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Pharmacology II > Nuclear Receptors > Flashcards

Nuclear Receptors Flashcards

1
Q

Pharmacodynamics

A

The effects of the drug on your body

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2
Q

Pharmacokinetics

A

The effects of your body on the drug

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3
Q

Is pharmacokinetics or pharmacodynamics the major contributor to differences in drug effects?

A

Pharmacokinetics

Absorption, distribution, metabolism**, and elimination

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4
Q

What are the 2 major ways drugs are excreted?

A

Through urine (kidneys) and bile (liver)

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5
Q

What -philicity are drugs in order to optimize oral absorption?
What is a problem with this?

A

Lipophilicity
But lipophilic drugs are poorly excreted by the kidney and liver, so metabolism needs to increase polarity and water solubility

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6
Q

Deactivation

A

When metabolites have less pharmacological activity than the initial compounds

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7
Q

Bioactivation

A

When the prodrugs are metabolized to pharmacologically active or toxic metabolites

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8
Q

First-pass effect

A

Drugs that are ingested orally first have to make it through the intestine and liver metabolism
Reduced bioavailability

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9
Q

CYP P450

A

Cytochrome P450 Gene Superfamily
CYP3A4 (family, subfam, isoform)
57 individual genes
Families 1, 2 and 3 are most relevant to human drug metabolism

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10
Q

Which CYP isoform is most important for drug metabolism?

A

CYP3A subfamily

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11
Q

CYP3A subfamily

A

Most relevant to human drug metabolism
Most abundant CYPs in intestine and liver (first pass effect)
Very broad substrate specificity
Metabolize 50-70% of drugs
May result in inhibition or induction of the metabolism of co-administered drugs

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12
Q

Nuclear Receptor Gene Superfamily

A 
49 individual genes
Ligand-activated transcription factors
Bind DNA and regulate gene expression
Activity is modified by ligands (drugs)
Ex: Pregnane X-receptor (PXR)
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13
Q

The Pregnane X-receptor

A

Highest level of expression in liver and intestine
Forms heterodimer with RXR
Resident in nucleus and bound to target genes in unliganded state
Binds to XREMs in promoter region of target genes (ex CYP3A)

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14
Q

XREM sequence

A

AGGTCA
Most are direct (this sequence with 3 rando nucleotides separating it) or everted (this backwards, 6 nucleotides, then this)

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15
Q

Pharmacokinetic consequences of induction of drug metabolism

A

Decreased bioavailability of the parent drug (more first pass metabolism)
Increased elimination of parent drug (systemic metabolism increased)
Decreased plasma concentration of parent drug (b/c more metabolism)
Increased plasma concentration of drug metabolites

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16
Q

Potential pharmacodynamic consequences of induction of drug metabolism

A

Loss of therapeutic benefit from parent drug (b/c it has been metabolized)
Increased toxicity or other adverse effects associated with drug metabolites
Potential for enhanced/excessive pharmacological effect of prodrug

17
Q

An inducer may enhance…

A 
Drug-drug interaction (the metabolism of co-adminstered drug)
Pharmacokinetic tolerance (its own metabolism)
18
Q

Beneficial effects of cyclosporine

A

Promotes survival of transplanted organs by causing immunosuppression
It’s dose dependent

19
Q

3 adverse effects of cyclosporine

A

Kidney damage
Gingival hyperplasia
Hirsutism (hair growth)

20
Q

St. John’s Wort

A

A herb used for centuries for medicinal purposes
Some evidence of effectiveness for treatment of mild depression
Hyperforin is the active ingredient - one of the most potent ligand activators for human PXR

21
Q

Similarities between lipodystrophy and obesity

A

Heterogenous disorders
Influenced by genetics, environment, and behaviour
Abnormal adipose tissue mass and function
Increased risk for various metabolic, reproductive, hormonal and developmental disorders
Can contribute to insulin resistance

22
Q

BMI

A

Body mass index

Weight in kilograms divided by the square of height in meters

23
Q

3 major medical complications of obesity

A

Diabetes
Dyslipidemia
Hypertension
They all contribute to coronary heart disease

24
Q

Type 1 vs Type 2 diabetes

A
  1. Reduced production of insulin

2. Reduced response to insulin

25
Q

Insulin vs Glucagon

A

Insulin: stimulates formation of glycogen, released when blood sugar is high, stimulates glucose uptake from the blood
Glucagon: stimulates breakdown of glycogen, released when blood sugar is low

26
Q

Reduced response of tissues to insulin results in…

5

A 
Decreased activation of membrane glucose transporters by insulin receptor
Decreased glucose uptake
Decreased glucose storage
Increased glucose synthesis
Elevated blood glucose levels
27
Q

Metabolic syndrome

A

Condition characterized by a cluster of CV risk factors including hypertension, hyperlipidemia, low HDL-cholesterol, systemic inflammation, procoagulation and type 2 diabetes

28
Q

Adipokines

A

Signalling molecules with hormone like actions
Synthesized and secreted by adipose tissue
Regulate energy metabolism in adipose as well as other tissues
Ex: leptin, adiponectin, TNFalpha

29
Q

What are some things that adipokines regulate? (8)

A 
Appetite and energy balance
Blood pressure
Angiogenesis
Vascular hemostasis
Inflammation and immunity
Lipid metabolism
Insulin sensitivity and glucose homeostasis
Nutrient transport
30
Q

What does lectin regulate?

A

Systemic energy intake and metabolism
Decreased food intake and increases energy expenditure
No leptin and you keep eating and become overweight

31
Q

Peroxisome Proliferator-Activated Receptors

A 
3 isoforms (alpha, beta and gamma)
Name comes from property of xenobiotic PPARa ligands to increase number and size of perioxisomes in liver
Endogenous ligands are fatty acids
32
Q

PPARy

A

High level of expression in adipocytes
Critical for adipocyte development
Regulates metabolic function of mature adipocytes
A therapeutic target for type 2 diabetes

33
Q

Result of PPARy knockout in the adipose tissue of mice

5

A

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

34
Q

Effect of PPARy loss of function mutations in humans (5)

A 
Partial lipodystrophy
Insulin resistance
Hepatic steatosis
Hypertension
Dyslipidemia
35
Q

Thiazolidinediones

A

Effective for treating type 2 diabetes
Improve insulin sensitivity in many tissues (liver, skeletal muscle, adipose)
Some evidence for a preventative effect
Protective role in mortality from CV disease
PPARy agonists

36
Q

2 examples of Thiazolidinediones

A

Avandia (rosiglitazone)
Actos (pioglitazone)
Ligand activators of PPARy

37
Q

PPARy needs to be present where in order for TZDs to work?

A

In adipose tissue

Not a big deal if its lacking in muscle or liver

38
Q

Clinical use of TZDs

A

Slow onset of action (weeks to months)
Used in combo with other antihyperglycemic therapies
Most common side effects are weight gain and edema
Concern of increased long term risk for heart failure and heart attack with Avandia

Pharmacology II (24 decks)

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