Glycopyrrolate and formoterol

Glycopyrrolate and formoterol Uses, Dosage, Side Effects, Food Interaction and all others data.

Formoterol fumarate is a long-acting β2-adrenergic receptor agonist (β2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at β2-receptors than at β1-receptors. Although β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the heart, there are also β2-receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective β2-agonists may have cardiac effects.

The pharmacologic effects of β2-adrenoceptor agonist drugs, including formoterol, 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.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

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.

Glycopyrronium bromide is a quarternary ammonium antimuscarinic. It blocks acetylcholine at parasympathomimetic sites and induces smooth muscle relaxation. It also reduces gastric acid secretions and controls pharyngeal, tracheal and bronchial secretions. It antagonises muscarinic symptoms such as bronchorrhoea, bronchospasm, bradycardia and intestinal hypermotility induced by anticholinesterases.

Glycopyrrolate and formoterol
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Glycopyrrolate and formoterol
Generic	Formoterol + glycopyrrolate
Type	Inhalation
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Treatment of Asthma: Formoterol Fumarate is used for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in adults and children 5 years of age and older with reversible obstructive airways disease, including patients with symptoms of nocturnal asthma.

Prevention of Exercise-Induced Bronchospasm: Formoterol Fumarate is also used for the acute prevention of exercise-induced bronchospasm in adults and children 5 years of age and older, when administered on an occasional, as-needed basis. Use of Formoterol Fumarate as a single agent for the prevention of exercise-induced bronchospasm may be clinically used for patients who do not have persistent asthma. In patients with persistent asthma, use of Formoterol Fumarate for the prevention of exercise-induced bronchospasm may be clinically used, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid.

Maintenance Treatment of Chronic Obstructive Pulmonary Disease: Formoterol Fumarate is used for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with Chronic Obstructive Pulmonary Disease including chronic bronchitis and emphysema.

In Anesthesia:

As a pre-operative antimuscarinic agent to reduce salivary, tracheobronchial and pharyngeal sections and to reduce the acidity of the gastric contents.
As a pre-operative or intra-operative antimuscarinic to attenuate or prevent intraoperative bradycardia with the use of suxamethonium or due to cardiac vagal reflexes.
To protect against the peripheral muscarinic actions of anticholinesterases such as neostigmine and pyridostigmine, used to reverse residual neuromuscular blockade produced by non- depolarising muscle relaxants.

In Peptic Ulcer:

For use in adults as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated.

Hyperhidrosis, Sialorrhea, Cerebral palsy.

Glycopyrrolate and formoterol is also used to associated treatment for these conditions: Asthma, Bronchial Asthma, Bronchoconstriction, Chronic Obstructive Pulmonary Disease (COPD), Exercise-Induced Bronchospasm, Moderate to Severe COPD

How Glycopyrrolate and formoterol works

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.

Dosage

Glycopyrrolate and formoterol dosage

Inhalation Acute bronchospasm; Reversible airways obstruction:

As inhalation cap: 12 mcg twice daily, up to 24 meg twice daily in severe cases.
As dry powder inhaler: 6 or 12 mcg 1 -2 times/day, up to to 24 mcg twice daily in sever cases. As metered doses from aerosol inhaler: 12 or 24 mcg twice daily.

Prevention of exercise-induced bronchospasm: 6 or 12 mcg at least 15 mins before exercise. Additional doses may be given 12 hr later.

For IM/IV administration-

Pre-Anaesthetic Use:

Adults:0.2 mg to 0.4 mg intravenously or intramuscularly before the induction of anesthesia. Alternatively, a dose of 0.004 to 0.005 mg/kg.
Children (1 month to 12 years of age): 0.004 to 0.008 mg/kg up. Larger doses may result in profound and prolonged antisialogogue effect which may be unpleasant for the patient.

Intraoperative Use:

Adults:A single dose of 0.2 to 0.4 mg (or 0.004 to 0.005 mg/kg) by intravenous injection should be used.
Children: (1 month to 12 years of age) - A single dose of 0.004 to 0.008 mg/kg by intravenous injection should be used. This dose may be repeated if necessary.

Reversal of Neuromuscular Blockade:

Adults:0.2 mg intravenously per 1 mg neostigmine or the equivalent dose of pyridostigmine.
Children (1 month to 12 years of age) - 0.01 mg/kg intravenously with 0.05 mg/kg neostigmine or the equivalent dose of pyridostigmine. Supotaria may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.

For oral administration-

Initiate dosing at 0.02 mg/kg orally three times daily and titrate in increments of 0.02 mg/kg every 5-7 days based on therapeutic response and adverse reactions. The maximum recommended dosage is 0.1 mg/kg three times daily not to exceed 1.5-3 mg per dose based upon weight.

During the four-week titration period, dosing can be increased with the recommended dose titration schedule while ensuring that theanticholinergicadverse events are tolerable. Prior to each increase in dose, review the tolerability of the current dose level with the patient's caregiver.

Glycopyrrolate should be dosed at least one hour before or two hours after meals. The presence of high fat food reduces the oral bioavailability of Glycopyrrolate if taken shortly after a meal

Side Effects

Common side effects are Viral infection, Bronchitis, Chest infection, Dyspnea , Chest pain, Tremor, Dizziness, Angina, Arrhythmias, Hypo/hypertension, Tachycardia, Hypokalemia, Hyperglycemia, Metabolic acidosis, Headache, Insomnia, Paradoxical bronchospasm, Severe asthma exacerbation

Anticholinergic symptoms (mydriasis, hyperthermia, tachycardia, cardiac arrhythmia), Dry mouth, Dry skin, Anhidrosis, Flushing, Blurred vision, Cycloplegia, Photophobia, Palpitation, Xerophthalmia, Constipation, Urinary retention

Toxicity

The oral LD₅₀ in rats is 3130 mg/kg.

Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc. Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis. Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring. Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate.

Precaution

Thyrotoxicosis; severe CV disorders e.g. ischaemic heart disease, tachyarrhythmias or severe heart burn; prolonged QT-interval. DM; pregnancy; lactation; children, do not initiate or increase the dose during an exacerbation. May produce paradoxical bronchospasm.

Antimuscarinics should be used with caution (due to increased risk of side effects) in Down's syndrome, in children and in the elderly.

They should also be used with caution in gastro-esophageal reflux disease, diarrhea, ulcerative colitis, acute myocardial infarction, hypertension, conditions characterized by tachycardia (including hyperthyroidism, cardiac insufficiency, cardiac surgery) because of the increase in heart rate produced by their administration, coronary artery disease and cardiac arrhythmias, pyrexia (due to inhibition of sweating), pregnancy and breastfeeding.

Because of prolongation of renal elimination, repeated or large doses of glycopyrronium bromide should be avoided in patients with uremia.

Large doses of quaternary anticholinergic compounds have been shown to block end plate nicotinic receptors. This should be considered before using glycopyrrolate in patients with myasthenia gravis.

It is known that the administration of anticholinergic agents during inhalation anesthesia can result in ventricular arrhythmias.

Lactation: Excretion in milk unknown; use with caution

Interaction

Concomitant treatment with xanthine derivatives, steroids or diuretics may potentiate a possible hypokalaemic effect of beta-agonists. Increased susceptibility to cardiac arrhythmias in patients treated with digitalis. Concomitant use with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, MAOI or TCAs can prolong the QT-interval and increase the risk of ventricular arrhythmias. L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2-sympathomimetics. beta-adrenergic blockers can inhibit the effect of formoterol. Increased risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

Decreases levodopa effects. Effects may be enhanced by using drugs with antimuscarinic properties or MAOIs concurrently. May antagonise the Gl effects of cisapride, metoclopramide and dompeidone.

Elimination Route

The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut).

Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol T_max ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, C_max and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, T_max ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, C_max and AUC_0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C_max and AUC_0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges.

Half Life

The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation.

Clearance

Renal clearance of formoterol following inhalation is approximately 157 mL/min.

Elimination Route

Elimination differs depending on the route and formulation administered. Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively. Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces. Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively.

Pregnancy & Breastfeeding use

Pregnancy Category-C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Lactation: Not known if it is excreted in breast milk or not.

Pregnancy Category B. Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

Contraindication

Hypersensitivity.

Angle-closure glaucoma; myasthenia gravis (large doses of quaternary ammonium compounds have been shown to block end plate nicotinic receptors); paralytic ileus; pyloric stenosis; prostatic enlargement. Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrronium should be avoided in patients with a prolonged QT interval.