Chemistry:Amitriptyline
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Pronunciation | /ˌæmɪˈtrɪptɪliːn/[1] |
Trade names | Elavil, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682388 |
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Routes of administration | By mouth, intramuscular injection |
Drug class | Tricyclic antidepressant (TCA) |
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Bioavailability | 45%[3]-53%[4] |
Protein binding | 96%[5] |
Metabolism | Liver (CYP2D6, CYP2C19, CYP3A4)[7][4][8] |
Metabolites | nortriptyline, (E)-10-hydroxynortriptyline |
Elimination half-life | 21 hours[3] |
Excretion | Urine: 12–80% after 48 hours;[6] feces: not studied |
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Formula | C20H23N |
Molar mass | 277.411 g·mol−1 |
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Melting point | 197.5 °C (387.5 °F) [9] |
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Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headaches.[10] Due to the frequency and prominence of side effects, amitriptyline is generally considered a second-line therapy for these indications.[11][12][13][14]
The most common side effects are dry mouth, drowsiness, dizziness, constipation, and weight gain. Of note is sexual dysfunction, observed primarily in males. Glaucoma, liver toxicity and abnormal heart rhythms are rare but serious side effects. Blood levels of amitriptyline vary significantly from one person to another,[15] and amitriptyline interacts with many other medications potentially aggravating its side effects.
Amitriptyline was discovered in the late 1950s by scientists at Merck and approved by the US Food and Drug Administration (FDA) in 1961.[16] It is on the World Health Organization's List of Essential Medicines.[17] It is available as a generic medication.[18] In 2020, it was the 81st most commonly prescribed medication in the United States, with more than 9 million prescriptions.[19][20]
Medical uses
Amitriptyline is indicated for the treatment of major depressive disorder and neuropathic pain and for the prevention of migraine and chronic tension headache. It can be used for the treatment of nocturnal enuresis in children older than 6 after other treatments have failed.[10]
Depression
Amitriptyline is effective for depression,[21] but it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability.[22] It can be tried for depression as a second-line therapy, after the failure of other treatments.[11] For treatment-resistant adolescent depression[23] or for cancer-related depression[24] amitriptyline is no better than placebo, however the number of treated patients in both studies was small. It is sometimes used for the treatment of depression in Parkinson's disease,[25] but supporting evidence for that is lacking.[26]
Pain
Amitriptyline alleviates painful diabetic neuropathy. It is recommended by a variety of guidelines as a first or second line treatment.[12] It is as effective for this indication as gabapentin or pregabalin but less well tolerated.[27] Amitriptyline is as effective at relieving pain as duloxetine. Combination treatment of amitriptyline and pregabalin offers additional pain relief for people whose pain is not adequately controlled with one medication, and is safe.[28][29] Amitriptyline in certain formulations may also induce the level of sciatic-nerve blockade needed for local anaesthesia therein.[30] Here, it has been demonstrated to be of superior potency to bupivacaine, a customary long-acting local anaesthetic.
Low doses of amitriptyline moderately improve sleep disturbances and reduce pain and fatigue associated with fibromyalgia.[31] It is recommended for fibromyalgia accompanied by depression by Association of the Scientific Medical Societies in Germany[31] and as a second-line option for fibromyalgia, with exercise being the first line option, by European League Against Rheumatism.[13] Combinations of amitriptyline and fluoxetine or melatonin may reduce fibromyalgia pain better than either medication alone.[32]
There is some (low-quality) evidence that amitriptyline may reduce pain in cancer patients. It is recommended only as a second line therapy for non-chemotherapy-induced neuropathic or mixed neuropathic pain, if opioids did not provide the desired effect.[33]
Moderate evidence exists in favor of amitriptyline use for atypical facial pain.[34] Amitriptyline is ineffective for HIV-associated neuropathy.[27]
In multiple sclerosis it is frequently used to treat painful paresthesias in the arms and legs (e.g., burning sensations, pins and needles, stabbing pains) caused by damage to the pain regulating pathways of the brain and spinal cord.[35]
Headache
Amitriptyline is probably effective for the prevention of periodic migraine in adults. Amitriptyline is similar in efficacy to venlafaxine and topiramate but carries a higher burden of adverse effects than topiramate.[14] For many patients, even very small doses of amitriptyline are helpful, which may allow for minimization of side effects.[36] Amitriptyline is not significantly different from placebo when used for the prevention of migraine in children.[37]
Amitriptyline may reduce the frequency and duration of chronic tension headache, but it is associated with worse adverse effects than mirtazapine. Overall, amitriptyline is recommended for tension headache prophylaxis, along with lifestyle advice, which should include avoidance of analgesia and caffeine.[38]
Other indications
Amitriptyline is effective for the treatment of irritable bowel syndrome; however, because of its side effects, it should be reserved for select patients for whom other agents do not work.[39] There is insufficient evidence to support its use for abdominal pain in children with functional gastrointestinal disorders.[40]
Tricyclic antidepressants decrease the frequency, severity, and duration of cyclic vomiting syndrome episodes. Amitriptyline, as the most commonly used of them, is recommended as a first-line agent for its therapy.[41]
Amitriptyline may improve pain and urgency intensity associated with bladder pain syndrome and can be used in the management of this syndrome.[42][43] Amitriptyline can be used in the treatment of nocturnal enuresis in children. However, its effect is not sustained after the treatment ends. Alarm therapy gives better short- and long-term results.[44]
In the US, amitriptyline is commonly used in children with ADHD as an adjunct to stimulant medications without any evidence or guideline supporting this practice.[45] Many physicians in the UK (and the US also) commonly prescribe amitriptyline for insomnia;[46] however, Cochrane reviewers were not able to find any randomized controlled studies that would support or refute this practice.[47] Similarly, a major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found little evidence to inform the use of amitriptyline for insomnia.[48]
Contraindications and precautions
The known contraindications of amitriptyline are:[10]
- History of myocardial infarction
- History of arrhythmias, particularly any degree of heart block
- Coronary artery disease
- Porphyria
- Severe liver disease (such as cirrhosis)
- Being under six years of age
- Patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days
Amitriptyline should be used with caution in patients with epilepsy, impaired liver function, pheochromocytoma, urinary retention, prostate enlargement, hyperthyroidism, and pyloric stenosis.[10]
In patients with the rare condition of shallow anterior chamber of eyeball and narrow anterior chamber angle, amitriptyline may provoke attacks of acute glaucoma due to dilation of the pupil. It may aggravate psychosis, if used for depression with schizophrenia, or precipitate the switch to mania in those with bipolar disorder.[10]
CYP2D6 poor metabolizers should avoid amitriptyline due to increased side effects. If it is necessary to use it, half dose is recommended.[49] Amitriptyline can be used during pregnancy and lactation when SSRIs have been shown not to work.[50]
Side effects
The most frequent side effects, occurring in 20% or more of users, are dry mouth, drowsiness, dizziness, constipation, and weight gain (on average 1.8 kg[51]).[21] Other common side effects are headache problems (amblyopia, blurred vision), tachycardia, increased appetite, tremor, fatigue/asthenia/feeling slowed down, and dyspepsia.[21]
A literature review about abnormal movements and amitriptyline found that this drug is associated with various movement disorders, particularly dyskinesia, dystonia, and myoclonus. Stuttering and restless legs syndrome are some of the less common associations.[52]
A less common side effect of amitriptyline is urination problems (8.7%).[21]
Amitriptyline-associated sexual dysfunction (occurring at a frequency of 6.9%) seems to be mostly confined to males with depression and is expressed predominantly as erectile dysfunction and low libido disorder, with lesser frequency of ejaculatory and orgasmic problems. The rate of sexual dysfunction in males treated for indications other than depression and in females is not significantly different from placebo.[53]
Liver tests abnormalities occur in 10–12% of patients on amitriptyline, but are usually mild, asymptomatic and transient,[54] with consistently elevated alanine transaminase in 3% of all patients.[55][56] The increases of the enzymes above the 3-fold threshold of liver toxicity are uncommon, and cases of clinically apparent liver toxicity are rare;[54] nevertheless, amitriptyline is placed in the group of antidepressants with greater risks of hepatic toxicity.[55]
Amitriptyline prolongs the QT interval.[57] This prolongation is relatively small at therapeutic doses[58] but becomes severe in overdose.[59]
Overdose
The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of serotonin syndrome and adverse cardiac effects. The British National Formulary notes that amitriptyline can be particularly dangerous in overdose,[60] thus it and other TCAs are no longer recommended as first-line therapy for depression. The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available. Activated charcoal may reduce absorption if given within 1–2 hours of ingestion. If the affected person is unconscious or has an impaired gag reflex, a nasogastric tube may be used to deliver the activated charcoal into the stomach. ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised. Body temperature should be regulated with measures such as heating blankets if necessary. Cardiac monitoring is advised for at least five days after the overdose. Benzodiazepines are recommended to control seizures. Dialysis is of no use due to the high degree of protein binding with amitriptyline.[5]
Interactions
Since amitriptyline and its active metabolite nortriptyline are primarily metabolized by cytochromes CYP2D6 and CYP2C19 (see Amitriptyline), the inhibitors of these enzymes are expected to exhibit pharmacokinetic interactions with amitriptyline. According to the prescribing information, the interaction with CYP2D6 inhibitors may increase the plasma level of amitriptyline.[10] However, the results in the other literature are inconsistent:[7] the co-administration of amitriptyline with a potent CYP2D6 inhibitor paroxetine does increase the plasma levels of amitriptyline two-fold and of the main active metabolite nortriptyline 1.5-fold,[61] but combination with less potent CYP2D6 inhibitors thioridazine or levomepromazine does not affect the levels of amitriptyline and increases nortriptyline by about 1.5-fold;[62] a moderate CYP2D6 inhibitor fluoxetine does not seem to have a significant effect on the levels of amitriptyline or nortriptyline.[63][64] A case of clinically significant interaction with potent CYP2D6 inhibitor terbinafine has been reported.[65]
A potent inhibitor of CYP2C19 and other cytochromes fluvoxamine increases the level of amitriptyline two-fold while slightly decreasing the level of nortriptyline.[63] Similar changes occur with a moderate inhibitor of CYP2C19 and other cytochromes cimetidine: amitriptyline level increases by about 70%, while nortriptyline decreases by 50%.[66] CYP3A4 inhibitor ketoconazole elevates amitriptyline level by about a quarter.[8] On the other hand, cytochrome P450 inducers such as carbamazepine and St. John's Wort decrease the levels of both amitriptyline and nortriptyline[62][67]
Oral contraceptives may increase the blood level of amitriptyline by as high as 90%.[68] Valproate moderately increases the levels of amitriptyline and nortriptyline through an unclear mechanism.[69]
The prescribing information warns that the combination of amitriptyline with monoamine oxidase inhibitors may cause potentially lethal serotonin syndrome;[10] however, this has been disputed.[70] The prescribing information cautions that some patients may experience a large increase in amitriptyline concentration in the presence of topiramate.[71] However, other literature states that there is little or no interaction: in a pharmacokinetic study topiramate only increased the level of amitriptyline by 20% and nortriptyline by 33%.[72]
Amitriptiline counteracts the antihypertensive action of guanethidine.[5][73] When given with amitriptyline, other anticholinergic agents may result in hyperpyrexia or paralytic ileus.[71] Co-administration of amitriptyline and disulfiram is not recommended due to the potential for the development of toxic delirium.[5][74] Amitriptyline causes an unusual type of interaction with the anticoagulant phenprocoumon during which great fluctuations of the prothrombin time have been observed.[75]
Pharmacology
Pharmacodynamics
Site | AMI | NTI | Species | Ref |
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NET | 19–102 | 1.8–21 | Human | [76][77] |
DAT | 3,250 | 1,140 | Human | [76] |
5-HT1A | 450–1,800 | 294 | Human | [78][79] |
5-HT1B | 840 | ND | Rat | [80] |
5-HT2A | 18–23 | 41 | Human | [78][79] |
5-HT2B | 174 | ND | Human | [81] |
5-HT2C | 4-8 | 8.5 | Rat | [82][83] |
5-HT3 | 430 | 1,400 | Rat | [84] |
5-HT6 | 65–141 | 148 | Human/rat | [85][86][87] |
5-HT7 | 92.8–123 | ND | Rat | [88] |
α1A | 6.5–25 | 18–37 | Human | [89][90] |
α1B | 600–1700 | 850–1300 | Human | [89][90] |
α1D | 560 | 1500 | Human | [90] |
α2 | 114–690 | 2,030 | Human | [77][78] |
α2A | 88 | ND | Human | [91] |
α2B | >1000 | ND | Human | [91] |
α2C | 120 | ND | Human | [91] |
β | >10,000 | >10,000 | Rat | [92][83] |
D1 | 89 | 210 (rat) | Human/rat | [93][83] |
D2 | 196–1,460 | 2,570 | Human | [78][93] |
D3 | 206 | ND | Human | [93] |
D4 | ND | ND | ND | ND |
D5 | 170 | ND | Human | [93] |
H1 | 0.5–1.1 | 3.0–15 | Human | [93][94][95] |
H2 | 66 | 646 | Human | [94] |
H3 | 75,900;>1000 | 45,700 | Human | [93][94] |
H4 | 34–26,300 | 6,920 | Human | [94][96] |
M1 | 11.0–14.7 | 40 | Human | [97][98] |
M2 | 11.8 | 110 | Human | [97] |
M3 | 12.8–39 | 50 | Human | [97][98] |
M4 | 7.2 | 84 | Human | [97] |
M5 | 15.7–24 | 97 | Human | [97][98] |
σ1 | 287–300 | 2,000 | Guinea pig/rat | [99][100] |
PARP1 | 1650 | ND | Human | [101] |
TrkA | 3,000 (agonist) |
ND | Human | [102] |
TrkB | 14,000 (agonist) |
ND | Human | [102] |
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. |
Amitriptyline inhibits serotonin transporter (SERT) and norepinephrine transporter (NET). It is metabolized to nortriptyline, a stronger norepinephrine reuptake inhibitor, further augmenting amitriptyline's effects on norepinephrine reuptake (see table in this section).
Amitriptyline additionally acts as a potent inhibitor of the serotonin 5-HT2A, 5-HT2C, the α1A-adrenergic, the histamine H1 and the M1-M5 muscarinic acetylcholine receptors (see table in this section).
Amitriptyline is a non-selective blocker of multiple ion channels, in particular, voltage-gated sodium channels Nav1.3, Nav1.5, Nav1.6, Nav1.7, and Nav1.8,[103][104][105] voltage-gated potassium channels Kv7.2/ Kv7.3,[106] Kv7.1, Kv7.1/KCNE1,[107] and hERG.[108]
Mechanism of action
Inhibition of serotonin and norepinephrine transporters by amitriptyline results in interference with neuronal reuptake of serotonin and norepinephrine. Since the reuptake process is important physiologically in terminating transmitting activity, this action may potentiate or prolong activity of serotonergic and adrenergic neurons and is believed to underlie the antidepressant activity of amitriptyline.[71]
Inhibition of norepinephrine reuptake leading to increased concentration of norepinephrine in the posterior grey column of the spinal cord appears to be mostly responsible for the analgesic action of amitriptyline. Increased level of norepinephrine increases the basal activity of alpha-2 adrenergic receptors, which mediate an analgesic effect by increasing gamma-aminobutyric acid transmission among spinal interneurons. The blocking effect of amitriptyline on sodium channels may also contribute to its efficacy in pain conditions.[4]
Pharmacokinetics
Amitriptyline is readily absorbed from the gastrointestinal tract (90–95%).[4] Absorption is gradual with the peak concentration in blood plasma reached after about 4 hours.[3] Extensive metabolism on the first pass through the liver leads to average bioavailability of about 50% (45%[3]-53%[4]). Amitriptyline is metabolized mostly by CYP2C19 into nortriptyline and by CYP2D6 leading to a variety of hydroxylated metabolites, with the principal one among them being (E)-10-hydroxynortriptyline[7] (see metabolism scheme),[4] and to a lesser degree, by CYP3A4.[8]
Nortriptyline, the main active metabolite of amitriptyline, is an antidepressant on its own right. Nortriptyline reaches 10% higher level in the blood plasma than the parent drug amitriptyline and 40% greater area under the curve, and its action is an important part of the overall action of amitriptyline.[3][7]
Another active metabolite is (E)-10-hydroxynortriptyline, which is a norepinephrine uptake inhibitor four times weaker than nortriptyline. (E)-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its cerebrospinal fluid level, which is a close proxy of the brain concentration of a drug, is twice higher than nortriptyline's. Based on this, (E)-10-hydroxynortriptyline was suggested to significantly contribute to antidepressant effects of amitriptyline.[109]
Blood levels of amitriptyline and nortriptyline and pharmacokinetics of amitriptyline in general, with clearance difference of up to 10-fold, vary widely between individuals.[110] Variability of the area under the curve in steady state is also high, which makes a slow upward titration of the dose necessary.[15]
In the blood, amitriptyline is 96% bound to plasma proteins; nortriptyline is 93–95% bound, and (E)-10-hydroxynortiptyline is about 60% bound.[5][111][109] Amitriptyline has an elimination half life of 21 hours,[3] nortriptyline – 23–31 hours,[112] and (E)-10-hydroxynortiptyline - 8–10 hours.[109] Within 48 hours, 12-80% of amitriptyline is eliminated in the urine, mostly as metabolites.[6] 2% of the unchanged drug is excreted in the urine.[113] Elimination in the feces, apparently, have not been studied.
Therapeutic levels of amitriptyline range from 75 to 175 ng/mL (270–631 nM),[114] or 80–250 ng/mL of both amitriptyline and its metabolite nortriptyline.[115]
Pharmacogenetics
Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body.[116] Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.[117][118][119][120]
Individuals can be categorized into different types of CYP2D6 or CYP2C19 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers,[49] and have "normal" metabolism of amitriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use amitriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.[117][118][49][120]
The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively. The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.[49] The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are CYP2D6 poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are CYP2D6 intermediate metabolizers.[121]
Chemistry
Amitriptyline is a highly lipophilic molecule having an octanol-water partition coefficient (pH 7.4) of 3.0,[122] while the log P of the free base was reported as 4.92.[123] Solubility of the free base amitriptyline in water is 14 mg/L.[124] Amitriptyline is prepared by reacting dibenzosuberane with 3-(dimethylamino)propylmagnesium chloride and then heating the resulting intermediate product with hydrochloric acid to eliminate water.[4]
History
Amitriptyline was first developed by the American pharmaceutical company Merck in the late 1950s. In 1958, Merck approached a number of clinical investigators proposing to conduct clinical trials of amitriptyline for schizophrenia. One of these researchers, Frank Ayd, instead, suggested using amitriptyline for depression. Ayd treated 130 patients and, in 1960, reported that amitriptyline had antidepressant properties similar to another, and the only known at the time, tricyclic antidepressant imipramine.[125] Following this, the US Food and Drug Administration approved amitriptyline for depression in 1961.[16]
In Europe, due to a quirk of the patent law at the time allowing patents only on the chemical synthesis but not on the drug itself, Roche and Lundbeck were able to independently develop and market amitriptyline in the early 1960s.[126]
According to research by the historian of psychopharmacology David Healy, amitriptyline became a much bigger selling drug than its precursor imipramine because of two factors. First, amitriptyline has much stronger anxiolytic effect. Second, Merck conducted a marketing campaign raising clinicians' awareness of depression as a clinical entity.[126][125]
Society and culture
English folk singer Nick Drake died from an overdose of Tryptizol in 1974.[127]
Senteni Masango, wife of Swaziland King Mswati, died on 6 April 2018 after overdosing on amytriptyline capsules.[128]
In the 2021 film The Many Saints of Newark, amitriptyline (referred to by the brand name Elavil) is part of the plot line of the movie.[129]
Generic names
Amitriptyline is the English and French generic name of the drug and its INN, BAN, and DCF, while amitriptyline hydrochloride is its USAN, USP, BANM, and JAN.[130][131][132][133] Its generic name in Spanish and Italian and its DCIT are amitriptilina, in German is Amitriptylin, and in Latin is amitriptylinum.[131][133] The embonate salt is known as amitriptyline embonate, which is its BANM, or as amitriptyline pamoate unofficially.[131]
Prescription trends
Between 1998 and 2017, along with imipramine, amitriptyline was the most commonly prescribed first antidepressant for children aged 5–11 years in England. It was also the most prescribed antidepressant (along with fluoxetine) for 12 to 17-year olds.[134]
Research
The few randomized controlled trials investigating amitriptyline efficacy in eating disorder have been discouraging.[135]
References
- ↑ "Amitriptyline" (in en). Oxford Dictionary. https://www.lexico.com/en/definition/amitriptyline.
- ↑ "Amitriptyline Use During Pregnancy". 2 September 2020. https://www.drugs.com/pregnancy/amitriptyline.html.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Discrepancies between pharmacokinetic studies of amitriptyline". Clin Pharmacokinet 10 (3): 257–68. 1985. doi:10.2165/00003088-198510030-00005. PMID 3893842.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Classics in Chemical Neuroscience: Amitriptyline". ACS Chem Neurosci 12 (3): 354–362. February 2021. doi:10.1021/acschemneuro.0c00467. PMID 33438398.
- ↑ 5.0 5.1 5.2 5.3 5.4 "Endep Amitriptyline hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 10 December 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04558-3.
- ↑ 6.0 6.1 "Elimination and pharmacological effects following single oral doses of 50 and 75 mg of amitriptyline in man". Arch Psychiatr Nervenkr (1970) 233 (6): 449–55. 1983. doi:10.1007/BF00342785. PMID 6667101.
- ↑ 7.0 7.1 7.2 7.3 "The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man". Drug Metab Rev 36 (3–4): 723–46. October 2004. doi:10.1081/dmr-200033482. PMID 15554244.
- ↑ 8.0 8.1 8.2 "Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies". J Clin Pharmacol 41 (10): 1043–54. October 2001. doi:10.1177/00912700122012634. PMID 11583471.
- ↑ "Amitriptyline Hydrochloride". Analytical Profiles of Drug Substances 3: 127–148. 1974. doi:10.1016/S0099-5428(08)60066-0. ISBN 9780122608032.
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 "Amitriptyline Tablets BP 50mg – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Actavis UK Ltd.. 24 March 2013. http://www.medicines.org.uk/emc/medicine/23738/SPC/Amitriptyline+Tablets+BP+50mg/.
- ↑ 11.0 11.1 Top 100 drugs : clinical pharmacology and practical prescribing. Churchill Livingstone. 2015. p. 50. ISBN 978-0-7020-5516-4.
- ↑ 12.0 12.1 "Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs". Drugs 80 (4): 363–384. March 2020. doi:10.1007/s40265-020-01259-2. PMID 32040849.
- ↑ 13.0 13.1 "EULAR revised recommendations for the management of fibromyalgia". Ann Rheum Dis 76 (2): 318–328. February 2017. doi:10.1136/annrheumdis-2016-209724. PMID 27377815.
- ↑ 14.0 14.1 "Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society". Neurology 78 (17): 1337–45. April 2012. doi:10.1212/WNL.0b013e3182535d20. PMID 22529202.
- ↑ 15.0 15.1 "Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine". CNS Drugs 31 (5): 389–403. May 2017. doi:10.1007/s40263-017-0430-3. PMID 28405886.
- ↑ 16.0 16.1 "Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part II: tricyclics and tetracyclics". Journal of Clinical Psychopharmacology 28 (1): 1–4. February 2008. doi:10.1097/jcp.0b013e3181627b60. PMID 18204333.
- ↑ Organization, World Health (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. WHO/MHP/HPS/EML/2021.02.
- ↑ "Amitriptyline Hydrochloride". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/amitriptyline-hydrochloride.html.
- ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx.
- ↑ "Amitriptyline – Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Amitriptyline.
- ↑ 21.0 21.1 21.2 21.3 "Amitriptyline versus placebo for major depressive disorder". Cochrane Database Syst Rev 12: CD009138. December 2012. doi:10.1002/14651858.CD009138.pub2. PMID 23235671.
- ↑ Rossi, S, ed (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- ↑ "Systematic review of management for treatment-resistant depression in adolescents". BMC Psychiatry 14: 340. November 2014. doi:10.1186/s12888-014-0340-6. PMID 25433401.
- ↑ "Reevaluating the role of antidepressants in cancer-related depression: a systematic review and meta-analysis". Gen Hosp Psychiatry 36 (5): 466–73. 2014. doi:10.1016/j.genhosppsych.2014.05.010. PMID 24950919.
- ↑ "Parkinson's disease". Merck Sharp & Dohme Corp.. August 2007. Archived from the original on 18 November 2013. https://web.archive.org/web/20131118154550/http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/movement_disorders/parkinsons_disease.html.
- ↑ "The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease". Mov Disord 26 (Suppl 3): S42–80. October 2011. doi:10.1002/mds.23884. PMID 22021174.
- ↑ 27.0 27.1 "Pharmacological Management of Painful Peripheral Neuropathies: A Systematic Review". Pain and Therapy 10 (1): 55–68. June 2021. doi:10.1007/s40122-020-00210-3. PMID 33145709.
- ↑ "Combination therapy for painful diabetic neuropathy is safe and effective" (in en). NIHR Evidence. 2023-04-06. doi:10.3310/nihrevidence_57470. https://evidence.nihr.ac.uk/alert/combination-therapy-for-painful-diabetic-neuropathy-is-safe-and-effective/.
- ↑ "Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial". Lancet 400 (10353): 680–690. August 2022. doi:10.1016/s0140-6736(22)01472-6. PMID 36007534.
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- ↑ "Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review". Pain Pract 17 (3): 409–419. March 2017. doi:10.1111/papr.12459. PMID 27207115.
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- ↑ "Insidious and prolonged antagonism of guanethidine by amitriptyline". JAMA 213 (9): 1487–8. August 1970. doi:10.1001/jama.1970.03170350053016. PMID 5468457.
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- ↑ "CHAPTER 132 ORAL ANTICOAGULATION | Free Medical Textbook". 9 February 2012. https://medtextfree.wordpress.com/2012/02/09/chapter-132-oral-anticoagulation/.
- ↑ 76.0 76.1 Cite error: Invalid
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- ↑ 77.0 77.1 Cite error: Invalid
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- ↑ 78.0 78.1 78.2 78.3 "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology 114 (4): 559–65. 1994. doi:10.1007/bf02244985. PMID 7855217.
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- ↑ "Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex". J. Neurochem. 47 (2): 529–40. 1986. doi:10.1111/j.1471-4159.1986.tb04532.x. PMID 2942638.
- ↑ "Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache?". Eur. J. Neurosci. 8 (5): 959–67. 1996. doi:10.1111/j.1460-9568.1996.tb01583.x. PMID 8743744.
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- ↑ "Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling". Mol. Pharmacol. 64 (6): 1295–308. 2003. doi:10.1124/mol.64.6.1295. PMID 14645659.
- ↑ "Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs". Mol. Pharmacol. 43 (3): 320–7. 1993. PMID 7680751.
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- ↑ 89.0 89.1 "The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha1B-adrenoceptors". Neuropharmacology 59 (1–2): 49–57. 2010. doi:10.1016/j.neuropharm.2010.03.015. PMID 20363235.
- ↑ 90.0 90.1 90.2 "The affinity and selectivity of α-adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-adrenoceptors". Pharmacol Res Perspect 8 (4): e00602. August 2020. doi:10.1002/prp2.602. PMID 32608144.
- ↑ 91.0 91.1 91.2 "High-throughput screening with a miniaturized radioligand competition assay identifies new modulators of human α2-adrenoceptors". Eur J Pharm Sci 47 (5): 941–51. December 2012. doi:10.1016/j.ejps.2012.08.021. PMID 22982401.
- ↑ "Beta adrenergic receptor binding in membrane preparations from mammalian brain". Mol. Pharmacol. 12 (4): 568–80. 1976. PMID 8699.
- ↑ 93.0 93.1 93.2 93.3 93.4 93.5 "Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics". Bioorg. Med. Chem. Lett. 19 (2): 538–42. 2009. doi:10.1016/j.bmcl.2008.09.012. PMID 19091563.
- ↑ 94.0 94.1 94.2 94.3 "Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics". Naunyn Schmiedebergs Arch. Pharmacol. 385 (2): 145–70. February 2012. doi:10.1007/s00210-011-0704-0. PMID 22033803.
- ↑ "Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes". Bioorg. Med. Chem. 14 (19): 6640–58. 2006. doi:10.1016/j.bmc.2006.05.077. PMID 16782354.
- ↑ "Discovery of a novel member of the histamine receptor family". Mol. Pharmacol. 59 (3): 427–33. 2001. doi:10.1124/mol.59.3.427. PMID 11179435. https://cdr.lib.unc.edu/record/uuid:d42d8e6e-1a6d-40fc-9371-e4a7ab63f3ea. Retrieved 11 December 2019.
- ↑ 97.0 97.1 97.2 97.3 97.4 "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochem. Pharmacol. 45 (11): 2352–4. 1993. doi:10.1016/0006-2952(93)90211-e. PMID 8100134.
- ↑ 98.0 98.1 98.2 "Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro". Schizophr. Res. 37 (1): 107–22. 1999. doi:10.1016/s0920-9964(98)00146-7. PMID 10227113.
- ↑ "1,3-Di(2-[5-3Htolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs"]. Proc. Natl. Acad. Sci. U.S.A. 83 (22): 8784–8. 1986. doi:10.1073/pnas.83.22.8784. PMID 2877462. Bibcode: 1986PNAS...83.8784W.
- ↑ "A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder". Exp Neurol 207 (2): 248–57. October 2007. doi:10.1016/j.expneurol.2007.06.013. PMID 17689532.
- ↑ "Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer". Scientific Reports 6 (1): 3. December 2016. doi:10.1038/s41598-016-0007-2. PMID 28442756.
- ↑ 102.0 102.1 "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity". Chemistry & Biology 16 (6): 644–56. June 2009. doi:10.1016/j.chembiol.2009.05.010. PMID 19549602.
- ↑ "Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes". Naunyn Schmiedebergs Arch Pharmacol 390 (12): 1255–1270. December 2017. doi:10.1007/s00210-017-1424-x. PMID 28905186.
- ↑ "A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy". Epilepsia 59 (4): 802–813. April 2018. doi:10.1111/epi.14037. PMID 29574705.
- ↑ "Block of human heart hH1 sodium channels by amitriptyline". J Pharmacol Exp Ther 292 (3): 1015–23. March 2000. PMID 10688618.
- ↑ "Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels". Anesthesia and Analgesia 104 (5): 1256–1264. May 2007. doi:10.1213/01.ane.0000260310.63117.a2. PMID 17456683. http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=17456683. Retrieved 15 October 2009.
- ↑ "Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline". Biochem Pharmacol 152: 264–271. June 2018. doi:10.1016/j.bcp.2018.03.016. PMID 29621539.
- ↑ Cite error: Invalid
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- ↑ 109.0 109.1 109.2 "Active hydroxymetabolites of antidepressants. Emphasis on E-10-hydroxy-nortriptyline". Clin Pharmacokinet 28 (1): 26–40. January 1995. doi:10.2165/00003088-199528010-00004. PMID 7712660.
- ↑ "Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states". Drugs Aging 8 (6): 459–76. June 1996. doi:10.2165/00002512-199608060-00008. PMID 8736630.
- ↑ "Pamelor, Aventyl (nortriptyline) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/pamelor-nortriptyline-342944#showall.
- ↑ "The pharmacokinetics of nortriptyline in patients with chronic renal failure". Br J Clin Pharmacol 12 (1): 39–45. July 1981. doi:10.1111/j.1365-2125.1981.tb01852.x. PMID 7248140.
- ↑ "Amitriptyline". https://www.drugbank.ca/drugs/DB00321.
- ↑ Kaplan & Sadock's Concise Textbook of Clinical Psychiatry. Lippincott Williams & Wilkins. 2008. pp. 18–. ISBN 978-0-7817-8746-8. https://books.google.com/books?id=ubG51n2NgfwC&pg=PA18.
- ↑ "Therapeutic monitoring of antidepressant drugs: guidelines updated". Therapeutic Drug Monitoring 11 (5): 497–507. September 1989. doi:10.1097/00007691-198909000-00002. PMID 2683251.
- ↑ "Metabolism of tricyclic antidepressants". Cell Mol Neurobiol 19 (3): 373–409. 1999. doi:10.1023/A:1006949816036. PMID 10319193.
- ↑ 117.0 117.1 "Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function". Mol Psychiatry 18 (3): 273–87. 2013. doi:10.1038/mp.2012.42. PMID 22565785.
- ↑ 118.0 118.1 "Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes". Biochim Biophys Acta 1770 (3): 489–94. 2007. doi:10.1016/j.bbagen.2006.09.019. PMID 17113714.
- ↑ "Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants". Clinical Pharmacology & Therapeutics 93 (5): 402–8. 2013. doi:10.1038/clpt.2013.2. PMID 23486447. PMC 3689226. https://deepblue.lib.umich.edu/bitstream/2027.42/109971/1/cptclpt20132.pdf. Retrieved 4 November 2018.
- ↑ 120.0 120.1 "Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype". Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). 2017. Bookshelf ID: NBK425165. https://www.ncbi.nlm.nih.gov/books/NBK425165/. Retrieved 6 February 2020.
- ↑ "Pharmacogenetics: from bench to byte—an update of guidelines". Clinical Pharmacology & Therapeutics 89 (5): 662–73. 2011. doi:10.1038/clpt.2011.34. PMID 21412232.
- ↑ The Pharmaceutical Codex. 1994. Principles and practice of pharmaceutics, 12th edn. Pharmaceutical press
- ↑ Hansch C, Leo A, Hoekman D. 1995. Exploring QSAR.Hydrophobic, electronic and steric constants. Washington, DC: American Chemical Society.
- ↑ "Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution—a validation study". J Pharm Sci 95 (6): 1298–307. June 2006. doi:10.1002/jps.20613. PMID 16552741.
- ↑ 125.0 125.1 The Antidepressant Era. Harvard University Press. 1997. pp. 74–76. ISBN 0674039572.
- ↑ 126.0 126.1 The Psychopharmacologists II. Arnold. 1999. pp. 565–566. ISBN 1860360106. https://www.researchgate.net/publication/24904879.
- ↑ Brown, M., "Nick Drake: the fragile genius" , The Daily Telegraph, 25 November 2014.
- ↑ "Swaziland King Mswati's Eighth Wife, Senteni Masango Commits Suicide" (in en). 8 April 2018. https://parentsafrica.com/swaziland-king-mswatis-eighth-wife-senteni-masango-commits-suicide/.
- ↑ "The Sopranos Fan's Guide to The Many Saints of Newark". Vanity Fair. 10 January 2021. https://www.vanityfair.com/hollywood/2021/10/many-saints-of-newark-the-sopranos-easter-eggs. Retrieved 10 January 2021. "Livia is already troubled enough in the yesteryear of Many Saints that her doctor wants to prescribe her the antidepressant Elavil, but she rejects it. "I'm not a drug addict!" she sneers. Tony pores over the Elavil pamphlet with great interest and even schemes with Dickie Moltisanti to get his suffering mother to take it: "It could make her happy.""
- ↑ The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 889–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA889.
- ↑ 131.0 131.1 131.2 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 48–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA48.
- ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 15–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA15.
- ↑ 133.0 133.1 "Amitriptyline". https://www.drugs.com/international/amitriptyline.html.
- ↑ "Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998–2017: A population-based cohort study". PLOS Medicine 17 (7): e1003215. July 2020. doi:10.1371/journal.pmed.1003215. PMID 32697803.
- ↑ "Evidence-based pharmacotherapy of eating disorders". International Journal of Neuropsychopharmacology 15 (2): 189–207. March 2012. doi:10.1017/S1461145711000381. PMID 21414249.
Further reading
- "Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype". Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). March 2017. https://www.ncbi.nlm.nih.gov/books/NBK425165/.
External links
- "Amitriptyline". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/amitriptyline.
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