Oral Hypoglycemic Agents Flashcards by Denisse Tiangco

Reduces hepatic insulin resistance
Reduces gluconeogenesis by as much as 75%
Decreases FASTING glucose levels

HbA1C reduction: 1-2%

Metformin

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Immediate release Merformin
Half life:
Peaks:

2-6 hours

1 hour after intake

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Extended release Merformin
Half life:
Peaks:

4-8 hours

7 hours

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Merformin clearance and metabolism:

Renal

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Metformin AE

GI intolerance: Nausea, diarrhea, crampy abdominal pain and dysgeusia
Vit B12 deficiency

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NO Hypoglycemia
Promotes weight loss/Neutral
Improvement in microvascular and macrovascular complications
Reduces LDL and procoagant factors

Metformin

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Potential SE for Metformin

Lactic acidosis

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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

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Metformin cab be used if the GFR is more

than > 30 ml/min

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Reduction of Metformin dose should be done if GFR is

<45 ml/min

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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

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Activates
AMP-activated protein kinase (AMPK) enzyme -> decreased gluconeogenesis
Increased insulin sensitivity

Metformin

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“glitazone”

Thiazolidinedione

Rosiglitazone, Pioglitazone

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Increases glucose utilization
Decreases glucose production in adipose, muscle and liver

Increases body’s sensitivity to insulin

Thiazolidinedione (glitazone)

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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

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PPAR-Y upregulates the hormone for increased insulin sensitivity and fatty acid oxidation

Adiponectin

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Pioglitazone half life:

3-4 h

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Activation of PPAR-Y by thiazolidinedione glitazone increases the differentiation and number of

adipocytes

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Thiazolidinedione glitazone SE

decreases serum TAG
weight gain esp if combined with sulfonylurea or insulin
fluid retention

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Thiazolidinedione glitazone also upregulates the receptor in peripheral tissues

GLUT4 increasing glucose uptake

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Thiazolidinedione glitazone clearance

Renal 15-30
Fecal >60

Metabolized with hydroxylation and oxidation

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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

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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

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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

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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