Tiotropium

Status : approved

Category

Cholinergic Antagonists

Description

Tiotropium is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Tiotropium is a muscarinic receptor antagonist, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect.

Used

Used in the management of chronic obstructive pulmonary disease (COPD).

Mechanism Of Action

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, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect.

Dosage

Form Route Strength
Solution inhalation 2.5 mcg
Capsule inhalation 18 mcg
Capsule oral; respiratory (inhalation) 18 ug
Solution inhalation 2.5 mcg
Spray, metered respiratory (inhalation) 1.562 ug
Spray, metered respiratory (inhalation) 3.124 ug

Pharmacodynamics

Tiotropium is a long–acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3–receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies prevention of methacholine–induced bronchoconstriction effects were dose–dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site–specific effect.

Toxic Effect

No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7,300, 120,000, and 850 times the recommended human daily dose on a mg/m2 basis, respectively.

Metabolism

The extent of biotransformation appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N–methylscopine and dithienylglycolic acid, neither of which bind to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450–dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. Via inhibition studies, it is evident that CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose.

Absorption

Bioavailability is 19.5% following administration by inhalation. Oral solutions of tiotropium have an absolute bioavailability of 2-3%.

Half Life

5-6 days

Protein Binding

72% bound to plasma proteins.

Elimination Route

Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces.

Clearance

* 880 mL/min [young healthy volunteers receiving IV administration] * Renal cl=326 mL/min [COPD patients (<58 years)] * Renal cl=163 mL/min [COPD patients (>70 years)]

Volume of Distribution

* 32 L/kg

Chemical Classification

This compound belongs to the class of organic compounds known as morpholines. These are organic compounds containing a morpholine moiety, which consists of a six-member aliphatic saturated ring with the formula C4H9NO, where the oxygen and nitrogen atoms lie at positions 1 and 4, respectively.

Morpholines

Organic compounds

Organoheterocyclic compounds

Oxazinanes

Morpholines

Salt : Tiotropium bromide

Brands

name Dosage form Country
Inspiolto Respimat solution Canada
Spiriva capsule US
Spiriva capsule US
Spiriva capsule Canada
Spiriva Respimat spray, metered US
Spiriva Respimat spray, metered US
Spiriva Respimat solution Canada

Drug Drug Interactions

  •  Aclidinium  : May enhance the anticholinergic effect of Anticholinergic Agents.
  •  Amitriptyline  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Amoxapine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Atropine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Azelastine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Benzatropine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Botulinum Toxin Type A  : Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA.
  •  Botulinum Toxin Type A  : Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA.
  •  Botulinum Toxin Type B  : Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB.
  •  Brompheniramine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Carbinoxamine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Cetirizine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Chlorphenamine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Chlorpromazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Clemastine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Clidinium  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Clomipramine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Clozapine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Codeine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Cyclizine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Cyclobenzaprine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Cyclopentolate  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Cyproheptadine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Darifenacin  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Desipramine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Desloratadine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Dexbrompheniramine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Dicyclomine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Difenoxin  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Dimenhydrinate  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Diphenhydramine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Diphenoxylate  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Disopyramide  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Doxepin  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Doxylamine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Droperidol  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Fenoterol  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Fesoterodine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Fexofenadine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Flavoxate  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Flupentixol  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Fluphenazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Fluticasone Propionate  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Glucagon recombinant  : Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased.
  •  Glycopyrrolate  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Haloperidol  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Hydroxyzine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Hyoscyamine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Imipramine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Ipratropium bromide  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Isocarboxazid  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Itopride  : Anticholinergic Agents may diminish the therapeutic effect of Itopride.
  •  Levocabastine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Levocetirizine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Loratadine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Loxapine  : Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine.
  •  Maprotiline  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Meclizine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Mepenzolate  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Methotrimeprazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Mianserin  : May enhance the anticholinergic effect of Anticholinergic Agents.
  •  Mirabegron  : Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron.
  •  Moclobemide  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Nortriptyline  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Olanzapine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Olopatadine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Orphenadrine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Oxybutynin  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Perphenazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Phenelzine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Pimozide  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Pizotifen  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Potassium Chloride  : Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride.
  •  Pramlintide  : May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract.
  •  Prochlorperazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Procyclidine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Promazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Promethazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Propantheline  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Protriptyline  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Quetiapine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Risperidone  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Scopolamine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Secretin  : Anticholinergic Agents may diminish the therapeutic effect of Secretin.
  •  Solifenacin  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Sulpiride  : Anticholinergic Agents may diminish the therapeutic effect of LevoSulpiride.
  •  Thioridazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Thiothixene  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Tolterodine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Topiramate  : Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate.
  •  Tranylcypromine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Trifluoperazine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Trihexyphenidyl  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Trimethobenzamide  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Trimipramine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Triprolidine  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Trospium  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
  •  Umeclidinium  : May enhance the anticholinergic effect of Anticholinergic Agents.
  •  Zuclopenthixol  : Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.

Calculated Property

kind Value Source
logP -0.55 ALOGPS
logS -4.4 ALOGPS
Water Solubility 1.56e-02 g/l ALOGPS
logP -1.8 ChemAxon
IUPAC Name (1R,2S,4R,5S)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0²,⁴]nonan-9-ium ChemAxon
Traditional IUPAC Name tiotropium ChemAxon
Molecular Weight 392.512 ChemAxon
Monoisotopic Weight 392.099024577 ChemAxon
SMILES C[N+]1(C)[C@H]2CC(C[C@@H]1[C@@H]1O[C@H]21)OC(=O)C(O)(C1=CC=CS1)C1=CC=CS1 ChemAxon
Molecular Formula C19H22NO4S2 ChemAxon
InChI InChI=1S/C19H22NO4S2/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15/h3-8,11-13,16-17,22H,9-10H2,1-2H3/q+1/t11?,12-,13+,16+,17- ChemAxon
InChIKey InChIKey=LERNTVKEWCAPOY-KYQOMENCSA-N ChemAxon
Polar Surface Area (PSA) 59.06 ChemAxon
Refractivity 109.18 ChemAxon
Polarizability 39.69 ChemAxon
Rotatable Bond Count 5 ChemAxon
H Bond Acceptor Count 3 ChemAxon
H Bond Donor Count 1 ChemAxon
pKa (strongest acidic) 10.35 ChemAxon
pKa (strongest basic) -4.3 ChemAxon
Physiological Charge 1 ChemAxon
Number of Rings 5 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 0 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Muscarinic acetylcholine receptor M3 : in Human
  • Muscarinic acetylcholine receptor M1 : in Human
  • Muscarinic acetylcholine receptor M2 : in Human