CIPZAMIST

Indications

• Seasonal allergic conjunctivitis
• Perennial allergic conjunctivitis

Dosage

Children: Child 4–17 years: Apply 1 drop into the affected eye(s) twice daily; may increase to 4 times daily if necessary.

Adults: Apply 1 drop into the affected eye(s) twice daily; may increase to 4 times daily if necessary.

Mechanism of action

Azelastine hydrochloride is a selective H1 receptor antagonist that inhibits the action of histamine, thereby reducing allergic symptoms such as itching, redness, and inflammation in the eyes.

Pharmacodynamics

Azelastine exhibits rapid onset of action, providing relief from allergic symptoms. It also has anti-inflammatory properties that contribute to its efficacy in treating allergic conjunctivitis.

Pharmacokinetics

Azelastine is absorbed topically when administered as eye drops. Its systemic absorption is minimal, leading to a lower risk of systemic side effects. The drug is metabolized in the liver and has a half-life that supports twice-daily dosing.

Adverse effects

• Drowsiness
• Eye irritation
• Headache
• Hyperhidrosis
• Hypertension
• Mydriasis
• Nausea
• Asthma exacerbation
• Facial swelling
• Conjunctival hemorrhage
• Dry mouth
• Skin reactions
• Blurred vision
• Eye discomfort
• Palpitations
• Vascular disorders
• Eye inflammation

Interactions

• Antihistamines, non-sedating

Pregnancy

Consult relevant guidelines for use in pregnancy.

Breast-feeding

Consult relevant guidelines for use in breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Eye drops 0.05%

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

• Allergic rhinitis
• Conjunctivitis (allergic origin)

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: For intranasal use, 1 spray (0.137 mg) in each nostril twice daily, or as directed by a healthcare professional. For ophthalmic use, 1 drop in the affected eye(s) twice daily.

Mechanism of action

Azelastine primarily acts as a selective antagonist of histamine H1-receptors, which are G-protein-coupled receptors located on nerve endings, smooth muscle cells, and glandular cells. By blocking H1-receptors, azelastine prevents the typical allergic symptoms caused by histamine release from mast cells, which occurs following allergen exposure. Furthermore, azelastine stabilizes mast cells, inhibiting the release of interleukin-6, tryptase, histamine, TNF-alpha, and leukotrienes, thereby attenuating allergic responses.

Pharmacodynamics

Azelastine effectively antagonizes histamine action, providing relief from allergy symptoms. The onset of action for intranasal formulations is within 15 minutes, while ophthalmic solutions can act as quickly as 3 minutes. The duration of action for intranasal formulations is relatively long, with peak effects occurring 4-6 hours post-administration and maintaining efficacy throughout a standard 12-hour dosing interval.

Pharmacokinetics

Azelastine is well absorbed following intranasal or ophthalmic administration, with a rapid onset of action. It undergoes extensive first-pass metabolism, leading to reduced systemic bioavailability. The pharmacokinetic profile demonstrates a distribution primarily in tissues, with metabolism occurring via hepatic pathways. Azelastine is excreted mainly in urine, with both unchanged drug and metabolites present.

Adverse effects

• drowsiness
• dry mouth
• nasal irritation
• headache
• throat irritation

Precautions

• Use with caution in patients with a history of seizures.
• May cause drowsiness; caution is advised when driving or operating machinery.

Pregnancy

Azelastine should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus. Consult healthcare professionals.

Breast-feeding

Azelastine is excreted in breast milk; caution is advised when administered to nursing mothers.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Intranasal spray
• Ophthalmic solution

Mechanism of action

Azelastine is primarily a selective antagonist of histamine H1-receptors, with a lesser affinity for H2-receptors, used for the symptomatic treatment of allergies. Histamine H1-receptors are G-protein-coupled receptors with 7 transmembrane spanning domains that are found on nerve endings, smooth muscle cells, and glandular cells. Following allergen exposure in sensitized individuals, IgE-receptor cross-linking on mast cells results in the release of histamine, which binds to H1-receptors and contributes to typical allergic symptoms such as itching, sneezing, and congestion. Though its primary mode of action is thought to be via H1-receptor antagonism, azelastine (like other second-generation antihistamines) appears to affect other mediators of allergic symptomatology. Azelastine has mast cell-stabilizing properties that prevent the release of interleukin-6, tryptase, histamine, and TNF-alpha from mast cells, and has been shown to reduce mediators of mast cell degranulation such as leukotrienes in the nasal lavage of patients with rhinitis, as well as inhibiting their production and release from eosinophils (potentially via inhibition of phospholipase A₂ and leukotriene C₄ synthase). Additionally, patients using oral azelastine were observed to have significantly reduced concentrations of substance P and bradykinin in nasal secretions, both of which may play a role in nasal itching and sneezing in patients with allergic rhinitis. Azelastine is a histamine H1-receptor antagonist. Azelastine, a phthalazinone derivative, is structurally unrelated to other currently available antihistamines and has been characterized a selective H1-receptor antagonist. Although azelastine has been referred to as a second generation ("nonsedating") antihistamine, adverse CNS effects (e.g., drowsiness) may occur with the drug, particularly at relatively high doses or when administered with CNS depressants (e.g., alcohol). The desmethyl metabolite also possesses antihistaminic activity. In addition, azelastine inhibits other mediators (e.g., leukotrienes, platelet activating factor (PAF)) involved in allergic reactions. Azelastine may inhibit the accumulation of eosinophils at the site of allergic inflammation and prevent eosinophil degranulation. Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C4/D4 synthesis. /Investigators/ have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC4 formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC4 formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC4 synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC4 generation may contribute to its mode of action and its therapeutic efficacy. Leukotrienes have been proposed as important chemical mediators of allergic inflammation, and there is evidence that azelastine (Astelin) can affect leukotriene-mediated allergic responses. One of the enzymes required for the synthesis of leukotrienes from arachidonic acid is 5-lipoxygenase (5-LO). Azelastine, which is preferentially taken up by the lung and alveolar macrophages, inhibits leukotriene generation in the airways. This property of azelastine may contribute to its therapeutic efficacy in the long-term treatment and management of rhinitis and asthma. Azelastine does not directly inhibit 5-LO in disrupted murine peritoneal cells and rat basophilic leukemia cells (IC50 > 100 microM)

Pharmacodynamics

Azelastine antagonizes the actions of histamine, resulting in the relief of histamine-mediated allergy symptoms. Onset of action occurs within 15 minutes with intranasal formulations and as quickly as 3 minutes with ophthalmic solutions. Intranasal formulations have a relatively long-duration of action, with peak effects observed 4-6 hours after the initial dose and efficacy maintained over the entirety of the standard 12 hour dosing interval.

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.