What Is Tiotropium?

Tiotropium bromide is a white solid chemical. Chemical name (1R, 2R, 4S, 5S, 7S) -7- [2-hydroxy-2,2-bis (2-thienyl) acetoxy] -9,9-dimethyl-3-epoxy-9 -Nitrogen cation tricyclooctane [3.3.1.02.4] nonane bromide, molecular formula is C ₁₉ H ₂₂ BrNO ₄ S ₂ , molecular weight is 472.41600, white or light yellow white powder. Slightly soluble in water, soluble in methanol. Tiotropium bromide is an anticholinergic bronchodilator. It is mainly used in the maintenance treatment of chronic obstructive pulmonary disease in clinical practice, including the maintenance treatment of chronic bronchitis, emphysema and dyspnea, and the prevention of acute attacks.

Chinese name: Tiotropium bromide
Foreign name: Tiotropium Bromide

CAS number: 136310-93-5
Molecular formula: C19H22BrNO4S2

Introduction to Tiotropium Bromide

Tiotropium bromide Basic information

Chinese alias: (1R, 2R, 4S, 5S, 7S) -7- [2-hydroxy-2,2-bis (2-thienyl) acetoxy] -9,9-dimethyl-3-epoxy- 9-nitrogen cation tricyclooctane [3.3.1.02.4] nonane bromide

English name: Tiotropium Bromide

English alias: TIOTROPIUM BROMIDE; Tiotropium bromide;

CAS number: 136310-93-5

Molecular formula: C ₁₉ H ₂₂ BrNO ₄ S ₂

Chemical structure:

Molecular weight: 472.41600

Exact mass: 471.01700

PSA: 115.54000 ^[1]

Physical and Chemical Properties of Tiotropium Bromide

Appearance and properties: white solid

Melting point: 218-220 ° C ^[1]

Calculated Chemical Data for Tiotropium Bromide

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen-bonded donors: 1

3.Number of hydrogen bond acceptors: 7

4.Number of rotatable chemical bonds: 5

5.Number of tautomers: none

6. Topological molecular polar surface area 116

7.Number of heavy atoms: 27

8.Surface charge: 0

9.Complexity: 564

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 4

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 2 ^[2]

Tiotropium bromide synthesis method

50.87 g of bis (2-thienyl) glycolic acid methyl ester (I) and 31.04 g of fake product (II) were dissolved in 100 ml of toluene, and 1.65 g of sodium metal was added in batches at 90 ° C, and then at 78-90 ° C and 50 kPa And distilled for 5h to remove the generated methanol. After treatment, 33.79 g of compound (III) was obtained. Then in a mixed solution of dichloromethane and acetonitrile, it is quaternized with methyl bromide to obtain the product. ^[2]

Tiotropium bromide uses

Atropine derivatives. Bronchodilators. Muscarinic receptor antagonist. ^[2]

Tiotropium bromide pharmacological action

This product is a quaternary ammonium derivative. It is a long-acting anticholinergic drug. It has the same affinity for five types of muscarinic receptors M1 to M5. It binds to muscarinic receptors on the bronchial smooth muscle to inhibit the release of parasympathetic nerve endings. Tracheal contraction caused by acetylcholine. In the human airway, this product has a high affinity to the receptor, and it dissociates slowly with the muscarinic M1 and M3 receptors, which can block cholinergic nerve-mediated bronchial smooth muscle contraction for a long time, and can permanently expand the bronchi , Effectively improve lung function, relieve breathing difficulties, reduce the frequency of exacerbation of chronic obstructive pulmonary disease (COPD), curb disease deterioration, and improve quality of life. This product improves the selectivity of M1 and M3 receptors and prolongs the action time, thereby avoiding side effects such as salivation and dilated pupils caused by M2 receptor blockade.

Study on Tiotropium Bromide Toxicology

Reproductive toxicity: The inhaled dose of rats reaches 1.689mg / kg / d (calculated based on body surface area, approximately 760 times the clinically recommended daily dose), which has no effect on fertility. The inhaled dose of rats reaches 0.078 mg / kg / d ( Calculated based on body surface area, about 35 times the clinically recommended daily dose). It has the effects of miscarriage, reduced number of live births and average fetal weight, delayed fetal sexual maturity; rabbit inhaled dose of 0.4 mg / kg / d (based on body surface area It is calculated to be about 360 times the clinically recommended daily dose), which increases the loss after implantation. However, the inhaled doses in rats and rabbits were 0.009 and 0.088 mg / kg / d (calculated based on body surface area, about 4 and 80 times the clinically recommended daily dose), and this effect was not seen.

Genotoxicity: This product is bacterial gene mutation test, V79 Chinese hamster non-cell chromosome aberration test, human lymphocyte in vitro chromosome aberration test, mouse micronucleus test, rat stem cell unscheduled DNA synthesis test results are all negative.

Carcinogenicity: Rats inhaled the dose of 0.059 mg / kg / d (based on body surface area, about 25 times the clinically recommended daily dose) for 104 weeks, and female mice inhaled the dose of 0.145 mg / kg / d ( Calculated based on body surface area, approximately 35 times the clinically recommended daily dose) 83 weeks, male mice inhaled the dose of this product reached 0.002 mg / kg / d (calculated based on body surface area, approximately 0.5 times the clinically recommended daily dose) for 101 weeks No carcinogenic effect was observed. ^[3]

Tiotropium bromide pharmacokinetics

a) Overview

Tiotropium bromide is an achiral tetravalent ammonium compound. Dissolved in small amounts in water. Tiotropium is administered as a dry powder by inhalation. When generally administered by inhalation, most of the drug is deposited in the gastrointestinal tract, and only a small amount of the drug reaches the target organ lung. Many of the pharmacokinetic data described below are obtained at higher doses than recommended treatments.

b) Characteristics of active ingredients

Absorption: After inhaling dry powder to young healthy volunteers. The measured absolute bioavailability was 19.5%, suggesting that the bioavailability of parts reaching the lungs is high. According to the chemical structure of the drug (tetravalent ammonium compound) and in vitro test results, it can be speculated that the absorption of tiotropium in the gastrointestinal tract is poor (10-15%). The absolute bioavailability of an oral solution of tiotropium bromide is only 2 to 3%. Tiotropium bromide reached its maximum plasma concentration 5 minutes after inhalation. Due to the characteristics of its tetravalent ammonium compound, food does not affect its absorption.

Distribution: The drug has a plasma protein binding rate of 72% and a distribution volume of 32L / kg. At steady state. The peak plasma concentration of COPD patients measured 5 minutes after inhaling 18 micrograms of dry powder was 17-19 pg / ml, and then decreased rapidly in a multi-chamber model. The steady state plasma concentration is 3 to 4 pg / ml. The local concentration of the lung is unknown, but the actual drug concentration in the lung can be seen from the mode of administration. Studies in rats have shown that tiotropium cannot pass the blood-brain barrier.

Biotransformation: The extent of biotransformation is very small, as evidenced by the fact that 74% of the dose of young healthy volunteers was excreted from the kidneys as a prototype after intravenous injection of the drug. Tiotropium bromide is an ester, which is non-enzymatically decomposed into an alcohol (N-methylscopolamine) and an acid (dithiophene glycolic acid), neither of which can bind to a muscarinic receptor.

In vitro experiments with human liver microsomes and human hepatocytes have shown that some drugs (less than 20% of the intravenous dose) rely on cytochrome P450 oxidation and subsequent binding to glutathione to form various phase II metabolites. In vitro liver microsomal tests show that this enzymatic pathway can be inhibited by CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole, and gestodene. Therefore, CYP 2D6 and 3A4 are included in the metabolic pathways and are involved in the elimination of a small number of drugs. Tiotropium bromide does not inhibit cytochromes CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A in liver microsomes even at higher concentrations.

Elimination: The terminal elimination half-life of tiotropium is between 5 and 6 days after inhalation. The total clearance rate of young healthy volunteers after intravenous injection was 880ml / min, and the individual variability was 22%. After intravenous administration of tiotropium bromide, it was mainly excreted in the form of the original drug (74%). After inhaling the dry powder, 14% of the dose is excreted through the urine. The remaining drugs are mainly drugs that are not absorbed in the intestine and are excreted in the feces. Tiotropium's renal clearance exceeds creatinine clearance, indicating that the drug is secreted into the urine. COPD patients inhaled once a day continuously and reached a pharmacokinetic steady state after 2-3 weeks without further drug accumulation thereafter.
Linear / Non-linear: The pharmacokinetics of tiotropium bromide within the therapeutic range after intravenous and dry powder inhalation proves to be linear pharmacokinetics.

c) patient specific

Elderly patients: As with all drugs that are mainly excreted by the kidneys, renal clearance is reduced in elderly patients with tiotropium bromide (COPD patients younger than 58 years of age have a clearance rate of 326 ml / min; COPD patients older than 70 years have a clearance rate of (163 ml / min). This may be related to decreased kidney function. Urinary excretion after inhalation of tiotropium bromide decreased from 14% (young healthy volunteers) to about 7% (COPD patients), however, variability between patients and within individuals (AUC0-4 increased after dry powder inhalation) (43%), compared with patients with COPD, plasma concentrations did not change significantly with age.
Patients with renal insufficiency: Like all other drugs that are mainly excreted by the kidneys, intravenous infusion or dry powder inhalation during renal insufficiency increases and the renal clearance of the drug decreases. Mild renal insufficiency (CLCR 50-80ml / min), which is more common in the elderly, can slightly increase the plasma concentration of tiotropium (39% increase in AUC0-4 after intravenous injection). In patients with COPD with moderate to severe renal insufficiency (CLCR <50ml / min). After intravenous administration of tiotropium bromide, the blood drug concentration doubled (82% increase in AUC0-4), and the blood drug concentration after dry powder inhalation also increased.

Patients with hepatic insufficiency: Hepatic insufficiency has no effect on the pharmacokinetics of tiotropium. Tiotropium is mainly excreted by the kidneys (74% of young healthy volunteers), and a small amount is decomposed into non-pharmacologically active products by non-enzymatic esters.

d) Correlation between pharmacokinetics and pharmacological properties

There is no direct correlation between pharmacokinetics and pharmacological properties. ^[3]

Tiotropium bromide indications

It is suitable for the maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, maintenance treatment accompanied by dyspnea and the prevention of acute attacks. ^[3]

Tiotropium bromide adverse reactions

1. The most common adverse reactions of tiotropium bromide are dry mouth and cough. Most patients continue to treat and the symptoms disappear without interrupting treatment.

2. Followed by pharyngitis, upper respiratory tract infection, bitter mouth, transient allergies, headache, nervousness, excitement, dizziness.

3. Rare systemic adverse reactions include urinary retention, prostatitis, constipation, tachycardia, and palpitations.

Contraindications to Tiotropium

1. Allergic to tiotropium bromide is prohibited.

2. Those who are allergic to atropine and its derivatives (such as ipratropium bromide and oxtropium bromide) are prohibited.

3. Not recommended for pregnant and lactating women.

Tiotropium bromide precautions

Tiotropium bromide as a bronchodilator for once-a-day maintenance therapy should not be used as the initial treatment for acute exacerbations of bronchospasm, that is, as a rescue medication.
An allergic reaction may occur immediately after inhaling tiotropium bromide powder.
As with other anticholinergic drugs, caution should be used in patients with narrow-angle glaucoma, prostate hyperplasia, or bladder neck obstruction.
Inhaling medication may cause inhaled bronchospasm.
As with all drugs that are mainly excreted by the kidney, for patients with moderate to severe renal insufficiency (creatinine clearance 50ml / min). Use tiotropium bromide only when the expected benefits outweigh the potential harm. There is no long-term experience with tiotropium in patients with severe renal insufficiency.
Capsules should be kept sealed in vesicles, and only taken out during medication, and should be used as soon as possible after removal, otherwise the efficacy will be reduced, and capsules that are accidentally exposed to the air should be discarded.
Patients need to be careful not to get the powder into their eyes. Patients must be informed that the accidental injection of powder into the eye may cause or exacerbate narrow-angle glaucoma, pain or discomfort in the eyes, transient blurred vision, visual halo or color images with red eyes and corneal edema caused by conjunctival hyperemia. If you have signs of narrow-angle glaucoma, you should stop using tiotropium bromide and see your doctor immediately.
Dry mouth is caused by anticholinergic treatment and can cause dental caries in the long term.
Tiotropium bromide should not be used more than once a day.
This capsule is for inhalation only and cannot be taken orally.
No studies have been conducted on the impact on the ability to drive and operate machines. Based on the pharmacological and adverse reaction characteristics obtained at the recommended doses, there is no evidence to influence the ability to drive and operate machines. ^[3]

Tiotropium for pregnant and lactating women:

For tiotropium bromide, there is no clinical data on medications in pregnancy. Animal studies have shown maternal-related reproductive toxicity. See toxicological information.

There is no information on the use of tiotropium in lactating women. According to studies on lactating rodents, small amounts of tiotropium bromide can be secreted into milk.

Therefore, tiotropium bromide should not be used in pregnant or lactating women unless the expected benefits outweigh the risks that may be brought to the unborn fetus or infant.

Tiotropium bromide for children:

There is no experience with tiotropium bromide in pediatric patients, so this product is not recommended for patients younger than 18 years old.

Tiotropium bromide for the elderly:

Elderly patients can use tiotropium at the recommended dose. ^[3]

Tiotropium drug interactions

Although no formal drug interaction studies have been conducted, no adverse effects have been found when tiotropium bromide inhaled powder is used with other drugs, including sympathetic bronchodilators, methylxanthine, oral or inhaled steroid Drugs and the like are drugs commonly used to treat chronic obstructive pulmonary disease (COPD).

Tiotropium bromide has not been studied in combination with other anticholinergics, so it is not recommended to be combined with other anticholinergics. ^[3]

Tiotropium bromide overdose

High doses of tiotropium bromide may cause anticholinergic symptoms and signs.

However, healthy volunteers did not develop systemic anticholinergic effects after a single inhalation of 340 micrograms of tiotropium bromide. In addition, healthy volunteers inhaled 170 micrograms of tiotropium bromide once a day for 7 days, except for dry mouth. No other adverse reactions were seen. In a multi-dose study of patients with chronic obstructive pulmonary disease (COPD), no significant adverse effects were observed after 4 weeks of treatment with a maximum daily dose of 43 micrograms of tiotropium bromide.

Acute poisoning caused by inadvertent administration of tiotropium bromide capsules is unlikely due to its low oral bioavailability. ^[3]

Tiotropium bromide storage conditions

Storage temperature: 15 ° C ~ 28 ° C. Do not store under extreme temperature and humidity. Do not remove the sealed blisters until use. Discard capsules if the blister is damaged or not used immediately. Do not store capsules in the inhalation device.