DEVATIDE 25 MCG/125 MCG AEROSOL INHALER

Indications

• Asthma maintenance therapy
• Chronic obstructive pulmonary disease (COPD)
• Allergic rhinitis
• Nasal polyps

Dosage

Adults: For asthma: 160 micrograms once daily, may be reduced to 80 micrograms once daily if control is maintained; may be increased to 320 micrograms twice daily if necessary. For allergic rhinitis:

Mechanism of action

Fluticasone propionate acts as a highly selective agonist at the human glucocorticoid receptor, exhibiting negligible activity at androgen, estrogen, or mineralocorticoid receptors. It activates glucocorticoid receptors and inhibits nuclear factor kappa B, which plays a crucial role in the inflammatory response. Additionally, fluticasone reduces the number of inflammatory mediator cells in the nasal mucosa and decreases nasal reactivity to allergens, leading to reduced release of inflammatory mediators and proteolytic enzymes.

Pharmacodynamics

Fluticasone's therapeutic effects are primarily local, resulting from the deposition of the inhaled drug on the nasal mucosa or lungs, rather than systemic effects from swallowed portions. Its anti-inflammatory action includes the inhibition of eosinophilia and other inflammatory cell types, contributing to the management of allergic conditions and symptoms of asthma. The drug is associated with vasoconstriction in the skin when used topically.

Pharmacokinetics

Fluticasone is administered via inhalation or intranasal routes, leading to low systemic absorption. Following inhalation, it is rapidly absorbed, with peak plasma concentrations occurring within one to two hours. The drug has a high protein binding rate and is extensively metabolized by the liver, primarily through cytochrome P450 enzymes. The elimination half-life is approximately 3 to 4 hours, with metabolites excreted primarily in feces and urine. Due to its significant first-pass metabolism, systemic exposure is minimized.

Contra-indications

• Hypersensitivity to fluticasone or any excipients
• Severe systemic fungal infections
• Untreated localized infections

Adverse effects

• Oral candidiasis
• Dysphonia
• Cough
• Nasal irritation
• Headache
• Throat irritation
• Nasal bleeding
• Increased risk of pneumonia in COPD patients

Interactions

• Cenobamate: Moderate interaction (decreases exposure)
• Cobicistat: Unknown interaction (increases exposure)
• Idelalisib: Unknown interaction (increases exposure)
• Mitotane: Unknown interaction (decreases exposure)
• Clarithromycin: Unknown interaction (increases exposure)
• Rifampicin: Unknown interaction (decreases exposure)

Precautions

• Caution in patients with tuberculosis, untreated systemic infections, or those with a history of severe allergies
• Monitor for signs of adrenal suppression in long-term use
• Use with caution in patients with hepatic impairment

Pregnancy

Fluticasone should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Consultation with a healthcare provider is recommended.

Breast-feeding

Fluticasone is excreted in breast milk. Caution is advised when administered to breastfeeding women.

Storage

Store at room temperature, away from direct sunlight and moisture. Keep out of reach of children.

Formulations

• Pressurized inhalation aerosol: 320 micrograms/9 micrograms per dose
• Nasal spray: 50 micrograms per actuation
• Dry powder inhaler: 200 micrograms per dose

Indications

• Asthma
• Chronic obstructive pulmonary disease (COPD)

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing recommendations.

Adults: Refer to the BNF for specific dosing information as it varies based on the condition being treated.

Mechanism of action

Salmeterol induces bronchodilation through beta-2 adrenoceptor stimulation, causing relaxation of bronchial smooth muscle. It binds to two sites on the beta-2 adrenoceptor, with its saligenin moiety engaging the active site and the hydrophilic tail adhering to leucine residues in the exo-site, resulting in an almost irreversible interaction that prolongs its action. Additionally, salmeterol inhibits the release of mast cell mediators, thus reducing bronchial hyper-responsiveness.

Pharmacodynamics

As a long-acting beta-2 adrenergic receptor agonist, salmeterol has a duration of action that surpasses that of short-acting beta agonists such as salbutamol. It is effective in reducing bronchoconstriction and enhancing airflow in patients with asthma and COPD. However, caution is advised regarding the risks of using LABAs alone, as well as potential side effects like hypokalemia and hypoglycemia, especially when combined with other LABAs.

Pharmacokinetics

Salmeterol is administered via inhalation, allowing for direct delivery to the lungs where it exerts its effects. The onset of action is typically within 15 to 30 minutes, with peak effects occurring at 3 to 4 hours and a duration of action lasting up to 12 hours. The drug is metabolized in the liver, and its pharmacokinetic profile supports its use in chronic management of respiratory conditions.

Contra-indications

• Hypersensitivity to salmeterol or any of its excipients
• Severe untreated asthma
• Acute asthma attacks
• Severe cardiovascular disorders

Adverse effects

• Tachycardia
• Palpitations
• Tremor
• Headache
• Dizziness
• Hypokalemia
• Hyperglycemia
• Nervousness

Interactions

• Other long-acting beta agonists (LABAs) should not be used concurrently
• Beta-blockers may reduce the effectiveness of salmeterol
• Diuretics may increase the risk of hypokalemia
• Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants may potentiate the cardiovascular effects

Precautions

• Use with caution in patients with cardiovascular disorders
• Monitor potassium levels in patients susceptible to hypokalemia
• Caution in patients with diabetes due to potential hyperglycemic effects
• Not to be used as a rescue medication for acute asthma attacks

Pregnancy

Salmeterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No significant teratogenic effects have been observed in animal studies.

Breast-feeding

It is not known whether salmeterol is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep the inhaler in a dry place.

Formulations

• Inhalation aerosol
• Dry powder inhaler

Indications

• Tinea pedis (athlete's foot)
• Tinea corporis (ringworm)
• Tinea cruris (jock itch)
• Onychomycosis (nail fungus)
• Candidiasis (fungal infections caused by Candida species)

Dosage

Children: For pediatric patients, refer to the BNF for Children for appropriate dosing guidelines based on age and weight.

Adults: For adults, refer to the specific product labeling and indications for use. Dosage may vary based on the formulation and site of infection.

Mechanism of action

Xinafoate primarily works by inhibiting the synthesis of ergosterol, an essential component of fungal cell membranes. By disrupting ergosterol production, xinafoate compromises the integrity of the fungal cell membrane, leading to cell lysis and death. This mechanism makes it effective against various dermatophytes and yeast species.

Pharmacodynamics

Xinafoate exerts its antifungal effects through the inhibition of fungal growth and reproduction. The drug demonstrates fungistatic and fungicidal properties depending on the concentration used. In lower concentrations, it may inhibit fungal growth, while at higher concentrations, it can kill the fungi. The onset of action can vary, but improvement in symptoms is generally observed within a few days of initiation of therapy.

Pharmacokinetics

Xinafoate is typically administered topically, leading to localized effects with minimal systemic absorption. Following topical application, it penetrates the stratum corneum and reaches the deeper layers of the skin where it exerts its antifungal action. The drug is metabolized in the liver, and its metabolites are excreted mainly via the urine. The half-life of xinafoate is not well-defined due to its topical application and limited systemic exposure.

Pregnancy

Xinafoate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult a healthcare provider for individual assessment.

Breast-feeding

It is not known whether xinafoate is excreted in human breast milk. Caution should be exercised when administering to breastfeeding women.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Mechanism of action

[DB08906] and [DB00588] work through an unknown mechanism to affect the action of various cell types and mediators of inflammation. In vitro experiments show [DB08906] activating glucocorticoid receptors, inhibiting nuclear factor kappa b, and inhibiting lung eosinophilia in rats. [DB00588] performs similar activity but is not stated to affect nuclear factor kappa b. Fluticasone propionate is a highly selective agonist at the human glucocorticoid receptor with negligible activity at androgen, estrogen, or mineralocorticoid receptors. In preclinical studies, fluticasone propionate reportedly exhibited weak progesterone-like activity. However, as plasma concentrations of fluticasone propionate are very low following intranasal administration of the drug in recommended doses, the clinical importance of this finding is not known. The therapeutic effects of fluticasone propionate are thought to result from local actions of the deposited inhaled dose on the nasal mucosa rather than from the systemic actions of the swallowed portion of the dose. The exact mechanism(s) of anti-inflammatory action of corticosteroids in allergic rhinitis remains unknown, but may involve reductions in the following: number of mediator cells (basophils, eosinophils, helper-inducer [CD4+, T4] T-cells, mast cells, and neutrophils) in the nasal mucosa, nasal reactivity to allergens, and release of inflammatory mediators and proteolytic enzymes. Following exposure of patients with a history of allergic rhinitis to allergen, eosinophils, basophils, mast cells, T cells, and neutrophils appear to infiltrate nasal secretions and mucosa, releasing inflammatory mediators that generate allergic responses such as pruritus, sneezing, rhinorrhea, and nasal edema. /Corticosteroids/ Other mechanisms by which corticosteroids may improve symptoms of allergic rhinitis may involve inhibition of postcapillary venule dilation and permeability and facilitation of nasomucociliary clearance of nasal secretions. Patients receiving short- and long-term treatment with intranasal fluticasone propionate have demonstrated decreases in nasal turbinate swelling and mucosal inflammation. As inflammatory changes occur during periods of increased nasal hyperresponsiveness, the degree of response to nasal secretory stimuli has been used as an indirect measure of inflammation. In patients with asymptomatic seasonal allergic rhinitis, pretreatment with intranasal fluticasone propionate for 2-6 weeks prior to challenge with allergens or inflammatory mediatorsgenerally reduced the release of tryptase, histamine, eosinophilic cationic protein, and prostaglandin D2 in nasal biopsies or nasal lavage fluid; concentrations of eosinophils or activated eosinophils, CD4+ T-cells, and basophils also were reduced. /Corticosteroids/ Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

Pharmacodynamics

Systemically, in vitro experiments show [DB08906] activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. [DB00588] performs similar activity but is not stated to affect nuclear factor kappa b. [DB00588] as a topical formulation is also associated with vasoconstriction in the skin.

Mechanism of action

Beta-2 adrenoceptor stimulation causes relaxation of bronchial smooth muscle, bronchodilation, and increased airflow. Salmeterol is hypothesized to bind to 2 sites on the beta-2 adrenoceptor. The saligenin moiety binds to the active site of the beta-2 adrenoceptor. The hydrophilic tail of salmeterol binds to leucine residues in the exo-site of the beta-2 adrenoceptor almost irreversibly, allowing salmeterol to persist in the active site, which is responsible for it's long duration of action. Another hypothesis is that the lipophilic drug diffuses into lipid bilayer of smooth muscle cells and provides a depot of drug to the cells over a longer period of time. In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol attenuate allergen-induced bronchial hyper-responsiveness. The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. Salmeterol is a long-acting beta-adrenergic agonist. In vitro studies and in vivo pharmacologic studies demonstrate that salmeterol is selective for beta2-adrenoceptors compared with isoproterenol, which has approximately equal agonist activity on beta1- and beta2-adrenoceptors. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these is not yet established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects. Salmeterol ... membrane binding is non-competitive and dissociation is slow so that its effects last for many hours. Despite this, salmeterol does not accumulate in tissues. Its mechanism of action can be explained by binding to a specific exo-site domain of the beta 2-receptor protein to produce continuous stimulation of the active site of the receptor, which gives salmeterol a profile of pharmacological activity unlike that of other beta 2-agonists. Due to its potent and prolonged activation of beta 2-adrenoceptors in airway smooth muscle cells, endothelial cells, mast cells and epithelial cells, salmeterol induces prolonged bronchodilatation, reduced vascular permeability, inhibition of inflammatory mediators, stimulation of ciliary function and modulation of ion and water transport across the bronchial mucosa.

Pharmacodynamics

Salmeterol is a long acting beta-2 adrenergic receptor agonist that binds to both the active and exo sites of the beta-2 adrenergic receptor. Salmeterol has a longer duration of action than other beta-2 agonists like [salbutamol]. Patients should be counselled regarding the risks of long acting beta agonist (LABA) monotherapy, hypokalemia, hypoglycemia, and not to take this drug with another LABA.