Sedative Hypnotic Drugs

Sleep- This is the state of partial unconsciousness from which person can be arousable through any stimulation. Consciousness- means person has perceptions of stimuli, control of voluntary movements; mentally alert (memory, judgment). Coma- In this state person cannot be arousable through any stimulation. CNS depression action- Sedation------Sleep (hypnosis)-----General anaesthesia------Respiratory depression-----Coma-----Death Diencephalon and Reticulating Activating System (responsible for wakefulness) in brain stem control normal sleep. Different sleep disorders- Insomnia, Sleep walking, Excessive day time sleep, Sleep paralysis. Components of sleep: REM (30%) and NREM (70%). Sleep is a cyclic process means REM and NREM repeats its cycle every 80—90 minutes. REM- Dreams mainly occur in REM stage. REM is the important part of sleep for refreshing cognitive functions. Lack of REM sleep cause tiredness, depression and irritability. Release of nor epinephrine and serotonin suppressed during REM stage of sleep. NREM has four stages- stage 1-4. Stage 3 and 4 also known as slow wave stage. Sleep cycle waves- 1.       Alpha wave (8-12 cycles per second and high amplitude) - They indicate brain is calm, relax but in wakeful state. Alpha waves disappear during drowsiness. 2.       Beta waves (13-30 cycles per second and low amplitude) - They indicate brain is alert or activate when we solve any problem or concentrate on visual stimulus. 3.       Theta waves (4-7 cycles per second and low amplitude) 4.       Delta waves (less than 4 cycles per second and high amplitude)-When person in deep sleep or during anaesthesia. But in awake adult they indicate brain is damage. Sedative- Those drugs which calm down person without inducing sleep. (Excitement decrease but drowsiness increase). Sedative drugs have slow action and long duration of action. Hypnotic- Those drugs which induce sleep. Hypnotic drugs show quick onset of action and short duration of action. In low dose hypnotics also act as sedative.  Sedative and hypnotics classification: BENZODIAZEPINES              BARBITURATES                    NON BENZODIAZEPINES      A. LONG ACTING                  A. ULTRA SHORT ACTING            ZALEPLON                             FLURAZEPAM                        THIOPENTONE                                                                                                                                                                                             ZOPICLONE                       DIAZEPAM                               METHOHEXITONE                          ZOLPIDEM                        MEPROBAMATE NITRAZEPAM                           B. SHORT ACTING                                                                      ANTIHISTAMINES QUAZEPAM                             BUTOBARBITONE                                                                       ETHANOL CLONAZEPAM                         PENTOBARBITONE                                                                    RAMELTEON B. INTERMEDIATE ACTING   C. LONG ACTING ALPRAZOLAM                             PHENOBARBITONE ESTAZOLAM LORAZEPAM TEMAZEPAM CHLORDIAZEPOXIDE C. SHORT ACTING OXAZEPAM CLORAZEPATE TRIAZOLAM MIDAZOLAM
Action On	Barbiturate	Benzodiazepine	Non benzodiazepine
Effect on REM/NREM sleep cycle	Cycle is disturbed. Barbiturate suppresses REM sleep but not affect  slow wave sleep (stage 3 and 4).	Cycle is less affected. BZD reduce slow wave sleep (stage 3 and 4) but less affect REM sleep.
Level of Depression	Cause more CNS depression as compare to BZD	Cause less CNS depression as compare to barbiturate
Effect on Anxiety	No anti anxiety effect	Have anti anxiety effect e.g. diazepam
Effect on Memory	Decrease	Decrease
Analgesic action	No analgesic even though cause Hyperalgesia	No analgesic effect
Respiratory system	Depress at high dose	No  or mild
CVS	Fall in BP and heart rate	No  or mild
GIT	Constipation
Enzyme induction /tolerance	Increase enzyme induction (tolerance developed)	No  tolerance or mild
Dependence	Physical as well as psychological dependence (drug abuse)	Very less physical and psychological dependence
Withdrawl symptoms develop	Yes (like hallucination, delirium, convulsions)	Very less withdrawl symptoms
Lipophilicity	Lipophilic (thiopental- highly lipophilic- fast ,short acting and phenobarbitone- less lipophilic- slow and long action )	lipophilic
Idiosyncracy	Cause excitement in   some persons
Euphoria	more	Less
Muscle relaxation	Cause muscle relaxation by action on neuromuscular junction	Cause muscle relaxation (by central action)
Therapeutic index/ safety margin	Low	High
Antidote for poisoning	No particular antidote	Flumazenil (competitive antagonist at BZD site)	Flumazenil
Hangover	More common	Less
Side effects	Idiosyncrasy- cause excitement, tolerance, dependence, rashes, swelling of lips, confusion, reaction time increase, hangover, withdrwal symptoms are more	Ataxia, amnesia, increase reaction time, dizziness, tolerance and dependence are very less, withdrawl symptoms are less
Uses	Thiopental- in anaesthesia Phenobarbitone- in epilepsy As hypnotic- BZD are preferred over barbiturate	Anti anxiety –diazepam Muscle relaxant- diazepam Anticonvulsant- diazepam, clonazepam, lorazepam, flurazepam, Diazepam also decrease nocturnal gastric secretion	Used as sedative and hypnotic but weak anti anxiety, anticonvulsant and muscle relaxant effect. Because alpha 1 unit of BZD RECEPTOR IS responsible for amnesia, sedative and hypnotic effect while alpha 2 unit of BZD RECEPTOR is responsible for antianxiety, muscle relaxant and anticonvulsant action.
Mechanism of action	1.       Reticular activating system (RAS) is responsible for wakefulness (in mid brain). they depress RAS system 2.       Potentiate GABAergic action by increasing the lifetime of chloride channel opening induced by GABA neurotransmitter 3.       They bind on alpha/beta site of GABA receptor 4.       At high dose GABA mimetic action 5.       Barbiturate increase the GABA neurotransmitter binding to GABA receptor 6.       At high dose inhibit glutamate receptor and voltage sensitive Na and K channels also.	1.       Reticular activating system (RAS) is responsible for wakefulness (in mid brain). they depress RAS system 2.       Potentiate GABAergic action by increasing the frequency of chloride channel opening induced by GABA neurotransmitter 3.       They bind to alpha and gamma interface of GABA receptor 4.       No GABA mimetic action 5.       BZD increase the GABA neurotransmitter binding to GABA receptor	1.       they bind to alpha 1 unit of BZD receptor site 2.       Alpha 1 unit of BZD receptor IS responsible for amnesia, sedative and hypnotic effect while alpha 2 unit of BZD receptor is responsible for anti anxiety, muscle relaxant and anticonvulsant action.

Some important pointes-

Phenobarbitone is acidic in nature so alkalization of urine causes excretion of Phenobarbitone.

Benzodiazepine undergo phase –I and phase-II metabolic reaction.

Phase-I e.g. Of some BZD drugs which metabolise through phase-I reaction: Chlordiazepoxide, Diazepam,Flurazepam.

Chlordiazepoxide, Diazepam, Flurazepam. Have long t_1/2 because of active metabolites.

Glucuronidation conjugation is the major route for metabolism (phase –ii metabolic reaction) - Estazolam, Lorazepam, Oxazepam BZD show muscle relaxation through central effect (GABA_B receptor involve)