This document discusses the mechanisms of action of benzodiazepines. It notes that benzodiazepines augment the effects of the inhibitory neurotransmitter GABA at GABA-A receptors. They can be selective for different GABA receptor subunits involved in sleep, anxiety, or addiction. The hypnotic and anxiolytic effects of benzodiazepines are explained by their actions on GABA receptors in the amygdala, hippocampus, and hypothalamic regions involved in sleep/wake regulation. Adverse effects and issues with dependence and withdrawal are also covered. Novel approaches to anxiolytic drugs targeting GABA receptors without addiction liability are mentioned.

1. Receptors, Neurons, Systems
Anxiolytic and Hypnotic Clinical Effects
Mechanisms of Sleep and Wakefulness
Selective and Nonselective Agents
Adverse Effects

2. Benzodiazepines Augment the Effects of GABA
*GABA is the main inhibitory neurotransmitter
in the brain.
*GABA neurons are inter-neurons.
*Benzodiazepines augment the effect of GABA.
*They exert their action only in the presence of
GABA – for this reason they are
called positive allosteric modulators (PAMs).

3. Benzodiazepines are Positive Allosteric
Modulators(PAMs) of GABA-A Receptors
Allosteric sites are all receptor sites where GABA itself does
not bind.
Allosteric modulators can be positive or negative.

4. GABA Cells are Inter-neurons

5. Cortical and limbic GABA Inter-Neurons are Implicated in
Neurodevelopmental Disorders (schizophrenia, autism, and
epilepsy).

6. The Interest in Benzodiazepines
Increased over the Past Decade
SELECTIVITY:
 For different GABA neurons
 For different receptor subtypes
 For the tonic GABA firing

7. Selectivity for GAB-A Receptor Subunits
GABA A receptors containing GABA A receptors containing
alpha 1 subunits are involved in alpha 2 or alpha 3 subunits are
sleep. involved in anxiety.

8. Alpha 1 Selective Hypnotics - Zaleplon and
Zolpidem
 The hypnotics zaleplon and zolpidem bind selectively to GABA-A receptors that contain
the alpha 1 subunit (sleep). This subunit is important for sedation and possibly for
anticonvulsant and amnesic actions.

9. Existing Benzodiazepines are Non-selective
 Benzodiazepines bind to GABA-A alpha subunits: alpha 1, alpha 2, alpha 3
and alpha 5.
 Each of these subunits is associated with different effects, and thus
benzodiazepines not only cause sedation but are also anxiolytic, cause muscle
relaxation, and have alcohol potentiating actions.

10. Selectivity for Phasic GABA Inhibition - Avoiding
Addiction
Benzodiazepine sensitive GABA A
receptors contain gamma and
alpha (1 through 3) and alpha 5
subunits are intra-synaptic and
mediate phasic inhibition triggered
by peak concentrations of
synaptically released GABA.
GABA A receptors containing
alpha 4, alpha 6 , gamma 1 or
delta subunits are located
extrasynaptically and
regulate tonic inhibition
(tonic inhibition is not addictive).

11. Benzodiazepines are Anxolytic as
well as Hypnotic Drugs
 ANXIOLYTIC EFFECT: Benzodiazepines inhibit the activation of
amygdala, by binding at GABA- A receptors in the amygdala.
 HYPNOTIC EFFECT: Benzodiazepines promote sleep by binding at
GABA-A receptors in the VLPO, causing sleepiness.

12. Activation of the Amygdala by the
Environment
Monoamines from the locus coeruleus
activate amygdala causing anxiety, panic
attacks, tremors, sweating, tachicardia,
hyperarousal and nightmares.
Benzodiazepines inhibit activation of
amygdala (silence the shout of amygdala).

13. Shout of Amygdala

14. Reexperiencing - Activation of the
Amygdala by Inner Cues
 Traumatic memories stored in the hippocampus can activate the amygdala,
causing the amygdala in turn to activate the hippocampus and generate a fear
response, REEXPERIENCING(PTSD).

15. Reexperiencing - Activation of the
Amygdala by the Hippocampus
Fear activated amygdala.

16. Hypnotic Effect of Benzodiazepines
Benzodiazepines are also hypnotic drugs.
The hypothalamus contains
the sleep and wakefulness
promoters:
VLPO (sleep promoter)
TMN (wakefulness promoter).

17. Arousal Spectrum
 The state of arousal is more complex than “awake” or “asleep”.
 Arousal exists as if on a dimmer switch, with many phases along the spectrum.

18. What Keeps Us Awake?
Histamine keeps the
brain awake.
HISTAMINE
(TMN)
Histamine promotes the CALM
wakefulness that helps problem
solving, creativity and cognition
(unlike the monoamines ).

19. Creative Wakefulness - Histamine

20. Tuberomammilary Nucleus (TMN) of Hypothalamus is the
Wakefulness Promoter (the coffee- house of the brain)
 TMN of hypothalamus contains histamine producing neurons that are
activated by glutamate and inhibited by GABA and Benzodiazepines.
 These neurons are the wakefulness promoter.
*Lateral hypothalamus
contains
orexin/hypocretin
neurons that promote
weight loss in addition
to wakefulness.

21. Ventro-Lateral Preoptic Nucleus of the
Hypothalamus(VLPO) - the Sleep Promoter
 VLPO nucleus contains GABA neurons that inhibit
TMN and thus promote sleep.
 Benzodiazepines augment the action of GABA in
VLPO nucleus.

22. The Balance of Sleep and Wakefulness
TMN SCN VLPO
SLEEP
PROMOTER:
INTERNAL CLOCK: Ventrolateral
WAKE PROMOTER: Suprachiasmatic nucleus preoptic area –
Tuberomammillary of the hypothalamus – VLPO-of the
nucleus –TMN-of the THE SWITCH (activated hypothalamus
hypothalamus promotes by light, melatonin). It promotes sleep
wakefulness( produces can promote either sleep (produces GABA )
histamine ) or wakefulness.

23. My Next Cup of Coffee
 Skinny Histamine Macchiato with orexin sprinkles

24. Exogenous GABA Does Not Cross the Blood Brain
Barrier(BBB)
 GABA is produced in the GABA-ergic neurons from the excitatory
neurotransmitter glutamate by the enzyme GAD (glutamic acid
decarboxilase).
SALE:
$12.99

25. Benzodiazepines – FDA Indications
 In addition to anxiety, benzodiazepines are indicated
for muscle tension, insomnia, status
epilepticus(diazepam), myoclonic
epilepsy(clonazepam), preoperative anesthesia, and
alcohol witdhrawal.
 Two benzodiazepines: alprazolam and lorazepam
have FDA indication for anxiety associated with
depression.
 Clonazepam and Alprazolam are indicated in the
treatment of panic disorder.

26. Benzodiazepines – Adverse Effects
 Sedation
 Lethargy
 Dependency/Withdrawal
 Respiratory depression
 Possible cognitive impairment.
 Safe in overdose: up to 30 times the normal daily dose. Usual
symptoms of overdose include sedation, drowsiness, ataxia, and
slurred speech. May result in respiratory depression in
combination with other CNS depressants. Management
includes gastric lavage, forced emesis, and assisted ventilation.
 Drug interactions:
1. drugs that increase benzodiazepine levels include P4503A4
inhibitors, ketoconazole, fluconazole, nefazodone.
2. drugs that decrease benzodiazepine levels include P4503A4
inducers such as carbamazepine.

27. What are Pro-Drugs?
 Three benzodiazepines are pro-drugs,(they are
inactive, but form active metabolites in the body):
 prazepam,
 clorazepate
 halazepam

28. Oxcarbazepine(pro-drug) is Converted to
Licarbazepine (active drug)

29. Lisdexamfetamine( Vyvanse) - a Pro-Drug
Lisdexamfetamine (a pro-drug) is converted in the
intestin to d-amphetamine (active form).
*Lisdexamphetamine is the only drug that has FDA approval for
adult ADHD.

30. Benzodiazepines - Subclasses
2-keto (chlordiazepoxide, clonazepam, clorazepate, diazepam,
halazepam, prazepam, and flurazepam).
The 2-keto drugs and their active metabolites are oxidized in the liver,
and because this process is relatively slow, these compounds have
relatively long half-lives.
3-hydroxy(lorazepam, oxazepam, temazepam)
The 3-hydroxy compounds are metabolized via direct conjugation with
a glucuronide radical, a process that is more rapid than oxidation
and does not involve the formation of active metabolites.
Triazolo (alprazolam, adinazolam, estazolam, and triazolam)
The triazolo compounds are also oxidized, however they have a more
limited active metabolites and thus shorter half-lives.

31. FDA Approved Benzodoazepine Hypnotics
Five benzodiazepines are FDA approved for insomnia are:
 flurazepam and quazepam, (ultra-long half-lives);
 triazolam (ultra-short half-life)
 estazolam and temazepam (moderate half-lives).

32. Benzodiazepine Properties
The effects of benzodiazepines depend on their
properties:
 1. half-life
 2. liposolubility
 3. receptor affinity

33. Liposolubility
 Highly lipophilic benzodiazepines such as diazepam
enter the brain more quickly, “turning on” the effect
promptly, but “turning off” the effect more quickly as
well as they disappear into body fat.
 Less lipophilic compounds such as lorazepam produce
clinical effects more slowly, but may provide more
sustained relief in spite of shorter half life.

34. Relative Receptor Affinity
 The higher their affinity for GABA-A receptors, the
more intense withdrawal symptoms they cause.
 High potency benzodiazepines such as lorazepam and
alprazolam have high receptor affinity – intense
withdrawal symptoms.
 Oxazepam has low receptor affinity – fewer
withdrawal symptoms.

35. Memory Impairment (fact or myth)
 Lucki et al. (1986) conducted a study on long-term
benzodiazepine treatment. It failed to show significant
cognitive impairment on psychometric tests.
 The most recent controlled study in this area failed to find
significant long-term cognitive effects for alprazolam XR in
panic disorder patients (Gladsjo et al. 2001).
 In spite of these studies some investigators believe that
cognitive impairment can occur, particularly in elderly
patients.

36. Benzodiazepines Might Cause
Memory Impairment in Elderly

37. How Addictive are Benzodiazepines?
 How long does one have to take a benzodiazepine before
withdrawal is seen with discontinuation?
 Studies in animals have indicated that benzodiazepines can
reinforce use and can produce physical dependence and
tolerance.
 Available data seem to reveal that benzodiazepines are
rarely sought after or craved in the sense that heroin or
cocaine are. Rather, they are used as part of a polysubstance
abuse pattern to modulate the effects of primary drug of
abuse(e.g. cocaine) or as a backup drug when more
euphoriant drugs are not available.

38. Benzodiazepines Potentiate the Effect of Alcohol

39. Tapering off Benzodiazepines
 Recommended reduction rate: no more than 10% per day.
 Common symptoms of withdrawal include jitteriness,
anxiety, palpitations, clamminess, sweating, nausea,
confusion and heightened sensitivity to light and
sound.
 Seizures represent the most worrisome of withdrawal
reactions, but fortunately they are rare.
 Seizures with abrupt diazepam withdrawal occur about 5-7
days after the drug is stopped.
 With shorter acting drugs (e.g. lorazepam, alprazolam)
withdrawal symptoms emerge more rapidly- 2 or 3 days.

40. Difficult Withdrawal
 Factors that make benzodiazepine withdrawal more
difficult include higher daily dose, shorter half-life,
longer duration of prior benzodiazepine therapy,
and more rapid taper.
 At the patient level, a diagnosis of panic disorder,
higher pretaper levels of anxiety or depression,
more personality disorder, and concomitant
alcohol or substance abuse make tapering more
difficult

41. Panic Control Treatment (PCT)
PCT is a type of CBT with an educational-experiential
approach aimed at having patients learn to tolerate somatic
symptoms of panic without undue anxiety.
A controlled study has shown that use of PCT in combination
with a very slow and cautious benzodiazepine taper (0.125 mg of
alprazolam every 2 days for patients taking more than 1 mg/day
initially, or 0.25 mg every 8 days once the dosage has been
reduced to 1 mg/day) is effective .
Most of the patients whose benzodiazepine use has been
successfully tapered with PCT were free of benzodiazepines 3
years later(Spiegel 1999).

42. Panic Control Treatment (CBT + very slow taper)

43. Novel GABA-A Anxiolytic Drugs
 Partial agonists that are selective for the alpha 2 or 3
subunits of the GABA-A receptors - anxiolytic without
causing sedation and without causing dependence.
 Inhibition of the GABA transporter (GAT) has been
shown to provide anxiolytic effects (like the anticonvulsant
TIAGABINE).
 It is possible that GABA-B receptors may have a role in
anxiety, thus positive modulators of those receptors are
potential therapeutic agents (the only GABA-B agents we
use today are Baclofen and sodium oxybate).

44. Happy Thaksgiving
Upon a day apart,
To praise the Lord with feast and song
In thankfulness of heart.
~Arthur Guiterman, The First Thanksgiving