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.