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Therapeutics P2 > Exam 2 Lecture 2 > Flashcards

Exam 2 Lecture 2 Flashcards

1
Q

Hypoglycemia

A

BG less than 60

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2
Q

Modification on insulin detemir

A

Fatty acid added to peptide to prolong action

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3
Q

signs of hypoglycemia

A

Weakness, sweating, hunger, tachycardia, increased irritability, tremor, blurred vision, seizures (neurologic symotoms)

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4
Q

Why are signs of hypoglycemia neurologic symptoms

A

low BG leads to increased sympathetic outout

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5
Q

Why does low BG cause increased sympathetic output

A

It is the brains way of bringing BG back up by mobilizing glucose from liver, which can cause these symptoms

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6
Q

Preferred fuel in nervous symptom

A

glucose

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7
Q

What are some drugs that can increase BG levels in diabetes

A

catecholamines
glucocorticoid
somatotropin (leads to insulin resistance)

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8
Q

How do catecholamine, glucocorticoids and somatotropin increase BG levels in diabetics

A

They have a pro-sympathetic effect on the liver and interfere with trying to keep BG levels down by stimulating release of glucose from liver

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9
Q

Agents with increased risk of hypoglycemia

A

ETHANOL
ACE inhibitor
B blocker
Fluoxetine

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10
Q

How does Ethanol increase the risk of hypoglycemia

A

Inhibits gluconeogenesis (which is one of the two ways that liver can export glucose into bloodstream and bring levels up.)

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11
Q

How do ACE inhibitors, B blockers and fluoxetine cause hypoglycemia

A

Inhibit enhanced sympathetic output from brain

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12
Q

What are adverse effects of insulin with regard to lipids

A

Lipodystrophy- changes in fat at over used inj site
Lipohypertrophy- accumulation of fat in SUbQ tissue

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13
Q

What was the mechanism for insulin glargine

A

It is soluble at acidic PH and insoluble at physiologic PH. Percipitates at site of inj

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14
Q

Which insulin preparation is not genetically modified?

A

NPH (only complexed with protamine) (has action peak)

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15
Q

2 Phases of normal insulin secretion

A

1st- high peak, quick onset
2nd- elevated for long time

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16
Q

Type 2 diabetes is a combination of

A

Insulin resistance and reduced insulin secretion

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17
Q

Why does the decline in glucose utilization in skeletal muscles in T2 diabetics have a big effect on oateint

A

Skeletal muscle accounts for a large percentage of the glucose uptake stimulated by insulin after a meal

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18
Q

How does insulin affect the liver

A

Inhibits glucose output from liver by inhibiting breakdown of glycogen and inhibiting gluconeogenesis

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19
Q

What happens to glucose export in non diabetic patients when insulin is secreted

A

Steep drop

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20
Q

T/F The ability of insulin to shut off exprt of glucose from liver is going to be compromised

A

True

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21
Q

What do pancreatic islet cells do? how does insulin affect this? how is this affected by diabetes

A

They secrete glucagon. Insulin inhibits glucagon secretion. This inhibition is blunted in diabetes T2

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22
Q

How does insulin affect lipolysis. How is this affected in diabetics

A

Insulin suppresses lipolysis. . This is blunted in diabetes

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23
Q

What are the drugs that have the ability to directly stimulate insulin secretion from pancreatic B cell.

A

Sulfonylurea- prolonged duration of action
meglitinides- rapid onset and short duration

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24
Q

Examples of sulfonylureas

A

Tolbutamide, Glipizide, Tolazemide

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25
Q

Examples of meglitinides

A

Nateglinide, Repaglinide

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26
Q

What is the predominant glucose transporter in pancreatic B cells?

A

GLUT-2

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27
Q

What is sepcial about GLUT-2

A

It has a high KM

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28
Q

What does high Km for GLUT-2 entail?

A

We need a high blood glucose to start uptake into pancreatic B cell

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29
Q

What happens after GLUT-2 uptakes glucose into blood stream

A

Glucose is phosphorylated to G-6-P, producing ATP

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30
Q

What happens after ATP is produced from G-6-P

A

There is a big swing in ratio of ATP to ADP, ADP decreases and ATP increases

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31
Q

When does K-ATP channel close? How many subunits of K-ATP?

A

Closes when bound to ATP, 2 subunits

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32
Q

What happens when K-ATP channel is closed?

A

membrane potential starts to go up

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33
Q

What happens when ATP binds K channel?

A

It closes it and reduces the efflux of potassium from cell. This causes membrane depolarization.

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34
Q

What happens when membrane is depolarized?

A

Opens voltage gated calcium channels. When voltage gated calcium channels open, calcium comes into the cell and stimulates release of insulin

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35
Q

What happens when calcium channels open?

A

Ca stimulates release of insulin

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36
Q

Why do we have low efflux of glucose when glucose levels are low?

A

GLUT-2 has a very high Km

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37
Q

What effect does GLUT-2 not uptaking glucose have during low blood glucose

A

There will be more ADP than ATP, ADP bunds KATP channel

38
Q

During low glucose, when ADP binds K-ATP, what happenss

A

ADP causes the K-ATP channel to remain open and maintain negative resting potential

39
Q

What is the K-ATP channel?

A

The key sensor of metabolic activity that regulates electric activity that determines insulin secretion

40
Q

K_ATP channel is made up of how many subunits

A

2 subunits
KIR 6.2- pore forming
SUR 1
both have 4 subunits

41
Q

where do sulfonylureas bind

A

Between KIR 6.2 and SUR 1 subunits in K-ATP channel

42
Q

What are some sulfonylurea drug names

A

Tolbutamide
Glyburide
Gluclazide

43
Q

Recognize the sulfonyl urea structure

A

.

44
Q

Sulfonylurea mechanism

A

Act like B cell. They bind K-ATP and block it. Causing membrane depolarization

45
Q

Which sulfonylurea has a faster effect? why?

A

Tolbutamide, it does not have to be metabolized

46
Q

which are the 1st gen sulfonylureas

A

tolbutamide- lowest potency and duration
Chlorpropramide- longest duration

47
Q

What differentiates 1st gen from second gen sulfonylureas

A

Potency, second is much more potent

48
Q

second gen sulfonyurea drugs

A

Glipizide
glyburide
glimepride

49
Q

difference between sulfonylureas and meglitinides

A

same function (blocking k-atp) different structure.
Meglitinides have repaglinide instead of sulfonylurea

50
Q

Name two meglitinides

A

Nateglinides, prandin

51
Q

DIfferentiate between nateglinide and prandin

A

Nateglinide is very specific for KATP channels in pancrease compared to CV
Nateglinide also has a shorter half life

52
Q

Adverse effects of sulfonylureas

A

Prolonged HYPOGLYCEMIA due to long t1/2 especially in 2nd gen (glipizide, glimepride)
risk of CV events
GI problems

53
Q

Why do sulfonylureas lead to loss of B cell mass

A

They stimulate persistent insulin secretion. This can be stressful on B cells leading to loss of BCM

54
Q

Drugs that may enhance the action of sulfonylureas and risk of hypoglyccemia

A

Salicylates, sulfonamides

55
Q

Drugs that cause hyperglycemia that may oppose sulfonylureas

A

OC
epinephrine
thiazide diuretics
corticosteroids

56
Q

What is the incretin effect?

A

Oral glucose elicits higher response that IV glucose

57
Q

Why does oral glucose stimulate larger insulin response than IV glucose

A

Small intestine increases the hormones called incretins in response to absorption of glucose. They incremetally increase the secretion of insulin and increase glucose utilization.

58
Q

Name 2 incretin hormones

A

GLP-1
GIP

59
Q

Difference between the two incretins

A

GLP-1 is secreted from the ileum and is stimulated by the uptake of glucose from the lumen
GIP- is secreted from duodenum

60
Q

Most important effect of incretins

A

Acutely increase insulin secretion through C-AMP stimulation in pancrease cell

61
Q

How does incretin increase insulin secretion

A

stimulate c-AMP in B cell in response to glucose

62
Q

How do incretins affect BCM

A

protect and maintain B cells

63
Q

What is DPP-IV

A

a protease that degrades GIP and GLP-1

64
Q

What inhibits DPP-IV? What effect does this have?

A

DPP-IV inhibitor . Helps raise levels of incretin

65
Q

Besides stimulating insulin production, what else do incretins do?

A

Suppress glucagon secretion
slow gastric emptying
decrease food intake
increase BCM
enhance glucose disposal and improves insulin sensitivity

66
Q

Is incretin glucose dependent or independent?

A

Dependent

67
Q

Why do incretins have a lower risk of hypoglycemia compared to sulfonylureas?

A

If there is no glucose around to depolarize the membrane potential, incretins will not stimulate insulin secretion. Sulfonyl ureas persistently stimulate insulin secretion

68
Q

does GLP-1 byitself stimulate insulin secretion?

A

No, it can amplify the ability of glucose to stimulate insulin secretion.

69
Q

Does GLP-1 stimulate membrane depolarization?

A

No, it increases CAMP inside the cell. This amplifies the effective membrane depolarization. causing more insulin to be secreted in response to glucose

70
Q

Incretins in Type 2 diabetes?

A

Incretin effect is diminished in t2 diabetes

71
Q

2 startegies to increase the incretin effect in t 2 DM

A

provide GLP analog
prevent degradation of endogenous GLP-1

72
Q

What are some GLP -1 analogs

A

Exenatide
Liraglutide (Victoza)
Dulaglutide (trulicity)
Lixisenatide (adlyxin)
Semaglutide (ozempic)
mounjaro (tirzepatide)

73
Q

warning for all GLP-1 analogs

A

Nausea, vomiting, pancreatitis

74
Q

Contraindication to all GLP-1 analogs

A

contraindicated in pts with FH of medullary thyroid cancer

75
Q

Liraglutide (victoza) modifications

A

Fatty acid added to enhance duration of action by binding serum albumin

76
Q

Dulaglutide (trulicity) modifications

A

GLP-1 peptides slowly released from IgG Fc domain by reduction of disulfide bonds.
Can be injected once a week due to ability to circulate for long periods

77
Q

Modifications of Lixisenatide (Adlyxin)

A

Not a derivative of GLP-1 sequence. It is a derivative of exenatide with a polylysine tail. Inj daily.
No fatty acid, no serum binding

78
Q

Which position is most susceptible to proteolysis

A

Position next to histidine

79
Q

Ozempic (semaglutide) half life?

A

1 week, binds serum albumin

80
Q

semaglutide (ozempic) modification

A

Has an artificial aa next to histidine, reducing susceptibility to cleavage. Has a hydrophobic spacer and fatty acid.

81
Q

How does semaglutide (ozempic) affect appetite

A

They have receptors in CNS that affect appetite, reducing food intake

82
Q

Only GLP-analog that is orally active

A

Semaglutide (rybelsus), poor oral bioavailability.

83
Q

semaglutide (rybellus) modifications

A

unnatural aa after histidine, hydrophobic spacer and fatty acid called salcaprozate (makes it absorbable from GI tract)

84
Q

What is salcaprozate

A

fatty acid in semaglutide (rybella) that makes it absorbable from GI tract

85
Q

How does mounjaro (tirzepatide work)

A

Reduces internalization (desensitization) of GLP-1 receptor to maintain effect.

86
Q

How does moounjaro affect GIP and GLP-1

A

Full agonist for GIP
biased agonist for GLP-1

87
Q

How does mounjaro reduce desensitization

A

activates CAMP over b-arrestin, b arrestin causes desensitization

88
Q

What is DPP-IV and what does DPP-IV inhibitor do?

A

DPP-IV cleaves hormones on luminal side of capillary. The inhibitor allow greater release of GLP-1 and GIP after a meal because we inhibit their breakdown

89
Q

What is amylin? main action?

A

A peptide secreted from B cell along with insulin that regulates the absorption of nutrients from the GI tract. main action- inhibits glucagon secretion

90
Q

Amylin drug

A

pramlintide(symlin)

91
Q

What does pramlintide do?

A

Blunts post prandial rise in BG

92
Q
A

Therapeutics P2 (41 decks)

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