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QuickView for tiotropium (compound)

Summary
General Info

PubChem

PubChem Compound 10649780

PubChem Compound 10649780

Name:	tiotropium
PubChem Compound ID:	10649780
Molecular formula:	C₃₂H₃₅NO₄Si
Molecular weight:	525.71 g/mol

DrugBank

Identification

Name:	tiotropium
Name (isomeric):	DB01409
Drug Type:	small molecule
Synonyms:	Tiotropium bromide
Brand:	Spiriva
Category:	Muscarinic Antagonists, Parasympatholytics, Cholinergic Antagonists, Anticholinergic Agents, Bronchodilator Agents
CAS number:	186691-13-4

Pharmacology

Indication:	Used in the management of chronic obstructive pulmonary disease (COPD).
Pharmacology:	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 ... show more » 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. show less «
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 eff... show more » 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. show less «
Absorption:	Bioavailability is 19.5% following administration by inhalation. Oral solutions of tiotropium have an absolute bioavailability of 2-3%.
Protein binding:	72% bound to plasma proteins.
Biotransformation:	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.
Route of elimination:	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.
Half Life:	5-6 days
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)]
Toxicity:	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.
Affected organisms:	Humans and other mammals

Interactions

Drug interaction:

Trimethobenzamide	Trimethobenzamide and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Pramlintide	The anticholinergic effects of Tiotropium may be enhanced by Pramlintide. Additive effects of reduced GI motility may occur. Pramlintide slows gastic emptying and should not be used with drugs that alter GI motility (e.g. anticholinergics). Consider alternative treatments or use caution during concomitant therapy.
Potassium Chloride	The ulcerative effects of solid oral dosage forms of KCl may be enhanced by Tiotropium, an anticholinergic. Anticholinergics slow gastric emptying, increasing the contact time between the gastrointestinal mucosa and KCl. Prolonged exposure to KCl increases the risk of gastric and intestinal irritation and ulceration. Solid oral dosage forms of KCl should be avoided; alternatives include liquid or effervescent potassium preparations.
Secretin	The stimulatory effect of Secretin may be reduced by anticholinergics such as Tiotropium. Concomitant use of Secretin and drugs with substantial anticholinergic effects should be avoided. If combination therapy must be used, Secretin efficacy should be closely monitored.
Trospium	Trospium and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Targets

Muscarinic acetylcholine receptor M3

Muscarinic acetylcholine receptor M1

Muscarinic acetylcholine receptor M2

Enzymes

Cytochrome P450 2D6

Cytochrome P450 3A4

Transporters

Organic cation/carnitine transporter 2

Organic cation/carnitine transporter 1