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Pharmacology II > Nuclear Receptors > Flashcards

Nuclear Receptors Flashcards

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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
Pregnane X-receptor (PXR, NR1l2) resides in the ______ and is bound to target genes in which state?
Nucleus | Unliganded
26
Pregnane X-receptor (PXR, NR1l2) binds where in the promoter region of target genes?
Xenobiotic Responsive Enhancer Modules (XREM's)
27
Two configuration of XREMs?
Direct : Consensus DR3 | Everted : Consensus ER6
28
Drugs that are PXR ligands and induce CYP3A4? (9)
``` Phenytoin Rifampicin Dexamethasone Verapamil Lovastatin Carbamazepine Clotrimazole Nifedipine Hyperforin ```
29
PK consequences of induction of drug metabolism? (4)
Decreased bioavailability (1st pass metabolism) Increased elimination (systemic metabolism) Decreased plasma concentration Increased plasma conc. of metabolites
30
PD consequences of induction of drug metabolism? (3)
Loss of therapeutic benefit Increased adverse effects If prodrug : enhanced/excessive pharmaco. activity
31
How are PXR and CYP3A4 similar? (2)
Expression patterns | Ligand diversity
32
Induction of CYP3A4 metabolism by PXR is what kind of response?
Adaptive
33
Inducers of CYP3A4 may enhance what? (2)
The metabolism of co-administered drug (drug-drug metabolism) Its own metabolism (PK tolerance)
34
Beneficial adverse effect of cyclosporine?
Promotes survival of transplanted organs
35
4 adverse affects of cyclosporine?
Increased risk of infection and cancer Kidney damage Gingival hyperplasia Rash, hives, itching, breathing difficulties
36
Is kidney damage and gingival hyperplasia (effects of cyclosporine) dose-dependent? Are they related to pharmacological activity?
Dose-dependent | No, they are just side effects
37
Active ingredient in St. John's Wort? | What is it's role?
Hyperforin | Potent ligand activator for human PXR
38
8 drugs contraindicated with St. John's Wort?
``` Erythromycin Atorvastatin Indinavir Cyclosporin Warfarin Fluoxetine Sumatriptan Oral contraceptives ```
39
Lipodystrophy and obesity are _______ disorders | They are influenced by ______, ______ and ________
Heterogenous Genetics Environment Behaviour
40
Lipodystrophy and obesity are characterized by abnormal.....?
Adipose tissue mass and function
41
Obesity is commonly defined by what?
BMI : weight (kg) divided by square of height (m)
42
What is a good indicator to see if a person will develop cardiovascular disease?
waist:hip ratio
43
3 risk factors for coronary heart disease?
Diabetes Dyslipidemia Hypertension
44
A high BMI is typically the cause for which disease?
Type II diabetes
45
MOA of insulin
High blood sugar : Insulin released from pancreas - Stimulates glucose uptake from bloodstream to tissue cells - Stimulates formation of glycogen in liver
46
Type I diabetes vs Type II diabetes?
Type I : reduced production of insulin | Type II : reduced response to insulin (insulin resistance)
47
``` What is insulin resistance? This results in: _______ activation of Glut-4 _________ glucose uptake _________ glucose storage _________ glucose synthesis ___________ blood glucose levels ```
``` Reduced response of tissues to insulin Decreased Decreased Decreased Increased Elevated ```
48
Chronic insulin resistance is associated with which syndrome? What is it?
Metabolic syndrome Cluster of cardiovascular risk factors (hypertension, hyperlipidemia, low HDL-cholesterol, systemic inflammation, procoagulation and insulin resistance)
49
Adipose tissue is an _____ organ
Endocrine
50
Molecules found in adipose tissue?
adipokines
51
Adipokines regulate ____ _________
energy metabolism
52
5 examples of adipokines
``` Leptin Adiponectin Chemerin Resistin TNFalpha ```
53
4 roles of adipokines
Appetite and energy balance Angiogenesis Inflammation and immunity Insulin sensitivity and glucose homeostasis
54
Systemic energy intake and metabolism (food intake and energy expenditure) is regulated by which adipokine?
leptin
55
Leptin deficiency is associated with _______
early onset obesity
56
Addition of leptin to leptin deficient person increases? (1) | It decreases what? (5)
HDL-cholesterol Body weight, BMI, food intake, cholesterol, TG
57
Pro-insulin resistance: | 3 adipokines that have increased levels of secretion in obesity?
Resistin TNFalpha, IL-6, other cytokines RBP4
58
Pro-insulin sensitivity: 2 adipokines that have increased secretion in obesity? 2 adipokines that decrease?
Increase : leptin, visfatin | Decrease : Adiponectin, Omentin
59
Normal adipose function is essential for what?
systemic energy homeostasis
60
With obesity, do proinflammatory adipokines increase/decrease?
Increase
61
With obesity, do insulin sensitizing adipokines increase or decrease?
Decrease
62
With obesity, do anti-inflammatory adipokines increase or decrease?
Decrease
63
Receptor located in adipocytes?
PPARgamma (Peroxisome Proliferator-Activated Receptors)
64
How many isoforms of PPAR? What are they?
alpha, betta and gamma | NR1C1, NR1C2, NR2C3
65
Endogenous ligands of PPAR?
Fatty acids
66
Does PPARgamma have high or low levels of expression?
high
67
Therapeutic target for type II diabetes?
PPARgamma
68
Roles of PPARy? (2)
Critical for adipocyte development | Regulates metabolic function of mature adipocytes
69
What happens when knocking out PPARy specifically in the adipose? (5)
Partial lipodystrophy Fewer, enlarged adipocytes Reduced levels of insulin sensitizing adipokines Hyperlipidemia Insulin resistance of adipose, liver and skeletal muscle
70
PPARy mutations cause ________ in humans
lipodystrophy
71
PPARy loss of function mutation major effects? (3) (all patients studied developed this) Three other diseases?
Dyslipidemia Partial lipodystrophy Insulin resistance Hypertension Hepatic steatosis PCOS
72
Effective treatment of diabetes?
Thiazolidinediones
73
Role of thiazolidinediones?
Improve insulin sensitivity in many tissues
74
Two thiazolidinediones in clinical use? They are PPARy _________
Rosiglitazone (avandia) Pioglitazone (actos) PPARy agonists
75
3 lines of evidence that adipose tissue is the primary site of action of TZDs?
- 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
MOA of thiazolidinediones to improve insulin sensitivity? It decreases... ? (4) It increases _________`
Activation of PPARy in adipose Modification of gene expression -Decrease of lipolysis, free fatty acids, TNFa, resistin -Increase adiponectin
77
What is the onset of acion of TZDs?
Slow (weeks-months)
78
TZDs are used in combination with _________ therapies
antihyperglycemic
79
TZDs have the following side effects (2) | This expands ______ ___________ and is concern for ___________
weight gain, edema Plasma volume Hypertension
80
TZDs have increased long-term risk for ________ and _____________ with rosiglitazone
Heart failure | Heart attack

Pharmacology II (21 decks)

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