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CHAPTER –III a New Methodology for Industrial Synthesis of Antidepressant Drug Desmethylvenlafaxine

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CHAPTER –III a New Methodology for Industrial Synthesis of Antidepressant Drug Desmethylvenlafaxine CHAPTER –III A new methodology for industrial synthesis of antidepressant drug Desmethylvenlafaxine. INTRODUCTION: Almost everyone experiences at one time or another, a sense of "feeling low" caused by a disturbing event in one's life but when depression persists, it is a matter of concern. Major depression is a serious condition where a person is not only in a depressed mood but also has a feeling of guilt, hopelessness, loss of interest or pleasure in normal activities including sex, oversleeping or sometimes sleeplessness, extreme fatigue, lack of energy, agitation and sometimes irritability and anxiety. Depression can strike at any age, including childhood. Often, depressed moods can be observed in early middle age as a result of the side effect of medication, hormonal changes (such as before the menstrual period or after child birth), fluctuating blood sugar levels, smoking, environmental factors like chronic exposure to solvents and heavy metals and vitamin deficiencies. Sometimes intestinal overgrowth of yeast (Candida albicans) can precipitate depression. However, the most common time of onset is at old age, that may be a reaction to the fact of growing older, the death of a spouse or close friend, limitations of movement associated with age and impending confrontation with death. Some of the symptoms of depression are poor appetite with weight loss or increased appetite with weight gain, insomnia or hypersomnia, physical hyperactivity or inactivity, loss of interest or pleasure in daily activities, or a decrease in sexual drive. Includes loss of energy or feelings of fatigue, feelings of worthlessness, self-reproach or inappropriate guilt, a diminished ability to think or concentrate and recurrent thoughts of death or suicide. Nearly one in four people experience some degree of clinical depression or mood disorder in his/her lifetime. Exposure to solvents and heavy metals may produce the psychological symptoms of depression. Disciplined regular exercise cannot be overstated; it improves mood and the ability to handle stress. An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Drugs including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors 94 (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are most commonly associated with the term. These medications are among those most commonly prescribed by psychiatrists and other physicians, and their effectiveness and adverse effects are the subject of many studies and competing claims. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy. The efficacy of modern thymoleptic anti-depressants has never been conclusively demonstrated to be greater than that of active placebo, according to two Cochrane Collaboration reviews. 1,2 A review off all studies of anti-depressants ever submitted to the FDA, published and unpublished, submitted to the FDA in 2004. In the published literature, anti-depressants had 94% success in treating depression. 1,2 In the withheld literature, they had below 50% success. 1 Combined, all studies showed 51% efficacy 1 - only two points better than that of placebo. This increased the apparent efficacy of different anti-depressants from 11% to 69% over placebo. 1 Possible exceptions are mirtazepine - a norepinephrine and serotonin antagonist, with effects opposite that of the SSRIs and SNRIS - and venlafaxine, an SNRI with substantial similarity in chemical structure to the opioid derivative tramadol. Opioids were used to treat major depression until the late 1950s. Amphetamines were used until the mid 1960s. Prescribing opioids or amphetamines for depression falls into a legal grey area. Research has only rarely been conducted in to the therapeutic potential of opioid derivatives for depression in the past sixty years, whereas amphetamines have found a thriving market for conditions as widely arrayed as attention deficit disorder, narcolepsy, and obesity, and continue to be studied for myriad applications. Both opioids and amphetamines induce a therapeutic response very quickly, showing results within twenty- four to forty-eight hours; the therapeutic ratios for both opioids and amphetamines are greater than those of the tricyclic anti-depressants. In some of this little, heavily restricted research, the opioid buprenorphine has shown the greatest potential for treating severe, treatment-resistant depression of any known pharmaceutical in a small study that is generally recognized and was published in 1995, but has never been pursued due to the social stigma attached to opioids in addition to that attached to mental illness in America. 3 95 Types of antidepressants: Tricyclic antidepressants (TCAs): Tricyclic antidepressants are the oldest class of antidepressant drugs. Tricyclics block the reuptake of certain neurotransmitters such as norepinephrine (noradrenaline) and serotonin. They are used less commonly now due to the development of more selective and safer drugs. Side effects include increased heart rate, drowsiness, dry mouth, constipation, urinary retention, blurred vision, dizziness, confusion, and sexual dysfunction. Toxicity occurs at approximately ten times normal dosages; these drugs are often lethal in overdoses, as they may cause a fatal arrhythmia. However, tricyclic antidepressants are still used because of their effectiveness, especially in severe cases of major depression. This class includes tertiary amine tricyclic antidepressants & secondary amine tricyclic antidepressants. Examples of tertiary amine tricyclic antidepressants are Amitriptyline, Clomipramine, Doxepin, Imipramine and Trimipramine. Examples of secondary amine tricyclic antidepressants are Desipramine, Nortriptyline, and Protriptyline. Monoamine oxidase inhibitor (MAOIs): These antidepressants may be used if other antidepressant medications are ineffective. Because there are potentially fatal interactions between this class of medication and certain foods (particularly those containing tyramine), red wine, as well as certain drugs, classic MAOIs are rarely prescribed anymore. However, this does not apply to Emsam, the transdermal patch form of selegiline, which due to its bypassing of the stomach has never 4 been reported to induce such events . MAOIs work by blocking the enzyme monoamine oxidase which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). MAOIs can be as effective as tricyclic antidepressants, although they can have a higher incidence of dangerous side effects (as a result of inhibition of cytochrome P450 in the liver). A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A (RIMA), acts in a more short-lived and selective manner and does not require a special diet. As one of the side effects is weight gain and could be extreme. These include: Isocarboxazid, Moclobemide, Phenelzine, Selegiline and Tranylcypromine. 96 Selective serotonin reuptake inhibitors (SSRIs) These are a class of antidepressants considered the current standard of drug treatment. A possible cause of depression is an inadequate amount of serotonin, a chemical used in the brain to transmit signals between neurons. SSRIs are said to work by preventing the reuptake of serotonin (also known as 5-hydroxytryptamine, or 5-HT) by the presynaptic neuron, thus maintaining higher levels of 5-HT in the synapse. Chemists Klaus Schmiegel and Bryan Molloy of Eli Lilly discovered the first SSRI, fluoxetine. This class of drugs includes Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline. Noradrenergic and specific serotonergic antidepressants (NaSSAs) This class of antidepressants which purportedly work to increase norepinephrine (noradrenaline) and serotonin neurotransmission by blocking presynaptic alpha-2 adrenergic receptors while at the same time blocking certain serotonin receptors. 5 Side effects may include drowsiness, increased appetite, and weight gain. 6 Examples of this class are Mianserin and Mirtazapine. Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) These antidepressants act via norepinephrine (also known as noradrenaline ). NRIs are thought to have a positive effect on the concentration and motivation in particular. These include: Atomoxetine, Mazindol, Reboxetine and Viloxazine. Norepinephrine-dopamine reuptake inhibitors (NDRIs): These classes of antidepressants inhibit the neuronal reuptake of dopamine and norepinephrine (noradrenaline). 7 These include: Bupropion Selective serotonin reuptake enhancers (SSREs): Example of this class is Tianeptine Norepinephrine-dopamine disinhibitors (NDDIs): These antidepressants act by antagonizing the serotonin 5-HT 2C receptor which normally acts to inhibit norepinephrine and dopamine release, thereby promoting outflow of these neurotransmitters. Example is Agomelatine. Serotonin-norepinephrine reuptake inhibitors (SNRIs) Biogenic amines such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are neurotransmitters found in areas of the central nervous system (CNS) known to be important for regulation of cognitive function, mood, thermoregulation, pain sensation, sexual function, and various aspects of endocrine function related to homeostasis.
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