Nuclear Receptors

Question 1

Pharmacodynamics

Answer 1

The effects of the drug on your body

Question 2

Pharmacokinetics

Answer 2

The effects of your body on the drug

Question 3

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

Answer 3

Pharmacokinetics

Absorption, distribution, metabolism**, and elimination

Question 4

What are the 2 major ways drugs are excreted?

Answer 4

Through urine (kidneys) and bile (liver)

Question 5

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

Answer 5

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

Question 6

Deactivation

Answer 6

When metabolites have less pharmacological activity than the initial compounds

Question 7

Bioactivation

Answer 7

When the prodrugs are metabolized to pharmacologically active or toxic metabolites

Question 8

First-pass effect

Answer 8

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

Question 9

CYP P450

Answer 9

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

Question 10

Which CYP isoform is most important for drug metabolism?

Answer 10

CYP3A subfamily

Question 11

CYP3A subfamily

Answer 11

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

Question 12

Nuclear Receptor Gene Superfamily

Answer 12

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

Question 13

The Pregnane X-receptor

Answer 13

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)

Question 14

XREM sequence

Answer 14

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

Question 15

Pharmacokinetic consequences of induction of drug metabolism

Answer 15

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

Question 16

Potential pharmacodynamic consequences of induction of drug metabolism

Answer 16

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

Question 17

An inducer may enhance…

Answer 17

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

Question 18

Beneficial effects of cyclosporine

Answer 18

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

Question 19

3 adverse effects of cyclosporine

Answer 19

Kidney damage
Gingival hyperplasia
Hirsutism (hair growth)

Question 20

St. John’s Wort

Answer 20

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

Question 21

Similarities between lipodystrophy and obesity

Answer 21

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

Question 22

BMI

Answer 22

Body mass index

Weight in kilograms divided by the square of height in meters

Question 23

3 major medical complications of obesity

Answer 23

Diabetes
Dyslipidemia
Hypertension
They all contribute to coronary heart disease

Question 24

Type 1 vs Type 2 diabetes

Answer 24

1. Reduced production of insulin

2. Reduced response to insulin

Question 25

Insulin vs Glucagon

Answer 25

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

Question 26

Reduced response of tissues to insulin results in... | 5

Answer 26

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

Question 27

Metabolic syndrome

Answer 27

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

Question 28

Adipokines

Answer 28

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

Question 29

What are some things that adipokines regulate? (8)

Answer 29

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

Question 30

What does lectin regulate?

Answer 30

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

Question 31

Peroxisome Proliferator-Activated Receptors

Answer 31

``` 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 ```

Question 32

PPARy

Answer 32

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

Question 33

Result of PPARy knockout in the adipose tissue of mice | 5

Answer 33

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

Question 34

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

Answer 34

``` Partial lipodystrophy Insulin resistance Hepatic steatosis Hypertension Dyslipidemia ```

Question 35

Thiazolidinediones

Answer 35

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

Question 36

2 examples of Thiazolidinediones

Answer 36

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

Question 37

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

Answer 37

In adipose tissue | Not a big deal if its lacking in muscle or liver

Question 38

Clinical use of TZDs

Answer 38

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