Sedative-Hypnotic Drugs

College of Pharmacy
Our Lady of Fatima University
 Terminologies
• Sedative
– Refers to quieting effect accompanied by
relaxation and rest but not sleep
• Hypnotic
– Refers to the production of sleep, drowsiness
• Anxiolytic
– Used for the treatment of anxiety
– AKA Antipanic or Antianxiety agent
 Anxiety
• Unpleasant state of tension, apprehensioon,
or uneasiness
• Refers to many state in which the px
experiences a sense of impending threat or
doom that is not well defined or realistically
based
• Symptoms are tachycardia, sweating,
palpitations, tachypnea, trembling, weakness
 Types of Anxiety
• Panic Disorder – recurrent unexpected panic
attacks
• Specific Phobia – particular objects of situations
• Social Phobia – intense fear of being scrutinized
• Generalized Anxiety Disorder – intense pervasive
worry over life
• Post-Traumatic Stress Disorder – persistent re-
experience of a trauma
• Obsessive-Compulsive Disorder – recurrent
obsessions and compulsions that cause
significant distress
 Chemical Classification
• Benzodiazepines
– Short acting - Oxazepam, Triazolam, Midazolam, Clonazepam
– Intermediate acting – Lorazepam, Alprazolam, Temazepam,
Estazolam
– Long acting – Diazepam, Flurazepam, Chlordiazepoxide,
Clorazepate, Quazepam, Halazepam, Prazepam
• Barbiturates
– Ultra-short acting – Thiopental, Thiamylal, Methohexital
– Short-acting – Hexobarbital, Pentobarbital, Amobarbital,
Secobarbital
– Intermediate –acting - Butabarbital
– Long-acting - Phenobarbital
• Miscellaneous
– Newer Drugs – Buspirone, Zolpidem, Zaleplon, Hydroxyzine
– Older Drugs (Alcohols, Piperidinediones, Carbamates)
 BZD Receptors
• Type 1:
– Most common throughout CNS, mediates
sedation and tolerance
• Type 2:
– Hyppocampus, striatum, spinal cord, mediates
anxiolysis
• Type 3:
– Cerebellar granule cells
 Benzodiazepine
• Alprazolam (Xanor) • Chlordiazepoxide
– For the mx of anxiety
disorders of for the short
term relief of anxiety
– Indicated for adjunctive
tx of anxiety with mental
depression
– Found effective for panic
disorder
– The drug has been used
effectively for 8 mos or
longer
(Librium)
– Indicted for the relief of
anxiety and tension,
withdrawal symptoms of
acute alcoholism
– During chronic admin,
accumulation occurs not
only on the parent
substances but also the
three active metabolites
 Benzodiazepine
• Chlorazepate (Tranxene) • Diazepam (Valium)
– For the symptomatic relief
of anxiety assoc with
neuroses, psychoneuroses
or with symptoms of
anxiety, acute alcohol
withdrawal
– Accumulates for 7 d and
then reaches ss
– Indicated for the relief of
anxiety and tension, acute
withdrawal sundrome and
adjunctive therapy in
skeletal muscle spasms
– Preferred to many
clinicians bcoz of its ability
to relieve anxiety, sedate
and cause light anesthesia
– It is well absorbed after
single oral doses, leading
to rapid onset of clinical
effects
 Benzodiazepine
• Estazolam (ProSom) • Flurazepam (Dalmane)
– A triazolebenzodiazepine – A BZD used in short
deriv that closely treatment (up to 4
resembles alprazolam wks)of all types such as
and triazolam difficulty of falling
– Can cause serious asleep, frequent
toxicity and withdrawal nocturnal awakenings
rxns than BZD – It is also used in acute
– It may cause renal and chronic medical
impairment situations in which sleep
is desirable
 Benzodiazepine
• Halazepam (Paxipam) • Lorazepam (Ativan)
– Indicated primarily for
anxiety disorders or for
the short term relief of
anxiety not controlled by
other more specific
medication
– A BZD used orally for
anxiety and transient
situational stress
– It is used parenterally to
preanesthetic
medication, producing
sedation and decrease
ability ro recall events
related to surgery
 Benzodiazepine
• Oxazepam (Serax)
– A congener of
chlordiazepoxide and
diazepam, it is mild
sedative useful in the mx
and control of anxiety,
tension, agitation,
irritability and related
symptoms
– It is useful for the control
acute tremolousness,
inebriation or anxiety assoc
with alcohol withdrawal
• Prazepam (Centrax)
– For the mx of anxiety
disorders or for the short
term relief of the
symptoms of anxiety
– Slowed after oral
administration
– CI in px with narrow-angle
glaucoma
 BZD Pharmacological Action
• Antianxiety effect – BZD reduce anxiety in doses that
does not induce sleep
• Anticonvulsant – the use of these drugs as
anticonvulsant is less due to development of tolerance
to anticonvulsant axn
• Skeletal muscle relaxant effect – BZD induce hypotonia
by stimulating glycine receptors in the spinal cord
• Hypnotic effect – they cause increase in total sleep
time
• Analgesic action – except diazepam, no other BZD has
analgesic axn
 Benzodiazepines P’kinetics
• Absorption
– Triazolam is rapidly absorbed through oral
administration compare to diazepam
– Clorazepate is converted to its active form.
Desmethyldiazepam, by acid hydrolysis in the
stomach
– Oxazepam, lorazepam, and temazepam are
absorbed from the gut at slower rates than others
– Diazepam and Triazolam are more lipid-solluble
than chlordiazepoxide and lorazepam
 Benzodiazepines P’kinetics
• Metabolism
– Undergo microsomal oxidation (Phase I), including N-
dealkylation and aliphatic hydroxylation
– The metabolites are subsequently conjugated (Phase
II)to form glucoronides that are excreted in the urine
– Desmethyldiazepam has an elimination half life of
40hrs. It is an active metabolite of chlordiazepoxide,
diazepam, prazepam and clorazepate
– Desmethyldiazepam in turn is biotransformed into
oxazepam.
 Barbiturates
• Biological effects
– Depression of CNS, Respiratory Depression, Enzyme
Induction
• Contraindications
– To px with porphyria, impaired hepatic and renal function,
px with history of addiction, pregnanet women, should not
be used if driving
• Drug-Interaction
– May induce the hepatic microsomal metabolizing enzyme
system and increase the rate of metabolism of coumarin,
TCA, OCP
– Completely inh the metabolism of some drugs such as
phenytoin
– Additive depressant effects with other CNS depressant
 Barbiturates P’kinetic
• Absorption
– The thiobarbiturates in which the oxygen on C2 is
replaced by sulfur, are very lipid-solubl, and a high
rate of entry into the CNS contributes to the rapid
onset on their central effects
– Phenobarbital and Meprobamate have quite low
lipid-solubility and penetrate the brain slowly
 Barbiturates P’kinetic
• Metabolism
– The major metabolic pathways involve oxidation by
hepatic enzymes of chemical groups attached to C5,
which are different from individual barbiturates
– The alcohols, acids and ketones formed appear in the
urine as glucoronide conjugates
– The elimination half-lives of secobarbital and
pentobarbital range from 18-48hrs in different
individuals
– The elimination half life of phenobarbital is 4-5days
Benzodiazepines MOA Barbiturates
• Binding of y-aminobutyric • Interfere with sodium and
acid (GABA) to GABAA potassium transport
receptor which trigger across cell membrane
opening of chloride leading to the inh of the
channel thus increase mesencephalic reticular
chloride conduction activating system
• Influx of chloride ions • It potentiates GABA axn
causes a small on chloride entry into the
hyperpolarization that neuron, although they do
moves the post-synaptic not bind at BZD receptor
potential thus inh
formation of axn
potential
Benzodiazepine ADR Barbiturates
• Drowsiness • Somnolence
• Fatigue • Agitation
• Confusion • Confusion
• Dizziness • Hyperkinesia
• Weakness • Ataxia
• Ataxia • Nightmares
• Syncope • Lethargy
• Phlebitis at the site of • Paradoxical Nervousness
injection • Hallucinations
• Venous thrombosis • Anxiety
• Dizziness
 Benefits of BZD over Barbiturates
• BZD do not effect other body systems
• BZD have comparatively high therapeutic index (safer
drug)
• They cause less disturbance in sleep patterns
• An antagonist, Flumazenil, is available that can be used
in poisoning

• BZD inc FREQUENCY of GABA-mediated chloride ion

channel opening
• Barbiturate inc DURATION of GABA-mediated chloride
ion channel opening
 Newer Drugs
• Buspirone (Buspar) • Zolpidem (Ambien)
– An azapirones drug
classified as 5-HT1A
receptor agonists
– Anti-anxiety agent
unrelated to BZD
– Rapidly absorbed and
undergoes FPE metab,
slow OA
– They lack the sedation and
the dependence assoc with
BZD and cause much less
cognitive impairment
– The drug has no abuse
potential and does not
induce tolerance
– An imidazopyridine deriv
structurally unrelated to BZD
– Has minimal muscle relaxing
and anticonvulsant fx
– Amnestic effects have been
reported with use of doses
greater then usual
– The drug has rapid onset of
action and DOA is close to
triazolam
– Causes minor fx on sleep
petterns at the recommended
hypnotic dose but can suppress
REM sleep
 Newer Drugs
• Zaleplon (Sonata)
– Binds selectively to the BZ1
receptor subtype,
facilitating the inhibitory
actions of GABA
– The drug is metabolized to
inactive metabolites by
hepatic aldehyde oxidase
and partly by CYP3A4
– Rapid OA and short DOA of
axn are favorable
properties for those px
who have difficulty falling
asleep
• Ramelteon
– Novel hypnotic drug that
activates melatonin
receptors in the CNS
therefore decreases the
latency of sleep onset with
minimal rebound insomnia
or withdrawal symptoms
– ADR: dizziness, fatigue
 Older Sedative-Hypnotics
• Ethchlorvynol (Placidyl) • Chloral Hydrate
– A mild hypnosis that
induces sleep within 15
mins to 1 hr and has
duration of
approximately 5hrs
– Should not be taken with
ROH bcoz of the additive
effects
– Ing in Knock-Out drops, used
to prepare a Mickey Finn
(drink with drug)
– Short term treatment of
insomnia
– Converted to TCE resp for
hypnotic axn
– Other metabolites are TCA
and
trichloroethanolglucoronide 1
Clinical Uses of Sedative-Hypnotics
• For relief of anxiety
• For insomnia
• For sedation and amnesia before medical procedures
• For treatment of epilepsy and seizures states
(clonazepam, phenobarbital)
• As component of balanced anesthesia (thiopental)
• For control of ethanol or other sedative-hypnotic
withdrawal states (chlordiazepoxide and diazepam)
• For muscle relaxation in specific neuromuscular
disorders
• As diagnostic aids or for the treatment in psychiatry, for
bipolar disorders (clonazepam)
 BZD Antagonist
• Flumazenil
– Have high affinity for the BZD receptor that act as
competitive antagonist
– Only BZD antagonist available
– Blocks any action of BZD but do not antagonize the
CNS effects of other sedative-hypnotics, ethanol,
opioids or gen anesthetics
– Is approved for use in reversing the CNS depressant fx
of BZD overdose and to hasten recovery following use
of these drugs in anesthetic and diagnostic
procedures
– ADR: agitation, confusion, dizziness and nausea