1. SEDATIVES AND HYPNOTICS
• Sedative is a drug that produces a calming or quietening effect and reduces
excitement. It may induce drowsiness.
• Hypnotic is a drug that induces sleep resembling natural sleep. Both
sedation and hypnosis may be considered as different grades of CNS
depression.
• All human beings need sleep. Approximately 1/3rd of our life is spent in
sleep. Sleep can be classified into two types depending on the physiological
characteristics:
1. Nonrapid eye movement (NREM) sleep
2. Rapid eye movement sleep (REM).
6. Insomnia is sleeplessness
it is insufficient or poor quality sleep, which could lead to undesirable
day time consequences.
Insomnia may be primary or secondary.
Primary insomnia is sleeplessness that is not attributable to medical,
psychiatric or environmental causes. This is uncommon.
Insomnia may be secondary to a variety of clinical conditions
including medical and psychiatric illness, stress, drug induced or
simply due to lack of adequate physical activity.
7. BENZODIAZEPINES
Chlordiazepoxide was the first Benzodiazepines (BZD)
Pharmacological actions:
The most important actions of BSDs are on the CNS and include:
Sedation and hypnosis
Reduction in anxiety
Anesthesia
Muscle relaxation
Anticonvulsant effects
Amnesia.
8. Hypnosis: BZDs hasten the onset of sleep and increase the duration of
sleep. The quality of sleep resembles natural sleep more closely when
compared to other hypnotics. Tolerance develops to this effect gradually.
Anxiolytic or sedative effects: BZDs reduce anxiety and aggression
and thus produce a calming effect. Alprazolam has additional
antidepressant properties.
9. Anesthesia: In higher doses BZDs produce general anesthesia.
Midazolam is used as an IV anesthetic and BZDs including
diazepam, lorazepam and midazolam are used as adjuvants to general
anesthetics.
Muscle relaxant action: BZDs reduce muscle tone by a central action.
Generally anxiety is associated with an increased muscle tone and may
be responsible for aches and pains in these patients. The muscle
relaxation by BZDs adds to their beneficial effects in such patient
10. Anticonvulsant effects: BZDs increase the seizure threshold and act as
anticonvulsants, Diazepam is used intravenously for the treatment of status
epilepticus and rectally in febrile convulsions.
Amnesia: BZDs produce anterograde amnesia, ie, loss of memory for the
events happening after the administration of BZDs. This property is an
advantage when BZDs are used in surgical procedures as the patient does not
remember the unpleasant events.
Other actions
In higher doses BZDs decrease BP and increase heart rate.
Diazepam decreases nocturnal gastric acid secretion.
BZDs in higher doses can cause respiratory depression.
11. Benzodiazepines
Bind to GABA, receptor
Increase Frequency of CI channel opening
Increase Flow of chloride ions into neurons
Hyperpolarization
Depresses synaptic transmission
CNS depression
12. Pharmacokinetics:
BZDs are completely absorbed on oral administration.
Intramuscular absorption is slow—hence oral route is preferred.
They are extensively bound to plasma proteins, metabolized in the
liver by glucuronide conjugation.
13. Adverse effects:
BZDs are generally well tolerated.
The common side effects include drowsiness, confusion, amnesia,
lethargy, weakness, headache, blurred vision, ataxia, day time
sedation and impaired motor coordination such as driving skills,
therefore, while on BZDs driving should be avoided.
In some patients it may cause paradoxical irritability and anxiety.
14. Tolerance and dependence:
Both tolerance and dependence liability are less with BZDs as
compared to barbiturates, Patients develop tolerance to the sedative
effects very slowly.
On long term administration, both physiological and psychological
dependence develop. The withdrawal symptoms are milder and
slower in onset
15. Acute overdoses:
• BZD overdoses induces sleep but the respiratory depression is mild.
Hence BZDs are safe and the availability of a specific antagonist—
flumazenil-makes it safer to use BZDs because poisoning can be
treated.
16. Uses of BZDs
Insomnia: When drugs are to be used to treat insomnia, BZDs are the agents of
choice. Lorazepam, oxazepam, temazepam, nitrazepam or triazolam may be used.
In anxiety states: BZDs are the most commonly used anxiolytics for the treatment
of anxiety states and anxiety neuroses. Any of the BZDs except the ultra short acting
ones may be used.
As anticonvulsants: IV diazepam is the drug of choice in the treatment of status
epilepticus.
Clonazepam or clobazam are used as adjuncts with other antiepileptic drugs.
17. Muscle relaxant: BZDs are centrally acting muscle relaxants used in chronic muscle spasm
and spasticity.
As preanesthetic medication: for their sedation and anxiolytic effects BZDs are useful.
During alcohol withdrawal: BZDs are useful in patients during withdrawal of alcohol or
other sedative-hypnotics.
General anesthesia: IV midazolam or diazepam is used as an intravenous anesthetic.
BZDs are also used to supplement anesthesia. Minor procedures, such as endoscopies,
fracture reduction, cardiac catheterization, prior to ECT intravenous diazepam is used.
In psychiatry: For the initial control of mania, diazepam is used as an adjuvant.
18. • BENZODIAZEPINE ANTAGONIST
Flumazenil is a BZD receptor antagonist which competes with BZDs
for the receptor Given intravenously flumazenil is rapid and short
acting. It may rarely induce seizures.
Uses
To reverse BZD sedation/anesthesia In BZD overdoses.
19. NEWER AGENTS
Melatonin and Congeners
Melatonin the hormone secreted by the pineal gland is known to
regulate sleep. It is secreted at night and play an important role in the
circadian rhythm. Melatonin acts on melatonin receptors; it does not
depress the CNS; it improves the quality of sleep and helps in
withdrawing benzodiazepines after long term use.
20. Uses
Insomnia: Administered orally at bed time in the dose of 2-10 mg,
melatonin is considered a natural remedy for insomnia and is free from
the disadvantages of BZDs
Jet Lag: Melatonin may be used to overcome jet lag and other
conditions of disturbed biorhythm
To help withdraw hypnotics in elderly dependents: The secretion of
melatonin decreases with age and therefore it is supplemented with the
hope that it retards aging.
21. Ramelteon
• Ramelteon an agonist at the melatonin receptors is a novel hypnotic drug.
Ramelteon reduces the latency of persistent sleep.
• Advantages are that it does not modify the sleep architecture, there is no
rebound insomnia or other major withdrawal symptoms. The duration of
action is prolonged by microsomal enzyme inhibitors and in liver failure.
• Adverse effects include dizziness and fatigue. There could be an increase in
prolactin levels ' and decrease in testosterone.
22. Z Hypnotics
‘Z’ Hypnotics include zolpidem, zopiclone, eszopiclone and zaleplon.
They are not BZDs but produce their effects by binding to benzodiazepine
site on the GABA, receptors and facilitate the inhibitory actions of GABA.
They are all rapid and short acting agents and produce minimum hangover.
Their actions are blocked by flumazenil.
They are well absorbed when given orally
They are well tolerated with mild side effects
They are metabolized in the liver
They are used for short periods when short acting hypnotics are needed.
23. Zolpidem is a good hypnotic but has weak anticonvulsant and muscle
relaxant effects.
It is short acting (t1/2 -2 hours) but the effects on sleep continue for a long
time even after stopping zolpidem. Dose should be reduced in hepatic
dysfunction.
Zaleplon is rapidly absorbed from the gut and has a short t 1/2 of about 1
hour. It has the advantages that no withdrawal symptoms are reported after
stopping it and no tolerance develops. It has rapid onset and short duration
of action. No side effects are reported.
Zopiclone actions resemble those of BZDs.
Eszopiclone an isomer of zopiclone prolongs the total sleep time. It is
metabolized by hepatic microsomal enzymes, has a half life of 6 hrs which
is altered by microsomal enzyme inducers and inhibitors.
24. Adverse effects
Dryness of mouth, metallic taste; higher doses can cause impaired
psychomotor performance.
Uses
‘Z' hypnotics are used in the treatment of insomnia with the advantages
of rapid action and minimum day-after drowsiness and less amnesia.
They are recommended for short periods as their long-term safety is yet
to be established.
25. BARBITURATES
Barbiturates are derivatives of barbituric acid and were the largest group of
hypnotics in clinical use until the 1960s.
Classification
Barbiturates can be classified based on their duration of action as:
Long-acting:
Phenobarbitone, Mephobarbitone.
Short-acting:
Pentobarbitone, Butobarbitone.
Ultra-short-acting:
Thiopentone, Hexobarbitone, Methohexitone.
26. • Mechanism of Action
Barbiturates bind to a specific site on the GABA receptor and facilitate
inhibitory neurotransmission by opening chloride ion channels and
hyperpolarize the neural membrane.
27. Pharmacological Actions
CNS:
• Barbiturates cause depression of all excitable tissues of which CNS is the most
sensitive
Sedation and hypnosis:
• In hypnotic doses, barbiturates induce sleep and prolong the duration of sleep.
• The REM-NREM sleep cycle is altered with decreased duration of REM and
prolonged NREM sleep. On waking up there is hangover with headache and residual
sedation, Barbiturates reduce anxiety, impair short term memory and judgment.
• In higher doses barbiturates produce general anesthesia. The ultra short acting
barbiturates are used intravenously for this effect.
28. Anticonvulsant effects:
All barbiturates have anticonvulsant actions. Phenobarbitone and
mephobarbitone have specific anticonvulsant activity in subhypnotic
doses and are used in the treatment of epilepsy.
Respiratory system:
Barbiturates depress the respiration. High doses bring about a direct
paralysis of the medullary respiratory center and can be fatal.
Cardiovascular system:
Hypnotic doses of barbiturates produce a slight reduction in blood
pressure and heart rate as seen during natural sleep. Toxic doses of
barbiturates produce a significant fall in BP due to direct decrease in
myocardial contractility and vasomotor center depression.
29. Pharmacokinetics:
Barbiturates are well absorbed and widely distributed in the body. The
highly lipid soluble barbiturates, such as thiopentone have a fast onset
of action and duration is short due to redistribution into adipose tissues.
Barbiturates are metabolized in the liver. They are hepatic microsomal
enzyme inducers. The metabolites are excreted in urine.
30. Adverse Reactions
Hangover—due to residual depression of the CNS may be accompanied
by nausea, vomiting, vertigo and diarrhea. Distortions of mood,
impaired judgment and fine motor skills may be evident. Barbiturates
may cause excitement and irritability in some patients particularly
children.
Barbiturates cause respiratory depression and in the presence of
respiratory disorders even the hypnotic doses of barbiturates can cause
serious respiratory depression.
Hypersensitivity reactions, such as skin rashes, swelling of the eyelids
and lips and rarely exfoliative dermatitis may be seen.
31. Tolerance and dependence:
On repeated administration, tolerance develops to the effects of
barbiturates.
Development of both psychological and physical dependence to
barbiturates make them one of the drugs with abuse liability.
Withdrawal symptoms include anxiety, rest lessness, abdominal cramps,
hallucinations, delirium and convulsions.
32. Acute barbiturate poisoning:
• The fatal dose of phenobarbitone is 6-10 g. Manifestations include
respiratory depression with slow and shallow breathing, hypotension,
skin eruptions, cardiovascular collapse and renal failure.
33. Treatment:
There is no specific antidote. The measures include:
Gastric lavage followed by administration of activated charcoal to
prevent further absorption of barbiturates.
General supportive measures, such as maintenance of BP, patent airway,
adequate ventilation and oxygen administration.
Forced alkaline diuresis with sodium bicarbonate, a diuretic and IV
fluids will hasten the excretion of long-acting barbiturates through the
kidneys since they are acidic drugs,
Hemodialysis should be done especially if there is renal failure.
34. Uses
Because of respiratory depression and abuse liability, barbiturates are
generally not preferred.
Neonatal jaundice:
• Phenobarbitone is a microsomal enzyme inducer and thereby enhances
the production of glucuronyl transferase—the enzyme required for
metabolism and excretion of bilirubin. It therefore helps in the
clearance of jaundice in the neonates
35. Anesthesia:
Thiopentone sodium is used IV for the induction of general
anesthesia.
Antiepileptic:
Phenobarbitone is used as an antiepileptic,
Sedation and hypnosis:
Benzodiazepines are preferred to barbiturates as sedative hypnotics.
36. BZDs as hypnotics—when compared to barbiturates:
BZDs induce sleep which more closely resembles natural sleep and has
less hangover.
In hypnotic doses they do not affect respiration or cardiovascular
functions.
BZDs have a higher safety margin and are safer than barbiturates even
in overdoses. The respiratory depression in overdoses is milder and
unlikely to be fatal.
In case of BZD overdoses, a specific BZD antagonist—flumazenil can be
used to reverse the symptoms.
BZDs do not cause microsomal enzyme induction and therefore do not
alter the blood levels of other drugs.
BZDs have lower abuse liability.
Because of the above reasons, BZDs are the most preferred sedative
hypnotics.
37. Nursing Responsibilities
Be aware that use for prolonged periods of time, even at therapeutic levels is
associated with a high incidence of addiction.
Counsel chronic users to note and report that appearance of sore throat, fever,
bruising, rash, jaundice are signs of possible hematologic toxicity.
When giving IV administer slowly to prevent respiratory depression and
hypotension.
Recognize that barbiturates given to patients in severe pain produce anxiety and
restlessness and may intensify the person’s reaction to the painful stimuli. Always
given in combination with an analgesic in the presence of pain.
