Pharmacodynamics and pharmacokinetics of inhaled glucocorticoids

Glucocorticoids (GCs) are widely used by several specialties for the treatment of a variety of diseases and conditions. The unfavorable effect of oral GCs on bone health is well-documented. The ensuing from their use glucocorticoid-induced osteoporosis (GIOP) is the most common cause of medication-induced osteoporosis and fractures. It is uncertain, however, if, and in what extent, GCs administered by other routes affect the skeleton. In the present review, we quote current evidence on the effect of inhaled GCs, epidural and intra-articular steroid injections, and topical GCs on bone outcomes. Although evidence is limited and weak, it seems that a small proportion of the administered GCs may be absorbed, enter the systemic circulation, and adversely affect the skeleton. Potent GCs, higher doses, and longer treatment duration seem to infer the greater risk for bone loss and fractures. There are scarce data, and only for inhaled GCs, regarding the efficacy of antiosteoporotic medications in patients receiving GCs through routes other than oral. Further studies are needed to clarify the relationship between GC administration through these routes and bone outcomes and to help establishing guidelines for the optimal management of such patients.

The differences in the pharmacokinetic (PK) characteristics of inhaled corticosteroids (ICSs) critically influence the profile of each of them, but also the significant differences in glucocorticoid receptor selectivity, potency, and physicochemical properties are critical in defining the pharmacodynamic (PD) profile of an ICS. The PK and PD properties of ICSs used in asthma and the importance of their interrelationship have been reviewed. The differences among the ICSs in PK and PD must be considered when an ICS should be prescribed to an asthmatic patient because a better understanding of the PK/PD interrelationship of ICSs could be important to better fit with the between-patient variability and within-patient repeatability in the response to ICSs that often complicate the therapeutic approach to the asthmatic patient. The role of the device in influencing the PK profile of an ICS must be always considered because it is crucial. Also patient-related factors and disease severity affect pulmonary deposition of ICS.

We have optimized a formulation of a prodrug of dexamethasone (DXM), dexamethasone palmitate (DXP) for pulmonary delivery as a dry powder. Formulations were prepared by spray drying DXP with 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Hyaluronic Acid (HA) as excipients. Large porous particles around 13 μm were produced with a tap density of 0.05 g/cm³ and a Fine particle fraction around 40%. The palmitate moiety favors DXP insertion into DPPC bilayers therefore limiting its in vitro release as shown by differential scanning calorimetry. After administering DXP powder intratracheally to rats by insufflation, bronchoalveolar lavage fluid (BALF) and blood samples were collected up to 24 h and DXP and DXM concentrations were determined by HPLC analysis after extraction. PK parameters were evaluated according to a non-compartmental model. We observe that DXP remains for up to 6 h in the epithelial lining fluid (ELF) of the lungs at very high concentration. In addition, DXP concentration decreases according to two characteristic times. Consequently, DXM can be detected at rather important concentration in ELF up to 24 h. The passage of DXP from the lungs to the bloodstream is very poor whereas DXM seems to be absorbed in the blood more easily. These results suggest that once administered DXP undergoes two different processes: hydrolysis into DXM due to the presence of esterases in the lungs and distribution in the lung tissue. This formulation appears promising to reduce systemic exposure and prolong the effect of the drug locally.

To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA glycopyrronium on the human airway smooth muscle (ASM) tone.

We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method.

The acute administration of beclomethasone and glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα – cyclic adenosine monophosphate (cAMP) – protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and glycopyrronium was associated with an increase of cAMP concentrations.

Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA.

Ritonavir is currently a commonly prescribed protease inhibitor for human immunodeficiency virus (HIV) infection. Its potent inhibition of hepatic cytochrome P450 3A4 isoenzyme may increase systemic glucocorticoids concentrations, leading to potential suppression of the hypothalamic pituitary adrenal axis (HPA) and iatrogenic Cushing's syndrome (CS).

We describe a case of a 43-year-old woman with HIV infection that presented with a clinical overt CS resulting from the interaction between ritonavir and intranasal budesonide at low doses. Similar cases have been described with long-term concomitant use of many glucocorticoids with ritonavir but very few concerning inhaled or intranasal budesonide.

This case reinforces the importance of physicians to be aware of this interaction, promoting its early recognition and providing a careful assessment of potentially serious drug–drug interactions, especially when ritonavir is prescribed to a HIV-patient with bronchial hyperresponsiveness or rhinitis.