Nuclear Receptors Flashcards
Pharmacodynamics
The effects of the drug on your body
Pharmacokinetics
The effects of your body on the drug
Is pharmacokinetics or pharmacodynamics the major contributor to differences in drug effects?
Pharmacokinetics
Absorption, distribution, metabolism**, and elimination
What are the 2 major ways drugs are excreted?
Through urine (kidneys) and bile (liver)
What -philicity are drugs in order to optimize oral absorption?
What is a problem with this?
Lipophilicity
But lipophilic drugs are poorly excreted by the kidney and liver, so metabolism needs to increase polarity and water solubility
Deactivation
When metabolites have less pharmacological activity than the initial compounds
Bioactivation
When the prodrugs are metabolized to pharmacologically active or toxic metabolites
First-pass effect
Drugs that are ingested orally first have to make it through the intestine and liver metabolism
Reduced bioavailability
CYP P450
Cytochrome P450 Gene Superfamily
CYP3A4 (family, subfam, isoform)
57 individual genes
Families 1, 2 and 3 are most relevant to human drug metabolism
Which CYP isoform is most important for drug metabolism?
CYP3A subfamily
CYP3A subfamily
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
Nuclear Receptor Gene Superfamily
49 individual genes Ligand-activated transcription factors Bind DNA and regulate gene expression Activity is modified by ligands (drugs) Ex: Pregnane X-receptor (PXR)
The Pregnane X-receptor
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)
XREM sequence
AGGTCA
Most are direct (this sequence with 3 rando nucleotides separating it) or everted (this backwards, 6 nucleotides, then this)
Pharmacokinetic consequences of induction of drug metabolism
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
Potential pharmacodynamic consequences of induction of drug metabolism
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
An inducer may enhance…
Drug-drug interaction (the metabolism of co-adminstered drug) Pharmacokinetic tolerance (its own metabolism)
Beneficial effects of cyclosporine
Promotes survival of transplanted organs by causing immunosuppression
It’s dose dependent
3 adverse effects of cyclosporine
Kidney damage
Gingival hyperplasia
Hirsutism (hair growth)
St. John’s Wort
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
Similarities between lipodystrophy and obesity
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
BMI
Body mass index
Weight in kilograms divided by the square of height in meters
3 major medical complications of obesity
Diabetes
Dyslipidemia
Hypertension
They all contribute to coronary heart disease
Type 1 vs Type 2 diabetes
- Reduced production of insulin
2. Reduced response to insulin
Insulin vs Glucagon
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
Reduced response of tissues to insulin results in…
5
Decreased activation of membrane glucose transporters by insulin receptor Decreased glucose uptake Decreased glucose storage Increased glucose synthesis Elevated blood glucose levels
Metabolic syndrome
Condition characterized by a cluster of CV risk factors including hypertension, hyperlipidemia, low HDL-cholesterol, systemic inflammation, procoagulation and type 2 diabetes
Adipokines
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
What are some things that adipokines regulate? (8)
Appetite and energy balance Blood pressure Angiogenesis Vascular hemostasis Inflammation and immunity Lipid metabolism Insulin sensitivity and glucose homeostasis Nutrient transport
What does lectin regulate?
Systemic energy intake and metabolism
Decreased food intake and increases energy expenditure
No leptin and you keep eating and become overweight
Peroxisome Proliferator-Activated Receptors
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
PPARy
High level of expression in adipocytes
Critical for adipocyte development
Regulates metabolic function of mature adipocytes
A therapeutic target for type 2 diabetes
Result of PPARy knockout in the adipose tissue of mice
5
Lipodystrophy
Fewer, enlarged adipocytes
Reduced levels of insulin sensitizing adipokines
Hyperlipidemia
Insulin resistance of adipose, liver and skeletal muscle
Effect of PPARy loss of function mutations in humans (5)
Partial lipodystrophy Insulin resistance Hepatic steatosis Hypertension Dyslipidemia
Thiazolidinediones
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
2 examples of Thiazolidinediones
Avandia (rosiglitazone)
Actos (pioglitazone)
Ligand activators of PPARy
PPARy needs to be present where in order for TZDs to work?
In adipose tissue
Not a big deal if its lacking in muscle or liver
Clinical use of TZDs
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
