Receptors, Neurons, SystemsAnxiolytic and Hypnotic Clinical Effects Mechanisms of Sleep and Wakefulness Selective and Nonselective Agents Adverse Effects
Benzodiazepines Augment the Effects of GABA*GABA is the main inhibitory neurotransmitterin 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 arecalled positive allosteric modulators (PAMs).
Benzodiazepines are Positive AllostericModulators(PAMs) of GABA-A ReceptorsAllosteric sites are all receptor sites where GABA itself doesnot bind.Allosteric modulators can be positive or negative.
Cortical and limbic GABA Inter-Neurons are Implicated inNeurodevelopmental Disorders (schizophrenia, autism, andepilepsy).
The Interest in BenzodiazepinesIncreased over the Past Decade SELECTIVITY: For different GABA neurons For different receptor subtypes For the tonic GABA firing
Selectivity for GAB-A Receptor SubunitsGABA A receptors containing GABA A receptors containingalpha 1 subunits are involved in alpha 2 or alpha 3 subunits aresleep. involved in anxiety.
Alpha 1 Selective Hypnotics - Zaleplon andZolpidem 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.
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.
Selectivity for Phasic GABA Inhibition - AvoidingAddiction 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).
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.
Activation of the Amygdala by the EnvironmentMonoamines from the locus coeruleusactivate amygdala causing anxiety, panicattacks, tremors, sweating, tachicardia,hyperarousal and nightmares.Benzodiazepines inhibit activation ofamygdala (silence the shout of amygdala).
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).
Reexperiencing - Activation of theAmygdala by the Hippocampus Fear activated amygdala.
Hypnotic Effect of Benzodiazepines Benzodiazepines are also hypnotic drugs. The hypothalamus contains the sleep and wakefulness promoters: VLPO (sleep promoter) TMN (wakefulness promoter).
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.
What Keeps Us Awake?Histamine keeps thebrain awake.HISTAMINE (TMN)Histamine promotes the CALMwakefulness that helps problemsolving, creativity and cognition(unlike the monoamines ).
Tuberomammilary Nucleus (TMN) of Hypothalamus is theWakefulness 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.
Ventro-Lateral Preoptic Nucleus of theHypothalamus(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.
The Balance of Sleep and Wakefulness TMN SCN VLPO SLEEP PROMOTER: INTERNAL CLOCK: VentrolateralWAKE PROMOTER: Suprachiasmatic nucleus preoptic area –Tuberomammillary of the hypothalamus – VLPO-of thenucleus –TMN-of the THE SWITCH (activated hypothalamushypothalamus promotes by light, melatonin). It promotes sleepwakefulness( produces can promote either sleep (produces GABA )histamine ) or wakefulness.
My Next Cup of Coffee Skinny Histamine Macchiato with orexin sprinkles
Exogenous GABA Does Not Cross the Blood BrainBarrier(BBB) GABA is produced in the GABA-ergic neurons from the excitatory neurotransmitter glutamate by the enzyme GAD (glutamic acid decarboxilase). SALE: $12.99
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.
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.
What are Pro-Drugs? Three benzodiazepines are pro-drugs,(they are inactive, but form active metabolites in the body): prazepam, clorazepate halazepam
Oxcarbazepine(pro-drug) is Converted toLicarbazepine (active drug)
Lisdexamfetamine( Vyvanse) - a Pro-DrugLisdexamfetamine (a pro-drug) is converted in theintestin to d-amphetamine (active form). *Lisdexamphetamine is the only drug that has FDA approval for adult ADHD.
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.
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).
Benzodiazepine Properties The effects of benzodiazepines depend on their properties: 1. half-life 2. liposolubility 3. receptor affinity
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.
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.
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.
Benzodiazepines Might CauseMemory Impairment in Elderly
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.
Benzodiazepines Potentiate the Effect of Alcohol
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.
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
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).
Panic Control Treatment (CBT + very slow taper)
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).
Happy Thaksgiving Upon a day apart, To praise the Lord with feast and song In thankfulness of heart. ~Arthur Guiterman, The First Thanksgiving