TCAs are used to treat depression. They include:
All of the TCAs are active pharmacologically, and some of their metabolites are also active. They’re absorbed completely when taken orally but undergo first-pass effect.
With first-pass effect, a drug passes from the GI tract to the liver, where it’s partially metabolized before entering the circulation. TCAs are metabolized extensively in the liver and eventually ex-creted as inactive compounds (only small amounts of active drug are excreted) in urine.
The extreme fat solubility of these drugs accounts for their wide distribution throughout the body, slow excretion, and long half-lives.
Researchers believe that TCAs increase the amount of norepi-nephrine, serotonin, or both in the CNS by preventing their reup-take into the storage granules in the presynaptic nerves. They also block acetylcholine and histamine receptors.
After a neurotransmitter has performed its job, several fates are possible, including rapidly reentering the neuron from which it was released (or reuptake). Preventing reuptake results in in-creased levels of these neurotransmitters in the synapses, reliev-ing depression.
TCAs are used to treat episodes of major depression. They’re es-pecially effective in treating depression of insidious onset accom-panied by weight loss, anorexia, or insomnia. Physical signs and symptoms may respond after 1 to 2 weeks of therapy; psychologi-cal symptoms, after 2 to 4 weeks.
TCAs are much less effective in patients with hypochondriasis, atypical depression, or depression accompanied by delusions. When given with a mood stabilizer, they may be helpful in treating acute episodes of depression in bipolar I disorder.
TCAs are also used for preventing migraine headaches and in treating phobias (panic disorder with agoraphobia), urinary incon-tinence, attention deficit disorder, obsessive-compulsive disorder, neuropathic pain (chronic pain that can occur with peripheral neuropathies, herpes zoster infections, traumatic nerve injuries, and some types of cancer or cancer treatments), diabetic neuropa-thy, and enuresis.
TCAs interact with several commonly used drugs:
· They increase the catecholamine effects of amphetamines and sympathomimetics, leading to hypertension.
· Barbiturates increase the metabolism of TCAs and decrease their blood levels.
· Cimetidine impairs metabolism of TCAs by the liver, increasing the risk of toxicity.
· Concurrent use of TCAs with MAOIs may cause an extremely el-evated body temperature, excitation, and seizures.
· An increased anticholinergic effect, such as dry mouth, urine re-tention, and constipation, is seen when anticholinergic drugs are taken with TCAs.
· TCAs reduce the antihypertensive effects of clonidine and guanethidine. (See Adverse reactions to TCAs.)