Amitriptyline

Structural formula
General
Non-proprietary name	Amitriptyline
other names	3- (10,11-Dihydro-5 H -dibenzo [ a , d ] cyclohepten-5-ylidene) - N , N -dimethylpropylamine
Molecular formula	C 20 H 23 N C 20 H 23 N · HCl (hydrochloride)
External identifiers / databases
CAS number 50-48-6 549-18-8 ( hydrochloride ) EC number 200-041-6 ECHA InfoCard 100,000,038 PubChem 2160 ChemSpider 2075 DrugBank DB00321 Wikidata Q58397
Drug information
ATC code	N06 AA09
Drug class	antidepressant
Mechanism of action	Non-selective monoamine - reuptake inhibitors Co-analgesic Sodium channel blockers
properties
Molar mass	277.40 g mol −1 313.87 g mol −1 (hydrochloride)
Melting point	198–200 ° C (amitriptyline hydrochloride)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Hydrochloride danger H and P phrases H: 301-319-410 P: 273-301 + 310-305 + 351 + 338-501
Toxicological data	320 mg kg −1 ( LD 50 ,  rat ,  oral ) 140 mg kg −1 ( LD 50 ,  mouse ,  oral ) 16 mg kg −1 ( LD 50 ,  mouse ,  iv ) 240 mg kg −1 ( LD 50 ,  rat ,  oral , hydrochloride) 14 mg kg −1 ( LD 50 ,  rat ,  iv , hydrochloride) 140 mg kg −1 ( LD 50 ,  mouse ,  oral , hydrochloride) 21 mg kg −1 ( LD 50 ,  mouse ,  iv , hydrochloride)
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Amitriptyline is a drug from the group of tricyclic antidepressants that is primarily used to treat depression and long-term pain management. In a 2001 overview study, it was referred to as the “ gold standard antidepressant”.

history

Amitriptyline was first synthesized in 1960 and launched on the market in 1962 by the drug manufacturer Lundbeck. For many years - until the advent of serotonin reuptake inhibitors - it was the most prescribed antidepressant in the world. In 2011, amitriptyline was still the 4th most prescribed psychotropic drug in Germany.

Clinical information

Application areas (indications)

Amitriptyline preparations are approved for the treatment of depression. They are used against all forms of depressive illnesses, preferably against those that are predominantly associated with fear and feelings of restlessness. Another approved field of application of the drug that reduces pain perception is long-term pain treatment as part of an overall therapeutic concept.

Due to its migraine prophylactic effect, amitriptyline is the first or second choice in the prophylaxis of migraines . Amitriptyline is also the best-studied drug for the preventive treatment of tension headaches . In contrast, hardly any data are available for a possible application for long-term treatment of trigeminal neuralgia .

Outside of the approved areas of application, amitriptyline, which also has a sedating effect, is often used as a hypnotic for sleep disorders . However, its effectiveness is considered little proven. Like other tricyclic antidepressants, it is also effective for treating irritable bowel syndrome and fibromyalgia . In addition, amitriptyline appears to be suitable for the treatment of post-traumatic stress disorder ( PTSD ). However, these areas of application outside of the drug approval represent what is known as off-label use .

Contraindications (contraindications)

In addition to a known hypersensitivity to the active ingredient, use in the immediate recovery phase after a heart attack , conduction disorders in the bundle of His , acute urinary retention, pyloric stenosis , intestinal obstruction , untreated narrow-angle glaucoma as well as acute alcohol, barbiturate and opiate poisoning are absolute contraindications .

Due to the risk of potentially life-threatening serotonin syndrome , amitriptyline must not be used concomitantly with MAOIs . A safety interval must be observed when changing therapy. Because of the risk of undesirable cardiac effects such as arrhythmias and conduction disorders , the simultaneous use of amitriptyline with drugs that prolong the QT time , such as cisapride , is contraindicated.

Other damage to the cardiovascular system, hyperthyroidism , impaired liver function, epilepsy , untreated narrow-angle glaucoma , urinary behavior , prostate hyperplasia and paranoid or predelirant conditions, as well as use in patients under 18 years of age, are considered to be relative restrictions on use. In these cases, amitriptyline should only be used with caution and after a risk-benefit assessment.

Use during pregnancy and breastfeeding

There is insufficient experience with the use of amitriptyline during pregnancy. Animal experiments suggest that the fetus may be harmed. Amitriptyline should only be used during pregnancy if absolutely necessary.

Effects on ability to drive and use machines

Amitriptyline has a sedating effect and can therefore have a pronounced influence on the ability to drive and use machines. This applies in particular at the start of treatment, when changing preparations and in conjunction with other centrally acting drugs (pain relievers, sleeping pills, psychotropic drugs) and when taking alcohol at the same time. Therefore, driving vehicles, operating machines or other dangerous activities should be avoided, especially during the first days of treatment. The decision is to be made in each individual case by the attending physician, taking into account the individual dosage and the respective reaction.

Interactions

The combination of MAO inhibitors (e.g. tranylcypromine ) with amitriptyline can lead to the life-threatening serotonin syndrome. Due to its potential to cause cardiac arrhythmias with QT time prolongation, torsade de pointes and sinus tachycardia , which can be observed especially at high doses , there is an increased risk of with the simultaneous use of amitriptyline and drugs with an effect on the QT time Cardiac arrhythmias. This danger also exists with the simultaneous use of drugs that lead to hypokalaemia or drugs that inhibit the metabolism of amitriptyline via the cytochrome P450 enzyme complex CYP3A4 in the liver. On the other hand, drugs that, such as carbamazepine and phenytoin , induce this enzyme system can accelerate the amitriptyline breakdown and lead to an inadequate amitriptyline effect.

Due to its inhibitory effect on acetylcholine and histamine receptors , the effects and side effects of anticholinergics and antihistamines can be increased when taken with amitriptyline. Amitriptyline also intensifies the effects of direct sympathomimetics . The effect of antihypertensive drugs such as guanethidine , on the other hand, is weakened.

Side effects

The most common side effects (> 10%) with the use of amitriptyline include central nervous disorders such as headache , vertigo , tremor and drowsiness, disorders of the cardiovascular system such as palpitation , tachycardia and orthostatic hypotension , gastrointestinal disorders such as dry mouth, constipation and nausea as well Weight gain, accommodation disorders and sweating. As with other tricyclic antidepressants, the undesirable anticholinergic drug effects are in the foreground.

Other side effects caused by the central nervous system include paresthesia , ataxia , fatigue (1–10%) and occasionally (0.1–1%) convulsions . The most common mental disorders (1-10%) followed confusion, difficulty concentrating and libido reduction, (0.1-1%) of hypomania , mania , anxiety, paradoxical insomnia and nightmares, as well as rare (<0.1%) loss of appetite, delirium at elderly patients and hallucinations in schizophrenic patients. Frequently (1–10%) ECG changes such as QTc time prolongation , AV block and impulse conduction disorders can be observed in the heart, but these are only rarely (<0.1%) expressed as arrhythmias . Occasionally, hypotension can be observed. An existing heart failure can be aggravated by amitriptyline. The New Zealand drug safety authority Medsafe reports on the risk of peripheral cold sensations in the hands and / or feet or the occurrence of Raynaud's syndrome .

Furthermore, changes in taste, diarrhea, nausea and vomiting , urinary behavior and impotence can occur.

pharmacology

Pharmacodynamics

Amitriptyline acts in the central nervous system as a relatively unselective inhibitor of monoamine reuptake from the synaptic cleft into the presynapse. In this way, the concentration of neurotransmitters (especially serotonin and noradrenaline ) in the synaptic gap increases . It is now assumed that the reduction in depressive symptoms can be explained by a modified sensitivity of the receptors to monoamines. The increase in sensitivity is based on a down-regulation of certain monoaminergic receptors due to the changed concentration ratios. This is also the reason for the fact that the mood-enhancing effect usually only occurs after a certain period of ingestion (about two to three weeks).

In addition, amitriptyline has effects on other transmission processes in the brain , for example it has an anticholinergic effect ( e.g. as an antagonist of certain acetylcholine effects) and slightly antihistaminic . This results in an overall psychomotor dampening effect; there are also characteristic side effects. The active sedative component usually diminishes over the course of the application. Amitriptyline also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

The pharmacological effectiveness of amitriptyline, tricyclic antidepressants and all sodium channel-blocking anti- epileptic drugs in neuropathic pain ( shingles ) is based on the reversible competitive blockade of voltage-dependent sodium channels , which cause pain genesis through autonomous spontaneous activity, whereby the pharmacological principle of " use-dependence " is not used physiological action potentials explained, since only the very quickly opening pathophysiological and pain-producing sodium channels are blocked.

The molecular mechanism of action can be explained by the principle of the ion trap ( local anesthetic ), according to which extracellular amitriptyline (pH = 7.4 (physiological)) occurs in equilibrium between unprotonated form and protonated form, but only the unprotonated form (free amine) has sufficient lipophilicity which is necessary to penetrate the double-layer lipid membrane of the cell intracellularly and to then accumulate in the cell by protonation. The protonated, positively charged and intracellular form of amitriptyline reaches the voltage-dependent sodium channels ( dendritic , somatic and axonal ) by diffusion, surrounded by a hydration shell , which are reversibly blocked by amitriptyline.

The sodium channel blocking or local anesthetic properties of amitriptyline can also be tested experimentally by breaking a tablet containing amitriptyline and placing it on the tongue , whereby a local anesthetic can be perceived.

Pharmacokinetics

The half-life in the body is 8–51 hours; the half-life of the amitriptyline metabolites is 30 hours. The metabolite nortriptyline is also active and is itself marketed as a medicinal product.

Absorption

After oral administration, amitriptyline is slowly but completely absorbed. Due to the frequently delayed gastrointestinal passage, maximum plasma concentrations are only reached after 1 to 5 (max. 8) hours. The systemic bioavailability is about 50% in relation to intravenous injection.

distribution

Due to its great lipophilicity, amitriptyline is distributed throughout the body. The volume of distribution is 14 to 18 l / kg. Amitriptyline is strongly bound to tissue and plasma proteins; only 3–6% are free in the plasma (8–13% of the active metabolite nortriptyline). Both amitriptyline and nortriptyline are excreted in breast milk.

Biotransformation

Amitriptyline is mainly metabolised in the liver. At therapeutic concentrations, amitriptyline is primarily metabolized by demethylation (CYP2C19) and hydroxylation (CYP2D6) , followed by conjugation with glucuronic acid. The main metabolite nortriptyline produced by N-demethylation is also pharmacologically active. Amitriptyline and nortriptyline are then hydroxylated; the resulting 10-hydroxy metabolites still have about half the biological activity of amitriptyline. About 5 - 14% of the Caucasian population are “poor metabolizers” due to genetic differences in the cytochrome P450 system CYP2D6. Therefore, very high plasma levels can occur in these patients. Obviously due to reduced biotransformation, higher plasma concentrations occur in older patients.

elimination

The metabolites are excreted in free or conjugated form. Unchanged amitriptyline was only found in small amounts in the urine. The plasma half-life of amitriptyline is approximately 10 to 28 hours after oral administration; the half-life is longer in the elderly. The plasma clearance is given as 0.17–0.32 l / kg / h and for older subjects as 0.18–0.45 l / kg / h.

Pathophysiological Variations

In patients with renal insufficiency, the concentration of unconjugated metabolites in the plasma is reduced compared to patients with healthy kidneys, whereas the concentration of conjugated metabolites is greatly increased.

toxicology

In vitro, amitriptyline blocks expressed HERG channels in micromolar concentrations that are in the upper range of therapeutic plasma concentrations. These channels are responsible for repolarization in the heart. Therefore, amitriptyline has the potential to certain forms of chamber arrhythmia ( torsades de pointes trigger).

The genotoxic potential of amitriptyline hydrochloride was investigated in various in vitro and in vivo test systems. Although the results are partly contradicting, a genotoxic potential, especially with regard to possible damage to chromosomes, cannot be ruled out. Long-term studies on a tumorigenic potential have not been carried out.

In studies of reproductive toxicity, foetotoxic and teratogenic effects were observed in various animal species after very high doses . There are indications of behavioral disorders in the prenatally exposed offspring of other antidepressants in animal experiments. No corresponding information is known for amitriptyline.

Trade names

Monopreparations

Saroten (D, A, CH), Amineurin (D), Syneudon (D), Tryptizol (D), numerous generics (D)

Other trade names: Elavil (worldwide), Laroxyl (worldwide), Endep (AUS, CDN, NZ, ZA)

Combination preparations

Limbatril (D), Limbitrol (CH): Amitriptyline + Chlordiazepoxid (One of the most popular psychotropic drugs in the 1970s and 1980s)

It is taken orally as a tablet , dragee or solution , but can also be used as an injection solution i. m. or I. v. be applied .

Individual evidence

1. ↑ ^{a b c} data sheet amitriptyline hydrochloride from Sigma-Aldrich , accessed on June 18, 2019 ( PDF ).
2. ↑ ^{a b c d e f g} A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications. 4th edition. Thieme-Verlag, Stuttgart 2000, ISBN 1-58890-031-2 .
3. ↑ C. Barbui, M. Hotopf: Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomized controlled trials . In: The British Journal of Psychiatry: The Journal of Mental Science . tape 178 , February 2001, p. 129-144 , PMID 11157426 .
4. ↑ U. Schwabe, D. Paffrath (ed.): Drug Ordinance Report 2012. Berlin-Heidelberg: Springer-Verlag, 2012. ( limited preview in Google book search)
5. ↑ ^{a b c d e f g h i j k} Specialist information from the Swiss Medicines Compendium: Saroten retard; Status: September 2006.
6. ↑ SD Silberstein: Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology . In: Neurology . tape 55 , no. 6 , September 2000, p. 754-762 , PMID 10993991 .
7. ↑ S. Evers, A. May, G. Fritsche, P. Kropp, C. Lampl, V. Limmroth, V. Malzacher, S. Sandor, A. Straube, HC Diener: Acute Therapy and Prophylaxis of Migraine - Guideline of the German Migraine - and headache society and the German Society for Neurology . In: Neurology . tape 27 , no. 10 , 2008, p. 933-949 ( dmkg.de [PDF]).
8. ↑ ME Bigal, AM Rapoport, R. Hargreaves: Advances in the pharmacologic treatment of tension-type headache . In: Curr Pain Headache Rep . tape 12 , no. 6 , December 2008, pp. 442-446 , PMID 18973738 .
9. ↑ L. He, B. Wu, M. Zhou: Non-antiepileptic drugs for trigeminal neuralgia . In: Cochrane Database Syst Rev . tape 3 , 2006, p. CD004029 , doi : 10.1002 / 14651858.CD004029.pub2 , PMID 16856027 .
10. ^ PM Becker: Pharmacologic and nonpharmacologic treatments of insomnia . In: Neurol Clin . tape 23 , no. 4 , November 2005, pp. 1149–1163 , doi : 10.1016 / j.ncl.2005.05.002 , PMID 16243620 .
11. ^ AC Ford, NJ Talley, PS Schoenfeld, EM Quigley, P. Moayyedi: Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis . In: Good . tape 58 , no. 3 , March 2009, p. 367–378 , doi : 10.1136 / gut.2008.163162 , PMID 19001059 .
12. ↑ N. Uçeyler, W. Hauser, C. Sommer: A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome . In: Arthritis Rheum . tape 59 , no. 9 , September 2008, p. 1279–1298 , doi : 10.1002 / art.24000 , PMID 18759260 .
13. ^ National Institute for Clinical Excellence: Post traumatic stress disorder: the management of PTSD in primary and secondary care. 2005. PMID 21834189
14. ^ Early Warning System - Monitoring Communication Archive. In: medsafe.govt.nz. Medsafe, accessed June 23, 2016 . 
15. ↑ J. Kornhuber, M. Muehlbacher, S. Trapp, S. Pechmann, A. Friedl, M. Reichel, C. Mühle, L. Terfloth, T. Groemer, G. Spitzer, K. Liedl, E. Gulbins, P Tripal: Identification of Novel Functional Inhibitors of Acid Sphingomyelinase . In: PLoS ONE . tape 6 , no. 8 , 2011, p. e23852 , doi : 10.1371 / journal.pone.0023852 .
16. ↑ ^{a b c d e f} fachinfo.de Saroten , accessed on June 18, 2019.

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