Tricyclic antidepressants: off-target receptor and channel effects
Many tricyclic antidepressants, medicines for depression, block serotonin and noradrenaline transporters, several receptors and, at high drug levels, cardiac sodium channels, so one molecule can combine wanted and unwanted effects.
Remember
Many tricyclics block receptors as well as the transporters, so each receptor predicts its own side-effect, such as dry mouth, drowsiness or a fall in blood pressure on standing. Many tricyclics also block cardiac sodium channels at high drug levels, which slows conduction (the spread of the electrical impulse through the heart) and is the main reason tricyclics are dangerous in overdose.
Memory aid
alpha-1 receptors squeeze vessels, so blocking them lets vessels relax and pressure drop
Link what the receptor normally does to what happens when a tricyclic blocks it.
Tricyclic antidepressants work mainly by blocking SERT (the serotonin transporter) and NET (the noradrenaline transporter), the proteins that carry those transmitters back into the nerve ending. They are not selective, however. Many also block three receptors, so one molecule can combine the wanted transporter action with several unwanted effects.
Each receptor predicts its own side-effect. Muscarinic receptors are acetylcholine receptors used by the parasympathetic nervous system, the rest-and-digest half of the autonomic system. Blocking them means less stimulation of the salivary glands, so the mouth dries. Gut movement slows, which can cause constipation. Bladder emptying becomes slower. Near vision blurs. Blocking histamine H1 receptors, which in the brain promote wakefulness, supports sedation and increased appetite. Blocking alpha-1 receptors, which normally keep blood vessels tight, lowers vascular tone (the background squeeze of the smooth muscle in the vessel walls). Blood pressure then falls on standing, which is postural hypotension, and older people are at particular risk of falls.
A different mechanism adds danger in overdose. Heart muscle cells depend on fast sodium channels opening at the start of each beat, and the resulting rush of sodium spreads the electrical impulse through the heart. Many tricyclics block these channels once the drug level is high enough. Conduction (the spread of that impulse) slows, and this effect is separate from the transporter and receptor actions. It is the main reason tricyclics are dangerous in overdose.
Key facts
- Wanted action
- blocking SERT and NET, the proteins that carry serotonin and noradrenaline back into the nerve ending.
- Muscarinic block
- dry mouth, constipation, blurred near vision and difficulty passing urine.
- Histamine H1 block
- sedation and increased appetite.
- Postural hypotension
- mainly reflects alpha-1 blockade, which reduces vascular tone, with a particular risk of falls in older people.
- Sodium channel block
- slows cardiac conduction at high drug levels and is the main reason tricyclics are dangerous in overdose.
- Side-effect cluster
- sedation, dizziness on standing and dry mouth together point to H1, alpha-1 and muscarinic blockade.
Exam traps
- Many tricyclics block muscarinic, H1 and alpha-1 receptors rather than activating them, and activation would cause the opposite effects, such as wakefulness, a wet mouth and a rise in blood pressure.
- Dopamine receptors in the pituitary gland have no direct role in conduction through the heart, so blocking them does not explain the slowed cardiac conduction seen with a tricyclic.
- Muscarinic stimulation gives more saliva, sweat and gut movement, but blocking muscarinic receptors generally reduces these responses, so that cluster runs in the wrong direction for muscarinic blockade.
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