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-InfectiveResearch 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)
cholesterol
Progestagens
Androgens
2-AcetylCoA
mevalonate
squalene
lanosterol
ergosterol
Progesterone
Deoxy-corticosterone
Mineralocorticoids
Kidneys(regulation of sodium and potassium)
Aldosterone
adrenal glands
in Aspergillus
Glucocorticoids
Testosterone Estradiol
Sex steroids
Liver, pancreas, other tissue(glucose production, metabolism)
Overview of steroid synthesis
Immune system(feedback mechanism
to control inflammation)
11-deoxycortisol
Drugs designed to target one of these pathwayshave the potential to affect multiple pathways
Cortisol
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
Mild disease
Minimalfibrosis
Minimalmuscle thickness
Minimalmucus
Effect of glucocorticoidon airway remodeling
Chronic diseasewith airway remodeling
Increasedfibrosis
Fungalspores
Increasedinflammatory cells Increased muscle
thickness
Increasedmucus
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
Image courtesy of NIAID/ NIHGilley, Godblatt and Judson . Aspergillosis: From Diagnosis to Prevention. 2009
Goals of treatment: Preserve lung function through suppression of inflammation to Aspergillus antigens andthe inflammatory response of asthma with the lowest possible (cumulative) exposure to steroids
What are the possible risks of staying on high doses of prednisone for prolonged periods?
cataractsglaucoma
Hypothalamus
Pituitary
Adrenal
Adrenal (HPA) suppression (your cortisol set point)
Ocular
CardiovascularHypertensionHyperlipidemiaArtherosclerosis
Muscle weakness
Diabetes mellitus
PsychologicalEuphoriaDepressionInsomniaPsychosis
Decreased bone densityOsteoperosis/necrosisIncreased risk of fractureGrowth inhibition
GastointestinalPeptic ulcer diseaseGastritis
Infections
Thinning skin/Fat re-distribution
high blood sugars
what are thespecific risks?
CRH
ACTH
What are the effects of glucocorticoids on immunity?
Neutrophils
Increased susceptibilityto bacterial and fungalinfections
Monocytes/ macrophages
Increased susceptibility to some intracellular bacterial and fungal infections
prednisone
Lymphocytes
Increased susceptibilityto intracellular bacterialpathogens, fungi and viruses
1. Suppressed cell-mediated immunity2. “Mask” symptoms of infection
CD4+CD8+
T-lymphocytes
XX
communication 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
`
Mouth and pharynx
~ 80-90% swallowed(↓spacer/mouth wash)
GI tractLiver
Inactivation in liver,including CYP 3A4(first pass metabolism)
Systemic circulation
Adverse effects
~ 10-20% inhaled
Lungs
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 alreadywater soluble, it is filtered by kidneys
Passed in urine
Some drugs canbe passed in stoolwithout modification
If drug is not water soluble,it must be chemically modifiedin 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 ifa patient is taking two ormore medications that:
• 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
Aspergilluscytochrome P450lanosterol a-demethylase (Erg11)
Humancytochrome P450 3A4
(responsible for metabolizing35% of all drugs used therapeuticallyin humans)
non-specific
broad(er)spectrum
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
Hypothalamus
Pituitary
Adrenal
Adrenal (HPA) axis
CRH
ACTH
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
Ng et al. Microbiology 1994;140:2475-2479.
Modest effect in the test tube, but the importance(relative to immunosuppression in the body) is notwell understood
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.