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MWU Pharmacology II > Lecture 13 / 14: Antidiabetic Agents > Flashcards

Lecture 13 / 14: Antidiabetic Agents Flashcards

1
Q

Name the following Insulin and Insulin analogs:
* Rapid-acting (1)
* Intermediate-acting (1)
* Long-acting (3)

A

Rapid-Acting: Regular Insulin
Intermediate Acting: NPH Insulin
Long-Acting: Insulin glargine, Insulin detemir, Insulin degludec

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2
Q

What are the two classes of Liver, Muscle and Adipose Agents, and the one drug in each class?

A
  1. Biguanides: Metformin
  2. Thiazolidinediones: Pioglitazone
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3
Q

2 Classes of Enhanced B-cell Insulin Release? Drugs in each class?

A
  • Sulfonylureas:
    1. Glyburide
    2. Glipizide
    3. Glimepiride
  • Meglitinides:
    1. Repaglinide
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4
Q

2 classes of drugs that Mimic or Prolong Gut Hormone Effects on B-cells?

3 drugs in each class?

A
  • Glucagon-Like Peptide-1 Receptor Agonists:
    1. Exenatide
    2. Liraglutide
    3. Dulaglutide
  • Dipeptidyl Peptidase-4 Inhibitors:
    1. Sitagliptin
    2. Saxagliptin
    3. Linagliptin
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5
Q

Drugs that enhance renal excretion of glucose (3)

A

Sodium-Glucose Co-Transporter 2 Inhibitors
agliflozin ending
1. Canaglifozin
2. Dapaglifozin
3. Empaglifozin

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6
Q

What disease can inhibit metformin drug therapy?

A

Chronic Kidney Disease

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7
Q

What drugs can preserve kidney function in T2DM patients?

A

ACE inhibitors or angiotensin II receptor blockers (ARB)

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8
Q

Describe structure of insulin, the drug

chains, T1/2, metabolism / elimination

A
  • 51 amino acid protein arranged in two chains (A and B; orange color); proinsulin is insulin with C peptide (green)
  • T1/2 = 3-5 min (little to no albumin binding)
  • 60% cleared in liver / 35-40% cleared in kidneys
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9
Q

What are the 2 therapeutic approaches for T2DM?

A
  1. Education
  2. Medications
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10
Q

What is the education provided to T2DM patients? Explain effects of bodyweight reduction on diabetes risk.

A
  • proper diet, adequate exercise, smoking cessation
  • If bodyweight reduced by 5-10% then risk of type II diabetes is reduced by 58%.
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11
Q

Diabetes medication for patients with NO underlying conditions?

A

Metformin

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12
Q

Medications for patients with NO underlying conditions: Additional med. if greater decrease in blood glucose is needed than on metformin alone?

A

Metformin + sulfonylurea

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13
Q

Medications for patients with NO underlying conditions: Greater glucose decrease than with metformin + sulfonylurea?

A

Metformin + sulfonylurea + insulin (or others)
Others:
* Dipeptidyl Peptidase-4 Inhibitor
* Glucagon-Like Peptide -1 Receptor Agonists
* Sodium-Glucose Co-Transporter 2 Inhibitors

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14
Q

What drugs to use for T2DM patients WITH atherosclerosis and cardiovascular disease

A
  1. Use glucagon-like peptide -1 receptor agonists; e.g. liraglutide, dulaglutide
  2. Increased weight loss with these drugs; helpful for these patients
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15
Q

Drugs for patients with T2DM patients WITH renal impairment or CKD. What else may be needed?

A
  1. Use sodium-glucose co transporter 2 (SGLT2) inhibitors; e.g. empagliflozin, canagliflozin, dapagliflozin
  2. Reduces progression of CKD
  3. SGLT2 inhibitors have less glycemic effect so additional medications may be needed
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16
Q

Insulin Therapy: Mechanism of Action

A

– binds to specific insulin receptors; overall effect is to
decrease blood levels of glucose and other nutrients (e.g. amino acids)

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17
Q

Insulin MOA in Liver?

A

Inhibit gluconeogenesis, inhibit conversion of amino acids to glucose/keto acids, promote glucose storage as glycogen

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18
Q

Insulin MOA in Muscle?
Banned substance?

A
  • Increase: protein synthesis, transport amino acids and glucose, muscle growth. ** Insulin is a banned
    substance according to World Anti-Doping Agency (not allowed in or out of competition)
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19
Q

Insulin MOA in Adipose tissue?

A

Increase storage of triglycerides, increase uptake of blood glucose

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20
Q

Side effects of insulin therapy?

blood sugar, weight, cancer, allergy, immune response

A
  • Hypoglycemia
  • Weight gain - not ideal (90% of T2DM patients are obese / overweight)
  • Possible increased cancer BUT confounding variables due to obese patients at higher risk of cancer anyway
  • Insulin allergy - rare; local or systemic urticarial, very rare: anaphylaxis
  • Immune Insulin resistance - IgG antibodies against insulin (dosage increase needed)
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21
Q

Symptoms of hypoglycemia due to insulin? When is it most prevalent?

A

hunger, headache, tremors, weakness, sweating,
seizures

can be especially prevalent at night while sleeping

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22
Q

Why does insulin given subcutaneously work more slowly than endogenous insulin secreted by the pancreas?

A
  • Tendency of reg. insulin to form non-covalent hexamers in solution
  • Breakdown of hexamers to monomers requires time
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23
Q

Which 3 insulin analogs more readily form monomers in solution? How does this affect speed of action?

A

Aspart, glulisine and lispro

velocity of action closer to meal-induced peak of pancreatic insulin

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24
Q

What is only insulin suitable for intravenous use?

A
  • Regular insulin (Humulin R and Novolin R)—a clear solution of human sequence insulin
25
Q

What is the intermediate acting preparation? Why is it longer acting?

A

NPH Insulin

Human sequence insulin aggregated w/ protamine and zinc

The time involved in breaking down these aggregates causes the delayed, longer time course of NPH versus regular insulin

26
Q

What is mechanism for longer acting insulin glargine?

Solubility at pH

A

Amino acids added that alter solubility, making it less so.

This insulin is soluble at pH 4 but poorly soluble at pH 7.

When injected subcutaneously, insulin glargine forms a fine precipitant in the interstitial fluids

27
Q

Mechanism for long acting insulin detemir

A

Long-acting due to self-association at subcutaneous
injection site and by binding to albumin in the blood stream

28
Q

Mechanism for long acting insulin degludec?

A

Long-acting due to self association at subcutaneous injection site and by binding to albumin in the blood stream

29
Q
A
30
Q

Why are multiple shots of a combo of intermediate or long acting, and short acting insulin administered?

What do short and longer acting insulins mimic?

A
  • to mimic the profile of insulin levels found in non-diabetics
  • Intermediate- and long-acting insulins are given to mimic 24-hour basal insulin secretion.
  • Short-acting insulins are given preprandial to mimic nutrient-stimulated insulin secretion
31
Q

Main 3 goals of insulin therapy? Do all patients achieve this?

fasting / post prandial / A1C

A
  • Fasting and preprandial blood glucose level of 70-130 mg/dL
  • Post-prandial blood glucose level two hours after meal of less than 180 mg/dL
  • Hemoglobin A1C (HbA1C) less than 7% (associated with a decreased risk of long-term complications)
  • Caveats: not all patients achieve these goals (hypoglycemia, cognition, age
32
Q

What is first line drug therapy for T2DM?

A

Metformin
4th most prescribed drug in US

33
Q

Metformin and hypoglycemia and weight gain?

A

Unlike insulin, it does not cause hypoglycemia and is termed an
“euglycemic” agent

also it does not cause weight gain; (insulin and sulfonylureas can cause weight gain)

34
Q

Metformin: Metabolism and pharmacokinetics

t1/2, dose, binding , metabolism, excretion, use w/ caution w/ who?

A
  • T1/2 1.5 to 3 hours
  • max dosing is 850mg 3X per day 2.55 grams/day!
  • Not bound to plasma proteins
  • Not metabolized
  • 100% excreted by kidneys as an active compound
  • Use with caution in patients with decreased GFR (e.g. eGFR 45 – 30 mL/min per 1.73m2)
35
Q

Metformin: MOA

A
  • Inhibits liver gluconeogenesis
36
Q

Metformin: Side Effects

GI, Metabolic, renal

A
  • Gastrointestinal: Diarrhea nausea, vomitting and flatulence
  • Infection (21%) - Lexicomp
  • Metabolic acidosis – can be severe (Black Box warning), results from impaired hepatic metabolism of lactic acid; other biguanides in US were discontinued due to this effect
  • For patients with renal impairment, metformin is not eliminated as expected resulting in increased risk of metabolic acidosis
37
Q

What are the 3 sulfonylureas? When are they used? What do they require? What are the considered to be?

A
  • Glyburide, Glimepiride, Glipizide
  • Used in early stage T2DM
  • require functioning beta cells;
  • considered insulin secretagogues (promotes secretion)
38
Q

Sulfonylureas: Metabolism and pharmacokinetics

metabolism, excretion, 2nd gen

A

metabolized in liver to inactive or partially active metabolites

excreted via kidney

second generation sulfonylureas also undergo bile excretion

39
Q

Sulfonylureas: MOA

channel / cause

A

Glyburide, Glimepiride, Glipizide

Mechanism of action: bind to 140 kDa receptor associated with ATP-sensitive inward rectifying K+ channel

cause β-cell depolarization and insulin secret

40
Q

Which sulfonylurea has shortest half life? When is it taken?

A

Glipizide – shortest half life (2 - 4hr); taken prior to individual meals

41
Q

Sulfonylureas: Side Effects

A
  • Hypoglycemia
  • Weight gain may occur due to an increase in appetite
  • A sulfur allergy may occur in susceptible patients
  • Increased cardiovascular mortality in 1st generation sulfonylureas has been associated with long-term sulfonylurea treatment although other studies do not show this association
42
Q

What class of drug is Repaglinide? How is it similar to sulfonylureas?

whats necessary / MOA?

A

Meglitinide

Similar to sulfonylureas in terms of:
* Require functioning pancreatic beta cells (T2DM patients) and is considered insulin secretagogue
* Mechanism of action: inhibit K+
ATP gated channels in pancreatic β-cells – depolarize cells

43
Q

Repaglinide: Side effects

A
  • Hypoglycemia
  • No sulfur, so can be used in patients with sulfur or sulfonylurea allergies
44
Q

What are the 3 Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists, and their MOA?

A

Exenatide, Liraglutide, Dulaglutide

MOA: GLP-1 receptor activation in pancreatic β-cells enhances or augments glucose stimulated insulin secretion (GSIS)

45
Q

What is a positive side effect of GLP1 receptor agonists?

A

In CNS, GLP-1 produces the feeling of satiety. Reduced body weight is a positive side effect… great for T2DM patients; 4.5 lbs lost over placebo group

46
Q

GLP-1 Receptor Agonists: Metabolism and Pharmacokinetics

route, metablisim enzyme, t1/2

A

Exenatide, Liraglutide, Dulaglutide

All drugs given by subcutaneous injection

metabolized in blood by dipeptidyl peptidase-4 (DPP-4)

half life widely varies 2.5 hours for exenatide to 5 days for dulaglutide

47
Q

What is GLP-1 Agonist a derivative of? T1/2? Dose? Metabolism?

A
  • Derivative of the exendin-4 peptide in Gila monster venom
  • Short half life 2.5 hours; dosed 60 minutes before meal
  • 53% homology with normal GLP-1

resists metabolism/degradation by DPP-4

48
Q

GLP-1 agonists: Side effects

do they improve?

A

nausea (up to 28%), vomiting (up to 10%); 4% of patients
dropped out of a clinical study due to nausea

nausea goes away with continued drug use

49
Q

What are the 3 Dipeptidyl Peptidase-4 (DPP-4) Inhibitors? Metabolism / pharmacokinetics?

route, t1/2,

A

Sitagliptin, Saxagliptin, Linagliptin

  • Given by oral administration (p.o.)
  • Metabolism and pharmacokinetics: half life 2 – 12 hours depending on drug
50
Q

which is only DPP4 inhibitor that is eliminated by biliary secretion?

A

Linagliptin

51
Q

Only DPP4 inhibitor that requires no dose adjustment for renal dysfunction or CKD?

A

Linagliptin

52
Q

DPP4 inhibitors: MOA

A

Sitagliptin, Saxagliptin, Linagliptin

Mechanism of action: Inhibit DPP-4 activity which inhibits degradation of GLP-1

extending actions of GLP-1 on pancreatic β-cells

53
Q

DPP4 Inhibitors: Side effects

A

increased risk of pancreatitis, can be severe

animal studies show DPP-4 inhibitors and GLP-1 agonists may increase risk of pancreatic cancer but no human data show increased risk.

54
Q

3 Sodium-glucose Co-transporter 2 (SGLT-2) Inhibitors:
1. How much glucose is reabsorbed
2. How much do they lower A1C
3. What reduces efficacy

A

Canaglifozin, Dapaglifozin, Empaglifozin

  1. 90% of filtered glucose in glomerular filtrate is reabsorbed by SGLT-2
  2. SGLT-2 inhibitors can lower A1C levels by up to 1%; on par with DDP-4 but not as good as GLP-1 agonists
  3. Due to effects on kidney, efficacy is reduced in patients with CDK
55
Q

SGLT-2 Inhibitors: Metabolism and Pharmacokinetics

route, metabolism

A

Canaglifozin, Dapaglifozin, Empaglifozin
* Given by oral administration
* Metabolism: mostly fecal elimination of active drug with some glucuronide conjugation and renal elimination of metabolites

56
Q

SGLT2 Inhibitors: MOA

A

Canaglifozin, Dapaglifozin, Empaglifozin

MOA: Inhibit SGLT-2 in renal proximal tubules to reduce glucose reabsorption from glomerular filtrate in nephron

Increased excretion of glucose

57
Q

SGLT2 Inhibitors: Side effects

A

: like GLP-1 agonists, reduced bodyweight – idea in T2DM patients
* For all: increased risk of genital or urinary tract infections (9%)
* **Canaglifozin: increased risk of bone fractures (30%), at least in one study **
* Ketoacidosis in insulin dependent type I or T2DM patients.

58
Q

Why can SGLT2 inhibitors cause ketoacidosis?

A

Because blood glucose remains normal while taking SGLT-2 inhibitors so insulin is withheld resulting in diabetic ketoacidosis. 2017 FDA warning issued

59
Q

2 alpha-glucosidase inhibitors: MOA and side effects (these are not bolded or even mentioned on drug list, but have some underlined areas in slides)

A

acarbose and miglitol

MOA: Delay digestion and absorption of ingested starches and disaccharides

Reduces postprandial glucose levels by 30-50%

NOT used often in US due to prominent side effects
related to GI; flatulence, diarrhea, and abdominal
pain/bloating due to fermentation of sugars in large
intestine

MWU Pharmacology II (8 decks)

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