Amitriptyline transporters

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

FIGURE 2.6 Serotonergic synapse. Serotonin binds to at least seven different receptors. The most relevant are the 5-HTi receptors (1), 5-HT2 receptors (2), and 5-HT3 receptors (3). Antagonists of the 5-HT2 receptor include nefazodone and the majority of atypical antipsychotic drugs. The serotonin transporter (4) pumps serotonin back into the serotonergic neuron, which can be blocked by drugs such as venlafaxine, clomipramine, imipramine, and amitriptyline. 

Coppen A, Ghose K, Montgomery S, et al Continuation therapy with amitriptyline in depression. Br J Psychiatry 133 28-33, 1978 Coppen A, Swade C, Wood K Lithium restores abnormal platelet 5-HT transport in patients with affective disorders. Br J Psychiatry 136 235-238, 1980 Coppen A, Swade C, Jones SA, et al Depression and tetrahydrobiopterin the folate connection. J Affect Disord 16 103-107, 1989 Cordell B 3-Amyloid formation as a potential therapeutic target for Alzheimer s disease. Annu Rev Pharmacol Toxicol 34 69-89, 1994 Corkin S Acetylcholine, aging, and Alzheimer s disease imphcations of treatment. Trends Neurosci 4 287-290, 1981... 

Some naturally occurring neurotransmitters may be similar to drugs we use. For example, it is well known that the brain makes its own morphine (i.e., beta endorphin), and its own marijuana (i.e., anandamide). The brain may even make its own antidepressants, it own anxiolytics, and its own hallucinogens. Drugs often mimic the brain s natural neurotransmitters. Often, drugs are discovered prior to the natural neurotransmitter. Thus, we knew about morphine before the discovery of beta-endorphin marijuana before the discovery of cannabinoid receptors and anandamide the benzodiazepines diazepam (Valium) and alprazolam (Xanax) before the discovery of benzodiazepine receptors and the antidepressants amitriptyline (Elavil) and fluoxetine (Prozac) before the discovery of the serotonin transporter site. This un-... 

Treatment with antidepressants will affect a person s ability to drive or operate machinery. Among the tricyclic antidepressants, amitriptyline and doxepin impair skills compared with imipramine and nortriptyline. Fluoxetine and dothiepin also show similar effects, such as affecting ability to work. The United Kingdom s Medical Commission on Accident Prevention has recommended that patients on long-term psychotropic medication are unsuitable drivers of heavy vehicles or public transport services.132,133... 

St John s wort can cause drug interactions by inducing hepatic microsomal drug-metabolizing enzymes or the drug transporter P-glycoprotein, which causes a net efflux of substrates, such as amitriptyline, from intestinal epithelial cells into the gut lumen (SEDA-24,12). In 12 patients (9 women, 3 men) the addition of St John s wort 900 mg/ day to amitriptyline 150 mg/day led to a 20% reduction in plasma amitriptyline concentrations, while nortriptyline concentrations were almost halved (210). 

St John s wort 1. TCAs (e.g. amitrypty-line, nortryptiline, clomipramine) 2. SSRIs (e.g. fluvoxamine, fluoxetine) 3. Venlafaxine Low blood amitriptyline levels (<20%). May potentially 1 therapeutic effects. Nortriptyline levels may be i by 50%. St John s wort t sedative effects (weakness, lethargy, fatigue, slow movements, incoherence) of SSRIs Due to induction of metabolizing CYP3A4 enzyme and P-gp transport proteins St John s wort inhibits uptake of serotonin and thereby t serotonin levels Avoid concomitant use... 

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, amitriptyline can increase dopamine neurotransmission in this part of the brain... 

Nortriptyline Hydrochloride, USP. Pertinent biological and chemical properties for nortriptyline. 3-(IO.II-di-hydro-5//-dibenzu(a.d cyclohepten-S-ylidcne)fV-mcthyl-1 -propanamine hydrochloride. 5-(3-methyl-aminoprupyli-denc)-IO.t l-hydro-S//-dibcnzo a.Metabolic inactivation and elimination are like tho.se of amitriptyline. Nortriptyline is a selective NE transporter (NET) inhibitor. ... 

Figure 18.5 Thefreeenergyofdmgbindingfrom the transporter (AC[j(l)) (hatched bar), water to the activating binding region of P-gp Amitriptyline (1), chlorpromazine (2), cis-...

SLC6A4 (SERT) SERT plays a role in the reuptake and clearance of serotonin in the brain. Like the other SLC6A family members, SERT transports its substrates in a Na+-dependent fashion and is dependent on CL and possibly on the countertransport of K+. Substrates of SERT include serotonin (5-HT), various tryptamine derivatives, and neurotoxins such as 3,4-methylene-dioxymethamphetamine (MDMA ecstasy) and fenfluramine. SERT is the specific target of the selective serotonin reuptake inhibitors (e.g., fluoxetine and paroxetine) and one of several targets of tricyclic antidepressants e.g., amitriptyline). Genetic variants of SERT have been associated with an array of behavioral and neurological disorders. The precise mechanism by which a reduced activity of SERT, caused by either a genetic variant or an antidepressant, ultimately affects mood and behavior is not known. 

Their in vitro potenoy for selectively inhibiting the 5-HT transporter more or less mirrors their clinical efficacy as SSRIs (11) paroxetine> sertraline> clomipramine> fluoxetine> citralopram> fluvoxamine> imipramine> amitriptyline> roboxetine> venlafaxine = milnacipran> desipramine. Clinically, however, all the SSRIs are equally effective over time, suggesting that these variations in potency do not affect efficacy or adverse effects. The SSRIs have less affinity for ai, 02, Hi, and musoarinic receptors, which may explain the adverse-effect profile differences between TCAs and SSRIs. 

Amitriptyline is rapidly absorbed from the Gl tract and from parenteral sites. Its pharmacokinetics are shown in Table 21.9. Amitriptyline and its active metabolite, nortriptyline, are distributed into breast milk. Amitriptyline is primarily (65%) metabolized by N-demethylation by CYP2D6 to nortriptyline and hydroxylation to its -10-hydroxy metabolite. Nortriptyline is pharmacologically active as a secondary amine TCA. Amitriptyline shows approximately equal affinity for 5-HT and NE transporters. 

Because doxepin is administered as an 85 15 mixture of geometric isomers, its mechanism of action and antidepressant properties refiects this ratio. Therefore, dioxepin s seiectivity for inhibiting presynaptic NE reuptake is most iikeiy caused by the 85% presence of the E-isomer in the geometric mixture. Its antidepressant activity is similar to amitriptyline. Data suggest NE reuptake inhibitory potency comparable to imipramine and clomipramine the fact that doxepin is an 85 15 mixture of - and Z-geometric isomers clouds its true efficacy for SERT or NET. The formation of N-desmethyIdoxepin results in inhibition of NE reuptake with enhanced noradrenergic activity. As a result of these mixed effects on the 5-HT and NE transporters, doxepin shares the pharmacological and adverse-effect profile of the other TCAs. 

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