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Flashcards in Last Quiz DM drugs Deck (44):
1

Biguanides 

Phenformin, Metformin, Buformin

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Biguanide MOA

  • Compared to sulfonylureas, nateglinide, rapaglinide. These do not require functioning B-cells 
  • Main effect is lowering basal hepatic glucose output
    • Inhibits glycogenesis
    • Inhibits gluconeogenesis
    • Decreases fatty acid oxidation leading to enhanced conversion of glucose into fatty acids 
  • Enhances glucose uptake in skeletal muscle by increasing translocation of GLUT 4 

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Biguanide- Indications and Precautions

 

  • Monotherapy management of T2D in conjuction with nutrion and exercise. 
  • May be used in combo with many other drugs 
  • Lactic Acidosis, due to decreased flux of metabolic acids such as lactate/pyruvate into gluconeogenesis very rare though 
  • Unmetabolized and cleared in the kidney 
    • Not indicated for patients with renal dysfunction greater risk for lactic acidosis 
  • Not recommended for any pts. with any type of hypoxic stress becasue of the increased risk in lactic acidosis 
    • Avoid in pts. with CHF, acute all- MI

4

Polycystic Ovarian Syndrome and metformin

  • Causes insulin resistance, hyperinsulinemia, hyperandrogenism 
    • Insulin inhibits production of sex hormone binding globulin 
    • Increases circulating levels of free androgens and estrogens 

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Overview of medications for T2D

  • Sulfonylureas 
  • Glinides
    • Both above secretagogues 
  • Biguanides
  • Thiazolidinediones (Glutazone)
    • Rosiglitazone
    • Pioglitazone
    • Troglitazone 
  • Alpha-Glucosidase Inhibitors 

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Thiazolidinedione - Glitazones 

Also known as? 

Monotherapy glitazones are effective _____ since they? 

  • Insulin sensitizers 
  • Euglycemics meaning they restore blood sugar levels to non diabetic levels without causing hypoglycemia 

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Thiazolidinedione - Glitazones Bind to? 

Stimulate the expression of?

peroxisome-proliferator-activated receptor (PPARy) 

Expression of GLUT1 and GLUT4 

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Thiazolidinedione - Glitazones 

Indications and precautions 

  • for use as monotherapeutics or in combination with metformin or sulfonylureas (only pioglitazone)
  •  low risk of inducing hypoglycemia since do not effect insulin secretion
  • due to the hepatic toxicity of troglitazone, hepatic function should be closely monitored when initiating therapy with thiazolidinediones
  • baseline hepatic transaminase levels should be determined and AST and ALT levels determined at least quarterly
  • weight gain and mild to moderate edema often occur, especially when combined with sulfonylureas or insulin

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Thiazolidinediones glitazones 

Not recommended for patients? 

  • in _____ women with anovulation secondary to insulin resistance may cause?
  •  Increase risk of?

  • Cardiac complications where increase cardiac expansion would increase preload 
  • pre menopausal, increase resumption of ovulation 
  • pregnancy 

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Glitazones 

Increase risk of _____ in both men and women?

Bone fracture 

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How can glitazones like affect bone metabolism?

3 ways 

  1. Decrease in osteoblast function
  2. Increasing adiposity of bone marrow 
  3. Reduced aromatase activity, which makes estrogen from androgens 

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Carbohydrate analog alpha glucosidase inhibitors 

  1. Acarbose 
  2. Miglitol 
  3. Voglibose
  4. Emiglitate

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What do alpha glucosidase inhibitors do? 

What is the overall effect?

 

  • Delay the breakdown of complex carbs and decrease the concentration of glucose and fructose which are readily transported out of the intestine and into the blood 
  • effect is to blunt sharp postprandial increase in blood glucose 

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MOA of Alpha glucosidase Inhibitors 

  • reversibly inhibit α-glucosidases such as sucrase, maltase, isomaltase, and glucoamylase which breakdown disaccharides and oligosaccharides to monosaccharides which can be absorbed by intestine
  •  neither compound inhibits lactase at clinically significant levels, digestion of diary products is not problematic
  • benefit of α-glucosidase inhibitors is that they allow control of postprandial glucose levels (PPG)
  • even if fasting blood glucose is well controlled, poorly controlled PPG levels may still result in HbA1C levels >7%

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Pharmacokinetics of Alpha glucosidase Inhibitors 

  • acarbose-extensively metabolized, parent drug excreted renally
  •  miglitol- essentially unmetabolized, excreted renally and through feces

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Alpha glucosidase inhibitors Indications and precautions?

Type of therapy mono/Combo?

Elimination?

Which one accumulates?

  • as a monotherapy or in combination with sulfonylureas, metformin (acarbose) or insulin 
  •  since eliminated primarily through renal excretion, patients with renal dysfunction should not use
  • miglitol may accumulate systemically in patients with renal dysfunction

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More indications and precautions of Alpha glucosidase inhibitors

Use in what pt is not indicated?

Doesnt cause ____ but may contribute?

Pts should take ___ if they are experiencing this?

Not be used in pts with? What diseases?

  •  not metabolized in liver but in cells of intestinal brush border, however, use in patients with hepatic disease is not indicated. Some small studies have indicated that acarbose is safe with severe hepatic impairment
  • does not cause hypoglycemia but may contribute to hypoglycemic episodes in patients on combination therapy
  •  since blocks carbohydrate metabolism, patients experiencing hypoglycemia should take glucose tablets
  •  should not be used in patients with gastrointestinal disorders  
    • inflammatory bowel disease, Crohn’s disease
    • ulcerative colitis, diverticulitis, intestinal blockage

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Exanatide?

  • Incretin memetic that is synthetic analog of exedin-4, a salivary hormone isolated

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Advantages of Exanatide?

  •  versus sulfonylurea and insulin- a lack of hypoglycemia
  •  versus metformin and glitazones- no need for clinical or laboratory assessments of vital organ (kidney, liver, or heart) function before initiating therapy or in monitoring therapy
  •  versus all anti diabetic agents- first glucose-lowering drug to demonstrate substantial and sustained weight loss

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Disadvantages of Exanatide

  • mild to moderate nausea, tends to diminish with use
  • injected twice daily, however, volumes administered are small and injection site pain is uncommon
  •  only provided in pen form for administration but no need for dose adjustments in response to the size of meals or activity

21

Lixisenatide?

Glipulin?

New drugs on the market 

  • Once a day GLP-1 agonist 
  • Mix of insulin glargine, metformin, exenatide 

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WHat is Diaminopeptidase 4? (DPP-4) 

If you inhibit this what do you cause?

 

  • Main enzyme that degrades GLP-1 and G1P
  • Reduces catabolism, decreases plasma Cl anf increases elimination half life 
  • Inhibition causes in an increase of GLP-1 levels 
  • Seem to be weight neutral 

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WHat are the DPP4 inhibitors?

Which one is the safest for people who are renally impaired? WHy?

  • Sitagliptin 
  • Saxagliptin 
  • Linagliptin 
  • Alogliptin 
  • Linagliptin because it is metabolized hepatically 

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What are the 9 differences of DPP4 inhibitors compared to GLP-1 agonists? 

  1. Orally bioavailable vs. SubQ for incretin mimetics 
  2. Less of a maximum effect, pts cannot be titrated as with GLP-1 agonists
  3. No effect on gastric emptying 
  4. No direct CNS effects ( lack of satiety effect no wt. reduction)
  5. Non-selective with respect to other enzymes DPP4 has many substrates
  6. Nontoxic of OD (except liver toxicity and QT prolongation) 
  7. DPP4 inhibitors (in reduced doses) are safe for treating pts. with moderate and severe renal failure where  GLP-1 agonists are contraindicated 
  8. Weaker A1C reduction then incretin mimetics
  9. Some pts have bad joint pain

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PrAMlintide? 

Metabolism

Route

MEchanism?

Inhibits ____ glucagon secretion thus ___ hepatic?

Doesnt suppress glucagon secretion due to?

Co admin especially in ___ pts. 

Warning of?

  • Soluble form of amylin 
  • Little hepatic metabolism
  • SC injection before meals
  • Inhibits postprandial, thus inhibiting hepatic gluconeogenesis
  • Due to insulin induced hypoglycemia over ridden 
  • with insulin with T1D 
  • hypoglycemic risk 

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PrAMlintide SLows?

Associated with?

  • Gastric emptying
  • Wt. loss

 

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SGLT2 inhibitors 

  • Canagliflozin 
  • Dapagliflozin 
  • Empagliflozin 

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Advantages of SGLT2 inhibitors 

  1. Improve blood sugar control wihtout insulin
  2. Wt. loss (maintenance) 
  3. Improve insulin sensitivity
  4. Indirect preservation of B-cells by lowering blood glucose
  5. No hypoglycemia, because there is no insulinotropic effect or inhibition of hepatic glucose production
  6. Reduction of blood pressure
  7. Possible reduction of comorbidities such as obesity, dyslipidemia, HF

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Disadvantages of SGLT2 inhibitors?

7

  1. Risk of negative effect of glucosuria on the kidneys, polyuria, and increased thirst, potential dehydration 
  2. Risk of bacterial or fungal infection of the urinary or genital tract
  3. Salt-wasting 
  4. Compensatory increase of feeding due to calorie loss
  5. Renal elimination, not appropriate in pts with severe renal impairment 
  6. Recent FDA warning, reports of ketoacidosis 
  7. Canaglifozin may increase risk of bone fracture and decrease bone mineral density at the hip lumbar spine in type 2 

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Euglycemic DKA?

What can contribute to this? 

How does it happen?

 

  • SGLT2 inhibitors in T2D patients 
  • SGLT2 induced glucosuria that artificially lowers plasma glucose levels and predisposes to increase ketogenesis 
  • SGLT2 inhibition induces rapid increase in urinary glucose excretion 
    • Plasma insulin levels fall, plasma glucagon increases, increased FA oxidation 

31

4 risks in T1D pts for Eu-DKA?

  1. Hyperglycemia higher than in T2D pts
  2. Early T1D glomerular filtration rate may be increased 
  3. Insulin may enhance the effect of SGLT2 inhibition on glycosuria 
  4. Changes in insulin dose are not infrequent and may be inappropriate for the amount and kind of carb intake 

32

If someone has Eu-DKA what should be done?

  • SGLT2 inhibitor should be stopped temporarily, take supplemental boluses of rapid insulin along with liquids and carbs 

33

What are the insulin secretagogues?

Sulfonylureas, Meglitinide, Nateglinide

Induce insulin secretion from the pancreatic b-cell

Not for T1D

34

6 sulfonylureas available in US

Chlorpropamide, tolbutamide, tolazamide, glyburide, glipizide, glimepiride, 

35

Sulfonylurea mechanism of action

Actons on?

Subunits?

Pancreatic effect

  • Acts on pancreatic B-cells to increase basal postprandial insulin secretion
  • Insulin secretion regulated by ATP-dependent potassium channels in plasma membrane of pancreatic b-cells
  • K channel consists of two protein subunits
  • one of the subunits functions as a sulfonylurea receptor and the other is the actual ion channel 

36

Sulfonylureas MOA

Binding of?

Accumulation?

Elevation of?

induces migration?

  • Binding of the rug to the sulfon receptor to the ATP dep K channel closes the channel
  • Accumulation of intracellular K induces depolarization of the b-cell and stimulates the influx of extra cellular calcium dowb the gradient
  • Elevated Ca induces release of insulin from granules
  • Binding of sulfonylureas to protein localized secretory granules induces migration to the plasma membrane release into portal vein 

37

Sulfonylureas MOA

Effects on?

Mechanism not fully understood butlikely related to?

Insulin from pancreas secrete into portal vein into the liver and undergoes?

Portal _____ may supress? 

Decreases plasma ___ may enhance? 

 

  • Liver, skeletal muscle, peripheral tissues
  • – insulin from pancreas secreted into portal vein into liver and undergoes first pass effect – portal hyperinsulinemia may suppress hepatic gluconeogenesis which decreases fasting glucose levels – decreased plasma glucose may enhance insulin sensitivity in skeletal muscle and adipose tissue which are the two main insulin-responsive tissues
  • – insulin from pancreas secreted into portal vein into liver and undergoes first pass effect – portal hyperinsulinemia may suppress hepatic gluconeogenesis which decreases fasting glucose levels – decreased plasma glucose may enhance insulin sensitivity in skeletal muscle and adipose tissue which are the two main insulin-responsive tissues

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What sulfonylureas are excreted into the urine?

Urine and feces?

half life pattern?

 

  • Tolbutamide, Tolazamide, Chlorpropamide, 

 

 

  • Glipizide, glyburide, glimiperide 
  • glipizide>tolbutamide>tolazamide>glimiperide>glyburide>chlorpropamide

Longer half life increased hypoglycemia risk

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Sulfonylurea indication

  • Adjunct when 4-6 wks of nutritional therapy and excersise fail to naturally lower 
  • Ideal
    • Sig insulin def but residual B-cell
    • Onset of hyperglycemia at>30 and for <5 years 
    • Normal wt or moderately obese and FBG<300
    • willing to exercise
    • If FBG > 300 pt should start nutrition and exercise and insulin therapy 
    •  

40

Meglitinides MOA

Require some?

Insulin secretion is ____-dependent and ____ as blood glucose levels?

Interact with?

Unlike sulfonylureas, has no?

  • Some B-cell function
  • Glucose dependent and decrease as blood glucose levels decline
  • Interact with ATP sensitive K channel on the Bcell and induce depolarization leading to calcium influx and insulin release
  • Has no direct effect on insulin exocytosis 

41

Meglitinides Pharmacokinetics and Indications

More ___ and ___ compared to sulfonyls

Peak plasma reached within?

Rapidly ____ and is extensively ____ to ____ and is primarily eliminated in the?

Rapid onset and elimination make it useful for? With minimum risk for?

Metabolized by? 

Should be used cautously in? 

  • Rapid onset and shorter DOA compared to sulfs
  • reached within 1 hour
  • Rapidly eliminated and is metabolized to inactive metabolite primarily in feces
  • useful for controlling postprandial glucose due to rapid elimination and low risk of hypoglycemia
  • CYP3A4
  • Caution in pts with impaired liver function 

42

Nateglinide is the least likely secretagogue to cause?

Cardiovascular events 

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Insulin secretagogue complications?

Hypoglycemia

  • Start with low dose 
  • Short acting secretegogue if history of hypoglycemia
  • Sulfonylureas caution in renal dysfunction try meglitinides 
  • Dont skip meal after taking 

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