Amitriptyline hydrochloride

Description

Amitriptyline (hydrochloride) (CRM) (Item No. 19031) is a certified reference material categorized as a tricyclic antidepressant. This product is intended for analytical forensic applications. This product is also available as a general research tool .

Chemical properties

White to Off-White Solid

Originator

Elavil HCl Merck Sharp and,Dohme,US,1961

The Uses of Amitriptyline hydrochloride

Amitriptyline hydrochloride is a tricyclic antidepressant drug. Amitriptyline hydrochloride inhibits the norepinephrine and serotonin transporters but has a high affinity for α1-adrenergic, serotonin and muscarinic acetylcholine receptors.

The Uses of Amitriptyline hydrochloride

vasoconstrictor

The Uses of Amitriptyline hydrochloride

Amitriptyline hydrochloride has been used:

• as an antidepressant to study its effects on social behavior and memory in transgenic for acid sphingomyelinase (t-ASM) mice
• as a tricyclic antidepressant to analyze its effects on glucocorticoid receptor function in whole human blood
• as an anti-depressant to study its effects on scratching and locomotion behavior in chloroquine-induced mouse

What are the applications of Application

Amitriptyline Hydrochloride is an antidepressant with anticholinergic and sedative properties

Definition

ChEBI: Amitriptyline hydrochloride is an organic tricyclic compound.

Manufacturing Process

Phthalic anhydride is reacted with phenylacetic acid to form 3- benzylidenephthalide which is then hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone, 5H-dibenzo[a,d]cyclohepten-5-one. The ketone undergoes a Grignard reaction with 3-(dimethylamino)propyl chloride to give 5-(γ- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene.
Then, as described in US Patent 3,205,264, a solution of 5-(γ- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene (42 grams; 0.153 mol) in 105 ml of ethanol is hydrogenated over Raney nickel (1.5 grams) at 65°C under an initial hydrogen pressure of 450 lb. After 1 mol of hydrogen is absorbed (3.5 hours), the reaction mixture is filtered to remove the catalyst and is acidified with 80 ml of 2.5 N hydrochloric acid (0.2 mol). The acidic solution is concentrated to dryness under vacuum and is flushed three times with 100 ml of benzene to remove residual water. The solid residue then is dried under vacuum at 40°C to yield 44.9 grams (94% of theory) of the product, MP 187-189.5°C, equivalent weight 307, ultraviolet absorption A% 2380432. Recrystallization from isopropyl alcohol and ether affords the product in high purity.
In practice it is usually used as hydrochloride.

brand name

Elavil (AstraZeneca); Endep (Roche).

Therapeutic Function

Antidepressant

General Description

Amitriptyline, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride,5-(3-dimethylaminopropylidene)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene hydrochloride (Elavil), is one ofthe most anticholinergic and sedative of the TCAs. Becauseit lacks the ring-electron–enriching nitrogen atom ofimipramine, metabolic inactivation mainly proceeds not at theanalogous 2-position but at the benzylic 10-position (i.e.,toluene-like metabolism predominates). Because of the 5-exocyclic double bond, E- and Z-hydroxy isomers are producedby oxidation metabolism. Conjugation produces excretablemetabolites. As is typical of the dimethyl compounds,N-demethylation occurs, and nortriptyline is produced, whichhas a less anticholinergic, less sedative, and more stimulantaction than amitriptyline. Nortriptyline is a SNERI; thecomposite action of drug and metabolite is nonselective.

Biochem/physiol Actions

Tricyclic antidepressant; inhibits the norepinephrine and serotonin transporters with Kis of 100 nM and 14.7 nM, respectively; high in vitro affinity for α1-adrenoceptors, serotonin and muscarinic acetylcholine receptors.

Clinical Use

Tricyclic antidepressant:
Depression, used especially where sedation is required
Neuropathic pain (unlicensed)
Migraine prophylaxis (unlicensed)

Safety Profile

Poison by ingestion, intraperitoneal, intravenous, and subcutaneous routes. Human systemic effects by ingestion: convulsions, respiratory depression, changes in sleep, hallucinations, muscle contractions, somnolence, blood pressure decrease, coma, cyanosis, dyspnea, and ataxia. An experimental teratogen. Other experimental reproductive effects. Mutation data reported. Used in the treatment of depression. When heated to decomposition it emits very toxic fumes of HCl and NOx. See also ELAVIL.

Veterinary Drugs and Treatments

Amitriptyline has been used for behavioral conditions such as separation anxiety or generalized anxiety in dogs, and excessive grooming, spraying and anxiety in cats. Amitriptyline may be useful for adjunctive treatment of pruritus, or chronic pain of neuropathic origin in dogs and cats. In cats, it potentially could be useful for adjunctive treatment of lower urinary tract disease. Amitriptyline has been tried to reduce feather plucking in birds.

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: increased sedative effect.
Analgesics: increased risk of CNS toxicity with tramadol; possibly increased risk of side effects with nefopam; possibly increased sedative effects with opioids.
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone - avoid; increased risk of ventricular arrhythmias with disopyramide, flecainide or propafenone; avoid with dronedarone.
Antibacterials: increased risk of ventricular arrhythmias with moxifloxacin and delamanid - avoid with moxifloxacin.
Anticoagulants: may alter anticoagulant effect of coumarins.
Antidepressants: possibly increased serotonergic effects with duloxetine; enhanced CNS excitation and hypertension with MAOIs and moclobemide; concentration possibly increased with SSRIs; risk of ventricular arrhythmias with citalopram and escitalopram - avoid; possible increased risk of convulsions with vortioxetine; concentration reduced by St John’s wort.
Antiepileptics: convulsive threshold lowered; concentration reduced by carbamazepine, phenobarbital and possibly fosphenytoin, phenytoin and primidone.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: increased risk of ventricular arrhythmias especially with droperidol, fluphenazine, haloperidol, pimozide, sulpiride and zuclopenthixol - avoid; increased antimuscarinic effects with clozapine and phenothiazines; concentration increased by antipsychotics.
Antivirals: increased risk of ventricular arrhythmias with saquinavir - avoid; concentration possibly increased with ritonavir.
Atomoxetine: increased risk of ventricular arrhythmias and possibly convulsions.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Clonidine: tricyclics antagonise hypotensive effect; increased risk of hypertension on clonidine withdrawal.
Cytotoxics: increased risk of ventricular arrhythmias with arsenic trioxide.
Dapoxetine: possibly increased risk of serotonergic effects - avoid. Dopaminergics: avoid with entacapone; CNS toxicity reported with selegiline and rasagiline.
Pentamidine: increased risk of ventricular arrhythmias.
Sympathomimetics: increased risk of hypertension and arrhythmias with adrenaline and noradrenaline; metabolism possibly inhibited by methylphenidate.

Metabolism

Amitriptyline undergoes extensive first-pass metabolism and is demethylated in the liver by the cytochrome P450 isoenzymes CYP3A4, CYP2C9, and CYP2D6 to its primary active metabolite, nortriptyline. Other paths of metabolism of amitriptyline include hydroxylation (possibly to active metabolites) by CYP2D6 and N-oxidation; nortriptyline follows similar paths. Amitriptyline is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form.

storage

Room temperature (desiccate)