Pharm 1 Type II Diabetes Pharmacology Flashcards
4 Strategies for Prevention of Complications of Type II Diabetes?
Glycemic Management
Cardiorenal protection – glucose lowering agents
Cardiovascular Risk Factor Management
Weight Management
Target HbA1c for nonpregnant type II diabetic?
A reasonable HbA1c (Glycated hemoglobin, linked to a sugar) target is 53 mmol/mol (7%) or less
Normal, Prediabetes and Diabetes Thresholds of HbA1c Test
Primary cause of mortality in Diabetes?
Cardiovascular Disease
Reducing ______________ decreases the onset and progression of microvascular and macrovascular complications in diabtetes.
Reducing hyperglycemia decreases the onset and progression of microvascular and macrovascular complications.
Glucose control is a major focus in the management of patients with diabetes
When to consider dual therapy for Type II diabtes?
HbA1c (Glycosylated Hemoglobin) is ≥ 9%
First Line monotherapy for Type II diabetes?
Advantages of this drug?
Metformin (Biguanides): Targets Insulin Resistance so has a LOW risk of hypoglycemia (One of the biggest concerns of therapy)
MOA of Metformin?
- Potent Activator of _______ => Improved Insulin _________
- Reduces ________ absorption from the gut
- Impedes ________ Signaling
- Inhibits Hepatic ________
- Potent Activator of AMPK => Improved Insulin Sensitivity
- Reduces glucose absorption from the gut
- Impedes Glucagon Signaling
- Inhibits Hepatic Gluconeogenesis
_______________ activates muscle AMPK=> Improved Insulin Sensitivity
- Improved ______________ Function
- Improved ______________ Transport
- Metabolic switch from fat __________ to fat ___________
Metformin (Type II Diabetes Drug) activates muscle AMPK=> Improved Insulin Sensitivity
- Improved Insulin Receptor Function
- Improved Glucose Transport
- Metabolic switch from fat synthesis to fat oxidation
Side Effects/Contraindications for Metformin?
Lactic acidosis is primary side-effect (lack of lactate shuttling into gluconeogenesis pathway)
Vitamin B12 deficiency with long-term use can occur
NOT indicated in pnts with renal/hepatic insufficiency (Renal insufficiency => metformin accumulation = incr. risk of lactic acidosis)
Generations of Sulfonylurea?
Benefits of 2nd vs. 1st?
First generation: Tolbutamide (Short Acting) - safest for elderly
Second/Third generation: 200X potent w/ fewer adverse effects and drug interactions
* Glipizide (Fastest Acting)
- Glyburide (Intermediate Acting)
- Glimepiride (Long Acting) - avoid in elderly
MOA of Sulfonylureas?
Sulfonylureas close K+ channels of Pancreatic Beta Cells (mimicking the effect of glucose)
=> stimulates calcium influx
==> increased insulin release from the pancreas
Sulfonylurea that is well absorbed, rapidly metabolized and is the safest sulfonylurea in elderly patients due to its short half life.
Tolbutamide (Short Acting, First Gen)
Sulfonylurea with a half life of 32h. Prolonged hypoglycemia can result in the elderly.
Chlorpropamide (Long-Acting)
Sulphonyurea that achieves blood glucose lowering with the lowest dose of any sulfonylurea compound, only requiring once daily dosing.
Glimepiride (Long Acting)
When are Sulfonylureas Effective?
When Are they no longer Effective?
Useful to treat early stages of Type 2 diabetes when there is an insulin reserve
WILL NOT WORK IN T1D OR LATER STAGES OF T2D WHEN INSULIN RESERVE IS DEPLETED (Check C Peptide Levels)
Insulin Secretagogues with similar MOA to sulfonylureas but don’t contain Sulphur (2 binding sites in common)
Meglitinides (Repaglinide and Nateglinide) close K+ channels of Pancreatic Beta Cells (mimicking the effect of glucose)
=> stimulates calcium influx
==> increased insulin release from the pancreas
Insulin Secretagogue with the lowest risk of hypoglycemia of all the insulin that is also safe in those with reduced renal function?
Nateglinide: Does not induce insulin in the presence of normoglycemia
Who are Thiazolidinediones (TZDs) well suited for?
Cohorts young, overweight individuals who are insulin resistant (Pioglitazone)
MOA of Thiazolidinediones (TZDs)
Thiazolidinediones (TZDs) are potent insulin sensitizers that enhance the action of endogenous insulin
TZDs are ligands of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in adipose, muscle cells => PPAR-gamma increases expression of genes involved in glucose/lipid metabolism (IRS-1, GLUT4)
Side Effects/Contraindications of Thiazolidinediones (TZDs)
Pioglitazone-risk of bladder cancer at high doses
Rosiglitazone-Increased cardiovascular risk
Both:
Increased deposition of subcutaneous fat (Weight gain)
Fluid retention (Contra heart failure)
Contraindications:
Individuals at risk of heart failure
Breastfeeding/Pregnancy
How to minimize side effects of Thiazolidinediones (TZDs)?
Risk of hypoglycemia minimal with monotherapy; increased risk with dual therapy
Side-effects can be mitigated by combining TZDs with other medications that promote weight loss (GLP1/SGLT2i).
Ideal T2D Therapeutic for someone with hypertension/overweight comorbidities?
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors (Empagliflozin/Dapagliflozin)
MOA of SGLT2 inhibitors?
Other Associations?
Blocks glucose (and Na+) reabsorption from the proximal renal tubule in the kidney, thereby increasing urinary glucose excretion
Also associated with weight loss and reduced blood pressure without effects on heart rate.
Major Side effects of SGLT2 inhibitors?
SGLT2 inhibitors (Empagliflozin/Dapagliflozin) can result in:
- Urinary tract and genital infections
- Increase in both LDL-C and HDL-C levels
- risk of hypoglycemia minimal with monotherapy; increased risk with dual therapy
T2D Therapeutic associated with a reduction in adverse cardiovascular events, overall CV death, reduction in risk of hospitalization for heart failure and reduction in risk of
kidney outcomes.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors (Empagliflozin/Dapagliflozin)
38% reduction in risk of death from cardiovascular causes!!
MOA of Incretins in regulating Glucose Homeostasis?
**Incretins (GLP-1/GIP)(( regulate glucose homeostasis through effects on Islet Cell Function
Ingestion of food=> release of incretin hormones from gut:
- Active GLP-1/GIP travel to Pancreatic BETA Cells=> Increase Insulin => Increase Glucose Uptake/Storage in Muscles/Adipose Tissue
- Active GLP-1/GIP travel to Pancreatic ALPHA Cells => Decreased Glucagon=> Decreased glucose release into bloodstream by liver
- GLP-1/GIP DEACTIVATED by DPP-4 Enzyme into inactive metabolites
Two synthetic GLP-1 agonists?
Exenatide and Liraglutide
MOA of GLP-1 (Incretin) agonists
Exenatide and Liraglutide decrease glucagon secretion, reduce appetite, slow gastric emptying, promote beta cell proliferation/prevent beta cell apoptosis
Recent evidence suggests adding ________ to basal insulin treatment regimen can reduce the need for prandial insulin injections
Recent evidence suggests adding GLP1 to basal insulin treatment regimen can reduce the need for prandial insulin injections
_____________________:
97% homology to native GLP1 but prolonged half-life
Once daily dosing; injectable; up to 1.8mg give daily
Currently given as a second line therapy with other oral hypoglycemic.
S/Es?
Liraglutide (Victoza) ($800 per month):
97% homology to native GLP1 but prolonged half-life
Once daily dosing; injectable; up to 1.8mg give daily
Currently given as a second line therapy with other oral hypoglycemic.
S/E’s: Headache, nausea, diarrhea, antibody formation, pancreatitis
_______________________:
53% homology with native GLP1; has a glycine substitution to reduce degradation by DPP 4
Injectable duration of action 10h; twice (5-10mcg)daily 1h before main meals
S/Es?
Exenatide (BYETTA):
53% homology with native GLP1; has a glycine substitution to reduce degradation by DPP 4
Injectable duration of action 10h; twice (5-10mcg)daily 1h before main meals
S/Es nausea (44% of users), vomiting, diarrhea; rare hemorrhagic pancreatitis.
T2D therapeutic that blocks natural endogenous GLP1 from being degraded?
Dipeptidyl Peptidase 4 (DPP4) Inhibitors:
Sitagliptin, saxagliptin, and linagliptin
Delivered orally & reduce HbA1c levels by 0.5-1% on average
Dipeptidyl Peptidase 4 (DPP4) Inhibitor Side Effects?
Most common S/Es of this class are nausea and headache
Sitagliptin–Risk of pancreatitis and allergy
Drug/MOA/MOD of Amylin Analogues?
Pramlinitide–synthetic analogue of amylin
MOD:
Injectable –given before meal in addition to insulin
Rapid acting insulin dose should be decreased by ~50% due to risk of hypoglycemia
Cannot be mixed with insulin for injection
MOA:
Suppresses glucagon, delays gastric emptying and has anorectic effects
Duration of action ~150mins
Combining __________ with insulin results in similar reductions in HbA1c as traditional insulin regimen but prevents the adverse effects of insulin on weight gain.
Combining Liraglutide (97% GLP1 Homologue) with insulin results in similar reductions in HbA1c as traditional
insulin regimen but prevents the adverse effects of insulin on weight gain.
Benefits of Incorporating GLP1 Agonists (Liraglutide) with Insulin?
Currently given as a second-line therapy with other oral hypoglycemic:
People on insulin alone require much higher doses than those injected w/ GLP1
Increased weight loss compared to lifestyle intervention
Improved glucose tolerance in both healthy and pre-diabetic individuals
Decreased rate of diabetes diagnosis
Effects of medication on weight in Type 2 Diabetes
Weight loss: Metformin, SGLT2, GLP1 agonists, and amylin mimetics
Weight neutral: DPP inhibitors
Weight gain: TZDs and Insulin
Strategies for Treating Diabetes (6)
- Give insulin to those lacking insulin –short-acting to long-acting insulin formulas
- Promote insulin sensitivity in those who are insulin resistant-TZDs, metformin
- Stimulate insulin secretion in those not producing enough insulin to compensate for insulin resistance –insulin secretagogues, GLP1-agonists, DPP-4 inhibitors
- Reduce glucose production –Metformin, amylin analog
- Reduce glucose absorption –alpha-glucosidase inhibitors, SGLT2 inhibitors
- Promote weight-loss –GLP-1 agonists, amylin analogue, SGLT2 inhibitors
Therapeutics that promote insulin sensitivity in those who are insulin resistant?
TZDs (Rosiglitazone, Pioglitazone)
Biguanide (Metformin)
Thereaputics that stimulate insulin secretion in those not producing enough insulin to compensate for insulin resistance?
Insulin Secretagogues (Sulfonylureas/Meglitinides)
GLP1-agonists (Liraglutide (Victoza))
DPP-4 inhibitors (Sitagliptin)
Therapeutics that reduce glucose production?
Biguanide (Metformin)
Amylin analog (Pramlinitide)
Therapeutics that reduce glucose absorption
SGLT2 inhibitors (Empagliflozin/Dapagliflozin)
Alpha-glucosidase inhibitors
Therapeutics that promote weight loss
GLP 1 agonists (Liraglutide (Victoza), Exenatide (BYETTA))
Amylin analog (Pramlinitide)
SGLT2 inhibitors (Empagliflozin/Dapagliflozin)
