1. Receptors, Neurons, SystemsAnxiolytic and Hypnotic Clinical Effects Mechanisms of Sleep and Wakefulness Selective and Nonselective AgentsAdverse Effects

2. 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). 3. 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. 4. GABA Cells are Inter-neurons 5. Cortical and limbic GABA Inter-Neurons are Implicated inNeurodevelopmental Disorders (schizophrenia, autism, andepilepsy). 6. The Interest in BenzodiazepinesIncreased over the Past DecadeSELECTIVITY: For different GABA neurons For different receptor subtypes For the tonic GABA firing 7. Selectivity for GAB-A Receptor SubunitsGABA A receptors containingGABA A receptors containingalpha 1 subunits are involved in alpha 2 or alpha 3 subunits aresleep. involved in anxiety. 8. Alpha 1 Selective Hypnotics - Zaleplon andZolpidem The hypnotics zaleplon and zolpidem bind selectively to GABA-A receptors that containthe alpha 1 subunit (sleep). This subunit is important for sedation and possibly foranticonvulsant and amnesic actions. 9. Existing Benzodiazepines are Non-selective Benzodiazepines bind to GABA-A alpha subunits: alpha 1, alpha 2, alpha 3and alpha 5. Each of these subunits is associated with different effects, and thusbenzodiazepines not only cause sedation but are also anxiolytic, cause musclerelaxation, and have alcohol potentiating actions. 10. Selectivity for Phasic GABA Inhibition - AvoidingAddictionBenzodiazepine sensitive GABA Areceptors contain gamma andalpha (1 through 3) and alpha 5subunits are intra-synaptic andmediate phasic inhibition triggeredby peak concentrations ofsynaptically released GABA.GABA A receptors containingalpha 4, alpha 6 , gamma 1 ordelta subunits are locatedextrasynaptically andregulate tonic inhibition (tonic inhibition is not addictive). 11. Benzodiazepines are Anxolytic as well as Hypnotic Drugs ANXIOLYTIC EFFECT: Benzodiazepines inhibit the activation ofamygdala, by binding at GABA- A receptors in the amygdala. HYPNOTIC EFFECT: Benzodiazepines promote sleep by binding atGABA-A receptors in the VLPO, causing sleepiness. 12. 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). 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 fearresponse, REEXPERIENCING(PTSD). 15. Reexperiencing - Activation of theAmygdala by the HippocampusFear 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 thebrain awake.HISTAMINE(TMN)Histamine promotes the CALMwakefulness that helps problemsolving, creativity and cognition(unlike the monoamines ). 19. Creative Wakefulness - Histamine 20. Tuberomammilary Nucleus (TMN) of Hypothalamus is theWakefulness Promoter (the coffee- house of the brain) TMN of hypothalamus contains histamine producing neurons that areactivated 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 theHypothalamus(VLPO) - the Sleep Promoter VLPO nucleus contains GABA neurons that inhibitTMN and thus promote sleep. Benzodiazepines augment the action of GABA inVLPO nucleus. 22. The Balance of Sleep and WakefulnessTMN SCNVLPO SLEEP PROMOTER:INTERNAL CLOCK:VentrolateralWAKE PROMOTER:Suprachiasmatic nucleuspreoptic area Tuberomammillaryof the hypothalamus VLPO-of thenucleus TMN-of the THE SWITCH (activatedhypothalamushypothalamus promotes by light, melatonin). It promotes sleepwakefulness( 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 BrainBarrier(BBB) GABA is produced in the GABA-ergic neurons from the excitatoryneurotransmitter glutamate by the enzyme GAD (glutamic aciddecarboxilase). 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. Usualsymptoms of overdose include sedation, drowsiness, ataxia, andslurred speech. May result in respiratory depression incombination with other CNS depressants. Managementincludes gastric lavage, forced emesis, and assisted ventilation. Drug interactions:1. drugs that increase benzodiazepine levels include P4503A4inhibitors, ketoconazole, fluconazole, nefazodone.2. drugs that decrease benzodiazepine levels include P4503A4inducers 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 toLicarbazepine (active drug) 29. 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. 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 HypnoticsFive 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 PropertiesThe effects of benzodiazepines depend on theirproperties: 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-termbenzodiazepine treatment. It failed to show significantcognitive impairment on psychometric tests. The most recent controlled study in this area failed to findsignificant long-term cognitive effects for alprazolam XR inpanic disorder patients (Gladsjo et al. 2001). In spite of these studies some investigators believe thatcognitive impairment can occur, particularly in elderlypatients. 36. Benzodiazepines Might CauseMemory Impairment in Elderly 37. How Addictive are Benzodiazepines? How long does one have to take a benzodiazepine beforewithdrawal is seen with discontinuation? Studies in animals have indicated that benzodiazepines canreinforce use and can produce physical dependence andtolerance. Available data seem to reveal that benzodiazepines arerarely sought after or craved in the sense that heroin orcocaine are. Rather, they are used as part of a polysubstanceabuse pattern to modulate the effects of primary drug ofabuse(e.g. cocaine) or as a backup drug when moreeuphoriant 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 andsound. Seizures represent the most worrisome of withdrawalreactions, but fortunately they are rare. Seizures with abrupt diazepam withdrawal occur about 5-7days 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 3subunits of the GABA-A receptors - anxiolytic withoutcausing sedation and without causing dependence. Inhibition of the GABA transporter (GAT) has beenshown to provide anxiolytic effects (like the anticonvulsantTIAGABINE). It is possible that GABA-B receptors may have a role inanxiety, thus positive modulators of those receptors arepotential therapeutic agents (the only GABA-B agents weuse today are Baclofen and sodium oxybate). 44. Happy ThaksgivingUpon a day apart,To praise the Lord with feast and songIn thankfulness of heart.~Arthur Guiterman, The First Thanksgiving