Tiotropium: a long-acting muscarinic antagonist for COPD
Tiotropium is a long-acting muscarinic antagonist (LAMA): it blocks acetylcholine at M3 receptors on airway smooth muscle, widening the airways (bronchodilation) in chronic obstructive pulmonary disease (COPD).
Remember
Tiotropium blocks M3 muscarinic receptors on airway smooth muscle to give bronchodilation for 24 hours, but muscarinic blockade in the bladder can cause urinary retention (the inability to empty the bladder), especially in men with prostatic hyperplasia (an enlarged prostate).
Memory aid
dry and retained
Two side effects of blocking muscarinic receptors to remember are the dry and retained ones, namely dry mouth and urinary retention.
Tiotropium (Spiriva) is a long-acting muscarinic antagonist (LAMA). Acetylcholine, the chemical messenger of the parasympathetic nerves, is released by the vagus nerve (the parasympathetic nerve to the lungs). In the airways it acts on M3 muscarinic receptors on smooth muscle and makes the muscle contract. Tiotropium blocks those receptors, so the muscle relaxes and the airway widens.
Its selectivity for M3 receptors is much greater than that of ipratropium, the older short-acting muscarinic antagonist. It also stays bound longer than ipratropium, because it dissociates (comes off the receptor) slowly, so one dose a day gives a 24-hour effect. In COPD, a substantial part of the airway narrowing is parasympathetic, which is why tiotropium is described as the cornerstone of drug treatment.
The detrusor (the smooth muscle in the bladder wall that squeezes urine out) also contracts through muscarinic receptors, so the same drug can weaken bladder emptying. Benign prostatic hyperplasia (BPH) is a non-cancerous enlargement of the prostate, the gland around the urethra (the tube that drains the bladder), and it already narrows the outflow. An older man with BPH can therefore develop urinary retention. A dry mouth is the commonest side effect. Tiotropium can also worsen glaucoma (an eye condition) if the aerosol reaches the eye.
Short-acting beta-2 agonists such as salbutamol work for only 4 to 6 hours, so a man who stays breathless on one needs a regular long-acting bronchodilator. The stepwise COPD pathway adds LABA plus LAMA dual therapy when symptoms persist on a short-acting bronchodilator, and an inhaled corticosteroid (a steroid that reduces airway inflammation) is also used if there are asthmatic features or steroid responsiveness. A LABA (a long-acting beta-2 agonist such as salmeterol) is the other long-acting bronchodilator in the dual therapy. Beta-2 stimulation is the action of the LABAs.
Key facts
- Class
- a long-acting muscarinic antagonist (LAMA), taken once daily
- Target
- M3 muscarinic receptors on airway smooth muscle, where blocking them relaxes the muscle
- Duration
- slow dissociation from the receptors gives a 24-hour effect
- Versus ipratropium
- tiotropium is more selective for M3 and longer acting, so dosing is once daily instead of about every 6 hours
- Side effects
- dry mouth and, especially in older men with prostatic hyperplasia, urinary retention
Exam traps
- Tiotropium's sustained bronchodilation does not come from blocking M2 muscarinic receptors, because it comes off M2 receptors faster than M3 receptors; the lasting effect comes from blocking the M3 receptors on airway smooth muscle.
- Ipratropium is also a muscarinic antagonist, but it is short-acting, dosed about every 6 hours, and less M3-selective than tiotropium, so it is not the long-acting maintenance drug.
- Stimulating beta-2 receptors also relaxes airway smooth muscle, but that is how salbutamol and the LABAs work; tiotropium does not act on beta-2 receptors and instead blocks muscarinic receptors.
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