Sedatives

SEDATIVES
&
HYPNOTICS
SEDATIVES & HYPNOTICS
• Sedatives:
• Sedation refers to decreased responsiveness to any level of
stimulation.
• Associated with some decrease in motor activity and ideation.
• Hypnotics:
• A drug that induces and/or maintains sleep, similar to normal
arousable sleep.
• Treatment of insomnia is the most important use of this class of
drugs.
CLASSIFICATION
BARBITURATES
• CNS depressants produce dose-dependant effects: sedation →
sleep → anaesthesia → coma.
• Hypnotic dose shortens the time taken to fall asleep and
increases sleep duration.
• Hangover (dizziness, distortions of mood, irritability and
lethargy) may occur in the morning after a nightly dose.
• Sedative dose (smaller dose of a longer acting barbiturate) given
at daytime can produce drowsiness, reduction in anxiety and
excitability.
• Also have anticonvulsant activity.
MECHANISM OF ACTION
• Act primarily at the GABA : BZD receptor–Cl¯ channel
complex and potentiate GABAergic inhibition by
increasing the lifetime of Cl¯ channel opening induced
by GABA.
• Depress glutamate induced neuronal depolarization
through AMPA receptors.
• Depress voltage sensitive Na+ and K+ channels as well
THERAPEUTIC USES
• Only phenobarbitone is used in the treatment of
epilepsy.
• Thiopentone is used for anesthetic purposes.
• Other barbiturates are not used nowadays.
• Phenobarbitone 30–60 mg oral OD–TDS;
• 100–200 mg i.m./i.v.
• GARDENAL 30, 60 mg tab, 20 mg/5 ml syr;
• LUMINAL 30 mg tab;
• PHENOBARBITONE SOD 200 mg /ml inj.
ADVERSE EFFECTS
• Hangover, produce tolerance and dependence on
repeated used, mental confusion, impaired
performance and traffic accidents may occur.
• Excitement in elderly
• Rashes, swelling of eyelids, lips
• Acute barbiturate poisoning Mostly suicidal,
sometimes accidental (nowadays reduced due to
in-availability).
DRUG-DRUG INTERACTION
• Induces CYP isoenzymes, metabolism of other e.g., warfarin,
steroids, contraceptives, tolbutamide, griseofulvin,
chloramphenicol, theophylline and reduce their action.
• Additive action with other CNS depressants —alcohol,
antihistamines, opioids, etc.
• Sodium valproate increases plasma concentration of
phenobarbitone.
• Phenobarbitone competitively inhibits as well as induces
phenytoin and imipramine metabolism: complex interaction.
• Decreases absorption of griseofulvin from the g.i.t.
BENZODIAZEPINES
• Have high therapeutic index.
• Hypnotic doses do not affect respiration or
cardiovascular functions.
• They have lower abuse liability.
• Tolerance is mild, psychological and physical
dependence, drug seeking and withdrawal syndrome
are less marked.
• A specific BZD antagonist flumazenil is available which
can be used in case of poisoning.
MECHANISM OF ACTION
• Act on midbrain ascending reticular formation (which
maintains wakefulness) and on limbic system (thought
and mental functions).
• Muscle relaxation is produced by a primary medullary
site of action and ataxia is due to action on cerebellum.
• Enhances presynaptic/postsynaptic inhibition through
a specific BZD receptor which is an integral part of the
GABAA receptor–Cl¯ channel complex.
PHARMACOKINETICS
• Rapidly absorbed orally
• Plasma protein binding is about 10-99%
• Widely distributed in all parts of body.
• Metabolized in liver mainly by CYP3A4 and CYP2C19
THERAPEUTIC USE
• Alcohol withdrawal
• Anxiety
• As a muscle relaxant
• Panic disorder
• Seizures
ADVERSE REACTION
• Safer drugs
• But sometimes dizziness, vertigo, ataxia, disorientation,
amnesia, prolongation of reaction time—impairment of
psychomotor skills (should not drive).
• Aggravate sleep apnoea.
• Cross tolerance to alcohol and other CNS depressants
occurs.
DRUG-DRUG INTERACTION
• Synergise with alcohol and other CNS depressants
leading to excessive impairment.
• Concurrent use with sod. valproate has provoked
psychotic symptoms.
ZOPICLONE
• Acts as an agonist at a subtype of BZD receptor
involved in the hypnotic action.
• Zopiclone has been used to wean off insomniacs taking
regular BZD medication.
• Its t½ is 5–6 hours.
• Indicated for short term (<2 weeks) treatment of
insomnia.
• Side effects are metallic or bitter after-taste, impaired
judgement and alertness, psychological disturbances,
dry mouth and milder dependence.
THERAPEUTIC USE
• As hypnotic: for acute/chronic insomnia to shorten sleep
latency, to reduce nocturnal awakenings, or to provide anxiolytic
effect the next day when insomnia is accompanied with marked
element of anxiety.
• As anxiolytic
• As anticonvulsant
• As centrally acting muscle relaxant
• For preanaesthetic medication, Before ECT
• Alcohol withdrawal symptoms
• Along with analgesics, NSAIDs, spasmolytics, antiulcer and as
adjuvants to treat ‘gas’ or nonspecific dyspeptic symptoms.
BENZODIAZEPINE ANTAGONIST
Flumazenil
• It is a BZD analogue which has little intrinsic activity but
competes with BZD agonists as well as inverse agonists for the
BZD receptor and reverses their depressant or stimulant effects
respectively.
• Abolishes the hypnogenic, psychomotor, cognitive and EEG
effects of BZDs.
• absorbed orally (oral bioavailability is ~16%, but it is not used
orally.
• On i.v. injection, action of flumazenil starts in seconds and lasts
for 1–2 hr; elimination t½ is 1 hr, due to rapid metabolism.
FLUMAZENIL
• To reverse BZD anaesthesia.
• BZD overdose
• safe and well tolerated.
• Agitation, discomfort, tearfulness, anxiety,
coldness and withdrawal seizures are the
occasional side effects.
FREQUENTLY ASKED QUESTIONS
• Define sedatives with example.
• Define hypnotics with example.
• Give two uses of barbiturates.
• Outline the signs, symptoms and treatment of
Barbiturate poisoning.
• Short notes on benzodiazepines.
• Write two uses of Benzodiazepines.
• diazepam

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