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MBBS Sedative Hypnotics

MBBS Sedative Hypnotics

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Published by: Dr.U.P.Rathnakar.MD.DIH.PGDHM on Mar 11, 2010
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Sedatives: Deppresses CNS-Calmness & Drowsiness(Sedation). Slow acting  Hypnotics: Produces drowsinesfacilitates onset and maintainance of sleep. Resembles natural sleep with EEG charecterstics  HYPNOSIS; Passive state of sugestibility by artificial means*


Sedatives Hypnotics


Alcohol & Herbs→ Since antiquity  Bromide, Chloral hydrate, Paraldehyde  Phenobarbital →1912  2500 barbiturates tested, 50 commercially available  Upto 1960 →No others  Then came chlordiazepoxide and other benzodiazepines*



CNS DEP: Sedation →Sleep →Unconciousness →GA → Dep. Of CVS & RS → Death

•Sleep-Absence wakefulness •Active process •1/3 of life spent in sleep •Biological clock regulates •Restoration of natural balance Among neuron

•Sleep-NREM &REM •NREM 90’-I,II,III,IV →REM 5-30 →Cycle repeates →REM prolongs →Wake up from •Children-sleep & growth

Physiology of sleep

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Peacefull P.Symp+ BMR, CO, HR, PVR-Low Infrequent dreams-no recall Muscle relax-except RS Hypotension No eye ball movement

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GH in stage 3 & 4* [Children]

Not Symp act+ High Vivid, bizarre, sexual Muscle flacid (Ob.apnoea) Hypertension Rapid eye ball movement*


1. Hypnotics: Diazepam, Nitrazepam, Alprazolam, Temazepam, Triazolam 2. Ant-anxiety: Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam, Alprazolam 3. Anti-convulsants: Diazepam, lorazepam, Clonazepam, Clobazam 4. Non[Novel]-Benzodizapine hypnotics: Zopiclone, Zolpidem, Zaleplon*


Benzene + Diazepine ring

 • • • • •

CNS: Sedative Hypnotic Anxiolytic Muscle relaxant Anterograde amnesia* Peripheral > Coronary vaso.dil. > N.M.Block[Toxic doses]

Ph.action contd…
        

CNS: Not a general depressant Action profile of all BZD same-selectivity difft. Does not produce “True anesthesia” Anti anxiety-not dependent on sedative action Anticonvulsant-Tolerance Sk.Muscle relaxation-central Analgesia-Only Diazepam-i.v. No hyperalgesia*

Ph.action contd…
      •

Sleep; Onset hastened Total sleeping time increased [stages 3&4 ↓] REM cycle increases ↑ but duration of REM ↓ Night terrors decrease Wakes up refreshed RS: Hypnotic doses no effect. Higher doses depress vent. & acidocis [OSA is CI] CVS: Low doses no effect. High-hypotension, tachycardia. i.v. increases cor.flow*

Sites of action

Sleep→Dep.of ascending reticular formation  Effect on mental function →Limbic system  Muscle relaxation →Medulla.  Ataxia →Cerebellum*

•Agonist •Antagonist •Novel •Inverse

•Versatile drug-responsive machine in the body •Benzodiazepines •Barbiturates, •Zolpidem •Flumazenil •Alcohol •Etomidate, •Propofol •Thiopental.

GABA modulation: Agonists: BZDP Inverse agonist: DMCM BZD antagonist: Flumazenil- Against agonist[BZD] and inverse agonist[DMCM] Receptor antagonism: Bicuculline [Competitive antagonist]

GABAA-Benzodiazepine- Receptor-Cl channel complex


GABA A Receptor




GABA Inhibition By action on GABA rec.  GABA rec. A & B & C  A. [Cl.channel]  GABA is primary ligand.  BZD binds to difft site & enhances GABA binding action  BZD ↑ frequency of Cl- channel opening  GABA facilitatory-Not GABA mimetic*

    

Absorption: PK variations- Variations in lipid solubility Absorbrd completely Clorazepate-Gastri juice-Nordazepam(Active) Prazepam, Flurazepam→Only active ingredients reach Syst.circulation Metabolism Metabolized by CYP Some yield active metabolites Eliminated after conjugation Enzyme inhibitors prolong action*

    

 

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Safe drugs Light headedness, increased reaction time, motor incordination,-IMPAIRS DRIVING-DANGEROUS WITH ALCOHOL Daytime sleepiness Weakness, headache, blurred vision, vertigo, nausea, vomiting, diarrhea, Jt.pain, incontinence Anticonvulsants may increase seizures Dependence-less than Barbiturates FLUNITRAZEPAM {ROHYPNOL]Date rape drug*

Drug interactions
  

BZD + Alcohol→ Excessive CNS dep;. BZD + Valproate → psychotic symptoms CYP3A4 inhibitors →Prolong metabolism of BZD

  

Duration of action:
Ultra short acting → Midazolam Short acting →Triazolam-(Zolpidem) Intermediate acting[6-24h) →Estazolam, Temazepam Long acting (>24h) →Diazepam, Flunazepam, Quazepam*

Acute toxicity
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Acute toxicity Benzodiazepines less dangerous -other anxiolytic/hypnotic drugs. Agents attempted suicide, this is an important advantage. Prolonged sleep, without depression of respiration or cardiovascular function. With alcohol, benzodiazepines can cause severe, even life-threatening, respiratory depression. Effective antagonist, flumazenil Not available for Barbiturates

Side effects during  Drowsiness, confusion, amnesia and impaired therapeutic use

coordination, -manual skills -driving performance. Benzodiazepines enhance the depressant effect of alcohol,. The long and unpredictable duration of action of many benzodiazepines is important in relation to side effects. Long-acting drugs such as nitrazepam are no longer used as hypnotics, .

Tolerance and dependence

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Tolerance (i.e. a gradual escalation of dose needed to produce the required effect) occurs with all benzodiazepines Less than barbiturates [Enz.inducer] Benzodiazepines produce dependence, and this is a major problem Withdrawal symptoms Short-acting benzodiazepines cause more abrupt withdrawal effects

Novel Benzodiazepine receptor agonists {Non-Benzodiazepine Hypnotics}

Chemical structure does not resemble  Agonists at BZD sites on GABA rec.  Short half life(1-2h)  Zaleplon. Zolpidem.Zopiclone. Eszopiclone  Amnesia, rarely hallucinations  Short term use*

Uses of BZD
      

Anxiolytic . Status epilepticus. Muscle relaxant. Short procedures. Alcohol withdrawal. With analgesics. FDC banned*

Insomnia-Nature of sleep  Difficulty falling asleep disruption (sleep onset insomnia)  Frequent or sustained awakenings (sleep maintenance insomnia)  Persistent sleepiness/fatigue despite sleep of adequate duration (non-restorative sleep).

 1.

2. 3.

Insomnia-Duration of symptoms Transient: <3 days. Stress. Sleep hygiene. Jet lag. Envn. Short term:3d-3weeks. Grief, Illness Long term: >3 weeks. Medical problems, psychiatric disorders.


Persistent insomnia can lead to impaired daytime function, injury due to accidents, and the development of major depression. Chronic insomnia - increased utilization of health care resources


   

Alcohol and antihistamines - nonprescription sleep aids[sleep disruption during the night and can escalate into abuse, dependence, and withdrawal ] Benzodiazepine- most effective and welltolerated zaleplon →→t½1–2 h; zolpidem and triazolam with t½2–3 h; Eszopiclone t½ of 5.5–8 h; Temazepam, lorazepam with t½ of 6–12 h

short durations of treatment, intermittent use, or gradual tapering of the dose To minimize rebound insomnia and tolerance

Ideal hypnotic
Will not disturb sleep architecture  No next day effects  No drug interactions  No dependence  REGULAR MOD. EX. IS IDEAL! *

Treatment of insomnia
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Psychological: Go to bed only when sleepy Use bed & bed room only for sleeping & sex If awake after 20 mts leave the bed room Getup same time every morning-regardless of sleep at night Discontinue coffee & Nicotine (at least evenings) Reg.ex.regimen Avoid alcohol Relaxation therapy*

Treatment of insomnia

Lorazepam-0.5mg.HS  Temazepam-7.5-15mg HS  Zolpidem, Zaleplon- 5-10mg. HS  Younger-Double dose  1-2 weeks.  Intermittent therapy  No Barbiturates*

BZd receptor antagonist  Against both agonist & inverse agonist  High I pass metabolism  Only i.v.  Used to reverse BZD anesthesia  BZD over dose
 

0.2mg/mt→If does not respond suspect

other drugs along with BZD like alcohol


Why BZDs preferred over Barbiturates?

High TI- Very high dose not fatal  Hypnotic doses- other systems not effected  Sleep architecture not disturbed  Rebound phenomenon less common  Does not induce enzymes  Lower abuse potential  Antidote available*

 Long

acting: Phenobarbitone  Short: Butobarbitone, Pentobarbitone,  Ultra short acting: Thiopentone, Methohexitone*



Site of action: General global CNS depression

 ↑Duration

of opening of Cl- channelsGABA facilitatory  Higher concn. GABA mimetic  Inhibit AMPA rec.  Depress Na & K channels  Multiple neuronal targets*

Pharmacological actions
         

CNS: Dose dependent depression Sedation→Sleep →Anesthesia →Coma → death. ↓Time taken to sleep ↑Sleep duration Hangover common Impairs learning Hyperalgesia(No analgesia) Anticonvulsant CVS: Hypotension RS: Depression*

  

Well absorbed CNS entry depend on lipid solubility Termination of action-Metabolism, excretion, redistribution Thiopentone-Highly lipid soluble→Penetrates CNS in 6-10 sec. →Anesthesia →Redistribution to other organs →Plasma concn.falls →Back diffuses from brain →Conciousness 6-10mts →Ultimate disposal by metabolism*

Uses and toxicity
o     o    

Uses Pheno-Epilepsy Thiopentone- i.v. anesthetic, Narcoanalysis Cong.non-hemolytic jaundice Not as hypnotic Toxicity Hangover PK & PD tolerance, dependence Confusion, paradoxical excitement Abuse liability, withdrawal symptoms, hypersensitivity*

Barbiturate poisoning

Suicidal or accidental  Gastric lavage with activated charcoal  Supportive-Airway, BP, Fluids  Alkaline diuresis  Hemodialysis  No anti dote*

CI And DI  C.I.  Intermittent porphyria  Liver and kidney disease  COPD  Sleep apnoea • D.I.  Enzyme inducer→ reduces effectiveness of Warfarin, OCP, Tolbutamide, Chloramphenicol  Complex interaction with PhenytoinCompetitively inhibits and induces*

The ELDERLY are at an increased risk of dependence and are more sensitive to the adverse effects such as memory problems, daytime sedation, impaired motor coordination and increased risk of motor vehicle accidents and falls Their use by EXPECTANT MOTHERS shortly before the delivery may result in a floppy infant syndrome, with the newborns suffering from hypotonia, hypothermia, lethargy and breathing and feeding difficulties

Why BZDs preferred

High TI- Very high dose not fatal  Hypnotic doses- other systems not effected  Sleep architecture not disturbed  Rebound phenomenon less common  Does not induce enzymes  Lower abuse potential  Antidote available*

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