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Sedative-Hypnotic Drugs (Classification of anxiolytic & hypnotic drugs…

- - - - pharmacodynamics
        
        Atypical Anxiolytic, No hypnotic, anticonvulsant or muscle relaxant
      - pharmacokinetics
        
        Not a GABAA-R drug; Acts at 5-HT1A (partial agonist) and D2
        
        Cannot substitute for a BDZ
      - Does not produce tolerance & physical dependence
      - Side effects: nausea, dizziness, headache, tachycardia,…
  - - - Organ effects
        
        General Uses: Anxiety- w/ or w/o Depression; Hypnosis; Panic Disorders (alprazolam); Spasticity (diazepam); Premedication for Surgery (midazolam in beginning of anesthesia); Alcohol Withdrawal; Adjunct in disorders where anxiety may worsen condition; Anticonvulsant (clonazepam, diazepam); *CENTRAL MUSCLE RELAXANT (DIAZEPAM)
      - mech of action
        
        Enhance GABAA-R responses by binding to different site of GABAA R/ Cl channel
        incr frequency of opening;
        Are NOT GABA mimetics; Enhance Neuronal Inhibition
    - - Mostly Psychomotor and Cognitive; more apparent in the elderly;
      - sometimes respiratory depression
        
        At therapeutic doses produce respiratory depression in px w/ pulmonary disease;
        
        Normal doses may cause depression in hypovolemic states,CHF and other cardiovascular disease
        
        Depression of medullary respiration cause death due to overdose.
      - Unwanted daytime sedation (esp w/ Diazepam, flurazepam)
        Daytime anxiety and amnesia (esp w/ triazolam)
    - - BDZ competitive Antagonist, no activity in its own right
      - Reverse effects of ingested or administered BDZ agonists; Ineffective for most other sedatives; It reverse CNS depressant effect of Benzodiazepines, Zolpidem and Zaleplone
      - I.V.,0.7-1.3 h
      - Side Effects: Agitation, Confusion, Dizziness, Nausea, Seizure & cardiac arrhytmia (px treated w/ TCA), Transient improvement in mental status reported in px w/ hepatic encephalopathy
    - - Ultra Short (4-6 h): Triazolam, Midazolam
      - Short (12-18 h): Lorazepam (quick tolerance and dependency), Oxazepam, Temazepam, Lormetazepam
      - Intermediate (24h): Alperazolam, Nitrazepam
      - Long (24-48 h): Diazepam, Chlordiazepoxide, Florazepam, Clonazepam (daytime sedation)
    - - Absorption:
        Oral absorption depend on lipophilicity (Triazolam extremely rapid and Diazepam more rapid than others)
      - Distribution:
        more lipid solubility--> more entrance CNS (Diazepam & Teriazolam)
        Pr binding (BDZ: 60-95%)
      - Metabolism:
        pharmacologically active component: some only parent compound (lorazepam & flurazepam), some only metabolite(s), some both (DIAZEPAM); Duration of all active compounds must be taken into consideration.
      - Clearance: trace amount of benzodiazepines excreted unchanged in urine
  - - - Absorption: Oral; Well + u. very rapidly absorbed
      - Lipophilicity, acidosis- CNS entry;
      - Potent inducer (cytochrome p450)--> drug interactions (ex anticoagulants, incr vit D metabolsim) & acute porphyria (incr porphyrin)
      - Redistribution- Lipophilicity; Thiopental
      - Oxidation & Glucuronide conjugation--> Renal Excretion: w/ exception of phenobarbital (20-30%), only insignificant quantities of barbiturates excreted unchanged
        Elimination can be incr by alkalinization of urine
      - Distribution: more lipid solubility-->more entrance CNS (Thiopental)
    - - organ effects
        
        CNS
        
        Sedation--> Hypnosis (not anymore)--> Anesthesia (Laryngospasm) (thiopental: since barbs don't have antagonists, overdose very dangerous)--> Respiratory Depression--> Death, Anticonvulsant action (phenobarbital), Cognitive Impairment,
        
        CV
        
        Slight decr in BP
        
        Depression of vasomotor centers at toxic doses -- > circulatory collapse
        
        Hepatic
        
        Induction of P450--> Enhanced Metabolism of Barbiturates and all drugs metabolized by P450
        
        Hepatic metabolic uses (Phenobarbital in hyperbilirubinemia & kernicterus in neonates)
        
        incr muscle tone
      - mech of action
        
        Enhance GABAA-R responses by binding to different site of GABAA R/ Cl channel
        (Barbs specificity < BDZ)
        incr duration of opening
        High doses--> don't need to act on Rs, open channel directly--> NEURONAL INHIBITION
        
        Block excitatory transmitter Glu
        
        At high [ ] block Na channels
    - - Phenobarbital- Alkalinize Urine; Consider lavage
      - General supportive measures Maintain airway/ Give O2 (caution: too much O2 destroys respiratory drive)
      - Severe Poisoning- CV, renal Collapse
      - NO CNS Stimulants (but in contrast we can use sedatives and anticonvulsants when CNS stimulant posioning)
    - - Ultra Short (8-10 h): Thiopental
      - Short (10-40 h): Amobarbital, Secobarbital, pentobarbital
      - Intermediate (35-50 h): Butabarbital
      - Long (80-120 h): Phenobarbital
    - - Respiratory and cardiovascular depression (esp w/ Barbiturates overdosage)
  - - - pharmacodynamics
        
        organ effects
        
        Good hypnotic, w/ less effects on stages of sleep; Can supress REM in higher doses; Low incidence of rebound insomnia, daytime sedation
        
        Minimal muscle relaxing & anticonvulsant effect;
        
        must sleep quickly after use otherwise hallucinations
        
        mech
        
        Not a BDZ but binds to BZ receptor
      - Antagonized by flumazenil
      - Side effects: Respiratory depression; Tolerance less than BZs
      - pharmacokinetics
        
        Half –life 1.5-3.5 h
    - - Anxiolytic
      - Out of market because of severe liver damage, Acute hepatitis
    - - pharmacodynamics
        
        organ effect
        
        Good hypnotic, w/ less effects on stages of sleep
        
        mech of action
        
        Not a BDZ but binds to BZ receptor
      - side effects: Low incidence of rebound insomnia, daytime sedation
      - pharmacokinetics
        
        Short half-life ~ 1 hour (less than zolpidem)
  - - - Tolerance/Dependence Withdrawal can be severe
      - pharmacokinetics
        
        Metabolized to trichloroethanol
        
        Short duration; u tolerance after 2 ws
        
        No E induction