Tiotropium

Chemical structure of tiotropium. Source: Wikimedia Commons

Tiotropium is a once a day inhaled prescription medication used to treat the shortness of breath caused by chronic obstructive pulmonary disease (COPD). Tiotropium is a bronchodilator, a class of medication that increases the diameter of the bronchi (breathing tubes) by relaxing smooth muscle. Tiotropium is used for disease maintenance rather than short-term flare-ups. Side effects of the medication are generally mild and infrequent.

Uses

Normal lung tissue vs. lungs with emphysema. Source: National Heart, Lung, and Blood Institute.

Tiotropium is used in patients with Chronic Obstructive Pulmonary Disease (COPD). COPD is a term that encompasses two conditions: chronic bronchitis and emphysema.

Bronchitis is an inflammation of the airways in the lungs. Chronic means the disease has been present for at least three months. The symptoms of chronic bronchitis include cough with increased mucus production, difficulty breathing, and chest tightness.

Emphysema is damage to the small airways and air sacks in the lungs. This damage causes difficulty with exhalation of air. Symptoms of emphysema include fatigue, difficulty breathing, cough, loss of appetite and weight loss.

Both types of COPD are most often caused by cigarette smoking. Other underlying diseases may also cause chronic bronchitis or emphysema.

In mild cases of COPD, treatment with a single medication may be appropriate and sufficient. In many cases, medications are combined. Thus, tiotropium may be combined with other drugs that influence lung function or reduce inflammation.

How Tiotropium is Taken

Tiotropium capsules contain 18 micrograms of powdered tiotropium. The capsules are placed in a device which allows the powder in the capsules to be inhaled into the lungs through the mouth. The capsules are not designed to be swallowed and are used immediately after opening the blister strip. Exposure to air may reduce the effectiveness of the powder. The Spiriva web site ^[1] includes written instructions and a video on how to use the HandiHaler.

Tiotropium is long-lasting, therefore it is used once a day.

How Tiotropium Works

The breathing difficulties often present in COPD are partly caused by constriction (narrowing) of the airways. This constriction is controlled by the neurotransmitter acetylcholine. Neurotransmitters are chemicals that transmit messages from one nerve cell to another, or from nerve cells to muscles. Tiotropium is an anticholinergic drug. It blocks the muscarinic receptors to which acetylcholine binds. Tiotropium has been developed to block the M1 and M3 subtypes of receptors and not the M2 subtype. This selectivity reduces the number of side effects and may increase effectiveness (see “Benefits”).

By blocking the receptors and preventing acetylcholine from binding, tiotropium relaxes the muscle in the tubes (bronchi and bronchioles) that carry air to the lungs (this is called bronchodilation). This can provide a degree of relief of breathlessness. However, because other factors also contribute to breathlessness, tiotropium does not work for all patients, or may only have a small effect in some patients.

How the Body Affects Tiotropium

The majority of an inhaled dose of tiotropium is deposited in the gastrointestinal tract. Much less is absorbed into the lungs. Tiotropium reaches a peak concentration in the blood approximately five minutes after inhalation. Only about 25% of the drug is metabolized (chemically altered) by enzymes in the liver. Most tiotropium is excreted unchanged in the urine. The time necessary for the concentration of tiotropium in the blood to be reduced by half, the half-life, is between five and six days.

Side Effects

Serious, but rare, side effects of tiotropium include the following:

• Allergic reactions
• Breathing problems (paradoxical bronchospasm)
• Glaucoma (elevated pressure in the eye)
• Worsening symptoms of narrow-angle glaucoma, Benign Prostatic Hyperplasia (BPH), and bladder outflow obstruction

Below are some more common, and less serious, side effects:

• Dry mouth
• Constipation
• Increased heart rate
• Blurred vision
• Problems with urination

Benefits

One advantage of tiotropium over other drugs used for COPD, such as ipratropium (Atrovent) is the selectivity for M1 and M3 muscarinic receptors. Iatropium blocks M1, M2, and M3 receptors. Blockade of the M2 receptors may inhibit bronchodilation and make the medication less effective.

Risks

Tiotropium is not used to treat a sudden onset of breathing difficulty, nor is it used in patients allergic to atropine, atropine-containing drugs, or any inactive component of the medication. Atropine and tiotropium have similar mechanisms of action, therefore an allergy to one indicates an allergy to the other.

Serious, but rare, allergic reactions such as itching, rash, swelling of the lips, tongue, or throat (trouble swallowing) may occur after taking tiotropium.

Because muscarinic receptors are located throughout the body, tiotropium may worsen conditions that are controlled by these receptors. Accordingly, caution is used in patients who have, or have a history of, glaucoma, or prostate problems. Tiotropium is used with caution in patients with kidney problems and bladder blockages because the drug is largely eliminated by the kidneys.

Whether tiotropium affects a fetus or is excreted into breast milk is not known.

Complications

Recently, the manufacturer of tiotropium alerted the FDA of a possible increased risk of stroke in patients taking the medication. The FDA released a Early Communication notice in March of 2008. ^[2] The FDA has not taken any regulatory action, nor has the use of tiotropium changed. Further research about this possible risk is ongoing.

Interactions

Tiotropium has the potential to interact with other drugs that affect lung function, or that affect the excretion of drugs by the kidney.

Overdose

An overdosage of 30 capsules taken over a 2.5 day period has been reported.^[3] The overdosage caused severe constipation, psychological changes, tremors, and abdominal pain. The patient fully recovered after discontinuation of the drug.

History

Tiotropium is co-marketed under the name Spiriva by Boehringer Ingelheim and Pfizer Pharmaceuticals. The drug was approved by the Food and Drug Administration on January 30, 2004.

Clinical Trials

For a list of completed, ongoing, and upcoming clinical trials on tiotropium, see [1].

Research

An analysis of nine clinical trials of patients with COPD found that tiotropium reduced the risk of exacerbation of symptoms by 27% and COPD-related hospitalizations by 32%.^[4]

There is also research underway to study the efficacy and safety of tiotropium in combination with other medications used to treat COPD. ^{[5] [6]}

References

1. ↑ Spirivia web site. How to take Spiriva
2. ↑ U.S. Food and Drug Administration. Early Communication about an Ongoing Safety Review of Tiotropium.
3. ↑ Pfizer. Spiriva HandiHaler. PDF
4. ↑ Barr RG, Bourbeau J, Camargo CA, Ram FS. Tiotropium for stable chronic obstructive pulmonary disease: A meta-analysis. Thorax. 2006 Oct;61(10):854-62. Epub 2006 Jul 14. Abstract
5. ↑ Rabke KF, Timmer W, Sagkriotis A, Viel K. Comparison of a combination of tiotropium and formoterol to salmeterol and fluticasone in moderate COPD. Chest. 2008 Apr 10. (Epub ahead of print) Abstract
6. ↑ Aaron SD, Vandemheen KL, Fergusson D, Matalis F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007 Apr 17;146(8):545-55. Epub 2007 Feb 19. Abstract | PDF

External Links

American Thoracic Society: Patient Information on COPD

National Institutes of Health: Tiotropium Oral Inhalation