Amitriptyline

Amitriptyline is FDA approved medication to treat depression in adults.[1]

The non-FDA approved indications are anxiety, post-traumatic stress disorder, insomnia, chronic pain (diabetic neuropathy, fibromyalgia), irritable bowel syndrome, interstitial cystitis (bladder pain syndrome), migraine prophylaxis, postherpetic neuralgia, and sialorrhea.[2]

Amitriptyline is in the tricyclic antidepressant (TCA) drug classification and acts by blocking the reuptake of both serotonin and norepinephrine neurotransmitters. The three-ring central structure, along with a side chain, is the basic structure of tricyclic antidepressants. Amitriptyline is a tertiary amine and has strong binding affinities for alpha-adrenergic, histamine (H1), and muscarinic (M1) receptors.[3] It is more sedating and has increased anticholinergic properties compared to other TCAs. 

Like other antidepressants, the onset of therapeutic action typically begins at approximately 2 to 4 weeks. 

Amitriptyline administration comes in various forms, the most common being oral form. The initial dose recommended for depression is 25 mg/day at bedtime, as it can be sedating. For off-label use such as for chronic pain, therapy can initiate at a much lower dose of 10 to 20 mg/day. It can be increased by 25 mg every 3 to 7 days, with a maximum of 150 to 300 mg/day. If the dose needs to be adjusted, it is preferable to change the dose at bedtime. Once the patient is stable, amitriptyline should be continued for three months or longer to prevent relapse of depression. In cases of therapy cessation, the clinician should gradually taper to avoid withdrawal.

Amitriptyline is not FDA approved for pediatric depression. The recommendation is to start with a lower dosage (around 10 mg/day) in the pediatric and geriatric population.

Its half-life is 10 to 28 hours, and it gets metabolized to nortriptyline. Its metabolism is primarily by CYP3A4 and CYP2C19.[4] 

Amitriptyline administration can also via the intramuscular route (peak concentration occurs within 2 to 12 hours of administration), and an intravenous route is another one.[5] 

The most commonly encountered side effects of amitriptyline include weight gain, gastrointestinal symptoms like constipation, xerostomia, dizziness, headache, and somnolence.

The following is a list of other adverse effects including serious side effects of amitriptyline:

1. Secondary to its alpha-adrenergic receptor blockade, it can cause orthostatic hypotension, dizziness, and sedation.  It can also cause heart rate variability, slow intracardiac conduction, induce various arrhythmias, and cause QTc (corrected QT) prolongation.[6]

2. Anticholinergic side effects include blurred vision, dry mouth, urinary retention, tachycardia, acute angle glaucoma, confusion, and delirium.[6]

3. Antihistamine side effects secondary to its H1 receptor binding property include sedation, increased appetite, weight gain, confusion, and delirium. 

4. Amitriptyline can lower the seizure threshold, and it should be used cautiously in patients with a history of seizure disorder.[7] Its seizure threshold reducing effect is dose-dependent, seizure rate is 1 to 4% at doses of 250 to 450 mg/day.

5. It is known to cause abnormalities in liver function tests in 10 to 20% of patients. It is uncommon for the liver function test to be over three times the upper limit of normal. Usually, the effect on the liver is mild, asymptomatic, transient, and reverses with discontinuation. It rarely causes acute liver injury.[8]

6. It can also cause impaired arousal, the risk of bone fracture, tremor, and (rare) bone marrow suppression.[9] 

7. In adolescents and young adults (ages less than 24 years), it can increase the risk of suicidal ideation and behavior (rarely). The risk is very low, but the patient and families require education regarding these risks. 

8. As an antidepressant, amitriptyline can rarely induce mania. Some of the risk factors that can predict amitriptyline inducing mania are a history of bipolar disorder, family history of mania, pharmacologically induced hypomania.

Contraindication considerations are one of the most critical aspects while administering a drug to a patient. The following are significant considerations for amitriptyline:

1. Hypersensitivity reactions are an essential consideration. Amitriptyline is contraindicated in patients with hypersensitivity to the drug or any of its dosage form inactive ingredients.

2. Amitriptyline should not be used if there is a history of QTc prolongation, arrhythmias, recent myocardial infarction, or heart failure. 

3. Its use requires caution in patients with angle-closure glaucoma, urinary retention, seizures.[10]

4. Do not use with MAOI (monoamine oxidase inhibitors) and also within 14 days use of MAOIs. 

5. It is essential to keep into account various drug-drug interactions. Considering amitriptyline causes QTc prolongation, the use of other drugs that prolong QTc can lead to cardiac problems, including arrhythmias. The following medications can increase QTc- astemizole, cisapride, disopyramide, ibutilide, indapamide, pentamidine, pimozide, procainamide, quinidine, sotalol, terfenadine.

6. Some drugs, when used along with amitriptyline, may cause an increase in serotonin concentrations, such drugs include isocarboxazid, phenelzine, procarbazine, safinamide, selegiline, tranylcypromine. These drugs can cause serotonin syndrome. 

7. Amitriptyline gets metabolized from CYP3A4. Several drugs alter the activity of CYP3A4, and thus dose should be cautiously regulated, as well as the entire patient medication regimen checked for CYP3A4 inducers and inhibitors. 

8. Lower doses are advisable in renal and hepatic impairment. 

9. Before elective surgery, the recommendation is to discontinue amitriptyline because of its possible interaction with anesthesia and as it may increase the risk of arrhythmia.[11]