Download Steroids, Aspergillus and antifungals

Steroids, Aspergillus, and
Antifungals
Russell E. Lewis, Pharm.D., FCCP, BCPS
Associate Professor
University of Houston College of Pharmacy &
The University of Texas M.D. Anderson Cancer Center
UH Anti-Infective
Research Laboratories
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?
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)
adrenal
glands
Overview of steroid synthesis
2-AcetylCoA
mevalonate
Drugs designed to target one of these pathways
have the potential to affect multiple pathways
Mineralocorticoids
squalene
lanosterol
cholesterol
Kidneys
Aldosterone
(regulation of sodium and potassium)
in Aspergillus
Glucocorticoids
Deoxycorticosterone
Liver, pancreas, other tissue
(glucose production, metabolism)
Progestagens
Progesterone
11-deoxycortisol
Cortisol
Immune system
(feedback mechanism
to control inflammation)
ergosterol
Androgens
Testosterone
Estradiol
Sex steroids
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
Glucocorticoids are used to control inflammation in
allergic bronchopulmonary aspergillosis
Fungal
spores
Mild disease
Prednisone 30 mg per day (0.5 mg/kg) 1-2 weeks;
then alternate days for 6-8 weeks
Decrease daily prednisone dose by 5-10 mg every 2 weeks
Minimal
fibrosis
Minimal
Minimal
mucus
muscle thickness
Increased
fibrosis
Increased
inflammatory cells
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
mucus
Increased muscle
thickness
Chronic disease
with airway remodeling
Effect of glucocorticoid
on airway remodeling
Image courtesy of NIAID/ NIH
Gilley, Godblatt and Judson . Aspergillosis: From Diagnosis to Prevention. 2009
What are the possible risks of staying on high doses of
prednisone for prolonged periods?
Hypothalamus
CRH
Pituitary
Muscle weakness
Ocular
ACTH
cataracts
glaucoma
Cardiovascular
Hypertension
Hyperlipidemia
Artherosclerosis
Adrenal
Adrenal (HPA) suppression
(your cortisol set point)
Diabetes mellitus
high blood sugars
Gastointestinal
Peptic ulcer disease
Gastritis
Psychological
Euphoria
Depression
Insomnia
Psychosis
Infections
Thinning skin/
Fat re-distribution
Decreased bone density
Osteoperosis/necrosis
Increased risk of fracture
Growth inhibition
what are the
specific risks?
What are the effects of
glucocorticoids on immunity?
1. Suppressed cell-mediated immunity
2. “Mask” symptoms of infection
Neutrophils
Monocytes/ macrophages
prednisone
Increased susceptibility
to bacterial and fungal
infections
Increased susceptibility to
some intracellular bacterial
and fungal infections
T-lymphocytes
CD4+
communication
CD8+
Lymphocytes
Increased susceptibility
to intracellular bacterial
pathogens, fungi and viruses
communication
What is the “threshold” glucocorticoid
dose for invasive aspergillosis?
Ribaud et al, Clin Infect Dis;1999;28:322
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)
Key point #2
• Synthetic glucocorticoids (e.g., prednisone) are often the
most effective therapy for preserving lung function in
patients with allergic/inflammatory 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
How does your body act on
medications?
If drug is not water soluble,
it must be chemically modified
in the liver to make the drug
more water soluble
Two major types of chemical modifications to
make drugs more water soluble:
1. Oxidative reactions (CYP enzymes)
2. Synthetic (water soluble molecule added)
Drug interactions can occur if
a patient is taking two or
more medications that:
If drug is already
water soluble, it is
filtered by kidneys
Some drugs can
be passed in stool
without modification
Passed in urine
• Are metabolized through the same
pathway
• Block these pathways
• Induce (accelerate) these pathways
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
highest potential for drug
interactions
Azole antifungals work by inhibiting an enzyme in fungi that is responsible for
making cell membrane sterol called ergosterol....
The newer (triazole) antifungals
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
broad(er)
spectrum
Aspergillus
cytochrome P450
lanosterol a-demethylase (Erg11)
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 body’s 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”
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
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
17β-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 1994;140:2475-2479.
Thank you
Neptune, Fontana di Trevi
Addendum
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 2009;43:519-27.
Kelly WH. Annals of Pharmacotherapy 2009;43:519-27.