Muscarinic antagonists: Uses, common brands, and safety info

The muscarinic antagonist drug class has a diverse list of applications, ranging from the treatment of overactive bladder and irritable bowel syndrome to the neurodegenerative condition of Parkinson’s disease. The most extensive use of muscarinic antagonists is likely in the form of inhalers for respiratory disease. Although beta-agonist inhalers like albuterol are the most renowned bronchodilators, muscarinic antagonists are a close second based on their ability to also open bronchial airways. Muscarinic antagonists are frequently used to control symptoms of asthma and chronic obstructive pulmonary disease (COPD). 

There are a variety of muscarinic antagonist agents including short- and long-acting versions as well as medications that are used in combination with other inhaled medications. We will explore different uses and products within the drug class and delve into the group’s mechanism of action, adverse effects, and expense.

Other muscarinic antagonists

• Ipratropium bromide nasal spray

• Incruse Ellipta (umeclidinium)

• Tudorza Pressair (aclidinium)

• Duaklir Pressair (aclidinium-formoterol)

• Yuperli (revefenacin)

• Lonhala Magnair (glycopyrrolate)

• Seebri (glycopyrrolate)

• Bevespi Aerosphere (formoterol-glycopyrrolate)

• Breztri Aerosphere (budesonide-formoterol-glycopyrrolate)

• Darifenacin

• Trospium

• Benztropine

• Scopolamine

RELATED: Incruse Ellipta vs. Spiriva

What are muscarinic antagonists?

Today’s inhaled muscarinic antagonists are synthetic derivatives of natural, plant-based substances that have been used for hundreds of years to relieve bronchospasm or tight bronchial tubes. Atropine and scopolamine are found in belladonna plants, and in the 19th century, prior to modern medicine, the smoke from their burning leaves was used to provide symptom relief in asthma. Over the last century, refined inhalers, nebulizer machines, and synthetic derivatives of atropine have allowed muscarinic antagonists to be everyday elements of asthma and COPD management. Taken orally, the bodily effects are much more widespread with typical intended action on the intestinal tract, bladder, or central nervous system (CNS).

How do muscarinic antagonists work?

Muscarinic antagonists for respiratory conditions

Our bronchial tubes have ribbons of smooth muscles wrapped around them. When these muscles contract, the airways are tightened. Excitement and control of these muscles is the responsibility of the autonomic nervous system, specifically the parasympathetic arm. The parasympathetic system has been termed the “rest and digest” side of subconsciously controlling body system functions, opposed to the “fight or flight” sympathetic system. A large part of the parasympathetic activation of bronchial smooth muscle is the responsibility of the vagal nerve. At the nerve ending’s synapse with the bronchial muscle, acetylcholine (ACh) is the neurotransmitter messenger that sends the signal for the muscle to contract. Muscarinic antagonists target this ACh action to prevent bronchoconstriction, and therefore, in pharmacology circles, the drug class is also considered an anticholinergic medication.

In order to block acetylcholine action, muscarinic antagonists block the chemical’s receptors within the synapse. Acetylcholine utilizes two varieties of receptors, nicotinic and muscarinic. Among the five muscarinic receptor subtypes, activation of the M1 and M3 receptors leads to bronchoconstriction and bronchial mucous secretion, unlike M2 receptors which reduce bronchoconstriction. Atropine blocks these muscarinic acetylcholine receptor subtypes. Unfortunately, it does not have much effect on neuronal nicotinic receptors, and any amount left in the mouth can be absorbed, leading to CNS effects, blurred vision, tachycardia (fast heart rate), and dry mouth. New atropine derivatives like ipratropium and tiotropium shed these negative attributes and CNS effects by not being significantly absorbed orally and by antagonizing both muscarinic and nicotinic receptors.

Muscarinic antagonists for gastrointestinal conditions

Similar to bronchial action, muscarinic receptor activation within the intestinal tract and bladder leads to muscular contraction of these organs. Muscarinic antagonists can relax these muscles by reducing contraction. The resultant bladder relaxation can help alleviate frequent urination in the setting of an overactive bladder. Intestinal muscle relaxation can decrease the cramps experienced in irritable bowel syndrome.

Muscarinic antagonists for Parkinson’s

The manner in which this drug class contributes to Parkinson’s treatment is different. Rather than trying to achieve smooth muscle relaxation within bodily organs, antimuscarinic usage for Parkinson’s disease aims to rebalance the neurotransmitter (natural brain chemical) activity of acetylcholine and dopamine. Dopamine deficiency is the central problem of Parkinson’s disease, and in its relative absence, acetylcholine is left to dominate. Consequently, anticholinergic drugs can be beneficial by inhibiting acetylcholine and keeping the neurotransmitters in better balance.

What are muscarinic antagonists used for?

• COPD maintenance, including emphysema and chronic bronchitis

• COPD exacerbation (off-label use)

• Asthma maintenance

• Asthma exacerbation (off-label use)

• Rhinorrhea (runny nose)

• Overactive bladder

• Irritable bowel syndrome (IBS)

• Parkinson’s disease

• Nausea

• Motion sickness

Types of muscarinic antagonists

Short-acting inhaled muscarinic antagonists

Ipratropium is the short-acting muscarinic antagonist in widespread use today. Packaged as a nebulizer solution or an Atrovent HFA inhaler, the drug can be inhaled every four hours if needed but typically is given four times daily as a COPD maintenance medication. The anticipated results are less shortness of breath and increased exercise tolerance, for the duration of its action, about four to eight hours. Ipratropium pairs with the beta-agonist medication albuterol to provide a dual mechanism for bronchodilation, specifically in the form of a nebulizer solution or Combivent Respimat inhaler. Ipratropium is even available as a nasal spray to help with rhinorrhea.

Long-acting inhaled muscarinic antagonists

The inconvenience of four times per day ipratropium treatment has largely been solved by replacing it with a long-acting muscarinic antagonist for control of COPD symptoms. Spiriva inhaler products, the Incruse Ellipta inhaler, and Yuperli nebulizer solutions can be given once daily and provide 24 hours of relief. Tudorza Pressair, Lonhala Magnair, and Seebri are twice-daily options. Of note, while their long duration of action is convenient, the long-acting anticholinergics take longer to get to peak effect, so unlike ipratropium, they are not used for urgent relief of bronchospasm.

Combination inhaled agents

Coupling a muscarinic antagonist with a beta-agonist makes sense by gaining additive bronchodilating effects. The long-acting Stiolto Respimat, Anoro Ellipta, Duaklir Pressair, and Bevespi Aerosphere do just that for the benefit of COPD maintenance therapy. Stiolto Respimat and Anoro do so with a once-daily format. It is important to note that long-acting beta-agonists are not to be used in the treatment of asthma unless combined with an inhaled corticosteroid. 

The short-acting inhaler combining ipratropium and albuterol, Combivent Respimat, and nebulized ipratropium-albuterol are approved for COPD treatment but require multiple daily doses for chronic maintenance therapy. By having a quicker time to peak effect, however, the combination of albuterol and ipratropium products are used off-label for acute COPD and asthma exacerbations.

Taking the notion of combination therapy another step, adding inhaled corticosteroids to bronchodilators provides an anti-inflammatory action to counter airway swelling in asthma and COPD. Long-acting bronchodilators reduce the risk of COPD exacerbation, and clinical studies have shown that combining the two bronchodilator categories and inhaled steroids lowers the risk even more. Trelegy Ellipta contains a long-acting muscarinic antagonist, long-acting beta-agonist, and inhaled corticosteroid for triple therapy that is approved for both COPD and asthma maintenance therapy. Another triple therapy option, Breztri Aerosphere, is only approved for COPD maintenance treatment.

Bladder muscarinic antagonists

Overactive bladder (OAB) can be more than just a nuisance. Frequent urination, urgency, and incontinence can take a toll on one’s social and professional life. Brand-name Detrol, Ditropan, Vesicare, and Toviaz are common choices within the muscarinic receptor antagonists for the treatment of OAB. Generic versions of these medications are available, as are darifenacin and trospium. 

Gastrointestinal muscarinic antagonists

Irritable bowel syndrome (IBS) can consist of diarrhea, constipation, or alternating bouts of both. Along with either form of altered bowel habits, painful abdominal cramps are another IBS symptom. Blocking intestinal muscarinic receptors can serve as a mechanism for IBS pain relief. Bentyl and Levsin can both offer this service.

Scopolamine patches have actions with the intestinal tract too. The antimuscarinic drug can be used as an antiemetic (nausea reliever) and motion sickness medicine. In addition, it functions as a histamine inhibitor and has evidence to support action similar to antidepressants.

Antiparkinson muscarinic antagonists

The tremor of Parkinson’s disease can be effectively treated with the muscarinic antagonists’ trihexyphenidyl or benztropine. Their use, particularly in seniors, is limited by an abundance of potential side effects.

Who can take muscarinic antagonists?

Can men take muscarinic antagonists?

Barring any contraindications to their use, men can take muscarinic receptor antagonists. Men with prostatic hypertrophy (prostate gland enlargement) need to be cautious because muscarinic antagonists can further increase the risk of urinary retention in this condition.

Can women take muscarinic antagonists?

Women can also use the inhaled cholinergic antagonists if there are no contraindications.

Can you take muscarinic antagonists while pregnant or breastfeeding?

Data from clinical studies is limited regarding the use of muscarinic antagonists during pregnancy and breastfeeding. Uncontrolled asthma is a risk of complications during pregnancy. Therefore, an asthmatic individual who is pregnant or breastfeeding may be better off using an inhaled muscarinic antagonist if needed to maintain control of their airway disease, but this benefit and risk analysis is best made between each patient and healthcare provider. Inhaled combination products warrant additional discussion due to the potential risks and benefits of beta-agonists and inhaled corticosteroids. Oral muscarinic antagonists have varying degrees of cautionary notes about use or avoidance in pregnancy and breastfeeding, based on limited information from clinical trials. RELATED: How to manage asthma during pregnancy

Can children take muscarinic antagonists?

Inhaled ipratropium products have approved uses in children of all ages. Among the long-acting inhaled antimuscarinics, the options are more limited; Spiriva Respimat is approved down to age 6 for chronic asthma maintenance therapy. Oral muscarinic antagonist use is even more limited in children. Depending on the child’s age, oxybutynin and hyoscyamine can be used, and dicyclomine can be used off-label.

Can seniors take muscarinic antagonists?

Seniors can use muscarinic antagonists. The higher incidence of coinciding health problems, like glaucoma and prostatic hypertrophy, and the longer average medication lists in seniors do require additional caution with the use of this drug class.

Are muscarinic antagonists safe?

Black box warnings

The Food and Drug Administration (FDA) has not placed any black box warnings on muscarinic antagonists.

Recalls

None of the muscarinic antagonists are currently recalled, but the FDA’s database can be checked for updates. 

Restrictions

The following restrictions apply to muscarinic antagonists:

• Anyone with a history of hypersensitivity allergic reactions to the product or drug class should avoid muscarinic antagonists. 

• In the case of dry powder inhalers, a history of milk protein allergy is another contraindication. 

• People with the following health conditions should avoid taking a muscarinic antagonist: 

  • Glaucoma

  • Severe ulcerative colitis

  • Gastrointestinal motility disorders

  • QT prolongation

  • Myocardial infarction

  • Autonomic neuropathy

  • Myasthenia gravis

  • Tardive dyskinesia

  • Prostatic hypertrophy

  • Bladder outlet obstruction

  • Urinary retention

Oral anticholinergic agents are more of a concern than inhaled drugs. Numerous other conditions warrant caution before the use of anticholinergics. Inhaled combination products have additional concerns based on their component drugs. For example, long-acting beta-agonists are not to be used for asthma unless combined with inhaled steroids, and beta-agonists, in general, require caution in the setting of conditions like cardiovascular disease and seizures. Inhaled corticosteroids generate concern as well, such as for those with osteoporosis (thin bones) or cataracts. 

Are muscarinic antagonists controlled substances?

Muscarinic antagonists are not listed by the Drug Enforcement Administration (DEA) as controlled substances.

Common muscarinic antagonists side effects

Inhaled combination products may have side effects attributable to non-muscarinic antagonist components. The following are some of the common adverse effects of muscarinic antagonists.

• Dry mouth, dry eye, or dry skin

• Blurred vision

• Drowsiness or weakness

• Tinnitus (ear ringing)

• Bronchitis (bronchial inflammation), sinusitis, or influenza-like symptoms

• Nausea or dyspepsia (upset stomach)

• Urinary tract infection, urinary retention, or urinary hesitancy

• Epistaxis (nosebleed)

• Shortness of breath

• Back pain

• Dizziness or ataxia (difficulty walking)

• Headache

• Edema (swelling from excess tissue fluid)

• Arthralgia (joint pain) or myalgia (muscle pain)

• Constipation or diarrhea

• Depression, anxiety, or insomnia

• Rash or pruritus (itching)

• Palpitations or tachycardia (fast heart rate)

• Flushing or lack of sweating

• Confusion or hallucinations

How much do muscarinic antagonists cost?

Generic combined ipratropium-albuterol nebulizer solution can cost about $60 for 30 doses. That price is much more affordable compared to the cost of the muscarinic antagonist inhaler products, which are brand-name prescriptions. These inhalers average about $500 for a one-month supply. Likewise, generic oral oxybutynin may cost $40 for a 30-day supply, while brand name Detrol LA can be upward of $400. Fortunately, you can get a discount on muscarinic antagonists by showing the pharmacist your SingleCare discount card.