Ipratropium

Ipratropium belongs to the Anti-Cholinergics Pharmacological class.

Ipratropium is approved for the treatment of Asthma, bronchospasm, COPD (Chronic Obstructive Pulmonary Disease), Asthma exacerbations, Rhinorrhea, and Sialorrhea.

Ipratropium is absorbed after oral administration with low bioavailability of 2%. Ipratropium achieved a volume of distributions of 4.6 L/kg. Following the orally administered dose, about 90% of the dose is excreted in an unchanged form. The absorbed dose is partially metabolized by ester hydrolysis to its inactive metabolites, tropic acid, and tropane.

The common side effects associated with Ipratropium are Dry mouth, Dizziness, Nausea, Dry nose, Nasal or throat irritation, Nosebleeds, Bad taste in the mouth, Constipation, Bronchitis, Chronic obstructive pulmonary disease exacerbation, Sinus infection, Shortness of breath, Urinary tract infection, Headache, Flulike symptoms, Back pain, Cough, and Indigestion.

Ipratropium is available in the form of Oral Inhalation, Nebulized Inhalation.

Ipratropium is available in India, U.K., U.S., Canada, India, E.U., China, Japan, and Australia.

Ipratropium belongs to the pharmacological class of Anticholinergics. Through its action on Muscarinic receptors, Ipratropium appears to inhibit the vagally mediated reflexes by antagonizing the action of acetylcholine which is said to be the transmitter agent released from the vagus nerve.

Ipratropium hence prevents the increase in intracellular concentration of cyclic guanosine monophosphate that is caused by the interaction of acetylcholine on the muscarinic receptor on bronchial smooth muscle.

Ipratropium has a quick onset of action is found to be 10-15 minutes, and the duration of action is around 3- 5 hours.

Ipratropium is available in Oral Inhalation metered dose inhalers and Inhalation Nebulizers

Metered Dose Inhalation.

1. The cap is removed from the MDI and chamber and Shaken well.
2. The MDI is inserted into the open end of the chamber opposite the mouthpiece.
3. The mouthpiece of the chamber is placed between your teeth and your lips are sealed tightly around it.
4. Now breathe out completely.
5. Then press the canister once.
6. Now breathe in slowly and completely through your mouth. If one hears a "horn-like" sound, then the person is breathing too quickly and needs to slow down.
7. Now hold your breath for 10 seconds and count to 10 slowly to allow the medication to reach the airways of the lung.
8. The above steps are repeated for each puff ordered by medical practitioners and wait about 1 minute in between puffs.
9. Lastly, replace the cap on your MDI when finished.

Nebulizer Inhalation

1. The compressor is placed where it can safely reach its power source and where you can reach the ON/OFF switch.
2. The patient must wash their hands prior to preparing each treatment.
3. Always a clean nebulizer must be used.
4. The correct dose of medication is measured and other solutions are prescribed by the physician and these are added to the nebulizer.
5. The air tubing is connected from the compressor to the nebulizer base.
6. Now a mouthpiece is attached to the nebulizer.
7. The mouthpiece is put into the mouth between your teeth and lips are closed around it tightly.
8. The nebulizer is held in an upright position. This prevents spilling and promotes nebulization.
9. Deep breathing throughout the treatment is assured. This allows the medication time to deposit in the airway.
10. Occasionally tapping the side of the nebulizer is done which helps the solution drop to where it can be misted.
11. Now continue these steps until the onset of inconsistent nebulization, i.e. sputtering.

Ipratropium can be used in the treatment of:

• Asthma
• Bronchospasm
• COPD(Chronic Obstructive Pulmonary Disease)
• Asthma exacerbations
• Rhinorrhea
• Sialorrhea

Ipratropium can help to relieve symptoms of Asthma, bronchospasm, COPD(Chronic Obstructive Pulmonary Disease), Asthma exacerbations, Rhinorrhea, Sialorrheaa

Ipratropium is approved for use in the following clinical indications:

• Asthma
• Bronchospasm
• COPD(Chronic Obstructive Pulmonary Disease)
• Asthma exacerbations
• Rhinorrhea
• Sialorrhea

Patients aged >12 years of age:

(Adults and children)

250 - 500 micrograms.

For treatment of acute bronchospasm, 500 micrograms.

Daily doses exceeding 2 mg in adults and children over 12 years of age should only be given under medical supervision.

Patients aged 6 - 12 years :

250 micrograms.

The time interval between doses should be determined by the physician.

Patients aged 0 – 5 years:

125 - 250 micrograms.

Ipratropium bromide should be administered less frequently about 6 hours in children under 5 years of age.

For acute bronchospasm, repeated doses might be administered until the patient is stable.

Only specialists in respiratory medicine should be allowed to initiate and clinically manage the use of nebulizers and associated nebulized medicines at home for the acute treatment of asthma in children and adolescents.

Oral Inhalation: 17mcg/actuation

Inhalation Nebulization: 0.02%,500 mcg/2.5 mL

Maintaining health and smoking cessation is a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions is needed to be individualized as per the patient's requirements.

Ipratropium may be contraindicated during the co-administration with the following drugs: Sympathomimetic amines

• Hypersensitivity to the ingredients of the medication
• Hypersensitivity to Atropine and other related derivatives

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Use for Maintenance Treatment Only

Ipratropium is said to be a bronchodilator for the maintenance treatment of bronchospasm associated with Chronic Obstructive Pulmonary Disease (COPD) and it is not indicated in the initial treatment of acute episodes of bronchospasm where rescue therapy is needed for rapid response.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions including bronchospasm, anaphylaxis, oropharyngeal edema, urticaria, angioedema, and rash, might occur after the administration of Ipratropium. In the clinical trials and postmarketing experience study reports with ipratropium-containing products, hypersensitivity reactions such as urticaria (including giant urticaria), skin rash, pruritus, angioedema of tongue, lips and face, laryngospasm and anaphylactic reactions have been reported. If such reactions occur, therapy with Ipratropium should be stopped at once and alternative treatment should be considered

Paradoxical Bronchospasm

Ipratropium might produce paradoxical bronchospasm which can be life-threatening. If it occurs, treatment with Ipratropium should be stopped and other treatments considered.

Ocular Effects

Ipratropium is said to be an anticholinergic and its use might increase intraocular pressure in the eyes. This may result in precipitation / worsening of narrow-angle glaucoma.

Therefore, Ipratropium should be used with caution in patients with narrow-angle glaucoma.

Patients should avoid spraying Ipratropium into their eyes. If a patient sprays Ipratropium into their eyes, it may cause eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos, etc. It is advised that the patients should consult the physician immediately if any of these symptoms develop while using Ipratropium Inhalation Aerosol.

Urinary Retention

Ipratropium is an anticholinergic and may cause urinary retention. Therefore caution is advised when administering Ipratropium to patients with prostatic hyperplasia, or bladder-neck obstruction

Avoid alcohol usage while on Ipratropium Medication as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision, etc.

It is unknown whether Ipratropium bromide is excreted in human milk. Although it is unlikely that ipratropium bromide would reach the infant to an extent, especially when taken by aerosol. However, as many drugs are excreted in human milk, caution should be exercised when Ipratropium Inhalation Aerosol is administered to a nursing woman.

Pregnancy Category B.

Reproduction studies were conducted on animals. The oral reproduction studies were conducted at doses of around 10 mg/kg/day in mice, 1,000 mg/kg in rats, and 125 mg/kg/day in rabbits which correspond to about 200, 40,000 and 10,000 times the maximum recommended daily inhalation dose in adults in each species respectively. Inhalation reproduction studies had been conducted in rats and rabbits at doses of about 1.5 and 1.8 mg/kg i.e. approximately 60 and 140 times the maximum recommended daily inhalation dose in adults on an mg/m2 basis. These studies have demonstrated that there is no evidence of teratogenic effects as a result of Ipratropium. At oral doses of about 90 mg/kg and above in rats which is approximately 3600 times the maximum recommended daily inhalation dose in adults embryotoxicity has been observed as increased resorption. This effect is not found to be considered relevant in human use due to the large doses and the difference in the route of administration. No adequate and well-controlled studies were found to have been conducted on pregnant women.

No sufficient scientific evidence is traceable regarding the use and safety of Ipratropium in concurrent use with any particular food. It has been found that caffeine-containing substances must be avoided as they may enhance the inotropic effects of beta-agonists.

The adverse reactions related to Ipratropium can be categorized as:

Common

• Frequent urge to urinate
• Lower back or side pain
• Shortness of breath
• Tightness in the chest
• Wheezing
• Bladder pain
• Bloody or cloudy urine
• Cough-producing mucus
• Difficult, burning, or painful urination
• Difficulty with breathing

Less common

• Loss of voice
• Runny nose
• Sneezing
• Sore throat
• Unusual tiredness or weakness
• Body aches or pain
• Chills
• Cough
• Ear congestion
• Fever
• Headache

Rare

• Severe eye pain
• Skin rash or hives
• Swelling of the face, lips, or eyelids
• Constipation or lower abdominal pain or bloating
• Irregular heartbeat or pulse

The clinically relevant drug interactions of Ipratropium are briefly summarized here:

Ipratropium had been used concomitantly with other drugs, such as sympathomimetic bronchodilators, methylxanthines, and oral or inhaled steroids which are commonly used in the treatment of Chronic Obstructive Pulmonary Disease. Except for albuterol, there are no formal studies fully evaluating the interaction effects of Ipratropium and these drug with respect to safety and efficacy.

Anticholinergic Agents

There is found to be potential for an additive interaction with the concomitant use of anticholinergic medications. Therefore, co-administration of Ipratropium with other

Anticholinergic-containing drugs should be avoided as it may lead to an increase in anticholinergic adverse effects.

The common side effects of Ipratropium include the following:

• Dry mouth
• Dizziness
• Nausea
• Dry nose
• Nasal or throat irritation
• Nosebleeds
• Bad taste in mouth
• Constipation
• Bronchitis
• Chronic obstructive pulmonary disease exacerbation
• Sinus infection
• Shortness of breath
• Urinary tract infection
• Headache
• Flulike symptoms
• Back pain
• Cough
• Indigestion

Pregnancy

Pregnancy Category B.

Reproduction studies were conducted on animals. The oral reproduction studies were conducted at doses of around 10 mg/kg/day in mice, 1,000 mg/kg in rats, and 125 mg/kg/day in rabbits which correspond to about 200, 40,000 and 10,000 times the maximum recommended daily inhalation dose in adults in each species respectively. Inhalation reproduction studies had been conducted in rats and rabbits at doses of about 1.5 and 1.8 mg/kg i.e. approximately 60 and 140 times the maximum recommended daily inhalation dose in adults on an mg/m2 basis. These studies have demonstrated that there is no evidence of teratogenic effects as a result of Ipratropium. At oral doses of about 90 mg/kg and above in rats which is approximately 3600 times the maximum recommended daily inhalation dose in adults embryotoxicity has been observed as increased resorption. This effect is not found to be considered relevant in human use due to the large doses and the difference in the route of administration. No adequate and well-controlled studies were found to have been conducted on pregnant women.

Nursing Mothers

It is unknown whether Ipratropium bromide is excreted in human milk. Although it is unlikely that ipratropium bromide would reach the infant to an extent, especially when taken by aerosol. However, as many drugs are excreted in human milk, caution should be exercised when Ipratropium Inhalation Aerosol is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of the pediatric population have not been established. 250 - 500 micrograms are used for the treatment of asthma. For the treatment of acute bronchospasm 500 micrograms are used.

Daily doses exceeding 2 mg in adults and children over 12 years of age should only be given under medical supervision.

Geriatric Use

In 12-week pivotal study, Ipratropium Inhalation was found to be effective in patients aged over 65 years and under 65 years. No overall differences in safety or effectiveness had been observed between these older and younger subjects.

Physicians should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Ipratropium.

No symptoms specific to overdosage have been known. In view of the wide therapeutic window and topical administration of Ipratropium, no serious anticholinergic symptoms are to be expected. Along with other anticholinergics, dry mouth, visual accommodation disturbances, and tachycardia would be the expected symptoms and signs of overdose.

Pharmacodynamics

Ipratropium is a short-acting agent that is found to inhibit the parasympathetic nervous system at the level of the airway which then leads to bronchodilatation. The effect starts after 1-2 hours and it has been known to last only from 4 to 6 hours. Additionally, Ipratropium relaxes the bronchial airways which reverse the narrowing of the airways

In clinical trials where ipratropium had been used in the initial management of status asthmaticus, it demonstrated a clear effect by enhancing the pulmonary function in children and adult patients. Although, the continuous use of ipratropium after an acute asthmatic attack has not been proven to be of a significant advantage nor the prophylactic administration of Ipratropium.

Pharmacokinetics

• Absorption

Ipratropium is a topically active but is poorly absorbed. The lack of potential for absorption in the mucosal surfaces is found to be associated with the presence of a charge in the 5-valent nitrogen in the molecule structure. The molecule itself presents a large topic effectiveness. However, it does not produce detectable systemic effects.

The serum levels of ipratropium after oral or inhaled administration were found to be very low, which corresponds to only 1-2% of the administered dose. These low levels peak were achieved after 1-2 hours and it presents a low bioavailability of 2%.

• Distribution

Ipratropium has a volume of distribution of 4.6 L/kg and hence, it is known to be highly distributed in the tissues.

• Metabolism

Ipratropium is found to be metabolized in the gastrointestinal tract by the activity of the cytochrome P-450 isoenzymes. From the orally administered dose, it has ben noted thatabout 90% of the dose is found to be excreted unchanged. The portion that gets absorbed is partially metabolized by ester hydrolysis to inactive metabolites, tropic acid, and tropane.

• Excretion

Of the administered dose of ipratropiumabout 80-90% is excreted in the urine, leaving about less than 20% of the dose has been found to be eliminated through the feces. From the urine eliminated, almost all the drug is found in the unchanged form.

When ipratropium was orally administered, due to its low absorption, most of the dose was found to be recovered in the feces with a very minimal amount was found in the urine.

1) Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2021 global strategy for prevention, diagnosis, and management of COPD. https://goldcopd.org/2021-gold-reports. Accessed October 22, 2021

2) Hodges IGC, Goggins RC, Milner AD, et al. Bronchodilator effect of inhaled ipratropium bromide in wheezy toddlers. Arch Dis Child. 1981;56(9):729-732.

3) Hughes DT, “The Use of Anticholinergic Drugs in Nocturnal Asthma,” Postgrad Med J, 1987, 63(Suppl 1):47-51.

4) Ipratropium bromide inhalation solution [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals Inc; May 2013.

5) Kamin W, Erdnüss F, Krämer I. Inhalation solutions--which ones may be mixed? Physico-chemical compatibility of drug solutions in nebulizers--update 2013. J Cyst Fibros. 2014;13(3):243-250. doi:10.1016/j.jcf.2013.09.006

6) Lee H, Arnon S, Silverman M. Bronchodilator aerosol administered by metered dose inhaler and spacer in subacute neonatal respiratory distress syndrome. Archives of Disease in Childhood. 1994;70:218-222.

7) Mann NP and Hiller RG, “Ipratropium Bromide in Children With Asthma,” Thorax, 1982, 37(1):72-4.

8) Middleton PG, Gade EJ, Aguilera C, et al. ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J. 2020;55(2):1901208. doi:10.1183/13993003.01208-2019

9) National Asthma Education and Prevention Program (NAEPP). Expert Panel Review Report 3: Guidelines for the diagnosis and management of asthma. National Heart, Blood, and Lung Institute. https://www.nhlbi.nih.gov/sites/default/files/media/docs/EPR-3_Asthma_Full_Report_2007.pdf. Published 2007.

10) Prendiville A, Green S, Silverman M. Ipratropium bromide and airways function in wheezy infants. Archives of Disease in Childhood. 1987;62:397-400.

11) Stokes GM, Milner AD, Hodges IGC, et al. Nebulized therapy in acute severe bronchitis in infancy. Archives of Disease In Childhood. 1983;58:279-282. [PubMed 6221700]

12) Stoller JK. COPD exacerbations: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 14, 2022.

13) Vézina K, Chauhan BF, Ducharme FM. Inhaled anticholinergics and short-acting beta(2)-agonists versus short-acting beta2-agonists alone for children with acute asthma in hospital. Cochrane Database Syst Rev. 2014(7): CD010283.

14) Atrovent HFA (ipratropium) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; February 2020.

15) Brundage KL Mohsini KG, Froese AB, et al. Bronchodilator response to ipratropium bromide in infants with bronchopulmonary dysplasia. Am Rev Respir Dis. 1990;142:1137-1142.

16) Burchett DK, Darko W, Zahra J, Noviasky J, Probst L, Smith A. Mixing and compatibility guide for commonly used aerosolized medications. Am J Health Syst Pharm. 2010;67(3):227-230. doi:10.2146/ajhp080261

17) Dweik RA. Role of muscarinic antagonist therapy in COPD. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 22, 2021.

18) https://www.uptodate.com. Accessed August 30, 2021.

19) Fayon M, Tayara N, Germain C, et al. Efficacy and tolerance of high-dose inhaled ipratropium bromide vs. terbutaline in intubated premature human neonates. Neonatology. 2007;91:167-173.

20) Ferguson GT. Stable COPD: initial pharmacologic management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc.

21) Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf. Updated 2021. Accessed January 6, 2022.