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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Thursday, March 15, 2012

Benzodiazepine Vault

Basic:

Benzodiazepines are widely used in the treatment of acute (and sometimes chronic) anxiety and panic attacks or disorders, muscle spasms, insomnia and sleep disorders, convulsions, seizures and epileptic disorders, and to a lesser extent as adjuncts or potentiators given alongside analgesics in the treatment of pain. Benzodiazepines are often used for their hypnotic properties as adjuncts to surgical anaesthesia.

The first benzodiazepine was chlordiazepoxide, synthesized by chemist Leo Sternbach at Hoffman La Roche in the 1950's & eventually marketed as Librium. It was soon followed by diazepam (i.e. Valium) in 1963.

Some of the more commonly used benzodiazepines (by trade name and ingredient) include Valium (diazepam), Xanax (alprazolam), Librium (chlordiazepoxide), Klonopin (clonazepam), and Versed (midazolam).

Most benzodiazepines are legally classified as schedule IV controlled substances. Use or possession without a prescription is illegal in the US.

Pharmacology:

Benzodiazepines act on GABAergic sites located throughout the limbic system, brainstem & upper spinal cord, and thalamic regions of the midbrain. GABA sites in these areas (including the the HPA axis) modulate autonomic arousal, emotion, and consciousness, by reducing neurotransmission in excitatory circuits.

Benzodiazepines produce their effects by binding to specific sub-units of the GABA-A receptor complex, in affect enhancing the inhibitory activity of GABA. GABA-A sites are targeted by various drugs (aside from benzodiazepines), including ethanol, nonbenzodiazepines, barbiturates, and inhalable anaesthetics.

The enhancement of GABA activity induced by benzodiazepines leads to reduced communication between neurons (i.e. inhibition). Result being, a calming effect on areas of the brain and CNS. The anxiolytic and sedative properties of a benzodiazepine are due to suppressed activity of the hypothalamic pituitary adrenal (HPA) axis; which consists of numerous areas of the brain responsible for mediating arousal and stress response.

GABA receptors mediate inhibition of the central nervous system; and bind the natural agonistic neurotransmitter gamma-aminobutyric acid. These receptors play a braking role on the nervous system, by slowing or stopping the firing of other neurotransmitters. Activation of GABA receptors at post synaptic sites inhibits the transduction of the neurotransmission which it receives, while activation of presynaptic GABA receptors inhibits neurotransmission into the synaptic cleft and on to the post synaptic neuron.

GABA activity at both pre and post synaptic sites leads to a net decrease in function of a particular visceral, cortical, or spinal area. GABAergic drugs play many roles in both primary and psychiatric practice or elsewhere, generally for their anxiolytic, sedative, hypnotic, amnesic, muscle relaxant, and apathetic effects.

More on the GABA-A receptor complex 

Safety:

Benzodiazepines have largely taken the place of barbiturates as the sedatives of choice for most purposes. They are safer and less toxic than their predecessors; an overdose on benzodiazepines alone is unlikely to occur. Overdose is most likely to occur when benzodiazepines are taken in conjunction with other CNS depressants such as alcohol or opioids.

However, acute toxicity and overdose is not the only consideration with benzodiazepines. Long term use is associated with some serious side effects and adverse events (see effects). It is for this reason that the appropriateness of chronic benzotherapy has been questioned.

Summary of Use:

Benzodiazepines are most popular in treating acute agitation, anxiety and panic attacks. Most recognize their value for the acute treatment of these states, while their efficacy and safety for chronic therapy is debated - none the less, daily benzodiazepine therapy for long term periods is relatively common.

In the case of protracted, severe anxiety - some practitioners endorse chronic benzodiazepine use, while others instead reccommend SSRI antidepressants for chronic use, with benzodiazepines reserved for short course therapy during the first few weeks of SSRI or MAOI treatment and/or intermittently thereafter - this is of course assuming that the anxiety is depression related, as opposed to being a manifestation of anxiety or panic disorder, in which case antidepressants may not even be worth trying. In treating protracted anxiety and panic, it is important to distinguish between symptomatic anxiety (often related to major depression), and actual anxiety or panic "disorders" (with no depressive component) - this distinction is relevant in selecting a drug for treatment, not to mention in establishing whether a particular drug is being given for the purpose of treatment or palliation.

Benzodiazepine Relative Potency Chart 
Benzodiazepines are useful in countering the the initial side effects associated with early SSRI therapy, and reducing anxiety symptoms temporarily while the antidepressants take effect over days to weeks (this is given the antidepressants are even effective - recent data shows they work no better than placebo, and the monoamine hypothesis of depression and anxiety spectrum disorders has long been discredited). 

Benzodiazepines are frequently used in the surgical setting, for their hypnotic-anaesthetic properties - i.e. surgical anaesthesia, procedural sedation/analgesia. In the emergency department, benzodiazepines are given to patients experiencing psychosis or severe agitation - often alongside antipsychotics. They are also useful in reducing the edginess or panic often associated with stimulant or psychedellic use.

Benzodiazepines are a first line treatment for alcohol detox and withdrawal. They will substitute fully for alcohol in alcohol-dependent subjects. Benzodiazepines are modestly effective in reducing some symptoms of opioid withdrawal.

Benzodiazepines are used, legally or illegally, to potentiate the sedative and analgetic effects of CNS depressants such as opioid analgesics. Also used to counter the edginess associated with stimulant or psychedellic use. Where it pertains to casual or illicit use, Benzodiazepines serve a supplemental role rather than a primary role.

Effects:

Short term effects include anxiolysis, relaxation, cognitive impairment, muscle-weakness & social disinhibition. Higher doses produce hypnosis, anaesthesia & anterograde amnesia.

Long term effects include mental dullness & cognitive impairment, memory loss, paradoxical anxiety & panic symptoms, tolerance & dependence.


Have potential to produce tolerance and dependence with extended use. Benzodiazepine withdrawal syndrome is similar to alcohol withdrawal and may lead to seizures and morbidity (i.e. death).

Benzodiazepines themselves produce little to no euphoria & theoretically should have little potential for abuse. Regardless, deadbeat drunks, teens, part animals & dull-witted individuals gravitate toward benzo's for the relaxation, social disinhibition and psychomotor & cognitive retardation they provide.

Short term effects include anxiolysis, relaxation, cognitive impairment, muscle-weakness & social disinhibition. Higher doses produce hypnosis, anaesthesia & anterograde amnesia.

Long term effects include mental dullness & cognitive impairment, memory loss, paradoxical anxiety & panic symptoms, tolerance & dependence.

Benzodiazepines have the potential to produce tolerance and dependence with extended use. Benzodiazepine withdrawal syndrome is similar to alcohol withdrawal and may lead to seizures and morbidity (i.e. death).

Will substitute for alcohol in alcohol withdrawal. Modestly helpful in treating symptoms of opioid withdrawal; reducing agitation, muscle spasms, and insomnia. Commonly used during alcohol & narco-withdrawal.

Benzodiazepines themselves produce little to no euphoria & theoretically should have little potential for abuse. Regardless, deadbeat drunks, teens, part animals & dull-witted individuals gravitate toward benzo's for the relaxation, social disinhibition and psychomotor & cognitive retardation they provide.

Commonly Used Benzodiazepines - Half Lives & Time to Peak:

Chlordiazepoxide - anxiolytic, hypnotic, muscle relaxant, amnestic

1-4h to peak, 24-100h half life

Diazepam - sedative, anxiolytic, anticonvulsant, hypnotic, muscle relaxant, amnestic

1-2h to peak, 30-200h half life (active metabolite half life)

Alprazolam - anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsant, amnestic

1-2h to peak, 9-20h half life (11.2h)

Clonazepam - anxiolytic, anticonvusant, sedative, amnestic

1-4h to peak, 10-60h half life

Triazolam - hypnotic, amnestic, anxiolytic, sedative, anticonvulsant, muscle relaxant

1-2h to peak, 1.5-5h half life

Estazolam - anxiolytic, sedative, anticonvulsant, muscle relaxant

0.5-0.6h to peak, 8-24h half life

Lorazepam - anxiolytics, sedative, hypnotic, amnestic, anticonvulsant, muscle relaxant, antiemetic

2-4h to peak,  8-24h half life

Temazepam - anxiolytic, anticonvulsant, muscle relaxant, hypnotic

2.5h to peak, 3-25h half life

Data Sources: 


Clinical Handbook of Psychiatric Drugs, 4th Revised Edition


http://www.mental-health-today.com/rx/benzo.htm 


References and Further Offsite Reading:

Intro to GABAergic Drug Action

Intro to Benzodiazepine Pharmacology

Benzodiazepine Potency and Half Life Reference 


1 comment:

  1. Great information shared by you !!! Keep posting like this i like the way of your writing style. . Anaesthesia Circuits

    ReplyDelete