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An Overview of the Pharmacology of Antidepressants

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Introduction

The pharmacology of antidepressants is not entirely clear.

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine). It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All antidepressants that have entered the market before 2011 have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway.

Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid (within 2 hours), robust and sustained (lasting for up to a fortnight) antidepressant effects. Monoamine precursor depletion also fails to alter mood. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don’t directly influence mood, but influence emotional perception biases.[9]

Monoamine Hypothesis

In 1965, Joseph Schildkraut published a review article stating that several researchers had found an association between depression and deficiency of the catecholamine family of monoamine neurotransmitters, which they had begun calling the “catecholamine hypothesis”, also known as the monoamine hypothesis.

By 1985, the monoamine hypothesis was mostly dismissed until it was revived with the introduction of SSRIs through the successful direct-to-consumer advertising, often revolving around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin within the brain.

Serotonin levels in the human brain is measured indirectly by sampling cerebrospinal fluid for its main metabolite, 5-hydroxyindole-acetic acid, or by measuring the serotonin precursor, tryptophan. In one placebo controlled study funded by the National Institute of Health, tryptophan depletion was achieved, but they did not observe the anticipated depressive response. Similar studies aimed at increasing serotonin levels did not relieve symptoms of depression. At this time, decreased serotonin levels in the brain and symptoms of depression have not been linked.

Although there is evidence that antidepressants inhibit the reuptake of serotonin, norepinephrine, and to a lesser extent dopamine, the significance of this phenomenon in the amelioration of psychiatric symptoms is not known. Given the low overall response rates of antidepressants, and the poorly understood causes of depression, it is premature to assume a putative mechanism of action of antidepressants.

While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2A receptors, suggesting it is too simplistic to say serotonin is a “happy neurotransmitter”. In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again – the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behaviour. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance.

Hypothalamic-Pituitary-Adrenal Axis

One manifestation of depression is an altered hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress, that of increased cortisol production and a subsequent impaired negative feedback mechanism. It is not known whether this HPA axis dysregulation is reactive or causative for depression. A 2003 briefing suggests that the mode of action of antidepressants may be in regulating HPA axis function.

A 2011 study combines aspects of the HPA axis theory and the neurogenic theory (see below). The researchers showed that mice under unpredictable chronic mild stress (a well-known animal model of depression) have impaired hippocampal neurogenesis and greatly reduced ability of the hippocampus to regulate the HPA axis, causing anhedonia as measured by the Cookie Test. Administration of fluoxetine (an SSRI) without removing the stressor causes increased hippocampal neurogenesis, normalisation of the HPA axis, and improvement of anhedonia. If X-ray irradiation is used on the hippocampus before drug treatment to prevent neurogenesis, no improvement of anhedonia occurs. However, if an irradiated mouse is given a corticotropin-releasing factor 1 antagonist – a drug that directly targets the HPA axis – anhedonia is improved. Combined with the fact that irridiation without stressing does not impair hippocampal control of the HPA axis, the authors conclude that fluoxetine works by improving hippocampal neurogenesis, which then helps restore the HPA axis, in turn leading to improvements in depression symptoms such as anhedonia.

Neurogenic Adaptations

The neurogenic hypothesis states that molecular and cellular mechanisms underlying the regulation of adult neurogenesis is required for remission from depression and that neurogenesis is mediated by the action of antidepressants. A broader view is that antidepressants help by increasing neuroplasticity in general.

Chronic use of SSRI antidepressant increased neurogenesis in the hippocampus of rats and mice. Other antidepressant treatments also appear associated with hippocampal neurogenesis and/or neuroplasticity: electroconvulsive therapy, which is known to be highly effective for depression, is associated with higher BDNF expression in the hippocampus as well as global rewiring; lithium and valporate, two mood stabilisers occasionally used as add-on treatment, are associated with increased survival and proliferation of neurons. Ketamine (see also esketamine), a new fast-acting antidepressant, can increase the number of dendritic spines and restore aspects of functional connectivity after a single infusion.

Other animal research suggests that long term drug-induced antidepressants effects modulate the expression of genes mediated by clock genes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes).

The delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment, including serotonin and norepinephrine uptake inhibitors, MAOIs, TCAs, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolised by cyclic nucleotide phosphodiesterases (PDEs).

Studies on human patients have used imaging approaches to measure the changes in density and volume of specific brain areas. The grey matter volume of parts of the brain are differently increased or decreased by SSRI use. It appears possible to use brain imaging to predict which patients are likely to respond to SSRI antidepressants.

Anti-Inflammatory and Iimmunomodulation

Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system.

Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes, may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones. SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10), as well as TNF-alpha and interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.

Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties.

These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy. Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Pharmacology_of_antidepressants >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Oxazepam?

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Introduction

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety, insomnia, and to control symptoms of alcohol withdrawal syndrome.

It is a metabolite of diazepam, prazepam, and temazepam, and has moderate amnesic, anxiolytic, anticonvulsant, hypnotic, sedative, and skeletal muscle relaxant properties compared to other benzodiazepines.

It was patented in 1962 and approved for medical use in 1964.

Medical Uses

Oxazepam is an intermediate-acting benzodiazepine with a slow onset of action, so it is usually prescribed to individuals who have trouble staying asleep, rather than falling asleep. It is commonly prescribed for anxiety disorders with associated tension, irritability, and agitation. It is also prescribed for drug and alcohol withdrawal, and for anxiety associated with depression. Oxazepam is sometimes prescribed off-label to treat social phobia, post-traumatic stress disorder, insomnia, premenstrual syndrome, and other conditions.

Side Effects

The side effects of oxazepam are similar to those of other benzodiazepines, and may include dizziness, drowsiness, headache, memory impairment, paradoxical excitement, and anterograde amnesia, but does not affect transient global amnesia.[citation needed] Withdrawal effects due to rapid decreases in dosage or abrupt discontinuation of oxazepam may include abdominal and muscle cramps, seizures, depression, insomnia, sweating, tremors, or nausea and vomiting.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, Dependence and Withdrawal

Oxazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from oxazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur, though, at standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.

Contraindications

Oxazepam is contraindicated in myasthenia gravis, chronic obstructive pulmonary disease, and limited pulmonary reserve, as well as severe hepatic disease.

Special Precautions

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders. Benzodiazepines including oxazepam are lipophilic drugs and rapidly penetrate membranes, so rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines in late pregnancy, especially high doses, may result in floppy infant syndrome.

Pregnancy

Oxazepam, when taken during the third trimester, causes a definite risk to the neonate, including a severe benzodiazepine withdrawal syndrome including hypotonia, reluctance to suck, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Interactions

As oxazepam is an active metabolite of diazepam, an overlap in possible interactions is likely with other drugs or food, with exception of the pharmacokinetic CYP450 interactions (e.g. with cimetidine). Precautions and following the prescription are required when taking oxazepam (or other benzodiazepines) in combinations with antidepressants or opioids. Concurrent use of these medications can interact in a way that is difficult to predict. Drinking alcohol when taking oxazepam is not recommended. Concomitant use of oxazepam and alcohol can lead to increased sedation, memory impairment, ataxia, decreased muscle tone, and, in severe cases or in predisposed patients, respiratory depression and coma.

Overdose

Oxazepam is generally less toxic in overdose than other benzodiazepines. Important factors which affect the severity of a benzodiazepine overdose include the dose ingested, the age of the patient, and health status prior to overdose. Benzodiazepine overdoses can be much more dangerous if a coingestion of other CNS depressants such as opiates or alcohol has occurred. Symptoms of an oxazepam overdose include:

  • Respiratory depression
  • Excessive somnolence
  • Altered consciousness
  • Central nervous system depression
  • Occasionally cardiovascular and pulmonary toxicity
  • Rarely, deep coma

Pharmacology

Oxazepam is an intermediate-acting benzodiazepine of the 3-hydroxy family; it acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system. The half-life of oxazepam is between 6 and 9 hours. It has been shown to suppress cortisol levels. Oxazepam is the most slowly absorbed and has the slowest onset of action of all the common benzodiazepines according to one British study.

Oxazepam is an active metabolite formed during the breakdown of diazepam, nordazepam, and certain similar drugs. It may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather, it is simply metabolised by glucuronidation, so oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver disease. Oxazepam is similar to lorazepam in this respect. Preferential storage of oxazepam occurs in some organs, including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of oxazepam during pregnancy and breast feeding is recommended, as oxazepam is excreted in breast milk.

Two milligrams of oxazepam equates to 1 mg of diazepam according to the benzodiazepine equivalency converter, therefore 20 mg of oxazepam according to BZD equivalency equates to 10 mg of diazepam and 15 mg oxazepam to 7.5 mg diazepam (rounded up to 8 mg of diazepam). Some BZD equivalency converters use 3 to 1 (oxazepam to diazepam), 1 to 3 (diazepam to oxazepam) as the ratio (3:1 and 1:3), so 15 mg of oxazepam would equate to 5 mg of diazepam.

Chemistry

Oxazepam exists as a racemic mixture. Early attempts to isolate enantiomers were unsuccessful; the corresponding acetate has been isolated as a single enantiomer. Given the different rates of epimerisation that occur at different pH levels, it was determined that there would be no therapeutic benefit to the administration of a single enantiomer over the racemic mixture.

Frequency of Use

Oxazepam, along with diazepam, nitrazepam, and temazepam, were the four benzodiazepines listed on the pharmaceutical benefits scheme and represented 82% of the benzodiazepine prescriptions in Australia in 1990–1991. It is in several countries the benzodiazepine of choice for novice users, due to a low chance of accumulation and a relatively slow absorption speed.

Society and Culture

Misuse

Oxazepam has the potential for misuse, defined as taking the drug to achieve a high, or continuing to take the drug in the long term against medical advice. Benzodiazepines, including diazepam, oxazepam, nitrazepam, and flunitrazepam, accounted for the largest volume of forged drug prescriptions in Sweden from 1982 to 1986. During this time, a total of 52% of drug forgeries were for benzodiazepines, suggesting they were a major prescription drug class of abuse.

However, due to its slow rate of absorption and its slow onset of action, oxazepam has a relatively low potential for abuse compared to some other benzodiazepines, such as temazepam, flunitrazepam, or triazolam. This is similar to the varied potential for abuse between different drugs of the barbiturate class.

Legal Status

Oxazepam is a Schedule IV drug under the Convention on Psychotropic Substances.

Brand Names

Oxazepam is marketed under many brand names worldwide, including: Alepam, Alepan, Anoxa, Anxiolit, Comedormir, durazepam, Murelax, Nozepam, Oksazepam, Opamox, Ox-Pam, Oxa-CT, Oxabenz, Oxamin, Oxapam, Oxapax, Oxascand, Oxaze, Oxazepam, Oxazépam, Oxazin, Oxepam, Praxiten, Purata, Selars, Serax, Serepax, Seresta, Séresta, Serpax, Sobril, Tazepam, Vaben, and Youfei.

It is also marketed in combination with hyoscine as Novalona and in combination with alanine as Pausafrent T.

Environmental Concerns

In 2013, a laboratory study which exposed European perch to oxazepam concentrations equivalent to those present in European rivers (1.8 μg/L) found that they exhibited increased activity, reduced sociality, and higher feeding rate. In 2016, a follow-up study which exposed salmon smolt to oxazepam for seven days before letting them migrate observed increased intensity of migratory behaviour compared to controls. A 2019 study associated this faster, bolder behaviour in exposed smolt to increased mortality due to a higher likelihood of being predated on.

On the other hand, a 2018 study from the same authors, which kept 480 European perch and 12 northern pikes in 12 ponds over 70 days, half of them control and half spiked with oxazepam, found no significant difference in either perch growth or mortality. However, it suggested that the latter could be explained by the exposed perch and pike being equally hampered by oxazepam, rather than the lack of an overall effect. Lastly, a 2021 study built on these results by comparing two whole lakes filled with perch and pikes – one control while the other was exposed to oxazepam 11 days into experiment, at concentrations between 11 and 24 μg/L, which is 200 times greater than the reported concentrations in the European rivers. Even so, there were no measurable effects on pike behaviour after the addition of oxazepam, while the effects on perch behaviour were found to be negligible. The authors concluded that the effects previously attributed to oxazepam were instead likely caused by a combination of fish being stressed by human handling and small aquaria, followed by being exposed to a novel environment.

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What is Opipramol?

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Introduction

Opipramol, sold under the brand name Insidon among others, is an anxiolytic and tricyclic antidepressant (TCA) that is used throughout Europe. Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is not a monoamine reuptake inhibitor like most other TCAs, and instead acts primarily as a sigma-1 receptor agonist. It was developed by Schindler and Blattner in 1961.

Brief History

Opipramol was developed by Geigy. It first appeared in the literature in 1952 and was patented in 1961. The drug was first introduced for use in medicine in 1961. Opipramol was one of the first TCAs to be introduced, with imipramine marketed in the 1950s and amitriptyline marketed in 1961.

Medical Uses

Opipramol is typically used in the treatment of generalised anxiety disorder (GAD) and somatoform disorders. Preliminary studies suggest that opipramol shows potential clinical significance in the treatment of severe sleep bruxism.

Contraindications

  • In patients with hypersensitivity to opipramol or another component of the formulation
  • Acute alcohol, sedative, analgesic, and antidepressant intoxications
  • Acute urinary retention
  • Acute delirium
  • Untreated narrow-angle glaucoma
  • Benign prostatic hyperplasia with residual urinary retention
  • Paralytic ileus
  • Pre-existing higher-grade atrioventricular blockages or diffuse supraventricular or ventricular stimulus conduction disturbances
  • Combination with monoamine oxidase inhibitor (MAOI)

Pregnancy and Lactation

Experimental animal studies did not indicate injurious effects of opipramol on the embryonic development or fertility. Opipramol should only be prescribed during pregnancy, particularly in the first trimester, for compelling indication. It should not be used during lactation and breastfeeding, since it passes into breast milk in small quantities.

Side Effects

Frequently (≥1% to <10%) reported adverse reactions with opipramol, especially at the beginning of the treatment, include fatigue, dry mouth, blocked nose, hypotension, and orthostatic dysregulation.

Adverse reactions reported occasionally (≥0.1% to <1%) include dizziness, stupor, micturition disturbances, vigilance, accommodation disturbances, tremor, weight gain, thirst, allergic skin reactions (rash, urticaria), abnormal ejaculation, erectile impotence, constipation, transient increases in liver enzymes, tachycardia, and palpitations.

Rarely (≥0.01% to <0.1%) reported adverse reactions include excitation, headache, paraesthesia especially in elderly patients, restlessness, sweating, sleep disturbances, oedema, galactorrhoea, urine blockage, nausea and vomiting, fever, collapse conditions, stimulation conducting disturbances, intensification of present heart insufficiency, blood profile changes particularly leukopenia, confusion, delirium, stomach complaints, taste disturbance, and paralytic ileus especially with sudden discontinuation of a longer-term high-dose therapy.

Very rarely (<0.01%) reported adverse reactions include seizures, motor disorders (akathisia, dyskinesia, ataxia), polyneuropathy, glaucoma, anxiety, hair loss, agranulocytosis, severe liver dysfunction after long-term treatment, jaundice, and chronic liver damage.

Overdose

Symptoms of intoxication from overdose include drowsiness, insomnia, stupor, agitation, coma, transient confusion, increased anxiety, ataxia, convulsions, oliguria, anuria, tachycardia or bradycardia, arrhythmia, AV block, hypotension, shock, respiratory depression, and, rarely, cardiac arrest.

Interactions

While opipramol is not a monoamine reuptake inhibitor, any irreversible MAOIs should still be discontinued at least 14 days before treatment. Opipramol can compete with other tricyclic antidepressants, beta blockers, antiarrhythmics (of class 1c), and other drugs for microsomal enzymes, which can lead to slower metabolism and higher plasma concentrations of these drugs. Co-administration of antipsychotics (e.g., haloperidol, risperidone) can increase the plasma concentration of opipramol. Barbiturates and anticonvulsants can reduce the plasma concentration of opipramol and thereby weaken its therapeutic effect.[3]

Pharmacology

Pharmacodynamics

Opipramol acts as a high affinity sigma receptor agonist, primarily of the σ1 subtype, but also of the σ2 subtype with lower affinity. In one study of σ1 receptor ligands that also included haloperidol, pentazocine, (+)-3-PPP, ditolylguanidine, dextromethorphan, SKF-10,047 ((±)-alazocine), ifenprodil, progesterone, and others, opipramol showed the highest affinity (Ki = 0.2–0.3) for the guinea pig σ1 receptor of all the tested ligands except haloperidol, which it was approximately equipotent with. The sigma receptor agonism of opipramol is thought to be responsible for its therapeutic benefits against anxiety and depression.

Unlike other TCAs, opipramol does not inhibit the reuptake of serotonin or norepinephrine. However, it does act as a high affinity antagonist of the histamine H1 receptor and is a low to moderate affinity antagonist of the dopamine D2, serotonin 5-HT2, and α1-adrenergic receptors. H1 receptor antagonism accounts for its antihistamine effects and associated sedative side effects. In contrast to other TCAs, opipramol has very low affinity for the muscarinic acetylcholine receptors and virtually no anticholinergic effects.

Sigma receptors are a set of proteins located in the endoplasmic reticulum. σ1 receptors play key role in potentiating intracellular calcium mobilisation thereby acting as sensor or modulator of calcium signalling. Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas (membranes) where the σ1 receptors cause neurotransmitter release. Opipramol is said to have a biphasic action, with prompt initial improvement of tension, anxiety, and insomnia followed by improved mood later. Hence, it is an anxiolytic with an antidepressant component. After sub-chronic treatment with opipramol, σ2 receptors are significantly downregulated but σ1 receptors are not.

Pharmacokinetics

Opipramol is rapidly and completely absorbed by the gastrointestinal tract. The bioavailability of opipramol amounts to 94%. After single oral administration of 50 mg, the peak plasma concentration of the drug is reached after 3.3 hours and amounts to 15.6 ng/mL. After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/mL. Therapeutic concentrations of opipramol range from 140 to 550 nmol/L. The plasma protein binding amounts to approximately 91% and the volume of distribution is approximately 10 L/kg. Opipramol is partially metabolised in the liver to deshydroxyethylopipramol. Metabolism occurs through the CYP2D6 isoenzyme. Its terminal half-life in plasma is 6–11 hours. About 70% is eliminated in urine with 10% unaltered. The remaining portion is eliminated through faeces.

Society and Culture

Generic Names

Opipramol is the English, German, French, and Spanish generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française, while opipramol hydrochloride is its USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name. Its generic name in Italian and its DCITTooltip Denominazione Comune Italiana is opipramolo and in Latin is opipramolum.

Brand Names

Opipramol is marketed under the brand names Deprenil, Dinsidon, Ensidon, Insidon, Insomin, Inzeton, Nisidana, Opipram, Opramol, Oprimol, Pramolan, and Sympramol among others.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Opipramol >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Nortiptyline?

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Introduction

Nortriptyline, sold under the brand name Aventyl, among others, is a tricyclic antidepressant (TCA). This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. Its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18–24 population initiating treatment. Nortriptyline is not a preferred treatment for ADHD or smoking cessation. It is taken by mouth.

Common side effects include dry mouth, constipation, blurry vision, sleepiness, low blood pressure with standing, and weakness. Serious side effects may include seizures, an increased risk of suicide in those less than 25 years of age, urinary retention, glaucoma, mania, and a number of heart issues. Nortriptyline may cause problems if taken during pregnancy. Use during breastfeeding appears to be relatively safe. It is a TCA and is believed to work by altering levels of serotonin and norepinephrine.

Nortriptyline was approved for medical use in the US in 1964. It is available as a generic medication. In 2022, it was the 191st most commonly prescribed medication in the US, with more than 2 million prescriptions.

Brief History

Nortriptyline was developed by Geigy. It first appeared in the literature in 1962 and was patented the same year. The drug was first introduced for the treatment of depression in 1963.

Medical Uses

Nortriptyline is used to treat depression. A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.

It is also used off-label for the treatment of panic disorder, ADHD, irritable bowel syndrome, tobacco-cessation, migraine prophylaxis and chronic pain or neuralgia modification, particularly temporomandibular joint disorder.

Irritable Bowel Syndrome

Nortriptyline has also been used as an off-label treatment for irritable bowel syndrome (IBS).

Contraindications

Nortriptyline should not be used in the acute recovery phase after myocardial infarction (heart attack). Use of TCAs along with a monoamine oxidase inhibitor (MAOI), linezolid, or IV methylene blue are contraindicated as it can cause an increased risk of developing serotonin syndrome.

Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, or seizures, as well as in persons with hyperthyroidism or receiving thyroid hormones.

Side Effects

The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects.

Overdose

Refer to Tricyclic Antidepressant Overdose.

The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including anticholinergic effects, serotonin syndrome and adverse cardiac effects. TCAs, particularly nortriptyline, have a relatively narrow therapeutic index, which increase the chance of an overdose (both accidental and intentional). Symptoms of overdose include: irregular heartbeat, seizures, coma, confusion, hallucination, widened pupils, drowsiness, agitation, fever, low body temperature, stiff muscles and vomiting.

Interactions

Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation.

It may interact with the following drugs:

  • Heart rhythm medications such as flecainide (Tambocor), propafenone (Rhythmol), or quinidine (Cardioquin, Quinidex, Quinaglute)
  • Cimetidine
  • Guanethidine
  • Reserpine

Pharmacology

Nortriptyline is a strong norepinephrine reuptake inhibitor and a moderate serotonin reuptake inhibitor. Additionally, nortriptyline inhibits the activity of histamine and acetylcholine.

Pharmacodynamics

Nortriptyline is an active metabolite of amitriptyline by demethylation in the liver. Chemically, it is a secondary amine dibenzocycloheptene and pharmacologically it is classed as a first-generation antidepressant.

Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors. In the short term, however, nortriptyline may disturb sleep due to its activating effect.

In one study, nortriptyline had the highest affinity for the dopamine transporter among the TCAs (KD = 1,140 nM) besides amineptine (a norepinephrine–dopamine reuptake inhibitor), although its affinity for this transporter was still 261- and 63-fold lower than for the norepinephrine and serotonin transporters (KD = 4.37 and 18 nM, respectively).

Pharmacogenetics

Nortriptyline is metabolised in the liver by the hepatic enzyme CYP2D6, and genetic variations within the gene coding for this enzyme can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of nortriptyline 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 categorised into different types of CYP2D6 metabolisers depending on which genetic variations they carry. These metaboliser types include poor, intermediate, extensive, and ultrarapid metabolisers. Most individuals (about 77–92%) are extensive metabolisers, and have “normal” metabolism of nortriptyline. Poor and intermediate metabolisers have reduced metabolism of the drug as compared to extensive metabolisers; patients with these metaboliser types may have an increased probability of experiencing side effects. Ultrarapid metabolisers use nortriptyline much faster than extensive metabolisers; patients with this metaboliser type may have a greater chance of experiencing pharmacological failure.

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who are CYP2D6 ultrarapid or poor metabolisers, due to the risk of a lack of efficacy and side effects, respectively. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolisers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in CYP2D6 poor or intermediate metabolisers, and selecting an alternative drug or increasing the dose in ultrarapid metabolisers.

Chemistry

Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene tricyclic antidepressants include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline. Nortriptyline is a secondary amine tricyclic antidepressant, with its N-methylated parent amitriptyline being a tertiary amine. Other secondary amine tricyclic antidepressants include desipramine and protriptyline. The chemical name of nortriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine and its free base form has a chemical formula of C19H21N1 with a molecular weight of 263.384 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely. The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3.

Society and Culture

Generic Names

Nortriptyline is the generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française, while nortriptyline hydrochloride is its USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name. Its generic name in Spanish and Italian and its DCITTooltip Denominazione Comune Italiana are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum.

Brand Names

Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensival, among many others.

Research

Although not approved by the US Food and Drug Administration (FDA) for neuropathic pain, randomised controlled trials have demonstrated the effectiveness of TCAs for the treatment of this condition in both depressed and non-depressed individuals. In 2010, an evidence-based guideline sponsored by the International Association for the Study of Pain recommended nortriptyline as a first-line medication for neuropathic pain. However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.

It may be effective in the treatment of tobacco-cessation.

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What is Nomifensine?

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Introduction

Nomifensine, sold under the brand names Merital and Alival, is a norepinephrine–dopamine reuptake inhibitor (NDRI), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters. This is a mechanism of action shared by some recreational drugs like cocaine and the medication tametraline (see DRI). Research showed that the (S)-isomer is responsible for activity.

The drug was developed in the 1960s by Hoechst AG (now Sanofi-Aventis), who then test marketed it in the United States. It was an effective antidepressant, without sedative effects. Nomifensine did not interact significantly with alcohol and lacked anticholinergic effects. No withdrawal symptoms were seen after 6 months treatment. The drug was however considered not suitable for agitated patients as it presumably made agitation worse. In January 1986 the drug was withdrawn by its manufacturers for safety reasons.

Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).

In a 1989 study it was investigated for use in treating adult ADHD and proven effective. In a 1977 study it was not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.

Clinical Uses

Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic.

Side Effects and Withdrawal From Market

During treatment with nomifensine there were relatively few adverse effects, mainly renal failure, paranoid symptoms, drowsiness or insomnia, headache, and dry mouth. Side effects affecting the cardiovascular system included tachycardia and palpitations, but nomifensine was significantly less cardiotoxic than the standard tricyclic antidepressants.

Due to a risk of haemolytic anaemia, the US Food and Drug Administration (FDA) withdrew approval for nomifensine on 20 March 1992. Nomifensine was subsequently withdrawn from the Canadian and UK markets as well. Some deaths were linked to immunohaemolytic anemia caused by this compound, although the mechanism remained unclear.

In 2012 structure-affinity relationship data (compare SAR) were published.

Synthesis

Nomifensine was a progenitor to Gastrophenzine (refer to Isatin derivatives).

The alkylation between N-methyl-2-nitrobenzylamine [56222-08-3] and phenacyl bromide gives CID:15326127. Catalytic hydrogenation over Raney Nickel reduces the nitro group to give CID:15113381. The reduction of the ketone group with sodium borohydride to alcohol gives [65514-97-8]. Acid catalysed ring closure completes the formation of nomifensine.

Research

Motivational Disorders

Nomifensine has been found to reverse tetrabenazine-induced motivational deficits in animals. It shares these pro-motivational effects with other NDRIs like bupropion and methylphenidate and with selective dopamine reuptake inhibitors like modafinil and its analogues. Conversely, selective norepinephrine reuptake inhibitors like desipramine and atomoxetine and selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and citalopram have not shown pro-motivational effects in animals.

Wakefulness

Nomifensine shows wakefulness-promoting effects in animals and might be useful in the treatment of narcolepsy.

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What is Nitrazolam?

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Introduction

Nitrazolam is a triazolobenzodiazepine (TBZD) , which are benzodiazepine (BZD) derivatives, that has been sold online as a designer drug.

It is closely related to clonazolam or flunitrazolam, only differing by the removal of a chlorine or fluorine group respectively at the benzene ring.

A study in mice indicated that nitrazolam can be several times more potent than diazepam as an antagonist of electroshock-induced tonic-extensor convulsions but less potent than diazepam at preventing the righting reflex

Nitrazolam has been used as an example compound to demonstrate the microscale synthesis of reference materials utilising polymer‐supported reagents.

Legal Status

United Kingdom

In the UK, nitrazolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.

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What is Haloperidol Decanoate?

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Introduction

Haloperidol decanoate, sold under the brand name Haldol Decanoate among others, is a typical antipsychotic which is used in the treatment of schizophrenia.

Refer to Haloperidol.

It is administered by injection into muscle at a dose of 100 to 200 mg once every 4 weeks or monthly. The dorsogluteal site is recommended. A 3.75-cm (1.5-inch), 21-gauge needle is generally used, but obese individuals may require a 6.5-cm (2.5-inch) needle to ensure that the drug is indeed injected intramuscularly and not subcutaneously.

Haloperidol decanoate is provided in the form of 50 or 100 mg/mL oil solution of sesame oil and benzyl alcohol in ampoules or pre-filled syringes. Its elimination half-life after multiple doses is 21 days. The medication is marketed in many countries throughout the world.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Haloperidol_decanoate >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Clopenthixol?

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Introduction

Clopenthixol (Sordinol), also known as clopentixol, is a typical antipsychotic drug of the thioxanthene class. It was introduced by Lundbeck in 1961.

Clopenthixol is a mixture of cis and trans isomers. Zuclopenthixol, the pure cis isomer, was later introduced by Lundbeck in 1962, and has been much more widely used. Both drugs are equally effective as antipsychotics and have similar adverse effect profiles, but clopenthixol is half as active on a milligram-to-milligram basis and appears to produce more sedation in comparison.

Clopenthixol is not approved for use in the United States.

What is Bromperidol Decanoate?

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Introduction

Bromperidol decanoate, sold under the brand names Bromidol Depot, Bromodol Decanoato, and Impromen Decanoas, is an antipsychotic which has been marketed in Europe and Latin America.

It is an antipsychotic ester and long-acting prodrug of bromperidol which is administered by depot intramuscular injection once every 4 weeks.