Introduction to Anxiolytic Drugs

Definition and purpose of anxiolytics

People can experience some time facing distress and feel insatiable. Did you ever think that overcoming the feeling of sadness, not feeling beneficial enough and a sense of sheer boredom would be harder to cope with, did you ever struggle or ever thought it was harder for you in comparison to anyone else, did you ever feel some decreased hope or did you ever be felt afraid of getting lost, ever come across with a change in your mood, alterations in your routines, sheer harshness to the people surrounding you, lack of inappropriate communication, hardness to find compatible baseline for your thoughts, lack of interest in daily life activities, did you ever felt accused of being not extrovert enough, having excuses for everything, difficulty of coping with your anger… etc. or expressed above, did you ever cope with anxiety?

Sometimes coexisting with depression, these two terms should not be confused with one another.³ In this piece, you can kindly find details of anxiolytics from a different scope of perspectives and different aspects.

Apart from adult cases, paediatric anxiety is also occurring. Dental fears can cause anxiety, too. This type of anxiety is called dental fear and anxiety (DFA) and it can worsen oral complications in paediatric patients.¹⁴ Novel strategies to overcome these specific problems should be included in the health agenda. Among the diseases with psychiatric conditions, the most widespread one is anxiety disorder.¹ 

Brief history of anxiolytic drug development

Four targets in this timeline, from 1960 to 2012, can be simply expressed chronologically as:

• 5-HT (Serotonin)¹
• Neuropeptide¹
• Glutamate¹
• Endocannabinoid¹

Twelve tests carried out with lab mice in anti-anxiety drug discovery period are:

• Conditioned fear (24 hours)¹
• Geller-seifter conflict (known as Geller Seifter Paradigm)¹
• Stress-induced hyperthermia (10 minutes)¹
• Ultrasonic distress vocalizations¹
• Elevated plus-maze¹
• Vogel conflict¹
• Conflict (other)¹
• Open-field¹
• Light/dark¹
• Social interactions¹

It can be said that the journey of anxiolytic drugs started with chlordiazepoxide approximately sixty years ago.² Without any controversy, this finding altered neuroscience concepts in depth. Furthermore, in a comparison, benzodiazepines can be found as the most commonly prescribed drug group among the other medications with a great prevalence rate. The synthesis of anxiolytic drugs has occurred since the 1960s.²

Mechanisms of Action

GABAergic System Modulation

Engaging GABA-A receptors through interaction

Apart from insomnia and general anaesthesia GABA-A receptors are also useful for the management of anxiety disorder.⁵ In order to express the significance of GABA-A receptors, its functionality should be understood well and therefore its use in neuro-pharmacology can be easily assessed. Therefore, the structure and the mechanism of action highlight great importance. GABA-A receptors are ligand-gated ion channels and these channels drive much of the fast neuronal inhibition observed in the brain.⁵

Improvements in inhibitory neurotransmission

Since the 1950s, alkyl carbamates have been used to treat epileptic seizures. As alkyl carbamates are also used for anxiety disorder treatment, As instance, Meprobamate, felbamate, retigabine, carisbamate, and flupirtine can be given as these kinds of anxiolytic agents with a danger to cause life-threatening adverse effects. All medically approved alkyl-carbamates have the ability to improve inhibitory neurotransmission by altering the GABA-A receptor, despite the fact that each has a different method of action.⁶

Impacts on the membrane potential and excitability of neurons

According to general scientific consensus, the excitability of neurons in the hippocampus leads to the occurrence of anxiety and thus, has a correlation with the development of anxiety disorders.⁷

Other Neurotransmitter systems

The modulation of Serotonin (5-HT) 

Buspirone can be used for some mild cases but a patient should be always cautious and aware of the occurrence of Serotonin toxicity, especially in combination therapies. In a case, it is observed that several side effects including confusion, incoordination, diarrhoea, diaphoresis, and myoclonus occurred when the second drug buspirone was added to the regimen of a patient who was already taking fluoxetine for his/her general anxiety disorder (GAD). The reason behind that was probably serotonin syndrome.⁸ In another case, combined serotonin toxicity is observed via the concurrent use of buspirone and citalopram.⁹ 

The role of Glutamate in anxiety

The attribution of hippocampus and anxiety correlation was aforementioned. Apart from that fact, it can be also expressed that the hippocampus is also associated with some neuro-inflammation. Nonetheless, it is important to understand that it is not related to all neuro-inflammation activity in the body. Glutamate can be evaluated as an alternative treatment for anxiety disorder; it is stated that drugs that target the glutamate system in DSM-5 anxiety disorders are now the subject of ongoing clinical trials. Furthermore, some glutamate receptors can be also beneficially used in the development of novel medications for the treatment of anxiety in the future.¹¹

Classification of Anxiolytic Drugs

Benzodiazepine use in the treatment of anxiety

Benzodiazepines target GABAergic systems.¹¹ One of the benzodiazepines that is most frequently administered to treat panic disorder and generalised anxiety disorder is Alprazolam. In addition, this active pharmaceutical ingredient carries a great risk of causing dependency as the substance has highly addictive properties.¹²

Lorazepam, a drug used on several occasions for anxiety disorder, and anxiety-related insomnia with rapid onset (if intravenous it extends from one to three minutes) is used for adults and favoured due to its quick onset of action. In addition to that, this agent can be also used off-label for its immediate tranquillising effects for agitated patients.¹³

Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin systems are the target of SSRIs, often known as second-generation antidepressants, which are used to treat anxiety disorders. Thus, its implication in pharmacological therapies for anxiolytic ailments proved its reputation with evidence-based outcomes.¹¹ 

Novel antidepressants with fewer side effects

Fewer side effects, but please do pay attention: “With side effects.” These side effects can be bothersome and perhaps novel therapy can be labelled as disappointing due to the fact that pharmacotherapy with newer agents can be still less effective in comparison to traditional agents.⁵

Side effects and safety considerations

Did you know that one-third of patients discontinue taking antidepressant medication because they have difficulty coping with the adverse effects, in case of tolerability issues?⁴ Apart from that, gastrointestinal problems, sleep disturbance, apathy, and fatigue are some widespread side effects.⁴ In accordance with the suggestion of the physician, the optimal choice should be considered in detail and from idealised consciousness for each patient in a tailor-made kind of manner.

Summary

Anxiety may exacerbate depression, while anxiety may worsen the depression. The correlation between them is still vague. In some cases also both of these ailments can co-exist.³ Implementation of the correct therapy based on the science of medicine and pharmacology carries great significance. Thus, clinical pharmacists and physicians have a great role and responsibility while ensuring a trustworthy atmosphere assisting patients in coping with anxiety, and providing scientific progress especially the continuum of publishing to educate the public and scientific audience. Elder patients should overcome the risk of polypharmacy and their medications should be regularly monitored and refrained from several dangers derived from the simultaneous use of drugs with a great quantity. Quality and the safety of the therapy should be firstly provided and then sustained. The aim of this health policy should be to eliminate and decrease the causes of anxiety, with international guidelines and amendments regulatory actions should be provided and it is best to remove the possibility of using active medicinal components improperly.¹⁶

Novel perspective

Nutritional supplements can be used in order to functionalize as reinforcements. Probiotics can be used to alleviate the symptoms of anxiety.¹⁵ Determining the use of dosages and the frequency of these ‘psychobiotics’ is critical. As it is said before, ‘the difference between poison and medicine is in the dose.’ Research in nutritional neuroscience should be carried out with consciousness and enhanced as a progressive process. Personalised therapies with the use of pharmacogenomics and epigenomics can be another milestone and thus, personalised medicine can be a milestone to diminish anxiety or anxiety-related complications.