Steroids, Aspergillus, and Antifungals

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Steroids, Aspergillus, and Antifungals

• Russell E. Lewis, Pharm.D., FCCP, BCPSAssociate
  Professor
• University of Houston College of Pharmacy
• The University of Texas M.D. Anderson Cancer
  Center

UH Anti-Infective Research Laboratories
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Outline

• How do steroids and antifungals act on your body
  (pharmacology)...how does your body act on these
  drugs (pharmacokinetics)?
• What are the benefits/risks associated with
  taking these medications alone or in combination?
• Do steroids directly affect Aspergillus?

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Key point 1

• Humans and Aspergillus use similar enzyme
  pathways to synthesize
• Sterols for their cell membrane
• Humans cholesterol
• Fungi ergosterol
• Steroids specifically for humans
• Sex steroids (e.g., testosterone, estrogen)
• Mineralocorticoids (e.g., aldosterone)
• Glucocorticoids (e.g., cortisone)
• Soluble metabolites of drugs (i.e. how drugs are
  eliminated in humans)

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Overview of steroid synthesis
adrenal glands
2-AcetylCoA
Mineralocorticoids
mevalonate
Drugs designed to target one of these
pathways have the potential to affect multiple
pathways
squalene
cholesterol
lanosterol
Kidneys (regulation of sodium and potassium)
Aldosterone
in Aspergillus
Glucocorticoids
Deoxy- corticosterone
Liver, pancreas, other tissue (glucose
production, metabolism)
Progestagens
11-deoxycortisol
Progesterone
Cortisol
Immune system (feedback mechanism to control
inflammation)
Androgens
ergosterol
Testosterone
Estradiol
Sex steroids
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Glucocorticoids (steroids)

• Glucocorticoids (Glucose cortex steroid)
• Cortisol is the glucocorticoid synthesized in our
  body that regulates a variety of important
  cardiovascular, metabolic, and immunologic
  functions
• Important for adapting to stress
• Part of the feedback mechanism in the immune
  system that turns immune activity (inflammation)
  down
• Synthetic glucocorticoids (e.g., prednisone) can
  be prescribed to suppress a damaging immune
  response

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Glucocorticoids are used to control inflammation
in allergic bronchopulmonary aspergillosis
Fungal spores
Mild disease
Minimal fibrosis
Minimal mucus
Minimal muscle thickness
Goals of treatment Preserve lung function
through suppression of inflammation to
Aspergillus antigens and the inflammatory
response of asthma with the lowest possible
(cumulative) exposure to steroids
Increased fibrosis
Increased mucus
Increased inflammatory cells
Increased muscle thickness
Effect of glucocorticoid on airway remodeling
Chronic disease with airway remodeling
Image courtesy of NIAID/ NIH Gilley, Godblatt and
Judson . Aspergillosis From Diagnosis to
Prevention. 2009
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What are the possible risks of staying on high
doses of prednisone for prolonged periods?
Hypothalamus
CRH
Pituitary
Muscle weakness
Ocular
ACTH
cataracts glaucoma
Adrenal
Diabetes mellitus
Adrenal (HPA) suppression (your cortisol set
point)
Cardiovascular Hypertension Hyperlipidemia Arthero
sclerosis
high blood sugars
Gastointestinal Peptic ulcer disease Gastritis
Psychological Euphoria Depression Insomnia Psychos
is
Infections
what are the specific risks?
Decreased bone density Osteoperosis/necrosis Incre
ased risk of fracture Growth inhibition
Thinning skin/ Fat re-distribution
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What are the effects of glucocorticoids on
immunity?

1. Suppressed cell-mediated immunity
2. Mask symptoms of infection

Neutrophils Increased susceptibility to
bacterial and fungal infections
Monocytes/ macrophages Increased susceptibility
to some intracellular bacterial and fungal
infections
prednisone
T-lymphocytes
X
X
CD4
CD8
communication
communication
Lymphocytes Increased susceptibility to
intracellular bacterial pathogens, fungi and
viruses
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What is the threshold glucocorticoid dose for
invasive aspergillosis?
Ribaud et al, Clin Infect Dis199928322
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Inhaled corticoisteroids reduce the risk of side
effects because of less drug delivery to the
systemic circulation

10-20 inhaled
Mouth and pharynx
Lungs
80-90 swallowed (?spacer/mouth wash)
Systemic circulation
GI tract
Liver
Adverse effects
Inactivation in liver, including CYP 3A4 (first
pass metabolism)
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Key point 2

• Synthetic glucocorticoids (e.g., prednisone) are
  often the most effective therapy for preserving
  lung function in patients with allergic/inflammato
  ry responses in the lung due to Aspergillus
• ....however, their long term use can be
  associated with side effects, including severe
  infections
• Therefore, the goal is to use the minimally
  effective dose (oral or inhaled) that provides
  benefit

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How does your body act on medications?

• Two major types of chemical modifications to make
  drugs more water soluble
• Oxidative reactions (CYP enzymes)
• Synthetic (water soluble molecule added)

If drug is not water soluble, it must be
chemically modified in the liver to make the drug
more water soluble
Drug interactions can occur if a patient is
taking two or more medications that Are
metabolized through the same pathway Block
these pathways Induce (accelerate) these
pathways
If drug is already water soluble, it is filtered
by kidneys
Some drugs can be passed in stool without
modification
Passed in urine
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Antifungals used to treat aspergillosis

• Amphotericin B (intravenous only)
• Must be administered intravenously
• Typically reserved for patients who have not
  responded to other therapies
• Can be toxic to the kidneys
• Echinocandins (intravenous only)
• caspofungin
• micafungin,
• anidulafungin
• Azoles (can be given by mouth)
• itraconazole
• voriconazole
• posaconazole

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Azole antifungals work by inhibiting an enzyme in
fungi that is responsible for making cell
membrane sterol called ergosterol....
The newer (triazole) antifungals
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Azole antifungals work by inhibiting an enzyme in
fungi that is responsible for making cell
membrane sterol called ergosterol....
...but they can also can inhibit human liver
enzymes that metabolize drugs, leading to
drug-drug interactions
Human cytochrome P450 3A4 (responsible for
metabolizing 35 of all drugs used
therapeutically in humans)
non-specific
Aspergillus cytochrome P450 lanosterol
a-demethylase (Erg11)
broad(er) spectrum
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An example of liver metabolizing drug interaction
with voriconazole-inhibition
voriconazole inhibits the metabolism of
cyclosporin resulting
cyclosporin voriconazole
cyclosporin placebo
Clin Pharmacol Ther 2002 71226-234.
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An example of liver metabolizing drug interaction
with voriconazole-induction
phenytoin accelerates the metabolism
(clearance) of voriconazole resulting in
ineffective bloodstream concentrations
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What is the risk of administering oral azole
antifungals with inhaled corticoisteroids?

• Administration of high doses of synthetic
  steroids (e.g., prednisone, inhaled budenoside)
  for prolonged periods may suppress the bodys
  cortisol set point
• Because some steroids are metabolized in the gut
  and liver, the co-administration of an azole
  antifungal can reduce the metabolism of some
  steroids by 30-60, resulting in higher steroid
  bloodstream concentrations and greater than
  expected suppression of the cortisol set point
• Your doctor can lower your steroid dose and
  monitor blood tests to make sure your steroid
  dose is not too high

Adrenal (HPA) axis
Hypothalamus
CRH
Pituitary
ACTH
Adrenal
your cortisol thermostat
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Key point 3

• If your doctor has prescribed you an azole
  antifungal, be aware that you are at higher risk
  for experiencing drug-drug interactions-including
  steroid medications
• This risk can be reduced by adjusting the doses
  of your other medications, and with blood tests
• In some patients, antifungal therapy can lesson
  the dependence on steroids

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Do steroids have a direct effect on Aspergillus?
Sterol (10-6 M) Growth increase relative to control P value
Hydrocortisone 44 0.03
Ergosterol 30 0.183
17ß-oestradiol 8 0.277
Progesterone 3 0.937
Testosterone 15 0.211
Modest effect in the test tube, but the
importance (relative to immunosuppression in the
body) is not well understood
Ng et al. Microbiology 19941402475-2479.
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Thank you
Neptune, Fontana di Trevi
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Addendum
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All formulations are inhibited by CYP
3A4. Clinicians should be aware of the need to
use lower doses of most inhaled corticosteroids
with co-administration of CYP3A4 inhibitors
Kelly WH. Annals of Pharmacotherapy
200943519-27.
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Kelly WH. Annals of Pharmacotherapy
200943519-27.
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