BREZTRI AEROSPHERE

Indications

• Chronic bowel disorders
• Crohn's disease affecting the ileum or ascending colon
• Ulcerative colitis
• Asthma management

Dosage

Children: For children 1-17 years: 3 mg three times a day for up to 8 weeks for Crohn's disease; 1 enema daily for 4 weeks for ulcerative colitis in children 12-17 years.

Adults: For Crohn's disease: 9 mg once daily for up to 8 weeks; for ulcerative colitis: 1 enema daily for 4 weeks. Dosage may vary, so refer to specific guidelines.

Mechanism of action

Budesonide exerts its effects by binding to corticosteroid receptors, modulating the expression of genes involved in inflammatory processes. This action leads to a significant reduction in inflammation and immune response.

Pharmacodynamics

As a potent anti-inflammatory agent, budesonide reduces the activity of inflammatory mediators and inhibits the recruitment of inflammatory cells to sites of inflammation, thus alleviating symptoms associated with conditions like asthma and inflammatory bowel disease.

Pharmacokinetics

Budesonide is rapidly absorbed after administration, with a significant first-pass metabolism resulting in a lower systemic exposure. It has a half-life of approximately 2-3 hours, and its effects can be prolonged due to its local action in the gut when used for bowel disorders.

Adverse effects

• Insomnia
• Stomatitis
• Taste disorders
• Diarrhoea
• Muscle twitching
• Oedema
• Anaemia
• Decreased appetite
• Ataxia
• Lymphadenopathy
• Macrocytosis
• Aseptic meningitis
• Severe cutaneous adverse reactions (SCARs)
• Parotitis
• Nephrotic syndrome
• Pseudomembranous enterocolitis
• Blood disorders

Interactions

• Grapefruit juice (severe - increases exposure)
• Cenobamate (moderate - decreases exposure)
• Mitotane (moderate - decreases exposure)
• Rifampicin (moderate - decreases exposure)
• Cobicistat (unknown - increases exposure)
• Idelalisib (unknown - increases exposure)
• Clarithromycin (unknown - increases exposure)

Precautions

• Caution in hepatic impairment
• Caution in renal impairment
• Monitor blood counts and liver function tests

Pregnancy

Theoretical risk of neonatal haemolysis; adequate folate supplements advised.

Breast-feeding

Small amounts may appear in milk; theoretical risk of neonatal haemolysis, especially in G6PD-deficient infants.

Storage

Store in a cool, dry place, protected from light.

Formulations

• Budenofalk® Capsules
• Entocort® Capsules
• Entocort® Enema
• Oral suspension

Indications

• Chronic asthma
• Chronic obstructive pulmonary disease (COPD)
• Reversible airways obstruction
• Prophylaxis of exercise-induced bronchospasm

Dosage

Children: Child 6–11 years: 12 micrograms twice daily (maximum daily dose 24 micrograms). Child 12–17 years: 12 micrograms twice daily, may

Adults: 6–12 micrograms by inhalation 1–2 times a day, increased if necessary up to 24 micrograms twice daily (max. per dose 36 micrograms), with a maximum daily dose of 48 micrograms.

Mechanism of action

Formoterol fumarate acts as an agonist at beta-2 adrenergic receptors located on bronchial smooth muscle. Upon binding, it activates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) levels, leading to relaxation of bronchial smooth muscle and bronchodilation. This mechanism results in improved airflow and reduced resistance in the airways.

Pharmacodynamics

The pharmacodynamic effect of formoterol fumarate includes bronchodilation and relief of bronchospasm associated with asthma and COPD. The duration of action is approximately 12 hours, allowing for twice-daily dosing in many cases. Formoterol also exhibits some anti-inflammatory effects, although its primary role is as a bronchodilator.

Pharmacokinetics

Formoterol fumarate is well-absorbed following inhalation, with peak plasma concentrations typically occurring within 15 to 30 minutes. It undergoes extensive metabolism in the liver, primarily via the cytochrome P450 system. The elimination half-life is approximately 10 hours. Renal impairment may necessitate dose adjustments, especially in severe cases, while hepatic impairment is advised against due to the risk of unpredictable conversion to terbutaline.

Contra-indications

• Hypersensitivity to formoterol or any component of the formulation
• Severe impairment or cirrhosis of liver
• Rapidly deteriorating asthma

Adverse effects

• Anxiety
• Abnormal behaviour
• Muscle cramps
• Sleep disorders
• Akathisia
• Angioedema
• Bronchospasm
• Circulatory collapse
• Dizziness
• Hypokalaemia
• Hypotension
• Myocardial ischaemia
• Nausea
• Skin reactions

Interactions

• Concomitant use with theophylline and its derivatives may potentiate hypokalaemia
• Corticosteroids may also increase the risk of hypokalaemia
• Diuretics can lead to additive effects on serum potassium levels

Precautions

• Caution in patients with a history of cardiovascular disease
• Monitor potassium levels in patients on high doses
• Use with caution in patients with severe asthma or those requiring high doses of beta-agonists

Pregnancy

Manufacturer advises to avoid use due to lack of information on safety during pregnancy.

Breast-feeding

Manufacturer advises to avoid use due to lack of information on safety during breastfeeding.

Storage

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

Formulations

• Inhalation powder (various dosage forms including 6 micrograms, 12 micrograms, and 24 micrograms per dose)

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

• Asthma
• Chronic obstructive pulmonary disease (COPD)

Dosage

Children: Refer to BNF for Children for specific dosing recommendations based on age and weight.

Adults: Refer to BNF for specific dosing guidance, typically involving the use of metered-dose inhalers or nebulizers.

Mechanism of action

Formoterol selectively binds to and activates beta2-adrenergic receptors, predominantly located in bronchial smooth muscle. This activation stimulates adenylyl cyclase, leading to increased levels of cyclic AMP (cAMP). Elevated cAMP causes relaxation of bronchial smooth muscle and dilation of the airways. Additionally, formoterol inhibits the release of hypersensitivity mediators, such as histamine and leukotrienes, from mast cells, further contributing to its bronchodilator effect.

Pharmacodynamics

As a bronchodilator, formoterol works locally in the lungs to relax smooth muscle and open the airways. It provides both a rapid onset of action and a prolonged duration, making it suitable for the management of chronic respiratory conditions. However, it should not be used as monotherapy in asthma management due to an associated increased risk of asthma-related death when not combined with inhaled corticosteroids.

Pharmacokinetics

Formoterol is administered via inhalation, allowing for direct delivery to the lungs. It has a rapid onset of action, typically within 2-3 minutes, and is characterized by a long duration of action, up to 12 hours. The pharmacokinetics of formoterol may vary based on individual patient factors, including age, lung function, and concurrent medications.

Contra-indications

• Hypersensitivity to formoterol or any of its components
• Severe uncontrolled asthma
• Acute bronchospasm
• Cardiovascular disorders
• Use of monoamine oxidase inhibitors (MAOIs) within 14 days

Adverse effects

• Tachycardia
• Palpitations
• Tremor
• Headache
• Nervousness
• Dizziness
• Nausea
• Muscle cramps
• Hypokalemia
• Hyperglycemia

Interactions

• Other sympathomimetics
• Beta-blockers (may reduce effectiveness of formoterol)
• Diuretics (may increase the risk of hypokalemia)
• Monoamine oxidase inhibitors (MAOIs)
• Tricyclic antidepressants

Precautions

• Caution in patients with cardiovascular disorders
• Caution in patients with diabetes mellitus
• Use with caution in patients with hyperthyroidism
• Monitor for worsening of asthma symptoms
• Avoid use as a rescue medication

Pregnancy

Formoterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult a healthcare provider.

Breast-feeding

It is not known whether formoterol is excreted in human milk. Caution should be exercised when prescribing to nursing women.

Storage

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

Formulations

• Aerosol inhaler
• Dry powder inhaler
• Nebuliser solution

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

The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. To investigate the roles of signal transduction and activator of transcription 6 (STAT6) and orosomucoid 1-like 3 (ORMDL3) in airway remodeling among asthmatic mice and to observe the effects of budesonide (BUD) on their expression, thirty mice were randomly divided into control, asthma, and BUD intervention group. The mice were sensitized and challenged with ovalbumin (OVA) to establish a mouse model of asthma. The BUD intervention group received aerosol inhalation of BUD dissolved in normal saline 30 minutes before each OVA challenge, while normal saline was used instead of OVA solution in the control group. The pathological changes in the airway were observed by hematoxylin-eosin staining and Masson staining. The interleukin-13 (IL-13) level in lung homogenate was measured by enzyme-linked immunosorbent assay. The mRNA expression of STAT6 and ORMDL3 was measured by RT-PCR. The asthma group showed more pathological changes in the airway than the control and BUD intervention groups, and the BUD intervention group had reduced pathological changes in the airway compared with the asthma group. The asthma and BUD intervention groups had significantly higher IL-13 levels and mRNA expression of STAT6 and ORMDL3 than the control group (P<0.05), and these indices were significantly higher in the asthma group than in the BUD intervention group (P<0.05). The Pearson correlation analysis showed that STAT6 mRNA expression was positively correlated with ORMDL3 mRNA expression (r=0.676, P=0.032). STAT6 and ORMDL3 may be involved in the airway remodeling of mice, and BUD can reduce airway remodeling in asthmatic mice, possibly by down-regulating mRNA expression of STAT6 and ORMDL3. Mucus hypersecretion from airway epithelium is a characteristic feature of severe asthma. Glucocorticoids (GCs) may suppress mucus production and diminish the harmful airway obstruction. We investigated the ability of GCs to suppress mRNA expression and protein synthesis of a gene encoding mucin, MUC5AC, induced by transforming growth factor (TGF)-alpha in human mucoepidermoid carcinoma (NCI-H292) cells and the molecular mechanisms underlying the suppression. We determined if GCs such as dexamethasone (DEX), budesonide (BUD), and fluticasone (FP) could suppress MUC5AC production induced by a combination of TGF-alpha and double-strand RNA, polyinosinic-polycytidylic acid (polyI:C). MUC5AC mRNA expression and MUC5AC protein production were evaluated. The signaling pathways activated by TGF-alpha and their inhibition by GCs were tested using a phosphoprotein assay and MUC5AC promoter assay. DEX significantly suppressed the expression of MUC5AC mRNA and MUC5AC protein induced by TGF-alpha. The activation of the MUC5AC promoter by TGF-alpha was significantly inhibited by DEX. DEX did not affect activation of downstream pathways of the EGF receptor or mRNA stability of MUC5AC transcripts. DEX, BUD, and FP suppressed MUC5AC protein expression induced by a combination of TGF-alpha and polyI:C in a dose-dependent manner. GCs inhibited MUC5AC production induced by TGF-alpha alone or a combination of TGF-alpha and polyI

Pharmacodynamics

Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression.

Mechanism of action

Formoterol is a relatively selective long-acting agonist of beta₂-adrenergic receptors, although it does carry some degree of activity at beta₁ and beta₃ receptors. Beta₂ receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta₁ receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta₂ receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta₂ receptors over beta₁ receptors. On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells. Formoterol is a long-acting selective stimulator of the beta2-adrenergic receptors in bronchial smooth muscle. This stimulation causes relaxation of smooth muscle fibers and produces bronchodilation. Formoterol stimulates beta2-adrenergic receptors and apparently has little or no effect on beta1- or alpha-adrenergic receptors. The drug's beta-adrenergic effects appear to result from stimulation of the production of cyclic adeno-3'-5'-monophosphate (cAMP)by activation of adenyl cyclase. Cyclic AMP mediate numerous cellular responses, increased concentrations of cAMP are associated with relaxation of bronchial smooth muscle and suppression of some aspects of inflammation, such as inhibition of release proinflammatory mast cell mediators(eg histamine, leukotrienes).

Pharmacodynamics

Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) and a long duration of action (up to 12 hours). The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death.

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.