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Pharmacology II > Nuclear Receptors > Flashcards

Nuclear Receptors Flashcards

1
Q

Variability of drug metabolism is a complicating factor in ? (3)

A

Drug development
Drug therapy
Toxicology

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2
Q

What is the major cause of adverse drug-drug interactions?

A

Inhibition and induction of CYP metabolism by environmental factors

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3
Q

2 elimination processes?

A

Metabolism

Excretion

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4
Q

2 types of excretion and examples for each?

A

Major : urine, bile

Minor : saliva, sweat, milk, other body fluids, exhalation

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5
Q

What type of compounds are better for oral absorption?

A

organic compounds

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6
Q

What polarity and ionization are best for absorption?

A

Low polarity

Low ionization

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7
Q

Lipophilic drugs are poorly excreted by the ____ and ____

A

kidney

liver

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8
Q

Metabolism increases _____ and ____ ________

A

polarity

water solubility

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9
Q

Deactivation?

A

Metabolite with less pharmacological activity

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10
Q

Bioactivation? What type of drug is involved?

A

Drugs that have more pharmacologically active or toxic metabolites
Prodrugs

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11
Q

First-pass effect?

A

Intestine has a significant metabolic capacity for some drugs

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12
Q

Major site for metabolism?

A

Liver

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13
Q

Most common CYP450 enzyme?

A

3A4

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14
Q

CYP450 enzymes have highest abundance in _____ and ______

A

liver

intestine

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15
Q

Activity of CYP3A is affected by what? (2)

This leads to ____ or ______ of the enzyme.

A

Drugs
Diet
Inhibition or induction

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16
Q

Two regions of the CYP3A4 gene?

A

Regulatory

Structural

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17
Q

What process does the structural part of CYP3A4 gene go through?

A

Transcription
Translation
Protein
Increased drug metabolism

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18
Q

What is the role of the regulatory region of CYP3A4?

It has various binding sites for _____ _____

A

Control rate of expression of structural component of gene

Transcription factors

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19
Q

What is a sensor/transducer useful for?

A

Senses drug/diet when it enters the body.

It then transduces the signal to produce a change in expression of CYP3A4

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20
Q

What gene superfamily fo the sensor/transducers belong?

A

Nuclear Receptor Gene Superfamily

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21
Q

NR gene superfamily are what kind of protein?

A

Ligand-activated transcription factors

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22
Q

NR1l’s are of greatest relevance to what type of metabolism?

Which two receptors are involved?

A

Xenobiotic

Pregnane X-receptor (PXR, NR1l2) and Constitutive Androstane Receptor (CAR, NR1l3)

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23
Q

The Pregnane X-receptor (PXR, NR1l2) has highest level of expression where? (2)

A

Liver

Intestine

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24
Q

Pregnane X-receptor (PXR, NR1l2) forms heterodimer with ______.
Is this active or inactive form?

A

Retinoid X-receptor (RXR ; NR2B)

Active

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25
Q

Pregnane X-receptor (PXR, NR1l2) resides in the ______ and is bound to target genes in which state?

A

Nucleus

Unliganded

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26
Q

Pregnane X-receptor (PXR, NR1l2) binds where in the promoter region of target genes?

A

Xenobiotic Responsive Enhancer Modules (XREM’s)

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27
Q

Two configuration of XREMs?

A

Direct : Consensus DR3

Everted : Consensus ER6

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28
Q

Drugs that are PXR ligands and induce CYP3A4? (9)

A 
Phenytoin
Rifampicin
Dexamethasone
Verapamil
Lovastatin
Carbamazepine
Clotrimazole
Nifedipine
Hyperforin
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29
Q

PK consequences of induction of drug metabolism? (4)

A

Decreased bioavailability (1st pass metabolism)
Increased elimination (systemic metabolism)
Decreased plasma concentration
Increased plasma conc. of metabolites

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30
Q

PD consequences of induction of drug metabolism? (3)

A

Loss of therapeutic benefit
Increased adverse effects
If prodrug : enhanced/excessive pharmaco. activity

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31
Q

How are PXR and CYP3A4 similar? (2)

A

Expression patterns

Ligand diversity

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32
Q

Induction of CYP3A4 metabolism by PXR is what kind of response?

A

Adaptive

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33
Q

Inducers of CYP3A4 may enhance what? (2)

A

The metabolism of co-administered drug (drug-drug metabolism)
Its own metabolism (PK tolerance)

34
Q

Beneficial adverse effect of cyclosporine?

A

Promotes survival of transplanted organs

35
Q

4 adverse affects of cyclosporine?

A

Increased risk of infection and cancer
Kidney damage
Gingival hyperplasia
Rash, hives, itching, breathing difficulties

36
Q

Is kidney damage and gingival hyperplasia (effects of cyclosporine) dose-dependent?
Are they related to pharmacological activity?

A

Dose-dependent

No, they are just side effects

37
Q

Active ingredient in St. John’s Wort?

What is it’s role?

A

Hyperforin

Potent ligand activator for human PXR

38
Q

8 drugs contraindicated with St. John’s Wort?

A 
Erythromycin
Atorvastatin
Indinavir
Cyclosporin
Warfarin
Fluoxetine
Sumatriptan
Oral contraceptives
39
Q

Lipodystrophy and obesity are _______ disorders

They are influenced by ______, ______ and ________

A

Heterogenous
Genetics
Environment
Behaviour

40
Q

Lipodystrophy and obesity are characterized by abnormal…..?

A

Adipose tissue mass and function

41
Q

Obesity is commonly defined by what?

A

BMI : weight (kg) divided by square of height (m)

42
Q

What is a good indicator to see if a person will develop cardiovascular disease?

A

waist:hip ratio

43
Q

3 risk factors for coronary heart disease?

A

Diabetes
Dyslipidemia
Hypertension

44
Q

A high BMI is typically the cause for which disease?

A

Type II diabetes

45
Q

MOA of insulin

A

High blood sugar : Insulin released from pancreas

  • Stimulates glucose uptake from bloodstream to tissue cells
  • Stimulates formation of glycogen in liver
46
Q

Type I diabetes vs Type II diabetes?

A

Type I : reduced production of insulin

Type II : reduced response to insulin (insulin resistance)

47
Q 
What is insulin resistance?
This results in:
\_\_\_\_\_\_\_ activation of Glut-4
\_\_\_\_\_\_\_\_\_ glucose uptake
\_\_\_\_\_\_\_\_\_ glucose storage
\_\_\_\_\_\_\_\_\_ glucose synthesis
\_\_\_\_\_\_\_\_\_\_\_ blood glucose levels
A 
Reduced response of tissues to insulin
Decreased
Decreased
Decreased
Increased
Elevated
48
Q

Chronic insulin resistance is associated with which syndrome?
What is it?

A

Metabolic syndrome
Cluster of cardiovascular risk factors (hypertension, hyperlipidemia, low HDL-cholesterol, systemic inflammation, procoagulation and insulin resistance)

49
Q

Adipose tissue is an _____ organ

50
Q

Molecules found in adipose tissue?

A

adipokines

51
Q

Adipokines regulate ____ _________

A

energy metabolism

52
Q

5 examples of adipokines

A 
Leptin
Adiponectin
Chemerin
Resistin
TNFalpha
53
Q

4 roles of adipokines

A

Appetite and energy balance
Angiogenesis
Inflammation and immunity
Insulin sensitivity and glucose homeostasis

54
Q

Systemic energy intake and metabolism (food intake and energy expenditure) is regulated by which adipokine?

55
Q

Leptin deficiency is associated with _______

A

early onset obesity

56
Q

Addition of leptin to leptin deficient person increases? (1)

It decreases what? (5)

A

HDL-cholesterol

Body weight, BMI, food intake, cholesterol, TG

57
Q

Pro-insulin resistance:

3 adipokines that have increased levels of secretion in obesity?

A

Resistin
TNFalpha, IL-6, other cytokines
RBP4

58
Q

Pro-insulin sensitivity:
2 adipokines that have increased secretion in obesity?
2 adipokines that decrease?

A

Increase : leptin, visfatin

Decrease : Adiponectin, Omentin

59
Q

Normal adipose function is essential for what?

A

systemic energy homeostasis

60
Q

With obesity, do proinflammatory adipokines increase/decrease?

61
Q

With obesity, do insulin sensitizing adipokines increase or decrease?

62
Q

With obesity, do anti-inflammatory adipokines increase or decrease?

63
Q

Receptor located in adipocytes?

A

PPARgamma (Peroxisome Proliferator-Activated Receptors)

64
Q

How many isoforms of PPAR? What are they?

A

alpha, betta and gamma

NR1C1, NR1C2, NR2C3

65
Q

Endogenous ligands of PPAR?

A

Fatty acids

66
Q

Does PPARgamma have high or low levels of expression?

67
Q

Therapeutic target for type II diabetes?

68
Q

Roles of PPARy? (2)

A

Critical for adipocyte development

Regulates metabolic function of mature adipocytes

69
Q

What happens when knocking out PPARy specifically in the adipose? (5)

A

Partial lipodystrophy
Fewer, enlarged adipocytes
Reduced levels of insulin sensitizing adipokines
Hyperlipidemia
Insulin resistance of adipose, liver and skeletal muscle

70
Q

PPARy mutations cause ________ in humans

A

lipodystrophy

71
Q

PPARy loss of function mutation major effects? (3) (all patients studied developed this)
Three other diseases?

A

Dyslipidemia
Partial lipodystrophy
Insulin resistance

Hypertension
Hepatic steatosis
PCOS

72
Q

Effective treatment of diabetes?

A

Thiazolidinediones

73
Q

Role of thiazolidinediones?

A

Improve insulin sensitivity in many tissues

74
Q

Two thiazolidinediones in clinical use? They are PPARy _________

A

Rosiglitazone (avandia)
Pioglitazone (actos)

PPARy agonists

75
Q

3 lines of evidence that adipose tissue is the primary site of action of TZDs?

A
  • Mice lacking adipose PPARy are refractory to insulin sensitizing effects of TZDs
  • Insulin sensitizing effects of TZDs are retained in mice lacking muscle or liver PPARy
  • The greatest impact upon gene expression in response to TZDs occurs in adipose tissue
76
Q

MOA of thiazolidinediones to improve insulin sensitivity?
It decreases… ? (4)
It increases _________`

A

Activation of PPARy in adipose
Modification of gene expression
-Decrease of lipolysis, free fatty acids, TNFa, resistin
-Increase adiponectin

77
Q

What is the onset of acion of TZDs?

A

Slow (weeks-months)

78
Q

TZDs are used in combination with _________ therapies

A

antihyperglycemic

79
Q

TZDs have the following side effects (2)

This expands ______ ___________ and is concern for ___________

A

weight gain, edema
Plasma volume
Hypertension

80
Q

TZDs have increased long-term risk for ________ and _____________ with rosiglitazone

A

Heart failure

Heart attack

Pharmacology II (21 decks)

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