Amitriptyline

Chemical Properties and Structure of Amitriptyline

This compound (3-(10,11-dihydro-5H-dibenzo[a,d]annulen-5-ylidene)-N,N-dimethylpropan-1-amine) [C20H23N] is a small molecule with a molecular weight of 277.41 Da. It is a tertiary amine tricyclic compound with no hydrogen bond donors and a single hydrogen bond acceptor. As a highly lipophilic molecule, this compound has an octanol-water partition coefficient (pH 7.4) of 3.0, while the log P of the free base was reported as 4.92. The solubility of the free base this compound in water is 14 mg/L.

The structure of this compound features a tricyclic system with a seven-membered central ring containing an exocyclic double bond. This double bond is a key structural element that distinguishes this compound from other related compounds and affects its synthetic pathways.

Traditional Synthesis Methods from Dibenzosuberone

Synthesis Methods for Key Intermediates

Modern Flow Chemistry Approaches

Preparation of this compound Hydrochloride for Pharmaceutical Use

Comparative Analysis of Synthesis Methods

Table 1. Comparison of Different Synthesis Methods for this compound and Its Intermediates

This comprehensive comparison highlights the evolution of synthesis methods for this compound and its intermediates, demonstrating a clear trend from traditional batch processes with significant drawbacks to modern approaches that offer improved yields, purity, safety profiles, and environmental compatibility. The table also reveals the trade-offs between simpler processes with environmental concerns versus more complex setups that provide better outcomes.

Recent Developments in this compound Formulation

Grignard Reaction Pathway

The traditional synthesis involves:

• Reactants : Dibenzosuberane and 3-(dimethylamino)propylmagnesium chloride.

• Reaction Conditions :

  • Heating with hydrochloric acid to eliminate water.

  • Forms the tricyclic structure via cyclization.

• Catalytic Improvements :

  • Use of nano nickel-based catalysts (90–99% Ni, 0.3–3.0% Co, 0.2–2.0% Al, Fe, Si) to enhance yield (98%) and purity (99%) under low-temperature (50°C) and low-pressure (5 kg/cm²) conditions.

Oxidation Reactions of this compound

Oxidation leads to the formation of this compound N-oxide and other derivatives, critical for pharmacological and analytical studies.

Oxidation by N-Bromo-p-Benzenesulphonamide (BAB)

• Reaction Conditions :

  • pH 1.2 acidic buffer.

  • 303K temperature.

• Kinetics :

  • First-order dependence on [BAB] and [this compound].

  • Inverse fractional order (-0.79) with respect to [H⁺].

• Product :

  • This compound N-oxide (molecular ion peak at 293 amu via GC-MS).

Permanganic Acid Oxidation

• Reaction Pathway :

  • Forms dibenzosuberone, 2-amino-3-methyl-1-butanol, and MnO₂.

• Mechanism :

  • Initial carbocation formation followed by hydrolysis and oxidation steps.

Table: Oxidation Conditions and Products

Degradation Pathways

This compound undergoes metabolic and environmental degradation, influencing its therapeutic efficacy and environmental impact.

Metabolic Degradation

• Primary Pathway :

  • CYP2D6 hydroxylation of nortriptyline to (Z)- and (E)-10-hydroxynortriptyline (1:3 ratio).

• Key Metabolites :

  • Nortriptyline (major), demethylnortriptyline.

• Pharmacogenetic Impact :

  • CYP2D6 poor metabolizers experience increased drug levels and side effects.

Environmental Degradation

• Hydrolysis :

  • Pseudo-first-order kinetics in basic conditions (pH 8).

• Photodegradation :

  • Hydroxylation and alkene hydration under UV light or Co-TiO₂ catalysts.

  • Primary products: Hydroxylated derivatives (e.g., TP-ami-296).

Table: Degradation Pathways

Kinetic Analysis

• Rate Law :

  • For BAB oxidation: $\text{Rate}=k[\text{this compound}][\text{BAB}][\text{H}^+]^{-0.79}$.

• pH Sensitivity :

  • Protonation state of oxidants (e.g., BAB → PhSO₂NHBr) alters reactivity.

Product Identification

• Spectroscopic Data :

  • This compound N-oxide: $m/z=293$ (GC-MS).

  • Hydroxylated derivatives: $m/z=278$ (LC-MS).

Depression Treatment

Amitriptyline is primarily recognized for its efficacy in treating major depressive disorder. A meta-analysis of randomized controlled trials indicated that this compound has a slightly higher response rate compared to other antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and other tricyclic antidepressants. The odds ratio favored this compound, suggesting its effectiveness in alleviating depressive symptoms.

Neuropathic Pain Management

This compound is frequently prescribed off-label for neuropathic pain conditions, such as diabetic neuropathy and postherpetic neuralgia. Research has shown that this compound can reduce pain intensity and improve quality of life in patients suffering from these chronic pain syndromes. A systematic review highlighted its role as a first-line treatment option for neuropathic pain.

Case Study: Diabetic Neuropathy

In a clinical study involving diabetic patients, those treated with this compound reported significant reductions in pain scores compared to placebo groups. The drug's mechanism appears to involve modulation of neurotransmitter levels and inhibition of pain pathways in the central nervous system.

Fibromyalgia

Fibromyalgia is another condition where this compound has shown promise. Studies indicate that low-dose this compound can help alleviate fibromyalgia symptoms, including widespread pain and sleep disturbances. A randomized controlled trial demonstrated that patients receiving this compound experienced significant improvements in their fibromyalgia impact scores compared to those receiving placebo.

Migraine Prophylaxis

This compound is also utilized for migraine prevention. Clinical evidence supports its efficacy in reducing the frequency and severity of migraine attacks. A study found that patients taking this compound had fewer migraine days per month compared to those on placebo, making it a valuable option for chronic migraine sufferers.

Irritable Bowel Syndrome (IBS)

Recent research has explored the use of this compound in managing irritable bowel syndrome symptoms. A large trial indicated that low-dose this compound significantly improved IBS symptom scores after six months of treatment, demonstrating its potential as an effective therapy for this condition.

Anxiety Disorders

This compound's anxiolytic properties have led to its use in treating anxiety disorders, particularly when these conditions co-occur with depression or chronic pain syndromes. While not first-line therapy for anxiety alone, it can be beneficial in complex cases where multiple symptoms overlap.

Chronic Pain Syndromes

Beyond neuropathic pain, this compound has been investigated for various chronic pain conditions, including complex regional pain syndrome (CRPS) and tension-type headaches. Its ability to modulate pain perception through central mechanisms makes it a relevant option in these contexts.

Summary Table of this compound Applications

Adverse Effect Profile

Effects on Cell Viability and Proliferation

Recent studies have shown that this compound affects cell viability in neuroblastoma cell lines (SH-SY5Y). Notably, it induces a concentration- and time-dependent reduction in cell viability. Key findings include:

• Cell Viability Reduction : At concentrations of 50 μM, cell viability decreased significantly over time; specifically, 81.03% at 24 hours, dropping to 43.60% by 72 hours.
• Clonogenic Capacity : this compound treatment reduced the clonogenic capacity of SH-SY5Y cells, indicating its potential cytotoxic effects.

Autophagy Modulation

This compound has been found to modulate autophagy in treated cells. However, its cytotoxic effects appear to be independent of autophagy modulation:

• Autophagy Inhibition Studies : When SH-SY5Y cultures were pre-treated with chloroquine (an autophagy inhibitor), this compound's effects on cell viability remained consistent, suggesting that its cytotoxicity does not rely on altering autophagic processes.
• Lysosomal Accumulation : this compound induced lysosomal accumulation without affecting lysosomal pH, further supporting its complex interaction with cellular homeostasis.

Additional Pharmacological Properties

Beyond its antidepressant activity, this compound exhibits several other biological activities:

• Antimicrobial Activity : Studies indicate that this compound possesses significant antibacterial properties against both Gram-positive and Gram-negative bacteria. In vivo experiments demonstrated a reduction in bacterial counts in mice treated with this compound after exposure to Salmonella typhimurium, highlighting its potential as an antimicrobial agent.

Case Studies and Clinical Implications

This compound's off-label use has been documented extensively. For instance:

• Chronic Pain Management : this compound is frequently prescribed for neuropathic pain management due to its analgesic properties.
• Sleep Disorders : Its sedative effects make it a common choice for treating insomnia associated with depression.

Basic Research Questions

Q. How can researchers design a robust randomized controlled trial (RCT) to assess amitriptyline’s efficacy in major depressive disorder (MDD)?

• Methodological Answer : Use the PICO framework (Population: MDD patients; Intervention: this compound; Comparison: Placebo; Outcome: Response rate) to structure the trial. Ensure double-blinding, adequate sample size (power analysis), and standardized diagnostic criteria (e.g., DSM-5). Monitor attrition bias by tracking withdrawal rates due to inefficacy or side effects, as seen in meta-analyses where this compound showed higher dropout rates due to adverse effects compared to placebo . Include validated depression scales (e.g., Hamilton Rating Scale for Depression [HRSD]) for outcome measurement .

Q. What statistical methods are recommended for analyzing contradictory efficacy data in this compound studies?

• Methodological Answer : Perform subgroup analyses (e.g., baseline severity, age) and meta-regression to explore heterogeneity. For instance, higher baseline depression severity correlates with greater this compound efficacy, while high placebo response rates diminish its perceived superiority . Use sensitivity analyses to assess robustness, such as excluding older trials with less rigorous randomization methods.

Q. How can researchers ensure adherence to ethical guidelines when designing this compound trials in vulnerable populations?

• Methodological Answer : Follow FINER criteria (Feasible, Interesting, Novel, Ethical, Relevant). Justify placebo use with equipoise and include rescue protocols for non-responders. Address anticholinergic side effects (e.g., dizziness, sedation) through proactive monitoring and dose titration . Obtain informed consent with explicit disclosure of withdrawal risks due to adverse events.

Advanced Research Questions

Q. What preclinical models best elucidate this compound’s dose-dependent neurotoxicity in peripheral nerves?

• Methodological Answer : Use rat sciatic nerve models to assess extraneural this compound application. Quantify neuropathologic injury via histopathology (e.g., axon degeneration, myelin disruption) and electrophysiological measurements (e.g., nerve conduction velocity). Dose-response studies (e.g., 6–8 nmol doses) reveal severe neurotoxicity, necessitating caution in clinical applications for neuropathic pain .

Q. How can network meta-analyses (NMAs) compare this compound’s efficacy against newer antidepressants?

• Methodological Answer : Conduct a Bayesian NMA integrating RCTs of this compound and FDA-approved drugs. Use standardized mean differences (SMDs) for continuous outcomes (e.g., HRSD scores) and odds ratios (ORs) for dichotomous outcomes (e.g., response rates). Adjust for confounding variables (e.g., study duration, dosing) and assess transitivity assumptions. Validate findings with node-splitting to detect inconsistency .

Q. What methodologies reconcile discrepancies in this compound’s clinical efficacy versus real-world prescription patterns?

• Methodological Answer : Perform retrospective cohort studies in LMICs using medicine use evaluations (MUEs). Analyze electronic health records for diagnosis concordance (e.g., adherence to Standard Treatment Guidelines) and dosing patterns. For example, a South African study found widespread off-label use and poor documentation, highlighting the need for clinician education and audit feedback .

Q. How do receptor-binding assays clarify this compound’s multimodal mechanisms in chronic pain management?

• Methodological Answer : Use radioligand binding assays to quantify affinity for serotonin (5-HT) and norepinephrine (NET) transporters. Pair with functional assays (e.g., cAMP inhibition) to assess downstream effects. Compare results with in vivo models (e.g., rodent neuropathic pain) to validate translational relevance. Note that sodium channel blockade contributes to local anesthetic effects but also neurotoxicity .

Q. Data and Reporting Standards

Q. What are best practices for reporting adverse events in this compound trials?

• Methodological Answer : Use CONSORT guidelines for adverse event reporting. Differentiate between common side effects (e.g., sedation, weight gain) and rare events (e.g., cardiac arrhythmias). Include severity grading (e.g., CTCAE criteria) and causality assessment (e.g., Naranjo Scale). Tabulate events by treatment arm with absolute risks and number needed to harm (NNH) .

Q. How should researchers address missing data in longitudinal studies of this compound’s long-term safety?

• Methodological Answer : Apply multiple imputation or mixed-effects models for repeated measures (MMRM) to handle missing data. Sensitivity analyses (e.g., worst-case scenario imputation) can assess robustness. For observational studies, use propensity score matching to reduce confounding by indication .

Q. Translational and Regulatory Challenges