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GIR Test 1 > B5.003 Diabetes Pharmacology > Flashcards

B5.003 Diabetes Pharmacology Flashcards

1
Q

diabetes mellitus definition

A

symptoms of hyperglycemia due to appropriate insulin secretion or function

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2
Q

type 1 diabetes

A

autoimmune destruction of B cells

insulin dependent

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3
Q

type 2 diabetes

A

noninsulin dependent diabetes associated with obesity and metabolic syndrome
B cells desensitized to a glucose challenge
peripheral tissues resistant to insulin actions

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4
Q

type 3 diabetes

A

non pancreatic causes

drugs that impair glucose tolerance (corticosteroids, thiazide diuretics, combination oral contraceptives)

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5
Q

type 4 diabetes

A

gestational diabetes

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6
Q

major goals of treatment of diabetes

A 
treat hyperglycemia to avoid long term complications
improve all aspects of metabolism:
-fasting glucose 90-120
-2 hr post prandial glucose <150
-HbA1c <7%
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7
Q

strategy of DM1 treatment

A

replacement of insulin

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8
Q

strategies of DM2 treatment

A

improve insulin sensitivity at early stages and replace insulin in later stage disease

  • change lifestyle
  • increase insulin sensitivity (liver and muscle)
  • increase insulin secretion
  • reduce glucose absorption in the gut
  • replacement insulin when compensation fails
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9
Q

what stimulates insulin secretion

A

increased ATP/ADP ratio (metabolic stimuli)

  • glucose and other sugars
  • amino acids
  • fatty acids
  • parasympathetic activity
  • GLP-1
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10
Q

discuss the pathway of insulin release in a B cell

A

glucose transported into cell by GLUT2
metabolism of glucose into ATP
ATP closes K+ channel and depolarizes cell
depolarization opens Ca2+ channel
Ca2+ influx stimulates exocytosis of insulin vesicles

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11
Q

discuss the action of the insulin tyrosine kinase receptor

A

IR autophosphorylation leads to phosphorylation and activation of downstream signaling proteins
acts in liver, muscle, and adipose tissues to decrease blood glucose levels and shift from energy use to storage

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12
Q

how is exogenous insulin made?

A

made from recombinant human DNA to avoid immune response issues

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13
Q

how are insulin preparations classified

A

duration of action (rapid, short, intermediate, long acting)

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14
Q

why is insulin administered subQ

A

to avoid quick rises and falls in response to digestive nutrients

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15
Q

adverse effects of insulin

A

hypoglycemia (can be severe or life threatening)

insulin allergy, lipoatrophy, weight gain and insulin edema

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16
Q

what type of insulin preparation is analogous to endogenous human insulin

A

short acting insulins

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17
Q

insulin treatment of DKA

A

IV infusion of regular insulin at a low rate
may administer glucose along with insulin to prevent hypoglycemia
add appropriate fluid and electrolytes

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18
Q

classes of DM2

A 
insulin secretagogues
insulin receptor sensitizers
inhibitors of glucose absorbance
incretins/mimics
inhibitors of glucose reuptake in the kidney
others
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19
Q

mechanism of action of sulfonylureas

A

activate residual B cells to release insulin by binding to and activating SUR1 ( a subunit of the K+/ATP channel)
replace Mg2+/ADP on SUR1 that activate the channel, similar to the fed state

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20
Q

effect of sulfonylureas

A

may decrease hepatic clearance of insulin

decrease serum glucagon by simulating somatostatin release

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21
Q

first gen sulfonylureas

A

tolbutamide
tolazamide
chlorpropamide

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22
Q

second gen sulfonylureas

A

binds to SUR1 with higher affinity, lower dose required
glyburide
glipizide
glimepiride

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23
Q

sulfonylureas pharmacokinetics

A

orally available
bound to plasma albumin
metabolized by the liver
metabolites excreted in the urine

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24
Q

adverse effects of sulfonylureas

A

infrequent

hypoglycemia and weight gain

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25
Q

contraindications for sulfonylureas

A

DM1
pregnancy
lactation
significant hepatic or renal insufficiency

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26
Q

what class of drugs are meglitinides

A

insulin secretagogues (along w sulfonylureas)

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27
Q

mechanism of action of meglitinides

A

similar to sulfonylureas

binds to SUR1 at a different site to activate the K+/ATP channel

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28
Q

specific meglitinides drugs

A

repaglinide
nateglinide
rapid onset of action

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29
Q

adverse effects of meglitinides

A

hypoglycemia

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30
Q

contraindications for meglitinides

A

hepatic insufficiency

cleared by liver

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31
Q

what class of drugs does metformin fall under?

A

insulin sensitizers

biguanides

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32
Q

what is the euglycemic effect

A

helps maintain normal blood glucose levels without producing hypoglycemia

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33
Q

mechanism of action of metformin

A

reduced hepatic gluconeogenesis (main therapeutic effect)
increases peripheral glucose uptake
activates AMP-activated protein kinase (AMPK)
inhibits mTOR-C1

34
Q

pharmacological actions of metformin

A

inhibits gluconeogenesis
does not promote weight gain or hypoglycemia
can reduce plasma TGs by 15-20%

35
Q

clinical uses of metformin

A

1st line therapy for DM2
oral dosage 500 mg- 2.55 g
take with or after food
also useful in treating polycystic ovary syndrome and non-alcoholic fatty liver disease (NAFLD)

36
Q

metabolism and excretion of metformin

A

orally effective
half life 1.5 - 3 h
not bound to plasma protein, not metabolized, excreted by the kidney as parent compound

37
Q

lactic acidosis in the context of metformin toxicity

A

rare but life threatening
blocking gluconeogenesis, may impair metabolism of lactic acid
more common in patients with renal insufficiency
dose related complication

38
Q

acute adverse effects of metformin

A

mostly GI related (20% of patients)

reduced B12 absorption

39
Q

what class of drugs due thiazolidinediones (TZDs) fall into

A

insulin sensitizers

40
Q

mechanism of action of TZDs

A

PPARy agonists with PPARa agonist activity
in adipose tissue, PPARy activators promote transport of serum lipids to adipose tissue
may also activate PPARy in other tissues to promote insulin sensitivity
-decrease hepatic gluconeogenesis
-enhance uptake of glucose by skeletal muscle cells

41
Q

specific TZD drugs

A

rosiglitazone

pioglitazone

42
Q

rosiglitazone affinity

A

10x more PPARy affinity than pioglitazone

43
Q

pioglitazone affinity

A

balances between PPARy and PPARa

44
Q

effect of TZD drugs

A

reduce glucose and TG levels

metabolized in liver

45
Q

adverse effects of TZDs

A

weight gain
hepatic toxicity by some
congestive heart failure exacerbation
losing popularity due to these effects

46
Q

inhibitors of intestinal glucose absorption

A

a-glucosidase inhibitors

acarbose and miglitol

47
Q

mechanism of action of a-glucosidase inhibitors

A

competitive and reversible inhibitors of pancreatic a-amylase and intestinal a-glucosidase enzymes

  • increased time required to absorb complex carbs
  • reduces postprandial glucose peak
48
Q

effect of a-glucosidase inhibitors

A

monotherapy reduces fasting glucose by 20-30 and postprandial by 40-50
reduces HbA1c by 0.7-0.9%
often used in combo with other agents
no risk for hypoglycemia

49
Q

adverse effects of a-glucosidase inhibitors

A

flatulence, bloating, and diarrhea

not recommended for those with inflammatory bowel conditions

50
Q

what are the incretins

A

GLP-1 and GIP

51
Q

secretion of GLP-1

A

enteroendocrine cells (L cells) in the ileum
encoded by proglucagon gene and derived from the natural proglucagon protein
release stimulated by nutrients entering the gut

52
Q

physiologic effects of GLP-1

A

pancreas: stimulate insulin and decrease glucagon secretion
stomach: delay gastric emptying
hypothalamus: decrease appetite

53
Q

what are the GLP-1 analogues

A

exenatide
liraglutide
albiglutide
duraglutide

54
Q

mechanism of action of GLP-1 analogues

A

increases insulin secretion
suppresses glucagon secretion
slows gastric emptying
central appetite suppression

55
Q

adverse effects of GLP-1 analogues

A

nausea, vomiting, diarrhea

low risk of hypoglycemia

56
Q

differences between GLP-1 analogues

A

duration of action, longer w newer drugs
exenatide- 30 min - 2 h
liraglutide and albiglutide- once daily dosing
duraglutide- once weekly dosing

57
Q

other class of incretin drugs

A

inhibitors of DDP-4

58
Q

function of DDP-4

A

degrades endogenous incretins as well as other structurally similar peptides

59
Q

mechanism of action of DDP-4 inhibitors

A

increase level of endogenous incretins

60
Q

specific DDP-4 inhibitors

A

sitagliptin
saxagliptin
linagliptin
alogliptin

61
Q

contraindication for DPP-4 inhibitors

A

don’t use in combo with GLP-1 analogs (less susceptible to DDP-4 degradation)

62
Q

what are inhibitors of glucose reuptake in the kidney

A

SGLT2 inhibitors

63
Q

what is the function of SGLTs

A

glucose is freely filtered by renal glomeruli and reabsorbed in the proximal tubules by sodium glucose transporters (SGLTs)
SGLT2 accounts for 90% of glucose reabsoprtion

64
Q

effect of inhibition of SGLT2

A

causes glycosuria and lowers glucose levels in patients with hyperglycemia

65
Q

contraindications of SGLT2 inhibitors

A

efficacy reduced in chronic kidney disease

66
Q

major side effects of SGLT2 inhibitors

A

increased incidence of genital infections and UTIs affecting 8-9% of patients
osmotic diuresis can cause intravascular volume contraction and hypotension
weight loss

67
Q

specific SGLT2 inhibitors

A

canagliflozin
dapagliflozin
empagliflozin

68
Q

what is pramlintide

A

amylin analog

69
Q

mechanism of action of pramlintide

A

mimics high dose pharmacologic effects of amylin
pancreas: increases insulin and decreases glucagon secretion
stomach: delays gastric emptying
hypothalamus: decreases appetite
similar to GLP-1 or GIP

70
Q

pharmacokinetics of pramlintide

A

preprandial use as adjunct to insulin improves postprandial glucose control in DM1 and DM2
renal metabolism and excretion

71
Q

adverse effects of pramlintide

A

hypoglycemia and GI symptoms

72
Q

what is covlesevalam

A

bile acid sequestrant, cholesterol lowering drug

73
Q

mechanism of action of covlesevalam

A

not fully understood
interrupts enterohepatic circulation
-decreases farnesoid X receptor (FXR) activation
-may impair glucose absorption

74
Q

what does FXR do

A

has multiple effects on cholesterol, glucose, and bile acid metabolism
bile acids are natural ligands

75
Q

adverse effects of covlesevalam

A

can exacerbate hypertriglyceridemia common in DM2

76
Q

what is bromocriptine

A

dopamine agonist

77
Q

mechanism of action of bromocriptine

A

unknown

78
Q

adverse effects of bromocriptine

A

nausea, fatigue, dizziness, vomiting, headache

79
Q

principles of combination therapy

A

combine different mechanisms of action
target different proteins
advantage of using lower doses
fewer adverse effects

80
Q

combination therapy in treating DM2

A

begin with monotherapy with metformin, GLP-1 mimic, SGLT2 inhibitor, or DDP-4 inhibitor
add additional agents as needed to attain target HbA1c
finally, add insulin therapy to other agents

GIR Test 1 (24 decks)

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