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SEDATIVE HYPNOTICS - Coggle Diagram
SEDATIVE HYPNOTICS
BARBITURATES
MOA
Low Dose
- GABA facilitatory action
- Enhance binding of GABA to GABA-A ®
- Enhance frequency of Cl- channel opening
High dose
- GABA mimetic action
- Directly ↑ Cl- conductance
- ↑ lifetime of Cl- channel opening induced by GABA
Other actions
- Inhibit Ca2+ dep. release of NT
- Depress glutamate induced neuronal depolarization through AMPA ®
Very high concentrations
- Depress voltage-sensitive K+/Na+ channels
Pharmacological actions
Sedative Hypnotic action
- Produce dose-dep. effects
- Sedation→ sleep→ anaesthesia→coma
- Hypnotic: ↓ time taken to fall asleep & ↑ sleep duration
- Night awakenings ↓
- Suppression of REM sleep & NREM stage 3,4
- Sleep cycle disturbed
- Rebound insomnia on discontinuation d/t tolerance. Increase in dose →toxicity
- Hangover in the morning after night dose
- Sedative dose: drowsiness, ↓ excitability. Can impair short term memory & judgment. Euphoria in addicts.
Anticonvulsant property-Phenobarbitone
- In doses lower than sedative-hypnotic doses
- No tolerance to anticonvulsant action
General anaesthetic action
- Surgical anaesthesia at higher doses
- Induction by thiopentone sodium
- No selective antianxiety action
- No analgesic action, small doses may cause hyperalgesia
Higher doses
- Resp. depr.
- ↓ BP
- Muscle tone/bowel motility/ urine o/p ↓
Toxic Doses
- Marked BP fall d/t vasomotor center depr., ganglionic blockade
- Direct decrease in cardiac contr.
- Reflex tachycardia
- Resp. failure/CVS collapse may occur
PHARMACOKINETICS
- Well absorbed, widely distributed in body + Highly lipid soluble thiopentone- instantaneous entry
- Less lipid soluble- phenobarbitone- slow entry
PPB
- Thiopentone 75%
- Phenobarbitone 20%
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No more preferred as sedative hypnotic
- Low therapeutic index, narrow safety margin
- Suppression of REM sleep→ withdrawal causes rebound phenomenon
- Potent enzyme inducers→drug interactions
- Abuse liability high
- Prolonged use→rapid dvpt. of tolerance & severe physical dependance
- Non specific CNS depression: affect vital systems in hypnotic doses
- No specific antidote in poisoning
USES
1. Epilepsy
○Grand mal& status epilepticus
○Thiopentone sod. →last resort in st. epi.
2.Congenital non hemolytic jaundice/Kernicterus
○Phenobarbitone→ enz. inducer
3. Induction of anaesthesia & short procedures
○Thiopentone sod. & methohexitone
4. Other uses
○Narcoanalysis/brain mapping- thiopentone
○Preanesthetic medication
○Control convulsions in tetanus, eclampsia & drug toxicities
Classification
- Long acting : Phenobarbitone
- Short acting: Butobarbitone, pentobarbitone, secobarbitone
- Ultra short acting : Thiopentone, methohexitone
Adverse Effects
- Hangover common after use as hypnotic: mental confusion, impaired performance
- Idiosyncrasy : occasionally produce excitement in elderly.
○ Precipitate porphyria
- Hypersensitivity: rashes, swelling of eyelids, lips
- Tolerance- sedative hypnotic action
○ Pharmacokinetic& pharmacodynamic tolerance
○ Partial cross tolerance with other CNS depressants
○ No tolerance to anticonvulsant action
- Dependence
○ Psychological& physical dependence
○ Withdrawal-excitement/ hallucinations/ delirium/ death
Acute Barbiturate Poisoning
- Lethal dose dep. on lipid solubility
- Manifestations-
○ Excessive CNS depr.→patient flabby & comatose with shallow/failing resp.
○ Fall in BP, CVS collapse & renal shutdown
○ Pulmonary complications, bullous eruptions
- Treatment
○ No specific antidote for barbiturates
○ Gastric lavage: oral activated charcoal, prevent absorption of drug from intestines
○ Supportive measures:
-Patent airway, assisted resp, O2, maintenance of blood vol. by fluid infusion
-Use of vasopressors→ dopamine preferred for its renal vasodiluting action
○ Forced alkaline diuresis
-Sod. bicarb 1mEq/kg IV with/without mannitol
-Long acting barbiturates eliminated by renal excr.
○ Hemodialysis & hemoperfusion
-Column of activated charcoal & other adsorbants→ remove LA & SA barbiturates
- Drug automatism
○ Patient do not fall asleep after particular dose of barb.
○ Patient confused & forget amount of drug confused
○ Repeat dose- toxic levels
○ A/c poisoning
Drug interactions
- Induce CYP isoenzymes, glucuronyl transferase
- ↑ Metabolism of drugs→ reduce effectiveness
○ Warfarin, tolbutamide, griseofulvin, steroids(incl. OCPs), chloramphenicol, theophylline
- Additive action with other CNS depressants
○ Alcohol/ antihistamines/ opioids
BENZODIAZEPINES
Has replaced barbiturates as sedative-hypnotic because→
- High safety of margin, high therapeutic index
- No loss of consciousness(amnesia+), patient can be aroused.
- No effect on resp/CVS functions in hypnotic doses.
- Higher doses→ mild resp. depr. & hypotension → problematic in resp. insufficiency/ cardiac abnormality
- Practically no action on other body systems
- Less distortion of sleep architecture REM sleep suppression least with BZDs
- Less/No rebound phenomenon on discontinuation
- Not an enzyme inducer, no drug interaction
- Abuse liability less, slow devpt. of physical dependence
- Specific BZD antagonist=> Flumazenil
MOA
Sites of action in brain
- Midbrain asc. RF
- Limbic system
- Medullary site
- Cerebellum
GABA A ® Cl⁻ channel Complex
- Composed of 5 α, ß, γ, and sometimes δ,ε,,Θ, π subunits
- Several isoforms of α,ß,γ have been cloned→ accordingly multiple subtypes of BZD ® present
- [ α₁2ß₂2γ₂ ] pentamer→ Most commonly expressed BZD ® isoform
- ® isoforms with α₁ → mediate sedative/ hypnotic/amnesic action of BZDs
+ α₂ subunit→ anxiolytic/ muscle relaxant action
- Newer non-BZD hypnotics Zaleplon/ Zolpidem etc have a high affinity for α₁ subunit isoform of ® → exert selective hypnotic-amnesic effect
Other GABA A ® Modulators
+ DMCM/ ß carboline→ inverse agonist @ BZD site→ impede GABA action
- Bicuculline→comp. antagonist @ GABA A ®
- Picrotoxin→ @ picrotoxin sensitive site→ non-competitive blockade of Cl⁻ channel
- Muscimol→ agonist at GABA A site
- BZD ® present on GABA A ® Cl⁻ channel complex
- Pentameric assembly
- After combining with GABA ®
○ BZDs facilitate opening of GABA activated Cl⁻ channels
○ ↑ Cl⁻ conductance & hyperpolarisation
○ Inhibitory response
PHARMACOLOGICAL ACTIONS
Sedative-Hypnotic action
- Low dose→ sedation, drowsiness
- Increase in dose→ hypnotic effect
- ↓ time taken to fall asleep, ↓ intermittent awakening, ↑ total sleep time
- Tolerance develops to hypnotic effect
Can induce sleep & following effects are noted
- duration of stage 2 sleep ↑
- duration of REM sleep ↓
- Number of REM cycles ↑
- duration of NREM stage 4 sleep ↓
Can cause anterograde amnesia: inability to recollect events subsequent to drug admn.
Anxiolytic action
- Selective antianxiety in lower doses than hypnotic dose
- Sedative action with relief of anxiety→ calming effect
- No tolerance to anxiolytic action
○ Alprazolam
○ Lorazepam
○ Oxazepam
○ Diazepam
○ Chlordiazepoxide
Anticonvulsant action
- Potent action
- Tolerance develops on c/c use
- Reserved for emergency control of status epilepticus: lorazepam, diazepam
- Febrile convulsions- clobazam,diazepam
- Myoclonic, petit mal seizure-clonazepam
- IV diazepam→ analgesia but in contrast to barbiturates, BZDs do not produce hyperalgesia
Skeletal muscle relaxant
- Centrally acting agent @ higher dose
- A/c muscle spasm
- Exerts inhibitory effect on polysynaptic reflexes
- Clonazepam→ cerebral palsy
- Diazepam sedative doses→ tetany
- Use in electroconvulsive therapy
Other actions
- Diazepam→ ↓ nocturnal gastric secr. & prevent stress ulcers
- IV diazepam→ short lasting coronary dilatation
- Higher dose/ IV admn→ hypotension, CVS collapse & resp depr. [Medullary depression]
- C/I- patients with obstructive sleep apnea
PHARMACOKINETICS
- Well absorbed orally.
- Attain peak plasma conc. within 1 hr
- Diazepam oral BA 100%
- IM: Diazepam, lorazepam, midazolam, chlordiazepoxide
PPB 10% -flurazepam 98% -diazepam
- Reach high conc. in brain, cross placenta, secreted in milk
- Diazepam- enterohep.circulation
Lipid solubility& Metabolism
- Variable
- Widely distributed in body
- Lipid sol. members enter brain rapidly
- Have 2-phase plasma conc. decay curve:
○ 1st- due to distribution to other tissues
○ 2nd- d/t elimination
- Drugs with long T½ or those with active metabolite cumulate- action extends to next day
- BZDs metabolised by CYP3A4 & CYP2C19 to dealkylated & hydroxylated metabolites
- Phase I metabolites & certain BZDs are conjugated with glucuronic acid.
- BZDs & phase I metabolites are excreted in urine as glucuronide conjugates
Elimination Kinetics
- Slow elimn. of parent drug/active metabolite→ Flurazepam
- Slow elimn, markd redistribution→Diazepam, nitrazepam
- Rapid elimn. & marked redistribution→ Alprazolam, Temazepam
- Ultrarapid elimn.→Triazolam, midazolam
DRUGS
Flurazepam
- Active metabolite→ has long T½
- Residual effects likely, cumulation on daily ingestion
- Use- frequent nocturnal awakenings
- C/I elderly→ risk of next day sedation/ ataxia/ mental confusion
Diazepam
- Anxiolytic/ hypnotic/ muscle relaxant/ premedicant/ anaesthetic and for emergency seizure control
- Broad spectrum action
- Rapid oral absorption→ suitable for sleep onset difficulty & sleep maintenance
- Active metabolites- desmethyl-diazepam, oxazepam
- Regular use→ accumulation & prolonged anxiolytic effect
- Rebound insomnia less likely
- Withdrawal phenomena mild.
Nitrazepam
- Equipotent as diazepam
- Accumulation/residual effects
- For frequent nocturnal awakenings, if some day time sedation is acceptable.
Lorazepam
- Slow absorption
- Prominent sedative/anxiolytic action
- Use: treatment of anxiety, promote sleep in tense patients
- No active metabolite→ no cumulative residual drowsiness
Alprazolam
- Potent, intermediate duration of action
- Use: anxiety disorder, & night time hypnotic (d/t rapid oral absorption)
- Active met. present but has short T½
- Discontinuation→ marked withdrawal effect
Temazepam
- Intermediate duration BZD
- Tablet→ slow abs.
- Gelatin capsule→ fast abs.
- Use: sleep onset difficulty
- Active metabolite→ short T½
- Free of residual effects
Triazolam
- Very potent BZD with peak effect in <1hr
- Good for sleep induction(not for maintenance→ d/t short action)
- Rebound insomnia may occur as withdrawal
- No accumulation, no residual effects
- Higher doses→ alter sleep architecture, produce anterograde amnesia & anxiety
- Cases of paranoia/ psychiatric disturbances noted → hence withdrawn from UK, but in use in some other countries for elderly/ shift workers/ travellers
Midazolam
- Extremely rapid absorption peak~20min
- A/E in elderly: ataxia, blackouts, and is more liable for abuse
- Not available now for oral use as hypnotic
- Mainly used as IV anaesthetic/ IM premedicant
USES
- Sleep disorders→ insomnia
○ diazepam, flurazepam,temazepam, triazolam,estazolam
- Anxiety neurosis→ diazepam
- Epilepsy-status epilepticus
○ diazepam, lorazepam
- Skeletal muscle spasm→ diazepam
- Sedation & amnesia before& during surgical procedures
- GA→ midazolam for induction
- Preanaesthetic medication
- Drug dependence by alcohol, morphine, barbiturates
- Stress ulcers→ ↓nocturnal gastric acid secretion& anxiolytic action
- A/c mania, schizophrenia, depression
- Diazepam→ calming/amnesic/ analgesic/muscle relaxant & safe drug
○ before ECT
○ electrical cardioversion of arrhythmias
○ cardiac catheterisation
○ endoscopies
○ many minor procedures
Adverse Effects
- Drowsiness/confusion/amnesia
- Impairment of coordination leading to ataxia& disorientation
- Difficulty to operate machinery→ driving (prolonged reaction time)
- Hypnotic doses→ headaches,dizziness, GI upset, skin rash
- Nightmares→ nitrazepam(↑ REM sleep)
- Admn during labor→ flaccidity & resp depr. in neonate
Tolerance & dependence
- Long term use→ tolerance to hypnotic/ sedative/ anticonvulsant effect
- No tolerance to anxiolytic effect
- Cross tolerance to alcohol& other CNS depressants.
- Low dependence producing liability
- Physical dependence→ diazepam, alprazolam
BZD Poisoning
- A/c overdosage→ prolonged sleep
- Rapid IV→ hypotension, apnea
- With other CNS depressants→ fatal resp.depr.
- BZD antagonist→ Flumazenil
○ Competes with BZD agonists & inverse agonists
○ Admn. as IV inj.
○ Reverse BZD anaesthesia→ early patient discharge
Interactions
- Alcohol, antihistamines, opioids potentiates CBS depressant effect of BZDs
- Metabolism of most BZDs is by CYP3A4→ Enzyme inhibitors like ketoconazole, erythromycin prolong BZD action
- Cimetidine, isoniazid, OCP also retard BZD metabolism
Classification
Hypnotic= DFNALTT
Diazepam, Flurazepam, Nitrazepam, Alprazolam, Lorazepam, Temazepam, Triazolam
Antianxiety=DChOLAC
Diazepam, Chlordiazeposide, Oxazepam, Lorazepam, Alprazolam, Clonazepam
Anticonvulsant=CCDL Clonazepam, Clobazam, Diazepam, Lorazepam
Duration of Action
- Short acting=MOCTr <6hrs
- Intermediate acting= NETeAL 6-24hrs
- Long acting=DFCh >24hrs
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NEWER AGENTS
Melatonin
- High doses(80mg) orally admn. can induce sleep
- Low doses can increase propensity of falling asleep.
- Use restricted to jet lag, elderly insomniacs, shift workers
- 2 subtypes of melatonin ®- MT1 & MT2→ both are GPCRs & facilitate sleep onset & timing
Ramelteon
- MT1, MT2 ® agonist
- Synthetic analogue of melatonin
- Does not alter GABAergic neurotransmission or produce usual BZD like S/E
- Effective in transient & c/c insomnia
- Dose- 8mg ½ hr before sleep→ hasten sleep onset & ↑ duration
- No morning sedation/impairment
- No dependence/ rebound phenomena/ withdrawal symptoms
- Extensive FPM in liver by CYP isoenzymes→ BA is low→ elimination T½=1-3 hrs
- Fluvoxamine, ciprofloxacin, fluconazole→ inhibit metabolism→ ↑ blood levels
+ Rifampicin→ ↓ blood levels by inducing degradation
- S/E- fatigue, sleepiness, dizziness
Suvorexant
- 1st member of novel class of insomnia drugs DORAs(Dual orexin ® antagonists)
- Orexins are neuropeptides found in lateral hypothalamus→ promote wakefulness by acting on OX1R & OX2R subtypes of orexin ®
- Suvorexant blocks both OX1R & OX2R
- Promotes sleep onset & duration
- Used in sleep disorders with difficulty in falling asleep
- Absorbed in 1-2 hrs
- Metabolism by CYP3A4. T½=12hrs, excreted via feces
- CYP3A4 inhibitors→ ↑ drug levels→ next day effects
- Low potential for addiction/dependence
- Sustained benefit for c/c insomnia