Tricyclic Antidepressants (TCAs)
Examples
- Amitriptyline
- Clomipramine
- Nortriptyline
Indications
- Depression - effective doses between 150mg - 250mg daily
- Panic disorder
- Nocturnal enuresis
- Painful diabetic neuropathy and other neuropathic pain syndromes - effective doses 10mg - 75mg daily
- Prophylaxis against migraine headache
- Phobic and obsessional states (clomipramine)
- Abdominal pain in patients who have not responded to laxatives, loperamide or antispasmodics (amitriptyline)
Tricyclic anti-depressants have been overtaken by SSRIs and are less widely used now, however amitriptyline is often used for neuropathic pain in low doses.
Contraindications
Contraindications
- Cardiac arrhythmias
- Mania
- Acute porphyria
Caution
- Closed-angle glaucoma
- Prostatic enlargement
- Cardiovascular disease
- Chronic constipation
- Bipolar disease
- Epilepsy and seizures
- Hepatic insufficiency
- Pregnancy
- Patients with a significant risk of suicide (overdosing associated with a high rate of fatality)
Mechanism
Monoamine (serotonin and noradrenaline) reuptake is blocked by the TCAs which antagonise the amine transporter, resulting in a greater monoamine concentration in the synapse. Pharmalogical interactions of the TCAs have been well described but the exact mechanism by which they exert their anti-depressant effect is not clearly understood. It is probable it involves adaptive responses within the brain to the changes in monoaminergic neurotransmission.
Administration
Oral
TCAs with sedative properties (e.g amitriptyline and clomipramine) should be administered at night.
Adverse Reactions
- Anti-cholinergic side effects such as dry mouth, blurred vision, constipation, hypotension and urinary retention
- Arrhythmias and heart block
- Sedation is variable, and insomnia, agitation and confusion can occur in the elderly
- Tricyclics reduce the seizure threshold
- Hyponatremia (due to SIADH) can occur, to which the elderly are particularly susceptible
Tolerance to anti-cholinergic effects tends to occur over time.
Overdose of tricyclics is highly dangerous.
Interactions
- Other sedative drugs - e.g. alcohol, opioids, antihistamines
- Drugs that prolong QT interval - e.g. amiodarone, sotalol, antipsychotic drugs
- Monoamine Oxidase Inhibitors and SSRIs should not be used with tricyclics
Education
Patients should be warned that anti-depressants take 7-10 days to begin to work, and a month before their full benefit is seen. If effective, they should be continued for 3-12 months to avoid recurrence of symptoms upon discontinuation. Some patients may experience drowsiness and should avoid driving if this occurs.
Explain about anti-cholinergic adverse effects (see ADRs) and that these will decrease with time.
Pharmacokinetics
Tricyclics are rapidly absorbed when given orally, and bind to plasma-albumin. They also bind to extravascular tissues which results in high distribution volumes and low excretion rates.
Metabolism is hepatic Inactivation of the drugs occurs by glucuronide conjugation of the hydroxylated metabolites, the glucuronides being excreted in the urine.
Drug half life varies with each drug from 10-20 hours to 80 hours, as such gradual accumulation is possible, particularly in the elderly, leading to increased side effects.
They have a narrow therapeutic index. Overdose of these drugs is extremely dangerous. They have active metabolites, which are increasingly absorbed because their anticholinergic effect slows gastrointestinal activity. Once absorbed, they are powerfully negatively inotropic.
