Pharmacodynamics + Molecular targets of<unk>  <unk>  and main active metabolite nortriptyline (NTI) Site Species Ref 2.8–36 15–279 Human 19–102 1.8–21 Human 3,250 1,140 Human 5-HT1A 450–1,800 294 Human 5-HT1B 840 Rat 5-HT2A 18–23 41 Human 5-HT2B 174 Human 5-HT2C 4-8 8.5 Rat 5-HT3 430 1,400 Rat 5-HT6 65–141 148 Human/rat 5-HT7 92.8–123 Rat α1A 6.5–25 18–37 Human α1B 600–1700 850–1300 Human α1D 560 1500 Human α2 114–690 2,030 Human α2A 88 Human α2B >1000 Human α2C 120 Human β >10,000 >10,000 Rat D1 89 210 (rat) Human/rat D2 196–1,460 2,570 Human D3 206 Human D4 D5 170 Human H1 0.5–1.1 3.0–15 Human H2 66 646 Human H3 75,900;>1000 45,700 Human H4 34–26,300 6,920 Human M1 11.0–14.7 40 Human M2 11.8 110 Human M3 12.8–39 50 Human M4 7.2 84 Human M5 15.7–24 97 Human σ1 287-300 2,000 Guinea pig/rat 3,260 31,600 Human PARP1 1650 Human TrkA 3,000(agonist) Human TrkB 14,000(agonist) Human Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.<unk>  inhibits serotonin transporter (SERT) and norepinephrine transporter (NET). It is metabolized to nortriptyline, a stronger norepinephrine reuptake inhibitor, further augmenting<unk> 's effects on norepinephrine reuptake (see the Table on the right).<unk>  additionally acts as a potent inhibitor of the serotonin 5-HT2A, 5-HT2C, the α1A-adrenergic, the histamine H1 and the M1-M5 muscarinic acetylcholine receptors (see the Table on the right).<unk>  is a non-selective blocker of multiple ion channels, in particular, voltage-gated sodium channels Nav1.3, Nav1.5, Nav1.6, Nav1.7, and Nav1.8, voltage-gated potassium channels Kv7.2/ Kv7.3, Kv7.1, Kv7.1/KCNE1, and hERG. Mechanism of action Inhibition of serotonin and norepinephrine transporters by<unk>  results in interference with neuronal reuptake of serotonin and norepinephrine. Since the reuptake process is important physiologically in terminating transmitting activity, this action may potentiate or prolong activity of serotonergic and adrenergic neurons and is believed to underlie the antidepressant activity of<unk> . Inhibition of norepinephrine reuptake leading to increased concentration of norepinephrine in the posterior grey column of the spinal cord appears to be mostly responsible for the analgesic action of<unk> . Increased level of norepinephrine increases the basal activity of alpha-2 adrenergic receptors, which mediate an analgesic effect by increasing gamma-aminobutyric acid transmission among spinal interneurons. The blocking effect of<unk>  on sodium channels may also contribute to its efficacy in pain conditions. Pharmacokinetics<unk>  is readily absorbed from the gastrointestinal tract (90-95%). Absorption is gradual with the peak concentration in blood plasma reached after about 4 hours. Extensive metabolism on the first pass through the liver leads to average bioavailability of about 50% (45%-53%).<unk>  is metabolized mostly by CYP2C19 into nortriptyline and by CYP2D6 leading to a variety of hydroxylated metabolites, with the principal one among them being (E)-10-hydroxynortriptyline (see metabolism scheme), and to a lesser degree, by CYP3A4. Metabolism of<unk>  to major active metabolites. Nortriptyline, the main active metabolite of<unk> , is an antidepressant on its own right. Nortriptyline reaches 10% higher level in the blood plasma than the parent drug<unk>  and 40% greater area under the curve, and its action is an important part of the overall action of<unk> . Another active metabolite is (E)-10-hydroxynortiptyline, which is a norepinephrine uptake inhibitor four times weaker than nortriptyline. (E)-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its cerebrospinal fluid level, which is a close proxy of the brain concentration of a drug, is twice higher than notriptyline's. Based on this, (E)-10-hydroxynortiptyline was suggested to significantly contribute to antidepressant effects of<unk> . Blood levels of<unk>  and nortriptyline and pharmacokinetics of<unk>  in general, with clearance difference of up to 10-fold, vary widely between individuals. Variability of the area under the curve in steady state is also high, which makes a slow upward titration of the dose necessary. In the blood,<unk>  is 96% bound to plasma proteins; nortriptyline is 93–95% bound, and (E)-10-hydroxynortiptyline is about 60% bound.<unk>  has an elimination half life of 21 hours, nortriptyline - 23–31 hours, and (E)-10-hydroxynortiptyline - 8–10 hours. Within 48 hours, 12-80% of<unk>  is eliminated in the urine, mostly as metabolites. 2% of the unchanged drug is excreted in the urine. Elimination in the feces, apparently, have not been studied. Therapeutic levels of<unk>  range from 75 to 175 ng/mL (270–631 nM), or 80–250 ng/mL of both<unk>  and its metabolite nortriptyline. Pharmacogenetics Since<unk>  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. Increased concentrations of<unk>  may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. 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, and have "normal" metabolism of<unk> . Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use<unk>  much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. The Clinical Pharmacogenetics Implementation Consortium recommends avoiding<unk>  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<unk>  is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of<unk>  in patients who are CYP2D6 poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are CYP2D6 intermediate metabolizers.
Amitriptyline
Nortriptyline
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Guanfacine
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