Amitriptyline (Elavil)
Elavil® , Endep® | Tryptanol™ | Vanatrip®
Classification:
Psychotropic Agents
- Antidepressants
- Tricyclic antidepressants
Description: Amitriptyline is an oral and parenteral tertiary amine tricyclic antidepressant. It is structurally related to the thioxanthene antipsychotics such as thiothixene. Amitriptyline is also related to the skeletal muscle relaxant cyclobenzaprine, although amitriptyline is not believed to possess muscle-relaxant properties. Amitriptyline is metabolized to nortriptyline, an active metabolite that is also marketed separately. Clinically, amitriptyline is used to treat depression, pain of neuropathic origin, attention-deficit hyperactivity disorder, functional enuresis in children, panic disorder, social anxiety disorder, and to manage some eating disorders. Amitriptyline was approved by the FDA in 1961. The brand name amitriptyline product Elavil® will be discontinued completely from manufacture; however, other brand and generic products remain available. As of May 2003, Elavil® injection is no longer available at AstraZeneca. The remaining inventory of Elavil® tablets will be depleted by December 31, 2003. AstraZeneca has no further plans to manufacture Elavil® tablets or injection. Information about the discontinuation is available by calling (800) - 236 - 9933 in the US. On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents in product labels. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006.
Mechanism of Action: The precise action of tricyclic antidepressants is not fully understood, but it is believed that the most important effect is the decreased reuptake of norepinephrine and serotonin. Amitriptyline appears to exert effects on both norepinephrine and serotonin (5-HT), although the selective-acting desipramine is a more potent inhibitor of norepinephrine transport. Amitriptyline is metabolized to nortriptyline, which accounts for most of the norepinephrine-reuptake inhibition after amitriptyline administration. Nortriptyline itself also possesses antidepressant activity. Additional hydroxy metabolites apparently are active as well. The down-regulation of limbic beta-receptors that results from this synaptic neurotransmitter increase occurs about 5 - 7 days after therapeutic concentrations are reached.
Monoamine oxidase is not inhibited by either amitriptyline or nortriptyline. Tricyclic antidepressants do not affect dopamine reuptake. Varying degrees of sedation can be produced, and the seizure threshold can be lowered. Amitriptyline possesses strong anticholinergic activity. Cardiac dysrhythmias can result from the direct quinidine-like effect on cardiac function combined with anticholinergic activity and norepinephrine potentiation. Changes in sex hormone concentrations and blood glucose can result from amitriptyline’s effect on the endocrine system.
Pharmacokinetics: Amitriptyline is well absorbed from the GI tract, but individual response can vary considerably. The full antidepressant effects can take several weeks to produce, although adverse effects can occur after the first dose. Peak plasma concentrations are obtained within 2 - 12 hours following oral or IM administration. Tricyclic antidepressants are highly protein-bound (predominantly to alpha1-acid glycoprotein) in plasma and tissues. Because tricyclic antidepressants are long-acting, a single daily dose may be given to improve patient compliance. Half-life values range from 10 - 50 hours for amitriptyline and 20 - 100 hours for nortriptyline.
Amitriptyline is metabolized in the liver to nortriptyline, which is lipophilic and crosses the blood-brain barrier. Amitriptyline and nortriptyline are distributed into the lungs, heart, brain, and liver. Nortriptyline is known to cross the placenta and is also distributed into breast milk. Both undergo enterohepatic circulation. Lipophilic metabolites, such as nortriptyline, are most likely to be reabsorbed and further metabolized. Between 25 - 50% of a single dose is excreted in urine as active metabolites within 24 hours. A small amount of excretion occurs in feces.
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[ Revised 10/11/2005 10:06:00 AM ]
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