Efficacy of Glucocorticoids

Glucocorticoids are the cornerstone of asthma therapy. The antiinflammatory effects of glucocorticoids reflect an inhibitory effect on essentially all phases of inflammation. Airway infiltration with eosinophils, mast cells, and basophils is decreased, although the effect on T cell population in the lungs is less clear. Glucocorticoids differentially downregulate Th 2 cytokines, including IL-4, IL-5, and IL-13, but appear to upregulate Th 1 cytokines, including IFN-γ and IL-12. Glucocorticoids reduce eotaxin and other eosinophil-associated chemokines but have little effect on IL-8 or cys-LTs. Glucocorticoids have a "permissive" effect on β-adrenergic receptors and help prevent desensitization, which may accompany therapy with long-acting drugs. Permissive effects on alpha adrenergic receptors (vasoconstriction) can reduce mucosal swelling. However, their efficacy for treatment of respiratory inflammatory disease depends on therapeutic concentrations in and below the epithelium of all diseased airways. However, whereas systemic therapy might provide the most consistent exposure to diseased airways, it also provides the greatest exposure to tissues other than the lungs, leading to adverse effects. Inhalant therapy is among the approaches used to minimize the systemic side effects of glucocorticoids used to treat inflammatory lung disease.

Inhalant Glucocorticoids

The preferred route in humans with mild disease is low-dose inhaled glucocorticoids. Beclomethasone was among the first aerosol glucocorticoids developed for inhalant therapy. Examples of corticosteroids marketed as inhalant metered devices (MDIs; see later discussion) in the United States include beclomethasone dipropionate (Beclovent), triamcinolone acetonide (Azmacort), flunisolide (Aerobid), budesonide (Pulmicort), fluticasone propionate (Flovent), and mometasone (Asmanex). However, control of inflammation in the peripheral airways is paramount to successful treatment of inflammatory lung disease. Several factors will impact the delivery of drug administered via the mouth or nares to the peripheral airways. The ideal inhalant device will easily and reproducibly deliver a predetermined dose of drugs to the lungs, with minimal deposition in other tissues. Turbulent airflow through contorted pathways (e.g., nares, sinuses, upper airways) will increase impaction of particles on mucosal surfaces precluding further delivery to peripheral airways. Rapid, shallow breathing will decrease delivery to the periphery. Use of a bronchodilator is indicated not only to reduce clinical signs but to increase effective delivery. Systemic treatment is indicated in bronchoconstricted conditions to ensure adequate delivery.

Drug can be delivered topically to the airways using three primary methods: nebulization, dry powder inhalers (DPI) (low or high to medium high resistance) and metered device inhaler (MDI) (pressurized MDIs). DPI and MDI deliver a specific amount of drug with each puff; the amount is specific to the device. With MDI, the drug is dissolved or suspended in a propellant (making up to 99% of the delivered dose) which is under pressure; stabilizers and excipients may be added. Phospholipids facilitate penetration and bioavailability by increasing surface area. Activation (breath or manual) releases a valve that delivers a predetermined volume of drug. Force of the volatile propellant followed by rapid evaporation causes disaggregation of the particles. The shelf life of MDI products has been prolonged by the addition of surface components. They commonly are associated with a face mask or spacer. Maximum particle size for airway deposition is 1 to 3 µm. Most are designed to deliver particles 1 to 5 µm in size; greater than 10 µm results in deposition in the oropharynx. Particle delivery with MDI is as little as 7–20% to the peripheral airways; the extent of delivery to cats, particularly using commercially available spacers, is not known although an MDI has been demonstrated to effectively deliver drug to the airways of cats. Note that the MDI may continue to deliver puffs, but may not contain drug; the number of puffs indicated on the label must be followed.

Chlorofluorocarbon propellants have been phased out because of their impact on ozone. Corticosteroid delivery of MDIs has been improved by the advent of hydrocarbon fluoroalkyl (HFA)-propelled MDI. Beclomethasone dipropionate delivery to peripheral airways increased from 5% to 15% for the chlorofluorocarbon-propelled preparation from 50% to 60% with the HFA propellant. Not only is total lung delivery increased, but the depth of penetration also is enhanced, which is critical to successful therapy. Manipulation of the drug has also proven to reduce side effects associated with inhalant glucocorticoids without decreasing efficacy.

Although inhalant delivery reduces side effects, they still occur. For example, systemic side effects associated with deposition of glucocorticoids on the pharynx and central airways and local side effects in the upper airway (e.g., dysphonia in up to 50% of the patients) led to the inclusion of "spacers" that removed larger particles before they penetrated the pharynx. Spacers with facemask designed for cats are commercially available (e.g., Aerotek, Trudell Medical International). The device indicates when the cat breathes and is effective despite the small tidal volume of cats. Spacers build up static electricity which may impact particle delivery. They should be washed and allowed to air dry intermittently (monthly). DPI are less likely to be used in veterinary medicine since delivery depends on patient inspiration.

Drugs

Differences in pharmaceutical (delivery) and pharmacokinetic properties largely determine variable responses to inhaled glucocorticoids. Characteristics that can be manipulated to influence efficacy or safety include potency (the amount of drug or number of molecules that impart a target response), thus allowing use in a MDI; retention at the site of action, thus prolonging local effect; and rapid metabolism, thus decreasing systemic effects.

Corticosteroids marketed in MDI vary up to fivefold or more in potency. The relative potency of drugs marketed as MDI roughly follows the following order: mometasone > fluticasone and budesonide >> beclomethasone. While potency does allow administration of a small dose, it does not predict clinical efficacy of inhaled glucocorticoids. Despite sixfold differences in potencies among inhaled glucocorticoids, comparative clinical trials in humans have failed to demonstrate differences in efficacy when drugs are administered at equipotent dosages. Further, dose response curves for inhaled glucocorticoids tend to be flat, indicating that increasing doses is not likely to enhance efficacy.

The term "soft glucocorticoids" has been used to refer to drugs that are potent for the glucocorticoid receptor (GR) but also rapidly metabolized should the drug be absorbed into systemic circulation via the oral route. These efforts generally reflect manipulation of chemical groups on the D ring of the GLC. Examples include beclomethasone, budesonide, and fluticasone propionate, steroids designed specifically for use in inhalant metered doses. Their potency when inhaled varies in clinical trials, with fluticasone propionate being most potent and budesonide and beclomethasone dipropionate approximately equipotent.

Drugs also have been manipulated to prolong local presence.

1.  Inhaled corticosteroids generally are delivered as microcrystals, which must dissolve in the epithelial mucosal fluid. Crystals must be water soluble to ensure local delivery before the mucociliary tract removes the drug. However, alteration of dissolution times may also affect local delivery and thus local effects. For example, the dissolution time for budesonide is 6 minutes compared with beclomethasone dipropionate (5 hours) and fluticasone (8 hours).

2.  Lipophilicity of the drug enhances uptake and the duration of local effects. This can be manipulated with the addition of a halogen which increases tissue retention compared with nonhalogenated drugs. Lipophilicity is greatest for beclomethasone and fluticasone followed by budesonide, with triamcinolone followed by dexamethasone and, finally, prednisolone as the least lipophilic. Not surprisingly, the most lipophilic of the drugs also is associated with the greatest number of side effects, including suppression of the hypothalamic pituitary adrenal axis. In humans, fluticasone is among the most potent and most lipophilic glucocorticoid. As such, it is characterized by the greatest evidence of systemic side effects when administered systemically.

Budesonide is rapidly metabolized in the liver by CYP3A4, with affinity of metabolites of the GCR being less than 1% of the parent. However, essentially 100% of topically (inhalant) administered drug in humans appears as metabolites in the urine, indicating that systemic absorption of the drug does occur. Indeed, inhaled drug is generally considered to be absorbed, and as much as 25% of the inhaled dose in humans circumvents hepatic metabolism before entering systemic circulation. Drugs that impaired CYP3A4 may increase the plasma drug concentration of budesonide over sevenfold.

Budesonide offers another unique characteristic that was revealed with efforts to find a drug that has minimal side effects even if absorbed and if not rapidly metabolized by the liver. Because of its structure (a free C21 hydroxyl group), excess intracellular budesonide complexes with long-chain fatty acids. The drug is inactive in this complex, bound form. Reversible esterification occurs as receptors are depleted of active drugs. Thus, local receptor binding of the drug is greater than peripheral receptor binding. As such, esterification serves as a storage site, with esterified drug being rereleased as the concentration of free drug declines with clearance. The ability to esterify varies among tissues, with pulmonary tissue apparently having a much higher capacity compared with other tissues, leading to greater storage in airways than in peripheral tissues. Fluticasone, beclomethasone dipropionate, and probably mometasone, do not form fatty acid esters. An advantage of prolonged effect at the site of administration is improved compliance due to longer dosing intervals. However, time to budesonide onset in humans is approximately 10 hours. Improvement can be expected over the next 1 to 2 days, with maximum effects potentially not being evident until 2 weeks after therapy has begun.

Budesonide suspension nebulizer is recommended by Consumer Reports for children and beclomethasone QVAR for adults and children older than 5 yr of age. In non-responders, the National Heart, Lung and Blood Institute recommends combining the glucocorticoid with a long-acting beta-adrenergic drug (formoterol, salmeterol). Caution is recommended with short-acting drugs such as albuterol. This is particularly true for albuterol which is marketed as a racemic mixture: the R enantiomer has been demonstrated to relax smooth muscle of the airways whereas the S enantiomer is associated with hyperreactivity and bronchoconstriction.

Therapy with inhaled glucocorticoids is not without side effects, particularly at high doses. Both local and systemic effects can occur. Local effects are not serious, but impact compliance in humans. They appear to be more common with low resistance DPI because more deposition occurs in the oropharynx. A proinflammatory effect has been attributed to the vehicle and MDI propellant in humans. Coughing due to irritation has been attributed to lactose-containing DPIs. Large volume spacers associated with pMDI may increase the risk of coughing in humans. Other local effects include perioral dermatitis, tongue hypertrophy, and laryngeal disorders. Dysphonia has been reported in 5 to 50% of patients using inhaled steroids. Dose-dependent hoarseness may emerge. Systemic effects include suppression of the HPAA axis and osteoporosis.

Despite their apparent popularity, little evidence supports the clinical efficacy of inhalant glucocorticoids. A MDI has been demonstrated to effectively deliver drug to the peripheral airways of cats. Inhaled glucocorticoids have been recommended for use in cats with asthma if they cannot be effectively dosed orally, although few studies have provided guidance. One abstract has reported a beneficial effect of flunisolide (250 μg/puff) but not zafirlukast (10 mg orally every 12 hours) in cats with experimental feline asthma. Reinero and coworkers compared the impact of inhaled flunisolide (250 μg puff twice daily) to that of oral prednisone (10 mg/day orally) and placebo on indices of inflammation and adrenal gland suppression in healthy cats (n = 6). No treatment effect was apparent with regard to serum immunoglobulin or cytokine activity. The inhaled glucocorticoid was associated with lower baseline cortisol compared with placebo and lower cortisol after adrenocorticotropic hormone stimulation compared with oral and placebo therapy. A limitation of the study may have been the use of prednisone rather than prednisolone, as is suggested by impact on cortisol concentrations, although oral therapy did impact both T and B cells. This study supports the potentially inappropriate use of prednisone in cats and suggests that topical flunisolide therapy may suppress the hypothalamic pituitary adrenal axis in cats with flunisolide. Note that clinical signs may not be a sufficient indicator of resolution of peripheral airway inflammation as was demonstrated in cats receiving oral prednisolone for 3 weeks. Despite clinical response, 7/10 cats still had inflammation in the peripheral airways. In cats, facial demodicosis has been reported in the muzzle area after mask delivery of fluticasone.

References

1.  Schulman RL, Crochik SS, Kneller SK, et al. Investigation of pulmonary deposition of a nebulized radiopharmaceutical agent in awake cats. Am J Vet Res. 2004;65:806–809.

2.  Cohn LA, DeClue AE, Cohen RL, et al. Effects of fluticasone propionate dosage in an experimental model of feline asthma. J Feline Med Surg. 2010;12:91–96.