Sedative hypnotics.ppt

B Pharm

1. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal
Definitions
Sedative
Decreases excitement, motor activity, & responsive
to stimuli; calms, produce drowsiness without sleep
Hypnotic
Induces/maintains arousable natural sleep, quicker
onset, steeper dose response; shorter duration of
action than sedatives
Large doses of hypnoticsGA
1857: Bromides
1869: Chloral hydrate
1903: Barbiturates
1960: Benzodiazepines (BZD); now most prescribed

2. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 2
Sleep Architecture
Different stages show different EEG waves
Rapid eye movement (REM) sleep:
Paradoxical sleep: eye movements, dreams,
Irregular respiration, HR & BP fluctuate; 20-30%
sleep time
NREM Sleep: Stage 1 to 4
 stage 0:awake
Stage I: dozing
II: Unequivocal
III: Deep sleep transition
IV: Cerebral sleep

3. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 3
Classification of sedative hypnotics
1. BARBITURATES
Ultra Short: thiopentone, hexobarbitone,
methohexitone
Short acting: Butobarbitone, secobarbitone,
pentobarbitone
Long acting: Phenobarbitone, Mephobarbitone
2. BENZODIAZEPINES:
Hypnotics: Diazepam, Nitrazepam, Midazolam,
triazolam
Antianxiety: Diazepam,oxazepam,lorazepam,
lprazolam
Anticonvulsant: Diazepam, clonazepam, clobazam
Newer Non BZD: Zopiclone, Zolpidem
Miscellaneous:Chloral hydrate, trichlophos, paraldehyde
[Opiates, antihistaminics not used as hypnotics]

4. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 4
Barbiturates
Malonic acid + urea barbituric acid

5. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 5
Pharmacology
1. CNS
Sedation sleepanaesthesiacoma
Depress whole CNS, reticular activating system most
affected
Decreases time to fall asleep & increases duration
Night awakenings are decreased
Sleep is arousable; Hangover (dizziness, irritability)
Decrease in REM and stage 3 & 4
REM-NREM rhythm upset
Small doses: sedation, decreases anxiety, excitability
Impair learning, short term memory and judgement
Euphoria in addicts
Hyperalgesia in patients with severe pain
Anticonvulsant action [independent of CNS
depression]

6. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 6
Mechanism of action of Barbiturates
Act on GABA:BZD chloride channel
complex, Potentiates GABA mediated
inhibition; increase Cl
-
conductance
(GABA Mimetic action)
Inhibits Ca
++
induced transmitter
release
Depresses glutamate induced
depolarisation via AMPA receptors
At high concentration depress Na
+
and K
+
also

7. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 7
Obtained from: Principles of Pharmacology: The pathophysiologic basis of drug
therapy, By; David E Golan et al, Lippincott Williums & Wilkins-2005

8. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 8
Obtained from: Principles of Pharmacology: The pathophysiologic basis of drug
therapy, By; David E Golan et al, Lippincott Williums & Wilkins-2005

9. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 9
Actions of barbiturates contd….
2. Respiration
Affected only at higher doses
They don’t have selective antitussive action
3. CVS
Hypnotic doses cause only slight decrease in BP, HR;
Toxic doses ganglionic blockade marked BP
Cardiac arrest occurs at 3 times the dose of
respiratory failure
4. Skeletal Muscles
Hypnotic dose have little effect on the muscles
5. Smooth muscles
At hypnotic dose GI motility slightly reduced
6. Kidney
Increases ADH + decrease in BP decreased urine
[poisoning oliguria]

10. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 10
Kinetics of barbiturates
Well absorbed from GIT, widely distributed
CNS entry is depends on lipid solubility
[thiopentone instantly enters CNS GA;
phenobarbitone enters slowly]
Crosses placenta & secreted in milk
Termination of action is by following:
Redistributionfrom CNS decreases duration of
action
Metabolism: in liver, by CYP; auto inducer of CYP
Excretion:lipid insoluble ones excreted unchanged
Induces hepatic microsomal enzymes

11. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 11
Uses of Barbiturates
1. Hypnotic to control mania/delirium –now
superseded by BZD
2. Sedative: Adjuncts; replaced by BZD
3. Anticonvulsant: phenobarbitone in epilepsy:
important
4. General Anesthesia: [Thiopentone] &
Preanesthetic
6. Congenital non hemolytic jaundice &
kernicterus: induces conjugation of bilirubin
and decreases jaundice

12. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 12
ADRs of Barbiturates
Side effects
Hangover, mental confusion, impaired performation,
road accidents
Idiosynchratic:Occasional stimulation
Hypersensitivity
Rashes, swelling of eyelids, lips
Tolerance
Cellular and Pharmacokinetic tolerance with repeated
doses Partial cross tolerance with CNS depressants
Dependence
Physical and psychological dependence; addiction
Withdrawal symptoms :
Excitement, delirium, hallucination, convulsions,

13. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 13
Acute Barbuturate poisoning
Mainly suicidal and drug automation
Flabby and comatose, shallow respiration,
CVS collapse, fall in BP, renal shutdown
Treatment
Gastric lavage, activated charcoal,
Assisted respiration, oxygen, vasopressors e.g.,
dopamine
Forced alkaline diruresis
Mannitol + sodium bicarbonate
Haemodialysis

14. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 14
Barbiturates Contd….
Contraindications for barbiturates
Porphyria, liver kidney disease,
Emphysema, obstructive sleepapnoea
Drug Interactions
1. Microsomal enzyme inducer increases
metabolism of tolbutamide, griseofulvin,
chloramphenicol & theophilline
2. Additive with depressants e.g. Alcohol,
opioids, antihistaminics
3. Valproate increases plasma
concentration of barbiturates

15. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 15
Benzodiazepines (BZDs)
BZDs have become more popular because
High therapeutic index [50 times therapeutic
doses no death]
No CVS , respiratory depression, & less action
on body systems
Less distortion sleep architecture; no rebound
phenomena
Low abuse potential, low tolerance, less
withdrawal symptoms, low physical &
psychological dependence
Additional muscle relaxant property
Specific antidote Flumazenil in poisoning

16. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 16
BZD Pharmacology
BZDs qualitatively similar but different selectivity &
duration of action
Anxiolytic, hypnotic, muscle relaxant & anticonvulsant
Decreases time to fall asleep & night awakenings
increase duration;
Decreases REM but less than barbiturates
[Nitrazepam increases REM]
Less Night terrors & body movements; Stages I & 0
are lessened
Skeletal muscle relaxants without impairing voluntary
activity
Tolerance develops to anticonvulsant action of
Clonazepam & Diazepam limited use in epilepsy

17. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 17
Mechanism of action of BZDs
Acts on ascending reticular formation [wakefulness] &
limbic system [emotions]
BZDMedulla / Cerebellummuscle relaxation /
ataxia
BZDBZD receptorof GABA-A receptor Cl
-
channel
BZD increase Cl
-
channel opening (GABA
Facilitatory)
BZD action is indirect; mediated via GABA-A receptor
Flumazenil
Competitive BZD antagonist; abolishes BZD

18. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 18
Kinetics
Varied; lipid solubility differ > 50 fold
Slow elimination: Flurazepam, Diazepam,
Nitrazepam
Long T1/2; flurazepam is good for night
awakenings
Rapid:Temazepam: good for sleep onset
difficulty
Ultra rapid:Triazolam ; rapid, good for
sleep induction
Midazolam: peak action in 20 min [also i.v
anesthetic]

19. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 19
Adverse reactions of BZDs
Vertigo, ataxia, disorientation, amnesia,
reaction time,psychomotor skills [no driving!]
Rarely paradoxical stimulation; irritability,
sweating, nightmares & behavioural changes
[especially nitrazepam]
Slow tolerance & cross tolerance with CNS
depressants
Low potential for Dependence, addiction, drug
seeking
Drug Interactions
Synergy with Alcohol, CNS depressants
Valproate psychotic symptoms
Cimetidine, INH & oral contraceptives 
decreases metabolism

20. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 20
Uses of BZDs
1.Hypnotic: sleep latency, night awakenings, anxiety
[Not for regular use; better to treat the root cause]
2. Anxiolytic for day time sedation
3. Anticonvulsant; especially status-epilepticus, febrile
convulsions, tetanus
4. Central muscle relaxant
5. Pre-anaesthetic medication
6. Before ECT, Cardiac catheterisation, endoscopies,
obstetrics, minor procedures, [ideal for calming +
muscle relaxant action]
7. Alcohol withdrawal
8. With analgesics, NSAIDs, etc.

21. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 21
BZD antagonist
FLUMAZENIL :
Competitive BZD receptor antagonist: no
intrinsic action Abolishes BZD action
Use
Overdose of BZD; reverses BZD induced
anaesthesia /sedation; abolishes
hypnogenic, psycho-motor, cognitive
actions of BZD [safe & well tolerated]

22. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal 22
ZOPICLONE
Cyclopyrolone derivative
Potentiates GABA By binding to some
other site
Used in short term insomnia
ZOLPIDEM derivative
Does not act on BZD receptors
Low abuse potential,
Short acting drug