:
- exercise, weight reduction & diet control
- if mild then add anti-diabetic agents - metformin
- oral combo therapy & diet
- add insulin
- reduce hypertension*
Future mode of therapy may include:
- CGM + insulin pump; beta islet cell transplantation
Diabetes in the elderly (oral agents):
in elderly people, sulfonylureas should be used w/ caution b/c the risk of hypoglycemia increases exponentially w/ age
in general, initial doses should be half those for younger people, & doses should be increased more slowly
