Tricyclic antidepressants
Tricyclic antidepressants
TCAs are used to treat depression. They include:
- amitriptyline
- amoxapine
- clomipramine
- desipramine
- doxepin
- imipramine
- nortriptyline
- protriptyline
- trimipramine.
Pharmacokinetics
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.
Distribution, metabolism, and excretion
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 excreted as inactive compounds (only small amounts of active drug are excreted) in urine.
They just melt in fat
The extreme fat solubility of these drugs accounts for their wide distribution throughout the body, slow excretion, and long half-lives.
Pharmacodynamics
Researchers believe that TCAs increase the amount of norepinephrine, serotonin, or both in the CNS by preventing their reuptake into the storage granules in the presynaptic nerves. They also block acetylcholine and histamine receptors.
The upside to preventing reuptake
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 increased levels of these neurotransmitters in the synapses, relieving depression.
Pharmacotherapeutics
TCAs are used to treat episodes of major depression. They’re especially effective in treating depression of insidious onset accompanied by weight loss, anorexia, or insomnia. Physical signs and symptoms may respond after 1 to 2 weeks of therapy; psychological symptoms, after 2 to 4 weeks.
Warning!Adverse reactions to TCAs
Adverse reactions to TCAs include:
- orthostatic hypotension (a drop in blood pressure on standing)
- sedation
- jaundice
- rashes
- photosensitivity reactions
- a fine resting tremor
- decreased sexual desire
- inhibited ejaculation
- transient eosinophilia
- reduced white blood cell count
- manic episodes (in patients with or without bipolar disorder)
- exacerbation of psychotic symptoms in susceptible patients.
Special effects
Although rare, TCA therapy may also lead to:
- granulocytopenia
- palpitations
- conduction delays
- rapid heartbeat
- impaired cognition, cardiovascular adverse reactions (in elderly patients).
Sudden death has occurred in children and adolescents taking desipramine. For this reason a baseline electrocardiogram is recommended before giving a TCA to patients in this age-group.
Problem patients
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.
Migraines and more
TCAs are also used for preventing migraine headaches and in treating phobias (panic disorder with agoraphobia), urinary incontinence, 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 neuropathy, and enuresis.
Drug interactions
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 elevated body temperature, excitation, and seizures.
- An increased anticholinergic effect, such as dry mouth, urine retention, and constipation, is seen when anticholinergic drugs are taken with TCAs.
- TCAs reduce the antihypertensive effects of clonidine and guanethidine.
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