Budesma Mechanism of Action

Corticosteroid.
Pharmacology: Pharmacodynamics: Budesonide is a non-halogenated glucocorticoid corticosteroid structurally related to 16-alphahydroxyprednisolone.
Corticosteroids have multiple mechanisms of action including anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions. Anti-inflammatory effects result from decreased formation, release, and activity of the mediators of inflammation (e.g., kinins, histamine, liposomal enzymes, prostaglandins, and leukotrienes). These effects reduce the initial manifestations of the inflammatory process. Corticosteroids inhibit margination and subsequent cell migration to the area of injury, and also reverse the dilation and increased vessel permeability in the area, resulting in decreased access of cells to the sites of injury. This vasoconstrictive action decreases serum extravasation, swelling, and discomfort. The immunosuppressive properties decrease the response to delayed and immediate hypersensitivity reactions (e.g., type III and type IV). This results from inhibition of the toxic effect from antigen and antibody complexes that precipitate in vessel walls creating cutaneous allergic vasculitis, and by inhibiting the action of lymphokines, target cells, and macrophages which together produce allergic contact dermatitis reactions. Additionally, the access of sensitized T lymphocytes and macrophages to target cells may also be prevented by corticosteroids.
The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.
A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.
In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.
Onset of effect: After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment, although maximum benefit may not be achieved for up to 4 weeks.
Airway reactivity: Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.
Exercise-induced asthma: Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.
Growth: Limited data from long term studies suggest that most children and adolescents treated with inhaled budesonide ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.
Pharmacokinetics: Absorption: After oral inhalation of budesonide, substantial absorption occurs from the lung (nearly 73%), peak plasma concentrations being attained within about 30 minutes. Onset of action occurs within 24 hours and the effect lasts for 12-24 hours. Peak response is seen within 1-2 weeks of drug treatment.
Distribution: The drug is 85% to 90% protein-bound and has a volume of distribution (V_d) of 3 L/kg.
Metabolism: Budesonide undergoes substantial hepatic first-pass metabolism mainly by the cytochrome P450, isoenzyme CYP3A4. The major metabolites, 6-betahydroxybudesonide and 16-alphahydroxyprednisolone have less than 1% of the glucocorticoid activity of unchanged budesonide. Metabolism is minimal in the lung which results in higher systemic bioavailability.
Excretion: Metabolites of Budesonide are eliminated by kidney. Budesonide is reported to have a terminal half-life of about 2 to 4 hours. Metabolism is minimal in the lung.
Renal excretion accounts for 60% of the total excretion of the drug and its metabolites. Only metabolites and not unchanged drug are eliminated via the kidney that accounts for 60% of the excretion. Biliary excretion is minimal and fecal elimination accounts for 15.1% to 29.6% of the excretion. Renal and fecal elimination is greater after oral administration than after oral inhalation.
Toxicology: The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).
Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.
No deaths occurred when budesonide was administered in the inhalation dose of 68 mg/kg in rats (approximately 430 times the maximum recommended daily inhalation dose in adults and approximately 510 times the maximum recommended daily inhalation dose in children on a mcg/m² basis). The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 320 times the maximum recommended daily inhalation dose in adults and approximately 380 times the maximum recommended daily inhalation dose in children on a mcg/m² basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children on a mcg/m² basis) and less than 100 mg/kg in rats (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children based on a mcg/m² basis).
Carcinogenesis, Mutagenesis and Impairment of Fertility: The carcinogenicity of budesonide was evaluated in mice which were exposed for a total of 91 weeks, at doses up to 200 mcg/kg/day (approximately ½ the maximum recommended daily inhalation dose in adults and children on a mcg/m² basis). There was no evidence of carcinogenicity in this study. Budesonide demonstrated a statistically significant increase in the incidence of gliomas at oral dose of 50 mcg/kg/day (approximately ¼ the maximum recommended daily inhalation dose on a mcg/m² basis) for 104 weeks in Sprague-Dawley rats; no such changes were seen in male rats receiving oral doses of 10 and 25 mcg/kg/day (approximately ¹/₂₀ and ¹/₈ the maximum recommended daily inhalation dose on a mcg/m² basis) or in female rats at oral doses up to 50 mcg/kg/day (approximately ¼ the maximum recommended human daily inhalation dose on a mcg/m² basis). There was no evidence of carcinogenicity in two other 104-week carcinogenicity studies (conducted with same dose in previous study) in male Sprague-Dawley and Fischer rats. Compared with concurrent controls, a statistically significant increase in the incidence of hepatocellular tumors was observed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in these studies.
Budesonide did not demonstrate any mutagenic or clastogenic effect in Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture.
Decreases in maternal body weight gain, prenatal vialibility, and viability of the young at birth and during lactation were observed following treatment with a dose of 20 mcg/kg/day (approximately ¹/₈ the maximum recommended daily inhalation dose in adults on a mcg/m² basis).
An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows no indication that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.