2nd gen sulfonylureas ____ (Glucotrol) ___ (DiaBeta, Glynase) ___ (Amaryl)

- glipizide - glyburide - glimepiride

AE of sulfonylureas - ____ due to long t1/2 - glipizide, glimepiride < ___ - ___ problems: N/V - weight ___ and increased numbers of ___ failures

- hypoglycemia - glyburide - GI - gain, secondary

Lecture 8: Diabetes (cont.) Flashcards by Reagan Smith

Adverse reactions to insulin

Hypoglycemia - blood glucose < ___ mg/dL
- too much insulin and/or not enough food (glucose)
- symptoms are ___ in nature
- treated with ___ or ___

60 mg/dL
- neurologic
- glucose, glucagon

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Adverse reactions to insulin (cont.)

Lipodystrophy - changes of fat at ___ injection site

Lipohypertrophy - ___ of fat in subcutaneous tissue

Lipoatrophy - ___of fat in subcutaneous tissue
- inflammatory response

rarely occurs (mostly in animal insulin)

over-used
accumulation
loss

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factors and agents which may alter insulin action

agents that increase blood glucose (esp in diabetics)

catecholamines
glucocorticoids
oral contraceptives
thyroid hormone
calcitonin
somatropin
isoniazid
phenothiazines
morphine

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factors and agents which may alter insulin action

agents that increase risk of insulin hypoglycemia

ethanol
ACE inhibitors
somatostatin
beta adrenergic blockers
fluoxetine anabolic steroids
MAO inhibitors
vigorous, unaccustomed exercise

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Overview of treatment of type I and type II

Type I: ___, diet, exercise
Type II:
1) diet + exercise
2) diet + exercise + ___ drugs
3) diet + exercise + ___

insulin
antidiabetic, insulin

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Insulin secretion defects in type II DM

___ phase not defined

First

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Patho of Type II

Type II is a combo of insulin ___ and reduced insulin ___
- tissues that normally respond to insulin become less and less ___

resistance, secretion
- responsive

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Agents that enhace insulin secretion

___ - tolbutamide, tolazamide, chlorpropamide, glyburide, glipizide, glimepiride

___ - nateglinide, repaglinide

Sulfonylureas

Meglitinides

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Type 2 diabetes and sulfonylureas

must have functioning ___
increased release of insulin
- may restore ___ phase insulin release
- increase beta cell ___ to glucose and ___ glucose stimulated insulin release

beta cells
- first
- sensitivity, increase

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effects of sulfonylureas on beta cell insulin release

1) binds to ___ receptors
2) inactivated ___ channel
3) decreases cell ___
4) activates voltage sensitive ___ channels
5) increases ___ and activity of ___
6) increased exocytosis of ___ containing granules

sulfonylurea
K
polarization
Ca
Ca, microfilaments
insulin

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insulin release from pancreatic beta cells

High glucose: K channel ___ , Ca channel ___ , insulin ___

Low Glucose: K channel, Ca channel ___, insulin ___

closed, open, released
open, closed, trapped

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drug class: ___
drug 1 name: ___
drug 2 name: ___

sulfonylureas
tolbutamide
glyburide

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1st generation sulfonylureas

in order of increasing potency and duration

not really used anymore

1) tolbutamide
2) tolazamide
3) chlorpropamide

not really used anymore

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2nd gen sulfonylureas

____ (Glucotrol)
___ (DiaBeta, Glynase)
___ (Amaryl)

glipizide
glyburide
glimepiride

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Meglitinides “Glinides”

____ (Prandin)
- MOA: like ___
- quick onset, ___ duration of action
- tablet taken ___ each meal (preprandial)

Repaglinide
- sulfonylureas
- short
- before

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Meglitinides “Glinides”

____ (Starlix)
- MOA: non-sulfonylurea ____ channel blocker
- very ____ for K-ATP channels
- in ___ vs cardiovascular tissue
- shorter t1/2 than ___ (less risk of ___ )
- synergistic with ___

Nateglinide
- K-ATP
- specific
- pancreas
- Repaglinide (Prandin), hypoglycemia
- metformin

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AE of sulfonylureas

____ due to long t1/2
glipizide, glimepiride < ___
___ problems: N/V
weight ___ and increased numbers of ___ failures

hypoglycemia
glyburide
GI
gain, secondary

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Drug interactions (sulfonylureas)

drugs which enhance the action of sulfonylureas and increase the risk of ____ (4 examples)
- displacement of sulfonylureas from ___ binding

hypoglycemia
- salicylates
- phenylbutazone
- sulfonamides
- clofibrate
- plasma protein

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Drug interactions (sulfonylureas)

drugs having their own ___ effects which may be additive to the sulfonylureas
- ___ (excessive acute intake) associated with severe sulfonylurea hypoglycemic reaction
- high dose ___

drugs which cause ___ which in turn oppose the action of sulfonylureas and insulin therapy
- oral ___, epinephrine, ___ diuretics, corticosteroids, thyroid

hypoglycemic
- alcohol
- salicylates

hyperglycemia
- contraceptives, thiazide

agents that enhance incretin effect

GLP-1R agonists (5)

exenatide
liraglutide
lixenatide
dulaglutide
semaglutide

agents that enhance incretin effect

GLP-1 & GIP Dual agonist (1)

tirzepatide

agents that enhance incretin effect

DPP-IV inhibitors (4)

saxagliptin
sitagliptin
linagliptin
alogliptin

agents that enhance incretin effect

amylin analogs (1)

pramlintide

the incretin effect

T or F: oral glucose stimulates a larger insulin response than IV glucose

T; incretin effect

# What is the incretin effect? Incretin hormones like ___ and ___ are gut peptides that are secreted after nutrient intake that stimulate insulin secretion through ___ pathway - also increase ___ proliferation and protection from apoptosis through ___ pathway

GLP-1, GIP, cAMP - beta cell, ERK 1/2

# Glucagon-Like Peptide 1 upon ingestion of food, GLP-1 is secreted from L cells in the intestine - stimulated insulin secretion is glucose-___

dependent

# GLP-1 Modes of action - stimulates ___ secretion - suppresses ___ secretion - slows ___ emptying - reduces ___ intake - increases ____ mass and function - improved insulin ___ - enhances ___ disposal | stimulated insulin secretion is glucose ___

- insulin - glucagon - gastric - food - beta cell - sensitivity - glucose | dependent

T or F: GLP-1 amplifies insulin secretion without glucose being present

F: glucose dependent

T or F: the incretin effect is enhanced in type II diabetics

F: it is diminished

GLP-1 levels may be ___ in type II diabetics 2 Strategies - provide a ____GLP-1 analog and prevent ___ of endogenous GLP-1 - positive ___ modulators for the GLP-1 Benefits reduce hyperglycemia with low risk of ___ - weight loss

decreased - long-lasting, degradation - allosteric - hypoglycemia

# GLP-1 Analogs ___ (Exendin 4; Byetta, Bydureon) - for treatment of type ___ - 39 amino acid peptide from ___ saliva - activates ___ receptors - enhances ___ phase secretion - longer ___ than GLP-1 Contraindicated in pts with family history of medullary ___ SE: N/V, pancreatitis ___ daily injections ___ weekly injections (Bydureon) | can be co-administered with metformin and TzDs

Exenatide - type II - Gila Monster - GLP-1 - 1st - t1/2 - thyroid cancer - twice - once

What is DPP-IV

enzyme that breaks down incretins | alanine is often replaced t oprevent enzyme from breaking down drug

# GLP-1 Analogs ___ (Victoza) hGLP-1 aa7-37 - ___ linker - ___ instead of alanine - t1/2 of ___ hours - SE: N/V, pancreatitis, risk of thyroid tumors, monitor ___ levels - can be co-administered with metformin, TzDs, and sulfonylureas - ___ injection

liraglutide - fatty acid - valine - 13 - calcitonin - daily

# GLP-1 Analogs ___ (Trulicity) - GLP-1 agonist peptides are slowly released from ___ domain by reduction of ___ bonds in linker region - SE: N/V, pancreatitis - containdicated in pts with family history of medullary ___ cancer - ___ injection

Dulaglutide - IgG Fc, disulfide - thyroid - weekly

# GLP-1 Analogs ___ (Adlyxin) - ___ amino acid peptide - ___ instead of alanine - injected ___ before breakfast - ___ with a polylysine tail Soliqua - 100 U ___ + 33 micro grams lixisenatide/mL - injected ___ - SE: N/V, pancreatitis - Contraindicated in pts with family history of medullary ___ cancer

Lixisenatide - 44 - glycine - GLP-1 - daily - exenatide - glargine - daily - thyroid

# GLP-1 Analogs ___ (Ozempic) - ___ amino acid peptide - Injected once ___ - extensively bound to ___ - vulnerable alanine is replaced with ____ - t1/2 about a ___ - has ___ spacer and ___ - SE: N/V, pancreatitis - Contraindicated in pts with family history of medullary ___ cancer

- 31 - weekly - serum albumin - 2-aminoisobutyrate - week - hydrophillic, fatty acid

# GLP-1 Analogs semaglutide oral ( ___ ) - dimethylalanine + ___ spacer + C-18 ___ - salcaprozate - absorbed from ___ - dosed ___

Rybelsus - hydrophilic, fatty acid - stomach - daily

# Basal Insulin/GLP-1 Soliqua - 100 U ___ + 33 micrograms ___/mL - max: 60U/20 micrograms Xultophy - 100 U ___ + 3.6 mg ___/mL - max: 50U/1.8 mg

* glargine, lixisenatide * degludec, liraglutide

___ (Mounjaro) - full ___ receptor agonist - biased ___ receptor - preferential coupling to ___ over beta-arrestin - reduces internalization or ___ of GLP-1 receptor to maintain effect. - ___ injection - reduces A1C and body weight more effectively than ___ receptor agonists

tirzepatide - GIP - GLP-1, cAMP - desensitization - weekly - GLP-1

# Inhibiting incretin proteolysis - DPP-4 DPP stands for ___ - if we inhibit it, there will be more ___ and ___

dipeptidyl peptidase - GLP-1, GIP

# DPP-IV inhibitors inhibitors of ___ (4 examples) - ___ (Januvia) - ___ (Onglyza) - ___ (Tradjenta) - ___ (Nesina)

DPP-4 - sitagliptin - saxagliptin - linagliptin - alogliptin

# GLP-1 modulators Januvia, Onglyza, Tradjenta, and Nesina - po once ___ - reduces ___ and ___ - low risk of ___ - considered ___ neutral - may be co-administered with ___ and ___

* daily * hyperglycemia, A1C * hypoglycemia * weight * metformin, TzDs

# GLP-1 modulators metabolism and excretion Januvia and Nesina - not extensively metabolized - excreted in ___ by ___ Tradjenta - not extensively metabolized, excreted in ___ by ___ Onglyza - ___ substrate, major ___ is active - excreted in ___ by ___

* urine, kidney * poopoo, liver * CYP3A4/5, metabolite * urine, kidney

# GLP-1 modulators side effects SE: N/V, constipation, headache, ___ , joint pain, heart ___ DPP-4 is also present on ___ cells - reduced ___ counts, lead to infection - potential increased risk of ___

pancreatitis, heart failure immune - WBC - cancer

# peptide hormones as diabetes therapeutics ____ (Symlin) ___ analog - alternative strategy than DPP-4 inhibitors (GLP-1 modulators) - ___ amino acid peptide, normally co-secreted with ___ - slows ___ emptying, decreases food intake, inhibits ___ secretion - blunts ___ rise in blood glucose - used in conjunction with ___ - useful in both type I and II

Pramlintide - 37, insuling - gastric, glucagon - postprandial - insulin

T or F: a peptide hormone like pramlintide (Symlin) is good for both type I and II

True