CNS - Sedative And Hypnotics Flashcards
Alzheimer’s disease is due to
Lack of Acetylcholine
Depression is due to
Depletion of Norepinephrine, Serotonin and Dopamine
Schizophrenia is due to
Excessive amount of Dopamine in the Frontal lobe
Parkinson’s disease is due to
Destruction of the substantia nigra and destruction of Dopamine
Epilepsy is due to
Lack of inhibitory neurotransmitters such as GABA or
Increase of excitatory neurotransmitters like GLUTAMATE
Huntington’s disease is due to
Chronic reduction of GABA
Different phases of sleep
Stage 0 (awake) - 1-2% of sleep time
Lying down to falling asleep
Eye movement - irregular or slowly moving
Stage 1 (dozing) - 3-6% of sleep time
Eye movement - reduced
Neck muscles - relaxed
Different phases of sleep
Stage 2 (unequivocal sleep)- 40-50% of sleep time
Eye movement - little
Subjects easily aroused
Stage 3 (deep sleep transition) - 5-8% of sleep time
Eye movement - very little
Subject not easily aroused
Different phases of sleep
Stage 4 (cerebral sleep) - 10-20% of sleep time
Deepest level of sleep
Metabolic rate is less
Growth hormone secretion is high
Eye movement - fixed
Subjects difficult to arouse
Night terror occurs at this time
Different phases of sleep
REM Sleep (Rapid eye movement) / Paradoxical sleep
20-30% of sleep
Eye movement - marked, irregular & rapid eye movement
Dreams and nightmares occur which can be recalled
HR & BP Fluctuates
Respiration - irregular
Muscles - fully relaxed
Erection - males
Stages 0-4 & REM Sleep - 80-100mins
Stages 1-4& REM sleep repeated cyclically
Classification of Benzodiazepines
Hypnotic -
diazepam, flurazepam, nitrazepam, alprazolam, lorazepam, temazepam, triazolam
Classification of Benzodiazepines
Antianxiety-
diazepam, chlordiazepoxide, oxazepam, lorazepam
Classification of Benzodiazepines
Anticonvulsants -
clonazepam, lorazepam, diazepam
Classification of Benzodiazepines
Non- benzodiazepine hypnotics
Zolpidem, zaleplon, zopiclone, eszopiclone
Barbiturates
Long-acting
Phenobarbitone
Barbiturates
Short acting
Butobarbitone, Pentonarbitol
Barbiturates
Ultra short-acting
Thiopental, Methohexital
Atypical Anxiolytics
Buspirone, Ipsapirone, Gepirone
Beta-adrenoreceptor antagonist
Propranolol
Miscellaneous
Melatonin, Ramelteon, Triclophor
MOA of Barbiturates
Acts at the GABA: BZD receptor chloride channel complex
Potentiates the GABA-mediated inhibitory effects by INCREASING THE DURATION OF CHLORIDE CHANNEL OPENING
At higher doses, it INCREASES THE CHLORIDE ION CONDUCTANCE (GABA mimetic action)
Pharmacokinetics of Barbiturates
Metabolized by phase 1 and 2 processes
Excreted through urine
Actions of Barbiturates on CNS
Sedation and hypnosis
Induce sleep
Prolong sleep duration
Alters NREM & REM sleep cycle
Anaesthesia
Anticonvulsant
Actions of Barbiturates on Respiratory System
Respiratory Depression
Actions of Barbiturates on CVS
Higher doses decrease BP & HR and depress Myocardium
Actions of Barbiturates on GIT
Decrease in tone and amplitude of GIT smooth muscles
Actions of Barbiturates on Liver
Enzyme induction drug interactions
Therapeutic Uses of Barbiturates
In anaesthesia -
ultra-short-acting (Thiopental) as inducing agent
Therapeutic Uses of Barbiturates
As Anticonvulsants -
long-acting (Phenobarbital)
Therapeutic Uses of Barbiturates
In Neonates
To treat Hyperbilirubinemia
Increases the activity of glucuronyl transferase - increase the conjugation of bilirubin - decrease the risk of Kernicterus
Contraindications in the use of Barbiturates
Liver dysfunction
Kidney Disease
Sever pulmonary insufficiency
Acute intermittent porphyria -
Barbiturates cause induction of ALA -synthase enzyme in mitochondria - leads to increased porphyrins
Acute barbiturate poisoning
Cause and presentation of pt.
Mostly suicidal, sometimes accidental
Patient is flabby and comatose with shallow and failing respiration, fall in BP
TXT of Acute barbiturate poisoning
No specific antidote
Maintenance of pt. Vitals
Gastric lavage - activated charcoal
* ALKALINE DIURESIS - SODIUM BICARBONATE
Hemodialysis and hemoperfusion
Drug Interaction with barbiturate
Induce metabolism of warfarin, steroids, OCP, chloramphenicol, tolbutamide
Alcohol, antihistamines, opioids - CNS Depression
Phenobarbitone reduces the absorption of Griseofulvin from gut
Benzodiazepines?
Enhances the effects of neurotransmitter GABA-A which is an inhibitory resulting in sedative, hypnotic, anxiolytic, Anticonvulsants and muscle relaxant properties
MOA of Benzodiazepines
Binds specific site at the GABA-BZD Receptor
Enhances the receptor affinity for GABA
*INCREASES THE FREQUENCY OF OPENING OF CL CHANNEL
Increase cl conduction
Neural membrane hyperpolarization
Decrease sympathetic transmission
CNS depression
Pharmacokinetics of Benzodiazepines; does it cross BBB & metabolised by?
Except Midazolam, all can be given orally
- Metabolised in liver by CYP3A4 and CYP2CI9
Excreted in urine
Crosses BBB
Contraindication of Benzodiazepines
Crosses BBB - Contraindicated in PREGNANCY
Therapeutic use of Benzodiazepines
Txt anxiety & insomnia
Preanaesthetic medication
Skeletal muscle relaxants
Anticonvulsant
*TXT ALCOHOL WITHDRAWAL
AE of Benzodiazepines
Dose-dependent drowsiness, fatigue, disorientation, lethargy and psychomotor skills impairment
Fast IV injection - cardiac arrest
BZD WITHDRAWAL INCLUDES Anxiety, insomnia, impaired conc., headache, irritability, tremors, palpitation and *VIVID DREAMS
Flunitrazepam use and effect
Sedative amnesic effect
Misused in sexual assaults to wipe out memory of events
Drug interaction of Benzodiazepines
*BZD potentiates the effects of CNS depressants like alcohol, hypnotic, neuroleptics
*Smoking decreases the activity of BZDS
*Enzyme inhibitors like Cimetidine and Ketoconazole enhance BZD action
Benzodiazepine antagonists
Flumazenil
Benzodiazepine antagonists MOA
Selective competitive antagonist of Benzodiazepine
Competes with BZD agonist and INVERSE AGONIST - reverse their action
Injected IV
Action starts in seconds and lasts for 1-2hrs
Elimination half-life - 1 hr
Benzodiazepine antagonists Use
Reverse BZD anaesthesia
BZD overdose
Benzodiazepines over Barbiturates as Sedative and Hypnotics. Why?
*BZD have flat DRC whereas Barbiturates have a steep DRC
BZD doesn’t effect REM sleep and cause less hangover whereas Barbiturates cause marked suppression of REM sleep, hence rebound increases REM sleep on withdrawal
*BZD are not enzyme inducers, less likely to cause drug interactions whereas Barbiturates are potent enzyme inducers
Benzodiazepines over Barbiturates as Sedative and Hypnotics. Why?
Bzds has low abuse liability whereas barbiturates exhibit tolerance as well as physical and psychological dependence
*Bzds cause amnesia with no phenomenon of automatism while barbiturates are characterized by amnesia with automatism
Benzodiazepines over Barbiturates as Sedative and Hypnotics. Why?
Bzds shows no hyperalgesia while it is seen with barbiturates
*Bzds poisoning can be treated with Flumazenil an antagonist while no antidote for barbiturates poisoning
Cause and Txt of Insomnia
Last < 7 days
Caused by Brief environmental or situational stressors (jet lag, overnight train journey, shift work)
Sleep hygiene rules
Hypnotics should be used at the lowest dose
Cause and Txt of Insomnia
1 to 3 weeks
Causes by personal stressors such as illness, grief or occupational problems
Education about sleep hygiene
Intermittent use of Hypnotics - with the pt. Skipping a dose after 1-2 days of good sleep
Cause and Txt of Insomnia
> 3 weeks
No specific stressor
Underlying disease or personality disorder
Non-pharmacological measures
Treatment of underlying illness
Intermittent use of long-acting hypnotic may be used
Importance of Non-pharmacological measures
Effective in reducing sleep onset latency
Non-benzodiazepine hypnotics
Zolpidem, Zopiclone, Zaleplon
Also called Z drugs
Moa of Non-benzodiazepine hypnotics
Not BZDs
*Acts on alpha 1 BZD site
Produce sedative and hypnotic and weak anxiolytic action with negligible anticonvulsant, central muscle relaxant and amnesic action
Least disruption of sleep architecture
Least abuse potential
Used for both transient and short-term insomnia
Overdose of Non-benzodiazepine hypnotics txt
Antagonized by Flumazenil (benzodiazepine competitive antagonist)
Moa of Zolpidem
Imidazopyridine derivative
Rapid onset (30-60mins)
*Reduces the sleep latency and prolongs the total sleep duration
Sedation action > anxiolytic
Moa of Zolpidem cont’d
Hypnotic is seen for a week without rebound insomnia after the withdrawal
*food reduces the absorption
In elderly and hepatic dysfunction dose should be reduced to half
Late night administration of Zolpidem may cause
Delayed reaction time, morning sedation and anterograde amnesia
Moa of Zaleplon
Pyrazolopyrimidine derivative
Sustained efficacy on prolonged use - no tolerance and no rebound insomnia
Late-night administration of Zaleplon may cause
Does not cause Delayed reaction time, morning sedation and anterograde amnesia - can be taken by pt. who is awake in the middle of the night and not able to sleep
Moa of Zolpiclone
Cuclopyrolone derivative
Useful for short-term treatment of insomnia
*Prolongs stage 3 and 4 sleep but does not suppress REM sleep
AE of Zolpiclone
Metallic taste, reduced alertness and mental disturbance
Moa of Eszopiclone
Active enantiomer of Zolpiclone
*Reduces sleep latency, number of awakenings, increase sleep time and helps in maintenance of sleep
Used for short and long term treatment of insomnia for 1 yr
AE of Eszopiclone
Bitter taste
Moa of Melatonin
Hormone synthesized and released from pineal gland during night
Maintains the circadian rythm and sleep-wakefulness cycle
Reset the circadian rythm which is disturbed in jet lag
Use of Melatonin
As Chronobiotic
Low dose - increases the tendency to fall asleep but no CNS depression
High dose - produce hypnotic effects
What is a Chronobiotic
Agents that reset the biological clock or timing of circadian rhythm
Types of melatonin receptors
3 types of melatonin receptors - MT1, MT2, MT3
Action of the 3 types of melatonin receptors
MT1 and MT2 concerned with circadian rhythm
MT3 - related to intraocular tension
Moa of Ramelteon
Selective MT1 and MT2 receptor agonist -
Used for txt of insomnia
Reduces sleep latency and improves sleep time
Suitable for sleep onset insomnia
More efficacious than melatonin but less efficacious than benzodiazepine
Moa of Ramelteon cont’d
No next day sedation
No rebound insomnia, no addiction liability
Ramelteon leads to
Increased level of prolactin
Decrease level of testosterone
AE of Ramelteon
Headache, dizziness, fatigue, somnolence
Modafinil moa
Sedative hypnotic
Wake promoting agent
Low abuse liability
Use of Modafinil
For hypersomnias (narcolepsy or sleep apnoea syndrome)
Maintain wakefulness in shift work sleep disorder
Suvorexant moa
Orexin receptor antagonist
Acts as a central promoter of wakefulness
Hasten sleep onset, sleep maintenance and increase the total sleep duration
Suvorexant is metabolized by
CYP3A4
Excreted in faeces
AE of Suvorexant
Dose-related
Day time somnolence. Impaired driving, unconscious night time behaviour
What are the atypical anxiolytics
Buspirone, Ipsapirone, Gepirone
Moa of atypical anxiolytics
- Acts as a Partial Agonist primarily at brain 5HT1A receptors
- Not suitable in case of acute anxiety
No muscle relaxant, anticonvulsant or hypnotic action
Minimum abuse liability
Less psychomotor skill impairment and does not potentiate the CNS depressant effects of alcohol
AE of atypical anxiolytics
Tachycardia, nervousness, GIT distress
What are the beta-adrenoreceptor antagonist
Propranolol
Use of beta-adrenoreceptor antagonist
To reduce anxiety under conditions which provoke nervousness and anxiety
Blocks peripheral manifestation of anxiety (palpitations, tremors)
Site of action of sedatives
Limbic system (that regulates thought and mental function)
Site of action of hypnotics
Midbrain and ascending reticular formation (which maintains wakefulness)
