ULTIBRO BREEZHALER

Indications

• Hyperhidrosis (excessive sweating)
• Premedication in anesthetic procedures

Dosage

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

Adults: Apply once daily to the affected area for hyperhidrosis, using the liquid formulation at body temperature.

Mechanism of action

Glycopyrronium bromide acts as a competitive antagonist of muscarinic acetylcholine receptors. By blocking these receptors, it inhibits glandular secretion and reduces the activity of smooth muscle, leading to a decrease in sweating and other secretory functions.

Pharmacodynamics

The pharmacodynamic effects of glycopyrronium bromide include a reduction in salivary, bronchial, and sweating secretions. The onset of action is generally rapid, with effects typically noted within 30 minutes after administration. These actions are particularly beneficial in managing conditions characterized by excessive secretion, such as hyperhidrosis.

Pharmacokinetics

Glycopyrronium bromide is poorly absorbed when applied topically, which minimizes systemic effects. When used systemically, it is well absorbed, with peak plasma concentrations achieved within 1-2 hours. The drug undergoes hepatic metabolism and has a half-life of approximately 1-2 hours. Renal excretion is a significant pathway for elimination, and thus caution is advised in patients with renal impairment.

Contra-indications

• Infections affecting the treatment site

Adverse effects

• Skin reactions
• Pain
• Paraesthesia

Precautions

• Avoid contact with eyes
• Avoid contact with mucous membranes
• Avoid use on broken or irritated skin
• Do not shave axillae or use depilatories within 12 hours of application

Pregnancy

Manufacturer advises caution, as specific studies on use during pregnancy are limited.

Breast-feeding

Manufacturer advises avoiding application to the breast area; no information available on presence in milk.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• 0.05% solution for topical use
• Powder for dry skin application

Indications

• Chronic obstructive pulmonary disease (COPD)
• Maintenance treatment of obstructive airway disease

Dosage

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

Adults: 150 to 300 micrograms once daily by inhalation.

Mechanism of action

Indacaterol stimulates adrenergic beta-2 receptors located in the smooth muscle of the airways. This stimulation leads to muscle relaxation, increasing airway diameter in conditions like asthma and COPD. The drug exhibits a high affinity for lipid raft domains in the airway membrane, allowing it to dissociate slowly from the receptors and providing long-acting effects. Additionally, indacaterol increases intracellular cyclic AMP levels through the activation of adenyl cyclase, contributing to bronchodilation.

Pharmacodynamics

Indacaterol is classified as an ultra-long-acting beta-2 agonist, demonstrating a duration of action of approximately 24 hours, allowing for once-daily administration. Its pharmacological profile indicates that it has more than 24-fold greater activity at beta-2 receptors compared to beta-1 and 20-fold more than beta-3 receptors, which enhances its bronchodilatory effects. Cough is the most common adverse effect associated with indacaterol, occurring shortly after inhalation but generally not leading to discontinuation of therapy.

Pharmacokinetics

Indacaterol is well absorbed when inhaled, with a rapid onset of action occurring within 5 minutes. Its long duration of action is attributed to its slow dissociation from beta-2 receptors, which allows for sustained bronchodilation. The pharmacokinetic parameters such as half-life and clearance may vary based on individual patient factors, but the drug is designed to maintain therapeutic levels for the entire 24-hour dosing period.

Contra-indications

• Hypersensitivity to indacaterol or any of its excipients
• Severe acute asthma exacerbation

Adverse effects

• Cough
• Headache
• Pharyngitis
• Nausea
• Dizziness
• Tachycardia
• Palpitations
• Muscle cramps

Interactions

• Beta-blockers may reduce the effectiveness of indacaterol
• Concurrent use with other adrenergic drugs may enhance cardiovascular side effects
• Caution with monoamine oxidase inhibitors

Precautions

• Caution in patients with cardiovascular disorders
• Use with caution in patients with convulsive disorders
• Not recommended for use in patients with a history of seizures
• Monitor patients with hepatic impairment

Pregnancy

Manufacturer advises avoiding use during pregnancy due to lack of adequate human studies.

Breast-feeding

Manufacturer advises caution; indacaterol is present in milk in animal studies.

Storage

Store in a cool, dry place below 30 degrees Celsius. Keep out of reach of children.

Formulations

• {'name': 'Onbrez Breezhaler', 'strength': '150 micrograms', 'form': 'Inhalation powder capsules with device'}
• {'name': 'Onbrez Breezhaler', 'strength': '300 micrograms', 'form': 'Inhalation powder capsules with device'}

Indications

• Chronic obstructive pulmonary disease (COPD)
• Asthma (as an adjunct therapy)
• Pre-operative medication to reduce secretions
• Management of excessive salivation

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations in pediatric patients.

Adults: Refer to the BNF for specific dosing information based on the indication and patient characteristics.

Mechanism of action

Glycopyrronium has the highest affinity for M1 muscarinic receptors, followed by M3, M2/M4, and M5. By antagonizing these receptors, particularly M3 which is responsible for bronchoconstriction and secretions, glycopyrronium decreases airway resistance and reduces the secretion of mucus in the airways, thereby facilitating easier breathing. It also decreases salivary and gastric secretions, contributing to its therapeutic effects in various conditions.

Pharmacodynamics

As a quaternary ammonium compound, glycopyrronium is one of the most commonly prescribed LAMAs with a long duration of action due to its slow dissociation from muscarinic receptors. It has a wider therapeutic index compared to other anticholinergic medications. Patients may experience side effects such as urinary retention, risk of overheating, and transient blurred vision as a result of its anticholinergic properties.

Pharmacokinetics

Glycopyrronium is well-absorbed following inhalation, with peak plasma concentrations occurring within a few hours. The drug undergoes hepatic metabolism, primarily via cytochrome P450 enzymes, and is excreted through both urine and feces. Its elimination half-life supports once-daily dosing in a clinical setting.

Adverse effects

• dry mouth
• blurred vision
• constipation
• urinary retention
• tachycardia
• confusion
• delirium

Interactions

• clozapine+glycopyrronium: Unknown (additive effect)
• antipsychotics, second generation+glycopyrronium: Unknown (additive effect)

Precautions

• use with caution in patients with urinary retention
• monitor for signs of overheating
• use with caution in elderly patients due to risk of confusion and delirium

Pregnancy

Glycopyrronium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known if glycopyrronium is excreted in human milk. Caution should be exercised when administering to breastfeeding women.

Storage

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

Formulations

• oral solution
• inhalation solution
• tablet

Mechanism of action

Glycopyrronium is a muscarinic antagonist with the highest affinity for M1 receptors, followed by M3, M2/M4, and M5. Muscarinic receptors M1 to M4 are found in the lung, although M3 is predominantly responsible for bronchoconstriction and airway secretions. Secretions from salivary and sweat glands, as well as gastric acid secretions, are also predominantly mediated by the M3 receptor. Salivary and gastric acid secretions are also partially mediated by the M1 receptor. Antagonism of these receptors decreases the volume of their respective secretions, and in the case of the gastrointestinal system, reduces the acidity of the stomach. In the cardiovascular system, muscarinic receptors M1 to M5 are all present, however the function of M5 has not been described in literature. Under normal circumstances, stimulation of the vagal nerve lowers the heart rate, potentially leading to intraoperative bradycardia. Studies in mice suggest that this stimulation is predominantly mediated by the M3 receptor, and mutant knockout mice are not susceptible to these effects.

Pharmacodynamics

Glycopyrronium is a quaternary ammonium compound that is one of the most commonly prescribed long acting muscarinic antagonists. Glycopyrronium slowly dissociated from muscarinic receptors, leading to a long duration of action. It has a wider therapeutic index than other anticholinergic medications, such as [tiotropium]. Patients should be counselled regarding the risk of worsening urinary retention, risk of overheating, and transient blurred vision.

Mechanism of action

Indacaterol works by stimulating adrenergic beta-2 receptors in the smooth muscle of the airways. This causes relaxation of the muscle, thereby increasing the diameter of the airways, which become constricted in asthma and COPD. It is also long acting due to its high affinity to the lipid raft domains in the airway membrane so it slowly dissociates from the receptors. Indacaterol also has a high intrinsic efficacy so it is also very rapid acting - onset of action occurs within 5 minutes. The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, 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 monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown.

Pharmacodynamics

Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Furthermore, this chiral compound it is given as the R-enantiomer and acts as a full agonist. Cough was the most commonly reported adverse effect with use of indacaterol. Compared to salmeterol, it has 35% more agonist activity. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. [PMID: 22499359]