Oral Hypoglycemic Agents Flashcards
Reduces hepatic insulin resistance
Reduces gluconeogenesis by as much as 75%
Decreases FASTING glucose levels
HbA1C reduction: 1-2%
Metformin
Immediate release Merformin
Half life:
Peaks:
2-6 hours
1 hour after intake
Extended release Merformin
Half life:
Peaks:
4-8 hours
7 hours
Merformin clearance and metabolism:
Renal
Metformin AE
GI intolerance: Nausea, diarrhea, crampy abdominal pain and dysgeusia
Vit B12 deficiency
NO Hypoglycemia
Promotes weight loss/Neutral
Improvement in microvascular and macrovascular complications
Reduces LDL and procoagant factors
Metformin
Potential SE for Metformin
Lactic acidosis
Metformin is CI in:
CKD GFR < 30 ml/min/1.73m2 Use with caution if: GFR <50 ml/min/1.73m2 Hepatic insufficiency Heavy alcohol abuse Hypoxia Acute illness Surgical indications Dehydration Use of contrast dyes Decompensated CHF
Metformin cab be used if the GFR is more
than > 30 ml/min
Reduction of Metformin dose should be done if GFR is
<45 ml/min
A biguanide first line oral agent for T2DM
Decreases hepatic glucose production
Decreases intestinal glucose absorption
Inhibits the mitochondrial enzyme glycerophosphate dehydrogenase -> decreased hepatic gluconeogenesis
Metformin
Activates
AMP-activated protein kinase (AMPK) enzyme -> decreased gluconeogenesis
Increased insulin sensitivity
Metformin
“glitazone”
Thiazolidinedione
Rosiglitazone, Pioglitazone
Increases glucose utilization
Decreases glucose production in adipose, muscle and liver
Increases body’s sensitivity to insulin
Thiazolidinedione (glitazone)
Ligands of peroxisome proliferator activated receptor gamma (PPAR-Y) an intranuclear receptor that regulates gene transcription
Slow improvement in glucose control
HbA1C reduction: 0.5-1.4%
Thiazolidinedione glitazone
PPAR-Y upregulates the hormone for increased insulin sensitivity and fatty acid oxidation
Adiponectin
Pioglitazone half life:
3-4 h
Activation of PPAR-Y by thiazolidinedione glitazone increases the differentiation and number of
adipocytes
Thiazolidinedione glitazone SE
decreases serum TAG
weight gain esp if combined with sulfonylurea or insulin
fluid retention
Thiazolidinedione glitazone also upregulates the receptor in peripheral tissues
GLUT4 increasing glucose uptake
Thiazolidinedione glitazone clearance
Renal 15-30
Fecal >60
Metabolized with hydroxylation and oxidation
Thiazolidinedione glitazone advantages:
Red progression of decreasing intimal medial thickness
Decreased rates of in-stent restenosis in PCI
Normalization of vascular endothelial function
Improvement in fibrinolytic and coagulation parameters, reduction in inflammatory markers
Treatment of fatty liver
Thiazolidinedione glitazone CI:
Not to be used for patients with ACTIVE hepatocellular disease
AST > 2.5x upper limit of normal
Caution against patients with CHF NYHA 3 and 4
Increased fracture rates due to dec osteoblast formation
Patients taking thiazolidinedione glitazone have inc risk for edema due increased Na reabsorption at the renal tubules especially if:
those treated with insulin with preexisting edema women obese patients known IHD, HF, diastolic dysfunction, renal insufficiency
Because thiazolidinedione glitazone are intranuclear receptor agents, the decrease in glucose will take effect after
several days
Islet amyloid polypeptide analogues
Decreases glucagon
Decreases gastric emptying
Decreases appetite
Amylin Pramlintide
Used in both type 1 and type 2 dm to control post prandial glucose spike
Amylin analogue Pramlintide
Pramlintide SE
Hypoglycemia
GI (nausea, vomiting, anorexia)
subcutaneous
Inhibits alpha glucosidase enzymes decreasing the conversion of disaccharides into absorbable monosaccharides in the brushborder of the intestine
Alpha glucosidase inhibitors Acarbose and Miglitol
These delay carbohydrate absorption blunting postprandial glucose spike by 30-50%
HbA1C reduction: 0.5 - 0.8%
Alpha glucosidase inhibitors
Acarbose
Miglitol
Acarbose half life:
2 hours
Alpha glucosidase inhibitors acarbose and miglitol SE:
GI: diarrhea, flatulence, abdominal pain due to fermentation of undigested carbohydrate by gut bacteria
Alpha glucosidase inhibitors
Acarbose and Miglitol, Voglibose are CI in
Patients with chronic intestinal conditions particularly inflammatory bowel disease
“flozin”
SGLT2 inhibitor
Inhibits reabsorption of glucose in renal tubules via SGLT2
Increases excretion of glucose in the urine
HbA1C reduction: 0.5-1.5%
SGLT2 inhibitor flozin
SLGT2 inhibitors act on this segment of the kidney
S1 segment of proximal tubule
90 reabsorption
SGLT2 flozin AE
UTI due to inc urine glucose concentration
Dapagliflozin half life:
12.9 h
Canagliflozin half life:
10-13 h
Empagliflozin half life:
5.6-13.1 h
SGLT2 flozin advantage:
Loss of calories (weight loss of 2-3kg)
80-85 g glucose/d
Decreases systolic blood pressure 2-3mmHg
SGLT2 flozin CI:
Renal insufficiency Induces osmotic diuresis UTI Candida infection Euglycemic ketoacidosis (inc glucagon) Signals for increased fracture (patients with osteoporosis)
Cleaved from proinsulin in secretory granule released with endogenous secretion of insulin
C peptide
C peptide is measured only when
Body produces endogenous insulin
Insulin can be used in hyperkalemia because
It promotes entry of K into cells via inc Na/KATPase in skeletal muscle
Insulin
Rapid acting
Short duration
Helpful for controlling rapid post prandial glucose spike
Glulisine
Aspart
Lispro
GAL
Insulin
Delayed onset
Intermediate duration of action
Administered IV becomes immediate for DKA and hyperkalemia
Regular insulin
Neutral Protamine Hagedorn (more delayed)
Insulin
Long acting
Provide a steady background level of insulin
For stable effect 2x daily
Detemir
Glargine (no peak) 24h
Most common complication of insulin therapy
Hypoglycemia
Taken orally to stimulate endogenous insulin release in beta cells
Sulfonylurea Glyburide Glipizide Glibenclamide Glimepiride
Bind the ATP dependent K channel on beta cells -> release of endogenous insulin
Sulfonylurea
Gliburide
Glipizide
1st gen of sulfonylurea “amide”
Long duration rarely used
Tolbutamide
Chlorpropamide
2nd gen sulfonylurea “ride”
Smaller dosing
Long duration of action
Glyburide
Glimepiride
Sulfonylurea with shortest duration of action and
Less risk of hyperglycemia
Glipizide
“glinide”
Meglitinde
Non sulfa drugs that Bind K channels shutting them off leading to depolarization of beta cell and release of endogenous insulin
Measures C peptide
Like sulfonylurea but rapid onset and shorter duration of action
Meglitinide glinide
Repaglinide
Nateglinide
Can be used in patients with allergies to sulfa
Meglitinide
Repaglinide
Nateglinide
Carry significant risk of hypoglycemia and weight gain
Sulfonylurea Gliburide Glipizide
Meglitinide Repaglinide
“Tide”
GLP 1 agonists
Activate glucagon-like peptide GLP-1 receptor (increased insulin release and satiety, dec glucagon release and gastric emptying)
GLP-1 agonist
Exenatide
Innibits dipeptidyl peptidase-4 DPP-4 inhibitors “gliptin” prevent breakdown of GLP-1
Increasing levels of GLP-1 (increased insulin release and satiety, decreased glucagon release and gastric emptying)
DPP-4 inhibitors gliptin
DPP-4 inbibitors gliptin can increase the risk of
nasopharyngitis
upper respiratory tract infections
GLP-1 agonists can cause
Pancreatitis
Necrotizing Pancreatitis
Thyroid cell C tumor
Exenatide
Exendin-4
Taspoglutide
Do not cause hypoglycemia
GLP-1 agonist tide
DPP-4 inhibitor gliptin
Sulfonylurea Gliburide Glipizide SE:
Hypoglycemia
Weight gain >/= 2 kg
Sulfonylurea gliburide glipizide CI:
Sulfa allergy
Cross reactivity with other drugs such as carbonic anhydrase inhibitors, loop diuretics, thiazide
Severe renal failure and liver failure
Clearance highly dependent on renal function
Blunting of ischemic preconditioning
Short acting
Dose with meal has better post prandial control
HbA1C reduction: 1-1.5%
Duration: 1/2 hour
Change fat distribution by decreasing visceral fat and increasing peripheral fat
Meglitinide
Meglitinide is completely metabolized by
biotransformation and conjugation by glucoronic acid
90% recovered in feces
8% in urine
Meglitinide SE
Risk of hypoglycemia (elderly)
Weight gain (~5 lb)
Should be used with caution in patients with Chronic Liver Disease
Synthetic form found in saliva of Gila monster
Reduces both fasting and PPG
T1/2: 2-4 hours
HbA1C reduction: 0.8 - 1.1%
Nausea, vomiting, diarrhea
Exenatide
GLP 1 Agonist
Acylated anogue of GLP1
97% homology to GLP1
T1/2: 9-14 hours
HbA1c reduction: 1.6%
Weight loss: 2.5 kg/30 weeks
Liraglutide
GLP1 agonist
Prandial GLP-1
Potent GLP-1 receptor agonist
HbA1c reduction: 1.7%
Weight loss
Lixesenatide
Increase insulin secretion
Decrease glucagon release
Delay gastric emptying
Supress appetite
DPP-IV inhibitors liptin
Orally active
Selective inhibitors of DPP-IV
DPP-IV inhibitors gliptin
Sitagliptin - 12.5 hours half life Linagliptin - 12.5 hours half life Vildagliptin Saxagliptin Septagliptin Allogliptin
DPP-IV inhibitors adverse effects
Nasopharyngitis because substance P is also a substrate for DPP-IV whose levels get elevated, GIT distress and diarrhea
Insulin enhancers
Sulfonylurea
Meglitinide
Drugs with incretin effect: DPP-4 inhibitors; GLP-1 analogues
Insulin sensitizers
Metformin
Thiazolidinedione
Sulfonylurea adverse effects
Hypoglycemia Weight gain Blood - agranulocytosis, thrombocytopenia, BM aplasia, RBC aplasia, hemolytic anemia Skin - SJS GI - nausea, vomiting, heart Liver abnormal function test
Thiazolidinedione SE
Edema Weight gain Dilution anemia Bladder Cancer Liver enzyme elevations rare GI discomfort
Thiazolidinedione CI
Heart disease NYHA III/IV Pregnancy Breastfeeding Children Fluid retention/signs and symptoms of heart failure
Phenylalanine meglitinide derivative
Nateglinide
2 incretin molecules inhibited by DPP4 Dipeptidyl Peptidase 4
Glucose Like Peptide 1 GLP-1
Gastric Inhibitory Peptide Glucose Dependent Insulonitropic Peptide GIP
SGLT 2 with improved CV risk
GLP-1
Empagliflozin (Jardiance)
Canagliflozin (Invokana)
Liraglutide (Victoza)
GLP is secreted by
Potent inhibition of gastric emptying
Potent inhibition of glucagon
Promotes Beta cell growth
Reduces appetite and body weight
L cells of distal GI tract (ileum and colon)
GIP is secreted by
K cells of proximal GI tract (duodenum and proximal jejunum)
Vacuolization and PAS positive glycogen accumulation within cytoplasm of tubular epithelial cells in DM
Armanni Ebstein lesion
Oral antihypoglycemic for patients with CKD because it is excreted through bile and gut
Linagliptin