Amitriptyline


Article Author:
Amit Thour


Article Editor:
Raman Marwaha


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
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Saad Nazir
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Hassam Zulfiqar
Steve Bhimji
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Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
1/23/2019 11:14:00 PM

Indications

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]

Mechanism of Action

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 Antidepressant. Amitriptyline is a tertiary amine and has strong affinities for alpha-adrenergic, Histamine (H1), and muscarinic (M1) receptors.[3] It is more sedating and has greater anticholinergic property compared to other TCAs. 

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

Administration

Amitriptyline can be administered 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 3 months or longer to prevent relapse of depression. In cases of therapy cessation, it should be gradually tapered to avoid withdrawal.

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

It is half-life is 10 to 28 hours and is metabolized to nortriptyline. Its metabolism is primarily by CYP3A and CYP2C19.[4] 

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

Adverse Effects

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 property includes 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 lowering effect is dose-dependent, seizure rate is 1 to 4% at doses of 250 to 450mg/day.

5. It is known to cause abnormalities in liver function test in 10 to 20 % of patients. It is uncommon for the liver function test to be > 3 times 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 about the 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.

Contraindications

Contraindication considerations are one of the most important aspects while administering a drug to a patient. The following are important considerations for Amitriptyline:

1. Hypersensitivity reaction is an important consideration. Amitriptyline is contraindicated in patients with hypersensitivity to the drug or any of its inactive ingredients.

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

3. It should be used with 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, 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, pizomide, procainamide, quinidine, sotalol, terfenadine.

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

7. Amitriptyline gets metabolized from CYP3A4. A number of 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, it is recommended to discontinue amitriptyline because of its possible interaction with anesthesia and as it may increase the risk of arrhythmia.[11]

Monitoring

In patients with a history of cardiac problems or patients over 50 years of age should have a baseline electrocardiogram. 

Considering the drug's side effect profile, the following parameters require monitoring - BMI, liver function test, thyroid function test, and serum amitriptyline levels.[10][11] 

While a patient is on amitriptyline, one should monitor for an increase in suicidality and unusual behavior changes, especially during the first 1-2 months of starting medication or during periods of dosage adjustment. 

Toxicity

Amitriptyline toxicity can is measurable by a level >5mg/kg. The clinical features of amitriptyline toxicity include:

1. Neurological symptoms include sedation, seizure, coma.

2. Cardiac symptoms include tachycardia, hypotension, conduction abnormalities include QTc prolongation.

3. Anticholinergic symptoms include dilated pupils, dry mouth, decreased (or absent) bowel sounds, urinary retention.

Amitriptyline toxicity can be serious and even fatal. In treating the toxicity, it is imperative to stabilize patient and patient may need admission to the ICU for monitoring. The most important steps include - protecting the airways, breathing, and stabilizing circulation. Some patients may need tracheal intubation; if required administer supplemental oxygen. If the patient is hypotensive, an IV bolus of isotonic crystalloid is a therapeutic option. If the patient remains hypotensive despite fluid resuscitation, vasopressors are the next choice. If QRS> 100 msec, intravenous sodium bicarbonate is given as it is cardioprotective (it increases extracellular sodium concentration) and diminishes the effect of amitriptyline on the cardiac membrane which results in less blockage of the sodium channel.[12][13]) Activated charcoal can also be given within two hours of amitriptyline ingestion to prevent gastrointestinal absorption.[14] Seizures secondary to overdose are treatable with diazepam or lorazepam.

Enhancing Healthcare Team Outcomes

Amitriptyline is a tricyclic antidepressant that is FDA approved to treat depression in adults. It is also used off label to treat chronic pain syndrome, anxiety, and insomnia. It has considerable side effects and is no longer commonly used as a first line agent to treat depression. It may be useful for patients who have insomnia, severe depression, treatment-resistant depression, and patients with comorbid chronic pain syndromes. Patients on amitriptyline can have anticholinergic, antihistaminic and alpha-adrenergic blocking effects. It may not be appropriate for patients with cardiac problems. It has many drug interactions which can increase the risk of arrhythmias and serotonin syndrome. Toxicity can be life-threatening, and patients will need to be stabilized and monitored closely. Providers also need to know the increased risk of suicidality in children, adolescents and young adults which will require discussion with families.[15]


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Amitriptyline - Questions

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Which of the following is a common side effect of amitriptyline?



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Which of the following drugs can cause urinary retention?



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Which of the following medications can cause long QT syndrome?



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The generic drug amitriptyline has which brand name?



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In which drug class does amitriptyline belong?



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A 29-year-old female presented with the complaint of difficulty concentrating at work. She has bilateral headaches most of the time. She complains of diffuse body aches. Her mother has a history of SLE. The inflammatory markers came back within normal limits. Which of the following medications has been most studied in randomized clinical trials involving this condition?



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Amitriptyline - References

References

Dopheide JA, Recognizing and treating depression in children and adolescents. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2006 Feb 1;     [PubMed]
Radley DC,Finkelstein SN,Stafford RS, Off-label prescribing among office-based physicians. Archives of internal medicine. 2006 May 8;     [PubMed]
Gillman PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British journal of pharmacology. 2007 Jul;     [PubMed]
Venkatakrishnan K,Schmider J,Harmatz JS,Ehrenberg BL,von Moltke LL,Graf JA,Mertzanis P,Corbett KE,Rodriguez MC,Shader RI,Greenblatt DJ, Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies. Journal of clinical pharmacology. 2001 Oct;     [PubMed]
Deisenhammer EA,Whitworth AB,Geretsegger C,Kurzthaler I,Gritsch S,Miller CH,Fleischhacker WW,Stuppäck CH, Intravenous versus oral administration of amitriptyline in patients with major depression. Journal of clinical psychopharmacology. 2000 Aug;     [PubMed]
Güloglu C,Orak M,Ustündag M,Altunci YA, Analysis of amitriptyline overdose in emergency medicine. Emergency medicine journal : EMJ. 2011 Apr;     [PubMed]
Nishimura T,Maruguchi H,Nakao A,Nakayama S, Unusual complications from amitriptyline intoxication. BMJ case reports. 2017 Oct 10;     [PubMed]
Voican CS,Corruble E,Naveau S,Perlemuter G, Antidepressant-induced liver injury: a review for clinicians. The American journal of psychiatry. 2014 Apr;     [PubMed]
Rabenda V,Nicolet D,Beaudart C,Bruyère O,Reginster JY, Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2013 Jan;     [PubMed]
Sabah KMN,Chowdhury AW,Islam MS,Saha BP,Kabir SR,Kawser S, Amitriptyline-induced ventricular tachycardia: a case report. BMC research notes. 2017 Jul 14;     [PubMed]
Yoshida A,Hisatome I,Nawada T,Sasaki N,Taniguchi S,Tanaka Y,Manabe I,Ahmmed GU,Sato R,Mori A,Hattori K,Ueta Y,Mitani Y,Watanabe M,Igawa O,Fujimoto Y,Shigemasa C, Amitriptyline inhibits the G protein and K channel in the cloned thyroid cell line. European journal of pharmacology. 1996 Sep 19;     [PubMed]
Sasyniuk BI,Jhamandas V,Valois M, Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate. Annals of emergency medicine. 1986 Sep;     [PubMed]
Ramasubbu B,James D,Scurr A,Sandilands EA, Serum alkalinisation is the cornerstone of treatment for amitriptyline poisoning. BMJ case reports. 2016 Apr 11;     [PubMed]
Hultén BA,Adams R,Askenasi R,Dallos V,Dawling S,Heath A,Volans G, Activated charcoal in tricyclic antidepressant poisoning. Human toxicology. 1988 Jul;     [PubMed]
Montgomery SA, Suicide and antidepressants. Annals of the New York Academy of Sciences. 1997 Dec 29;     [PubMed]

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