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ENDO 2 Exam II (2017) > Diabetes pharm - Martin > Flashcards

Diabetes pharm - Martin Flashcards

1
Q

rapid-acting insulin drugs

A

insulin lispro, aspart, glulisine

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2
Q

short-acting insulin drugs

A

regular insulin

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3
Q

intermediate acting insulin drugs

A

NPH and NPL

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4
Q

ultra-long acting insulin drugs

A

Glargine insulin

insulin deetmir

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5
Q

Fixed – Mix Insulins

A 
NPH / Regular (50%/50%)
NPH / Regular (70%/30%)
NPL / Lispro (75%/25%)
NPL/ Lispro (50%/50%)
Aspart protamine/aspart (70%/30%)
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6
Q

Hypoglycemic Agents

A 
biguanides
sulfonylureas
meglitinides
alpha-glucosidase inhibitors
TZDs
glucagon-like Peptide-1 (GLP-1) agonists
dipeptidyl-peptidase-4 inhibitors (DPP-4)
Amylin analog 
Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors
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7
Q

Biguanides

A

Metformin

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8
Q

Sulfonylureas

A

Glipizide, Glyburide, Glimepiride

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9
Q

Meglitinides

A

(“Glinides” or Non-sulfonylurea Insulin Releasers)

Repaglinide, Nateglinide

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10
Q

a-Glucosidase Inhibitors

A

Acarbose, Miglitol

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11
Q

TZDs

A

Rosiglitazone, Pioglitazone

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12
Q

Glucagon-like Peptide-1 (GLP-1) Agonists

A

Exenatide

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13
Q

Dipeptidyl-Peptidase-4 (DPP-4) Inhibitors

A

“Gliptins”

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14
Q

Amylin analog

A

Pramlintide

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15
Q

Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

A

flozins”

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16
Q

Insulin: Biosynthesis and Chemistry

A

Biosynthesis of Insulin
 cells of pancreatic islet
Preproinsulin - proinsulin - insulin
A and B chains, C peptide

Chemistry:
monomers, dimers, hexamers
Zn2+
Soluble versus semi-crystalline states of the molecule - onset and duration of action

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17
Q

Regulation of Insulin Secretion

A 
Insulin secretion is tightly regulated by the interplay of:
nutrients, especially glucose
GI hormones
pancreatic hormones
autonomic neurotransmission

**Glucose is the principal stimulus of insulin secretion

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18
Q

Biphasic Insulin Secretion

A

Normal individuals have two phases of insulin secretion in response to a meal

Phase I - rapid rise and fall
Phase II - slower, more gradual increase

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19
Q

things that can stimulate insulin secretion

A

glucose, of course
amino acids, ketoacids
ach, CCK
Glucagon, GLP-1

Epi, Norepi, Somatostatin inhibit

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20
Q

insulin and diabetes

A

Type 1 diabetes mellitus
no insulin secretion

Type 2
initially, Type 2 DM patient may have elevated plasma insulin levels and tissue insulin resistance, but often 1st phase of insulin release is dysregulated
years later, beta cells fail and insulin levels are low

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21
Q

Distribution and Degradation of Insulin

A

Insulin circulates as the free monomer
Degradation in the liver operates at near maximal capacity
Degradation in the kidney after tubular reabsorption
Uptake by the muscle
t1/2 of insulin is about 5 - 15 minutes
Plasma levels measured by RIA (if necessary)

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22
Q

Insulin- Molecular Mechanism of Action

A

All cells have insulin receptors

Insulin receptor stimulates phosphorylation or dephosphorylation of cell-specific intracellular signal transduction proteins

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23
Q

The Insulin Receptor

A

The insulin receptor is an integral plasma membrane protein complex
Receptor is a heterodimer of alpha and b subunits
Intracellular beta subunits have *** tyrosine kinase enzyme activity
Insulin binding to the receptor stimulates autophosphorylation of the receptor beta subunits and activation of tyrosine kinase activity
Docking proteins bind to the receptor and recruit other mediator proteins to the plasma membrane

24
Q

Regulation of Glucose Transport

A

Glucose transport is a crucial component of the physiological effects of insulin
Glucose is transported into cells by facilitated diffusion by means of Glucose Transporters (GLUT)
Insulin stimulates reversible translocation of glucose transporters to the plasma membrane
GLUT-4 - muscle and fat cells
GLUT-2 pancreas, liver
Insulin increases synthesis of GLUT1 and GLUT4

25
Q

Regulation of Glucose Metabolism

A

Insulin stimulates glucose uptake
Insulin stimulates glucose storage and utilization

Insulin inhibits glycogen breakdown (glycogenolysis)
Insulin inhibits glucose synthesis (gluconeogenesis)

26
Q

Central Features of Diabetes Mellitus

A

Insulin deficiency

Insulin resistance

Hyperglycemia

27
Q

Type I vs Type II DM

A

Type 1- young, frequently undernourished, 10-20% prevalence, moderate genetic predisposition, beta cells are destroyed- eliminating the production of insulin

Type 2- often over age 35, obesity usually present, 80-90 percent of diagnosed diabetics, very strong genetic predisposition, inability of beta cells to produce appropriate quantities of insulin; insulin resistance; other defects

28
Q

ACCORD Trial

A

The ACCORD Trial was a large clinical trial
in >10,000 patients with patients with Type 2 D, with or at high-risk for CV disease.
This trial found that treating patients intensively to a HbA1C target of under 6.0% did not significantly reduce the incidence of major CV events and was associated with increased all-cause mortality compared to patients treated to a target HbA1C of 7.0-7.9%

29
Q

Diabetes Control and Complications Trial (DCCT)

A

Conclusion: Intensive therapy to attain euglycemia dramatically reduces the incidence of and severity of long-term complications

Major problem: * Hypoglycemia
The more intense the attempt to maintain “normal” glucose levels, the greater the risk of hypoglycemia
Maintenance of Intensive Insulin Therapy requires educated, motivated patient

30
Q

Hemoglobin A1c

A 
A convenient index of long-term exposure to elevated glucose.
Hemoglobin becomes glycosylated
t1/2 120 days
Used to monitor therapeutic goals
** Recommendation: Hemoglobin A1c < 7.0%
31
Q

Diagnosis of Diabetes

A 
Classic signs and symptoms
Unequivocally high FPG >126 mg/dL
Random glucose of  >200 mg/dL
FPG of >126 mg/dL on two or more occasions
Failure on Oral Glucose Tolerance Test
32
Q

Typical Insulin Regimen

A

Example: 30 Units (U) per day
2/3 total dose before breakfast
- 2/3 NPH (14U)
- 1/3 Regular (6U)

1/3 total dose in the evening

  • 1/3 Regular before dinner (3U)
  • 2/3 NPH at bedtime (7U)
33
Q

Adverse Reaction to Insulin Therapy: Hypoglycemia

A 
Hypoglycemia due to:
inappropriate dose
mismatch of time of injection versus food intake
exercise-induced glucose demand
increase need for insulin
34
Q

hypoglycemia- signs and symptoms, treatment

A

Signs and Symptoms
Sweating, hunger, paresthesias, palpitations, tremor, anxiety
confusion, weakness, drowsiness, blurred vision, loss of consciousness

** Treatment
Glucose
Glucagon

35
Q

Type 2 Diabetes Mellitus

A 
Diminished insulin secretion
Tissue resistance to insulin
Enhanced glucagon
Enhanced gluconeogenesis
Obesity
36
Q

Metformin [Glucophage]

A

Antihyperglycemic action, ** not hypoglycemic
increases insulin action, glycolysis, uptake and utilization by muscle

DECREASES gluconeogenesis, hepatic glucose output, intestinal absorption of glucose

37
Q

Metformin [Glucophage] therapy and advantages

A

Drug of first choice for type II diabetes

Monotherapy
or added to GLP-1 agonist, DPP-4 inhibitor, glinide, sulfonylurea, or TZD
step-up to daily divided doses

Advantages:

  • no weight gain
  • no hypoglycemia
  • favorable lipid profile
38
Q

Metformin [Glucophage] side effects

A

Metformin has advantages over SUs & insulin in some obese, insulin-resistant patients

Concern is lactic acidosis (but rare) especially in patients with:

  • renal or hepatic insufficiency
  • CV disease

Common side effects
GI: anorexia, nausea, abdominal discomfort, diarrhea

39
Q

Combinations with metformin

A 
Since most patient end up needing more than one drug a number of combination products have been introduced including:
Metformin plus:
Glipizide
Glyburide
Linagliptin
Pioglitazone
Repaglinide
Sitagliptin
Saxagliptin

Combination products simplify dosing but reduce the flexibility in adjusting doses

40
Q

Oral Hypoglycemic Agents Sulfonylureas - the generations

A

[First Generation: No longer used- Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide]

Second Generation

  • Glipizide
  • Glyburide

“Third” Generation
* Glimeperide

41
Q

Sulfonylureas (SUs): Mechanism of Action

A

Block ATP-sensitive K+ channel
Leads to depolarization and influx of Ca++

  • Results in insulin secretion
  • Adverse Effects: Weight gain and Hypoglycemia
42
Q

Sulfonylureas- key points

A
  • stimulate insulin release
    SUs indirectly increase tissue sensitivity to insulin, i.e., help overcome insulin resistance
    Help suppress hepatic glucose output
    Success depends on functionality of b-cells20-25% of patients fail to respond adequately
    Subsequent failures result from eventual b-cell failure
43
Q

2nd or 3rd generation Sulfonylureas

A

Glimeperide
Glipizide
Glyburide

same mechanism, release insulin
equally efficacious
more potent than 1st generation
most costly than 1st generation
less severe/persistent hypoglycemia
44
Q

Glimepiride

A

appears to cause * less weight gain than all the other SUs
contraindications include sulfa allergy, pregnancy, type 1 DM, ketoacidosis, renal failure, hepatic failure, and major surgery.
Once daily doses possible

45
Q

Glipizide and Glyburide

A

Glipizide
Intermediate-acting
QD dosing, if >15 mg per day give BID
inactive metabolites, no special precautions

Glyburide
greater incidence of severe prolonged hypoglycemia than glipizide
use cautiously in elderly or anyone predisposed to hypoglycemia

46
Q

Non-Sulfonylurea Secretogogues

A

Repaglinide & Nateglinide

Non-sulfonylurea insulin releasing agents
Blocks ATP-sensitive K+ channel
Binds at different site than sulfonylureas
* Short half-life; rapid action
* Taken right before meals

47
Q

a-Glucosidase Inhibitors

A

Acarbose
Miglitol

Inhibit digestion of complex sugars
Decrease sugar uptake after a meal
* Cause flatulence and GI upset
- leads to poor acceptance & compliance
Watch out for hypoglycemia when used with insulin or sulfonylurea

48
Q

Glucagon-like Peptide 1 (GLP-1 agonists)

A

Exenatide, Liraglutide, Albiglutide, Dulaglutide

GLP-1 is a peptide hormone produced from cleavage of the proglucagon precursor

  • Secreted by intestinal L cells
  • First discovered from saliva of the Gila monster
  • Exenatide is an analog of GLP-1 that is highly resistant to inactivation by dipeptidyl peptidase-4 (DPP-4)
  • Binds to GLP-1 receptor as an agonist
49
Q

GLP-1 Agonists

A

GLP-1 agonists stimulate:

  • Glucose-dependent enhancement of insulin secretion
  • Inhibition of glucagon secretion
  • Appetite suppression and satiety induction
  • Reduction of gastric emptying
  • Possible stimulation of islet cell growth, differentiation, and regeneration

*decreases HbA1c, decreases postprandial glucose, causes weight loss
* Little hypoglycemia
GI upset most common adverse effects but there appears to be some risk for pancreatitis.

50
Q

GLP-1 Agonists therapy regimens

A

Use as monotherapy or in combination with:

  • Metformin (in dual therapy)
  • Metformin + TZD (triple therapy)
  • Metformin + Sulfonylurea (triple therapy)

Not approved for use with insulin
Exenatide requires twice-daily SQ injections or there is an extended-release formulations that is injected once per week
Liraglutide requires only once-daily injections

51
Q

Dipeptidyl Peptidase-4 Inhibitors(DPP-4 Inhibitors)- administration

A 
Sitagliptin, Saxagliptin, Linagliptin
DPP-4 hydrolyzes:
Glucagon-like peptide-1 (GLP-1) 
Glucose-dependent insulinotropic peptide (GIP)
These drugs are administered * orally*
  • Monotherapy or combined with metformin, SUs, or TZD
  • Increases insulin secretion, decreases glucagon and hepatic glucose production, * increases peripheral glucose uptake and utilization
52
Q

DPP-4 Inhibitors side effects/ DDIs

A

Little hypoglycemia
because DPP-4 effects are glucose-dependent

Not approved for use with insulin

53
Q

Pramlintide

A

Pramlintide is a synthetic analog of amylin, a peptide co-secreted with insulin from pancreatic b-cells.
The identified metabolic effects of pramlintide are:
- centrally-mediated induction of satiety
and DECREASE:
- of endogenous glucagon production, especially in the postprandial state.
- of postprandial hepatic glucose production.
- of gastric emptying time.
- of postprandial glucose levels
Used in Type 1 or type 2 diabetics already using insulin, especially those with insulin resistance requiring large doses of insulin

***Require SQ injections prior to meals and cannot be mixed with insulin

54
Q

Thiazolidinediones (TZDs)

A
  • Pioglitazone
  • Rosiglitazone
  • Insulin Sensitizers
55
Q

Thiazolidinediones (TZDs) MOA, uses, risks

A

Bind to nuclear transcription factors involved in insulin action
decreased insulin resistance
increased peripheral action of insulin
increased glucose uptake, and GLUT-1 & GLUT-4
decreased hepatic glucose output

Takes several weeks to develop clinical effect
Useful effect since many Type 2 patients are “insulin-resistant”
Liver enzyme tests required - idiosyncratic hepatocellular injury

Long-term risks have been debated, * ↑ risk of MI with rosiglitazone was reported but was never substantiated; both drugs cause * weight gain; rosiglitazone was restricted in use in the USA but restriction now lifted; pioglitazone taken off the market in Germany and France because of increased risk of bladder cancer.
* Cause fluid retention and CHF (2X risk) and increase risk of

56
Q

Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

A
  • Canagliflozin, Dapagliflozin, Empagliflozin

New drugs just approved in the last several years
Oral treatment (once per day) of Type 2 diabetes; in combination with insulin or metformin, ± sulfonylurea or pioglitazone
SGLT2 is a membrane protein expressed mainly in the kidney. It transports filtered glucose from the proximal renal tubule into tubular epithelial cells. By inhibiting SGLT2, “flozins” decrease glucose reabsorption, increase urinary glucose excretion, and lower blood glucose levels.
Flozins are modestly effective in reducing HbA1c, systolic blood pressure and weight, with a low risk of hypoglycemia.
Genital mycotic infections can occur in both men and women; long-term safety still unknown.

ENDO 2 Exam II (2017) (19 decks)

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