Ashley Fletcher - School of Medicine

Pyoderma gangrenosum: the hazards of polypharmacy in patients with
impaired clearance mechanisms
Ashley Fletcher, Colleen Reisz
UMKC School of Medicine
•Pyoderma gangrenosum (PG) is a devastating
ulcerative skin disease. It typically occurs on the
lower legs in the setting of debility, impaired
clearance mechanisms and polypharmacy.
Inflammatory bowel disease as the most
frequent co-morbidity.1
•FXR is the link between xenobiotic sensing and BA regulation.
Control of BA metabolism is essential for clearance of toxic bile
acid salts.
Nuclear Receptor for Xenobiotics
•.FXRα is expressed in the liver, kidney, intestine and and renal
•We theorized that the uncontrolled pathergy
seen in PG was related to compromised endo
and xenobiotic clearance in patients with
polypharmacy. Debilitated patients with
compromised clearance mechanisms at the
intestinal lumen, liver or kidney often have the
dual burden of polypharmacy. Improvement in
pathergy may be facilitated by drug reduction.
• Drug reduction strategies included
cessation of specific drugs, dose reduction,
increase in dosing interval, class switch or
selection of another drug within class.
Vitamins and supplements were removed
except for vitamin D and renal vitamins in
patients with renal failure. Danazol, an
androgen with fibrinolytic effects, was added
to those with a known hypercoag disorder.
•FXR is the central receptor in hepatoprotection from BA
toxicity and has been shown to activate transcription of the
PXR gene, providing the mechanism by which FXR protects
the liver from the toxic effects of excess BA.4
• Farnesoid X, (FXR) the nuclear receptor that
regulates bile acid synthesis, directly affects
drug transport at the intestinal lumen.2
•. This is a case series of 13 female patients
with PG. We included biometric data,
comorbid states, Fitzpatrick phototyping, and
drug lists.
Nuclear Receptor for Bile Acids
•The nuclear receptors that control BA metabolism have dual
function in drug clearance
• Bile acid (BA) metabolism is controlled by
receptors that have dual functions in drug
• FXR-dependent hepatoprotection also involves the induction
of proteins involved in transporting bile acids and phospholipids
•PG may arise in patients with aberrant molecular
into the bile, including multidrug resistant protein 2.4
communication between bile and drug metabolism.
•FXR induces the expression of BSEP (ABCB11), a major
canalicular bile salt export pump, which belongs to the family of
ATP-binding cassette (ABC) transporters. This transporter
class is on the apical surface of the intestinal lumen.5
• All but two patients were obese.
• 6 of the 13 patients were on more than four drugs.
•The most complex drug lists included drug combinations for
pain control.
•Two patients were on early generation synthetic progestins.
•One patient developed vulvar ulceration one month after
starting a nutraceutical program for weight loss .
•Two patients had documented hypercoaguable states.
•Three exhibited early graying.
• One had pediatric onset restless leg syndrome.
Pt 1. 10 months after cessation of PPI and MVI, dose reduction Neurontin,
Probenacid. Addition of Danazol due to hypercoag state.
•Alterations in BA production and transporter activity change
drug metabolism and activity. The application of this
information is underutilized in patients with complex medical
situations and polypharmacy, such as those found in patients
with PG.
•Limitations: This is a small case series of women with PG
and the clinical results are not generalizable. They had
received many different treatments for their skin disease,
including steroids, immune suppressants, and locally applied
therapies from wound care clinics. Conclusions are theorized
because there is no hard evidence or tests to confirm.
•The initial evaluation of patients with PG should
include a careful medication history, specifically
targeting drugs that impact cholesterol metabolism, BA
formation and steroidogenesis.
• Reduction of polypharmacy should be given the
highest priority. This will require a coordinated
approach that seeks input from all caregivers.
Powell FC, Su WPD, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol.1996;34:395-409
Halilbasic E. Bile Acid Transporters and Regulatory Nuclear Receptors in the Liver and beyond. J Hepatol 2013: 58.1: 155-68.
Zollner G et al. Nuclear Receptors as Drug Targets in Cholestasis and Drug-induced Hepatotoxicity. Pharm & Ther 126.3 2010: 228-43.
Jonker, JW. et al. FXR and PXR: Potential Therapeutic Targets in Cholestasis. J. Steroid Biochem. Mol. Biol. 130.3-5 (2012): 147-58.
Albermann, N. et al. Expression of the Drug Transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in
Peripheral Blood Mononuclear Cells and Their Relationship with the Expression in Intestine and Liver. Biochem. Pharmacol. 70.6
(2005): 949-58.
6. Klaassen CD. "Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation." Rev. of Pharmacological Reviews.
American Society for Pharmacology and Experimental Therapeutics Mar. 2010: 1-96.
7. Wilkinson GR. Drug Metabolism and Variability among Patients in Drug Response. N Engl J Med.2005: 352: 2211-21.

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