Compounds Commonly Administered To The Lung

Chapters 2 and 4 thoroughly reviewed the compounds administered to the lung and their chemical origins and activity.

Most compounds administered to the lung are bronchodilators [68 -76]. These fall in the general categories of catecholamines [74,77], resorcinols [74,78-80], saligenins [74,81], and prodrugs [74,82,83], all of which exhibit or result in P-adrenergic receptor agonist activity. Other common agents are anticholinergic and corticosteroid agents [44,84-88] and cromolyn sodium [89-91], which is known to stabilize mast cells to inhibit the production of histamine, leukotrenes, and other substances known to cause hypersensitivity. Combination therapy with P-adrenergic receptor agonists and anti-inflammatory agents has been used [91,92]. These agents are administered to the lung for their local activity. Ergotamine tartrate, an a-adrenergic receptor antagonist, is administered to the upper airways for the treatment of vascular headaches, or migraines, indicating the potential of this route for the administration of systemically acting agents [9,64]. Antibiotic agents have also been administered to the lung, notably for the treatment of cystic fibrosis [93-98]. In recent years the approval of tobramycin has added another antibiotic to the therapy for cystic fibrosis [99,100]. In addition, DNAase was approved for aerosol administration as a means of cleaving leukocyte DNA to reduce the viscosity of mucus and facilitate expectoration by cystic fibrosis patients [101,102]. Some more common materials have been administered to relieve respiratory distress, including water, saline, detergent, mucolytics, and proteolytics [103]. A variety of additives are used in the formulation of pharmaceutical aerosols [104]. Some of these are shown in Table 1. Oleic acid is included as a suspending agent and valve lubricant in pressurized-pack inhalers. Although there is no evidence that this material has toxic effects when delivered in small quantities from an aerosol to the airways, it is known to induce pulmonary edema at high systemic concentrations [105,106]. Sodium metabisulfite and benzalkonium chloride have been included in some nebulizer aerosol formulations as a preservative. Recent

Table 1 Additives in Currently Manufactured Oral and Nasal Inhalants

Inhalant

Manufacturer

Additives

Oral

Beclovent Glaxo

Norisodrine sulfate Abbott aerohaler

Proventil inhaler Schering

Acrobid Key

Ventolin Glaxo

Alupent inhalant solution Boehringer

Ingelheim

Duo-Medihaler Riker

Isuprel hydrochlo- ride Breon solution

Isuprel Mistometer Breon

Medihaler-ISO Riker

Norisodrine Abbott Aerotrol

Primatene mist Whitehall Nasal

Beconase Glaxo

Dristan Whitehall

Nasalcronm Fisons

Anti-inflammatory8

Bronchial dilatorb

Bronchial dilatorc Bronchial dilator c Bronchial dilator c Bronchial dilatorc

Bronchial dilator c Bronchial dilator c

Bronchial dilator c Bronchial dilator b Bronchial dilator b

Bronchial dilator b

Anti-inflammatory a Relieve nasal congestion Treat allergic rhinitisd

Complex: trichloromono fluoromethane clathrate Lactose

Oleic acid Sorbitan trioleate Oleic acid Saline

Sorbitan trioleate, cetylpyridiniurn chloride Sodium chloride, citric acid, glycerin chlorbutanol, sodium bisulfite Alcohol, ascorbic acid Sorbitan trioleate Alcohol, ascorbic acid

Alchol, ascorbic acid

Complex: Trichloronionofluoroniethane clathrate

Thimersol preservative, benzalkonium chloride, alcohol Benzalkonium chloride, EDTA

Nasal icle

Syntex

Treat allergic rhinitis

Vancenase

Schering Anti-inflammatory a

Decadron turbinaire

Merck, Sharp Anti-inflammatory

& Dohme Sandoz Induce lactation a

Syntocinon

Corticosteroid. bSympathomimetic. Cß-Adrenergic stimulant. dCromolyn sodium.

Source: Physicians' Desk Reference, 1985.

Propylene glycol, PEG 3350, citric acid sodium citrate, butylated hydroxyanisole, EDTA, ben-zalkoniurn chloride, NaOH/HC Complex: trichlorotnonofluoromethane clathrate, oleic acid Alcohol

Dried sodium phosphate, citric acid, sodium chloride, glycerin, sorbitol solution, methylpa-raben, propylparaben chlorbutanol studies focused on bronchoconstriction induced by the presence of these materials [107-109]. In light of these observations, the addition of preservatives has been frowned upon, and regulatory agencies prefer nebulizer solutions to be prepared as sterile products. Propylene glycol and ethanol are used in nasal aerosols and have been suggested as solvents in oral aerosol formulations [110,111]. Other carboxylic acid additives, selected to improve drug delivery, may also be included in powder aerosol formulations [112]. Propylene glycol and carboxylic acids are known to irritate mucous membranes when present at certain concentrations, and alcohols will cause bronchoconstriction. Manipulating the drug molecule may achieve the same ends as reformulating. Pentamidine is used to treat Pneumocystis carinii pneumonia infections in AIDS patients. This has been prepared in various salt forms to improve the bioavailability [113]. In circumstances such as this, it is essential to establish that the increased bioavailability does not increase the toxicity of the drug. These examples, of additives and formulations, are given to indicate that great caution must be exercised in the selection and use of materials in the lung because the potential for local toxicity exists.

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