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Additional information about the drug Amitriptyline


Amitriptyline, sold under the brand name Elavil among others, is a medicine primarily used to treat a number of mental illnesses.
Common side effects include a dry mouth, trouble seeing, low blood pressure on standing, sleepiness, and constipation.
Amitriptyline was discovered in 1960
Contents
1 Medical uses
2 Contraindications
3 Side effects
4 Overdose
5 Interactions
6 Pharmacology
6.1 Pharmacodynamics
6.2 Pharmacokinetics
6.3 Pharmacogenetics
7 Chemistry
8 History
9 Society and culture
9.1 Generic names
9.2 Brand names
10 Research
11 References
Medical uses
Amitriptyline is used for a number of medical conditions including major depressive disorder (MDD).
It is TGA-labeled in Australia for migraine prevention, also in cases of neuropathic pain disorders,
Contraindications
The known contraindications of amitriptyline are:
Hypersensitivity to TCAs or to any of its excipients
History of myocardial infarction
History of arrhythmias, particularly heart block to any degree
Congestive heart failure
Coronary artery insufficiency
Mania
Severe liver disease
Being under 7 years of age
Breast feeding
Patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days.
Side effects
Common (≥1% frequency) side effects include dizziness, headache, weight gain, side effects common to anticholinergics, but more such effects than other TCAs, cognitive effects such as delirium and confusion, mood disturbances such as anxiety and agitation, cardiovascular side effects such as orthostatic hypotension, sinus tachycardia, and QT-interval prolongation,
Overdose
Main article: Tricyclic antidepressant 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,
The possible symptoms of amitriptyline overdose include:
Drowsiness
Hypothermia (low body temperature)
Tachycardia (high heart rate)
Other arrhythmic abnormalities, such as bundle branch block
ECG evidence of impaired conduction
Congestive heart failure
Dilated pupils
Convulsions (e.g. seizures, myoclonus )
Severe hypotension (very low blood pressure)
Stupor
Coma
Death
Polyradiculoneuropathy
Changes in the electrocardiogram, particularly QT-interval prolongation and change in QRS axis or width
Agitation
Hyperactive reflexes
Muscle rigidity
Vomiting
The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available.
Interactions
Amitriptyline is known to interact with:
Monoamine oxidase inhibitors as it can potentially induce a serotonin syndrome
CYP2D6 inhibitors and substrates such as fluoxetine due to the potential for an increase in plasma concentrations of the drug to be seen
Guanethidine as it can reduce the antihypertensive effects of this drug
Anticholinergic agents such as benztropine, hyoscine (scopolamine) and atropine, because the two might exacerbate each other’s anticholinergic effects, including paralytic ileus and tachycardia
Antipsychotics due to the potential for them to exacerbate the sedative, anticholinergic, epileptogenic and pyrexic (fever-promoting) effects. Also increases the risk of neuroleptic malignant syndrome
Cimetidine due to the potential for it to interfere with hepatic metabolism of amitriptyline and hence increasing steady-state concentrations of the drug
Disulfiram due to the potential for the development of delirium
ECT may increase the risks associated with this treatment
Antithyroid medications may increase the risk of agranulocytosis
Thyroid hormones have a potential for increased adverse effects such as CNS stimulation and arrhythmias.
Analgesics, such as tramadol and pethidine due to the potential for an increase in seizure risk and serotonin syndrome.
Medications subject to gastric inactivation (e.g. levodopa) due to the potential for amitriptyline to delay gastric emptying and reduce intestinal motility
Medications subject to increased absorption given more time in the small intestine (e.g. anticoagulants)
Serotonergic agents such as the SSRIs and triptans due to the potential for serotonin syndrome.
Pharmacology
Pharmacodynamics
See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Amitriptyline (and metabolite)
Site
AMI
NTI
Species
Ref
SERT
2.8–4.3
15–18
Human
NET
19–35
1.8–4.4
Human
DAT
3,250
1,140
Human
5-HT 1A
450–1,800
294
Human
5-HT 1B
840
ND
Rat
5-HT 2A
18–23
5.0–41
Human/rat
5-HT 2B
174 13.4 (K B )
ND
Human
5-HT 2C
4.0
8.5
Human/rat
5-HT 3
430
1,400
Rat
5-HT 6
65–141
148
Human/rat
5-HT 7
92.8–123
ND
Rat
α 1
4.4–24
55
Human
α 2
114–690
2,030
Human
β
>10,000
>10,000
Rat
D 1
89
ND
Human
D 2
196–1,460
2,570
Human
D 3
206
ND
Human
D 4
ND
ND
ND
ND
D 5
170
ND
Human
H 1
0.5–1.1
3.0–15
Human
H 2
66
646
Human
H 3
75,900
45,700
Human
H 4
26,300
6,920
Human
mACh
9.6
37
Human
   M 1
11.0–14.7
40
Human
   M 2
11.8
110
Human
   M 3
12.8–39
50
Human
   M 4
7.2
84
Human
   M 5
15.7–24
97
Human
σ 1
300
2,000
Guinea pig
σ 2
ND
ND
ND
ND
hERG
>3,000
ND
Human
Values are K i (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.
Amitriptyline is classified as a tricyclic antidepressant (TCA), with strong actions on the serotonin transporter (SERT) and moderate effects on the norepinephrine transporter (NET).
Amitriptyline additionally acts as an antagonist or inverse agonist of the serotonin 5-HT 2A, 5-HT 2C, 5-HT 3, 5-HT 6, and 5-HT 7 receptors, the α 1 -adrenergic receptor, the histamine H 1 and H 2 receptors,
Amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.
Pharmacokinetics
Amitriptyline is a highly lipophilic molecule having a log D (octanol/water, pH 7.4) of 3.0,
Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolized on first pass through the liver.
Therapeutic levels of amitriptyline range from 75 to 175 ng/ml (270–631 nM).
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.
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,
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.
Chemistry
Amitriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure.
History
Amitriptyline was first synthesized in 1960 and was introduced for medical use in United States in 1961 and in the United Kingdom in 1962, in both countries under the brand name Elavil.
Society and culture
Two boxes of amitriptyline (Endep) in 10- and 25-mg doses
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.
Brand names
As of September 2018, amitriptyline was marketed under many brand names worldwide alone and as a combination drug with each of chlordiazepoxide, perphenazine, and medazepam.
Brands include Adepril, ADT, Ambival, Amicon, Amilavil, Amilin, Amiline, Amineurin, Amiplin, Amirol, Amit, Amitin, Amitone, Amitrac, Amitrip, Amitriptilina, Amitriptilino, Amitriptilins, Amitriptine, Amitriptylin, Amitriptyline, Amitriptylinhydrochlorid, Amitriptylini, Amitriptylinum, Amitryp, Amotrip, Amyline, Amypres, Amytril, Amyzol, Anapsique, Arpidox, Deprelio, Elatrol, Elatrolet, Elavil, Endep, Fiorda, Laroxyl, Latilin, Levate, Maxitrip, Maxivalet, Mitryp, Modup, Normaln, Odep, Pinsaun, Polytanol, Protanol, Qualitriptine, Redomex, Saroten, Sarotex, Stelminal, Syneudon, Teperin, Trepiline, Triamyl, Trilin, Trip, Tripta, Triptiline, Triptizol, Triptric, Triptyl, Triptyline, Tripyline, Trynol, Tryptalgin, Tryptanol, Tryptin, Tryptizol, and Tryptomer.
Brands as of that date for the combination with chlordiazepoxide included Amicon Forte, Amitrac-CZ, Amypres-C, Antalin, Antalin Forte, Arpidox-CP, Axeptyl, Diapatol, Diaztric-A, Emotrip, Klotriptyl, Libotryp, Limbitrol, Limbitryl, Limbival, Limbritol, Maxitrip-CZ, Mitryp Forte, Morelin, Ristryl, and Sedans.
Brands as of that date for the combination with perphenazine included Levazine, Minitran, Mutabase, Mutabon, Pertriptyl, and Triptafen.
Brands as of that date for the combination with medazepam included Nobritol.
Research
Amitriptyline has been studied in several disorders:
Eating disorders :
Insomnia : As of 2004, amitriptyline was the most commonly prescribed off-label prescription sleep aid in the United States.
Urinary incontinence. An accepted use for amitriptyline in Australia is the treatment of urinary urge incontinence.
Cyclic vomiting syndrome
Preventive treatment for patients with recurring biliary dyskinesia ( sphincter of Oddi dysfunction)
Attention deficit/hyperactivity disorder (in addition to, or sometimes in place of ADHD stimulant drugs)
Retching/dry heaving, especially after the anti-reflux procedure Nissen fundoplication

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