Lecture 7: Medications in Diabetes Flashcards
How does LADA present?
It has the same pathogenesis as T1D but once it gets to pre-diabetes, it does not drop off to diabetes
What are the types of antihyperglycemic agents for Type 2 diabetes?
- Metformin (AMPK, acts on liver and muscle, decrease glucose production and increase glucose uptake)
- Sulfonylureas (inhibits K channel in B cell)
- Thiazolidinediones (PPARgamma, sensitizes tissues to insulin, upregulate GLUT4)
- Meglitinides/glinides (inhibits K channel in B cell)
- Glucosidase inhibitors (inhibits glucose uptake in gut)
- Incretin Mimetics (GLP-1 agonist)
- Incretin enhancers (DPP-4 inhibitors)
- Insulin
What are the principles of glucose lowering agents in type 2 diabetes?
- Multiple drugs available, each with tissue specific action
- All of these drugs, except insulin, are used for type 2 diabetes ONLY
- All are contraindicated in pregnancy except for Glyburide (sulfonylurea) and metformin
- Can be used in any combination except sulfonylureas should not be used with meglitinides
- Metformin is generally first drug of choice
- Can start with multiple classes of drugs
What is the first drug of choice?
Metformin
What are the two type 2 diabetes drugs that are NOT contraindicated in pregnancy?
- Glyburide (sulfonylurea)
2. Metformin
What are the two drugs that cannot be used in combination with one another?
- Sulfonylureas + Meglitinides (because they have the same fucking MoA)
What is the MOA of metformin (a biguanide drug)?
Works at the liver Try to prevent production of glucose from liver Activation/phosphorylation of AMPK (amp-activated protein kinase) Funciton: 1. increase muscle glucose transport 2. decrease hepatic glucose production 3. sensitizes insulin 4. reduces glycogenolysis 5. Reduces triglycerides
What are the characteristics of metformin?
- improves pre-meal glucose with MODEST effect on post-prandial glucose
- Weight neutral but can induce weight loss
- NOT metabolized so can accumulate in patient if there is renal insufficiency
- Lowers A1c as much as 2%
- the higher the A1c, the greater the efficacy of the drug
What are the side effects of metformin? Contraindications?
Side effects: nausea, anorexia, diarrhea, lactic acidosis
Contraindications: prone to metabolic acidosis, hypoxic states, renal failure, cardiac ischemia
REQUIRES INSULIN FOR ACTION
What are the goals of treatments?
- Weight loss/neutral
- no hypoglycemia
- frequency of administration
- oral pill vs. injectable
What are side effects of treatment?
- weight gain
- fluid retention
- hypoglycemia
- frequency of delivery
- injectable
Is metformin used for pre-diabetics?
No because lifestyle changes do a lot more than for metformin
What are the types of insulin secretagogues?
- Sulfonylureas
2. Meglitinides/Glinides
What is sulfonylurea?
An insulin secretagogue
What is meglitinides/glinides?
An insulin secretagogues
Induces insulin release
What is the MOA of sulfonylurea?
Binds to the sulfonyl receptor in Beta cell resulting in INHIBITION of ATP-dependent potassium channels, leads to depolarization of Calcium channel that leads to insulin secretory granule secretion
Stimulates pancreatic insulin secretion for 12-24 hours
Long acting
What are the characteristics of sulfonylureas?
Has an immediate effect on pre-meal glucose
Metabolized in liver
Contraindication: T1DM, DKA, sulfa allergy
Adverse effects: hypoglycemia, WEIGHT GAIN, hunger
Lowers HbA1c up to 1.5%
What is the MOA of meglitinides/glinides?
Stimulates insulin release by regulating (inhibiting) ATP-sensitive K+ channels on Beta cells
Stimulates pancreatic insulin secretion for 3-4 hours
Short acting
What are the characteristics of meglitinides/glinides?
FAST ONSET
Side effects: low glucose 2-4 hours after meal, WEIGHT GAIN, patient compliance
Contraindications: T1DM, liver failure, DKA, sulfa allergy
Metabolism: hepatic by cytochrome P 450 enzyme system
Lowers A1c by 0.4%
Disadvantage is patient compliance because you have to take so many fucking pills!
What is the MOA of thiazolidinediones?
Binds to nuclear PPAR(gamma) receptor causing increased transcription of GLUT 4 transporter
Action: DECREASES peripheral INSULIN RESISTANCE in skeletal muscle, adipose tissue, liver
Because more GLUT4 transporters are recruited
Works on
i. skeletal muscle
ii. adipose tissue
iii. liver
What are the characteristics of thiazolidinediones?
Effects = lowers pre-meal and post-meal glucose
Pill by mouth once or twice daily
Side effects: WEIGHT GAIN, hepatocellular injury
Contraindications: active liver disease, heart failure, renal insufficiency
Reduces plasma triglycerides but increases LDL
SLOW motherfucking onset
DOES NOT INDUCE LOW BLOOD GLUCOSE
Lowers A1c up to 1.8%
What is the MOA of alpha-glucosidase inhibitors?
Competitively inhibit the ability of enzymes in the small intestinal brush border to breakdown oligosaccharides and disaccharides into monosaccharides
Action: Delays GUT carb absorption, increases GLP-1
DECREASES GLUCOSE ABSORPTION IN GUT
What are the key characteristics of alpha-glucosidase?
Post-prandial glucose only
Pill taken with meals
Side effects: Flatulence, abdominal bloating
Contraindications: GI disorders, esp in inflammatory bowel disease
Does not induce low glucose (because it just doesn’t allow glucose to get in in the first place)
Lowers A1c by 0.4%
What T2D drug makes you fart?
Alpha-glucosidase
Ben Franklin
What are exenatide and liraglutide? MOA?
GLP-1 agonists
Same actions as GLP-1
Synthetic verison of exendin 4, a protein found in the saliva of the GILA MONSTER
What are the key characteristics of exenatide and liraglutide (GLP-1 agonists)?
Increased insulin
Lower glucagon
Slow gut motility
Induces satiety
What is DPP-4?
Dipeptidyl peptidase-4
- uibiquitous serine protease - cleaves N-terminal dipeptide - inactivates GLP in 1 minute and GIP in 7 min
What is the MOA of DPP-IV inhibitors
Action: increases duration of action of GLP-1 (prevents its breakdown)
Prevents dipeptidyl peptidase-4 with 80% inhibition at 24 hours
What are the characteristics of DPP-IV inhibitors?
IMMEDIATE effect mostly on post-meal glucose
Not metabolized, excreted unchanged through kidneys
PO once daily
NO contraindications
Adverse effects = GI
Does not induce hypoglycemia
A1c lower bye 0.7%
What is the MOA of Canagliflozin (SGLT2 inhibitor)?
Inhibits SGLT2
SGLT2 mediates glucose reabsorption in the kidney in the proximal tubule (lumen)
Allows you to secrete all your glucose without reabsorbing it
What are the key characteristics of Canagliflozin?
- Cotnraindications: ESRD, renal impairment
- Side effects: vulvovaginal candidiasis, vulvovaginal mycotic infection, UTI, polyuria
- lowers A1c by 0.7%
- Weight loss of 2.2%
What are the drugs that increase weight gain?
- Sulfonylurea
- Meglitinides
- thiazolidinediones
What are the drugs that cause weight loss or is neutral?
- Metformin
- Exenatide (GLP-1 agonist)
- Incretin enhancers (DPP-IV antagonist)
- alpha-glucosidase
What are the initial therapies for T2D?
- Lifestyle changes
2. Metformin
What drugs have GI side effects?
- Metformin
- A-glucosidase
- incretin enhancers
- Exenatide (GLP-1 agonist)
