Treatment of anxiety

Insomnia is sleep disturbance and can be manifest as difficulty falling asleep, poor quality of sleep or premature awakening. Insomnia can be secondary to other conditions, for example anxiety or depression. Other causes are factors such as stress and excessive noise, jet lag, shift work, physical illness and pain, stimulants (coffee and tea), sleep apnoea or poor habits at bedtime. 

Drug therapy is not the only possibility. Psychotherapy therapy techniques such as relaxation, cognitive behavioural therapy and counselling can benefit some patients. 

Drug therapy of anxiety is mainly with a group of dmgs called benzodiazepines. 

For treatment of anxiety, benzodiazepines such as diazepam and oxazepam are used because they have a slower onset of action with a longer duration than others. 

Benzodiazepine anxiolytics have been prescribed to almost anyone with stress-related symptoms, unhappiness or minor physical trauma. This kind of use is now considered unsuitable. Neither are they considered appropriate for treating depression, phobic or obsessional states or chronic psychosis. 

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Ethanol (1) is the most widely used antianxiety agent. In the 1950s, the pioneering work of Berger on the muscle relaxant mephenesin [59-47-17, (71), led to the identification of meprobamate (24) as an effective agent for the treatment of anxiety. 

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Benzodiazepines, ie, the hiU BZR agonists, are prescribed for anxiety, insomnia, sedation, myorelaxation, and as anticonvulsants (97). Those benzodiazepines most commonly prescribed for the treatment of anxiety disorders are lorazepam (19), alprazolam (20), diazepam (21), bromazepam (22), chlorazepate (23), and oxazepam (24). These dmgs together represent about 70% of total... 

Dia2epam [439-14-5] (60) and clona2epam [1622-61 -3] (61) suppress cough induced by electrical stimulation of the lower brainstem of cats (90). Clona2epam and dia2epam adrninistered intravenously are about thirty-five times and six times more potent than codeine, respectively. Nevertheless, the compounds have not been widely used as antitussives in humans. Dia2epam is used in the treatment of anxiety, and clona2epam as an anticonvulsant. 

Esterification of the corresponding quinoline-4-carboxylic acid gave the ester 511 which upon reaction with pyrrolidine in THE gave the amide 512. Its phosphorylation and reaction with 513 in presence of KOBu afforded 514 which is useful in the treatment of anxiety, sleep disorders, panic states, convulsions, muscle disorders (95WOP9514020) and chronic neurodegen-erative diseases (97WOP9700074) (Scheme 87). 

More then a dozen representatives of the above ring systems were introduced into the human therapy. Actisomide (2) and trequinsin (3) are used as antiarrhytmic and antihypertensive agents, respectively. Sunepitron (4), a a 2-adrenoceptor antagonist, is under clinical trials for the treatment of anxiety and depression. Representatives of the third generation of antibacterial quinolone-3-carboxylic acids the blockbluster ofloxacin (5), its levorotatory enantiomer, levofloxacin (6), and rufloxacin (7) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (8) is under development. Praziquantel (9) is widely applied for the treatment of schistosomes- and cestode-caused infection in both veterinary and human therapies (Scheme 4). 

Anxiolytics are drugs used for the treatment of anxiety disorders. Apart from benzodiazpines, a frequently used anxiolytic is the 5HT1A (serotonin) receptor agonist buspiron, which has no sedative, amnestic or muscle-relaxant side effects, but whose action takes about a week to develop. Furthermore, it is less efficaceous than the benzodiazepines. Buspiron s mechanism of action is not fully understood. 

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

Benzodiazepines are amongst the most frequently prescribed drugs they have well-established uses in the treatment of anxiety disorders (anxiolytics) and insomnia, preanaesthetic sedation, suppression of seizures, and muscle relaxation. 

The definition of desired therapeutic and side effects in the case of the benzodiazepines very much depends on the clinical problem in question. The sedative and hypnotic actions are desired effects in the treatment of insomnia, but undesired effects in the treatment of anxiety disorders. Effects that are usually undesired include daytime drowsiness, potentiation of the sedative effects of ethanol, and anterograde amnesia. They are mediated via the benzodiazepine site of GABAa receptors, since they can be antagonized with flumazenil. 

Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146—150, 1981 Ciraulo DA, Nace E Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Jaffe JH, et al Intravenous pharmacokinetics of 2-hydroxy-imipramine in alcoholics and normal controls. J StudAlcohol 51 366-372, 1990 Ciraulo DA, Knapp CM, LoCastro J, et al A benzodiazepine mood effect scale reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism. Am J Drug Alcohol Abuse 27 339—347, 2001 Collins MA Tetrahydropapaveroline in Parkinson s disease and alcoholism a look back in honor of Merton Sandler. Neurotoxicology 25 117-120, 2004 COMBINE Study Research Group Testing combined pharmacotherapies and behavioral interventions in alcohol dependence rationale and methods. Alcohol Clin Exp Res 27 1107-1122, 2003a... 

Goldberg HL, Finnerty RJ The comparative efficacy of buspirone and diazepam in the treatment of anxiety. Am J Psychiatry 136 1184-1187, 1979 Goldman D Recent developments in alcoholism genetic transmission. Recent Dev Alcohol 11 231-248, 1993... 

McRae AL, Sonne SC, Brady KT, et al A randomized, placebo-controlled trial of buspirone for the treatment of anxiety in opioid-dependent individuals. Am J Addict 13 53-63, 2004... 

Lejoyeux et al. 1998). Similar to opioid-dependent persons, these patients reported that they use benzodiazepines to self-medicate anxiety, insomnia, and alcohol withdrawal and, less commonly, to enhance the effects of ethanol. Approximately l6%-25% of patients presenting for treatment of anxiety disorders abuse alcohol (Kushner et al. 1990 Otto et al. 1992). Controversy exists concerning appropriate benzodiazepine prescribing in this population (Cir-aulo and Nace 2000 Posternak and Mueller 2001). 

The ultra-short-acting barbiturates include methohexital sodium (Brevi-tal) and thiopental sodium (Pentothal). These agents are used as anesthetics and are administered intravenously. Barbiturates with short-to-intermediate duration of action are used for their sedative-hypnotic effect in the treatment of anxiety. These medications include amobarbital (Amytal), butabarbital (Butisol), sodium pentobarbital (Nembutal), and secobarbital (Seconal). 

Ciraulo DA, Nace EP Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Greenblatt DJ, et al Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men. J Clin Psychiatry 49 333—337, 1988a... 

Pigott TA (1999). Gender differences in the epidemiology and treatment of anxiety disorders./Clin Psychiatry 60 (suppl. 18),... 

Bandelow B, Zohar J, Hollander E, et al. Guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders. World J Biol Psychiatry 2002 3 171-199. 

This type of action is found in kanna, or Sceletium expansum and Sceletium tortuosum (Aizoaceae), which have been used by South African shamans from prehistoric times to enhance animal spirits, sparkle the eyes, and to stimulate gaiety. The active constituent of kanna is a serotonin-like alkaloid called mesembrine, which is a potent serotonin re-uptake inhibitor—hence, some potential for the treatment of anxiety and depression however, careful clinical trials must be performed. 

The family Myristicaceae has about 16 genera and 380 species of tropical lowland rainforest trees that are easily recognizable in field collection because of their bloodlike sap, conical crown, and nutmeg-like fruits. A very interesting feature of Myristi-caeae species are their ability to elaborate series of neuroactive indole alkaloids, because it produces neuroactive indole alkaloids, which might hold potential for the treatment of anxiety, mood disorders, and other psychological disturbances. 

How might drugs with CNS depressant properties aid in the treatment of anxiety disorders ... 

Argyropoulous SV, Sandford JJ and Nutt DJ (2000). The psychobiology of anxiolytic drugs. Part 2 Pharmacological treatments of anxiety. Pharmacology and Therapeutics, 88, 213-227. 

Ilaria RL, Thornby JI and Fann WE (1981). Nabilone, a cannabinoid derivative, in the treatment of anxiety neuroses. Current Therapeutic Research, 29, 943-949. 

Charney, D. S. and Deutch, A. A functional neuroanatomy of anxiety and fear implications for pathophysiology and treatment of anxiety disorders. Crit. Rev. Neurobiol. 10 419 46,1996. 

A number of medications used in the treatment of anxiety have effects on serotonin neurotransmission (Ch. 13). These medications include tricyclic antidepressant medications, SSRIs, and monoamine oxidase inhibitors (MAOIs). However, because these medications take weeks to exert their full anxiolytic effects, it is unlikely that blocking the reuptake (and thus increasing synaptic levels) of either serotonin or norepinephrine selectively is responsible for their anxiolytic properties — rather it is suspected that the therapeutic effects are due to changes in gene expression, protein levels, and eventually changes in synaptic connections between neurons. 

GABA. The GABA system is the primary target for the acute treatment of anxiety. The benzodiazepines (BDZs)... 

Data from American Psychiatric Association. Diagnostic and Statistical Manuai of Mental Disorders, 4th edv text revision. Washington, DC American Psychiatric Association, 2000 429-484 and Baldwin DS, Anderson iMr Nutt DJr et al. Evidence-based guidelines hr the pharmacological treatment of anxiety disorders Recommendations from the British Society for Psychopharmacology. J Psychopharmacology 2005 19 567-596. 

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