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Drug Action II > Block 3: T2DM > Flashcards

Block 3: T2DM Flashcards

1
Q

What are the PO medications fot T2DM?

A
  1. Biguanides (metformin)
  2. Incretin-mimetics (GLP-1 agonist, Rybelsus)
  3. Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitors
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2
Q

What are the non-insulin injectables for diabetes?

A
  1. Incretin-mimetics (GLP-1 / GIP drugs)
  2. Amylin Analogs
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3
Q

What are the insulin injectables?

A
  1. Basal Insulins (Glargine)
  2. Regular and NPH Insulins
  3. Bolus Insulins (Lispro)
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4
Q

What are the major sites of action of antihyperglycemic agents?

A
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5
Q

What are the non-pharms for diabetes?

A

Lifestyle modifications: diet and exercise

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6
Q

What are the benefits of exercise?

A
  1. Improves blood glucose control
  2. Helps manage weight
  3. Reduces CV risk factors
  4. Improves overall health and well-being
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7
Q

What are the treatment goals of diabetes?

A
  1. Non-pharm tx
  2. Stepwise and combinational pharmacological intervention
  3. Diabetes education is essential
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8
Q

What are the pharmacological effects of metformin?

A
  1. Lowers glucose levels by decreasing hepatic glucose production (gluconeogenesis)
  2. Does not diretly effect beta-cells
  3. Improves insulin resistance (liver&raquo_space;> muscle) without increasing insulin levels however does requires the presence of insulin to have effect
  4. Some patients can experience weight loss
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9
Q

How much does metformin decrease A1c?

A

1.5-2%

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10
Q

Metformin’s place in therapy?

A
  1. Monotherapy or Combination Therapy
  2. First-line therapy for management of type-2 diabetic patients and patients with “pre-diabetes
    * Preferred in obese patients
    * Approved in pediatric pathients at 10
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11
Q

Metformin

Brand, Class, Metabolism, ADR, CI, DDI

A

Glucophage
Class: Biguanides
Metabolism: Renal elimination
ADR: GI upset, diarrhea, lactic acidosis (sx worsens at higher doses)
CI: Lactic acidosis causes complications for those with renal insufficienct, CHF, liver disease, and hypoxia
* Avoid with renal and hepatic problems
DDI: Contrast dyes
* Withhold metformin 48 hrs after procedure

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12
Q

What are the thiazolidinediones?

A

Pioglitazone (Actos) and Rosiglitazone (Avandia)

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13
Q

Pharmacology of TZDs?

A
  1. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist
  2. Insulin sensitizer
  3. Lowers glucose levels by increases insulin sensitivity in muscle, fat, and lesser extent in liver
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14
Q

Describe the MOA of glitazones?

A
  1. Glitazone binds to PPARy in the cytosol
  2. Forms a heterodimer with RXR and binds to DNA sequences, Peroxisome Proliferator Hormone Response Elements (PPREs)
  3. Regulates numerous genes including those associated with improving glucose uptake and disposal in muscle and fat tissues
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15
Q

Describe the effectiveness of TZDs?

A
  1. Improves insulin resistance in muscle and fat&raquo_space;> liver
  2. Improves HgbA1c by ~1-1.5%
  3. 4 week onset
  4. Lower risk of hypoglycemia
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16
Q

Thiazolidinediones (TZDs)

Brand, Class, Indications, Metabolism, ADR, CI, DDI

A

Pioglitazone (Actos) or Rosiglitazone (Avandia)
Indications: T2DM
PK: extensive absorption, highly protein bound, hepatically metabolized, feces and urine
ADR: Hepatotoxicity, fluid retention, edema, CHF (Rosiglitazone or in combo with insulin)
CI: Severe CHF (Class III and IV)
DDI: Pioglitazone induces CYP3A4

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17
Q

Types of 2nd gen sulfonylureas?

A

Glimepiride (Amaryl)
Glipizide (Glucotrol XL)
Glyburide (DiaBeta, Micronase)
Glyburide micronized (Glynase)

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18
Q

Pharmacology/MOA of sulfonylureas?

A
  1. Lowers glucose levels by increasing basal and postprandial insulin secretion from beta cells
  2. Binds to the “sulfonylurea site” on the potassium channel of β-cells, closing the channel and depolarizing β-cell
  3. Requires functioning β-cells

Increase Insulin Secretion -> Secretagogues

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19
Q

What are the first gen sulfonylureas?

A
  1. Tolbutamide
  2. Acetohexamide
  3. Chlorpropamide
  4. Tolazamide

All have been D/C’d

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20
Q

Effectiveness of Sulfonylureas?

A

Decrease in HgA1c: 1.5-2%

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21
Q

Sulfonylureas

Indications, Place in therapy, PK, ADR, CI, DDI

A

Indications: T2DM
P-in-T: Requires functioning β-cells, avoid in patients with hypoglycemic problems
PK: Increased half-life -> increased accumulation -> increased risk of hypoglycemia
* Glyburide (10 hour half-life)
* Glimepiride (9 hour half-life)
* Glipizide (2-5 hour half-life)

ADR: Hypoglycemia, weight gain
CI: G6PD deficiency (sulfa drugs), T1DM, elderly
DDI: Second-generation typically have fewer drug interactions due to mixed metabolism

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22
Q
A
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23
Q

What are the Short acting Insulin Secretagogues (Meglitinides)?

A

Nateglinide (Starlix) and Repaglinide (Prandin)

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24
Q

MOA and Pharmacology of Meglitinides?

A
  1. Lowers glucose levels by increases insulin secretion from beta cells in the pancreas in the presence of glucose
  2. Binds to potassium channels on β-cells at different site than sulfonylurea
  3. Requires functioning b-cells

Increase Insulin Secretion -> Rapid Acting “Secretagogues”

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25
Q

Meglinitides

Indications, Place in therapy, PK, CI, ADR, DDI

A

Indications: T2DM
P-in-T: Primarily used to decrease post-prandial glucose levels Never combined with sulfonylureas)
PK: Short half-life, high PB, hepatic metabolism, rapidly eliminated
CI: T1DM, hypersensitivity, liver dysfunction
ADR: Hypoglycemia, weight gain
DDI: Repaglinide/gemfibrozil

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26
Q

Describe the location of SGLT transporters?

A

SGLT1 is in the straight section of the proximal tubule (S3)
* 10% glucose absorption

SGLT2 is in the convoluted section on the proximal tubule (S1).
* 90% glucose absoprtion

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27
Q

What is the difference between SGLT1 and 2?

A
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28
Q

What are the types of SGLT2-I?

A
  1. Bexaglifloxin (Brenzavvy)
  2. Canagliflozin (Invokana)
  3. Dapagliflozin (Farxiga)
  4. Empagliflozin (Jardiance)
  5. Ertugliflozin (Steglatro)
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29
Q

How does sotagloflozin differ from other SGLT2 inhibitors?

A

Dual inhibitor of SGLT1 (intestinal) and SGLT2 (renal).

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30
Q

What is the MOA of SGLT2 inhibitors?

A

Inhibits renal tubular Na-glucose co-transporter that reverses hyperglycemia -> reversal of gluco-tox
1. ↑ insulin sensitivity in muscle: ↑ GLUT4 translocation, ↑ insulin signaling
2. ↑ insulin sensitivity in liver: ↓ G6P
3. ↓ Gluconeogenesis
4. Improves beta cell function

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31
Q

Advantages of SGLT2 Is?

A
  1. Lowers A1C around 0.6-0.8%
  2. Lowers fasting glucose
  3. Improved postprandial glucose levels
  4. Weight loss (up to 3.5%)
  5. Lower risk of hypoglycemia (<3.5%)
  6. Improves cardiovascular and renal outcomes
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32
Q

how does SGLT-2 Inhibitors effect renal function?

A

SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfilt

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33
Q

SGLT-2 Inhibitors?

Indications, PK, CI, DI

A

Indications: Adjunct to diet and exercise in T2DM, used in HF and kidney disease
PK: high PB, extensive hepatic metabolism via glucuronidation to inactive metabolites
CI: Ketoacidosis, severe renal dysfunction
DI: Diuretics, Insulin secretagogues (hypoglycemia), UGT Inducer (Canagliflozin)

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34
Q

SGLT-2 Inhibitor ADRs?

A
  1. Fungal genital infections: Vulvovaginal candidiasis in women
  2. Bacterial UTI with canagliflozin
  3. Polyuria (>5%), hypoglycemia, DKA
  4. Hyperkalemia
  5. Dose-related increases in LDL-C
  6. Symptomatic and orthostatic hypotension (hypovolemia)
  7. Malignancies
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35
Q

What are the monitoring parameters of SGLT2-Inhibitors?

A

Efficacy: blood glucose levels, A1c
Toxicity: Renal function, Potassium, Magnesium, Phosphate levels, LDL, Genital infections, BP

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36
Q

What are the types of alpha-glucosidase inhibitors?

A

Acarbose (Precose) and Miglitol (Glyset)

37
Q

MOA and pharmacology of Alpha-glucosidase Inhibitors?

A
  1. Lowers glucose levels by Reversibly inhibiting glucosidases and Reversibly inhibiting glucosidases
  2. Primarily used to control postprandial glucose
  3. Delays absorption of glucose in the intestine, lowering the plasma peak.
38
Q

Alpha-glucosidase Inhibitors

Indications, Place in therapy, PK, ADR, CI, DDI, Dosing

A

Indications: T2DM
Place in therapy: Decreases postprandial blood glucose levels, Combo therapy
PK
* Metabolism: Acarbose is metabolized by GI amylases to inactive metabolites, Miglitol is not metabolized
* Excretion: acarbose is systemically absorbed, Miglitol is excreted unchanged in the urine

ADR: Flatulence, diarrhea, ab pain
CI: Treat hypoglycemia with glucose nor sucrose, Renal impariment, Cirrhosis, GI conditions
DDI: Effects absorption of some drugs in the GI tract
DOsing: start low, go slow

39
Q

What is incretin?

A

Glucagon-like peptide-1 (GLP-1) gut hormone that helps with weight loss
1. Delays gastric emptying
2. Decreases glucogon excretion
3. Improves glycemic controly reducing fasting and postprandial glucose concentrations
4. Enhances glucose dependent insulin secretion

40
Q

Describe the MOA and effectiveness of GLP-1 protein?

A
  1. Rapidly released from ileal cells within 15 minutes of eating a meal: GLP1 receptor (Gs)
  2. Induces insulin release only if blood glucose is >70-90 mg/dL
  3. Lowers FBS 10-20 mg/dl, A1c ≈ 1%
  4. Rapid metabolism in blood by dipeptidyl peptidase-IV (DPP-IV)
41
Q

What are the types of incretin mimetics?

A

Exenatide (Byetta, Bydureon)
Liraglutide (Victoza, Saxenda)
Dulaglutide (Trulicity)
Lixisenatide (Adlyxin)
* Soliqua: Insulin Glargine and Lixisenatide

Semaglutide (Ozempic: inj and Rybelsus: PO)

42
Q

Exenatide (Byetta)

Dosage form, Administration

A

MOA: Synthetic form of exendin-4
Admin: SC BID
* 60-minutes before two main meals of the day
* Should not be administered after a meal

43
Q

Exenatide (Bydureon BCise)

Dosage form, Dosing, ADR

A

Form: Extended-release formulation of Byetta
Dosing: 2 mg weekly with or without food
ADR: thyroid tumors, pancreatitis

44
Q

Effectiveness of Exenatide

A

Lowers hemoglobin A1c by 1.6% compared to 0.9% reduction for Byetta

45
Q

Storage of Exenatide?

A
  1. Regrigerate
  2. A pen can be kept at a room temperature for 30 days
  3. Do not freeze
  4. Protect from light
  5. Do not store with the needle attached
46
Q

How does Liraglutide an improvement from Exenatide?

A
  1. Lysine at 34 is replaced with arginine
  2. Albumin binding
  3. Self-association from SQ
  4. Long plasma half-life
47
Q

Liraglutide (Victoza)

Dosing, Admin, Efficacy

A

Dosing: QW with or without food
Admin: SC
Efficacy: Lowers A1C by 1.0 to 1.5%, on average

48
Q

How does Saxenda differ from Victoza?

A

Higher dose approved for weight loss

49
Q

What is Xultophy?

Dosing, Admin, Efficacy

A

insulin degludec (long-acting) and liraglutide
Dosing: Anytime, but at the same time each day
Admin: SC
Efficacy: Lowers A1C by 1.7%, on average

50
Q

Describe the structure of Albiglutide?

A

Two copies of a modified human GLP-1, the alanine at position 2 is exchanged for glycine for DPP-4 resistance, remaining sequence is albumin

51
Q

Albuigutide

Brand, Dosing, Admin, Efficacy

A

Tanzeum
Dosing: Weekly SC
Admin: Allow pen to sit for 15 mins to 30 mins after reconstitution before injecting for complete mixing. Inject within 8 hours of reconstitution
Efficacy: Lowers A1C by 1.0%

52
Q

Dulaglutide structure?

A

GLP-1 analog (7-37) covalently linked to an IgG4 Fc domain

53
Q

Dulaglutide

Brand, Dosing, Admin, Efficacy

A

Trulicity
Dosing: QW
Admin: SC
Efficacy: Lowers A1C by 1.3-1.5%

54
Q

Lixisenatide

Brand, Structure, Efficacy

A

Adlyxin
Structure: exendin-4 sequence
Efficacy: Lowers A1C by 0.5-0.7%

55
Q

What is Soliqua?

A

Lixisenatide and insulin glargine

56
Q

Semaglutide (Ozempic)

Structure, Admin, Efficacy

A

Structure: The lysine at position 26 is acylated with stearic diacid, increasing plasma protein binding to albumin
Dosing: QW
Admin: SC
Efficacy: Lowers A1C by up to 1.5%

57
Q

Semaglutide (Rybelsus)

Dosing

A

Take RYBELSUS by mouth on an empty stomach when you first wake up with a sip of plain water

After 30 minutes, you can eat, drink, or take other medications

58
Q

What is Wegovy?

A

QW semaglutide approved for weight loss

59
Q

Tirzepatide

Brand, MOA

A

Mounjaro
MOA: GIP (glucose- dependent insulinotropic polypeptide) and GLP-1 receptor

60
Q

How does Tirzepatide differ from Ozempic?

A

Better reduction in HbA1C levels

61
Q

Incretin mimetics

Indications, I, PK, DDI, ADR, BBW

A

Indications: T2DM
CI: Hx of thyroid c-cell tumor, MENS2
PK: Excreted in the feces and urine
DDI: Medications that may be affected by a delay in gastric emptying
ADR: Nausea, GI upset, risk of pancreatitis, gastroparesis, and bowel obstruction
BBW: Thyroid C-cell tumors

62
Q

What are the types of DPP4 inhibitors?

A

Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)

63
Q

MOA of DPP-4 inhibitors?

A
  1. Inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down incretins (GLP-1) and Glucose-dependent insulinotropic peptide (GIP)
  2. Increases incretin concentrations, prolonging anti-glycemic effects
64
Q

DPP4 Inhibitors

Indications, PK, CI, Effectiveness, Place in therapy, ADR

A

Indications: T2DM
PK: Minimally metabolized by CYP450, Excreted in the feces and urine
CI: T1DM
* Monitor renal function

Effectiveness: Decreases HbA1c 0.5-0.8%
P-in-T: Monotherapy, Combination Therapy
ADR: Respiratory infections, HA, Ab pain, N/D

65
Q

What are the benefits of DPP-4 inhibitors and Metformin combos?

A
  1. Sitagliptin improves beta-cell function and increases insulin synthesis and release.
  2. Sitagliptin reduces HGO through suppression of glucagon from alpha cells.
  3. Metformin has insulin- sensitizing properties.
  4. Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.
66
Q

CV Effects of DPP4 inhibitors

A
67
Q

What is amylin?

A
  1. Co-located and secreted with insulin from b-cels
  2. Amylin deficiency accompanies insulin deficiency
68
Q

Types of Synthetic Modified Amylin analog?

A

Pramlintide (Symlin)

69
Q

MOA of Pramlinitide?

A
  1. Slows gastric emptying
  2. Inhibits glucagon secretion from pancreatic alpha cells
  3. Reduces postprandial glucose. Reduces glucose fluctuations
  4. NO effect of pancreatic beta cells or insulin secretion
  5. Modest weight loss 1-2 kg
70
Q

What are the action sites of Symlin?

A

Liver: Reduces hepatic glucose output by inhibiting glycogenolysis and glucose release
CNS: Promotes satiety and reduction of appetite
Alpha cell: Inhibits glucagon secretion
Beta cell: None
Stomach: Slow gastric emptying

71
Q

Pramlinitide

Indications, Dosing, ADR, BBW

A

Indications: T1DM, T2DM can only be used in combo with insulin to lower glucose in the 3 hr after meals
Dosing: before major meals
* Begin with the low starting dose and gradually titrate
* Differing doses based on type-1 or type-2 diabetes and nausea level
* When first starting reduce the amount of mealtime insulin by 50% to reduce the chance of hypoglycemia

ADR: Hypoglycemia
BBW: Must be able to monitor BG or is not considered suitable for drug due to hypoglycemia
* Do not mix in syringe with any type of insulin

72
Q

Bile acid sequestrants for diabetes?

A

Colesevelam

73
Q

MOA of Colsevelam?

A

Absorbs glucose for excretion in feces

74
Q

Colesevelam

Indication, Effectiveness, Place-in-therapy, ADR, DDI, CI,

A

Indication: T2DM
Effectiveness:
* Decreases HgA1c by ≤0.5% (0.32%)
* Decreases LDL
* Increases Triglycerides

Place in therapy: Combo not mono
ADR: N/C, ab pain, dyspepsia, hyperTG, pancreatitis
DDI: Separate by 4 hrs from drugs with narrow therapeutic index i.e., warfarin, phenytoin
* Decreases levels of levothyroxine, oral contraceptives

CI: TG >500, caution with >300

75
Q

MOA of Bromocriptine?

A

Dopamine D2 receptor agonist that effects the circadian neuronal activity in the hypothalamus in insulin-resistant patients

76
Q

Bromocriptine

Brand, Indications, Place in therapy, ADR, CI, DDI

A

Cycloset
Indications: Reduce HbA1c and plasma triglyceride and FFA concentrations in type-2 diabetic patients
Place in therapy: Adjunctive therapy
* Decreases HgA1c by ~0.3%
* As monotherapy, has a very low risk of hypoglycemia

PK: CYP450 metabolism, high PB
ADR: Somnolence, Erythromelalgia and Raynaud’s phenomena
CI: T1DM, Lactation, renal/hepatic, hypersensitivity
DDI: Use of ergots (migraine medication) within 6 hours of bromocriptine is NOT recommended

77
Q

What is the approaches for diabetis tx?

A

Treatment should always be directed at the individual patient and their underlying pathophysiology

78
Q

Considerations in Pharmacologic Treatment of Type 2 Diabetes

A
  1. Mechanisms of action of drugs
  2. Impact on weight gain
  3. Cost
79
Q

Medications for postprandial hyperglycemia?

A
  1. a-glucosidase inhibitor
  2. short acting sulfonylurea,
  3. meglitinides
  4. short acting regular insulin or insulin analog
80
Q

Medications for fasting hyperglycemia?

A
  1. biguanide
  2. long acting sulfonylurea
  3. glitazone
  4. long acting insulin or insulin analog
81
Q

Medications for insulin resistance?

A
  1. biguanide
  2. glitazone
82
Q

Medications for insulin deficiency?

A
  1. Insulin
  2. sulfonylurea
  3. meglitinide
83
Q

Why is it important to address insulin resistance?

A

Leads to atherosclerosis

84
Q

Benefits of metformin + insulin combos

A

Improves insulin sensitivity at the liver and reduces hepatic glucose production

85
Q

Benefits of glitazones + insulin combos

A

Improve insulin action in peripheral tissues and enhance glucose uptake

86
Q

Benefits of a-glucosidase inhibitors + insulin combos

A

Decrease postprandial glucose absorption

87
Q

Benefits of Sulfonylureas and Meglitinides
inhibitors + insulin combos

A

Increase levels of endogenous insulin and enhance meal-mediated insulin release

88
Q

Benefits of GLP-1 agonists and DPP-4 inhibitors + insulin combos

A

Improve endogenous insulin release, reduce effects of glucagon, increase satiety

89
Q

Benefits of SGLT-2 inhibitors + insulin combos

A

Block the reabsorption of filtered glucose in kidneys, resulting in increased urinary glucose excretion and an Insulin independent correction of hyperglycemia

Drug Action II (28 decks)

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