Anti anxiety

• Sedative


  Induces drowsiness or sleep
• Hypnotic


  Induces sleep
• Limbic system


  • Emotional / irrational behavior
• ANS


  • Modified "fight or flight"; CVS, GI, sweating, tremors, loss appetite
• Reticular formation


  • Activation of RAS, hypervigilance, increased muscle tension, insomnia
• ANTIANXIETY DRUGS


  • Benzodiazepines
  • Barbiturates
• Mechanism of Action of GABA

  1. GABA is an inhibitory transmitter that hyperpolarizes neurons by allowing the influx of negatively charged Cl ions

  2. GABA A receptor activation requires binding of 2 molecules of GABA, one to each alpha subunit, generates fast IPSPs (inhibitory post-synaptic potentials)
• Benzodiazepines


  Increase the inhibitory effect of GABA by increasing the frequency of ion channel opening & greater Cl ion influx; only work if GABA is present / bound to receptors
• Barbiturates

  Can open the Cl channel independent of GABA
• Main Pharmacologic Sites of Benzodiazepine Action

  • Limbic system - antianxiety effect (alpha 2 subtype of Cl ion channel)
  • Reticular formation - sedation / hypnosis (alpha 1 subtype of Cl ion channel
  • Cortex - anticonvulsant effect (alpha 1 subtype)
  • Spinal cord - skeletal muscle relaxation (alpha 2 subtype)
• Benzodiazepine receptor


  Part of the GABA A receptor complex
• Short-Acting Benzodiazepine Drugs


  • Elimination t1/2 less than 20 hrs
  • Do not form active metabolites, or the metabolites formed do not significantly contribute to the pharmacologic effect
  • Generally only require phase 2 biotransformation, i.e. glucuronidation
• Long-Acting Benzodiazepine Drugs


  • Elimination half-life over 20 hrs
  • Form multiple active metabolites with long half-lives of 50-200 hrs
  • Require phase 1 oxidation/hydroxylation and phase 2 biotransformation before elimination
  • Phase 1 oxidation decreases with age, therefore the half-life increases ~ age
• Pharmacokinetics of Single Dose Diazepam

  • Very lipid soluble
  • Rapid redistribution from brain to other tissues
  • Duration of action after one single dose is short, 2-4 hrs, less than lorazepam
  • Chronic dosing required for duration to increase
• Pharmacokinetics of Lorazepam


  • Lower degree of lipid solubility, more water soluble than diazepam
  • Slower rate of redistribution from brain to other tissues
  • Extrahepatic conjugation (does not exert excessive CNS depression)
  • Single dosage provides a longer duration of action than single dosage of diazepam
• Benzodiazepines are not indicated for breathing disorder insomnia
• Anterograde Amnesia


  Can't recall events after some point in time (new memory)
• Retrograde Amnesia


  Can't recall events before certain point in time (long-term memory)
• CNS depressants usually affect new memory to cause anterograde amnesia, demonstrated by poor recall and confusion about events while under the influence of drug
• Flunitrazepam "roofies", date-rape drug, not available in USA
• Adverse Effects of Benzodiazepines


  • Initial sedation, 1-3 days, tolerance 1-2 weeks
  • Lightheadedness, mental confusion
  • Anterograde amnesia, usually with IV / higher oral doses
  • Respiratory depression usually only with preexisting respiratory conditions or drug interactions with other depressants, alcohol, barbs, etc.
  • Increase in CNS depressant effects if combined with antidepressant drugs (i.e., TCA's), antihistamines and some antihypertensive drugs
  • Dependency / abuse potential
• Flumazenil


  • Benzodiazepine competitive antagonist
  • Used to reverse depression in OD or after IV anesthesia with benzodiazepine
  • Short duration of action, ~ 1 hr; may have to be repeated
  • May precipitate anxiety and panic attacks, withdrawal, and/or convulsions in dependent or benzo-treated epileptics
• Drug Tolerance


  • Pharmacodynamic tolerance, some physiologic adaptation to CNS effect, especially the sedative effects
  • No evidence of pharmacokinetic tolerance (enzyme induction) has been demonstrated
• Types of Benzodiazepine Dependence


  • Drug not being used therapeutically (Abuse Dependency)
  • Reliance on drug for therapeutic use (Therapeutic Use Dependency)
• Abuse Dependency


  • Progressive escalation of dosage
  • Development of tolerance and awareness of dependency when drug not present
  • Withdrawal is variable, mild to severe and may include seizures
• Therapeutic Use Dependency


  • Dosage usually remains constant, tolerance to antianxiety usually minimal
  • May experience withdrawal symptoms after chronic use & abrupt cessation
  • Withdrawal symptoms of insomnia, tremors (hyperreflexia), sweating, anxiety, agitation; drug t1/2 determines appearance of symptoms
  • Need to wean pt off drug gradually
• Buspirone


  • First of new drug class, azapirones
  • Antianxiety effect, no anticonvulsant or significant sedation / hypnosis effects; slow onset of action, 1-2 weeks
  • Main indication: Generalized anxiety disorder
  • Partial agonist on postsynaptic 5HT1A serotonin receptors (decs 5HT activity); other actions on presynaptic 5HT receptors
  • Pharmacokinetics: undergoes 1st pass metabolism, t1/2 2-3 hrs
  • Headache, dizziness, dry mouth, drowsy
  • No cross tolerance with benzos, no evidence of dependency
• Drug Classes


  • Barbiturates
  • Benzodiazepines
  • Miscellaneous Drugs (zolpidem, zaleplon, eszopiclone)
  • Chloral hydrate and other older drugs
• Barbiturates


  • No longer recommended for sedation/hypnosis
• Miscellaneous Drugs


  • Non-benzodiazepines: selective for alpha 1 subtype of Cl ion channel
  • Have less effect on REM and slow wave sleep, less rebound insomnia & tolerance development/abstinence withdrawal; less amnestic and day-after psychomotor depression than benzos
• Barbiturate Classification


  • Long Acting - Phenobarbital 6-12 hr
  • Intermediate/Short Acting - Pentobarbital 4-6 hr, Secobarbital 2-4 hr
  • Ultrashort Acting - Thiopental 15-30 min
• Barbiturate Site of Action

  • Reticular activating system > cortex for sedation/hypnosis
• Barbiturate Mechanism of Action

  • Facilitation of GABA / Cl - influx\ hyperpolarization, channels stay open longer vs benzos/open more frequently
  • Can open channel independently of GABA, no "ceiling effect" compared to benzodiazepines
  • Nonspecific depression ~ lipid solubility
  • CNS depression also caused by reduction of glutamate-induced depolarizations, esp. at higher doses
• Barbiturate Pharmacokinetics


  • Redistribution ~ to lipid solubility
  • Biotransformation ~ to lipid solubility
  • Microsomal liver enzyme induction (lipid solubility and long t1/2) esp. phenobarb
  • Tolerance, both pharmacokinetic (enzyme induction) and pharmacodynamic (CNS adaptation)
  • Renal excretion (primary); alkalinization of urine will facilitate excretion
• Barbiturate CNS Effects


  • SED>HYP>ANES>COMA>DEATH
  • Paradoxical excitement in elderly sed/hyp^NREM 2; decreased SWS & REM, REM rebound
  • Psychological effect\ wellbeing
  • Anticonvulsant \ antiepileptic
  • Decreased hypothalamic function
  • Respiratory depression / laryngospasm; more pronounced when given IV