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ENDO II Exam II > Drugs- Insulin and oral hypoglycemic agents (Martin) > Flashcards

Drugs- Insulin and oral hypoglycemic agents (Martin) Flashcards

1
Q

GLUT 2

A

on B cells

mediates glucose uptake into pancreatic Beta cells

defects in GLUT 2 mediated transport may contribute to diminished insulin secretion in type II DM

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2
Q

GLUT 4

A

pools of GLUT 4 are maintained in vesicles in the cytoplasm of insulin-sensitive cells

when the insulin receptors are activated , the vesicles fuse with membrane and insert into the cell membrane

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3
Q

humalog

A 
insulin lispro (human)
rapid acting
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4
Q

novolog

A

insulin aspart

rapid acting

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5
Q

apidra

A

insulin glulisine

rapid acting

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6
Q

regular human insulin

A

humulin R, Novolin R

short acting

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7
Q

NPH (N)

A

isophane insulin suspension

intermediate acting

AKA–> Humulin N, Novolin N

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8
Q

Lantus

A

long acting insulin glargine

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9
Q

levemir

A

insulin detemir long acting

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10
Q

Novolin 70/30

A

NPH/Regular mix

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11
Q

Humalog 75/25

A

NPL/Humalog Mix

75% neutral protamine lispro/25% lispro)

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12
Q

Novolog Mix 70/30

A

NPA (aspart protamine) / aspart

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13
Q

Metformin

A

Biguanide

glucophage

it is an antihyperglycemic (oral) agent

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14
Q

what are the three main sulfonylureas

A

Glimepiride- amaryl

glipizide- glucotrol

glyburide - Diabeta, micronase

oral

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15
Q

what do sulfonylureas do

A

stimulate insulin secretion

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16
Q

repaglinide

A

a non-sulfonylurea secretagogue (Meglitinide)

stimulates insulin secretion

oral

AKA prandin

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17
Q

Nateglinide

A

a non-sulfonylurea secretagogue (Meglitinide)

stimulates insulin secretion

oral

AKA- Starlix

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18
Q

Pioglitazone

A

oral thiazolidinediones (TZD’s)

insulin sensitizer

aka Actos

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19
Q

Acarbose

A

aka Precose

α-GLUCOSIDASE INHIBITORS

Prevent complex carbohydrate hydrolysis and delay carbohydrate absorption (oral)

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20
Q

exenatide

A

aka Byetta–> SC bid

OR

Bydureon (extended release) SQ 1x week

this is a glucagon like peptide (GLP-1) agonist

Potentiate glucose-dependent insulin secretion, suppress glucagon secretion, slow gastric emptying, and promote satiety

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21
Q

Miglitol

A

aka Glyset

α-GLUCOSIDASE INHIBITORS

Prevent complex carbohydrate hydrolysis and delay carbohydrate absorption (oral)

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22
Q

what is exubera

A

inhaled insulin

rapid acting

taken off the market

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23
Q

what is the intensive insulin therapy (IIT)

A

1:1 basal;bolus ratio SQ

Basal–> Glarginine QD or Determir QD-BID

Bolus–> Rapid acting insulin or regular insulin before each meal. if skipped meal then skip dose

for the bolus:
1 unit RAI covers 500/total daily insulin dosage units (TDI) grams carbohydrate from meal
-use insulin to correct for high self monitored blood glucose (SMBG)
-use for exercise considerations

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24
Q

1 unit of RAI lower plasma glucose by how much

A

approximately 1800/TDI mg/dL

whereas regular lowers it by 1500/TDI

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25
Q

what is TDI

A

0.3-0.5 units/kg/day and titrate to glycemic targets

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26
Q

what is the split mix insulin therapy regimen

A

1) 2/3 of the total dose is given before breakfast

    • 2/3 of this is NPH
    • 1/3 is Regular (injection #1)

2) 1/3 of the total dose is taken later in the day

    • 1/3 of this is Regular taken just before dinner (injection #2)
  • -2/3 of this dose is NPH taken at bedtime (injection #3)
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27
Q

what is the dawn phenomena

A

Dawn phenomena: both normal and diabetic patients have an increased requirement for insulin in the early morning, making the kinetics and timing of the evening dose of insulin extremely important.

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28
Q

what is the Glargine or Determir Basal bolus regimen

A

A pre-breakfast dose of Glargine (or detemir) and rapid-acting or regular insulin is taken along with additional doses of rapid-acting or regular insulin at lunchtime and dinnertime. Glargine insulin provides a basal requirement for insulin, while the rapid acting insulin meets the postprandial demand. To achieve more uniform basal levels, the dose of basal insulin is sometimes divided into morning and evening doses.

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29
Q

what is the continuous subcutaneous insulin infusion ? (CSII)

A

a system composed of a battery-operated pump and a computer than can program the pump to deliver predetermined amounts of insulin from a reservoir to a subcutaneous inserted catheter or needle. These systems are portable and designed to deliver basal amounts of insulin throughout the day as well as meal-related bolus injections that the patient can initiate at 0-30 minutes prior to food intake. Regular, aspart, glulisine, and lispro insulin can be used in subcutaneous infusion pumps

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30
Q

what is the value in measuring HbA1c

A

to determine long term hyperglycemic control

“Normal values” vary from laboratory to laboratory but usually range from 4% to 6% in nondiabetic patients. Each 1% increase in HbA1c can reflect an increase of 25 to 35 mg/dL in mean blood glucose concentration. HbA1c < 6.5% is a recommended target.

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31
Q

where is the preferred site for insulin injection in the am

A

abdomen

absorption is fastest from this site

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32
Q

what can you mix with insulin glargine

A

Insulin glargine should not be mixed with any other form of insulin.

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33
Q

what are the effects of mixing regular insulin with NPH or NPL insulin

A

can slow absorption of the regular insulin

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34
Q

why does hypoglycemia occur with insulin therapy

A

due to 1) inappropriate dose, 2) mismatch of time of injection vs food intake, 3) exercise-induced increased glucose utilization, or 4) other factors that increase the sensitivity to insulin (adrenal insufficiency, pituitary insufficiency).

The more rigorous the attempt to achieve euglycemia, the greater the risk of hypoglycemia.

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35
Q

what are the normal responses of the body to hypoglycemia

A

Decreased insulin secretion

b. Counter-regulatory hormones released at glucose <=70 mg/dL (epinephrine, glucagon, GH, cortisol, norepinephrine).
c. Autonomic symptoms: sweating, hunger, paresthesias, palpitations, tremor, anxiety.
d. Neuroglycopenia symptoms: difficulty concentrating, confusion, weakness, drowsiness, a feeling of warmth, dizziness, blurred vision, and loss of consciousness.

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36
Q

what is the pre-dominant counter-regulatory hormone in hypoglycemia

A

glucagon

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37
Q

in Type I DM, what happens with glucagon secretion and how does the counter-regulatory mechanism in hypoglycemia run?

A

normally, glucagon is the predominant counter-regulatory hormone.

In Type 1 DM of long duration, glucagon secretion in response to hypoglycemia becomes deficient and epinephrine becomes the dominant glucose-mobilizing hormone.

However, if the patient also suffers from autonomic neuropathy, the epinephrine response is also deficient and night-time severe hypoglycemia can result in convulsions and coma.

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38
Q

what is the treatment for dangerously low blood sugar

A

Treatment of Hypoglycemia: consists of ingesting glucose. If severe, IV glucose or glucagon injections can be employed.

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39
Q

what are the most frequent insulin allergy rxns

A

The most frequent allergic reactions are IgE-mediated local cutaneous reactions, but occasionally patients may develop a life-threatening anaphylactic reaction or insulin resistance due to circulating IgG antibodies.

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40
Q

how do you treat diabetic ketoacidosis

A

Diabetic ketoacidosis (DKA) is a serious condition that often calls for constant intravenous infusion of insulin. (Only regular or ultra-short acting insulins can be given IV).

A relatively low dose of insulin (0.1 U/ kg /hr) is usually sufficient to inhibit lipolysis and gluconeogenesis completely and to produce near-maximal stimulation of glucose uptake.

Blood glucose levels fall by about 10%/hr; the acidosis is corrected more slowly.

Appropriate replacement of fluid and electrolytes is an integral part of the therapy. ***

Insulin must be administered by SQ injection prior to discontinuing IV infusions because of the short plasma t1/2 of insulin.

41
Q

what are two other conditions besides DKA that can be controlled with IV insulin infusion

A

perioperative control and childbirth

42
Q

what are the 3 most common drugs that induce hypoglycemic states

A

ethanol

b-blockers-

salicylates

43
Q

how do b-blockers pose a risk of hypoglycemia

A

β-antagonists pose a risk of hypoglycemia because of their capacity to inhibit the effects of catecholamines on gluconeogenesis and glycogenolysis. These agents also mask the sympathetically mediated symptoms associated with the fall in blood glucose, e.g., tremors and palpitations.

44
Q

how do salicylates cause hypoglycemia

A

inhance pancreatic b-cell sensitivity to glucose and potentiate insulin secretion

45
Q

how does ethanol cause hypoglycemia

A

inhibits gluconeogenesis

46
Q

epinephrine, glucocorticoids, oral contraceptives cause what

A

direct hyperglycemic effect

47
Q

phenytoin, clonidine, Ca2+ channel blockers cause what….

A

hyperglycemia by inhibiting insulin secretion

48
Q

some diuretics have what effect on insulin

A

deplete K+ and indirectly inhibit insulin secretion

49
Q

what is the initial monotherapy for patient’s with Type II DM who have failed diet and exercise therapy

A

metformin

The rare patient in which metformin is contraindacated may begin therapy with a sulfonylurea, insulin, or pioglitazone

It is now recommended that the initial step of treatment for newly diagnosed Type 2 DM should be lifestyle changes to decrease weight and to increase activity along with metformin therapy.

50
Q

can you treat type I DM patients with oral hypoglycemia patients

A

no!! they must be treated with insulin

51
Q

Metformin MOA

A

has an antihyperglycemic action; not a hypoglycemic action.

Unlike the sulfonylurea drugs, it does not directly effect insulin release. It does not cause hypoglycemia even at high doses. Metformin appears to produce the following effects:
• reduces hepatic glucose output by inhibiting gluconeogenesis

  • increases insulin action in peripheral tissues (increases anaerobic glycolysis), i.e., decreases insulin resistance
  • increases glucose uptake and utilization by muscle
  • reduces intestinal absorption of glucose
52
Q

if only partial reductions in plasma glucose have been achieved with metformin alone, what else can be added ?

A

sulfonylurea or a TZD

53
Q

why is metformin advantageous over sulfonylureas and insulin in treating obese insulin resistant pt’s

A

Because metformin is an insulin sparing agent and does not cause weight gain or provoke hypoglycemia, it offers advantages over sulfonylureas and insulin in treating obese, insulin-resistant patients. It also has a a significant lipid-lowering effect, i.e., it decreases total cholesterol, LDL, and triglycerides.

54
Q

what are the ADR’s of metformin

A

abdominal discomfort, anorexia, nausea, metallic taste, and diarrhea.

55
Q

in which pt’s should metformin use be avoided

A

Metformin should not be administered to patients with renal impairment, hepatic disease, a history of lactic acidosis, cardiac failure, or chronic hypoxic lung disease because of the concern for the development of lactic acidosis.

56
Q

what is the administration regimen of metformin

A

E. Metformin is usually administered two to three times daily with meals. It is rapidly absorbed and cleared through the kidneys.

57
Q

in what patients must you use glyburide with caution

A

use in caution with elderly pt’s with renal failure and others predisposed to hypoglycemia

58
Q

what are the three second generation sulfonylureas

A

glipizide
glyburide
glimepriride

59
Q

what is the MOA of sulfonylureas

what happens to plasma insulin levels initially and later on in therapy

A

Sulfonylureas bind to and block an ATP-sensitive K+ channel. Blockade of this channel reduces K+ conductance causing membrane depolarization and influx of Ca2+ through voltage-sensitive Ca2+ channels. Ca2+ influx leads to insulin secretion.

Initially (first few months of treatment), fasting plasma insulin levels and insulin responses to oral glucose are increased. With chronic administration, circulating insulin levels decline to those that existed before treatment, but, reduced plasma glucose levels are maintained.

60
Q

what are the extrahepatic effects of sulfonylureas

A

increased numbers of insulin receptors, increased glucose transporters, and purported enhanced tissue responsiveness to insulin. Hepatic gluconeogenesis is suppressed. Whether these are direct effects of the sulfonylurea drugs or a result of lower blood glucose levels is controversial.

61
Q

what is the success rate of sulfonylureas

A

Primary failure to respond to sulfonylureas occurs in 20%-25% of patients. Secondary failure occurs at a rate of approximately 10% - 15% per year due to progressive β-cell failure and insulin resistance or because of poor compliance.

62
Q

in terms of potency, how do 2nd generation sulfonylureas compare to 1st generation

A

100x more potent

63
Q

what metabolizes the sulfonylureas and in what pt’s must caution be practiced

A

All of the sulfonylureas are metabolized by the liver and the metabolites are excreted in the urine. These drugs should be administered with caution in patients with either renal or hepatic insufficiency.

64
Q

which patients are the best candidates for sulfonylureas

A

recently diagnosed

over 30

not overtly obese

have residual B-cell function

fasting blood glucose <300

65
Q

what percentage of type II DM pt’s receiving sulfonylureas fail to respond to therapy

A

30% - most often due to dietary noncompliance

add metformin to regimen or treat with insulin

Replacing one sulfonylurea agent with another sulfonylurea is unlikely to produce substantially different results and is not recommended.

66
Q

what are the ADR’s of sulfonylureas

A

hypoglycemia, including coma

  • most often in elderly with impaired hepatic or renal function
  • can mimic cerebrovascular accident
  • treat with glucose or glucagon

Nausea, vomiting

Cholestatic jaundice 
Hyponatremia
agranulocytosis
aplastic anemia
generalized hypersensitivity rxns
67
Q

what is the DDI of sulfonylureas with ethanol

A

may enhance the action of sulfonylureas by causing hypoglycemia.

68
Q

what are the contraindications for use of sulfonylureas

A

type I DM

sulfa allergies

pregnant or nursing mothers

significant hepatic or renal insufficiency

69
Q

what are the meglitinides

A

non-sulfonylurea rapid acting insulin releasing agents

includes Repaglinide and Nateglinide

70
Q

what is the MOA of meglitinides

A

Meglitinides binds to the ATP-sensitive potassium channel on pancreatic beta cells at a different site than sulfonylureas. The subsequent depolarization of the beta cell opens the calcium channel and rapidly increases insulin secretion. Thus, these drugs are sometimes called non-sulfonylurea secretagogues.

71
Q

what is the clinical use of meglitinides

A

developed to manage meal related glucose loads

The rapid action of these drugs (taken right before a meal) makes them useful for patients who are erratic eaters. For example, if a meal is skipped so is that dose of drug and hypoglycemia is avoided. Only the first phase of insulin secretion is stimulated because of the rapid metabolism of the drugs.

monotherapy OR combined with metformin

72
Q

adverse reactions of meglitinides

A

Adverse effects are comparable to sulfonylureas but these drugs should be used cautiously in the elderly and those with liver dysfunction. They can cause hypoglycemia, must be taken three times a day (i.e., with meals), and are expensive

73
Q

what are the alpha-glucosidase inhibitors

MOA?

A

acarbose
miglitol

MOA:
oligosaccharide analogs that bind to the intestinal brush border enzymes that digest complex sugars
-competitive inhibition of sugar digestion by these drugs delays the absorption of carbohydrates and limits postprandial rise in glucose

74
Q

what are the alpha-glucosidase inhibitors most useful for?

what if they are combined with other drugs?

A

newly diagnosed type II pt’s with mild hyperglycemia

used by themselves they do NOT cause hypoglycemia

, if combined with insulin or sulfonylureas, these drugs increase the risk of hypoglycemia.

75
Q

common side effects of alpha glucosidase inhibitors

A

flatulence
diarrhea
GI upset due to undigested carbohydrates

can lead to poor patient compliance

76
Q

alpha glucosidase inhibitors are contraindicated in what patients

A

Diabetic ketoacidosis

cirrhosis

inflammatory bowel disease

colonic ulcers

partial intestinal obstruction

77
Q

what are the thiazolidinediones

A

insulin sensitizers
-Pioglitazone

indicated as an adjunct to diet and exercise or for concomitant use with a sulfonylurea or insulin to improve glycemic control

78
Q

MOA of pioglitazone

A

bind to nuclear transcription factors that may be involved in the insulin receptor signaling cascade (PPAR-gamma site)

resensitize tissues to insulin

TZDs increase glucose uptake and glucose oxidation in both muscle and adipose tissue, while reducing hepatic glucose output and lipid synthesis in muscle and fat cells.

Insulin release is not directly stimulated.

79
Q

what are the effects of pioglitazone

A

reduce insulin resistance

improve peripheral action of insulin

  • reduce hyperglycemia by increasing glucose uptake (may increase insulin responsive genes and increase GLUT-1 and GLUT-4 transport proteins.
  • reduce hepatic glucose production
  • produce a small improvement in serum lipids, decrease triglycerides, FFA, increase HDL, in increase large “fluffy” LDL.
80
Q

why is pioglitzaone used with insulin

A

• When taken with insulin, allow reduction in insulin dose or facilitate discontinuation of insulin.

81
Q

ADR’s of pioglitzaone

A

Current data suggest that liver toxicity may be less of a problem with these drugs.
Pioglitazone may cause moderate weight gain, edema and mild anemia, all due at least partly to fluid retention.

Fractures (particularly in women) - distal upper or lower limb

Black box warning–> fluid retention with resultant CHF

82
Q

what is pramlintide

A

amylin analog

Amylin is a naturally occurring 37-amino acid peptide that is normally co-secreted with insulin from the pancreatic β-cells. Amylin secretion is delayed or diminished in both Type 1 and Type 2 diabetics. Pramlintide is a synthetic analog of amylin that has improved physical properties that make it more stable in solution, thus rendering it more suitable for mass production, storage, and use

83
Q

what are the metabolic effects of pramlintide

A
  • suppression of endogenous glucagon production, especially in the postprandial state.
  • reduction of postprandial hepatic glucose production.
  • reduction of gastric emptying time.
  • centrally-mediated induction of satiety
  • reduction of postprandial glucose levels
84
Q

in what patient’s is pramlintide most useful

A

This agent is most useful for patients who experience wide glycemic swings or those who are insulin-resistant and require large amounts of insulin.

85
Q

how do you deliver pramlintide and what are the ADR’s

A

Pramlintide is delivered by subcutaneous injection before meals and cannot be mixed with insulin.

Thus, use of pramlintide requires additional 2 to 3 injections per day. Adverse effects include increased risk of hypoglycemia and nausea. Other side effects include decreased appetite, vomiting, stomach pain, tiredness, dizziness, or indigestion.

86
Q

what are the GLP-1 analogs

A

Exenatide

87
Q

what are the metabolic effects of exenatide

A
  • glucose-dependent enhancement of endogenous insulin secretion and perhaps insulin sensitivity.
  • inhibition of endogenous glucagon secretion.
  • possible appetite suppression and satiety induction.
  • reduction in speed of gastric emptying.
  • possible stimulation of islet growth, differentiation and regeneration.

reduces HbA1 c levels, post prandial glucose, and weight

88
Q

with what other drugs do you use exenatide

A

approved for use with metformin alone, a sulfonylurea alone, or in combination with metformin and a sulfonylurea

89
Q

what are the ADR’s of exenatide

A

nausea, vomiting, diarrhea, upper resp symptoms

incidents of hypoglycemia are low

The biggest drawback is the need for additional twice-daily subcutaneous injections.

POSSIBle pancreatitis

90
Q

what are the dipeptidyl peptidase 4 inhibitors (DPP-4)

A

“gliptin’s”

block the enzyme that breaks down the two incretin hormones glucagon peptide like peptide 1 (GLP-1) and GIP which help regulate glucose metabolism via increased insulin release, suppressed glucagon release and delayed gastric emptying

91
Q

what are the sodium glucose co transporter 2 (SGLT2) inhibitors

A

the “flozins”

SGLT2, a membrane protein expressed mainly in the kidney, transports filtered glucose from the proximal renal tubule into tubular epithelial cells. SGLT2 inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion, resulting in a reduction in blood glucose levels.

associated with genital infections and UTI’s

92
Q

what are the 2 phases of insulin secretion in response to a meal

A

phase 1 rapid rise and fall

phase 2 slower, more gradual release

93
Q

what is the t1/2 life of insulin

A

5-15 minutes

degraded in the liver, degraded in the kidney

94
Q

by what means is glucose transported into cells

A

by facilitated diffusion by GLUT

95
Q

where are GLUT 2 receptors

A

in pancreas and liver

96
Q

where are GLUT 4 receptors

A

muscle and fat cells

97
Q

hypoglycemia can occur with insulin therapy….. ho w?

A

inappropriate dose

mismatch of time of injection versus food intake

exercise induced glucose demand

increase need for insulin

98
Q

how do you treat hypoglycemia

A

glucose

glucagon

99
Q

how are DPP-4 inhibitors administered

A

orally

ENDO II Exam II (8 decks)

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