Aclidinium bromide ( INN) is a long-acting, inhaled

muscarinic antagonist A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the ...

(LAMA) approved in the United States on July 24, 2012 as a maintenance treatment for

chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...

(COPD). Evidence shows that it can improve

quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

and prevent hospitalization in those with COPD. However, it does not appear to affect the risk of death or the frequency steroids are needed. It is unclear if it differs from the similar medication tiotropium or other commonly used medications from the class of LAMAs. Aclidinium is delivered via a multidose dry powder inhaler, the Genuair inhaler. It is on the World Health Organization's List of Essential Medicines.

Adverse effects

The substance is generally well tolerated. Common side effects (in more than 1% of patients) are

sinusitis Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, head ...

nasopharyngitis The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exp ...

, headache, cough,

diarrhoea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

and nausea. The latter is less common under the drug than under

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

. Skin reactions such as

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

, as well as side effects that are typical of muscarinic antagonists (

fast heart rate Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (s ...

palpitations Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rap ...

, and urinary retention), occur in less than 1% of patients. on Tudorza Pressair. A small increase of

cardiovascular risk Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...

cannot be excluded from available data. Patients with relevant cardiovascular diseases were excluded from studies.

Interactions

No systematic interaction studies have been performed. It is expected that adverse effects of aclidinium increase if it is combined with other muscarinic antagonists. In clinical practice, no interactions with other COPD medications such as glucocorticoids, β₂-adrenergic agonists and

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...

have been described. As aclidinium does not relevantly interact with

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

liver enzymes or

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

, and is quickly

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

as soon as it reaches the bloodstream, it is considered to have a very low potential for interactions.

Pharmacology

Mechanism of action

Aclidinium is a long-acting, reversible antagonist at

muscarinic receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...

s, with similar affinity to all five subtypes, but with a dissociation half-life from subtype M₃ of 29.2 hours, or six times longer than that from M₂. For comparison, M₃ dissociation half-lives of the related drugs ipratropium and tiotropium are 0.47 hours and 62.2 hours, respectively. Its action at subtype M₃ at the

smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...

of the

bronchiole The bronchioles or bronchioli (pronounced ''bron-kee-oh-lee'') are the smaller branches of the bronchial airways in the lower respiratory tract. They include the terminal bronchioles, and finally the respiratory bronchioles that mark the start ...

s is responsible for its desired effect: it reduces contraction of these muscles and improves the airflow. M₂ affinity is the main reason for adverse effects at the heart.

Pharmacokinetics

About 30% of inhaled aclidinium are deposited in the lung. Its action there lasts for more than 24 hours. From the lung, it is absorbed into the bloodstream, reaching highest

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...

concentrations after five minutes in healthy persons and after 10 to 15 minutes in COPD patients. The substance is quickly hydrolysed to the

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...

and the alcohol, so that less than 5% of the inhaled dose are found unchanged in the plasma. Hydrolysis is both non-enzymatic and enzymatic, the latter mainly by butyrylcholinesterase. The acid metabolite has a plasma protein binding of 87%, and the alcohol of 15%. These

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

are found to 65% in the urine and to 33% in the faeces. Elimination half-life is two to three hours. Unchanged aclidinium accounts for only 0.1% of the excreted dose.

Chemistry

Aclidinium is a

quaternary ammonium cation In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cation ...

with an asymmetric carbon atom. It is used as the pure ''R''-

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...

. The salt, aclidinium bromide, is a crystalline powder that is hardly soluble in water or

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

Society and culture

Brand names

It is marketed under the brand name ''Tudorza Pressair'' in the US, ''Eklira Genuair'' in the UK, and ''Tudorza Genuair'' in Canada; licensed to Menarini under the brand name ''Bretaris Genuair'' for majority of EU member states. An inhalable combination with formoterol is marketed as ''Brimica Genuair'' and ''Duaklir Genuair'' in the European Union.

References

{{Muscarinic acetylcholine receptor modulators Muscarinic antagonists Bromides Quaternary ammonium compounds AbbVie brands AstraZeneca brands Quinuclidines Thiophenes Phenol ethers