Source: Health Products and Food Branch (CA) Revision Year: 2018
Amitriptyline hydrochloride is a tricyclic antidepressant with sedative properties. Its mechanism of action in man is not known. Amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain. Amitriptyline has pronounced anticholinergic properties and produces EKG changes and quinidine-like effects on the heart (See ADVERSE REACTIONS). It also lowers the convulsive threshold and causes alterations in EEG and sleep patterns.
Orally administered amitriptyline is readily absorbed and rapidly metabolized. Steady-state plasma concentrations vary widely and this variation may be genetically determined. Amitriptyline is primarily excreted in the urine, mostly in the form of metabolites, with some excretion also occurring in the feces.
Amitriptyline has qualitatively similar pharmacologic actions to other tricyclic antidepressants in experimental animals. It is more sedative than imipramine, reducing spontaneous motor activity at lower doses. It also prolongs hexobarbital sleeping time, produces ataxia and has a disruptive effect on EEG activity and conditioned behaviour. Amitriptyline antagonizes or reverses the depressant effects of reserpine and tetrabenazine and potentiates the pressor effects of norepinephrine and various behavioural effects of amphetamine. It possesses anticholinergic, antihistaminic and weak antiserotonin action. Amitriptyline also decreases body temperature, lowers blood pressure in the anesthetized dog and has a quinidine-like effect on the heart.
Amitriptyline is absorbed slowly from the gastrointestinal tract in experimental animals. The drug is distributed in liver, lung, and brain tissue. Amitriptyline is detoxified in the liver where it undergoes N-demethylation to nortriptyline, which is further demethylated. Amitriptyline is excreted in the urine and bile as conjugates of the cis and trans isomers of 10- hydroxynortriptyline.
| SPECIES | ROUTE | SEX | LD50 (mg of base/kg) | 95% FUDUCIAL LIMITS |
|---|---|---|---|---|
| Mice | PO | F | 289 | (249-335) |
| IP | F | 76 | (71-81) | |
| SO | F | 328 | (279-386) | |
| Rats | PO | F | 464 | (370-583) |
| PO | M | 600 | (403-872) | |
| IP | F | 67 | (59-76) | |
| IP | M | 77 | (67-88) | |
| SC | F | 1350 | (1130-1162) | |
| SC | M | 1235 | (1010-1510) |
Signs of toxicity included sedation, ataxia, ptosis, lacrimation, decreased respiratory rate, partial loss of righting reflex and convulsions.
Dogs: Oral doses of 20 and 40 mg/kg/day were tolerated for 6 months without hematologic, biochemical or anatomical evidence of drug toxicity. Signs of drug effect included slight to marked sedation, a slight tachycardia, slight ataxia, and occasionally, excessive salivation and emesis. Oral doses of 80 mg/kg/day in a 6 month study were not well tolerated: 2 of 4 dogs died within 3 weeks after exhibiting severe ataxia and sedation. No other drug-related effects were observed. Doses of 100 mg/kg/day or greater were not tolerated for more than a few days. The only effect observed was a small amount of fat in the periportal region of the liver without evidence of necrosis.
Rats: 0, 15, 30 or 60 mg/kg/day were given orally by gavage, 5 days a week, for periods up to 48 weeks. Doses of 60 mg/kg/day produced a moderate depression of body weight and a slight increase in liver weight.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
