3-oxa-9-azoniatricyclo[18.104.22.168 2,4]nonane bromide
administration Inhalation (oral)
Bioavailability 19.5% (inhalation)
( CYP2D6, CYP3A4)
Biological half-life 5–6 days
186691-13-4 ( cation)
C 19 H 22 Br N O 4 S 2
Molecular mass 472.416 g/mol
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Tiotropium bromide ( INN) is a long-acting, 24-hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Tiotropium bromide capsules for inhalation are co-promoted by Boehringer-Ingelheim and Pfizer under the trade name Spiriva. It is also manufactured and marketed by Cipla under trade name Tiova.
Medical uses [ edit ]
Tiotropium is used for maintenance treatment of
chronic obstructive pulmonary disease (COPD) which includes chronic bronchitis and emphysema. It is not however used for [1 ] acute exacerbations. [1 ]
Adverse effects [ edit ]
Adverse effects are mainly related to its antimuscarinic effects. Common
adverse drug reactions (≥1% of patients) associated with tiotropium therapy include: dry mouth and/or throat irritation. Rarely (<0.1% of patients) treatment is associated with: urinary retention, constipation, acute angle closure glaucoma, palpitations (notably supraventricular tachycardia and atrial fibrillation) and/or allergy (rash, angioedema, anaphylaxis). [2 ]
Tiotropium and another member of its class
ipratropium were linked to increased risk of heart attacks, stroke and cardiovascular death. The FDA requested further trials; these are now complete, and adequately resolve the previous safety concerns. [3 ] [4 ]
Tiotropium mist inhaler (
Respimat) has been found to be associated with an increase of all cause mortality in people with COPD. [5 ]
The standard dose of tiotropium is 18 mcg which is administered by a HandiHaler inhalation device.
Mechanism of action [ edit ]
Tiotropium is a
muscarinic receptor antagonist, often referred to as an antimuscarinic or anticholinergic agent. Although it does not display selectivity for specific muscarinic receptors, when topically applied it acts mainly on M muscarinic receptors 3 located on smooth muscle cells and submucosal glands. This leads to a reduction in [7 ] smooth muscle contraction and mucus secretion and thus produces a bronchodilatory effect.
Mode of delivery [ edit ]
The patient removes one tiotropium capsule from the blister pack, places it into the piercing chamber of the inhalation device and closes the mouthpiece.
The capsule is manually pierced, and the medication is inhaled through the mouthpiece. It is recommended that inhalations be repeated 2 to 3 times to ensure all medication is drawn from the capsule. When properly done, the capsule will make a distinctive flutter or rattle, audible to the patient.
Once the powder capsules are removed from the blister pack, it should be taken immediately via the inhalation device. If a capsule is exposed to the air, it will rapidly degrade to the point the dose will become ineffective. Any previously exposed capsules should be discarded.
The capsules cannot be taken orally - they will not be effective as respiratory medication if absorbed through the gastrointestinal tract and may have side effects if absorbed via this route.
A previously pierced Spiriva capsule
Synthesis [ edit ]
Muscarinic receptor antagonist:
Scopine ( 1) and methyl di-(2-thienyl)glycolate ( 2) and sodium are combined under a water jet vacuum at 90°C for 2.5 hr. The product of the last step Scopine di-(2-thienyl)glycolate ( 3) is reacted with methyl bromide and the product of this step is Tiotropium bromide ( 4).
References [ edit ]
^ a b "Spiriva Handihaler". The American Society of Health-System Pharmacists . Retrieved . 3 April 2011
^ Rossi S, ed. (2006). . Adelaide. Australian Medicines Handbook
^ Singh S, Loke YK, Furberg CD (September 2008). "Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis". JAMA 300 (12): 1439–50. doi: 10.1001/jama.300.12.1439. PMID 18812535.
^ FDA. Follow-Up to the October 2008 Updated Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler). FDA 2010
^ Singh, S; Loke, YK; Enright, PL; Furberg, CD (Jun 14, 2011). "Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials.". BMJ (Clinical research ed.) 342: d3215. doi: 10.1136/bmj.d3215. PMC 3114950. PMID 21672999.
^ Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, et al. Tiotropium respimat inhaler and the risk of death in COPD. N Engl J Med. 2013 08/30; 2013/10.
^ Kato M, Komamura K, Kitakaze M (December 2006). "Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure". Circ. J. 70 (12): 1658–60. doi: 10.1253/circj.70.1658. PMID 17127817.
^ R. Banholzer et al., EP 418716 ; eidem, (1991, 1997 both to U.S. Patent 5,610,163 Boehringer Ingelheim).
External links [ edit ]
Antagonists: 3-Quinuclidinyl benzilate
Antihistamines (first-generation) (e.g., brompheniramine, chlorphenamine, cyproheptadine, dimenhydrinate, diphenhydramine, doxylamine, mepyramine (pyrilamine), phenindamine, pheniramine, promethazine, tripelennamine, triprolidine)
Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, zotepine)
Mamba toxin 3
Mamba toxin 7
Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin, mirtazapine)
Tricyclic antidepressants (e.g., amitriptyline, butriptyline, clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine)
Typical antipsychotics (e.g., chlorpromazine, loxapine, thioridazine)
Nicotine ( tobacco)
α-Neurotoxins (e.g., α-bungarotoxin, α-cobratoxin, α-conotoxin, many others)
Barbiturates (e.g., pentobarbital, sodium thiopental)
Bungarotoxins (e.g., α-bungarotoxin, κ-bungarotoxin)
Trimetaphan camsilate (trimethaphan camsylate)